T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 states . For motor sequence learning , P14416 genotype mediated DB01235 effects such that DB01235 associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 =- 2 . 71 , p = 0 . 022 ) , whereas G homozygotes showed no performance change with DB01235 . For the grooved pegboard test , performance improved with DB01235 independent of patients ' P14416 genotype . Collectively these results demonstrate that common P14416 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .","___MASK51___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .","[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK14___ GITS , Diaprel MR ) . One daily dose of ___MASK14___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .","Differential treatment regimen - related effects of cannabinoids on D1 and D2 receptors in adolescent and adult rat brain . Animal studies suggest differential effects of cannabinoids on dopamine - related behaviours in adolescence and adulthood however few studies have investigated the underlying neurochemical effects of cannabinoids during adolescence . The aim of the present study was to compare the effects of treatment with the synthetic cannabinoid , HU210 , on dopamine receptor density in adolescent and adult rats . Adolescent ( postnatal day ( P01160 ) 35 ) and adult ( P01160 70 ) rats received a single dose of 100μg / kg HU210 or 25 , 50 or 100μg / kg HU210 for 4 or 14 days . P21728 ( D1R ) or D2 receptor ( D2R ) density was measured in the medial and lateral ( CPUL ) caudate putamen , nucleus accumbens , olfactory tubercle ( TU ) and substantia nigra ( D1R only ) using in vitro autoradiography . D1R and D2R densities were 1 . 6 - 1 . 7 - and 1 . 1 - 1 . 4 - fold higher respectively in adolescent control rats compared to adults . In adult rats , D1R density was increased by 1 . 2 - and 1 . 3 - fold ( p < 0 . 05 ) in CPUL and TU respectively compared to controls , after 14 days of HU210 treatment . A significant overall effect of treatment ( p < 0 . 05 ) on D2R density was also observed in adults after the single dose and 4 and 14 days administration of HU210 . In adolescents , an overall effect of treatment on D1R density after a single exposure to HU210 was seen ( p = 0 . 0026 ) but no changes in D1R or D2R densities were observed in other treatment groups . These results suggest that the adolescent rat brain does not display the same compensatory mechanisms activated in the adult brain following cannabinoid treatment .","Interaction between serotonin transporter gene , catechol - O - methyltransferase gene and stressful life events in mood disorders . It is well established that stress is a risk factor for onset of mood disorders . Emerging evidence suggests that genetic vulnerability may also moderate individual responsiveness to stress . The most compelling evidence regards the polymorphism within the promoter region of the serotonin transporter gene ( SERTPR ) , which has been reported to moderate the risk for depression , in conjunction with life stressors . In the present paper we analysed SERTPR in the onset of mood disorders , along with adverse life events , and other candidate genes : the serotonin receptor 1A ( P08908 ) , the dopamine receptor D4 ( P21917 ) and the catechol - O - methyltransferase ( P21964 ) . The sample was composed of 686 Italian subjects , affected by major depression and bipolar disorder . Patients were asked to report about life stressors within the year preceding onset of their first mood - disorder episode and genotyped . A ' case - only ' design was employed to investigate the interaction between genes and stressors . P21964 was associated with depression following exposure to stressors ( chi2 = 13 . 05 , d . f .= 2 , p = 0 . 0015 ) and SERTPR also showed a positive association ( chi2 = 6 . 70 , d . f .= 2 , p = 0 . 035 ) , mainly among women and among major depressives . The interaction between P21964 and SERTPR was also significant ( p = 0 . 0005 ) . In our retrospective study SERTPR is hypothesized to lead to the onset of major depression via its influence on reaction to adversities , particularly in females . Moreover , P21964 was risk factor for onset of both major depression and bipolar disorder , in conjunction with adversities .","The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK100___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK100___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK100___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK100___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .","The interleukin 10 promoter haplotype ACA and the long - form variant of the P21917 uVNTR polymorphism are associated with vulnerability to schizophrenia . A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin - 10 ( P22301 ) promoter and P21917 uVNTR polymorphisms . P21917 long - form variants ( namely , those with ≥ 5 repeats ) , homozygosity for the 4 - repeat allele , and the P22301 haplotype ACA were associated with schizophrenia , respectively . No obvious interactions among the potential polymorphisms were found , which suggests that P22301 and P21917 confer vulnerability to schizophrenia independently .","Transactivation of PDGFRbeta by dopamine D4 receptor does not require PDGFRbeta dimerization . Growth factor - induced receptor dimerization and cross - phosphorylation are hallmarks of signal transduction via receptor tyrosine kinases ( RTKs ) . G protein - coupled receptors ( GPCRs ) can activate RTKs through a process known as transactivation . The prototypical model of RTK transactivation involves ligand - mediated RTK dimerization and cross - phosphorylation . Here , we show that the platelet - derived growth factor receptor beta ( PDGFRbeta ) transactivation by the dopamine receptor D4 ( P21917 ) is not dependent on ligands for PDGFRbeta . Furthermore , when PDGFRbeta dimerization is inhibited and receptor phosphorylation is suppressed to near basal levels , the receptor maintains its ability to be transactivated and is still effective in signaling to P27361 / 2 . Hence , the P21917 - PDGFRbeta - P27361 / 2 pathway can occur independently of a PDGF - like ligand , PDGFRbeta cross - phosphorylation and dimerization , which is distinct from other known forms of transactivation of RTKs by GPCRs .","[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK70___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .","Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re - validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague - Dawley rats were treated with chronic DB01235 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 ( the D ( 1 ) and P14416 antagonists , P35240 - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti - dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .","Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK18___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .","Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .","Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .","Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .","Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 ) at 11p15 , tyrosinase ( P14679 ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 ) at 11q22 - q23 , as well as with the c - Harvey - ras oncogene ( P01112 ) and insulin gene ( P01308 ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected - sib - pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two - point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 and P01308 excluded the 11p15 region encompassing both P21917 and TH . In agreement with the negative linkage results , affected - sib - pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 , TH , P14679 , and P14416 in the pathogenesis of bipolar illness .","___MASK66___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol ."],"string":"[\n \"Support for association between ADHD and two candidate genes : NET1 and P21728 . Attention deficit hyperactivity disorder ( ADHD ) is a common , multifactorial disorder with significant genetic contribution . Multiple candidate genes have been studied in ADHD , including the norepinephrine transporter ( NET1 ) and dopamine D1 receptor ( P21728 ) . NET1 is implicated in ADHD because of the efficacy of atomoxetine , a selective noradrenergic reuptake inhibitor , in the treatment of ADHD . P21728 is primarily implicated through mouse models of ADHD . DNA from 163 ADHD probands , 192 parents , and 129 healthy controls was used to investigate possible associations between ADHD and polymorphisms in 12 previously studied candidate genes ( P28222 , 5 - Q13049 , P28335 , P08913 , P43681 , P21964 , Q01959 , P21728 , P21917 , P21918 , NET1 , and P60880 ) . Analyses included case - control and family - based methods , and dimensional measures of behavior , cognition , and anatomic brain magnetic resonance imaging ( Q9BWK5 ) . Of the 12 genes examined , two showed a significant association with ADHD . Transmission disequilibrium test ( P04053 ) analysis revealed significant association of two NET1 single nucleotide polymorphisms ( SNPs ) with ADHD ( P < or = 0 . 009 ) ; case - control analysis revealed significant association of two P21728 SNPs with ADHD ( P < or = 0 . 008 ) . No behavioral , cognitive , or brain Q9BWK5 volume measurement significantly differed across NET1 or P21728 genotypes at an alpha of 0 . 01 . This study provides support for an association between ADHD and polymorphisms in both NET1 and P21728 ; polymorphisms in ten other candidate genes were not associated with ADHD . Because family - based and case - control methods gave divergent results , both should be used in genetic studies of ADHD .\",\n \"Rottlerin , a PKC isozyme - selective inhibitor , affects signaling events and cytokine production in human monocytes . The implication of select protein kinase C ( PKC ) isoenzymes in cytokine production by human monocytes was investigated using an isozyme - selective inhibitor of PKC , rottlerin . We found that lipopolysaccharide ( LPS ) triggers cytosol - to - membrane translocation of PKCalpha and delta isoenzymes , whereas phorbol ester ( PMA ) induces translocation of several PKC isoforms . Moreover , we show that in LPS - and PMA - stimulated monocytes rottlerin affects several cellular responses . ( 1 ) At low ( 15 microM ) concentration it blocks translocation of PKCdelta , diminishes DNA binding activity of AP - 1 transcription factor , and attenuates cytokine production [ tumor necrosis factor alpha ( P01375 ) > interleukin - 1beta ( IL - 1beta ) ] . ( 2 ) At high ( 50 microM ) concentration it prevents translocation of PKCalpha , and subsequently inhibits P27361 / P28482 phosphorylation , DNA binding activities of AP - 1 and nuclear factor - KB transcription factors , and the production of both tested cytokines . Thus , we propose that cytosol - to - membrane translocation of PKCalpha and PKdelta isoenzymes may represent early steps in the signaling cascades that lead to P01375 and IL - 1beta production in human monocytes .\",\n \"17 DB00783 overcomes a P55008 block induced by P04035 inhibitors and fosters cell cycle progression without inducing P27361 and - 2 Q96HU1 kinases activation . P04035 inhibitors , such as ___MASK51___ and Simvastatin , cause cell cycle arrest by interfering with the mitogenic activity of mitogens present in culture media . Cells are induced to pause in P55008 and can readily resume growth upon removal of the enzymatic block . DB00286 , acting via their nuclear receptor , are mitogens for different normal and transformed cell types , where they foster cell cycle progression and cell division . In estrogen - responsive MCF - 7 human breast cancer cells , but not in non responsive cells , 17 beta - estradiol ( E2 ) induces cells arrested with ___MASK51___ or Simvastatin to proliferate in the presence of inhibitor , without restoring P04035 activity or affecting the protein prenylation pattern . Mitogenic stimulation of P55008 - arrested MCF - 7 cells with E2 includes primary transcriptional activation of c - fos , accompanied by transient binding in vivo of the estrogen receptor and / or other factors to the ERE and the estrogen - responsive DNA region of this proto - oncogene , as detected by dimethylsulphate genomic footprinting analysis . Mitogenic stimulation of growth - arrested MCF - 7 cells by E2 occurs , under these conditions , without evident activation of P27361 and - 2 kinases , and thus independently from the mitogen - responsive signal transduction pathways that converge on these enzymes .\",\n \"Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .\",\n \"Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .\",\n \"Regulation of Q9UD71 phosphorylation by Delta9 - tetrahydrocannabinol . P21554 receptor agonists increase the state of phosphorylation of the dopamine and DB02527 - regulated phosphoprotein of 32 kDa ( Q9UD71 ) at the DB02527 - dependent protein kinase site , DB00156 34 . This effect , which occurs in the medium spiny neurons of the striatum , has been proposed to mediate the motor depressant action of cannabinoids . In this study , we have examined the effect produced by systemic administration of Delta ( 9 )- tetrahydrocannabinol ( THC ) , the major component of marihuana and hashish , on Q9UD71 . We show that THC increases Q9UD71 phosphorylation at DB00156 34 both in dorsal striatum and nucleus accumbens . Time - course and dose - response experiments indicate that Q9UD71 phosphorylation is maximal 30 min following administration of 10mg / kg of THC . The THC - mediated increase in Q9UD71 phosphorylation is reduced by administration of the P21554 receptor antagonist , SR141716A ( 3mg / kg ) . A similar attenuation of the effect of THC is also exerted by suppression of DB02527 signaling achieved using the dopamine D1 receptor antagonist , SCH23390 ( 0 . 125 mg / kg ) , or the adenosine A2A receptor antagonist , KW6002 ( 3mg / kg ) . These results indicate that , in the striatum , THC promotes PKA - dependent phosphorylation of Q9UD71 in striatal medium spiny neurons expressing dopamine D1 and adenosine A2A receptors .\",\n \"Pharmacological characterization of mitogen - activated protein kinase activation by recombinant human P28335 , 5 - Q13049 , and P41595 receptors . The type 2 serotonin ( 5 - HT ( 2 ) ) receptor subfamily is known to couple to phosphoinositide hydrolysis ( PI ) and the subsequent mobilization of intracellular Ca ( 2 +) , as well as the release of arachidonic acid ( AA ) . Less is known of 5 - HT ( 2 )- mediated activation of the mitogen - activated protein kinase ( MAPK ) or extracellular signal - regulated kinase ( P27361 / 2 ) signaling . The present study measured the relative efficacies and potencies of 5 - HT agonists to activate P28482 in non - neuronal cells expressing recombinant human 5 - HT ( 2A ) , 5 - HT ( 2B ) , and 5 - HT ( 2C ( ISV )) receptors . 5 - HT agonists stimulated P28482 activity via all three 5 - HT ( 2 ) subtypes . There were no meaningful differences in the potencies or relative efficacies of these agonists to affect P28482 activity vs . PI accumulation or Ca ( 2 +) mobilization , suggesting that these pathways may be sequentially linked . Indeed , P28482 activity was very sensitive to PKC inhibition and calcium chelation and insensitive to tyrosine kinase and P19957 - kinase inhibition . 5 - HT ( 2 ) receptors efficiently couple to MAPK activation via sequential PI hydrolysis , and Ca ( 2 +) mobilization . This profile differs from reports of \\\" agonist - directed trafficking of receptor stimulus \\\" between PI / Ca ( 2 +) and AA pathways activated by 5 - HT ( 2 ) receptors .\",\n \"MGC9753 gene , located within Q9UD71 - Q14849 - P04626 - Q14451 amplicon on human chromosome 17q12 , encodes the seven - transmembrane receptor with extracellular six - cystein domain . MYC , P04626 , MET , P21802 , P24864 , P04198 , P09544 , P16070 , Q00987 , Q9Y6Q9 , P46940 and O14965 loci are amplified in human gastric cancer . It has been reported that the gene corresponding to EST H16094 is co - amplified with P04626 gene in human gastric cancer . Here , we identified and characterized the gene corresponding to EST H16094 by using bioinformatics . BLAST programs revealed that EST H16094 was derived from the uncharacterized MGC9753 gene . Two ORFs were predicted within human MGC9753 mRNA , and ORF1 ( nucleotide position 18 - 980 of NM_033419 . 1 ) was predicted as the coding region of human MGC9753 mRNA based on comparative genomics . Nucleotide sequence of mouse Mgc9753 mRNA was next determined in silico by modification of AK052486 cDNA ( deleting C at the nucleotide position 37 ) . Human MGC9753 and mouse Mgc9753 proteins were 320 - amino - acid seven - transmembrane receptors with the N - terminal six - cysteine domain and an N - glycosylation site ( 85 . 0 % total - amino - acid identity ) . Human MGC9753 protein showed 90 . 6 % total - amino - acid identity with human CAB2 aberrant protein , which lacked the third - transmembrane domain of MGC9753 due to frame shifts within ORF . Human MGC9753 gene , consisting of eight exons , were clustered with Q9UD71 , Q14849 , O15273 , PNMT , P04626 , MGC14832 and Q14451 genes within the 120 - kb region . Q9UD71 , Q14849 , MGC9753 , P04626 and Q14451 genes are co - amplified in several cases of gastric cancer . This is the first report on comprehensive characterization of the amplicon around the Q9UD71 - Q14849 - O15273 - PNMT - MGC9753 - P04626 - MGC14832 - Q14451 locus on human chromosome 17q12 .\",\n \"Integrative gene network analysis provides novel regulatory relationships , genetic contributions and susceptible targets in autism spectrum disorders . Autism spectrum disorders ( ASDs ) are a group of diseases exhibiting impairment in social drive , communication / language skills and stereotyped behaviors . Though an increased number of candidate genes and molecular interactions have been identified by various approaches , the pathogenesis remains elusive . Based on clinical observations , data from accessible GWAS and expression datasets we identified ASDs gene candidates . Integrative gene network and a novel CNV - centric Node Network ( CNN ) analysis method highlighted ASDs - associated key elements and biological processes . Functional analysis identified neurological functions including synaptic cholinergic receptor ( CHRNA ) families , dopamine receptor ( P14416 ) , and correlations between social behavior and oxytocin related pathways . CNN analysis of genome - wide genetic and expression data identified inheritance - related clusters related to P60484 / Q92574 / Q06787 and mTor / PI3K regulation . Integrative analysis identified potential regulators of networks , specifically P01375 and beta - estradiol , suggesting a potential central role in ASDs . Our data provide information on potential disease mechanisms , and key regulators that may generate novel postulations , and diagnostic molecular biomarkers .\",\n \"The interaction of thymidylate synthase expression with p53 - regulated signaling pathways in tumor cells . P04818 ( TS ) is a chemotherapeutic target for the fluoropyrimidine 5 - fluorouracil ( ___MASK96___ ) and antifolate tomudex ( TDX ) . Using the MCF - 7 breast cancer line , we have developed a cell line with inducible TS expression termed M7TS90 . Inducible TS expression in this line resulted in a moderate ( approximately 3 - fold ) increase in ___MASK96___ 50 % inhibitory concentration at 72 hours ( IC - 50 ( 72 h ) ) dose and a dramatic ( approximately 24 - fold ) increase in the IC - 50 ( 72 h ) dose of TDX , but did not affect chemosensitivity to cisplatin , oxaliplatin , irinotecan , and paclitaxel . In the absence of drug treatment , inducible TS expression had no effect on expression of the p53 tumor suppressor gene . However , TS induction abrogated p53 , P38936 , Fas , and Bak induction in response to TDX , but not ___MASK96___ . Similarly , downregulation of Bcl - 2 was reversed by inducible TS expression in TDX , but not ___MASK96___ - treated cells . Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX , but not ___MASK96___ .\",\n \"Unfavourable expression of pharmacologic markers in mucinous colorectal cancer . Patients with mucinous colorectal cancer generally have worse prognoses than those with the nonmucinous variety . The reason for this disparity is unclear , but may result from a differential response to adjuvant chemotherapy . We examined known molecular markers for response to common chemotherapy in these two histological subtypes . In all , 21 patients with mucinous and 30 with nonmucinous Dukes C colorectal cancer were reviewed for demographic data and outcome . Total RNA from the tumours and adjacent normal mucosa was isolated and reverse transcribed . Quantitative expression levels of drug pathway genes were determined using TaqMan RT - PCR ( 5 - fluorouracil ( ___MASK96___ ) : P04818 , Q12882 , P19971 ; oxaliplatin : P09211 ( glutathione S - transferase pi ) , P07992 and 2 ; irinotecan : P08183 , Q9UNQ0 , P08684 , P22309 , CES2 , P11387 ) . Mucinous tumours significantly overexpressed both P04818 and P09211 relative to nonmucinous tumours and patient - matched normal mucosa . No significant differences in expression of the remaining markers were found . Mean follow - up was 20 months ; 17 patients had recurrent disease . Among patients receiving ___MASK96___ , those with mucinous tumours experienced shorter disease - free survival ( DFS ) than those with nonmucinous tumours ( median DFS 13 . 8 vs 46 . 5 months , P = 0 . 053 ) . Mucinous colorectal cancer overexpresses markers of resistance to ___MASK96___ and oxaliplatin . Likewise , DFS may be decreased in patients with mucinous tumours who receive ___MASK96___ . The presence of mucin should be carefully evaluated in developmental trials of new agents for treating colorectal cancer .\",\n \"DB01235 - treatment in primates disrupts the expression of A ( 2A ) adenosine - CB ( 1 ) cannabinoid - P14416 heteromers in the caudate nucleus . The molecular basis of priming for DB01235 - induced dyskinesias in Parkinson ' s disease ( PD ) , which depends on the indirect pathway of motor control , is not known . In rodents , the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A ( 2A ) adenosine , CB ( 1 ) cannabinoid and D ( 2 ) dopamine receptors that regulate dopaminergic neurotransmission . The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson ' s disease and to determine whether their expression and pharmacological properties are altered upon DB01235 treatment . By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint , we discovered a regional distribution of A ( 2A )/ CB ( 1 ) / D ( 2 ) receptor heteromers that predicts differential D ( 2 )- mediated neurotransmission in the caudate - putamen of Macaca fascicularis . Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP - treated monkeys , DB01235 treatment blunted the biochemical fingerprint and led to weak heteromer expression . These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A ( 2A )- CB ( 1 ) - D ( 2 ) receptor heteromers may be successful to either normalize basal ganglia output or prevent DB01235 - induced side effects .\",\n \"[ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out - such as the renin - angiotensin - aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance - , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR = 3 . 0 ; p = 0 . 023 ) ; P21728 , rs686 ( OR = 0 . 38 ; p = 0 . 012 ) and P07550 , rs1042718 ( OR = 10 . 0 ; p = 0 . 008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure .\",\n \"P21554 knockout mice display significant changes in striatal opioid peptide and D4 dopamine receptor gene expression . Antagonism of the CB ( 1 ) cannabinoid receptor ( CB ( 1 ) receptor ) by rimonabant ( SR141716 ) reduces self - administration of alcohol and other drugs of abuse in animal models . These findings suggest that the CB ( 1 ) receptor may be a target for genetic differences that modify the salient features of rewarding drugs . In the present study , wild - type ( CB ( 1 ) ( +/+ ) ) are compared to transgenic mice deficient in CB ( 1 ) receptors ( CB ( 1 ) ( -/- ) ) . The goal was to investigate the influences of the cannabinoid receptor system on opioid peptide gene expression and on dopamine receptor gene expression which is commonly influenced by substances of abuse . We demonstrate using reverse transcription and real - time polymerase chain reaction ( PCR ) that striatal mRNA for preproenkephalin ( PPENK ) and preprodynorphin ( PPDYN ) in the CB ( 1 ) ( -/- ) striatum increases when compared to CB ( 1 ) ( +/+ ) . Real - time PCR analyses to evaluate D ( 2 ) and P21917 gene expression in striatum isolated from CB ( 1 ) ( +/+ ) and CB ( 1 ) ( -/- ) revealed a nearly 2 - fold increase in D ( 4 ) receptor mRNA in the striatum from CB ( 1 ) ( -/- ) mice and no significant change in D ( 2 ) expression . In contrast , treatment of C57BL / 6 mice with the CB ( 1 ) receptor antagonist , rimonabant , produced a reduction of both D ( 2 ) and P21917 expression in the striatum . These data suggest that genetic differences in CB ( 1 ) receptor may exert a modulatory effect on P21917 and opioid peptide gene expression .\",\n \"Dopamine receptor agonists reverse behavioral abnormalities of alpha - synuclein transgenic mouse , a new model of Parkinson ' s disease . Parkinson ' s disease ( PD ) is characterized by loss of nigral dopaminergic ( DAergic ) neurons and presence of Lewy bodies , whose major component is alpha - synuclein . We had previously generated transgenic mice termed Syn130m that express truncated human alpha - synuclein ( amino acid residues 1 - 130 ) in DAergic neurons . Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta . Subsequently , the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly . In the present study , we investigated behavioral responses of Syn130m mice to DB01235 and DA receptor agonists . Administration of DB01235 dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice . Similarly , D ( 2 ) agonists , quinpirole and talipexole , and a D1 / D2 agonist , pergolide , were effective against the reduction . Syn130m mice also showed significant reduction in exploratory behavior compared with non - Tg littermates when they were placed in a novel environment , but this abnormality was ameliorated by treatment with pergolide . These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content . On the other hand , the expression of postsynaptic D ( 2 )- like receptors ( P14416 ) in the striatum was not increased in Syn130m mice , although the low striatal DA level is known to induce compensatory expression of P14416 . Because the abnormalities could be rectified by treatment with DA receptor agonists , it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease .\",\n \"Dysregulation of gene expression in primary neuron models of Huntington ' s disease shows that polyglutamine - related effects on the striatal transcriptome may not be dependent on brain circuitry . Gene expression changes are a hallmark of the neuropathology of Huntington ' s disease ( HD ) , but the exact molecular mechanisms of this effect remain uncertain . Here , we report that in vitro models of disease comprised of primary striatal neurons expressing N - terminal fragments of mutant huntingtin ( via lentiviral gene delivery ) faithfully reproduce the gene expression changes seen in human HD . Neither viral infection nor unrelated ( enhanced green fluorescent protein ) transgene expression had a major effect on resultant RNA profiles . Expression of a wild - type fragment of huntingtin [ htt171 - 18Q ] also caused only a small number of RNA changes . The disease - related signal in htt171 - 82Q versus htt171 - 18Q comparisons was far greater , resulting in the differential detection of 20 % of all mRNA probe sets . Transcriptomic effects of mutated htt171 are time - and polyglutamine - length dependent and occur in parallel with other manifestations of polyglutamine toxicity over 4 - 8 weeks . Specific RNA changes in htt171 - 82Q - expressing striatal cells accurately recapitulated those observed in human HD caudate and included decreases in P01210 ( proenkephalin ) , P49798 ( regulator of G - protein signaling 4 ) , dopamine D ( 1 ) receptor ( P21728 ) , P14416 , P21554 ( cannabinoid CB ( 1 ) receptor ) , and Q9UD71 ( dopamine - and DB02527 - regulated phosphoprotein - 32 ; also known as Q9UD71 ) mRNAs . HD - related transcriptomic changes were also observed in primary neurons expressing a longer fragment of mutant huntingtin ( htt853 - 82Q ) . The gene expression changes observed in cultured striatal neurons are not secondary to abnormalities of neuronal firing or glutamatergic , dopaminergic , or brain - derived neurotrophic factor signaling , thereby demonstrating that HD - induced dysregulation of the striatal transcriptome might be attributed to intrinsic effects of mutant huntingtin .\",\n \"Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells . Sorting nexin 5 ( Q9Y5X3 ) belongs to the P20073 family , which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins , receptors , and transporters . Q9Y5X3 is important in the resensitization of the dopamine D1 - like receptor ( D1R ) . D1R is uncoupled from its effector proteins in hypertension and diabetes , and treatment of diabetes restores D1R function and insulin receptor ( IR ) expression . We tested the hypothesis that the D1R and Q9Y5X3 regulate IR by studying the expression , distribution , dynamics , and functional consequences of their interaction in human renal proximal tubule cells ( hRPTCs ) . D1R , Q9Y5X3 , and IR were expressed and colocalized in the brush border of RPTs . P01308 promoted the colocalization of Q9Y5X3 and IR at the perinuclear area of hRPTCs . Unlike Q9Y5X3 , the D1R colocalized and coimmunoprecipitated with IR , and this interaction was enhanced by insulin . To evaluate the role of Q9Y5X3 and D1R on IR signaling , we silenced via RNA interference the endogenous expression of Q9Y5X3 or the D1R gene P21728 in hRPTCs . We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B , which are crucial components of the IR signal transduction pathway . Our data indicate that Q9Y5X3 and D1R are necessary for normal IR expression and activity . It is conceivable that D1R and Q9Y5X3 may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling .\",\n \"Blockade of globus pallidus adenosine A ( 2A ) receptors displays antiparkinsonian activity in 6 - hydroxydopamine - lesioned rats treated with D ( 1 ) or P14416 agonists . We have recently demonstrated how antagonism of adenosine A ( 2A ) receptors within the globus pallidus ( GP ) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor DB01235 in 6 - hydroxydopamine - lesioned hemiparkinsonian rats . To further characterize the influence of pallidal A ( 2A ) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation , hemiparkinsonian rats were infused with the water - soluble A ( 2A ) antagonist P35240 BT2 in the GP , alone or in combination with systemic administration of either SKF 38393 or quinpirole , to stimulate dopamine D ( 1 ) or D ( 2 ) receptors , respectively . P35240 BT2 alone ( 5 mug / 1 mul ) neither altered motor behavior nor produced postural asymmetry . In contrast , the contralateral rotations elicited by SKF 38393 ( 1 . 5 mg / kg ) as well as quinpirole ( 0 . 05 mg / kg ) were potentiated by the concomitant intrapallidal infusion of P35240 BT2 . The results of this study demonstrate that blockade of pallidal A ( 2A ) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D ( 1 ) or D ( 2 ) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A ( 2A ) receptor antagonists .\",\n \"Direct analysis of candidate genes in impulsive behaviours . Antisocial behaviour is both heterogeneous and the product of interacting genetic and environmental factors acting at different levels of causation . Heritability studies show that individual differences in predisposition to antisocial behaviour are transmitted vertically in families by genetic mechanisms . Owing to aetiological heterogeneity and complexity , study of a variety of other behavioural phenotypes may shed more light on the antecedents of antisocial behaviour than direct studies on antisocial behaviour . Identification of genetic vulnerability factors would clarify mechanisms of vulnerability and the role of the environment . Direct gene analysis and genetic linkage analysis have identified structural variants in genes involved in neurotransmitter function , and some progress has been made towards relating these genetic variants to antisocial personality and other behaviours . Thyroid hormone receptor variants can cause attention deficit / hyperactivity disorder , and a monoamine oxidase A variant leads to aggressive behaviour in one family . Direct gene analyses have revealed non - conservative amino acid substitutions and structural variants ( generally rare ) at P14416 , P35462 and P21917 dopamine receptors and P08908 , 5 - Q13049 , P28335 and P34969 serotonin receptors . The stage is set to identify the phenotypic significance of these as well as genetic variants at other loci which may be relevant as candidate genes for antisocial behaviour and related behavioural differences .\",\n \"Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .\",\n \"P35462 stimulation underlies the development of DB01235 - induced dyskinesia in animal models of Parkinson ' s disease . Development of DB01235 - induced dyskinesia ( LID ) remains a major problem in the long - term treatment of Parkinson ' s disease ( PD ) . Sensitization to DB01235 correlates with ectopic expression of D3 dopamine receptors in the striatum , implicating D3 receptors in development of LID . We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP - lesioned marmosets without effecting the anti - parkinsonian actions of DB01235 . Furthermore , following a 14 day washout , when challenged with DB01235 in the absence of S33084 , these animals continued to exhibit reduced LID . In the 6 - OHDA - lesioned rat , S33084 similarly attenuated development of behavioural sensitization to DB01235 . Additionally , DB01235 - induced elevations in striatal pre - proenkephalin - A ( PPE - A ) ( but not PPE - B , phospho [ DB00156 ( 34 )] Q9UD71 , D1 , and D2 receptor mRNA or D3 receptor levels ) were reduced in S33084 treated animals . Our data suggest a role for D3 receptors in the development of LID and suggest that initiating DB01235 treatment with a D3 antagonist may reduce the development of LID in PD .\",\n \"Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK96___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK96___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK96___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .\",\n \"Sustained increase of PKA activity in the postcommissural putamen of dyskinetic monkeys . Levodopa - induced dyskinesias ( LID ) are a frequent complication of Parkinson ' s disease pharmacotherapy that causes significant disability and narrows the therapeutic window . Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood . Here , our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication . We examined the expression and downstream activity of dopamine receptors ( DR ) in the striatum of 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 tetrahydropiridine ( MPTP ) - lesioned monkeys with and without DB01235 treatment . Four monkeys were made dyskinetic and other four received a shorter course of DB01235 and did not develop LID . Our results show that DB01235 treatment induces an increase in P14416 and P35462 expression in the postcommissural putamen , but only P35462 is correlated with the severity of LID . Dyskinetic monkeys show a hyperactivation of the canonical P21728 - signaling pathway , measured by an increased phosphorylation of protein kinase A ( PKA ) and its substrates , particularly Q9UD71 . In contrast , activation of the P14416 - signaling pathway , visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9 , is associated with DB01235 treatment , independently of the presence of dyskinesias . Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the P35462 receptor and the P21728 pathway with a sustained increase of PKA activity in the postcommissural putamen . Importantly , we found that all signaling changes related to long - term DB01235 administration are exquisitely restricted to the postcommissural putamen , which may be related to the recurrent failure of pharmacological approaches .\",\n \"P12821 inhibitors could be therapeutic for antisocial personality disorder . Antisocial personality traits are an important topic for research . The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes . Catecholamine genes are being studied to facilitate this understanding , and some tentative findings are being reached about several of these genes . It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious . One conclusion that could be drawn from the current research findings is that DA2 like receptors ( P14416 , P35462 , P21917 ) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors . DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition . When these receptors are less active by genetically decreased density , lower affinity , or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state . Peripheral metabolism is increased and behavioral activation is noted . P00797 is disinhibited in this setting thus allowing sympathetic nervous system activation . The fight or flight behaviors thus produced , in the extreme , would be the setting of antisocial behavior . Research validates this hypothesis . Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others . P12821 inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders .\",\n \"DNA methylation profiles in diffuse large B - cell lymphoma and their relationship to gene expression status . In an initial epigenetic characterization of diffuse large B - cell lymphoma ( DLBCL ) , we evaluated the DNA methylation levels of over 500 CpG islands . Twelve CpG islands ( AR , P49918 , DLC1 , P14416 , P43694 , P39905 , Q13224 , P42898 , P15172 , Q13562 , O95948 and P05549 ) showed significant methylation in over 85 % of tumors . Interestingly , the methylation levels of a CpG island proximal to FLJ21062 differed between the activated B - cell - like ( ABC - DLBCL ) and germinal center B - cell - like ( GCB - DLBCL ) subtypes . In addition , we compared the methylation and expression status of 67 genes proximal ( within 500 bp ) to the methylation assays . We frequently observed that hypermethylated CpG islands are proximal to genes that are expressed at low or undetectable levels in tumors . However , many of these same genes were also poorly expressed in DLBCL tumors where their cognate CpG islands were hypomethylated . Nevertheless , the proportional reductions in Q12983 , P16455 , RBP1 , P43694 , Q9BY67 , P29762 and FLJ21062 expression with increasing methylation suggest that epigenetic processes strongly influence these genes . Lastly , the moderate expression of several genes proximal to hypermethylated CpG tracts suggests that DNA methylation assays are not always accurate predictors of gene silencing . Overall , further investigation of the highlighted CpG islands as potential clinical biomarkers is warranted .\",\n \"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK18___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .\",\n \"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .\",\n \"Expression of P00533 and molecules downstream to PI3K / Akt , P04049 - MEK - 1 - Q96HU1 ( Erk1 / 2 ) , and JAK ( P40763 ) pathways in invasive lung adenocarcinomas resected at a single institution . Therapies targeting P00533 are effective in treating tumors that harbor molecular alterations ; however , there is heterogeneity in long - term response to these therapies . We retrospectively analyzed protein expression of P00533 , Stat3 , phospho - Akt , and phospho - Erk1 / 2 by immunohistochemistry in a series of resected cases from a single institution , correlated with clinicopathological variables . There were 96 patients , with the majority of cases being of low stage tumors ( 17 pT1a , 23 pT1b , 30 pT2a , and 18 pT2b ) . Histologic subtypes were 45 acinar predominant , 2 cribriform , 25 solid , 7 papillary , 11 lepidic , and 4 mucinous tumors . The P00533 score was higher in tumors with vascular invasion ( P = 0 . 013 ) , in solid and cribriform acinar histology , and in high stage tumors ( P = 0 . 006 and P = 0 . 01 ) . P00533 was more likely overexpressed in solid compared to lepidic tumors ( P = 0 . 02 ) . Acinar tumors had the highest rate of P27361 / 2 positivity ( 19 % ) . There was a strong correlation among positivity for P07992 and other markers , including P40763 ( P = 0 . 003 ) , Akt ( P = 0 . 02 ) , and P27361 / P28482 ( P = 0 . 0005 ) . Expression of molecules downstream to P00533 varied from 12 % to 31 % of tumors ; however , the expression did not directly correlate to P00533 expression , which may suggest activation of the cascades through different pathways . The correlation of protein expression and the new lung adenocarcinoma classification may help in the understanding of activated pathways of each tumor type , which may act in the oncogenesis and drug resistance of these tumors .\",\n \"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK74___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .\",\n \"The P38936 codon 31 * C - and P14416 codon 313 * T - related genotypes / alleles , but not P18887 codon 399 , hOGG1 codon 326 , and P21728 - 48 polymorphisms , are correlated with the presence of leiomyoma . OBJECTIVE : To investigate whether the gene polymorphisms for P38936 , X - ray repair cross - complementing group 1 ( P18887 ) , human 8 - oxoguanine glycosylase 1 ( hOGG1 ) , and dopamine D1 and D2 receptors ( P21728 , - 2 ) are associated with leiomyoma susceptibility . DESIGN : Prospective study . SETTING : Departments of gynecology and genetics in a medical center . PATIENT ( S ) : Women were divided into two groups : leiomyoma ( n = 120 ) and nonleiomyoma ( n = 112 ) . INTERVENTION ( S ) : The P38936 codon 31 , P18887 codon 399 , hOGG1 codon 326 , P21728 - 48 , and P14416 codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions ( Blp I , MspI , Fnu4HI , Dde I , and NcoI , respectively ) . MAIN OUTCOME MEASURE ( S ) : Genotypes and allelic frequencies . RESULT ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyomas . The proportions of P38936 (*) CC / CA / AA and P14416 (*) CC / CT / TT in both groups were 27 . 5 / 68 . 3 / 4 . 2 % and 12 . 5 / 51 . 7 / 35 . 8 % ( leiomyoma ) ; and 14 . 3 / 51 . 8 / 33 . 9 % and 33 . 9 / 40 . 2 / 25 . 9 % ( nonleiomyoma ) . P18887 , hOGG1 , and P21728 were not correlated with the presence of leiomyomas . P18887 (*) GG / GA / AA , hOGG1 (*) TT / TA / AA , and P21728 (*) GG / GA / AA were 54 . 2 / 37 . 5 / 8 . 3 % , 36 . 7 / 44 . 2 / 19 . 1 % , and 3 . 3 / 25 . 8 / 70 . 8 % ( leiomyoma ) ; and 48 . 2 / 47 . 3 / 4 . 5 % , 43 . 6 / 41 / 15 . 4 % , and 3 . 6 / 25 / 71 . 4 % ( nonleiomyoma ) . CONCLUSION ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyoma . P18887 , hOGG1 , and P21728 were not correlated with leiomyoma development .\",\n \"[ The effect of bunazosin vs captopril on hemodynamic and neurohumoral parameters in patients with congestive heart failure ] . The hemodynamic parameters ( right atrial pressure , mean pulmonary artery pressure , pulmonary capillary wedge pressure , cardiac index , heart rate , blood pressure ) and neurohumoral responses ( alpha - P01160 , plasma renin activity , aldosterone , angiotensin II ) of ___MASK70___ , oral P12821 inhibitor , and Bunazosin , oral alpha 1 - blocker , were investigated in 28 patients with congestive heart failure at rest and after exercise . These data were analysed in both acute and chronic phases . 1 ) Acute effect . ___MASK70___ produced significant improvement of neurohumoral factors at rest and also after exercise . Bunazosin reduced alpha - P01160 , but other neurohumoral factors did not change . Bunazosin produced significant hemodynamic improvement both at rest and after exercise . 2 ) Chronic effect . ___MASK70___ produced significant hemodynamic improvement both at rest and after exercise . Improvement of neurohumoral factors in acute phase was also preserved at chronic phase . On Bunazosin , improvement of hemodynamics at acute phase was also preserved at chronic phase without deterioration of neurohumoral factors .\",\n \"The role of the subthalamic nucleus in DB01235 induced dyskinesia in 6 - hydroxydopamine lesioned rats . DB01235 is the most effective treatment for Parkinson ' s disease ( PD ) , but prolonged use leads to disabling motor complications including dyskinesia . Strong evidence supports a role of the subthalamic nucleus ( Q05639 ) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy . Here , we investigated the involvement of Q05639 in dyskinesia , using single - unit extracellular recording , behavioural and molecular approaches in hemi - parkinsonian rats rendered dyskinetic by chronic DB01235 administration . Our results show that chronic DB01235 treatment does not modify the abnormal Q05639 activity induced by the 6 - hydroxydopamine lesion of the nigrostriatal pathway in this model . Likewise , we observed a loss of Q05639 responsiveness to a single DB01235 dose both in lesioned and sham animals that received daily DB01235 treatment . We did not find any correlation between the abnormal involuntary movement ( AIM ) scores and the electrophysiological parameters of Q05639 neurons recorded 24 h or 20 - 120 min after the last DB01235 injection , except for the axial subscores . Nonetheless , unilateral chemical ablation of the Q05639 with ibotenic acid resulted in a reduction in global AIM scores and peak - severity of dyskinesia . In addition , Q05639 lesion decreased the anti - dyskinetogenic effect of buspirone in a reciprocal manner . Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB , phosphoDARPP - 32 , dopamine receptor ( DR ) D3 and P14416 / P21728 ratio . The Q05639 lesion attenuated the striatal molecular changes and normalized the P14416 / P21728 ratio . Taken together , our results show that the Q05639 plays a role , if modest , in the physiopathology of dyskinesias .\",\n \"Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK18___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .\",\n \"P01308 action in cultured human myoblasts : contribution of different signalling pathways to regulation of glycogen synthesis . A key metabolic action of insulin is the stimulation of non - oxidative glucose utilization in skeletal muscle , by increasing both glucose uptake and glycogen synthesis . The molecular mechanism underlying this process has been investigated using a variety of experimental systems . We report here the use of cultured human myoblasts to study insulin control of glycogen synthesis in humans . In these cells insulin stimulates glycogen synthesis approx . 2 . 2 - fold , associated with a similar activation of glycogen synthase ( GS ) which occurs within 5 - 10 min of the addition of insulin . P01308 also causes inactivation of glycogen synthase kinase - 3 ( GSK - 3 ) and activation of protein kinase B , both processes being sufficiently rapid to account for the effects of insulin on GS . Activation by insulin of the protein kinases p70s6K , p90s6K and extracellular signal - regulated kinase 2 ( P28482 ) is observed , but is significantly slower than the activation of GS . Selective inhibitors of the p70s6K pathway ( rapamycin ) , the P28482 / p90s6K pathway ( PD98059 ) and phosphatidylinositol 3 - kinase ( wortmannin ) have been used to probe the contribution of these components to insulin signalling in human muscle . Wortmannin blocks activation of both glycogen synthesis and GS and inactivation of GSK - 3 . PD98059 is without effect on these events , while rapamycin is without effect on inactivation of GSK - 3 but partially blocks activation of glycogen synthesis and GS . Taken together , these findings suggest that protein kinase B is responsible for the inactivation of GSK - 3 , but that an additional rapamycin - sensitive mechanism may contribute to the activation of GS and stimulation of glycogen synthesis .\",\n \"LG839 : anti - obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA - customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D . I . E . T . study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self - identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi - square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0 . 01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0 . 05 ) , and increased energy ( P < 0 . 001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 - gamma2 , P42898 , 5 - Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r = 0 . 42 , P = 0 . 045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA - directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity .\",\n \"Effects of the total saponins from Rosa laevigata Michx fruit against acetaminophen - induced liver damage in mice via induction of autophagy and suppression of inflammation and apoptosis . The effect of the total saponins from Rosa laevigata Michx fruit ( RLTS ) against acetaminophen ( ___MASK66___ ) - induced liver damage in mice was evaluated in the present paper . The results showed that RLTS markedly improved the levels of liver SOD , CAT , DB00143 , DB00143 - Px , MDA , NO and P35228 , and the activities of serum ALT and Q9NRA2 caused by ___MASK66___ . Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT - mediated dUTP nick end labeling ( TUNEL ) and transmission electron microscopy ( TEM ) assays . In addition , RLTS decreased the gene or protein expressions of cytochrome P450 ( P05181 ) , pro - inflammatory mediators ( IL - 1β , P05112 , P05231 , P01375 - α , P35228 , Bax , HMGB - 1 and P35354 ) , pro - inflammatory transcription factors ( NF - κB and AP - 1 ) , pro - apoptotic proteins ( cytochrome C , p53 , caspase - 3 , caspase - 9 , p - JNK , p - p38 and p - P29323 ) , and increased the protein expressions of Bcl - 2 and Bcl - xL . Moreover , the gene expression of P22301 , and the proteins including LC3 , Q14457 and Atg5 induced by ___MASK66___ were even more augmented by the extract . These results demonstrate that RLTS has hepatoprotective effects through antioxidative action , induction of autophagy , and suppression of inflammation and apoptosis , and could be developed as a potential candidate to treat ___MASK66___ - induced liver damage in the future .\",\n \"P21728 behavioral responsitivity following selective lesions of the striatal patch compartment during development . The behavioral effects of selective destruction of the dopamine ( DA ) input to the patch compartment of rat striatum early in development was investigated . Rat pups were given bilateral intrastriatal ( i . s . ) injections of the neurotoxin 6 - hydroxydopamine ( 6 - OHDA ) on day of birth ( P0 ) or postnatal day 1 ( P1 ) , which resulted in selective behavioral alterations following DA agonist treatment in adulthood . Neonatally - lesioned rats exhibited self - biting behavior following treatment with the DA precursor L - dihydroxyphenylalanine ( DB01235 ) . In response to treatment with the selective D1 agonist SKF38393 , there was an increased incidence of abnormal perioral movements . The cataleptogenic effects of the D1 antagonist SCH23390 and the D2 antagonist haloperidol were also studied . Neonatally - lesioned rats were significantly less cataleptic compared to control rats following D1 antagonist treatment , but not following D2 antagonist treatment . Autoradiographs of [ 3H ] mazindol binding to DA uptake sites ( a measure of DA terminal density ) showed a ' patchy ' loss of approx . 40 - 50 % in striatal tissue sections derived from the i . s . lesioned rats . These data suggest that injections of 6 - OHDA into the striatum during this early postnatal period cause a DA lesion that results in long - term effects on a D1 receptor system .\",\n \"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK23___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .\",\n \"Selective cyclooxygenase - 2 blocker delays healing of esophageal ulcers in rats and inhibits ulceration - triggered c - DB00134 / hepatocyte growth factor receptor induction and extracellular signal - regulated kinase 2 activation . Nonsteroidal anti - inflammatory drugs , both nonselective and cyclooxygenase - 2 ( P35354 ) selective , delay gastric ulcer healing . Whether they affect esophageal ulcer healing remains unexplored . We studied the effects of the P35354 selective inhibitor , celecoxib , on esophageal ulcer healing as well as on the cellular and molecular events involved in the healing process . Esophageal ulcers were induced in rats by focal application of acetic acid . Rats with esophageal ulcers were treated intragastrically with either celecoxib ( 10 mg / kg , once daily ) or vehicle for 2 or 4 days . Esophageal ulceration triggered increases in : esophageal epithelial cell proliferation ; expression of P35354 ( but not P23219 ) ; hepatocyte growth factor ( P14210 ) and its receptor , c - DB00134 ; and activation of extracellular signal - regulated kinase 2 ( P28482 ) . Treatment with celecoxib significantly delayed esophageal ulcer healing and suppressed ulceration - triggered increases in esophageal epithelial cell proliferation , c - DB00134 mRNA and protein expression , and P28482 activity . In an ex vivo organ - culture system , exogenous P14210 significantly increased P28482 phosphorylation levels in esophageal mucosa . A structural analog of celecoxib , SC - 236 , completely prevented this effect . These findings indicate that celecoxib delays esophageal ulcer healing by reducing ulceration - induced esophageal epithelial cell proliferation . These actions are associated with , and likely mediated by , down - regulation of the P14210 / c - DB00134 - P28482 signaling pathway .\",\n \"Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells . Histone deacetylase inhibitors are promising anti - tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies . However , little is known about any effects of these drugs on the central nervous system . The aim of the present study was to analyze the effects of trichostatin A ( P32119 ) -- a broad - spectrum histone deacetylase inhibitor -- on the transcriptional regulation of several genes involved in dopamine - and serotonergic neurotransmission . To this end , short - term parallel cultures of SK - NF - I neuroblastoma cells were treated with P32119 either alone or in combination with hypoxia , and mRNA levels of dopamine receptor D3 ( P35462 ) and D4 ( P21917 ) , dopamine transporter ( Q01959 ) , dopamine hydroxylase ( P09172 ) , dopamine receptor regulating factor ( DRRF ) , catechol - O - methyltransferase ( P21964 ) , serotonin receptor 1A ( P08908 ) , monoamino oxidase A ( P21397 ) , serotonin transporter ( P31645 ) and tryptophan hydroxylase 2 ( Q8IWU9 ) were determined by quantitative PCR . We found that P32119 did not antagonize the hypoxia - induced activation of D3 and D4 dopamine receptor genes , implying that induction of these genes is not mediated directly by hypoxia inducible factor - 1alpha . On the other hand , P32119 dramatically upregulated the expression of Q01959 and P31645 ( 45 - fold and 15 - fold , respectively ) , while transcript levels of P21397 and P21964 were significantly reduced ( by 70 % and by more than 90 % , respectively ) . Induction of Q01959 protein expression was detected by western blotting . These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons .\",\n \"Dopamine selectively reduces GABA ( B ) transmission onto dopaminergic neurones by an unconventional presynaptic action . The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement . In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine ( DA ) release in the brain . Here , we report a concentration - dependent depressant action of dopamine on the GABA ( B ) IPSPs intracellularly recorded from dopaminergic neurones . Such effect was observed in spite of the presence of D ( 1 )/ P14416 antagonists . A reduction of the GABA ( B ) IPSPs was also caused by noradrenaline ( norepinephrine ) and by L - beta - 3 , 4 - dihydroxyphenylalanine ( DB01235 ) , which is metabolically transformed into DA . The DA - induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine . DA did not change the postsynaptic effects of the GABA ( B ) agonist baclofen , suggesting a presynaptic site of action . Furthermore , DA did not modulate the GABA ( A )- mediated IPSP . The DA - induced depression of the GABA ( B ) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists . The DA - and 5 - HT - induced depression of the GABA ( B ) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals . These results describe an unconventional presynaptic , D ( 1 ) and D ( 2 ) independent action of DA on the GABA ( B ) IPSP . This might have a principal role in determining therapeutic / side effects of DB01235 and antipsychotics and could be also involved in drug abuse .\",\n \"Dopamine agonists upregulate P05231 and P10145 production in human keratinocytes . AIM : Catecholamines regulate functions of the nervous , neuroendocrine and immune systems . Dopamine may modulate the activity of keratinocytes , which play a role in secreting cytokines and chemokines . The aim of this study was to evaluate the effect of dopaminergic agonists on the production of P05231 and P10145 by a non - tumoral human keratinocyte cell line ( HaCaT ) . METHODS : Cells were stimulated with dopamine and the P14416 agonist cabergoline . Levels of P05231 and P10145 in culture supernatants were then determined . Cell proliferation was also assessed . Assays were carried out in the presence or absence of the dopaminergic and β - adrenergic receptor antagonists ( sulpiride and propranolol , respectively ) and ascorbic acid . RESULTS : Dopamine stimulated the production of P05231 and P10145 in a concentration - dependent manner . The effects observed on the secretion of P05231 were more potent than those corresponding to P10145 and were reduced by ascorbic acid . The dopamine - induced P05231 secretion was partially reduced by sulpiride and abrogated by propranolol . The latter drug was able to block the effect of dopamine on the secretion of P10145 . The cabergoline - induced P05231 release was reduced by sulpiride . Cell viability was not affected by any of the drugs . CONCLUSIONS : Dopaminergic agonists can stimulate keratinocytes to produce P05231 and P10145 which are related to inflammatory cutaneous processes . These effects are mediated by dopaminergic and β - adrenergic receptors and by receptor - independent oxidative mechanisms .\",\n \"The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L - amino acid decarboxylase in healthy subjects . The A1 allele of the TaqI restriction fragment length polymorphism ( RFLP ) of the human dopamine D2 receptor gene ( P14416 ) is associated with a low density of D2 dopamine receptors in the striatum . Because of the important role of D2 autoreceptors in regulating dopamine synthesis , we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain . We also studied the effects of two other P14416 polymorphisms , C957 T and -- 141C Ins / Del , which have been suggested to affect D2 receptor levels in brain . The relationships between the TaqIA RFLP , C957 T and -- 141C Ins / Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18F ] fluorodopa ( [ 18F ] FDOPA ) , a radiolabelled analog of the dopamine precursor DB01235 . Heterozygous carriers of the A1 allele ( A1 / A2 ; 10 subjects ) had significantly higher ( 18 % ) [ 18F ] FDOPA uptake in the putamen than subjects without the A1 allele ( A2 / A2 ; 23 subjects ) . C957 T and -- 141C Ins / Del polymorphisms did not significantly affect [ 18F ] FDOPA Ki values . These results demonstrate that the A1 allele of P14416 gene is associated with increased striatal activity of aromatic L - amino acid decarboxylase , the final enzyme in the biosynthesis of dopamine and the rate - limiting enzyme for trace amine ( e . g . beta - phenylethylamine ) synthesis . The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function , and suggests that dopamine and / or trace amine synthesis rate is increased in the brains of A1 allele carriers .\",\n \"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .\",\n \"Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair . We present an oligonucleotide microarray ( \\\" MetaboChip \\\" ) based on the arrayed primer extension ( P27695 ) technique , allowing genotyping of single nucleotide polymorphisms ( SNPs ) in genes of interest for cancer susceptibility and pharmacogenetics . P27695 consists of a sequencing reaction primed by an oligonucleotide anchored with its 5 ' end to a glass slide and terminating one nucleotide before the polymorphic site . The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism . Ninety - three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project , using a set of 102 reference DNA samples from the Coriell Biorepository . Selected SNPs belong to the following genes : P00325 , P05091 , P27695 , CDKN2A , P21964 , P04798 , P05177 , Q16678 , P11509 , P33261 , P11712 , P05181 , P08684 , P14416 , P21917 , P07099 , P07992 , P18074 , Q92889 , P28715 , P30550 , O15217 , P21266 , P09211 , GSTT2 , LIG3 , Q00987 , P16455 , P05164 , NAT1 , NAT2 , P15559 , O15527 , P12004 , P06746 , Q01959 , P04179 , P04637 , P18887 , O43543 , O43542 , and O15287 . We assessed the performance of P27695 by comparing the results obtained with MetaboChip against those reported by the SNP500 . Among 88 SNPs that yielded signals , 6 showed less than 99 % of concordance , whereas 82 performed accurately , showing that P27695 is a reliable and sensitive genotyping method .\",\n \"Dopamine receptor D4 polymorphism predicts the effect of DB01235 on gambling behavior . BACKGROUND : There is ample evidence that a subgroup of Parkinson ' s disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling . The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors . These are potentially of genetic origin , since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 ( P21917 ) gene . Using a pharmacogenetic approach , we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects . METHODS : We administered 300 mg of L - dihydroxyphenylalanine ( DB01235 ) or placebo to 200 healthy male subjects who were all genotyped for their P21917 polymorphism . Subjects played a gambling task 60 minutes after DB01235 administration . RESULTS : Without considering genetic information , DB01235 administration did not lead to an increase in gambling propensity compared with placebo . As expected , however , an individual ' s P21917 polymorphism accounted for variation in gambling behavior after the administration of DB01235 . Subjects who carry at least one copy of the 7 - repeat allele showed an increased gambling propensity after dopaminergic stimulation . CONCLUSIONS : These findings demonstrate that genetic variation in the P21917 gene determines an individual ' s gambling behavior in response to a dopaminergic drug challenge . They may have implications for the treatment of Parkinson ' s disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior .\",\n \"Q9UD71 and inhibitor - 1 are expressed in pancreatic beta - cells . P01308 secretion from pancreatic beta - cells has to be tightly regulated to ensure accurate glucose homeostasis . The capacity of beta - cells to respond to extracellular stimulation is determined by several signaling pathways . One important feature of these pathways is phosphorylation and subsequent dephosphorylation of a wide range of cellular substrates . Protein phosphatase 1 ( P50391 ) is a major eukaryotic serine / threonine protein phosphatase that controls a multitude of physiological processes . We have investigated the expression and cellular distribution of two endogenous inhibitors of P50391 activity in beta - cells . RT - PCR , Western blotting , and immunohistochemistry showed that Q9UD71 and inhibitor - 1 are present in insulin - secreting endocrine beta - cells . Subcellular fractionation of mouse islets revealed that both P50391 inhibitors predominantly localized to cytosol - enriched fractions . Inhibitor - 1 was also present in fractions containing plasma membrane - associated proteins . These data indicate a potential role for Q9UD71 and inhibitor - 1 in the regulation of P50391 activity in pancreatic beta - cell stimulus - secretion coupling .\",\n \"Task - dependent interactions between dopamine D2 receptor polymorphisms and DB01235 in patients with Parkinson ' s disease . Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning . In the current study , we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with DB01235 during motor tasks in patients with Parkinson ' s disease ( PD ) . Forty - five PD patients were genotyped for the P14416 polymorphism ( rs 1076560 , G > T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 states . For motor sequence learning , P14416 genotype mediated DB01235 effects such that DB01235 associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 =- 2 . 71 , p = 0 . 022 ) , whereas G homozygotes showed no performance change with DB01235 . For the grooved pegboard test , performance improved with DB01235 independent of patients ' P14416 genotype . Collectively these results demonstrate that common P14416 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .\",\n \"___MASK51___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .\",\n \"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK14___ GITS , Diaprel MR ) . One daily dose of ___MASK14___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .\",\n \"Differential treatment regimen - related effects of cannabinoids on D1 and D2 receptors in adolescent and adult rat brain . Animal studies suggest differential effects of cannabinoids on dopamine - related behaviours in adolescence and adulthood however few studies have investigated the underlying neurochemical effects of cannabinoids during adolescence . The aim of the present study was to compare the effects of treatment with the synthetic cannabinoid , HU210 , on dopamine receptor density in adolescent and adult rats . Adolescent ( postnatal day ( P01160 ) 35 ) and adult ( P01160 70 ) rats received a single dose of 100μg / kg HU210 or 25 , 50 or 100μg / kg HU210 for 4 or 14 days . P21728 ( D1R ) or D2 receptor ( D2R ) density was measured in the medial and lateral ( CPUL ) caudate putamen , nucleus accumbens , olfactory tubercle ( TU ) and substantia nigra ( D1R only ) using in vitro autoradiography . D1R and D2R densities were 1 . 6 - 1 . 7 - and 1 . 1 - 1 . 4 - fold higher respectively in adolescent control rats compared to adults . In adult rats , D1R density was increased by 1 . 2 - and 1 . 3 - fold ( p < 0 . 05 ) in CPUL and TU respectively compared to controls , after 14 days of HU210 treatment . A significant overall effect of treatment ( p < 0 . 05 ) on D2R density was also observed in adults after the single dose and 4 and 14 days administration of HU210 . In adolescents , an overall effect of treatment on D1R density after a single exposure to HU210 was seen ( p = 0 . 0026 ) but no changes in D1R or D2R densities were observed in other treatment groups . These results suggest that the adolescent rat brain does not display the same compensatory mechanisms activated in the adult brain following cannabinoid treatment .\",\n \"Interaction between serotonin transporter gene , catechol - O - methyltransferase gene and stressful life events in mood disorders . It is well established that stress is a risk factor for onset of mood disorders . Emerging evidence suggests that genetic vulnerability may also moderate individual responsiveness to stress . The most compelling evidence regards the polymorphism within the promoter region of the serotonin transporter gene ( SERTPR ) , which has been reported to moderate the risk for depression , in conjunction with life stressors . In the present paper we analysed SERTPR in the onset of mood disorders , along with adverse life events , and other candidate genes : the serotonin receptor 1A ( P08908 ) , the dopamine receptor D4 ( P21917 ) and the catechol - O - methyltransferase ( P21964 ) . The sample was composed of 686 Italian subjects , affected by major depression and bipolar disorder . Patients were asked to report about life stressors within the year preceding onset of their first mood - disorder episode and genotyped . A ' case - only ' design was employed to investigate the interaction between genes and stressors . P21964 was associated with depression following exposure to stressors ( chi2 = 13 . 05 , d . f .= 2 , p = 0 . 0015 ) and SERTPR also showed a positive association ( chi2 = 6 . 70 , d . f .= 2 , p = 0 . 035 ) , mainly among women and among major depressives . The interaction between P21964 and SERTPR was also significant ( p = 0 . 0005 ) . In our retrospective study SERTPR is hypothesized to lead to the onset of major depression via its influence on reaction to adversities , particularly in females . Moreover , P21964 was risk factor for onset of both major depression and bipolar disorder , in conjunction with adversities .\",\n \"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK100___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK100___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK100___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK100___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .\",\n \"The interleukin 10 promoter haplotype ACA and the long - form variant of the P21917 uVNTR polymorphism are associated with vulnerability to schizophrenia . A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin - 10 ( P22301 ) promoter and P21917 uVNTR polymorphisms . P21917 long - form variants ( namely , those with ≥ 5 repeats ) , homozygosity for the 4 - repeat allele , and the P22301 haplotype ACA were associated with schizophrenia , respectively . No obvious interactions among the potential polymorphisms were found , which suggests that P22301 and P21917 confer vulnerability to schizophrenia independently .\",\n \"Transactivation of PDGFRbeta by dopamine D4 receptor does not require PDGFRbeta dimerization . Growth factor - induced receptor dimerization and cross - phosphorylation are hallmarks of signal transduction via receptor tyrosine kinases ( RTKs ) . G protein - coupled receptors ( GPCRs ) can activate RTKs through a process known as transactivation . The prototypical model of RTK transactivation involves ligand - mediated RTK dimerization and cross - phosphorylation . Here , we show that the platelet - derived growth factor receptor beta ( PDGFRbeta ) transactivation by the dopamine receptor D4 ( P21917 ) is not dependent on ligands for PDGFRbeta . Furthermore , when PDGFRbeta dimerization is inhibited and receptor phosphorylation is suppressed to near basal levels , the receptor maintains its ability to be transactivated and is still effective in signaling to P27361 / 2 . Hence , the P21917 - PDGFRbeta - P27361 / 2 pathway can occur independently of a PDGF - like ligand , PDGFRbeta cross - phosphorylation and dimerization , which is distinct from other known forms of transactivation of RTKs by GPCRs .\",\n \"[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK70___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .\",\n \"Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re - validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague - Dawley rats were treated with chronic DB01235 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 ( the D ( 1 ) and P14416 antagonists , P35240 - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti - dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .\",\n \"Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK18___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .\",\n \"Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .\",\n \"Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .\",\n \"Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .\",\n \"Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 ) at 11p15 , tyrosinase ( P14679 ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 ) at 11q22 - q23 , as well as with the c - Harvey - ras oncogene ( P01112 ) and insulin gene ( P01308 ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected - sib - pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two - point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 and P01308 excluded the 11p15 region encompassing both P21917 and TH . In agreement with the negative linkage results , affected - sib - pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 , TH , P14679 , and P14416 in the pathogenesis of bipolar illness .\",\n \"___MASK66___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .\"\n]"},"candidates":{"kind":"list like","value":["___MASK100___","___MASK14___","___MASK18___","___MASK23___","___MASK51___","___MASK66___","___MASK70___","___MASK74___","___MASK96___"],"string":"[\n \"___MASK100___\",\n \"___MASK14___\",\n \"___MASK18___\",\n \"___MASK23___\",\n \"___MASK51___\",\n \"___MASK66___\",\n \"___MASK70___\",\n \"___MASK74___\",\n \"___MASK96___\"\n]"},"answer":{"kind":"string","value":"___MASK70___"},"id":{"kind":"string","value":"MH_train_470"}}},{"rowIdx":471,"cells":{"query":{"kind":"string","value":"interacts_with DB08918?"},"supports":{"kind":"list like","value":["___MASK7___ : kinetic and dynamic profile in the treatment of pain . ___MASK7___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK7___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK7___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK7___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .","Q9BXS0 triggers and promotes Alzheimer ' s disease - like pathology in vivo . Collagen XXV alpha 1 ( Q9BXS0 ) is a collagenous type II transmembrane protein purified from senile plaques of Alzheimer ' s disease ( AD ) brains . Q9BXS0 alleles have been associated with increased risk for AD in a Swedish population . Q9BXS0 is specifically expressed in neurons and binds to aggregated Abeta in vitro . However , its contribution to the pathogenesis of AD and in vivo function are unknown . Here , we report that over - expression of Q9BXS0 in transgenic mice increases p35 / p25 and beta - site P05067 - cleaving enzyme 1 ( P56817 ) levels , facilitates intracellular aggregation and extracellular matrix deposits of Abeta , and causes synaptophysin loss and astrocyte activation . Q9BXS0 mice displayed reduced anxiety - like behavior in elevated plus maze and open field tests and significantly slower swimming speed in Morris water maze . In stable cell lines , motifs in noncollagenous domains of Q9BXS0 were important for the induction of P56817 expression . These findings demonstrate that Q9BXS0 leads to AD - like pathology in vivo . Modulation of Q9BXS0 function may represent an alternative therapeutic intervention for AD .","Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK24___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .","Transcriptional regulation of beta - secretase by p25 / cdk5 leads to enhanced amyloidogenic processing . P12004 - dependent kinase 5 ( cdk5 ) has been implicated in Alzheimer ' s disease ( AD ) pathogenesis . Here , we demonstrate that overexpression of p25 , an activator of cdk5 , led to increased levels of P56817 mRNA and protein in vitro and in vivo . A p25 / cdk5 responsive region containing multiple sites for signal transducer and activator of transcription ( P42224 / 3 ) was identified in the P56817 promoter . P40763 interacts with the P56817 promoter , and p25 - overexpressing mice had elevated levels of pSTAT3 and P56817 , whereas cdk5 - deficient mice had reduced levels . Furthermore , mice with a targeted mutation in the P40763 cdk5 responsive site had lower levels of P56817 . Increased P56817 levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor . These data demonstrate a pathway by which p25 / cdk5 increases the amyloidogenic processing of P05067 through P40763 - mediated transcriptional control of P56817 that could have implications for AD pathogenesis .","Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome : a Children ' s Cancer Group Study . PURPOSE : ___MASK91___ is a major component of current treatment regimens for children with acute lymphocytic leukemia ( ALL ) . Potential mechanisms of methotrexate resistance include impaired drug uptake , decreased drug retention , and dihydrofolate reductase ( P00374 ) amplification . The purpose of this study was to assess whether reduced folate carrier ( P41440 ) and P00374 expression in untreated leukemic blasts correlated with outcome . METHODS : Quantitative real - time RT - PCR was used to measure P41440 and P00374 mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children ' s Cancer Group studies . RESULTS : Low P41440 expression at diagnosis correlated significantly with an unfavorable event free survival . Surprisingly , low , not high , P00374 expression correlated significantly with an unfavorable event - free survival . Proliferative cell nuclear antigen ( P12004 ) expression demonstrated a weak inverse relationship between sample P12004 and P00374 or P41440 expression , suggesting that P00374 and P41440 expression may be markers for factors other than drug resistance . CONCLUSIONS : These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL , and P00374 expression also may be an important prognostic factor in ALL . Additional studies are necessary to clarify the mechanism for the correlation of low P00374 expression with poor outcome .","Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer ' s disease . Epidemiological studies demonstrate that chronic use of nonsteroidal anti - inflammatory drugs ( NSAIDs ) in normal aging populations reduces the risk of developing Alzheimer ' s disease ( AD ) . NSAIDs inhibit the enzymatic activity of cyclooxygenase - 1 ( P23219 ) and inducible P35354 , which catalyze the first committed step in the synthesis of prostaglandins . These studies implicate P36551 - mediated inflammation as an early and potentially reversible preclinical event ; however , the mechanism by which P36551 activity promotes development of AD has not been determined . Recent studies implicate the prostaglandin E2 ( DB00917 ) E prostanoid subtype 2 ( EP2 ) receptor in the development of the innate immune response in brain . Here , we report that deletion of the DB00917 EP2 receptor in the APPSwe - PS1DeltaE9 model of familial AD results in marked reductions in lipid peroxidation in aging mice . This reduction in oxidative stress is associated with significant decreases in levels of amyloid - beta ( Abeta ) 40 and 42 peptides and amyloid deposition . Aged APPSwe - PS1DeltaE9 mice lacking the EP2 receptor harbor lower levels of beta C - terminal fragments , the product of beta - site P05067 cleaving enzyme ( P56817 ) processing of amyloid precursor protein . Increases in P56817 processing have been demonstrated in models of aging and AD and after oxidative stress . Our results indicate that DB00917 signaling via the EP2 receptor promotes age - dependent oxidative damage and increased Abeta peptide burden in this model of AD , possibly via effects on P56817 activity . Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD , and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD .","Combined treatment with a P56817 inhibitor and anti - Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice . Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer ' s disease . Among the agents explored in clinical trials are anti - Aβ peptide antibodies and secretase inhibitors . Most anti - Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid , although secretase inhibitors reduce the de novo production of Aβ . Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment . We performed a chronic study in APPLondon transgenic mice that received treatment with anti - Aβ antibody gantenerumab and P56817 inhibitor RO5508887 , either as mono - or combination treatment . Treatment aimed to evaluate efficacy on amyloid progression , similar to preexisting amyloidosis as present in Alzheimer ' s disease patients . Mono - treatments with either compound caused a dose - dependent reduction of total brain Aβ and amyloid burden . Combination treatment with both compounds significantly enhanced the antiamyloid effect . The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number , which suggests effective inhibition of de novo plaque formation . Moreover , significantly enhanced clearance of pre - existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887 . P56817 inhibition led to a significant time - and dose - dependent decrease in P04141 Aβ , which was not observed for gantenerumab treatment . Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance .","The cell adhesion protein P16109 glycoprotein ligand - 1 is a substrate for the aspartyl protease P56817 . The aspartyl protease P56817 cleaves the amyloid precursor protein and the sialyltransferase P15907 and is important in the pathogenesis of Alzheimer ' s disease . The normal function of P56817 and additional physiological substrates have not been identified . Here we show that P56817 acts on the Q14242 ( Q14242 ) , which mediates leukocyte adhesion in inflammatory reactions . In human monocytic U937 and human embryonic kidney 293 cells expressing endogenous or transfected P56817 , Q14242 was cleaved by P56817 to generate a soluble ectodomain and a C - terminal transmembrane fragment . No evidence of the cleavage fragment was seen in primary cells derived from mice deficient in P56817 . By using deletion constructs and enzymatic deglycosylation of the C - terminal Q14242 fragments , the cleavage site in Q14242 was mapped to the juxtamembrane region within the ectodomain . In an in vitro assay P56817 catalyzed the formation of the Q14242 products seen in vivo . The cleavage occurred at a DB00149 - DB00133 peptide bond as identified by mass spectrometry using a synthetic peptide . We conclude that Q14242 is an additional substrate for P56817 .","P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK64___ ) in castrated male and female mice subjected to ___MASK64___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK64___ in mice CPs .","___MASK33___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK33___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .","A critical importance of polyamine site in DB01221 receptors for neurite outgrowth and fasciculation at early stages of P19 neuronal differentiation . We have investigated the role of N - methyl - d - aspartate receptors ( NMDARs ) and gamma - aminobutyric acid receptors type A ( GABA ( A ) Rs ) at an early stage of P19 neuronal differentiation . The subunit expression was profiled in 24 - hour intervals with RT - PCR and functionality of the receptors was verified via fluo - 3 imaging of Ca ( 2 +) dynamics in the immature P19 neurons showing that both DB01221 and GABA excite neuronal bodies , but only polyamine - site sensitive NMDAR stimulation leads to enhanced Ca ( 2 +) signaling in the growth cones . Inhibition of Q9UHB4 / Q13224 NMDARs by 1 muM ifenprodil severely impaired P19 neurite extension and fasciculation , and this negative effect was fully reversible by polyamine addition . In contrast , GABA ( A ) R antagonism by a high dose of 200 microM bicuculline had no observable effect on P19 neuronal differentiation and fasciculation . Except for the differential NMDAR and GABA ( A ) R profiles of Ca ( 2 +) signaling within the immature P19 neurons , we have also shown that inhibition of Q9UHB4 / Q13224 NMDARs strongly decreased mRNA level of P13591 - 180 , which has been previously implicated as a regulator of neuronal growth cone protrusion and neurite extension . Our data thus suggest a critical role of Q9UHB4 / Q13224 NMDARs during the process of neuritogenesis and fasciculation of P19 neurons via differential control of local growth cone Ca ( 2 +) surges and P13591 - 180 signaling .","Fetzima ( levomilnacipran ) , a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta - site amyloid precursor protein cleaving enzyme - 1 . Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters ( P31645 ) to increase the synaptic concentrations of serotonin . Beta - site amyloid precursor protein cleaving enzyme - 1 ( P56817 - 1 ) is responsible for amyloid β plaque formation . Hence it is an interesting target for Alzheimer ' s disease ( AD ) therapy . This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named ' Fetzima ' with P56817 - 1 and P31645 . Fetzima is chemically known as levomilnacipran . The study has explored a possible link between the treatment of Depression and AD . ' Autodock 4 . 2 ' was used for docking study . The free energy of binding ( ΔG ) values for ' levomilnacipran - P31645 ' interaction and ' levomilnacipran - P56817 ' interaction were found to be - 7 . 47 and - 8 . 25 kcal / mol , respectively . DB08918 was found to interact with S438 , known to be the most important amino acid residue of serotonin binding site of P31645 during ' levomilnacipran - P31645 ' interaction . In the case of ' levomilnacipran - P56817 ' interaction , levomilnacipran interacted with two very crucial aspartic acid residues of P56817 - 1 , namely , D32 and D228 . These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain . Hence , Fetzima ( levomilnacipran ) might act as a potent dual inhibitor of P31645 and P56817 - 1 and expected to form the basis of a future dual therapy against depression and AD . It is an established fact that development of AD is associated with Major Depressive Disorder . Therefore , the design of new P56817 - 1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial .","aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK40___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .","Inhibition of ADP - induced P16109 expression and platelet - leukocyte conjugate formation by clopidogrel and the Q9H244 receptor antagonist AR - C69931MX but not aspirin . Platelet - leukocyte interactions are recognised to have pro - inflammatory effects , which may be important in the pathophysiology of ischaemic heart disease . ___MASK13___ and the novel intravenous antithrombotic agent AR - C69931MX act at the level of the platelet Q9H244 receptor , which is known to amplify platelet activation , aggregation and other responses induced by numerous platelet agonists . We studied the effects of clopidogrel and aspirin on ADP - induced platelet - leukocyte conjugate formation and P16109 expression in healthy volunteers . The effects of clopidogrel and AR - C69931MX administered to patients with ischaemic heart disease were also assessed . AR - C69931MX and aspirin were also studied in vitro . ___MASK13___ and AR - C69931MX suppressed ADP - induced platelet aggregation , P16109 expression and platelet - leukocyte conjugate formation whereas aspirin had no inhibitory effect . These effects of clopidogrel and AR - C69931MX may confer therapeutic benefits in the management of acute coronary syndromes .","Q9Y5Z0 plays a role in the insulin receptor trafficking in pancreatic ß - cells . P56817 ( β - site amyloidogenic cleavage of precursor protein - cleaving enzyme 1 ) is a β - secretase protein that plays a central role in the production of the β - amyloid peptide in the brain and is thought to be involved in the Alzheimer ' s pathogenesis . In type 2 diabetes , amyloid deposition within the pancreatic islets is a pathophysiological hallmark , making crucial the study in the pancreas of P56817 and its homologous Q9Y5Z0 to understand the pathological mechanisms of this disease . The objectives of the present study were to characterize the localization of P56817 proteins in human pancreas and determine their function . High levels of P56817 enzymatic activity were detected in human pancreas . In normal human pancreas , P56817 was observed in endocrine as well as in exocrine pancreas , whereas Q9Y5Z0 expression was restricted to β - cells . Intracellular analysis using immunofluorescence showed colocalization of P56817 with insulin and Q9Y5Z0 with clathrin - coated vesicles of the plasma membrane in MIN6 cells . When P56817 and - 2 were pharmacologically inhibited , P56817 localization was not altered , whereas Q9Y5Z0 content in clathrin - coated vesicles was increased . P01308 internalization rate was reduced , insulin receptor β - subunit ( IRβ ) expression was decreased at the plasma membrane and increased in the Golgi apparatus , and a significant reduction in insulin gene expression was detected . Similar results were obtained after specific Q9Y5Z0 silencing in MIN6 cells . All these data point to a role for Q9Y5Z0 in the IRβ trafficking and insulin signaling . In conclusion , Q9Y5Z0 is hereby presented as an important enzyme in β - cell function .","Novel systemic markers for patients with Alzheimer disease ? - a pilot study . Almost 2 % of the population of western industrialized countries are affected by Alzheimer ' s disease ( AD ) . Nevertheless the pathogenetic process leading to this neurodegenerative disease is widely unknown . Thus , we focus on novel pathophysiological aspects of AD . We hypothesize that AD patients reveal increased levels of peripheral blood mononuclear cells ( PBMCs ) expressing proinflammatory ( P35354 , P01375 , P25942 ) , proapoptotic ( P09874 ) , adhesion - relevant ( P28907 ) or AD associated ( C99 , P56817 , P49768 ) proteins as well as elevated proinflammatory biochemical plasma parameters . Therefore , PBMCs of AD patients and age - matched control subjects were studied by two color fluorescence - activated cell sorter ( FACS ) analysis . Furthermore , concentration of plasma oxidized low - density lipoprotein ( oxLDL ) and P01375 were measured by enzyme - linked immunosorbent assay ( ELISA ) . We found a significantly increased percentage of P01375 , P35354 , P09874 , P28907 , C99 or presenilin - 1 positive PBMCs in AD patients compared with healthy subjects . FACS analyses revealed that the percentage of C99 or presenilin - 1 positive PBMCs , which also express P01375 , P35354 , P09874 or P28907 is also increased in AD patients . Additionally , AD patients had significantly increased plasma oxLDL and P01375 levels . Furthermore , we found positive correlations between plasma oxLDL or P01375 concentrations and the percentage of TNFalpha + , P35354 + or P09874 + , as well as P49768 + , C99 + or P56817 + PBMCs . Our findings suggest that immunocytological investigations , based on immunophenotyping of AD relevant proteins combined with measurement of proinflammatory , proapoptotic and adhesion - relevant proteins in PBMCs may provide more insight into the pathophysiology of AD .","P56817 elevation is associated with aberrant limbic axonal sprouting in epileptic CD1 mice . The brain is capable of remarkable synaptic reorganization following stress and injury , often using the same molecular machinery that governs neurodevelopment . This form of plasticity is crucial for restoring and maintaining network function . However , neurodegeneration and subsequent reorganization can also play a role in disease pathogenesis , as is seen in temporal lobe epilepsy and Alzheimer ' s disease . β - Secretase - 1 ( P56817 ) is a protease known for cleaving β - amyloid precursor protein into β - amyloid ( Aβ ) , a major constituent in amyloid plaques . Emerging evidence suggests that P56817 is also involved with synaptic plasticity and nerve regeneration . Here we examined whether P56817 immunoreactivity ( IR ) was altered in pilocarpine - induced epileptic CD1 mice in a manner consistent with the synaptic reorganization seen during epileptogenesis . P56817 - IR increased in the P07451 mossy fiber field and dentate inner molecular layer in pilocarpine - induced epileptic mice , relative to controls ( saline - treated mice and mice 24 - 48 h after pilocarpine - status ) , and paralleled aberrant expression of neuropeptide Y . Regionally increased P56817 - IR also occurred in neuropil in hippocampal area P00915 and in subregions of the amygdala and temporal cortex in epileptic mice , colocalizing with increased IR for growth associated protein 43 ( P17677 ) and polysialylated - neural cell adhesion molecule ( PSA - P13591 ) , but reduced IR for microtubule - associated protein 2 ( P11137 ) . These findings suggest that P56817 is involved in aberrant limbic axonal sprouting in a model of temporal lobe epilepsy , warranting further investigation into the role of P56817 in physiological vs . pathological neuronal plasticity .","Vessel wall , not platelet , Q9H244 potentiates early atherogenesis . AIMS : Platelets have a fundamental role in atherothrombosis , but their role in early atherogenesis is unclear . The Q9H244 receptor is responsible for amplifying and sustaining platelet activation and Q9H244 inhibition is crucial in modulating the vessel wall response to injury . We therefore examined the role of platelet vs . vessel wall Q9H244 in early atherogenesis and considered the use of Q9H244 antagonists ticagrelor and clopidogrel in modulating this process . METHODS AND RESULTS : ApoE (-/-) and ApoE (-/-) Q9H244 ( -/- ) male mice underwent bone marrow transplantation and were fed a western diet for 4 weeks before assessing atherosclerotic burden . Compared with ApoE (-/-) controls , platelet Q9H244 deficiency profoundly reduced platelet reactivity but had no effect on atheroma formation , whereas vessel wall Q9H244 deficiency significantly attenuated atheroma in the aortic sinus and brachiocephalic artery ( both P < 0 . 001 ) . ApoE (-/-) and ApoE (-/-) Q9H244 ( -/- ) male mice fed western diet plus either twice - daily doses of ticagrelor ( 100 mg / kg ) or daily clopidogrel ( 20 mg / kg ) for 4 weeks exhibited no significant reduction in atheroma compared with control mice fed mannitol . Attenuated P16109 expression confirmed platelet Q9H244 inhibition in drug - treated mice . CONCLUSIONS : Despite its major contribution to platelet reactivity , platelet Q9H244 has no effect on early atheroma formation , whereas vessel wall Q9H244 is important in this process . ___MASK16___ and clopidogrel effectively reduced platelet reactivity but were unable to inhibit early atherogenesis , demonstrating that these Q9H244 inhibitors may not be effective in preventing early disease .","Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo . The mechanisms through which blockade of metabotropic glutamate receptors 5 ( P41594 ) results in anxiolytic and antidepressant effects are currently unknown . In the present study , we therefore hypothesized that the anxiolytic - and antidepressant - like profile of the noncompetitive P41594 receptor antagonist 2 - ethyl - 6 -( phenylethynyl )- pyridine ( MPEP ) may be mediated by inhibition of the norepinephrine transporter ( NET ) . Accordingly , we first examined the potency of MPEP to bind to or inhibit uptake at the NET as well as the dopamine and serotonin transporters ( Q01959 and P31645 , respectively ) . We also examined the simultaneous in vivo effects of MPEP and desipramine ( ___MASK10___ ) on both NE - like oxidation current in the amygdala ( Q9BXS0 ) and cell firing in the locus coeruleus ( LC ) by means of differential pulse voltammetry ( DPV ) coupled with electrophysiology . MPEP completely displaced the binding of [ 3H ] - nisoxetine on human NET with a pKi of 6 . 63 +/- 0 . 02 . In addition , MPEP was able to inhibit [ 3H ] - NE uptake in LLCPK cells expressing human NET , with a pIC50 of 5 . 55 +/- 0 . 09 . In vivo DPV data revealed that both MPEP ( 30 mg / kg i . p . ) and ___MASK10___ ( 10 mg / kg i . p . ) significantly increased NE - like voltammetric responses levels in the Q9BXS0 , whereas both compounds also significantly decreased cell firing monitored concomitantly from the second microelectrode in the LC . Collectively , the results of the present study provide potential new mechanisms through which MPEP exerts its anxiolytic and antidepressant effects ."],"string":"[\n \"___MASK7___ : kinetic and dynamic profile in the treatment of pain . ___MASK7___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK7___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK7___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK7___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .\",\n \"Q9BXS0 triggers and promotes Alzheimer ' s disease - like pathology in vivo . Collagen XXV alpha 1 ( Q9BXS0 ) is a collagenous type II transmembrane protein purified from senile plaques of Alzheimer ' s disease ( AD ) brains . Q9BXS0 alleles have been associated with increased risk for AD in a Swedish population . Q9BXS0 is specifically expressed in neurons and binds to aggregated Abeta in vitro . However , its contribution to the pathogenesis of AD and in vivo function are unknown . Here , we report that over - expression of Q9BXS0 in transgenic mice increases p35 / p25 and beta - site P05067 - cleaving enzyme 1 ( P56817 ) levels , facilitates intracellular aggregation and extracellular matrix deposits of Abeta , and causes synaptophysin loss and astrocyte activation . Q9BXS0 mice displayed reduced anxiety - like behavior in elevated plus maze and open field tests and significantly slower swimming speed in Morris water maze . In stable cell lines , motifs in noncollagenous domains of Q9BXS0 were important for the induction of P56817 expression . These findings demonstrate that Q9BXS0 leads to AD - like pathology in vivo . Modulation of Q9BXS0 function may represent an alternative therapeutic intervention for AD .\",\n \"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK24___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .\",\n \"Transcriptional regulation of beta - secretase by p25 / cdk5 leads to enhanced amyloidogenic processing . P12004 - dependent kinase 5 ( cdk5 ) has been implicated in Alzheimer ' s disease ( AD ) pathogenesis . Here , we demonstrate that overexpression of p25 , an activator of cdk5 , led to increased levels of P56817 mRNA and protein in vitro and in vivo . A p25 / cdk5 responsive region containing multiple sites for signal transducer and activator of transcription ( P42224 / 3 ) was identified in the P56817 promoter . P40763 interacts with the P56817 promoter , and p25 - overexpressing mice had elevated levels of pSTAT3 and P56817 , whereas cdk5 - deficient mice had reduced levels . Furthermore , mice with a targeted mutation in the P40763 cdk5 responsive site had lower levels of P56817 . Increased P56817 levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor . These data demonstrate a pathway by which p25 / cdk5 increases the amyloidogenic processing of P05067 through P40763 - mediated transcriptional control of P56817 that could have implications for AD pathogenesis .\",\n \"Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome : a Children ' s Cancer Group Study . PURPOSE : ___MASK91___ is a major component of current treatment regimens for children with acute lymphocytic leukemia ( ALL ) . Potential mechanisms of methotrexate resistance include impaired drug uptake , decreased drug retention , and dihydrofolate reductase ( P00374 ) amplification . The purpose of this study was to assess whether reduced folate carrier ( P41440 ) and P00374 expression in untreated leukemic blasts correlated with outcome . METHODS : Quantitative real - time RT - PCR was used to measure P41440 and P00374 mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children ' s Cancer Group studies . RESULTS : Low P41440 expression at diagnosis correlated significantly with an unfavorable event free survival . Surprisingly , low , not high , P00374 expression correlated significantly with an unfavorable event - free survival . Proliferative cell nuclear antigen ( P12004 ) expression demonstrated a weak inverse relationship between sample P12004 and P00374 or P41440 expression , suggesting that P00374 and P41440 expression may be markers for factors other than drug resistance . CONCLUSIONS : These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL , and P00374 expression also may be an important prognostic factor in ALL . Additional studies are necessary to clarify the mechanism for the correlation of low P00374 expression with poor outcome .\",\n \"Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer ' s disease . Epidemiological studies demonstrate that chronic use of nonsteroidal anti - inflammatory drugs ( NSAIDs ) in normal aging populations reduces the risk of developing Alzheimer ' s disease ( AD ) . NSAIDs inhibit the enzymatic activity of cyclooxygenase - 1 ( P23219 ) and inducible P35354 , which catalyze the first committed step in the synthesis of prostaglandins . These studies implicate P36551 - mediated inflammation as an early and potentially reversible preclinical event ; however , the mechanism by which P36551 activity promotes development of AD has not been determined . Recent studies implicate the prostaglandin E2 ( DB00917 ) E prostanoid subtype 2 ( EP2 ) receptor in the development of the innate immune response in brain . Here , we report that deletion of the DB00917 EP2 receptor in the APPSwe - PS1DeltaE9 model of familial AD results in marked reductions in lipid peroxidation in aging mice . This reduction in oxidative stress is associated with significant decreases in levels of amyloid - beta ( Abeta ) 40 and 42 peptides and amyloid deposition . Aged APPSwe - PS1DeltaE9 mice lacking the EP2 receptor harbor lower levels of beta C - terminal fragments , the product of beta - site P05067 cleaving enzyme ( P56817 ) processing of amyloid precursor protein . Increases in P56817 processing have been demonstrated in models of aging and AD and after oxidative stress . Our results indicate that DB00917 signaling via the EP2 receptor promotes age - dependent oxidative damage and increased Abeta peptide burden in this model of AD , possibly via effects on P56817 activity . Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD , and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD .\",\n \"Combined treatment with a P56817 inhibitor and anti - Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice . Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer ' s disease . Among the agents explored in clinical trials are anti - Aβ peptide antibodies and secretase inhibitors . Most anti - Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid , although secretase inhibitors reduce the de novo production of Aβ . Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment . We performed a chronic study in APPLondon transgenic mice that received treatment with anti - Aβ antibody gantenerumab and P56817 inhibitor RO5508887 , either as mono - or combination treatment . Treatment aimed to evaluate efficacy on amyloid progression , similar to preexisting amyloidosis as present in Alzheimer ' s disease patients . Mono - treatments with either compound caused a dose - dependent reduction of total brain Aβ and amyloid burden . Combination treatment with both compounds significantly enhanced the antiamyloid effect . The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number , which suggests effective inhibition of de novo plaque formation . Moreover , significantly enhanced clearance of pre - existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887 . P56817 inhibition led to a significant time - and dose - dependent decrease in P04141 Aβ , which was not observed for gantenerumab treatment . Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance .\",\n \"The cell adhesion protein P16109 glycoprotein ligand - 1 is a substrate for the aspartyl protease P56817 . The aspartyl protease P56817 cleaves the amyloid precursor protein and the sialyltransferase P15907 and is important in the pathogenesis of Alzheimer ' s disease . The normal function of P56817 and additional physiological substrates have not been identified . Here we show that P56817 acts on the Q14242 ( Q14242 ) , which mediates leukocyte adhesion in inflammatory reactions . In human monocytic U937 and human embryonic kidney 293 cells expressing endogenous or transfected P56817 , Q14242 was cleaved by P56817 to generate a soluble ectodomain and a C - terminal transmembrane fragment . No evidence of the cleavage fragment was seen in primary cells derived from mice deficient in P56817 . By using deletion constructs and enzymatic deglycosylation of the C - terminal Q14242 fragments , the cleavage site in Q14242 was mapped to the juxtamembrane region within the ectodomain . In an in vitro assay P56817 catalyzed the formation of the Q14242 products seen in vivo . The cleavage occurred at a DB00149 - DB00133 peptide bond as identified by mass spectrometry using a synthetic peptide . We conclude that Q14242 is an additional substrate for P56817 .\",\n \"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK64___ ) in castrated male and female mice subjected to ___MASK64___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK64___ in mice CPs .\",\n \"___MASK33___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK33___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .\",\n \"A critical importance of polyamine site in DB01221 receptors for neurite outgrowth and fasciculation at early stages of P19 neuronal differentiation . We have investigated the role of N - methyl - d - aspartate receptors ( NMDARs ) and gamma - aminobutyric acid receptors type A ( GABA ( A ) Rs ) at an early stage of P19 neuronal differentiation . The subunit expression was profiled in 24 - hour intervals with RT - PCR and functionality of the receptors was verified via fluo - 3 imaging of Ca ( 2 +) dynamics in the immature P19 neurons showing that both DB01221 and GABA excite neuronal bodies , but only polyamine - site sensitive NMDAR stimulation leads to enhanced Ca ( 2 +) signaling in the growth cones . Inhibition of Q9UHB4 / Q13224 NMDARs by 1 muM ifenprodil severely impaired P19 neurite extension and fasciculation , and this negative effect was fully reversible by polyamine addition . In contrast , GABA ( A ) R antagonism by a high dose of 200 microM bicuculline had no observable effect on P19 neuronal differentiation and fasciculation . Except for the differential NMDAR and GABA ( A ) R profiles of Ca ( 2 +) signaling within the immature P19 neurons , we have also shown that inhibition of Q9UHB4 / Q13224 NMDARs strongly decreased mRNA level of P13591 - 180 , which has been previously implicated as a regulator of neuronal growth cone protrusion and neurite extension . Our data thus suggest a critical role of Q9UHB4 / Q13224 NMDARs during the process of neuritogenesis and fasciculation of P19 neurons via differential control of local growth cone Ca ( 2 +) surges and P13591 - 180 signaling .\",\n \"Fetzima ( levomilnacipran ) , a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta - site amyloid precursor protein cleaving enzyme - 1 . Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters ( P31645 ) to increase the synaptic concentrations of serotonin . Beta - site amyloid precursor protein cleaving enzyme - 1 ( P56817 - 1 ) is responsible for amyloid β plaque formation . Hence it is an interesting target for Alzheimer ' s disease ( AD ) therapy . This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named ' Fetzima ' with P56817 - 1 and P31645 . Fetzima is chemically known as levomilnacipran . The study has explored a possible link between the treatment of Depression and AD . ' Autodock 4 . 2 ' was used for docking study . The free energy of binding ( ΔG ) values for ' levomilnacipran - P31645 ' interaction and ' levomilnacipran - P56817 ' interaction were found to be - 7 . 47 and - 8 . 25 kcal / mol , respectively . DB08918 was found to interact with S438 , known to be the most important amino acid residue of serotonin binding site of P31645 during ' levomilnacipran - P31645 ' interaction . In the case of ' levomilnacipran - P56817 ' interaction , levomilnacipran interacted with two very crucial aspartic acid residues of P56817 - 1 , namely , D32 and D228 . These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain . Hence , Fetzima ( levomilnacipran ) might act as a potent dual inhibitor of P31645 and P56817 - 1 and expected to form the basis of a future dual therapy against depression and AD . It is an established fact that development of AD is associated with Major Depressive Disorder . Therefore , the design of new P56817 - 1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial .\",\n \"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK40___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .\",\n \"Inhibition of ADP - induced P16109 expression and platelet - leukocyte conjugate formation by clopidogrel and the Q9H244 receptor antagonist AR - C69931MX but not aspirin . Platelet - leukocyte interactions are recognised to have pro - inflammatory effects , which may be important in the pathophysiology of ischaemic heart disease . ___MASK13___ and the novel intravenous antithrombotic agent AR - C69931MX act at the level of the platelet Q9H244 receptor , which is known to amplify platelet activation , aggregation and other responses induced by numerous platelet agonists . We studied the effects of clopidogrel and aspirin on ADP - induced platelet - leukocyte conjugate formation and P16109 expression in healthy volunteers . The effects of clopidogrel and AR - C69931MX administered to patients with ischaemic heart disease were also assessed . AR - C69931MX and aspirin were also studied in vitro . ___MASK13___ and AR - C69931MX suppressed ADP - induced platelet aggregation , P16109 expression and platelet - leukocyte conjugate formation whereas aspirin had no inhibitory effect . These effects of clopidogrel and AR - C69931MX may confer therapeutic benefits in the management of acute coronary syndromes .\",\n \"Q9Y5Z0 plays a role in the insulin receptor trafficking in pancreatic ß - cells . P56817 ( β - site amyloidogenic cleavage of precursor protein - cleaving enzyme 1 ) is a β - secretase protein that plays a central role in the production of the β - amyloid peptide in the brain and is thought to be involved in the Alzheimer ' s pathogenesis . In type 2 diabetes , amyloid deposition within the pancreatic islets is a pathophysiological hallmark , making crucial the study in the pancreas of P56817 and its homologous Q9Y5Z0 to understand the pathological mechanisms of this disease . The objectives of the present study were to characterize the localization of P56817 proteins in human pancreas and determine their function . High levels of P56817 enzymatic activity were detected in human pancreas . In normal human pancreas , P56817 was observed in endocrine as well as in exocrine pancreas , whereas Q9Y5Z0 expression was restricted to β - cells . Intracellular analysis using immunofluorescence showed colocalization of P56817 with insulin and Q9Y5Z0 with clathrin - coated vesicles of the plasma membrane in MIN6 cells . When P56817 and - 2 were pharmacologically inhibited , P56817 localization was not altered , whereas Q9Y5Z0 content in clathrin - coated vesicles was increased . P01308 internalization rate was reduced , insulin receptor β - subunit ( IRβ ) expression was decreased at the plasma membrane and increased in the Golgi apparatus , and a significant reduction in insulin gene expression was detected . Similar results were obtained after specific Q9Y5Z0 silencing in MIN6 cells . All these data point to a role for Q9Y5Z0 in the IRβ trafficking and insulin signaling . In conclusion , Q9Y5Z0 is hereby presented as an important enzyme in β - cell function .\",\n \"Novel systemic markers for patients with Alzheimer disease ? - a pilot study . Almost 2 % of the population of western industrialized countries are affected by Alzheimer ' s disease ( AD ) . Nevertheless the pathogenetic process leading to this neurodegenerative disease is widely unknown . Thus , we focus on novel pathophysiological aspects of AD . We hypothesize that AD patients reveal increased levels of peripheral blood mononuclear cells ( PBMCs ) expressing proinflammatory ( P35354 , P01375 , P25942 ) , proapoptotic ( P09874 ) , adhesion - relevant ( P28907 ) or AD associated ( C99 , P56817 , P49768 ) proteins as well as elevated proinflammatory biochemical plasma parameters . Therefore , PBMCs of AD patients and age - matched control subjects were studied by two color fluorescence - activated cell sorter ( FACS ) analysis . Furthermore , concentration of plasma oxidized low - density lipoprotein ( oxLDL ) and P01375 were measured by enzyme - linked immunosorbent assay ( ELISA ) . We found a significantly increased percentage of P01375 , P35354 , P09874 , P28907 , C99 or presenilin - 1 positive PBMCs in AD patients compared with healthy subjects . FACS analyses revealed that the percentage of C99 or presenilin - 1 positive PBMCs , which also express P01375 , P35354 , P09874 or P28907 is also increased in AD patients . Additionally , AD patients had significantly increased plasma oxLDL and P01375 levels . Furthermore , we found positive correlations between plasma oxLDL or P01375 concentrations and the percentage of TNFalpha + , P35354 + or P09874 + , as well as P49768 + , C99 + or P56817 + PBMCs . Our findings suggest that immunocytological investigations , based on immunophenotyping of AD relevant proteins combined with measurement of proinflammatory , proapoptotic and adhesion - relevant proteins in PBMCs may provide more insight into the pathophysiology of AD .\",\n \"P56817 elevation is associated with aberrant limbic axonal sprouting in epileptic CD1 mice . The brain is capable of remarkable synaptic reorganization following stress and injury , often using the same molecular machinery that governs neurodevelopment . This form of plasticity is crucial for restoring and maintaining network function . However , neurodegeneration and subsequent reorganization can also play a role in disease pathogenesis , as is seen in temporal lobe epilepsy and Alzheimer ' s disease . β - Secretase - 1 ( P56817 ) is a protease known for cleaving β - amyloid precursor protein into β - amyloid ( Aβ ) , a major constituent in amyloid plaques . Emerging evidence suggests that P56817 is also involved with synaptic plasticity and nerve regeneration . Here we examined whether P56817 immunoreactivity ( IR ) was altered in pilocarpine - induced epileptic CD1 mice in a manner consistent with the synaptic reorganization seen during epileptogenesis . P56817 - IR increased in the P07451 mossy fiber field and dentate inner molecular layer in pilocarpine - induced epileptic mice , relative to controls ( saline - treated mice and mice 24 - 48 h after pilocarpine - status ) , and paralleled aberrant expression of neuropeptide Y . Regionally increased P56817 - IR also occurred in neuropil in hippocampal area P00915 and in subregions of the amygdala and temporal cortex in epileptic mice , colocalizing with increased IR for growth associated protein 43 ( P17677 ) and polysialylated - neural cell adhesion molecule ( PSA - P13591 ) , but reduced IR for microtubule - associated protein 2 ( P11137 ) . These findings suggest that P56817 is involved in aberrant limbic axonal sprouting in a model of temporal lobe epilepsy , warranting further investigation into the role of P56817 in physiological vs . pathological neuronal plasticity .\",\n \"Vessel wall , not platelet , Q9H244 potentiates early atherogenesis . AIMS : Platelets have a fundamental role in atherothrombosis , but their role in early atherogenesis is unclear . The Q9H244 receptor is responsible for amplifying and sustaining platelet activation and Q9H244 inhibition is crucial in modulating the vessel wall response to injury . We therefore examined the role of platelet vs . vessel wall Q9H244 in early atherogenesis and considered the use of Q9H244 antagonists ticagrelor and clopidogrel in modulating this process . METHODS AND RESULTS : ApoE (-/-) and ApoE (-/-) Q9H244 ( -/- ) male mice underwent bone marrow transplantation and were fed a western diet for 4 weeks before assessing atherosclerotic burden . Compared with ApoE (-/-) controls , platelet Q9H244 deficiency profoundly reduced platelet reactivity but had no effect on atheroma formation , whereas vessel wall Q9H244 deficiency significantly attenuated atheroma in the aortic sinus and brachiocephalic artery ( both P < 0 . 001 ) . ApoE (-/-) and ApoE (-/-) Q9H244 ( -/- ) male mice fed western diet plus either twice - daily doses of ticagrelor ( 100 mg / kg ) or daily clopidogrel ( 20 mg / kg ) for 4 weeks exhibited no significant reduction in atheroma compared with control mice fed mannitol . Attenuated P16109 expression confirmed platelet Q9H244 inhibition in drug - treated mice . CONCLUSIONS : Despite its major contribution to platelet reactivity , platelet Q9H244 has no effect on early atheroma formation , whereas vessel wall Q9H244 is important in this process . ___MASK16___ and clopidogrel effectively reduced platelet reactivity but were unable to inhibit early atherogenesis , demonstrating that these Q9H244 inhibitors may not be effective in preventing early disease .\",\n \"Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo . The mechanisms through which blockade of metabotropic glutamate receptors 5 ( P41594 ) results in anxiolytic and antidepressant effects are currently unknown . In the present study , we therefore hypothesized that the anxiolytic - and antidepressant - like profile of the noncompetitive P41594 receptor antagonist 2 - ethyl - 6 -( phenylethynyl )- pyridine ( MPEP ) may be mediated by inhibition of the norepinephrine transporter ( NET ) . Accordingly , we first examined the potency of MPEP to bind to or inhibit uptake at the NET as well as the dopamine and serotonin transporters ( Q01959 and P31645 , respectively ) . We also examined the simultaneous in vivo effects of MPEP and desipramine ( ___MASK10___ ) on both NE - like oxidation current in the amygdala ( Q9BXS0 ) and cell firing in the locus coeruleus ( LC ) by means of differential pulse voltammetry ( DPV ) coupled with electrophysiology . MPEP completely displaced the binding of [ 3H ] - nisoxetine on human NET with a pKi of 6 . 63 +/- 0 . 02 . In addition , MPEP was able to inhibit [ 3H ] - NE uptake in LLCPK cells expressing human NET , with a pIC50 of 5 . 55 +/- 0 . 09 . In vivo DPV data revealed that both MPEP ( 30 mg / kg i . p . ) and ___MASK10___ ( 10 mg / kg i . p . ) significantly increased NE - like voltammetric responses levels in the Q9BXS0 , whereas both compounds also significantly decreased cell firing monitored concomitantly from the second microelectrode in the LC . Collectively , the results of the present study provide potential new mechanisms through which MPEP exerts its anxiolytic and antidepressant effects .\"\n]"},"candidates":{"kind":"list like","value":["___MASK10___","___MASK13___","___MASK16___","___MASK24___","___MASK33___","___MASK40___","___MASK64___","___MASK7___","___MASK91___"],"string":"[\n \"___MASK10___\",\n \"___MASK13___\",\n \"___MASK16___\",\n \"___MASK24___\",\n \"___MASK33___\",\n \"___MASK40___\",\n \"___MASK64___\",\n \"___MASK7___\",\n \"___MASK91___\"\n]"},"answer":{"kind":"string","value":"___MASK33___"},"id":{"kind":"string","value":"MH_train_471"}}},{"rowIdx":472,"cells":{"query":{"kind":"string","value":"interacts_with DB00549?"},"supports":{"kind":"list like","value":["DB01411 inhibits renal epithelial cyst progression via activation of AMP - activated protein kinase . Q9Y271 ( CysLT1 receptor ) antagonists were found to inhibit chloride secretion in human airway epithelial cells . Since chloride secretion in renal epithelial cells , which shares common mechanisms with airway epithelial cells , plays important roles in renal cyst progression in polycystic kidney disease ( Q15139 ) , this study was aimed to investigate effects of drugs acting as CysLT1 receptor antagonists on renal cyst progression and its underlying mechanisms . Effects of CysLT1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney ( MDCK ) cyst models . Mechanisms of actions of CysLT1 receptor antagonists were determined using short - circuit current measurement , assays of cell viability and cell proliferation , and immunoblot analysis of signaling proteins . Of the three drugs acting as CysLT1 receptor antagonists ( montelukast , pranlukast and zafirlukast ) tested , pranlukast was the most promising drug that inhibited MDCK cyst growth and formation without affecting cell viability . Its effect was independent of the inhibition of CysLT1 receptors . Instead , it reduced DB02527 - activated chloride secretion and proliferation of MDCK cells in an AMP - activated protein kinase ( AMPK ) - dependent manner and had no effect on P13569 protein expression . Interestingly , pranlukast enhanced AMPK activation via calcium / calmodulin - dependent protein kinase kinase beta ( CaMKKβ ) with consequent activation of acetyl - DB01992 carboxylase ( ACC ) and suppression of mammalian target of rapamycin ( P42345 ) pathway . These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting DB02527 - activated chloride secretion and cell proliferation via CaMKKβ - AMPK - P42345 pathway . Therefore , pranlukast represents a class of known drugs that may have potential utility in Q15139 treatment .","___MASK76___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .","Leukotriene D4 - induced increases in cytosolic calcium in THP - 1 cells : dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists . Agonist - induced changes in intracellular calcium ion concentration ( [ Ca ++] i ) were examined in human monocytic leukemia THP - 1 cells loaded with fura 2 / acetoxymethyl ester ( fura 2 / AM ) . Leukotriene ( LT ) D4 induced a concentration - dependent biphasic response consisting of a transient phase ( up to 5 - fold peak increase ) followed by a sustained phase , showing characteristics of a receptor - operated calcium channel . Homologous desensitization to LTD4 was observed . The responses to LTD4 were reduced by 80 to 90 % in calcium - free buffer . The responses to LTD4 in a calcium - free buffer were dependent upon the duration of prior exposure of the cells to a calcium - free environment . The response at 30 or 60 min after exposure to calcium - free buffer was greater than that at earlier time points ( time - dependent sensitization ) . Similar responses were obtained with THP - 1 cells exposed to DB00974 - containing buffer . It is speculated that such time - dependent sensitization is a result of changes at the receptor level . The responses to LTD4 were blocked by two specific LTD4 antagonists , MK - 0571 and DB00549 , in a concentration - dependent manner . When given after addition of LTD4 , MK - 0571 or DB00549 reversed the sustained phase of the LTD4 - induced response , suggesting that maintenance of the response requires persistent activation of the Q9Y271 . DB00549 was 5 to 10 times more potent than MK - 0571 ( IC50 values of 1 . 1 and 9 . 3 nM , respectively ) , in agreement with results from radioligand binding studies reported separately .","Leukotriene B4 modulates in vivo expression of delayed - type hypersensitivity by a receptor - mediated mechanism : regulation by lipoxin A4 . Leukotriene B4 ( LTB4 ) is a potent proinflammatory arachidonic acid metabolite whose actions are mediated by specific receptors . Recent characterization of a high - affinity LTB4 receptor on the surface of guinea pig P01730 + T lymphocytes prompted examination of a possible role of LTB4 in modulating in vivo expression of delayed - type hypersensitivity ( DTH ) to tuberculin ( PPD ) . In the absence of PPD , intradermal injections of LTB4 or LTB4 / Q9Y271 antagonists did not elicit delayed - onset erythema at 24 h . When injected together with PPD , LTB4 ( 1 fmol to 1 pmol ) caused a significant 25 to 30 % decrease in DTH expression , whereas LTB4 receptor antagonists SC - 41930 , LY - 223982 , ONO - 4057 ( 0 . 1 - 10 nmol ) , caused a highly significant ( P < . 01 ) 25 to 50 % increase . The effect of SC - 41930 on DTH expression was inhibited by a 10 - fmol dose of LTB4 . Q9Y271 antagonist LY - 171883 had no effect on DTH expression . Lipoxin A4 ( LXA4 ) interferes with binding of LTB4 to T lymphocytes or neutrophils by reducing LTB4 receptor density . It caused a small but significant enhancement of DTH expression at 1 - nmol doses when injected with PPD . Lipoxin B4 had no effect . Enhancement or inhibition of grossly visible delayed skin responses to PPD by LTB4 . LTB4 receptor antagonists or LXA4 was not associated with qualitative or quantitative changes in superficial or deep dermal mononuclear cell infiltrates at the reaction site . We conclude that LTB4 modulates visible expression of DTH in vivo by a receptor - mediated mechanism .","Effects of ozone exposure mediated by BEAS - 2B cells on T cells activation : a possible link between environment and asthma . OBJECTIVE : To explore the possible link between ozone and asthma through analyzing Th1 / Th2 differentiation of T cells following incubation with conditioned medium from the BEAS - 2B cells exposed to ozone in vitro . METHOD : Bronchial epithelial cell line , BEAS - 2B , was cultured using an air - liquid interface culture system in a CO2 incubator and exposed to 0 or 0 . 16 or 0 . 25 mg / m3 of ozone for 8 h . The amounts of IL - 1β , P05231 and RANTES in the cell supernatant were detected . The cell culture supernatants were collected and used as conditioned medium in the next experiment . T cells from children recruited were incubated with conditioned medium for 12 h . Activation rate of Q07108 and Th1 / Th2 / Th17 differentiation were analyzed . RESULTS : BEAS - 2B cells exposed to different ozone concentrations showed morphological changes . Cells exposed to 0 . 16 and 0 . 25 mg / m3 ozone produced higher amounts of IL - 1β , P05231 and RANTES than that in the control group . Children with allergic asthma had upregulated expression of genes related with asthma , including P13500 , CCR4 , P19875 , Q9Y271 , Q99665 , Q14627 , Q13478 , P01584 , P10145 , P25025 and O75888 . Q07108 expression in T cells was significantly elevated irrespective of ozone exposure in children with allergic asthma . Following ozone exposure , in asthmatic children group , expression levels of cytokines of Th1 cells were collectively higher than those from Th2 cells . Ozone - exposed conditioned media could slightly increase all the Th1 , Th2 and Th17 cytokines in T cells from allergic asthmatic children . CONCLUSIONS : Our results suggested that Th1 cells activation might be predominant over Th2 activation upon ozone exposure in asthmatic children , which might help to clarify the mechanisms of asthma related to environmental factors like ozone .","Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK8___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .","Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK69___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK69___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .","Maxi - anion channel as a candidate pathway for osmosensitive DB00171 release from mouse astrocytes in primary culture . In the present study , we aimed to evaluate the pathways contributing to DB00171 release from mouse astrocytes during hypoosmotic stress . We first examined the expression of mRNAs for proteins constituting possible DB00171 - releasing pathways that have been suggested over the past several years . In RT - PCR analysis using both control and osmotically swollen astrocytes , amplification of cDNA fragments of expected size was seen for connexins ( P08034 , P35212 , P17302 ) , pannexin 1 ( Px1 ) , the Q99572 receptor , MRP1 and P08183 , but not P13569 . Inhibitors of exocytotic vesicular release , gap junction hemi - channels , P13569 , MRP1 , P08183 , the Q99572 receptor , and volume - sensitive outwardly rectifying chloride channels had no significant effects on the massive DB00171 release from astrocytes . In contrast , the hypotonicity - induced DB00171 release from astrocytes was most effectively inhibited by gadolinium ( 50 muM ) , an inhibitor of the maxi - anion channel , which has recently been shown to serve as a pathway for DB00171 release from several other cell types . Thus , we propose that the maxi - anion channel constitutes a major pathway for swelling - induced DB00171 release from cultured mouse astrocytes as well .","Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone . The hypothalamus - pituitary - adrenal ( Q9Y251 ) axis is the major neuroendocrine stress response system . P06850 ( P06850 ) neurons in the parvocellular paraventricular nucleus ( pPVN ) play a key role in coordinating responses of this system to stressors . The cytokine interleukin - 1beta ( IL - 1beta ) , mimicking infection , robustly activates these P06850 neurons via a noradrenergic input arising from the nucleus tractus solitarii ( P30990 ) . In late pregnancy , Q9Y251 axis responses to stressors , including IL - 1beta , are attenuated by a central opioid mechanism that auto - inhibits noradrenaline release in the PVN . Here we show that the neuroactive progesterone metabolite allopregnanolone induces these changes in Q9Y251 responsiveness to IL - 1beta in pregnancy . In late pregnancy , inhibition of 5alpha - reductase ( an allopregnanolone - synthesizing enzyme ) with finasteride restored Q9Y251 axis responses ( rapidly increased pPVN P06850 mRNA expression , ___MASK31___ , and corticosterone secretion ) to IL - 1beta . Conversely , allopregnanolone reduced Q9Y251 responses in virgin rats . In late pregnancy , activity of the allopregnanolone - synthesizing enzymes ( 5alpha - reductase and 3alpha - hydroxysteroid dehydrogenase ) was increased in the hypothalamus as was mRNA expression in the P30990 and PVN . Naloxone , an opioid antagonist , restores Q9Y251 axis responses to IL - 1beta in pregnancy but had no additional effect after finasteride , indicating a causal connection between allopregnanolone and the endogenous opioid mechanism . Indeed , allopregnanolone induced opioid inhibition over Q9Y251 responses to IL - 1beta in virgin rats . Furthermore , in virgin rats , allopregnanolone treatment increased , whereas in pregnant rats finasteride decreased proenkephalin - A mRNA expression in the P30990 . Thus , in pregnancy , allopregnanolone induces opioid inhibition over Q9Y251 axis responses to immune challenge . This novel opioid - mediated mechanism of allopregnanolone action may alter regulation of other brain systems in pregnancy .","Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy . The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model . One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin ( 20 mg / kg per os ) . Three hours after indomethacin , the extent of macroscopically visible gastric damage was determined , and gastric LTB4 synthesis was determined . The compounds tested were PF - 5901 , A - 64077 , nordihydroguaiaretic acid , and L - 698 , 037 . Each compound produced dose - related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin - induced damage . The antioxidant properties of these compounds was assessed using an in vitro assay . There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin - induced gastric damage . In the second part of the study , the effects of intravenous , administration of LTD4 and LTB4 receptor antagonists on indomethacin - induced gastric epithelial damage ( measured by permeability to [ 51Cr ] DB00974 ) were assessed . The two Q9Y271 antagonists ( MK - 571 and DB00549 ) significantly reduced the permeability changes induced by indomethacin , while the two LTB4 antagonists ( SC - 41930 and LY - 255 , 283 ) were without significant effect . Despite the reduction of gastric epithelial injury , blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury . These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs . However , it remains unclear to what extent leukotrienes are involved in the initiation of the injury , as opposed to its amplification .","P18509 , interleukin - 6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells . There is increasing evidence that hormones play an important role in the control of endothelial cell function and growth by regulating the production of vascular endothelial growth factor ( P15692 ) . P15692 regulates vascular permeability and represents the most powerful growth factor for endothelial cells . In the normal anterior pituitary , P15692 has been detected only in folliculostellate ( FS ) cells . In the present study , the regulation of the release of P15692 from FS - like mouse TtT / GF cells , and from FS cells of rat pituitary monolayer cell cultures was investigated using a specific P15692 ELISA . Basal release of P15692 was demonstrated in cultures of both TtT / GF cells and rat pituitary cells . Interestingly , the P15692 secretion was stimulated by both forms of pituitary adenylate cyclase - activating polypeptide ( PACAP - 38 and PACAP - 27 ) , indicating that this hypothalamic peptide regulates endothelial cell function and growth within the pituitary . P15692 secretion was also stimulated by interleukin - 6 ( P05231 ) whereas basal , P05231 - and PACAP - stimulated secretion was inhibited by the synthetic glucocorticoid dexamethasone . The inhibitory action of dexamethasone was reversed by the glucocorticoid receptor antagonist ___MASK6___ , suggesting that in FS cells functional glucocorticoid receptors mediate the inhibitory action of glucocorticoids on the P15692 secretion . The endocrine and auto -/ paracrine control of P15692 production in pituitary FS cells by PACAP , P05231 and glucocorticoids may play an important role both in angiogenesis and vascular permeability regulation within the pituitary under physiological and pathophysiological conditions .","5 - Lipoxygenase mediates O14788 - induced osteoclast formation via the cysteinyl leukotriene receptor 1 . 5 - Lipoxygenase ( P09917 ) catalyzes the formation of two major groups of leukotrienes , leukotriene B4 and cysteinyl leukotrienes ( CysLTs ) , and it has been implicated as a promising drug target to treat various inflammatory diseases . However , its role in osteoclastogenesis has not been investigated . In this study , we used mouse bone marrow - derived macrophages ( BMMs ) to show that P09917 inhibitor suppresses O14788 - induced osteoclast formation . Inhibition of P09917 was associated with impaired activation of multiple signaling events downstream of Q9Y6Q6 , including P29323 and p38 phosphorylation , and IκB degradation , followed by a decrease in O95644 expression . Ectopic overexpression of a constitutively active form of O95644 partly rescued the antiosteoclastogenic effect of P09917 inhibitor . The knockdown of P09917 in BMMs also resulted in a significant reduction in O14788 - induced osteoclast formation , accompanied by decreased expression of O95644 . Similar effects were shown with CysLT receptor ( CysLTR ) 1 / 2 antagonist and small RNA for Q9Y271 in BMMs , indicating the involvement of CysLT and Q9Y271 in P09917 - mediated osteoclastogenesis . Finally , P09917 inhibitor suppressed LPS - induced osteoclast formation and bone loss in the in vivo mouse experiments , suggesting a potential therapeutic strategy for treating diseases involving bone destruction . Taken together , the results of this study demonstrate that P09917 is a key mediator of O14788 - induced osteoclast formation and possibly a novel therapeutic target for bone - resorption diseases .","___MASK89___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK89___ , in the USA in 2003 .","___MASK80___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK80___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .","Genetic mechanism of aspirin - induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin - related hypersensitivity often associated with aspirin - intolerant asthma . Genetic studies on aspirin - intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin - induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin - induced urticaria / angioedema . A polymorphism study that examined nine single - nucleotide polymorphisms of five leukotriene - related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 - activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( - 1708A > G ) and Q9Y271 ( - 634C > T ) were significantly different between aspirin - intolerant asthma and aspirin - induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine - related genes , did not find any significant associations with aspirin - induced urticaria / angioedema for the genes P50135 ( encoding histamine N - methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high - affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin - induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin - induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .","Program death - 1 engagement upon TCR activation has distinct effects on costimulation and cytokine - driven proliferation : attenuation of Q9Y6W8 , P05112 , and Q9HBE4 , but not P10747 , P13232 , and P40933 responses . The program death 1 ( P18621 ) receptor and its ligands , P18621 ligand ( PD - L ) 1 and Q9BQ51 , define a novel regulatory pathway with potential inhibitory effects on T , B , and monocyte responses . In the present study , we show that human P01730 (+) T cells express P18621 , Q9NZQ7 , and Q9BQ51 upon activation , and Abs to the receptor can be agonists or antagonists of the pathway . Under optimal conditions of stimulation , Q9Y6W8 but not P10747 costimulation can be prevented by P18621 engagement . P60568 levels induced by costimulation are critical in determining the outcome of the P18621 engagement . Thus , low to marginal P60568 levels produced upon Q9Y6W8 costimulation account for the greater sensitivity of this pathway to P18621 - mediated inhibition . Interestingly , exogenous P60568 , P13232 , and P40933 but not P05112 and Q9HBE4 can rescue P18621 inhibition , suggesting that among these cytokines only those that activate P42229 can rescue P18621 inhibition . As P42229 has been implicated in the maintenance of IL - 2Ralpha expression , these results suggest that P13232 and P40933 restore proliferation under conditions of P18621 engagement by enhancing high - affinity IL - 2R expression and hence , P60568 responsiveness .","P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV - associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . ___MASK14___ , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV - induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R .","Is Q13304 a P2Y / leukotriene receptor ? examination of uracil nucleotides , nucleotide sugars , and cysteinyl leukotrienes as agonists of Q13304 . The orphan receptor Q13304 has been reported to be activated by UDP , UDP - sugars , and cysteinyl leukotrienes , and coupled to intracellular Ca ( 2 +) mobilization and inhibition of DB02527 accumulation , but other studies have reported either a different agonist profile or lack of agonist activity altogether . To determine if Q13304 is activated by uracil nucleotides and leukotrienes , the hemagglutinin - tagged receptor was expressed in five different cell lines and the signaling properties of the receptor were investigated . In P13671 , 1321N1 , or Chinese hamster ovary ( CHO ) cells stably expressing Q13304 , UDP , UDP - glucose , DB03501 , and cysteinyl leukotriene C4 ( LTC4 ) all failed to promote inhibition of forskolin - stimulated DB02527 accumulation , whereas both UDP and UDP - glucose promoted marked inhibition ( > 80 % ) of forskolin - stimulated DB02527 accumulation in P13671 and CHO cells expressing the Q15391 receptor . Likewise , none of these compounds promoted accumulation of inositol phosphates in COS - 7 or human embryonic kidney 293 cells transiently transfected with Q13304 alone or cotransfected with Gαq / i5 , which links Gi - coupled receptors to the Gq - regulated phospholipase C ( P98160 ) signaling pathway , or PLCε , which is activated by the Gα12 / 13 signaling pathway . Moreover , none of these compounds promoted internalization of Q13304 in 1321N1 - Q13304 cells . Consistent with previous reports , coexpression experiments of Q13304 with cysteinyl leukotriene receptor 1 ( Q9Y271 ) suggested that Q13304 acts as a negative regulator of Q9Y271 . Taken together , these data suggest that UDP , UDP - glucose , DB03501 , and LTC4 are not the cognate ligands of Q13304 .","Preservation of the glomerular capillary ultrafiltration coefficient during rat nephrotoxic serum nephritis by a specific leukotriene D4 receptor antagonist . Leukotriene D4 , a potent biologically active lipoxygenase derivative of arachidonic acid in activated leukocytes , depresses the glomerular capillary ultrafiltration coefficient ( Kf ) and contracts mesangial cells in culture . We therefore investigated its potential role in mediating the reduction in nephron filtration rate seen after induction of experimental nephrotoxic serum ( P30990 ) - induced glomerulonephritis in the rat . Micropuncture measurements were performed in euvolemic Munich - Wistar rats 2 h after i . v . administration of 0 . 8 ml of rabbit serum ( group 1 , n = 6 ) , 0 . 8 ml of rabbit anti - rat glomerular basement membrane antibody in the absence ( group 2 , n = 8 ) , or presence ( group 3 , n = 7 ) of the new highly specific Q9Y271 antagonist SK & F 104353 . Quantitation of antibody binding and neutrophil infiltration revealed no differences between groups 2 and 3 . Antagonism of endogenous LTD4 actions , however , was associated with prevention of the P30990 - induced fall in SNGFR because of the abrogation of the fall in Kf which characterizes this form of experimental glomerulonephritis . Antagonism of endogenous LTD4 had no effect on the P30990 - induced increases in pre - and postglomerular arteriolar resistances , and did not affect nephron plasma flow rate or net transcapillary hydraulic pressure difference . The observed highly localized protective action of the LTD4 antagonist on the glomerular capillary points to a possibly major functional role for intraglomerularly released LTD4 , likely originating from infiltrating leukocytes , in the pathophysiology of this form of glomerulonephritis .","P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p - Src ) , P04049 , and P29323 . The levels of p - Src and p - Src - progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , ___MASK6___ . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up - regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant - negative P28482 prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor - κB ( NF - κB ) nuclear translocation and NF - κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4 - induced up - regulation of the p53 promoter activity was prevented by preadministration with dominant - negative P28482 or NF - κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 / P28482 / NF - κB signaling pathway contributes to the P4 - induced up - regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .","P42892 and β - arrestins exert spatiotemporal control of DB05875 - induced inflammatory signals . Although the intracellular trafficking of G protein - coupled receptors controls specific signaling events , it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation . By using bioluminescence resonance energy transfer and superresolution microscopy , we found that DB05875 ( SP ) induces the association of the neurokinin 1 receptor ( P25103 ) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes : the scaffolding proteins β - arrestin ( βARRs ) 1 and 2 and the transmembrane metallopeptidases ECE - 1c and ECE - 1d . In HEK293 cells and non - transformed human colonocytes , we observed that G protein - coupled receptor kinase 2 and β P49407 / 2 terminate plasma membrane Ca ( 2 +) signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus . βARRs deliver the SP - P25103 endosomes , where P42892 associates with the complex , degrades SP , and allows the P25103 , freed from βARRs , to recycle . Thus , both P42892 and βARRs mediate the resensitization of P25103 Ca ( 2 +) signaling at the plasma membrane . Sustained exposure of colonocytes to SP activates NF - κB and stimulates P10145 secretion . This proinflammatory signaling is unaffected by inhibition of the endosomal P29323 pathway but is suppressed by P42892 inhibition or β P32121 knockdown . Inhibition of protein phosphatase 2A , which also contributes to sustained P25103 signaling at the plasma membrane , similarly attenuates P10145 secretion . Thus , the primary function of βARRs and P42892 in SP - dependent inflammatory signaling is to promote resensitization , which allows the sustained P25103 signaling from the plasma membrane that drives inflammation .","Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK1___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks ."],"string":"[\n \"DB01411 inhibits renal epithelial cyst progression via activation of AMP - activated protein kinase . Q9Y271 ( CysLT1 receptor ) antagonists were found to inhibit chloride secretion in human airway epithelial cells . Since chloride secretion in renal epithelial cells , which shares common mechanisms with airway epithelial cells , plays important roles in renal cyst progression in polycystic kidney disease ( Q15139 ) , this study was aimed to investigate effects of drugs acting as CysLT1 receptor antagonists on renal cyst progression and its underlying mechanisms . Effects of CysLT1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney ( MDCK ) cyst models . Mechanisms of actions of CysLT1 receptor antagonists were determined using short - circuit current measurement , assays of cell viability and cell proliferation , and immunoblot analysis of signaling proteins . Of the three drugs acting as CysLT1 receptor antagonists ( montelukast , pranlukast and zafirlukast ) tested , pranlukast was the most promising drug that inhibited MDCK cyst growth and formation without affecting cell viability . Its effect was independent of the inhibition of CysLT1 receptors . Instead , it reduced DB02527 - activated chloride secretion and proliferation of MDCK cells in an AMP - activated protein kinase ( AMPK ) - dependent manner and had no effect on P13569 protein expression . Interestingly , pranlukast enhanced AMPK activation via calcium / calmodulin - dependent protein kinase kinase beta ( CaMKKβ ) with consequent activation of acetyl - DB01992 carboxylase ( ACC ) and suppression of mammalian target of rapamycin ( P42345 ) pathway . These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting DB02527 - activated chloride secretion and cell proliferation via CaMKKβ - AMPK - P42345 pathway . Therefore , pranlukast represents a class of known drugs that may have potential utility in Q15139 treatment .\",\n \"___MASK76___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .\",\n \"Leukotriene D4 - induced increases in cytosolic calcium in THP - 1 cells : dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists . Agonist - induced changes in intracellular calcium ion concentration ( [ Ca ++] i ) were examined in human monocytic leukemia THP - 1 cells loaded with fura 2 / acetoxymethyl ester ( fura 2 / AM ) . Leukotriene ( LT ) D4 induced a concentration - dependent biphasic response consisting of a transient phase ( up to 5 - fold peak increase ) followed by a sustained phase , showing characteristics of a receptor - operated calcium channel . Homologous desensitization to LTD4 was observed . The responses to LTD4 were reduced by 80 to 90 % in calcium - free buffer . The responses to LTD4 in a calcium - free buffer were dependent upon the duration of prior exposure of the cells to a calcium - free environment . The response at 30 or 60 min after exposure to calcium - free buffer was greater than that at earlier time points ( time - dependent sensitization ) . Similar responses were obtained with THP - 1 cells exposed to DB00974 - containing buffer . It is speculated that such time - dependent sensitization is a result of changes at the receptor level . The responses to LTD4 were blocked by two specific LTD4 antagonists , MK - 0571 and DB00549 , in a concentration - dependent manner . When given after addition of LTD4 , MK - 0571 or DB00549 reversed the sustained phase of the LTD4 - induced response , suggesting that maintenance of the response requires persistent activation of the Q9Y271 . DB00549 was 5 to 10 times more potent than MK - 0571 ( IC50 values of 1 . 1 and 9 . 3 nM , respectively ) , in agreement with results from radioligand binding studies reported separately .\",\n \"Leukotriene B4 modulates in vivo expression of delayed - type hypersensitivity by a receptor - mediated mechanism : regulation by lipoxin A4 . Leukotriene B4 ( LTB4 ) is a potent proinflammatory arachidonic acid metabolite whose actions are mediated by specific receptors . Recent characterization of a high - affinity LTB4 receptor on the surface of guinea pig P01730 + T lymphocytes prompted examination of a possible role of LTB4 in modulating in vivo expression of delayed - type hypersensitivity ( DTH ) to tuberculin ( PPD ) . In the absence of PPD , intradermal injections of LTB4 or LTB4 / Q9Y271 antagonists did not elicit delayed - onset erythema at 24 h . When injected together with PPD , LTB4 ( 1 fmol to 1 pmol ) caused a significant 25 to 30 % decrease in DTH expression , whereas LTB4 receptor antagonists SC - 41930 , LY - 223982 , ONO - 4057 ( 0 . 1 - 10 nmol ) , caused a highly significant ( P < . 01 ) 25 to 50 % increase . The effect of SC - 41930 on DTH expression was inhibited by a 10 - fmol dose of LTB4 . Q9Y271 antagonist LY - 171883 had no effect on DTH expression . Lipoxin A4 ( LXA4 ) interferes with binding of LTB4 to T lymphocytes or neutrophils by reducing LTB4 receptor density . It caused a small but significant enhancement of DTH expression at 1 - nmol doses when injected with PPD . Lipoxin B4 had no effect . Enhancement or inhibition of grossly visible delayed skin responses to PPD by LTB4 . LTB4 receptor antagonists or LXA4 was not associated with qualitative or quantitative changes in superficial or deep dermal mononuclear cell infiltrates at the reaction site . We conclude that LTB4 modulates visible expression of DTH in vivo by a receptor - mediated mechanism .\",\n \"Effects of ozone exposure mediated by BEAS - 2B cells on T cells activation : a possible link between environment and asthma . OBJECTIVE : To explore the possible link between ozone and asthma through analyzing Th1 / Th2 differentiation of T cells following incubation with conditioned medium from the BEAS - 2B cells exposed to ozone in vitro . METHOD : Bronchial epithelial cell line , BEAS - 2B , was cultured using an air - liquid interface culture system in a CO2 incubator and exposed to 0 or 0 . 16 or 0 . 25 mg / m3 of ozone for 8 h . The amounts of IL - 1β , P05231 and RANTES in the cell supernatant were detected . The cell culture supernatants were collected and used as conditioned medium in the next experiment . T cells from children recruited were incubated with conditioned medium for 12 h . Activation rate of Q07108 and Th1 / Th2 / Th17 differentiation were analyzed . RESULTS : BEAS - 2B cells exposed to different ozone concentrations showed morphological changes . Cells exposed to 0 . 16 and 0 . 25 mg / m3 ozone produced higher amounts of IL - 1β , P05231 and RANTES than that in the control group . Children with allergic asthma had upregulated expression of genes related with asthma , including P13500 , CCR4 , P19875 , Q9Y271 , Q99665 , Q14627 , Q13478 , P01584 , P10145 , P25025 and O75888 . Q07108 expression in T cells was significantly elevated irrespective of ozone exposure in children with allergic asthma . Following ozone exposure , in asthmatic children group , expression levels of cytokines of Th1 cells were collectively higher than those from Th2 cells . Ozone - exposed conditioned media could slightly increase all the Th1 , Th2 and Th17 cytokines in T cells from allergic asthmatic children . CONCLUSIONS : Our results suggested that Th1 cells activation might be predominant over Th2 activation upon ozone exposure in asthmatic children , which might help to clarify the mechanisms of asthma related to environmental factors like ozone .\",\n \"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK8___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .\",\n \"Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK69___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK69___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .\",\n \"Maxi - anion channel as a candidate pathway for osmosensitive DB00171 release from mouse astrocytes in primary culture . In the present study , we aimed to evaluate the pathways contributing to DB00171 release from mouse astrocytes during hypoosmotic stress . We first examined the expression of mRNAs for proteins constituting possible DB00171 - releasing pathways that have been suggested over the past several years . In RT - PCR analysis using both control and osmotically swollen astrocytes , amplification of cDNA fragments of expected size was seen for connexins ( P08034 , P35212 , P17302 ) , pannexin 1 ( Px1 ) , the Q99572 receptor , MRP1 and P08183 , but not P13569 . Inhibitors of exocytotic vesicular release , gap junction hemi - channels , P13569 , MRP1 , P08183 , the Q99572 receptor , and volume - sensitive outwardly rectifying chloride channels had no significant effects on the massive DB00171 release from astrocytes . In contrast , the hypotonicity - induced DB00171 release from astrocytes was most effectively inhibited by gadolinium ( 50 muM ) , an inhibitor of the maxi - anion channel , which has recently been shown to serve as a pathway for DB00171 release from several other cell types . Thus , we propose that the maxi - anion channel constitutes a major pathway for swelling - induced DB00171 release from cultured mouse astrocytes as well .\",\n \"Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone . The hypothalamus - pituitary - adrenal ( Q9Y251 ) axis is the major neuroendocrine stress response system . P06850 ( P06850 ) neurons in the parvocellular paraventricular nucleus ( pPVN ) play a key role in coordinating responses of this system to stressors . The cytokine interleukin - 1beta ( IL - 1beta ) , mimicking infection , robustly activates these P06850 neurons via a noradrenergic input arising from the nucleus tractus solitarii ( P30990 ) . In late pregnancy , Q9Y251 axis responses to stressors , including IL - 1beta , are attenuated by a central opioid mechanism that auto - inhibits noradrenaline release in the PVN . Here we show that the neuroactive progesterone metabolite allopregnanolone induces these changes in Q9Y251 responsiveness to IL - 1beta in pregnancy . In late pregnancy , inhibition of 5alpha - reductase ( an allopregnanolone - synthesizing enzyme ) with finasteride restored Q9Y251 axis responses ( rapidly increased pPVN P06850 mRNA expression , ___MASK31___ , and corticosterone secretion ) to IL - 1beta . Conversely , allopregnanolone reduced Q9Y251 responses in virgin rats . In late pregnancy , activity of the allopregnanolone - synthesizing enzymes ( 5alpha - reductase and 3alpha - hydroxysteroid dehydrogenase ) was increased in the hypothalamus as was mRNA expression in the P30990 and PVN . Naloxone , an opioid antagonist , restores Q9Y251 axis responses to IL - 1beta in pregnancy but had no additional effect after finasteride , indicating a causal connection between allopregnanolone and the endogenous opioid mechanism . Indeed , allopregnanolone induced opioid inhibition over Q9Y251 responses to IL - 1beta in virgin rats . Furthermore , in virgin rats , allopregnanolone treatment increased , whereas in pregnant rats finasteride decreased proenkephalin - A mRNA expression in the P30990 . Thus , in pregnancy , allopregnanolone induces opioid inhibition over Q9Y251 axis responses to immune challenge . This novel opioid - mediated mechanism of allopregnanolone action may alter regulation of other brain systems in pregnancy .\",\n \"Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy . The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model . One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin ( 20 mg / kg per os ) . Three hours after indomethacin , the extent of macroscopically visible gastric damage was determined , and gastric LTB4 synthesis was determined . The compounds tested were PF - 5901 , A - 64077 , nordihydroguaiaretic acid , and L - 698 , 037 . Each compound produced dose - related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin - induced damage . The antioxidant properties of these compounds was assessed using an in vitro assay . There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin - induced gastric damage . In the second part of the study , the effects of intravenous , administration of LTD4 and LTB4 receptor antagonists on indomethacin - induced gastric epithelial damage ( measured by permeability to [ 51Cr ] DB00974 ) were assessed . The two Q9Y271 antagonists ( MK - 571 and DB00549 ) significantly reduced the permeability changes induced by indomethacin , while the two LTB4 antagonists ( SC - 41930 and LY - 255 , 283 ) were without significant effect . Despite the reduction of gastric epithelial injury , blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury . These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs . However , it remains unclear to what extent leukotrienes are involved in the initiation of the injury , as opposed to its amplification .\",\n \"P18509 , interleukin - 6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells . There is increasing evidence that hormones play an important role in the control of endothelial cell function and growth by regulating the production of vascular endothelial growth factor ( P15692 ) . P15692 regulates vascular permeability and represents the most powerful growth factor for endothelial cells . In the normal anterior pituitary , P15692 has been detected only in folliculostellate ( FS ) cells . In the present study , the regulation of the release of P15692 from FS - like mouse TtT / GF cells , and from FS cells of rat pituitary monolayer cell cultures was investigated using a specific P15692 ELISA . Basal release of P15692 was demonstrated in cultures of both TtT / GF cells and rat pituitary cells . Interestingly , the P15692 secretion was stimulated by both forms of pituitary adenylate cyclase - activating polypeptide ( PACAP - 38 and PACAP - 27 ) , indicating that this hypothalamic peptide regulates endothelial cell function and growth within the pituitary . P15692 secretion was also stimulated by interleukin - 6 ( P05231 ) whereas basal , P05231 - and PACAP - stimulated secretion was inhibited by the synthetic glucocorticoid dexamethasone . The inhibitory action of dexamethasone was reversed by the glucocorticoid receptor antagonist ___MASK6___ , suggesting that in FS cells functional glucocorticoid receptors mediate the inhibitory action of glucocorticoids on the P15692 secretion . The endocrine and auto -/ paracrine control of P15692 production in pituitary FS cells by PACAP , P05231 and glucocorticoids may play an important role both in angiogenesis and vascular permeability regulation within the pituitary under physiological and pathophysiological conditions .\",\n \"5 - Lipoxygenase mediates O14788 - induced osteoclast formation via the cysteinyl leukotriene receptor 1 . 5 - Lipoxygenase ( P09917 ) catalyzes the formation of two major groups of leukotrienes , leukotriene B4 and cysteinyl leukotrienes ( CysLTs ) , and it has been implicated as a promising drug target to treat various inflammatory diseases . However , its role in osteoclastogenesis has not been investigated . In this study , we used mouse bone marrow - derived macrophages ( BMMs ) to show that P09917 inhibitor suppresses O14788 - induced osteoclast formation . Inhibition of P09917 was associated with impaired activation of multiple signaling events downstream of Q9Y6Q6 , including P29323 and p38 phosphorylation , and IκB degradation , followed by a decrease in O95644 expression . Ectopic overexpression of a constitutively active form of O95644 partly rescued the antiosteoclastogenic effect of P09917 inhibitor . The knockdown of P09917 in BMMs also resulted in a significant reduction in O14788 - induced osteoclast formation , accompanied by decreased expression of O95644 . Similar effects were shown with CysLT receptor ( CysLTR ) 1 / 2 antagonist and small RNA for Q9Y271 in BMMs , indicating the involvement of CysLT and Q9Y271 in P09917 - mediated osteoclastogenesis . Finally , P09917 inhibitor suppressed LPS - induced osteoclast formation and bone loss in the in vivo mouse experiments , suggesting a potential therapeutic strategy for treating diseases involving bone destruction . Taken together , the results of this study demonstrate that P09917 is a key mediator of O14788 - induced osteoclast formation and possibly a novel therapeutic target for bone - resorption diseases .\",\n \"___MASK89___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK89___ , in the USA in 2003 .\",\n \"___MASK80___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK80___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .\",\n \"Genetic mechanism of aspirin - induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin - related hypersensitivity often associated with aspirin - intolerant asthma . Genetic studies on aspirin - intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin - induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin - induced urticaria / angioedema . A polymorphism study that examined nine single - nucleotide polymorphisms of five leukotriene - related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 - activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( - 1708A > G ) and Q9Y271 ( - 634C > T ) were significantly different between aspirin - intolerant asthma and aspirin - induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine - related genes , did not find any significant associations with aspirin - induced urticaria / angioedema for the genes P50135 ( encoding histamine N - methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high - affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin - induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin - induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .\",\n \"Program death - 1 engagement upon TCR activation has distinct effects on costimulation and cytokine - driven proliferation : attenuation of Q9Y6W8 , P05112 , and Q9HBE4 , but not P10747 , P13232 , and P40933 responses . The program death 1 ( P18621 ) receptor and its ligands , P18621 ligand ( PD - L ) 1 and Q9BQ51 , define a novel regulatory pathway with potential inhibitory effects on T , B , and monocyte responses . In the present study , we show that human P01730 (+) T cells express P18621 , Q9NZQ7 , and Q9BQ51 upon activation , and Abs to the receptor can be agonists or antagonists of the pathway . Under optimal conditions of stimulation , Q9Y6W8 but not P10747 costimulation can be prevented by P18621 engagement . P60568 levels induced by costimulation are critical in determining the outcome of the P18621 engagement . Thus , low to marginal P60568 levels produced upon Q9Y6W8 costimulation account for the greater sensitivity of this pathway to P18621 - mediated inhibition . Interestingly , exogenous P60568 , P13232 , and P40933 but not P05112 and Q9HBE4 can rescue P18621 inhibition , suggesting that among these cytokines only those that activate P42229 can rescue P18621 inhibition . As P42229 has been implicated in the maintenance of IL - 2Ralpha expression , these results suggest that P13232 and P40933 restore proliferation under conditions of P18621 engagement by enhancing high - affinity IL - 2R expression and hence , P60568 responsiveness .\",\n \"P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV - associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . ___MASK14___ , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV - induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R .\",\n \"Is Q13304 a P2Y / leukotriene receptor ? examination of uracil nucleotides , nucleotide sugars , and cysteinyl leukotrienes as agonists of Q13304 . The orphan receptor Q13304 has been reported to be activated by UDP , UDP - sugars , and cysteinyl leukotrienes , and coupled to intracellular Ca ( 2 +) mobilization and inhibition of DB02527 accumulation , but other studies have reported either a different agonist profile or lack of agonist activity altogether . To determine if Q13304 is activated by uracil nucleotides and leukotrienes , the hemagglutinin - tagged receptor was expressed in five different cell lines and the signaling properties of the receptor were investigated . In P13671 , 1321N1 , or Chinese hamster ovary ( CHO ) cells stably expressing Q13304 , UDP , UDP - glucose , DB03501 , and cysteinyl leukotriene C4 ( LTC4 ) all failed to promote inhibition of forskolin - stimulated DB02527 accumulation , whereas both UDP and UDP - glucose promoted marked inhibition ( > 80 % ) of forskolin - stimulated DB02527 accumulation in P13671 and CHO cells expressing the Q15391 receptor . Likewise , none of these compounds promoted accumulation of inositol phosphates in COS - 7 or human embryonic kidney 293 cells transiently transfected with Q13304 alone or cotransfected with Gαq / i5 , which links Gi - coupled receptors to the Gq - regulated phospholipase C ( P98160 ) signaling pathway , or PLCε , which is activated by the Gα12 / 13 signaling pathway . Moreover , none of these compounds promoted internalization of Q13304 in 1321N1 - Q13304 cells . Consistent with previous reports , coexpression experiments of Q13304 with cysteinyl leukotriene receptor 1 ( Q9Y271 ) suggested that Q13304 acts as a negative regulator of Q9Y271 . Taken together , these data suggest that UDP , UDP - glucose , DB03501 , and LTC4 are not the cognate ligands of Q13304 .\",\n \"Preservation of the glomerular capillary ultrafiltration coefficient during rat nephrotoxic serum nephritis by a specific leukotriene D4 receptor antagonist . Leukotriene D4 , a potent biologically active lipoxygenase derivative of arachidonic acid in activated leukocytes , depresses the glomerular capillary ultrafiltration coefficient ( Kf ) and contracts mesangial cells in culture . We therefore investigated its potential role in mediating the reduction in nephron filtration rate seen after induction of experimental nephrotoxic serum ( P30990 ) - induced glomerulonephritis in the rat . Micropuncture measurements were performed in euvolemic Munich - Wistar rats 2 h after i . v . administration of 0 . 8 ml of rabbit serum ( group 1 , n = 6 ) , 0 . 8 ml of rabbit anti - rat glomerular basement membrane antibody in the absence ( group 2 , n = 8 ) , or presence ( group 3 , n = 7 ) of the new highly specific Q9Y271 antagonist SK & F 104353 . Quantitation of antibody binding and neutrophil infiltration revealed no differences between groups 2 and 3 . Antagonism of endogenous LTD4 actions , however , was associated with prevention of the P30990 - induced fall in SNGFR because of the abrogation of the fall in Kf which characterizes this form of experimental glomerulonephritis . Antagonism of endogenous LTD4 had no effect on the P30990 - induced increases in pre - and postglomerular arteriolar resistances , and did not affect nephron plasma flow rate or net transcapillary hydraulic pressure difference . The observed highly localized protective action of the LTD4 antagonist on the glomerular capillary points to a possibly major functional role for intraglomerularly released LTD4 , likely originating from infiltrating leukocytes , in the pathophysiology of this form of glomerulonephritis .\",\n \"P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p - Src ) , P04049 , and P29323 . The levels of p - Src and p - Src - progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , ___MASK6___ . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up - regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant - negative P28482 prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor - κB ( NF - κB ) nuclear translocation and NF - κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4 - induced up - regulation of the p53 promoter activity was prevented by preadministration with dominant - negative P28482 or NF - κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 / P28482 / NF - κB signaling pathway contributes to the P4 - induced up - regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .\",\n \"P42892 and β - arrestins exert spatiotemporal control of DB05875 - induced inflammatory signals . Although the intracellular trafficking of G protein - coupled receptors controls specific signaling events , it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation . By using bioluminescence resonance energy transfer and superresolution microscopy , we found that DB05875 ( SP ) induces the association of the neurokinin 1 receptor ( P25103 ) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes : the scaffolding proteins β - arrestin ( βARRs ) 1 and 2 and the transmembrane metallopeptidases ECE - 1c and ECE - 1d . In HEK293 cells and non - transformed human colonocytes , we observed that G protein - coupled receptor kinase 2 and β P49407 / 2 terminate plasma membrane Ca ( 2 +) signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus . βARRs deliver the SP - P25103 endosomes , where P42892 associates with the complex , degrades SP , and allows the P25103 , freed from βARRs , to recycle . Thus , both P42892 and βARRs mediate the resensitization of P25103 Ca ( 2 +) signaling at the plasma membrane . Sustained exposure of colonocytes to SP activates NF - κB and stimulates P10145 secretion . This proinflammatory signaling is unaffected by inhibition of the endosomal P29323 pathway but is suppressed by P42892 inhibition or β P32121 knockdown . Inhibition of protein phosphatase 2A , which also contributes to sustained P25103 signaling at the plasma membrane , similarly attenuates P10145 secretion . Thus , the primary function of βARRs and P42892 in SP - dependent inflammatory signaling is to promote resensitization , which allows the sustained P25103 signaling from the plasma membrane that drives inflammation .\",\n \"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK1___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .\"\n]"},"candidates":{"kind":"list like","value":["___MASK14___","___MASK1___","___MASK31___","___MASK69___","___MASK6___","___MASK76___","___MASK80___","___MASK89___","___MASK8___"],"string":"[\n \"___MASK14___\",\n \"___MASK1___\",\n \"___MASK31___\",\n \"___MASK69___\",\n \"___MASK6___\",\n \"___MASK76___\",\n \"___MASK80___\",\n \"___MASK89___\",\n \"___MASK8___\"\n]"},"answer":{"kind":"string","value":"___MASK6___"},"id":{"kind":"string","value":"MH_train_472"}}},{"rowIdx":473,"cells":{"query":{"kind":"string","value":"interacts_with DB00952?"},"supports":{"kind":"list like","value":["A common single nucleotide polymorphism can exacerbate long - QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO - P04264 ) and COS - 1 cells . An asymptomatic woman presenting after the death of her 2 - day - old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long - QT syndrome - mediated arrhythmias and sudden infant death .","DB00952 mitigates CGRP1 - associated motor neuron degeneration caused by an expanded polyglutamine repeat tract . Spinal and bulbar muscular atrophy ( SBMA ) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor ( AR ) gene . Here , we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene - related peptide α ( CGRP1 ) . In neuronal cells , overexpression of CGRP1 induced cellular damage via the activation of the c - Jun N - terminal kinase ( JNK ) pathway , whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR . The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA . DB00952 , a serotonin 1B / 1D ( 5 - hydroxytryptamine 1B / 1D , or P28222 / 1D ) receptor agonist , decreased CGRP1 expression via the induction of dual - specificity protein phosphatase 1 ( P28562 ) , attenuated JNK activity and mitigated pathogenic AR - mediated neuronal damage in cellular and mouse SBMA models . These observations suggest that pharmacological activation of the P28222 / 1D receptor may be used therapeutically to treat SBMA and other polyglutamine - related neurodegenerative diseases .","Serotonin via P34969 receptors activates p38 mitogen - activated protein kinase and protein kinase C epsilon resulting in interleukin - 6 synthesis in human U373 MG astrocytoma cells . Serotonin [ 5 - hydroxytryptamine ( 5 - HT ) ] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes . Previously , it has been demonstrated that 5 - HT may induce interleukin ( IL ) - 6 expression in primary rat hippocampal astrocytes . The present study was undertaken to investigate the molecular pathways underlying this induction of P05231 synthesis . As a model system , we used the human astrocytoma cell line U373 MG , which synthesizes P05231 upon stimulation with various inducers . 5 - HT dose - and time - dependently induced P05231 protein synthesis . We identified several 5 - HT receptors to be expressed on U373 MG cells , including the P28221 , 5 - Q13049 , 5 - Q9H205 and P34969 receptors . In this report , we show that the 5 - HT - induced P05231 release is mediated by the P34969 receptor based on several agonist / antagonists that were used . 5 - HT - induced P05231 synthesis is inhibited by the partially selective P34969 receptor antagonist , pimozide , and the selective antagonist SB269970 . Furthermore , P05231 synthesis was induced by the P34969 receptor agonist carboxamidotryptamin . In addition , we found p38 MAPKs and protein kinase C ( PKC ) epsilon to be involved in 5 - HT - induced P05231 synthesis as specific inhibitors of these enzymes ( SB202190 and RO - 31 - 8425 , respectively ) blocked 5 - HT - induced P05231 synthesis . Furthermore , 5 - HT mediated the phosphorylation of both p38 MAPK as well as the PKC epsilon isoform . The Q8NFH3 / 44 MAPKs , however , were not involved in 5 - HT - induced P05231 synthesis . This study shows , for the first time , a central role of P34969 receptor linked to p38 MAPK and PKC epsilon for the induction of cytokine synthesis in astrocytic cells .","Emerging therapeutic options for acute migraine : focus on the potential of lasmiditan . The serotonin receptor agonist DB00669 drugs ( P28222 / 1D receptor agonists ) have been in use for over 20 years in the abortive management of migraine . Although clearly effective , their ability to produce vasoconstriction in cerebral and coronary arteries , thought to be mediated by their high affinity for the P28222 receptor , has been a limitation to their use in certain patient populations . Variable potency DB00669 binding at the P30939 receptor occurs in addition to binding at the P28222 and P28221 receptors . A more selective serotonin agonist without P28222 - mediated vasoconstriction might prove efficacious yet safer . The P30939 receptor has been targeted as a site of action for such a drug . In experimental models , P30939 receptor agonists have been shown to block neurogenic inflammation and c - Fos expression in neural tissue and , as well , show no evidence of vasoconstriction in vascular tissue models in vitro . In clinical trials , efficacy in the abortive management of migraine has been established . Lasmiditan ( LY573144 ) , a selective P30939 receptor agonist ( P04264 = 2 . 21 μM ) , showed efficacy in its primary endpoint , with a 2 - hour placebo - subtracted headache response of 28 . 8 % , though with frequent reports of dizziness , paresthesias , and vertigo . Study results support an emerging central neuronal mechanism of migraine pathophysiology . This review traces the history and use of P30939 receptor agonists , now referred to as neurally acting anti - migraine agents in migraine management .","Structure functional expression and spatial distribution of a cloned cDNA encoding a rat P28221 - like receptor . Using polymerase chain reaction ( PCR ) a complementary DNA ( cDNA ) encoding a 5 - hydroxytryptamine ( 5 - HT ) receptor was isolated from rat forebrain . The amplified cDNA specifies an open reading frame of 374 amino acids comprising seven putative transmembrane regions . Expression of the cloned cDNA in human embryonic kidney cells ( P29320 293 ) was used to establish the pharmacological profile of the encoded receptor polypeptide . Membranes containing the cloned receptor showed high affinity binding of [ 3H ] - 5 - HT . Competition binding experiments with a variety of serotonin receptor ligands displayed a rank order of affinities corresponding to a P28221 subtype : 5 - CT > 5 - HT = metergoline > CGS 12066 > methysergide > sumatriptan > mianserin = (-) alpha - Me - 5 - HT = yohimbine > 8 - OH - DPAT > or = rauwolscine > spiperone > DOI > propranolol > or = 2 - Me - 5 - HT > or = ICS 205930 . Ketanserin and ritanserin displaced [ 3H ] - 5 - HT - binding in a biphasic manner . In situ hybridization revealed highest expression of the corresponding mRNA in the pyramidal layer of the olfactory tubercle and the nucleus caudatus and accumbens .","Constitutive G ( i2 )- dependent activation of adenylyl cyclase type II by the P08908 receptor . Inhibition by anxiolytic partial agonists . The P08908 receptor is implicated in depression and anxiety . This receptor couples to G ( i ) proteins to inhibit adenylyl cyclase ( AC ) activity but can stimulate AC in tissues ( e . g . hippocampus ) that express ACII . The role of ACII in receptor - mediated stimulation of DB02527 formation was examined in P29320 - 293 cells transfected with the P08908 receptor , which mediated inhibition of basal and G ( s )- induced DB02527 formation in the absence of ACII . In cells cotransfected with P08908 receptor and ACII plasmids , P08908 agonists induced a 1 . 5 - fold increase in DB02527 level . Cotransfection of P08908 receptor , ACII , and Galpha ( i2 ) , but not Galpha ( i1 ) , Galpha ( i3 ) , or Galpha ( o ) , resulted in an agonist - independent 6 - fold increase in the basal DB02527 level , suggesting that G ( i2 ) preferentially coupled the receptor to ACII . The P28222 receptor also constitutively activated ACII . Constitutive activity of the P08908 receptor was blocked by pertussis toxin and the Gbetagamma antagonist , betaCT , suggesting an important role for Gbetagamma - mediated activation of ACII . The DB00156 - 149 --> Ala mutation in the second intracellular domain of the P08908 receptor disrupted Gbetagamma - selective activation of ACII . Spontaneous P08908 receptor activity was partially attenuated by P08908 receptor partial agonists with anxiolytic activity ( e . g . buspirone and flesinoxan ) but was not altered by full agonists or antagonists . Thus , anxiolytic activity may involve inhibition of spontaneous P08908 receptor activity .","[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK85___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .","P03372 - immunoreactive neurons contain calcitonin gene - related peptide , methionine - enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene - related peptide ( P80511 ) - , methionine - enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 ) and the medial preoptic area ( ___MASK63___ ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 and ___MASK63___ contain P80511 , DB00134 - Enk , or TH using a double - labeling immunohistochemical method and investigated changes in the number of double - labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen - treated rat were stained using the avidin - biotin - peroxidase complex method followed by the peroxidase - anti - peroxidase method . The sections were first incubated with an anti - ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P80511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double - labeled for ER and P80511 , DB00134 - Enk or TH were investigated in the Q9H237 and ___MASK63___ . The number of doubly labeled ER / P80511 - and ER / TH - IR neurons was large , whereas the number of ER / DB00134 - Enk - IR neurons was small . These results suggest that ER in the Q9H237 and ___MASK63___ may be more closely related to the mechanism of changes in P80511 - and TH - IR intensities upon estrogen treatment than that in DB00134 - Enk - IR intensity .","[ Pharmacy - clinic medication of the month . DB00952 ( naramig ) ] . DB00952 , launched by Glaxo Wellcome under the trade name Naramig , is a potent and selective agonist of P28222 and P28221 vascular receptors . Available as tablets of 2 . 5 mg , it is indicated in the acute treatment of migraine , with or without aura . A single oral dose of 2 . 5 mg naratriptan is characterized by a satisfactory clinical efficacy ( already significant after one hour , maximum after 4 hours and persisting during 24 hours ) , a reduction by half of the recurrence of the migraine crisis within the 24 hours and an excellent tolerance profile .","MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .","Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .","Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .","DB00952 has a selective inhibitory effect on trigeminovascular neurones at central P08908 and 5 - HT ( 1B / 1D ) receptors in the cat : implications for migraine therapy . The triptans are agonists at serotonin ( 5 - HT ) 1B / 1D receptors ; however , they are also active at P08908 and P30939 receptors . We conducted this series of experiments to further elucidate the site of action of naratriptan using a well - established animal model of trigeminovascular stimulation . Following electrical stimulation of the superior sagittal sinus of the cat , single cell responses ( n = 83 ) were recorded in the trigeminal nucleus caudalis . Most cells ( 91 % ) also responded to electrical and mechanical stimulation of cutaneous or mucosal facial receptive fields . The microiontophoretic application of naratriptan resulted in a significant suppression of the response to sagittal sinus stimulation ( response suppressed by 47 +/- 4 % , P < 0 . 001 ) . The effect of naratriptan was significantly attenuated by application of either the 5 - HT ( 1B / 1D ) receptor antagonist GR - 127935 ( P < 0 . 001 ) or the P08908 antagonist WAY - 100635 ( P < 0 . 05 ) . The response of single cells to receptive field stimulation was also suppressed by microiontophoretic application of naratriptan , but by only 20 +/- 3 % . Intravenous administration of naratriptan resulted in a similar selective suppression of sagittal sinus vs . receptive field responses in trigeminal neurones . These results indicate that naratriptan has a central effect in the trigeminovascular system , selectively inhibiting afferent activity in craniovascular neurones , via both 5 - HT ( 1B / 1D ) and P08908 receptors .","Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )","Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK77___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .","Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK54___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .","___MASK80___ induces insulin sensitization in Zucker lean and fatty rats . BACKGROUND : The 3 - hydroxy - 3 - methyl glutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors ( ' statins ' ) have been implicated in preventing new onset type 2 diabetes , whereas the mechanism of this effect is not known . We investigated the effects of an P04035 inhibitor , atorvastatin , on insulin sensitization in Zucker lean and fatty rats . METHODS AND RESULTS : In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg / kg / day ( ATORVA_50 ) and results were compared to Zucker lean and fatty rats treated with drug vehicle only ( CONT ) . Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25mg / kg / day ( ATORVA_25 ) . Treatment with atorvastatin resulted in a dose - dependent improvement in whole body insulin sensitivity in both lean and fatty rats , with an approximately two - fold increase in glucose infusion rate and glucose disposal ( Rd ) in ATORVA_50 versus CONT ( p < 0 . 01 ) . ___MASK80___ 50mg / kg / day resulted in an increase in DB08831 ( 2 - DOG ) uptake by skeletal muscles ( approximately two - fold increase in 2 - DOG uptake in quadriceps ( p = 0 . 06 ) and gastrocnemius ( p < 0 . 01 ) ) in lean Zucker rats . P01308 - stimulated phosphorylation of Akt / P31749 was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats . CONCLUSION : ___MASK80___ induces insulin sensitization in Zucker lean and fatty rats . This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans .","TATA - driven transcriptional initiation and regulation of the rat serotonin P08908 receptor gene . The transcriptional initiation and regulation of the rat serotonin P08908 receptor gene were characterized . By three types of analyses , a single brain - specific site of transcriptional initiation was localized to - 967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line . This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element , suggesting TATA - driven transcription of the rat P08908 receptor . To identify the promoter activity of the receptor gene , progressive 5 ' deletions of the - 2 , 719 /- 117 - bp fragment of the P08908 promoter linked to luciferase gene were transfected into P08908 - negative ( pituitary GH4C1 , Q9BTT4 myoblast , and P13671 glioma ) and P08908 - positive ( septal SN - 48 and raphe RN46A ) cell lines . Enhancer regions were identified within a fragment between nucleotides - 426 and - 117 that selectively enhanced transcription in P08908 - positive cells . A nonselective enhancer / promoter that mediated expression in all cell lines was located upstream between - 1 , 519 and - 426 bp in a DNA segment containing consensus TATA , CCAAT , SP - 1 , and AP - 1 elements as well as a poly - GT26 dinucleotide repeat . Strong repression of transcription in all cell lines was conferred by the region upstream of - 1 , 519 bp that contains a 152 - bp DNA segment with > 80 % identity to RANTES , tumor necrosis factor - beta , and other immune system genes . Our results indicate that TATA - driven expression of the P08908 receptor is regulated by a novel proximal tissue - specific enhancer region , a nonselective promoter , and an upstream repressor region that is distinct from previously identified neuron - specific repressors .","Evidence for serotonin ( 5 - HT ) 1B , P28221 and P30939 receptor inhibitory effects on trigeminal neurons with craniovascular input . Development of serotonin ( 5HT ( 1B / 1D ) ) agonists for the acute attack of migraine resulted in considerable interest in their action . The superior sagittal sinus ( SSS ) was isolated in alpha - chloralose ( 60 mg / kg , i . p . and 20 mg / kg i . v . i . supplementary 2 hourly ) anaesthetised cats . The SSS was stimulated electrically ( 100 V , 250 micros duration , 0 . 3 Hz ) and neurons of the trigeminocervical complex monitored using electrophysiological methods . To test 5 - HT ( 1B ) receptor - mediated activity common carotid blood flow ( CCF ) was monitored with a transonic flow probe placed around the vessel . DB00952 ( 5 - HT ( 1B / 1D / 1F ) receptor agonist ) and alniditan ( 5 - HT ( 1B / 1D ) receptor agonist ) produced reductions in carotid blood flow of 38 +/- 5 % and 42 +/- 6 % , respectively . These effects were attenuated by the 5 - HT ( 1B ) receptor antagonist SB224289 ( P < 0 . 05 ) . LY344864 ( 5 - HT ( 1F ) receptor agonist ) had no effect on CCF . DB00952 inhibited SSS - evoked activity ( 61 +/- 7 % ) , an effect partially inhibited by the 5 - HT ( 1B ) receptor antagonist SB224289 ( 30 +/- 5 % ) , or by the 5 - HT ( 1D ) receptor antagonist O95696 - 15572 ( 37 +/- 6 % ) . There remained an inhibitory effect of naratriptan after both 5 - HT ( 1B ) and 5 - HT ( 1D ) receptor blockade ( 22 +/- 5 % ) . Alniditan inhibited SSS - evoked trigeminal activity ( 53 +/- 6 % ) , an effect abolished after 5 - HT ( 1B ) and 5 - HT ( 1D ) receptor blockade . LY344864 ( 5 - HT ( 1F ) receptor agonist ) inhibited SSS - evoked trigeminal activity ( 28 +/- 5 % ) , an effect unaltered by either SB224289 or O95696 - 15572 . It can be concluded that there are inhibitory 5 - HT ( 1B ) , 5 - HT ( 1D ) and 5 - HT ( 1F ) receptors in the trigeminocervical complex of the cat . 5 - HT ( 1B ) receptor - mediated inhibition is the most potent of the three in terms of inhibition of trigeminovascular nociceptive traffic .","GLC756 decreases P01375 via an alpha2 and beta2 adrenoceptor related mechanism . GLC756 , a polyvalent anti - glaucoma drug showed in an endotoxin - induced - uveitis model ( EIU ) in rats a significant tumor necrosis factor - alpha ( P01375 ) decrease in serum , indicating an additional anti - inflammatory potential of this compound . The receptors on which GLC756 binds ( D1 , D2 , D4 , alpha - 1 , alpha - 2 , P08908 , P28335 , P28221 , 5 - HT2 A , beta - 1 , and beta - 2 ) were suggested to play a role . In order to identify a receptor type mediating the P01375 lowering response , GLC756 was combined with various counteracting compounds ( CP ) . For EIU , 8 - week - old Lewis rats were intravenously injected at 160 microg lipopolysaccharide ( LPS ) from Salmonella typhimurium . Before EIU - induction animals received either one of the CP ' s or GLC756 alone , or GLC756 in combination with one of the CP ' s . P01375 was determined in serum 2h post EIU - induction . Treatment with CP ' s alone indicated that agonistic effects on beta - 2 adrenoceptors and antagonistic effects on alpha - 2 , P08908 and P28221 receptors resulted in statistically significant decreased P01375 levels in comparison to the LPS - control group . In combination with GLC756 , the counteracting CP ' s domitor ( alpha - 2 adrenoceptor agonist ) and ICI 118551 ( beta - 2 adrenoceptor antagonist ) inhibited completely the P01375 decreasing effect of GLC756 . Counteracting the P08908 receptor with the P08908 agonist 8 - OH - DPAT could not prevent the P01375 decreasing effect of GLC756 . In conclusion , the antagonistic effect on alpha - 2 adrenoceptors and the agonistic effect on beta - 2 adrenoceptors were identified as mechanism for the P01375 decreasing effect of GLC756 .","Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK75___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .","Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK91___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK91___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK91___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK91___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK91___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .","Purification and characterization of a high molecular weight histone deacetylase complex ( Q92769 ) of maize embryos . The dynamic state of core histone acetylation is maintained by histone acetyltransferases and deacetylases . In germinating maize embryos , four nuclear histone deacetylases can be distinguished . From a chromatin fraction prepared at 72 h after start of embryo germination , we have purified the nuclear histone deacetylase Q92769 to homogeneity . Using a sequence of chromatographic steps , we achieved the purification of an enzymatically active high molecular weight protein complex with an apparent molecular mass of 400 kDa , as determined by gel filtration chromatography . The purified enzyme was characterized in terms of enzymatic and kinetic properties , and sensitivity to several histone deacetylase inhibitors . In SDS - polyacrylamide gels , Q92769 split into three polypeptides of 45 , 42 , and 39 kDa , suggesting that the native enzyme is a multimer - protein complex . Electrophoresis under nondenaturing conditions in combination with second dimension SDS - gel electrophoresis indicated that all three protein components of the Q92769 complex were enzymatically active . Polyclonal antibodies against each of the three polypeptides were raised in rabbits . Each antiserum reacted with all three polypeptides on Western blots , suggesting that P29466 , Q8NFH3 , and p39 are highly homologous . This homology was confirmed by amino acid sequencing of peptides generated from each of the three Q92769 components .","Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .","Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .","Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .","Functional characterization of a novel serotonin receptor ( 5 - HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full - length cDNA , coding for a novel serotonin receptor ( 5 - HTap2 ) . The receptor protein bears the characteristics of G protein - coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5 - HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5 - HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [ 3H ] LSD binding was : methiothepin > metergoline > 5 - CT > PAPP > 5 - HT > ketanserin > NAN - 190 > 8 - OH - DPAT > clozapine . RT - PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5 - HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5 - HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg - laying behavior .","Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK27___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .","Short - and long - term influences of calcitonin gene - related peptide on the synthesis of acetylcholinesterase in mammalian myotubes . The present study analyses the short - ( 15 min - 2 h ) and long - term ( 24 - 48 h ) influences of calcitonin gene - related peptide ( P80511 ) on acetylcholinesterase ( P22303 ) expression in the rat cultured skeletal muscle and the signal transduction events underlying P80511 actions . To assess the effect of P80511 on P22303 synthesis , myotubes were pre - exposed to the irreversible P22303 inhibitor diisopropyl fluorophosphate ( ___MASK72___ ) and treated with P80511 or forskolin , an adenylyl cyclase ( AC ) activator . Treatment of myotubes with 1 - 100 nM P80511 for 2 h increased by up to 42 % the synthesis of catalytically active P22303 with a parallel increase in the intracellular cyclic AMP . The stimulation of P22303 synthesis induced by P80511 was mimicked by direct activation of AC with 3 - 30 microM forskolin . In contrast , pre - treatment of cultures with 100 nM P80511 for 20 h reduced by 37 % the subsequent synthesis of P22303 , resulting in a 15 % decrease in total P22303 activity after 48 h P80511 treatment . Moreover , 24 h treatment of myotubes with 100 nM P80511 reduced by 54 % the accumulation of cyclic AMP induced by a subsequent P80511 treatment . These findings indicate that , in skeletal muscle cells , P80511 modulates the P22303 expression in a time - dependent manner , initially stimulating the enzyme synthesis through a cyclic AMP - dependent mechanism . The decreased P22303 synthesis observed after long - term P80511 treatment suggests that P80511 signalling system is subject to desensitization or down - regulation , that might function as an important adaptative mechanism of the muscle fibre in response to long - term changes in neuromuscular transmission .","Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .","Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK80___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .","Exposure to an organophosphate ( ___MASK72___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK72___ ( ___MASK72___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK72___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK72___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK72___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .","Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK63___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK63___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK63___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK63___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .","Donitriptan , but not sumatriptan , inhibits capsaicin - induced canine external carotid vasodilatation via P28222 rather than P28221 receptors . BACKGROUND AND PURPOSE : It has been suggested that during a migraine attack capsaicin - sensitive trigeminal sensory nerves release calcitonin gene - related peptide ( P80511 ) , resulting in cranial vasodilatation and central nociception ; hence , trigeminal inhibition may prevent this vasodilatation and abort migraine headache . This study investigated the effects of the agonists sumatriptan ( 5 - HT ( 1B / 1D ) water - soluble ) , donitriptan ( 5 - HT ( 1B / 1D ) lipid - soluble ) , PNU - 142633 ( 5 - HT ( 1D ) water - soluble ) and PNU - 109291 ( 5 - HT ( 1D ) lipid - soluble ) on vasodilator responses to capsaicin , alpha - P80511 and acetylcholine in dog external carotid artery . EXPERIMENTAL APPROACH : 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone . Blood pressure and heart rate were recorded with a pressure transducer , connected to a cannula inserted into a femoral artery . A precalibrated flow probe was placed around the common carotid artery , with ligation of the internal carotid and occipital branches , and connected to an ultrasonic flowmeter . The thyroid artery was cannulated for infusion of agonists . KEY RESULTS : Intracarotid infusions of capsaicin , alpha - P80511 and acetylcholine dose - dependently increased blood flow through the carotid artery . These responses remained unaffected after intravenous ( i . v . ) infusions of sumatriptan , PNU - 142633 , PNU - 109291 or physiological saline ; in contrast , donitriptan significantly attenuated the vasodilator responses to capsaicin , but not those to alpha - P80511 or acetylcholine . Only sumatriptan and donitriptan dose - dependently decreased the carotid blood flow . Interestingly , i . v . administration of the antagonist , SB224289 ( 5 - HT ( 1B ) ) , but not of BRL15572 ( 5 - HT ( 1D ) ) , abolished the inhibition by donitriptan . CONCLUSIONS AND IMPLICATIONS : Our results suggest that the inhibition produced by donitriptan of capsaicin - induced external carotid vasodilatation is mainly mediated by 5 - HT ( 1B ) , rather than 5 - HT ( 1D ) , receptors , probably by a central mechanism .","Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .","Accelerated and long - term hematopoietic engraftment in mice transplanted with ex vivo expanded bone marrow . Using a murine experimental model , we investigated whether ex vivo expansion of BM grafts under P08700 / P05231 stimulation accelerates the early hematopoietic recovery of recipients of BM transplants . To facilitate the ex vivo expansion of hematopoietic progenitors , BM was first enriched in proliferatively active hematopoietic stem cells by a single treatment with 5 - fluorouracil ( 5FU ) 4 days prior to the BM harvest . The results showed that the number of CFU - GM and CFU - P28222 progenitors in the graft was significantly increased ( 56 - fold and 14 - fold , respectively ) , as a result of a 3 day incubation in the presence of P08700 and P05231 . Daily analysis of animals transplanted with 5 x 10 ( 4 ) BM cells , either freshly harvested or expanded for 3 days , showed that the expanded grafts consistently allowed a faster hematopoietic recovery of recipients . Differences between both groups of transplanted animals were most evident when the number of either femoral or splenic CFU - GMs were compared , with increases close to 70 - fold at the fifth day of engraftment being observed . Similarly , mice transplanted with expanded grafts showed a hastened recovery in the cellularity of both organs that was most significant during the second week following transplantation , with maximal increases of 15 and 40 - fold in the BM and spleen , respectively . Differences in peripheral leukocyte numbers between both groups of recipients were much less remarkable than those observed in the hematopoietic organs , although from the nadir period to the 11th day post - transplantation differences ranging from twofold to sixfold were apparent , consistent with a higher rate of mouse survival . ( ABSTRACT TRUNCATED AT 250 WORDS )","DB00952 . The new P28222 / 1D agonist naratriptan , introduced in many countries in 1997 and 1998 for the acute treatment of migraine , was designed to complement the sumatriptan portfolio of offerings ( including the injection , the tablets , the nasal spray , and in some countries , the suppository ) by offering patients excellent tolerability and a sustained duration of action . Clinical studies on naratriptan , including more than 4000 patients treating more than 15 , 000 migraine attacks , show that naratriptan tablets 2 . 5 mg are distinguished from other P28222 / 1D agonists for migraine on the basis of their excellent tolerability profile , which does not differ from that of placebo . In addition to its tolerability , naratriptan tablets 2 . 5 mg possess a long duration of action with a low incidence of headache recurrence ( 17 - 28 % in phase II and III clinical trials ) . With its tolerability profile and long duration of action , naratriptan tablets 2 . 5 mg may be particularly appropriate as a single - dose alternative to NSAIDs and analgesics , which often are not effective in migraine but are used because of tolerability considerations .","Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .","Human P30939 receptor - stimulated [ 35S ] GTPgammaS binding : correlation with inhibition of guinea pig dural plasma protein extravasation . To determine the potency and efficacy of P30939 receptor ligands , a [ 35S ] GTPgammaS binding assay was developed and optimized for the human P30939 receptor . Compounds which are known to be effective in the abortive treatment of migraine were tested for efficacy and potency in this assay . DB00952 , sumatriptan , zolmitriptan , and rizatriptan all had agonist activity . The P30939 receptor ligand LY334370 ( 4 - fluoro - N -[ 3 -( 1 - methyl - 4 - piperidinyl )- 1H - indol - 5 - yl ]- benzamide ) was the most potent compound tested with an EC50 of 2 . 13 +/- 0 . 15 nM . LY302148 ( 5 - fluoro - 3 -[ 1 -[ 2 -( 1 - methyl - 1H - pyrazol - 4 - yl ) ethyl ]- 4 - piperidinyl ]- 1H - ind ole ) , methysergide , LY306258 ( 3 - dimethylamino - 2 , 3 , 4 , 9 - tetrahydro - 1H - carbazol - 6 - ol ) , dihydroergotamine ( DHE ) , L - 694 , 247 and CP - 122 , 288 were also investigated for potency and efficacy . There was a statistically significant correlation between the pEC50 for the stimulation of [ 35S ] GTPgammaS binding and the pID50 for the inhibition of trigeminal nerve - stimulated dural plasma protein extravasation in the guinea pig . In the course of these studies , it was found that the purportedly selective P28221 receptor antagonist GR127935 inhibited P30939 receptor - stimulated [ 35S ] GTPgammaS binding with a Ki of 39 . 6 +/- 9 . 5 nM . These studies demonstrate that P30939 receptor - mediated stimulation of [ 35S ] GTPgammaS binding in a clonal cell system is a reproducible , high throughput assay that is predictive of an in vivo model of P30939 receptor activation .","DB00952 : a review . Even though naratriptan and sumatriptan are both P28222 / P28221 receptor agonists , the biological and pharmacokinetic profile of naratriptan differs significantly from that of sumatriptan . With a plasma half - life of 6 h , very high oral bioavailability of 63 - 74 % and higher lipophilicity than sumatriptan , naratriptan exhibits a distinct clinical therapeutic profile . The similar tolerability to placebo , prolonged efficacy for 24 h or more and very low headache recurrence rate make naratriptan an attractive option in the treatment of acute migraine ."],"string":"[\n \"A common single nucleotide polymorphism can exacerbate long - QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO - P04264 ) and COS - 1 cells . An asymptomatic woman presenting after the death of her 2 - day - old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long - QT syndrome - mediated arrhythmias and sudden infant death .\",\n \"DB00952 mitigates CGRP1 - associated motor neuron degeneration caused by an expanded polyglutamine repeat tract . Spinal and bulbar muscular atrophy ( SBMA ) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor ( AR ) gene . Here , we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene - related peptide α ( CGRP1 ) . In neuronal cells , overexpression of CGRP1 induced cellular damage via the activation of the c - Jun N - terminal kinase ( JNK ) pathway , whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR . The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA . DB00952 , a serotonin 1B / 1D ( 5 - hydroxytryptamine 1B / 1D , or P28222 / 1D ) receptor agonist , decreased CGRP1 expression via the induction of dual - specificity protein phosphatase 1 ( P28562 ) , attenuated JNK activity and mitigated pathogenic AR - mediated neuronal damage in cellular and mouse SBMA models . These observations suggest that pharmacological activation of the P28222 / 1D receptor may be used therapeutically to treat SBMA and other polyglutamine - related neurodegenerative diseases .\",\n \"Serotonin via P34969 receptors activates p38 mitogen - activated protein kinase and protein kinase C epsilon resulting in interleukin - 6 synthesis in human U373 MG astrocytoma cells . Serotonin [ 5 - hydroxytryptamine ( 5 - HT ) ] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes . Previously , it has been demonstrated that 5 - HT may induce interleukin ( IL ) - 6 expression in primary rat hippocampal astrocytes . The present study was undertaken to investigate the molecular pathways underlying this induction of P05231 synthesis . As a model system , we used the human astrocytoma cell line U373 MG , which synthesizes P05231 upon stimulation with various inducers . 5 - HT dose - and time - dependently induced P05231 protein synthesis . We identified several 5 - HT receptors to be expressed on U373 MG cells , including the P28221 , 5 - Q13049 , 5 - Q9H205 and P34969 receptors . In this report , we show that the 5 - HT - induced P05231 release is mediated by the P34969 receptor based on several agonist / antagonists that were used . 5 - HT - induced P05231 synthesis is inhibited by the partially selective P34969 receptor antagonist , pimozide , and the selective antagonist SB269970 . Furthermore , P05231 synthesis was induced by the P34969 receptor agonist carboxamidotryptamin . In addition , we found p38 MAPKs and protein kinase C ( PKC ) epsilon to be involved in 5 - HT - induced P05231 synthesis as specific inhibitors of these enzymes ( SB202190 and RO - 31 - 8425 , respectively ) blocked 5 - HT - induced P05231 synthesis . Furthermore , 5 - HT mediated the phosphorylation of both p38 MAPK as well as the PKC epsilon isoform . The Q8NFH3 / 44 MAPKs , however , were not involved in 5 - HT - induced P05231 synthesis . This study shows , for the first time , a central role of P34969 receptor linked to p38 MAPK and PKC epsilon for the induction of cytokine synthesis in astrocytic cells .\",\n \"Emerging therapeutic options for acute migraine : focus on the potential of lasmiditan . The serotonin receptor agonist DB00669 drugs ( P28222 / 1D receptor agonists ) have been in use for over 20 years in the abortive management of migraine . Although clearly effective , their ability to produce vasoconstriction in cerebral and coronary arteries , thought to be mediated by their high affinity for the P28222 receptor , has been a limitation to their use in certain patient populations . Variable potency DB00669 binding at the P30939 receptor occurs in addition to binding at the P28222 and P28221 receptors . A more selective serotonin agonist without P28222 - mediated vasoconstriction might prove efficacious yet safer . The P30939 receptor has been targeted as a site of action for such a drug . In experimental models , P30939 receptor agonists have been shown to block neurogenic inflammation and c - Fos expression in neural tissue and , as well , show no evidence of vasoconstriction in vascular tissue models in vitro . In clinical trials , efficacy in the abortive management of migraine has been established . Lasmiditan ( LY573144 ) , a selective P30939 receptor agonist ( P04264 = 2 . 21 μM ) , showed efficacy in its primary endpoint , with a 2 - hour placebo - subtracted headache response of 28 . 8 % , though with frequent reports of dizziness , paresthesias , and vertigo . Study results support an emerging central neuronal mechanism of migraine pathophysiology . This review traces the history and use of P30939 receptor agonists , now referred to as neurally acting anti - migraine agents in migraine management .\",\n \"Structure functional expression and spatial distribution of a cloned cDNA encoding a rat P28221 - like receptor . Using polymerase chain reaction ( PCR ) a complementary DNA ( cDNA ) encoding a 5 - hydroxytryptamine ( 5 - HT ) receptor was isolated from rat forebrain . The amplified cDNA specifies an open reading frame of 374 amino acids comprising seven putative transmembrane regions . Expression of the cloned cDNA in human embryonic kidney cells ( P29320 293 ) was used to establish the pharmacological profile of the encoded receptor polypeptide . Membranes containing the cloned receptor showed high affinity binding of [ 3H ] - 5 - HT . Competition binding experiments with a variety of serotonin receptor ligands displayed a rank order of affinities corresponding to a P28221 subtype : 5 - CT > 5 - HT = metergoline > CGS 12066 > methysergide > sumatriptan > mianserin = (-) alpha - Me - 5 - HT = yohimbine > 8 - OH - DPAT > or = rauwolscine > spiperone > DOI > propranolol > or = 2 - Me - 5 - HT > or = ICS 205930 . Ketanserin and ritanserin displaced [ 3H ] - 5 - HT - binding in a biphasic manner . In situ hybridization revealed highest expression of the corresponding mRNA in the pyramidal layer of the olfactory tubercle and the nucleus caudatus and accumbens .\",\n \"Constitutive G ( i2 )- dependent activation of adenylyl cyclase type II by the P08908 receptor . Inhibition by anxiolytic partial agonists . The P08908 receptor is implicated in depression and anxiety . This receptor couples to G ( i ) proteins to inhibit adenylyl cyclase ( AC ) activity but can stimulate AC in tissues ( e . g . hippocampus ) that express ACII . The role of ACII in receptor - mediated stimulation of DB02527 formation was examined in P29320 - 293 cells transfected with the P08908 receptor , which mediated inhibition of basal and G ( s )- induced DB02527 formation in the absence of ACII . In cells cotransfected with P08908 receptor and ACII plasmids , P08908 agonists induced a 1 . 5 - fold increase in DB02527 level . Cotransfection of P08908 receptor , ACII , and Galpha ( i2 ) , but not Galpha ( i1 ) , Galpha ( i3 ) , or Galpha ( o ) , resulted in an agonist - independent 6 - fold increase in the basal DB02527 level , suggesting that G ( i2 ) preferentially coupled the receptor to ACII . The P28222 receptor also constitutively activated ACII . Constitutive activity of the P08908 receptor was blocked by pertussis toxin and the Gbetagamma antagonist , betaCT , suggesting an important role for Gbetagamma - mediated activation of ACII . The DB00156 - 149 --> Ala mutation in the second intracellular domain of the P08908 receptor disrupted Gbetagamma - selective activation of ACII . Spontaneous P08908 receptor activity was partially attenuated by P08908 receptor partial agonists with anxiolytic activity ( e . g . buspirone and flesinoxan ) but was not altered by full agonists or antagonists . Thus , anxiolytic activity may involve inhibition of spontaneous P08908 receptor activity .\",\n \"[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK85___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .\",\n \"P03372 - immunoreactive neurons contain calcitonin gene - related peptide , methionine - enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene - related peptide ( P80511 ) - , methionine - enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 ) and the medial preoptic area ( ___MASK63___ ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 and ___MASK63___ contain P80511 , DB00134 - Enk , or TH using a double - labeling immunohistochemical method and investigated changes in the number of double - labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen - treated rat were stained using the avidin - biotin - peroxidase complex method followed by the peroxidase - anti - peroxidase method . The sections were first incubated with an anti - ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P80511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double - labeled for ER and P80511 , DB00134 - Enk or TH were investigated in the Q9H237 and ___MASK63___ . The number of doubly labeled ER / P80511 - and ER / TH - IR neurons was large , whereas the number of ER / DB00134 - Enk - IR neurons was small . These results suggest that ER in the Q9H237 and ___MASK63___ may be more closely related to the mechanism of changes in P80511 - and TH - IR intensities upon estrogen treatment than that in DB00134 - Enk - IR intensity .\",\n \"[ Pharmacy - clinic medication of the month . DB00952 ( naramig ) ] . DB00952 , launched by Glaxo Wellcome under the trade name Naramig , is a potent and selective agonist of P28222 and P28221 vascular receptors . Available as tablets of 2 . 5 mg , it is indicated in the acute treatment of migraine , with or without aura . A single oral dose of 2 . 5 mg naratriptan is characterized by a satisfactory clinical efficacy ( already significant after one hour , maximum after 4 hours and persisting during 24 hours ) , a reduction by half of the recurrence of the migraine crisis within the 24 hours and an excellent tolerance profile .\",\n \"MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .\",\n \"Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .\",\n \"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .\",\n \"DB00952 has a selective inhibitory effect on trigeminovascular neurones at central P08908 and 5 - HT ( 1B / 1D ) receptors in the cat : implications for migraine therapy . The triptans are agonists at serotonin ( 5 - HT ) 1B / 1D receptors ; however , they are also active at P08908 and P30939 receptors . We conducted this series of experiments to further elucidate the site of action of naratriptan using a well - established animal model of trigeminovascular stimulation . Following electrical stimulation of the superior sagittal sinus of the cat , single cell responses ( n = 83 ) were recorded in the trigeminal nucleus caudalis . Most cells ( 91 % ) also responded to electrical and mechanical stimulation of cutaneous or mucosal facial receptive fields . The microiontophoretic application of naratriptan resulted in a significant suppression of the response to sagittal sinus stimulation ( response suppressed by 47 +/- 4 % , P < 0 . 001 ) . The effect of naratriptan was significantly attenuated by application of either the 5 - HT ( 1B / 1D ) receptor antagonist GR - 127935 ( P < 0 . 001 ) or the P08908 antagonist WAY - 100635 ( P < 0 . 05 ) . The response of single cells to receptive field stimulation was also suppressed by microiontophoretic application of naratriptan , but by only 20 +/- 3 % . Intravenous administration of naratriptan resulted in a similar selective suppression of sagittal sinus vs . receptive field responses in trigeminal neurones . These results indicate that naratriptan has a central effect in the trigeminovascular system , selectively inhibiting afferent activity in craniovascular neurones , via both 5 - HT ( 1B / 1D ) and P08908 receptors .\",\n \"Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK77___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .\",\n \"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK54___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .\",\n \"___MASK80___ induces insulin sensitization in Zucker lean and fatty rats . BACKGROUND : The 3 - hydroxy - 3 - methyl glutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors ( ' statins ' ) have been implicated in preventing new onset type 2 diabetes , whereas the mechanism of this effect is not known . We investigated the effects of an P04035 inhibitor , atorvastatin , on insulin sensitization in Zucker lean and fatty rats . METHODS AND RESULTS : In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg / kg / day ( ATORVA_50 ) and results were compared to Zucker lean and fatty rats treated with drug vehicle only ( CONT ) . Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25mg / kg / day ( ATORVA_25 ) . Treatment with atorvastatin resulted in a dose - dependent improvement in whole body insulin sensitivity in both lean and fatty rats , with an approximately two - fold increase in glucose infusion rate and glucose disposal ( Rd ) in ATORVA_50 versus CONT ( p < 0 . 01 ) . ___MASK80___ 50mg / kg / day resulted in an increase in DB08831 ( 2 - DOG ) uptake by skeletal muscles ( approximately two - fold increase in 2 - DOG uptake in quadriceps ( p = 0 . 06 ) and gastrocnemius ( p < 0 . 01 ) ) in lean Zucker rats . P01308 - stimulated phosphorylation of Akt / P31749 was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats . CONCLUSION : ___MASK80___ induces insulin sensitization in Zucker lean and fatty rats . This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans .\",\n \"TATA - driven transcriptional initiation and regulation of the rat serotonin P08908 receptor gene . The transcriptional initiation and regulation of the rat serotonin P08908 receptor gene were characterized . By three types of analyses , a single brain - specific site of transcriptional initiation was localized to - 967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line . This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element , suggesting TATA - driven transcription of the rat P08908 receptor . To identify the promoter activity of the receptor gene , progressive 5 ' deletions of the - 2 , 719 /- 117 - bp fragment of the P08908 promoter linked to luciferase gene were transfected into P08908 - negative ( pituitary GH4C1 , Q9BTT4 myoblast , and P13671 glioma ) and P08908 - positive ( septal SN - 48 and raphe RN46A ) cell lines . Enhancer regions were identified within a fragment between nucleotides - 426 and - 117 that selectively enhanced transcription in P08908 - positive cells . A nonselective enhancer / promoter that mediated expression in all cell lines was located upstream between - 1 , 519 and - 426 bp in a DNA segment containing consensus TATA , CCAAT , SP - 1 , and AP - 1 elements as well as a poly - GT26 dinucleotide repeat . Strong repression of transcription in all cell lines was conferred by the region upstream of - 1 , 519 bp that contains a 152 - bp DNA segment with > 80 % identity to RANTES , tumor necrosis factor - beta , and other immune system genes . Our results indicate that TATA - driven expression of the P08908 receptor is regulated by a novel proximal tissue - specific enhancer region , a nonselective promoter , and an upstream repressor region that is distinct from previously identified neuron - specific repressors .\",\n \"Evidence for serotonin ( 5 - HT ) 1B , P28221 and P30939 receptor inhibitory effects on trigeminal neurons with craniovascular input . Development of serotonin ( 5HT ( 1B / 1D ) ) agonists for the acute attack of migraine resulted in considerable interest in their action . The superior sagittal sinus ( SSS ) was isolated in alpha - chloralose ( 60 mg / kg , i . p . and 20 mg / kg i . v . i . supplementary 2 hourly ) anaesthetised cats . The SSS was stimulated electrically ( 100 V , 250 micros duration , 0 . 3 Hz ) and neurons of the trigeminocervical complex monitored using electrophysiological methods . To test 5 - HT ( 1B ) receptor - mediated activity common carotid blood flow ( CCF ) was monitored with a transonic flow probe placed around the vessel . DB00952 ( 5 - HT ( 1B / 1D / 1F ) receptor agonist ) and alniditan ( 5 - HT ( 1B / 1D ) receptor agonist ) produced reductions in carotid blood flow of 38 +/- 5 % and 42 +/- 6 % , respectively . These effects were attenuated by the 5 - HT ( 1B ) receptor antagonist SB224289 ( P < 0 . 05 ) . LY344864 ( 5 - HT ( 1F ) receptor agonist ) had no effect on CCF . DB00952 inhibited SSS - evoked activity ( 61 +/- 7 % ) , an effect partially inhibited by the 5 - HT ( 1B ) receptor antagonist SB224289 ( 30 +/- 5 % ) , or by the 5 - HT ( 1D ) receptor antagonist O95696 - 15572 ( 37 +/- 6 % ) . There remained an inhibitory effect of naratriptan after both 5 - HT ( 1B ) and 5 - HT ( 1D ) receptor blockade ( 22 +/- 5 % ) . Alniditan inhibited SSS - evoked trigeminal activity ( 53 +/- 6 % ) , an effect abolished after 5 - HT ( 1B ) and 5 - HT ( 1D ) receptor blockade . LY344864 ( 5 - HT ( 1F ) receptor agonist ) inhibited SSS - evoked trigeminal activity ( 28 +/- 5 % ) , an effect unaltered by either SB224289 or O95696 - 15572 . It can be concluded that there are inhibitory 5 - HT ( 1B ) , 5 - HT ( 1D ) and 5 - HT ( 1F ) receptors in the trigeminocervical complex of the cat . 5 - HT ( 1B ) receptor - mediated inhibition is the most potent of the three in terms of inhibition of trigeminovascular nociceptive traffic .\",\n \"GLC756 decreases P01375 via an alpha2 and beta2 adrenoceptor related mechanism . GLC756 , a polyvalent anti - glaucoma drug showed in an endotoxin - induced - uveitis model ( EIU ) in rats a significant tumor necrosis factor - alpha ( P01375 ) decrease in serum , indicating an additional anti - inflammatory potential of this compound . The receptors on which GLC756 binds ( D1 , D2 , D4 , alpha - 1 , alpha - 2 , P08908 , P28335 , P28221 , 5 - HT2 A , beta - 1 , and beta - 2 ) were suggested to play a role . In order to identify a receptor type mediating the P01375 lowering response , GLC756 was combined with various counteracting compounds ( CP ) . For EIU , 8 - week - old Lewis rats were intravenously injected at 160 microg lipopolysaccharide ( LPS ) from Salmonella typhimurium . Before EIU - induction animals received either one of the CP ' s or GLC756 alone , or GLC756 in combination with one of the CP ' s . P01375 was determined in serum 2h post EIU - induction . Treatment with CP ' s alone indicated that agonistic effects on beta - 2 adrenoceptors and antagonistic effects on alpha - 2 , P08908 and P28221 receptors resulted in statistically significant decreased P01375 levels in comparison to the LPS - control group . In combination with GLC756 , the counteracting CP ' s domitor ( alpha - 2 adrenoceptor agonist ) and ICI 118551 ( beta - 2 adrenoceptor antagonist ) inhibited completely the P01375 decreasing effect of GLC756 . Counteracting the P08908 receptor with the P08908 agonist 8 - OH - DPAT could not prevent the P01375 decreasing effect of GLC756 . In conclusion , the antagonistic effect on alpha - 2 adrenoceptors and the agonistic effect on beta - 2 adrenoceptors were identified as mechanism for the P01375 decreasing effect of GLC756 .\",\n \"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK75___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .\",\n \"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK91___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK91___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK91___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK91___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK91___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .\",\n \"Purification and characterization of a high molecular weight histone deacetylase complex ( Q92769 ) of maize embryos . The dynamic state of core histone acetylation is maintained by histone acetyltransferases and deacetylases . In germinating maize embryos , four nuclear histone deacetylases can be distinguished . From a chromatin fraction prepared at 72 h after start of embryo germination , we have purified the nuclear histone deacetylase Q92769 to homogeneity . Using a sequence of chromatographic steps , we achieved the purification of an enzymatically active high molecular weight protein complex with an apparent molecular mass of 400 kDa , as determined by gel filtration chromatography . The purified enzyme was characterized in terms of enzymatic and kinetic properties , and sensitivity to several histone deacetylase inhibitors . In SDS - polyacrylamide gels , Q92769 split into three polypeptides of 45 , 42 , and 39 kDa , suggesting that the native enzyme is a multimer - protein complex . Electrophoresis under nondenaturing conditions in combination with second dimension SDS - gel electrophoresis indicated that all three protein components of the Q92769 complex were enzymatically active . Polyclonal antibodies against each of the three polypeptides were raised in rabbits . Each antiserum reacted with all three polypeptides on Western blots , suggesting that P29466 , Q8NFH3 , and p39 are highly homologous . This homology was confirmed by amino acid sequencing of peptides generated from each of the three Q92769 components .\",\n \"Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .\",\n \"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .\",\n \"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .\",\n \"Functional characterization of a novel serotonin receptor ( 5 - HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full - length cDNA , coding for a novel serotonin receptor ( 5 - HTap2 ) . The receptor protein bears the characteristics of G protein - coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5 - HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5 - HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [ 3H ] LSD binding was : methiothepin > metergoline > 5 - CT > PAPP > 5 - HT > ketanserin > NAN - 190 > 8 - OH - DPAT > clozapine . RT - PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5 - HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5 - HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg - laying behavior .\",\n \"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK27___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .\",\n \"Short - and long - term influences of calcitonin gene - related peptide on the synthesis of acetylcholinesterase in mammalian myotubes . The present study analyses the short - ( 15 min - 2 h ) and long - term ( 24 - 48 h ) influences of calcitonin gene - related peptide ( P80511 ) on acetylcholinesterase ( P22303 ) expression in the rat cultured skeletal muscle and the signal transduction events underlying P80511 actions . To assess the effect of P80511 on P22303 synthesis , myotubes were pre - exposed to the irreversible P22303 inhibitor diisopropyl fluorophosphate ( ___MASK72___ ) and treated with P80511 or forskolin , an adenylyl cyclase ( AC ) activator . Treatment of myotubes with 1 - 100 nM P80511 for 2 h increased by up to 42 % the synthesis of catalytically active P22303 with a parallel increase in the intracellular cyclic AMP . The stimulation of P22303 synthesis induced by P80511 was mimicked by direct activation of AC with 3 - 30 microM forskolin . In contrast , pre - treatment of cultures with 100 nM P80511 for 20 h reduced by 37 % the subsequent synthesis of P22303 , resulting in a 15 % decrease in total P22303 activity after 48 h P80511 treatment . Moreover , 24 h treatment of myotubes with 100 nM P80511 reduced by 54 % the accumulation of cyclic AMP induced by a subsequent P80511 treatment . These findings indicate that , in skeletal muscle cells , P80511 modulates the P22303 expression in a time - dependent manner , initially stimulating the enzyme synthesis through a cyclic AMP - dependent mechanism . The decreased P22303 synthesis observed after long - term P80511 treatment suggests that P80511 signalling system is subject to desensitization or down - regulation , that might function as an important adaptative mechanism of the muscle fibre in response to long - term changes in neuromuscular transmission .\",\n \"Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .\",\n \"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK80___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .\",\n \"Exposure to an organophosphate ( ___MASK72___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK72___ ( ___MASK72___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK72___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK72___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK72___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .\",\n \"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK63___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK63___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK63___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK63___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .\",\n \"Donitriptan , but not sumatriptan , inhibits capsaicin - induced canine external carotid vasodilatation via P28222 rather than P28221 receptors . BACKGROUND AND PURPOSE : It has been suggested that during a migraine attack capsaicin - sensitive trigeminal sensory nerves release calcitonin gene - related peptide ( P80511 ) , resulting in cranial vasodilatation and central nociception ; hence , trigeminal inhibition may prevent this vasodilatation and abort migraine headache . This study investigated the effects of the agonists sumatriptan ( 5 - HT ( 1B / 1D ) water - soluble ) , donitriptan ( 5 - HT ( 1B / 1D ) lipid - soluble ) , PNU - 142633 ( 5 - HT ( 1D ) water - soluble ) and PNU - 109291 ( 5 - HT ( 1D ) lipid - soluble ) on vasodilator responses to capsaicin , alpha - P80511 and acetylcholine in dog external carotid artery . EXPERIMENTAL APPROACH : 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone . Blood pressure and heart rate were recorded with a pressure transducer , connected to a cannula inserted into a femoral artery . A precalibrated flow probe was placed around the common carotid artery , with ligation of the internal carotid and occipital branches , and connected to an ultrasonic flowmeter . The thyroid artery was cannulated for infusion of agonists . KEY RESULTS : Intracarotid infusions of capsaicin , alpha - P80511 and acetylcholine dose - dependently increased blood flow through the carotid artery . These responses remained unaffected after intravenous ( i . v . ) infusions of sumatriptan , PNU - 142633 , PNU - 109291 or physiological saline ; in contrast , donitriptan significantly attenuated the vasodilator responses to capsaicin , but not those to alpha - P80511 or acetylcholine . Only sumatriptan and donitriptan dose - dependently decreased the carotid blood flow . Interestingly , i . v . administration of the antagonist , SB224289 ( 5 - HT ( 1B ) ) , but not of BRL15572 ( 5 - HT ( 1D ) ) , abolished the inhibition by donitriptan . CONCLUSIONS AND IMPLICATIONS : Our results suggest that the inhibition produced by donitriptan of capsaicin - induced external carotid vasodilatation is mainly mediated by 5 - HT ( 1B ) , rather than 5 - HT ( 1D ) , receptors , probably by a central mechanism .\",\n \"Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .\",\n \"Accelerated and long - term hematopoietic engraftment in mice transplanted with ex vivo expanded bone marrow . Using a murine experimental model , we investigated whether ex vivo expansion of BM grafts under P08700 / P05231 stimulation accelerates the early hematopoietic recovery of recipients of BM transplants . To facilitate the ex vivo expansion of hematopoietic progenitors , BM was first enriched in proliferatively active hematopoietic stem cells by a single treatment with 5 - fluorouracil ( 5FU ) 4 days prior to the BM harvest . The results showed that the number of CFU - GM and CFU - P28222 progenitors in the graft was significantly increased ( 56 - fold and 14 - fold , respectively ) , as a result of a 3 day incubation in the presence of P08700 and P05231 . Daily analysis of animals transplanted with 5 x 10 ( 4 ) BM cells , either freshly harvested or expanded for 3 days , showed that the expanded grafts consistently allowed a faster hematopoietic recovery of recipients . Differences between both groups of transplanted animals were most evident when the number of either femoral or splenic CFU - GMs were compared , with increases close to 70 - fold at the fifth day of engraftment being observed . Similarly , mice transplanted with expanded grafts showed a hastened recovery in the cellularity of both organs that was most significant during the second week following transplantation , with maximal increases of 15 and 40 - fold in the BM and spleen , respectively . Differences in peripheral leukocyte numbers between both groups of recipients were much less remarkable than those observed in the hematopoietic organs , although from the nadir period to the 11th day post - transplantation differences ranging from twofold to sixfold were apparent , consistent with a higher rate of mouse survival . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"DB00952 . The new P28222 / 1D agonist naratriptan , introduced in many countries in 1997 and 1998 for the acute treatment of migraine , was designed to complement the sumatriptan portfolio of offerings ( including the injection , the tablets , the nasal spray , and in some countries , the suppository ) by offering patients excellent tolerability and a sustained duration of action . Clinical studies on naratriptan , including more than 4000 patients treating more than 15 , 000 migraine attacks , show that naratriptan tablets 2 . 5 mg are distinguished from other P28222 / 1D agonists for migraine on the basis of their excellent tolerability profile , which does not differ from that of placebo . In addition to its tolerability , naratriptan tablets 2 . 5 mg possess a long duration of action with a low incidence of headache recurrence ( 17 - 28 % in phase II and III clinical trials ) . With its tolerability profile and long duration of action , naratriptan tablets 2 . 5 mg may be particularly appropriate as a single - dose alternative to NSAIDs and analgesics , which often are not effective in migraine but are used because of tolerability considerations .\",\n \"Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .\",\n \"Human P30939 receptor - stimulated [ 35S ] GTPgammaS binding : correlation with inhibition of guinea pig dural plasma protein extravasation . To determine the potency and efficacy of P30939 receptor ligands , a [ 35S ] GTPgammaS binding assay was developed and optimized for the human P30939 receptor . Compounds which are known to be effective in the abortive treatment of migraine were tested for efficacy and potency in this assay . DB00952 , sumatriptan , zolmitriptan , and rizatriptan all had agonist activity . The P30939 receptor ligand LY334370 ( 4 - fluoro - N -[ 3 -( 1 - methyl - 4 - piperidinyl )- 1H - indol - 5 - yl ]- benzamide ) was the most potent compound tested with an EC50 of 2 . 13 +/- 0 . 15 nM . LY302148 ( 5 - fluoro - 3 -[ 1 -[ 2 -( 1 - methyl - 1H - pyrazol - 4 - yl ) ethyl ]- 4 - piperidinyl ]- 1H - ind ole ) , methysergide , LY306258 ( 3 - dimethylamino - 2 , 3 , 4 , 9 - tetrahydro - 1H - carbazol - 6 - ol ) , dihydroergotamine ( DHE ) , L - 694 , 247 and CP - 122 , 288 were also investigated for potency and efficacy . There was a statistically significant correlation between the pEC50 for the stimulation of [ 35S ] GTPgammaS binding and the pID50 for the inhibition of trigeminal nerve - stimulated dural plasma protein extravasation in the guinea pig . In the course of these studies , it was found that the purportedly selective P28221 receptor antagonist GR127935 inhibited P30939 receptor - stimulated [ 35S ] GTPgammaS binding with a Ki of 39 . 6 +/- 9 . 5 nM . These studies demonstrate that P30939 receptor - mediated stimulation of [ 35S ] GTPgammaS binding in a clonal cell system is a reproducible , high throughput assay that is predictive of an in vivo model of P30939 receptor activation .\",\n \"DB00952 : a review . Even though naratriptan and sumatriptan are both P28222 / P28221 receptor agonists , the biological and pharmacokinetic profile of naratriptan differs significantly from that of sumatriptan . With a plasma half - life of 6 h , very high oral bioavailability of 63 - 74 % and higher lipophilicity than sumatriptan , naratriptan exhibits a distinct clinical therapeutic profile . The similar tolerability to placebo , prolonged efficacy for 24 h or more and very low headache recurrence rate make naratriptan an attractive option in the treatment of acute migraine .\"\n]"},"candidates":{"kind":"list like","value":["___MASK27___","___MASK54___","___MASK63___","___MASK72___","___MASK75___","___MASK77___","___MASK80___","___MASK85___","___MASK91___"],"string":"[\n \"___MASK27___\",\n \"___MASK54___\",\n \"___MASK63___\",\n \"___MASK72___\",\n \"___MASK75___\",\n \"___MASK77___\",\n \"___MASK80___\",\n \"___MASK85___\",\n \"___MASK91___\"\n]"},"answer":{"kind":"string","value":"___MASK75___"},"id":{"kind":"string","value":"MH_train_473"}}},{"rowIdx":474,"cells":{"query":{"kind":"string","value":"interacts_with DB05812?"},"supports":{"kind":"list like","value":["Use of prednisone with abiraterone acetate in metastatic castration - resistant prostate cancer . DB05812 acetate , a prodrug of the P05093 inhibitor abiraterone that blocks androgen biosynthesis , is approved for treatment of patients with metastatic castration - resistant prostate cancer ( mCRPC ) in combination with prednisone or prednisolone 5 mg twice daily . This review evaluates the basis for the effects of prednisone on mineralocorticoid - related adverse events that arise because of P05093 inhibition with abiraterone . Coadministration with the recommended dose of glucocorticoid compensates for abiraterone - induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone . Consequently , 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate , analogous to use of glucocorticoid replacement therapy for certain endocrine disorders . We searched PubMed to identify safety concerns regarding glucocorticoid use , placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer . In general , glucocorticoid - related adverse events , including bone loss , immunosuppression , hyperglycemia , mood and cognitive alterations , and myopathy , appear dose related and tend to occur at doses and / or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC . Although glucocorticoids are often used to manage tumor - related symptoms or to prevent treatment - related toxicity , available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC . Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone , the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens .","New agents and strategies for the hormonal treatment of castration - resistant prostate cancer . IMPORTANCE OF THE FIELD : Hormonal therapy with medical or surgical castration is the mainstay of systemic therapy for advanced prostate cancer . Depletion of gonadal testosterone in circulation is typically initially effective , although responses are transient and metastatic disease progresses as castration - resistant prostate cancer ( CRPC ) . AREAS COVERED IN THIS REVIEW : CRPC is accompanied by a gain of function in the androgen receptor ( AR ) , which may occur at the level of AR itself or through intratumoral repletion of androgens that in turn stimulate AR . Investigational drugs in clinical trials have promising activity in CRPC . DB05812 acetate is a P05093 inhibitor that blocks the synthesis of adrenal androgens . MDV3100 is a nonsteroidal AR antagonist with a greater binding affinity than other AR antagonists currently in clinical use . Insights into the mechanisms of intratumoral steroidogenesis in CRPC have defined other potential targets . Metabolism from DB01708 to testosterone and dihydrotestosterone requires 3 - hydroxyl oxidation and Delta ( 5 ) isomerization to Delta ( 4 ) by 3beta - hydroxysteroid dehydrogenase ( 3betaHSD ) and 17 - keto reduction by 17beta - hydroxysteroid dehydrogenase ( 17betaHSD ) - 3 or - 5 . AR activation in CRPC by intratumoral steroids requires these enzymatic steps . Investigation into specific inhibitors of 3betaHSD and 17betaHSD are required to determine their efficacy and potential roles in the treatment of CPRC . WHAT THE READER WILL GAIN : Readers will gain an understanding of the biology of CRPC , new investigational hormonal agents and novel approaches to the treatment of CRPC . TAKE HOME MESSAGE : Intratumoral androgens drive CRPC progression . New investigational hormonal agents that inhibit intratumoral androgens are highly active in the treatment of CRPC . Alternative strategies hold the promise for the development of other agents with novel mechanisms of action .","Transforming growth factor - beta1 induces tumor stroma and reduces tumor infiltrate in cervical cancer . Cervical carcinomas consist of tumor cell nests surrounded by varying amounts of intratumoral stroma containing different quantities and types of immune cells . Besides controlling ( epithelial ) cell growth , the multifunctional cytokine transforming growth factor - beta ( 1 ) ( TGF - beta ( 1 ) ) is involved in the formation of stroma and extracellular matrix ( Q13201 ) and in immunosuppression . Several malignancies are known to be associated with enhanced production of TGF - beta ( 1 ) , repression or mutation of TGF - beta transmembrane receptors , or mutations at the postreceptor intracellular signaling pathway . The aim of our study was to investigate the role of tumor cell - derived TGF - beta ( 1 ) on the amount of intratumoral stroma ; the deposition of collagen IV , fibronectin , and laminin ; and the tumor infiltrate in cervical carcinoma . The expression of TGF - beta ( 1 ) mRNA in 108 paraffin - embedded cervical carcinomas was detected by mRNA in situ hybridization . Immunohistochemistry was used to investigate the amount of tumor stroma and Q13201 proteins and the extent of the tumor infiltrate . P00747 activator inhibitor - 1 ( P05121 ) protein expression in tumor cells was determined to verify the biological activity of TGF - beta ( 1 .) Cytoplasmatic TGF - beta ( 1 ) mRNA expression in tumor cells was significantly correlated with the amount of intratumoral stroma and the deposition of collagen IV . TGF - beta ( 1 ) mRNA expression in every tumor was accompanied by P05121 expression , indicating biological activity of TGF - beta ( 1 ) . An inverse relationship between TGF - beta ( 1 ) mRNA expression in tumor cells and the extent of the tumor infiltrate was demonstrated . Our results indicate that cervical cancer cells affect the amount and the composition of the intratumoral stroma and the tumor infiltrate by the production and secretion of TGF - beta ( 1 ) .","Antitumour activity of docetaxel following treatment with the P05093 inhibitor abiraterone : clinical evidence for cross - resistance ? BACKGROUND : DB05812 and docetaxel are both approved treatments for men with metastatic castration - resistant prostate cancer ( mCRPC ) . DB05812 pre - docetaxel is currently undergoing evaluation in a phase III study . In vitro studies indicate that taxanes may act by disrupting androgen receptor signalling . We hypothesised that prior abiraterone exposure would adversely impact docetaxel efficacy . PATIENTS AND METHODS : We retrospectively evaluated activity of docetaxel in mCRPC patients previously treated with abiraterone , using Prostate Cancer Working Group and radiological criteria . RESULTS : Of the 54 patients treated with abiraterone , 35 subsequently received docetaxel . DB01248 resulted in a prostate - specific antigen ( PSA ) decline of ≥ 50 % in nine patients [ 26 % , 95 % confidence interval ( CI ) 13 % to 43 % ] , with a median time to PSA progression of 4 . 6 months ( 95 % CI 4 . 2 % to 5 . 9 % ) . PSA declines ≥ 30 % were achieved by 13 patients ( 37 % , 95 % CI 22 % to 55 % ) . The median overall survival was 12 . 5 months ( 95 % CI 10 . 6 - 19 . 4 ) . All patients who failed to achieve a PSA fall on abiraterone and were deemed abiraterone - refractory were also docetaxel - refractory ( N = 8 ) . In the 24 patients with radiologically evaluable disease , partial responses were reported in four patients ( 11 % ) , none of whom were abiraterone - refractory . CONCLUSION : The activity of docetaxel post - abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone - refractory patients .","Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK10___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .","Effect of dietary NaCl on tyrosine hydroxylase in the superior cervical ganglia of Dahl rats . To investigate the involvement of peripheral catecholamines in the development of Dahl - Iwai salt - sensitive ( Q8IX12 / Eis ) hypertension , we performed immunohistochemical staining of tyrosine hydroxylase ( TH ) in the superior cervical ganglia ( SCG ) of Q8IX12 / Eis rats and Dahl - Iwai salt - resistant ( P30518 / Eis ) rats , and in situ hybridization histochemistry for demonstration of TH mRNA localization in the SCG of these rats . Q8IX12 / Eis and P30518 / Eis rats were fed on a high ( 8 % ) salt diet or on a low ( 0 . 3 % ) salt diet for 4 weeks . Nerve cells in the SCG of Q8IX12 / Eis high salt rats exhibited more intense TH - immunoreactivity ( P < 0 . 01 ) and hybridization signals ( P < 0 . 01 ) than those of the other experimental groups . These findings suggest that activation of peripheral sympathetic nerves may account for hypertension in Q8IX12 / Eis rats on a high salt diet .","17 ( E )- picolinylidene androstane derivatives as potential inhibitors of prostate cancer cell growth : antiproliferative activity and molecular docking studies . We report a rapid and efficient synthesis of A - ring modified 17α - picolyl and 17 ( E )- picolinylidene androstane derivatives from dehydroepiandrosterone . Compounds were validated spectroscopically and structurally characterized by X - ray crystallography . Virtual screening by molecular docking against clinical targets of steroidal anticancer drugs ( ERα , AR , P11511 and P05093 ) suggests that 17 ( E )- picolinylidene , but not 17α - picolyl androstanes could specifically interact with P05093 ( 17α - hydroxylase ) with similar geometry and affinity as DB05812 , a 17 - pyridinyl androstane drug clinically used in the treatment of prostate cancer . In addition , several 17 ( E )- picolinylidene androstanes demonstrated selective antiproliferative activity against PC3 prostate cancer cells , which correlates with DB05812 antiproliferative activity and predicted P05093 binding affinities . Based on these preliminary results , 17 ( E )- picolinylidene androstane derivatives could be a promising starting point for the development of new compounds for the treatment of prostate cancer .","[ DB05812 acetate ( ZYTIGA ®)- development and literature review ] . DB05812 acetate ( AA ) has been approved in more than 80 countries for the treatment of patients with metastatic castration - resistant prostate cancer ( mCRPC ) . In July 2013 , a marketing approval application for AA was submitted to the Japanese Ministry of Health , Labour , and Welfare . AA is a selective inhibitor of P05093 , a crucial enzyme for androgen biosynthesis . AA exerts its anti - tumor activity by directly inhibiting androgen production at all three sources , i . e . , the testes , adrenal glands , and tumor itself . Data from international phase III studies and phase I and II studies in Japan have indicated that AA improves the overall survival and quality of life ( QoL ) of patients with mCRPC . Herein , we have summarized the development of AA and the results of important international and local clinical trials in Japan . In addition , the effect of food on AA bioavailability , concomitant steroid use , and liver function test abnormalities have been discussed regarding the appropriate use of AA .","Highly - selective 4 -( 1 , 2 , 3 - triazole )- based P450c17a 17 , 20 - lyase inhibitors . The orally - active P05093 inhibitor abiraterone acetate ( AA ) decreases adrenal and intratumoral androgen biosynthesis and is an effective agent for the treatment of prostate cancer . DB05812 potently inhibits both reactions catalyzed by P05093 , the 17α - hydroxylase ( hydroxylase ) reaction as well as the 17 , 20 - lyase ( lyase ) transformation . P05093 hydroxylase inhibition prevents the synthesis of adrenal glucocorticoids and causes an accumulation of circulating mineralocorticoids . As a consequence of potent P05093 hydroxylase inhibition ( i . e . , lack of lyase selectivity ) , AA must be co - administered with the cortisol replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome ( MES ) . Herein , we describe rationally - designed , P05093 lyase - selective inhibitors that could prove safer and more effective than abiraterone . Using proprietary methodology , the high - affinity pyridine or imidazole metal - binding group found in current clinical P05093 inhibitors was replaced with novel , less avid , metal - binding groups in concert with potency - enhancing molecular scaffold modifications . This process produced a unique series of P05093 lyase - selective inhibitors that included the oral agent 6 ( VT - 464 ) , now in Phase 2 prostate cancer clinical trials . The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases .","Mapping of 13 horse genes by fluorescence in - situ hybridization ( Q5TCZ1 ) and somatic cell hybrid analysis . We report fluorescence in - situ hybridization ( Q5TCZ1 ) and somatic cell hybrid mapping data for 13 different horse genes ( P01160 , P06729 , P10909 , P54108 , P05093 , P02679 , P18510 , P22301 , P45452 , PRM1 , P35354 , P01375 and P04637 ) . Primers for PCR amplification of intronic or untranslated regions were designed from horse - specific DNA or mRNA sequences in GenBank . Two different horse bacterial artificial chromosome ( BAC ) libraries were screened with PCR for clones containing these 13 Type I loci , nine of which were found in the libraries . BAC clones were used as probes in dual colour Q5TCZ1 to confirm their precise chromosomal origin . The remaining four genes were mapped in a somatic cell hybrid panel . All chromosomal assignments except one were in agreement with human - horse ZOO - Q5TCZ1 data and revealed new and more detailed information on the equine comparative map . P10909 was mapped by synteny to ECA2 while human - horse ZOO - Q5TCZ1 data predicted that P10909 would be located on ECA9 . The assignment of P18510 permitted analysis of gene order conservation between HSA2 and ECA15 , which identified that an event of inversion had occurred during the evolution of these two homologous chromosomes .","[ Mechanisms of resistance to P05093 inhibitors in castrate resistant prostate cancer ] . INTRODUCTION : DB05812 acetate has increased the overall survival of patients with metastatic castration - resistant prostate cancer . However , despite an initial response to treatment , many patients develop resistance to the drug . In this paper we present different hypotheses that may explain the emergence of resistance . METHOD : This review was conducted from the PubMed database . The most relevant articles were selected and analyzed . RESULTS : The molecular mechanisms of resistance to abiraterone acetate remain largely elusive . We detailed some of them including the reactivation of the androgen receptor through alternative biosynthesis of androgens , over expression or mutation of the androgen receptor gene , or the action of co - activators . The over expression of P05093 or the alteration of other genes ' expression involved in steroidogenesis could also contribute to the resistance . CONCLUSION : Some of the molecular mechanisms involved in the resistance to abiraterone acetate were detailed . Better understanding of these mechanisms is a key step to allow the emergence of new therapeutic options and personalized treatments of castration resistant prostate cancer .","Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration - resistant prostate cancer . PURPOSE : DB05812 is the active metabolite of the pro - drug abiraterone acetate ( AA ) and a selective inhibitor of P05093 , a key enzyme in testosterone synthesis , and improves overall survival in postdocetaxel metastatic castration - resistant prostate cancer ( mCRPC ) . This open - label , single - arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval . METHODS : The study was conducted in 33 patients with mCRPC . Patients received AA 1 , 000 mg orally once daily + prednisone 5 mg orally twice daily . Electrocardiograms ( ECGs ) were collected in triplicate using 12 - lead Holter monitoring . Baseline ECGs were obtained on Cycle 1 Day - 1 . Serial ECG recordings and time - matched pharmacokinetic ( PK ) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1 . Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8 . RESULTS : After AA administration , the upper bound of the 2 - sided 90 % confidence interval ( CI ) for the mean baseline - adjusted QTcF change was < 10 ms ; no patients discontinued due to QTc prolongation or adverse events . No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [ estimated slope ( 90 % CI ) : 0 . 0031 ( - 0 . 0040 , 0 . 0102 ) ] . CONCLUSIONS : There is no significant effect of AA plus prednisone on the QT / QTc interval in patients with mCRPC .","DB05812 acetate : oral androgen biosynthesis inhibitor for treatment of castration - resistant prostate cancer . Prostate cancer is the second leading cause of cancer death in men in the US and Europe . The treatment of advanced - stage prostate cancer has been androgen deprivation . Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes , but adrenal glands and even prostate cancer tissue continue to produce androgens , which eventually leads to continued prostate cancer growth despite castrate level of androgens . This stage is known as castrate - resistant prostate cancer ( CRPC ) , which continues to be a challenge to treat . Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate - specific antigen levels further , but has not actually translated into life - prolonging options . The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer . Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting . One such agent is abiraterone acetate , which significantly reduces androgen production by blocking the enzyme , cytochrome P450 17 alpha - hydroxylase ( P05093 ) . This has provided physicians with another treatment option for patients with CRPC . The landscape for prostate cancer treatment has changed with the approval of cabazitaxel , sipuleucel - T and abiraterone . Here we provide an overview of abiraterone acetate , its mechanism of action , and its potential place for therapy in CRPC .","Synthesis , biological evaluation , and molecular modeling of abiraterone analogues : novel P05093 inhibitors for the treatment of prostate cancer . DB05812 , a steroidal cytochrome P450 17alpha - hydroxylase - 17 , 20 - lyase inhibitor ( P05093 ) , is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen - dependent prostate cancer . Since steroidal compounds often show side effects attributable to their structure , we have tried to replace the sterane scaffold by nonsteroidal core structures . The design and synthesis of 20 new abiraterone mimetics are described . Their activities have been tested with recombinant human P05093 expressed in E . coli . Promising compounds were further evaluated for selectivity against P15538 , P19099 , and the hepatic P08684 . Compounds 19 and 20 showed comparable activity to abiraterone ( IC50 values of 144 and 64 nM vs 72 nM ) and similar or even better selectivity against the other CYP enzymes . Selected compounds were also docked into our homology model , and the same binding modes as for abiraterone were found .","Q8IX12 promotes chromatin loading of androgen receptor ( AR ) transcription complex by stabilizing the association between AR and P23769 . P10275 ( AR ) , a ligand - dependent transcription factor , plays a critical role in prostate cancer onset and progression , and its transcriptional function is mediated largely by distinct nuclear receptor co - regulators . Here , we show that cell cycle and apoptosis regulator 1 ( Q8IX12 ) functions as an AR co - activator . Q8IX12 interacted with and enhanced the transcriptional activity of AR . Depletion of Q8IX12 caused reduction in androgen - dependent expression of a subset of AR target genes . We further showed that Q8IX12 is required for recruitment of AR , MED1 and RNA polymerase II to the enhancers of AR target genes and for androgen - induced long - range prostate specific antigen enhancer - promoter interaction . The molecular mechanism underlying Q8IX12 function in AR - mediated transcription involves Q8IX12 - mediated enhanced recruitment of P23769 , a pioneer factor for AR , to AR - binding sites . Q8IX12 stabilized the interaction between AR and P23769 by interacting directly with both proteins , thereby facilitating AR and P23769 occupancy on the enhancers . Furthermore , Q8IX12 depletion inhibited the growth , migration , invasion of prostate cancer cells and reduced the tumorigenicity of prostate cancer cells in vivo . Our results firmly established Q8IX12 as an AR co - activator that plays a key role in AR transcription complex assembly and has an important physiological role in androgen signaling and prostate tumorigenesis .","Beyond castration and chemotherapy : novel approaches to targeting androgen - driven pathways . In castrate - resistant prostate cancer , beyond chemotherapy , existing guidelines suggest only supportive care . However , recent evidence suggests that continued targeting of androgen - dependent pathways may be an efficacious approach . Clinical data is now available for two mechanistically distinct agents ( abiraterone and MDV3100 ) that both ultimately target these pathways . DB05812 is a potent and irreversible inhibitor of P05093 , a critical enzyme in androgen biosynthesis . Phase II studies indicate substantial declines in PSA amongst castrate - resistant patients treated with abiraterone , both prior to and following cytotoxic chemotherapy . In contrast to abiraterone , MDV3100 is a direct inhibitor of the androgen receptor , binding the receptor irreversibly with substantially higher affinity as compared to bicalutamide . A recent phase I / II trial of MDV3100 in castrate - resistant prostate cancer demonstrated tolerability of the agent with activity at the lowest dose level . On the basis of these compelling data , both abiraterone and MDV3100 will be examined in the phase III setting .","Genetic variants associated with myocardial infarction and the risk factors in Chinese population . BACKGROUND : Recent genome - wide association ( GWA ) studies in Caucasians identified multiple single nucleotide polymorphisms ( SNPs ) associated with coronary artery disease ( CAD ) . The associations of those SNPs with myocardial infarction ( MI ) have not been replicated in Asian populations . Among those previously identified SNPs , we selected nine ( rs10953541 , rs1122608 , rs12190287 , rs12413409 , rs1412444 , rs1746048 , rs3798220 , rs4977574 , rs579459 , in or near genes 7q22 , P01130 , O43680 , P05093 , P38571 , P48061 , P08519 , CDKN2A , P16442 , respectively ) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with MI and MI related risk factors in Chinese population . METHODS AND RESULTS : We conducted a case - control association study on a cohort of 2365 MI patients and 2678 unrelated controls from the Chinese population . Genotyping of 9 SNPs were performed by the TaqMan Real Time PCR method . After age , sex , and BMI adjustment , we observed the SNPs rs12190287 , rs12413409 , rs1412444 , rs1746048 and rs4977574 , were significantly associated with MI in additive models and rs12190287 , rs12413409 , rs4977574 were significantly associated with phenotypes of MI at the same time . We also found three SNPs rs1122608 , rs3798220 and rs579459 were significantly associated with risk factors of MI , although they had no association with MI in Chinese population . CONCLUSION : Results of this study indicate that 5 SNPs were associated with MI and 3 SNPs were associated with associated with lipoprotein levels but not with MI in a Chinese population . The present study supports some CAD - related genes in Caucasian as important genes for MI in a Chinese population .","Anti - angiogenic and anti - tumor effects of P50750 - 593 , a potent and selective inhibitor of vascular endothelial growth factor and platelet - derived growth factor receptor tyrosine kinase . We recently reported that P50750 - 593 , a novel imidazo [ 1 , 2 - b ] pyridazine derivative , is a highly potent and selective inhibitor of the vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) receptor tyrosine kinase families . Moreover , P50750 - 593 exhibits a uniquely long - acting inhibitory profile towards P15692 receptor 2 ( P35968 ) and PDGF receptor β ( PDGFRβ ) . In this study , we demonstrated that P50750 - 593 potently inhibits P15692 - and PDGF - stimulated cellular phosphorylation and proliferation of human umbilical vein endothelial cells and human coronary artery smooth muscle cells . P50750 - 593 also potently inhibits P15692 - induced tube formation of endothelial cells co - cultured with fibroblasts . Oral administration of P50750 - 593 exhibited strong anti - tumor effects against various human cancer xenografts along with good tolerability despite a low level of plasma exposure . Even after the blood and tissue concentrations of P50750 - 593 decreased below the detectable limit , a pharmacodynamic marker ( phospho P35968 ) was almost completely suppressed , indicating that its long duration of enzyme inhibition might contribute to the potent activity of P50750 - 593 . Immunohistochemical staining indicated that P50750 - 593 showed anti - proliferative and pro - apoptotic effects on tumors along with a decrease of vessel density and inhibition of pericyte recruitment to microvessels in vivo . Furthermore , dynamic contrast - enhanced magnetic resonance imaging revealed that P50750 - 593 reduced tumor vessel permeability prior to the onset of anti - tumor activity . In conclusion , P50750 - 593 is an extremely potent VEGFR / P09619 kinase inhibitor whose potent anti - angiogenic activity suggests therapeutic potential for the treatment of solid tumors .","DB05812 acetate , a first - in - class P05093 inhibitor , establishes a new treatment paradigm in castration - resistant prostate cancer .","Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .","[ DB05812 acetate : a novel therapeutic option in hormone - refractory prostate cancer ] . Until recently , only therapy with docetaxel and prednisone has been shown to prolong survival in men with hormonorefractory metastatic prostate cancer . With approvals of sipuleucel - T , cabazitaxel , and abiraterone acetate , all based on improvement in overall survival , the scenary for management of men with metastatic prostate cancer has dramatically changed . DB05812 acetate was developed to specifically inhibit cytochrome P450 ( CYP ) 17A1 , which is an essential enzyme in the biosynthesis of testosterone . In the phase III , the trial treatment with abiraterone acetate plus prednisone prolongs overall survival relative to prednisone alone in patients with metastatic castration - resistant prostate cancer who have disease progression after treatment with docetaxel and associated with an acceptable tolerability profile , which was generally similar to that of the placebo plus prednisone group . However , adverse events resulting from elevated mineralocorticoid levels because of P05093 inhibition , fluid retention and oedema , hypokalaemia , hypertension occurred in significantly more in abiraterone acetate plus prednisone than in placebo plus prednisone .","Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK78___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .","Limited in vitro efficacy of P05093 inhibition on human castration resistant prostate cancer . Although accumulating evidence indicates high expression of P05093 ( P45017A1 ) allows castration resistant prostate cancer ( CRPC ) to maintain high intratumoral androgen levels , the potential P45017A1 activity has not been characterized yet . The aim of this study was to examine the potential P05093 activity including 17α - hydroxylase and 17 , 20 - lyase activities in human CRPC and the effect of a CYP17A inhibitor . We used three human CRPC cell lines : C4 - 2 and C4 - 2AT6 which was established from C4 - 2 under androgen ablation conditions for 6months , and PC3 . To ascertain the potential P05093 activity , we cultured with the steroid precursors : ( 13 ) C -[ 2 , 3 , 4 ]- progesterone ( 13C - Prog ) , and analyzed the sequential biosynthesis ( 13 ) C -[ 2 , 3 , 4 ]- 17 - hydroxyprogesterone ( 13C - 17OHP ) and ( 13 ) C -[ 2 , 3 , 4 ]- androstenedione ( 13C - Adione ) by liquid chromatography / mass spectrometry ( LC / MS / MS ). The C4 - 2AT6 cells showed significantly higher P05093 expression than C4 - 2 cells ( p < 0 . 001 ) . LC / MS / MS analysis enabled us to detect the 13C - 17 - OHP and 13C - A - dione in these cell lines . The concentration ratio of 13C - Adione / 13C - 17OHP ( Adione - 17OHP ratio ) , which is thought to reflect the differences between 17 - hydroxylase and 17 , 20 - lyase activities , was then determined . The Adione - 17OHP ratio in C4 - 2AT6 cells was significantly higher than that of C4 - 2 cells ( p < 0 . 001 ) . DB05812 were able to inhibit the CYP17A activities , although abiraterone did not have anti - proliferative effects on C4 - 2 and C4 - 2AT6 cells at clinically achievable concentrations of < 1000nM in vitro . The present study clearly demonstrates CRPC have the dual activities of P05093 mediated by 17 - hydroxylase activity and 17 , 20 - lyase activity . DB05812 does n ' t have an in vitro anti - proliferative efficacy in CRPC cells , suggesting limited efficacy in vitro .","Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate . BACKGROUND : DB05812 acetate ( AA ) , a highly potent P05093 inhibitor , has demonstrated marked clinical benefit in patients with metastatic castration - resistant prostate cancer ( CRPC ) . Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations . The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor ( AR ) activity in prostate cancer ( PC ) cells . METHODS : Fluorescence resonance energy transfer ( FRET ) assay was used to assess the effect of mineralocorticoids on androgen - induced conformational change of the AR . LAPC4 , LNCaP and LN - AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations , including levels measured in the serum of AA - treated patients in a phase I trial . AR - dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells . RESULTS : Corticosterone ( CS ) and deoxycorticosterone ( DOC ) inhibited androgen - induced conformational change of the AR in the FRET assay . CS inhibited AR - dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA - treated patients . DOC inhibited AR transcriptional activity and cell growth at 10 - fold greater concentrations than measured in the serum of AA - treated patients . CONCLUSIONS : Mineralocorticoids directly inhibit androgen - induced conformational change of the AR . CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA . Further investigation of the potential therapeutic implications of mineralocorticoids in AA - treated CRPC patients is warranted .","Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK73___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .","The V2 vasopressin receptor stimulates P27361 / 2 activity independently of heterotrimeric G protein signalling . The V2 vasopressin receptor ( P30518 ) activates the mitogen activated protein kinases ( MAPK ) P27361 / 2 through a mechanism involving the scaffolding protein beta arrestin . Here we report that this activating pathway is independent of G alpha s , G alpha i , G alpha q or G betagamma and that the P30518 - mediated activation of G alpha s inhibits P27361 / 2 activity in a DB02527 / PKA - dependent manner . In the HEK293 cells studied , the beta arrestin - promoted activation was found to dominate over the PKA - mediated inhibition of the pathway , leading to a strong vasopressin - stimulated P27361 / 2 activation . Despite the strong MAPK activation and in contrast with other GPCR , P30518 did not induce any significant increase in DNA synthesis , consistent with the notion that the stable interaction between P30518 and beta arrestin prevents signal propagation to the nucleus . Beta arrestin was found to be essential for the P27361 / 2 activation , indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues . Based on the use of selective pharmacological inhibitors , dominant negative mutants and siRNA , we conclude that the beta arrestin - dependent activation of P27361 / 2 by the P30518 involves c - Src and a metalloproteinase - dependent trans - activation event . These findings demonstrate that beta arrestin is a genuine signalling initiator that can , on its own , engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand .","Vascular endothelial growth factor gene polymorphism is associated with calcium oxalate stone disease . Growth factor - related genes regulate cell growth , differentiation and apoptosis in the kidney in response to cellular injury . One of the theories of stone formation is that cellular injury , and thus growth factors , play a role . We therefore investigated the association between growth factor genes and calcium oxalate stone disease . The most frequently seen polymorphism of the vascular endothelial growth factor ( P15692 ) gene is Bst U I C / T , which is located upstream at the - 460th nucleotide . Other growth factor - related gene polymorphisms include the cytochrome P450c17alpha enzyme ( P05093 ) gene MspA I C / T polymorphism at the 5 '- UTR promoter region , the epidermal growth factor receptor ( P00533 ) gene Bsr I polymorphism ( A to T ) at position 2 , 073 , and the insulin - like growth factor - 2 ( IGF - 2 ) gene Apa I A / G at exon 9 . All four polymorphisms were used as genetic markers in this study in the search for an association between stone disease and growth factor related genes . A normal control group of 230 healthy people , and 230 patients with calcium oxalate stone , were examined . The polymorphism was seen following polymerase chain reaction based restriction analysis . The result revealed a significant difference between normal individuals and stone patients ( P = 0 . 0003 , Fisher ' s exact test ) in the distribution of the P15692 gene polymorphism as well as an odds ratio of 1 . 30 ( 95 % confidence interval = 0 . 993 - 1 . 715 ) per copy of the \" T \" allele . Whereas , the IGF - 2 , P00533 and P05093 gene polymorphisms did not reveal a significant association with stone disease . We conclude that the P15692 gene Bst U I polymorphism is a suitable genetic marker of urolithiasis .","Prostate cancer - from steroid transformations to clinical translation . The survival benefit conferred by two hormonal agents in phase III trials has clinically validated the long suspected and now widely recognized phenomenon of castration - resistant prostate cancer ( CRPC ) hormone dependence . DB05812 inhibits steroid 17α - hydroxylase / 17 , 20 - lyase ( P05093 ) and blocks androgen synthesis , whereas enzalutamide directly binds and antagonizes the androgen receptor . Both agents are highly effective against CRPC and significantly prolong survival following docetaxel treatment . However , this clinical validation of the androgen pathway has led to questions regarding the fundamental mechanisms of CRPC , as well as resistance to abiraterone and enzalutamide . Our understanding of the predominant steroid transformation pathways that lead to dihydrotestosterone synthesis in CRPC is evolving . The role of steroidogenesis in the development of resistance to abiraterone and enzalutamide remains uncertain . The specific roles of candidate enzyme targets in the development of resistance to these agents must be defined if we are to identify novel targets for improved pharmacologic therapies .","___MASK25___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK25___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK25___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .","Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( DB02901 ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .","A - ring modified steroidal azoles retaining similar potent and slowly reversible P05093 inhibition as abiraterone . DB05812 acetate is a potent inhibitor of human cytochrome P450c17 ( P05093 , 17α - hydroxylase / 17 , 20 - lyase ) and is clinically used in combination with prednisone for the treatment of castration - resistant prostate cancer . Although many studies have documented the potency of abiraterone ( Abi ) in a variety of in vitro and in vivo systems for several species , the exact potency of Abi for human P05093 enzyme has not yet been determined , and the structural requirements for high - potency steroidal azole inhibitors are not established . We synthesized 4 Abi analogs differing in the A - B ring substitution patterns : 3α - hydroxy - Δ ( 4 )- Abi ( 13 ) , 3 - keto - Δ ( 4 )- Abi ( 11 ) , 3 - keto - 5α - Abi ( 6 ) , and 3α - hydroxy - 5α - Abi ( 5 ) . We measured the spectral binding constants ( Ks ) using purified and modified human P05093 along with the determination constants ( Ki ) applying a native human P05093 enzyme in yeast microsomes for these compounds as well as for ketoconazole . For Abi , 3 - keto - Δ ( 4 )- Abi , 3 - keto - 5α - Abi , and 3α - hydroxy - 5α - Abi , the type 2 spectral changes gave the best fit for a quadratic equation , since in these experiments Ks values were 0 . 1 - 2 . 6nM , much lower than that for ketoconazole and 3α - hydroxy - Δ ( 4 )- Abi ( Ks values were 140 and 1660nM , respectively ) . Inhibition experiments showed mixed inhibition patterns with Ki values of 7 - 80nM . Abi dissociation from the P05093 - Abi complex was incomplete and slow ; the t1 / 2 for dissociation was 1 . 8h , with 55 % of complex remaining after 5h . We conclude that Abi and the 3 related steroidal azoles ( 3 - keto - Δ ( 4 )- Abi , 3 - keto - 5α - Abi , and 3α - hydroxy - 5α - Abi ) , which also mimic natural substrates , are extraordinarily potent inhibitors of human P05093 , whereas the 3α - hydroxy - Δ ( 4 )- Abi is moderately potent and comparable to ketoconazole .","Clinical appraisal of abiraterone in the treatment of metastatic prostatic cancer : patient considerations , novel opportunities , and future directions . While androgen - deprivation therapy can induce dramatic clinical responses in advanced and metastatic prostate cancer , refractory disease ( castration - resistant prostate cancer [ CRPC ] ) eventually emerges . In recent years , several studies have demonstrated the importance of residual intratumoral androgens in maintaining androgen receptor ( AR ) transcriptional activity in CRPC . The cytochrome P450 enzyme P05093 is an obligatory step in androgen synthesis , and therefore a critical therapeutic target in CRPC . DB05812 acetate is a selective , irreversible inhibitor of P05093 and can suppress adrenal synthesis of androgen precursors , and possibly in situ steroidogenesis in the tumor microenvironment . In a phase III multicenter study , abiraterone in combination with prednisone improved median overall survival of men with docetaxel - refractory CRPC by 3 . 9 months compared to placebo plus prednisone , and also resulted in higher objective prostate - specific antigen and radiographic response rates . The study led to the FDA approval in April 2011 of abiraterone for treatment of chemotherapy - refractory CRPC patients , validating steroidogenesis and the AR axis in general as therapeutic targets in CRPC . The FDA indication for abiraterone was expanded to all CRPCs in December 2012 , while evaluation in even earlier disease states is ongoing . We propose a comprehensive AR axis - targeting approach via simultaneous , frontline enzymatic blockade of several steroidogenic enzymes ( eg , P05093 and P42330 ) in combination with gonadotropin - releasing hormone analogs and potent , second - generation AR antagonists ( eg , enzalutamide ) in order to improve outcomes in patients with prostate cancer .","The AP - 1 family member P01100 blocks transcriptional activity of the nuclear receptor steroidogenic factor 1 . Steroid production in the adrenal zona glomerulosa is under the control of angiotensin II ( Ang II ) , which , upon binding to its receptor , activates protein kinase C ( PKC ) within these cells . PKC is a potent inhibitor of the steroidogenic enzyme P05093 . We have demonstrated that , in the ovary , PKC activates expression of P01100 , a member of the AP - 1 family , and increased expression of this gene is linked to P05093 downregulation . However , the pathway and the molecular mechanism responsible for the inhibitory effect of PKC on P05093 expression are not defined . Herein , we demonstrated that Ang II inhibited P05093 through PKC and P27361 / 2 - activated P01100 and that blocking P01100 expression decreased PKC - mediated inhibition . Although P05093 transcription was activated by the nuclear receptor Q13285 , expression of P01100 resulted in a decrease in Q13285 - mediated gene transcription . P01100 physically interacted with the hinge region of Q13285 and modulated its transactivity , thus preventing binding of cofactors such as SRC1 and CBP , which were necessary to fully activate P05093 transcription . Collectively , these results indicate a new regulatory mechanism for Q13285 transcriptional activity that might influence adrenal zone - specific expression of P05093 , a mechanism that can potentially be applied to other steroidogenic tissues .","Novel P05093 inhibitors : synthesis , biological evaluation , structure - activity relationships and modelling of methoxy - and hydroxy - substituted methyleneimidazolyl biphenyls . Recently , the steroidal P05093 inhibitor DB05812 entered phase II clinical trial for the treatment of androgen - dependent prostate cancer . As 17alpha - hydroxylase - 17 , 20 - lyase ( P05093 ) catalyzes the last step in androgen biosynthesis , inhibition of this target should affect not only testicular but also adrenal androgen formation . Therefore P05093 inhibitors should be advantageous over existing therapies , for example with DB00644 analogues . However , steroidal drugs are known for side effects which are due to affinities for steroid receptors . Therefore we decided to synthesize non - steroidal compounds mimicking the natural P05093 substrates pregnenolone and progesterone . The synthesis and biological evaluation of a series of 15 novel and highly active non - steroidal P05093 inhibitors are reported . The compounds were prepared via Suzuki - cross - coupling , Grignard reaction and CDI - assisted S ( N ) t - reaction with imidazole and their inhibitory activity was examined with recombinant human P05093 expressed in Escherichia coli . Promising compounds were further tested for their selectivity against the hepatic enzyme P08684 and the glucocorticoid - forming enzyme P15538 . All compounds turned out to be potent P05093 inhibitors . The most active compounds 7 and 8 were much more active than Ketoconazole showing activity comparable to DB05812 ( IC ( 50 ) values of 90 and 52nM vs . 72nM ) . Most compounds also showed higher selectivities than Ketoconazole , but turned out to be less selective than DB05812 . Docking studies using our P05093 protein model were performed with selected compounds to study the interactions between the inhibitors and the amino acid residues of the active site .","Status of the down - regulated canine testis using two different P01148 agonist implants in comparison with the juvenile testis . Testicular function in the dog was down - regulated using two different P01148 agonist implants , with adult and juvenile testes serving as controls . Treatment resulted in an increased percentage of the interstitial area and decreased area of Leydig cell nuclei . Expression of P49675 and the steroidogenic enzymes cytochrome P450 side - chain cleavage enzyme ( P450scc , P05108 ) and cytochrome P450 17α - hydroxylase - 17 , 20 - lyase ( P450c17 , P05093 ) in Leydig cells was blocked at the mRNA and protein level , showing no differences between the two agonists . Staining for androgen receptor ( AR ) by immunohistochemistry was positive in Sertoli , Leydig and peritubular cells and some spermatogonia , with in situ hybridization confirming expression in Sertoli cells . At the mRNA level , expression of AR was not affected ; however , translation was blocked ( reduced percentage of AR - positive Sertoli cells ) , with the number of nuclei in basal position being decreased . In the juvenile testes , mRNA expression of P49675 , P05108 and P05093 was higher compared with the other groups but distinctly lower for the AR . At the protein level , the expression was at the limit of detection for P49675 ; AR - positive Sertoli cells were not detected . Our observations show that the down - regulated testis is different from the juvenile one rather resembling the testicular status in seasonal breeders out of season .","DB05812 acetate : targeting persistent androgen dependence in castration - resistant prostate cancer . DB05812 acetate is the first second - line hormonal agent proven to improve survival in metastatic castration - resistant prostate cancer . It selectively inhibits cytochrome P450 17 ( P05093 ) α - hydroxylase and cytochrome17 , 20 ( C17 , 20 ) - lyase , which are enzymes critical for androgen synthesis . DB05812 acetate was initially approved in the United States in 2011 after demonstrating a 4 - month survival benefit in docetaxel - refractory metastatic prostate cancer . The FDA recently expanded its indication for use in the pre - chemotherapy setting after it elicited significant delays in disease progression and a strong trend for increased overall survival in phase III studies . Ongoing investigations of abiraterone are evaluating its efficacy in earlier disease states , exploring its synergy in combination with other therapeutic agents , and assessing the necessity for administration of concurrent steroids and gonadal suppression . The identification and development of predictive biomarkers will optimize the incorporation of abiraterone into the management of advanced prostate cancer .","DB05812 acetate : redefining hormone treatment for advanced prostate cancer . Prostate cancer has long since been recognised as being hormonally driven via androgen receptor signalling . DB05812 acetate ( AA ) is a rationally designed P05093 inhibitor that blocks the conversion of androgens from non - gonadal precursors effectively , thus reducing testosterone to undetectable levels . AA has recently been proved to extend survival for men with metastatic castration - resistant prostate cancer who have progressive disease after first - line chemotherapy treatment . In addition , it is currently being tested in a Phase III trial in the pre - chemotherapy setting . This paper will review the preclinical discovery and clinical development of AA and will outline the strategy of parallel translational research .","___MASK24___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK24___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK24___ is a promising pharmacological tool in the treatment of renal edema .","Genetic polymorphisms of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes in adolescent girls with polycystic ovary syndrome . BACKGROUND : Polycystic ovary syndrome ( PCOS ) , whose genetic basis is not completely well understood , is the most common endocrine disorder in women and it typically develops during adolescence . The aim of this study is to investigate the possible association between single nucleotide polymorphisms ( SNPs ) of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes and PCOS in adolescent girls . METHODS : DNA samples from forty - four adolescent girls with PCOS and 50 healthy controls were analyzed by PCR - RFLP and direct DNA sequencing to determine the genotypic frequency of 17 different polymorphic loci on the P23945 ( A307T , N680S ) , P05093 ( - 34 T / C ) , P04798 ( T6235C ) , Q9HC96 ( 44 , 43 , 19 , 63 ) , P06213 ( exon 17 C / T ) , P05121 ( 4G / 5G ) genes . Genotyping of exon 12 ( six polymorphisms ) and intron 12 ( one polymorphism ) of P06213 gene by direct DNA sequencing was performed for the first time in this study . RESULTS : No significant differences were observed in the genotype and allele distributions of above mentioned polymorphisms between cases and control groups . CONCLUSION : Our data does not support an association between SNPs of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes and susceptibility to PCOS or related traits in Turkish adolescent girls .","Androgen synthesis inhibitors in the treatment of castration - resistant prostate cancer . Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer . However , in the majority of patients who develop castration - resistant prostate cancer ( CRPC ) , it is possible to detect persistent activation of the androgen receptor ( AR ) through androgens produced in the adrenal gland or within the tumor itself . DB05812 acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme P05093 with activity as a 17α - hydroxylase and 17 , 20 - lyase . P05093 is necessary for production of nongonadal androgens from cholesterol . Regulatory approval of abiraterone in 2011 , based on a phase III trial showing a significant improvement in overall survival ( OS ) with abiraterone and prednisone versus prednisone , represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC . Inhibition of 17α - hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol - mediated suppression of pituitary adrenocorticotropic hormone ( DB01285 ) , providing a rationale for development of P05093 inhibitors with increased specificity for 17 , 20 - lyase ( orteronel , galeterone and VT - 464 ) that can potentially be administered without exogenous corticosteroids . In this article , we review the development of abiraterone and other P05093 inhibitors ; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality - of - life , potential early predictors of response , and optimal sequencing of abiraterone with respect to other agents ; and results of translational studies providing insights into resistance mechanisms to P05093 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity .","Cytochrome P450 17 ( P05093 ) is involved in endometrial cancinogenesis through apoptosis and invasion pathways . Cytochrome P450 17 ( P05093 ) encodes cytochrome P450c17α , an enzyme with 17α - hydroxylase and 17 , 20 - lyase activities involved in estradiol biosynthesis . Here we examine the role of P05093 gene in endometrial carcinogenesis . Immunohistochemistry staining of endometrial carcinoma and corresponding uninvolved tissues showed that P05093 is upregulated in endometrial cancers ( 15 of 24 , 62 . 5 % ) . To understand the functional significance of this upregulation , we silenced P05093 gene by introduction of siRNA into endometrial cancer cell line KLE followed by functional studies . Further , to understand the molecular basis of the role of P05093 , we profiled the expression of key pathway - specific genes and identified several components of the apoptosis and invasion pathways that are potentially regulated by P05093 . Silencing of P05093 caused decreased cell proliferation and induced apoptosis . Significantly , P05093 depletion leads to downregulation of anti - apoptotic genes B cell lymphoma 2 ( Bcl - 2 ) and telomerase reverse transcriptase ( O14746 ) , indicating induced apoptosis . Also , attenuation of P05093 decreased the cellular invasion ability and regulated expression of several invasion pathway components such as melanoma cell adhesion molecule ( P43121 ) , matrix metallopeptidase 2 and 9 ( P08253 and P14780 ) , and tissue inhibitor of metalloproteinase 3 ( P35625 ) . In conclusion , this is the first report documenting that upregulation of P05093 in endometrial cancers play a crucial role in endometrial carcinogenesis by targeting multiple components of apoptosis and invasion pathways . Further studies are required to understand the detailed mechanisms underlying P05093 - mediated regulation of these components .","Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK41___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .","Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK15___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .","DB05812 inhibits 3β - hydroxysteroid dehydrogenase : a rationale for increasing drug exposure in castration - resistant prostate cancer . PURPOSE : Treatment with abiraterone ( abi ) acetate prolongs survival in castration - resistant prostate cancer ( CRPC ) . Resistance to abi invariably occurs , probably due in part to upregulation of steroidogenic enzymes and / or other mechanisms that sustain dihydrotestosterone ( DB02901 ) synthesis , which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes . On the basis of the 3β - hydroxyl , Δ ( 5 )- structure , we hypothesized that abi also inhibits 3β - hydroxysteroid dehydrogenase / isomerase ( 3βHSD ) , which is absolutely required for DB02901 synthesis in CRPC , regardless of origins or routes of synthesis . EXPERIMENTAL DESIGN : We tested the effects of abi on 3βHSD activity , androgen receptor localization , expression of androgen receptor - responsive genes , and CRPC growth in vivo . RESULTS : Abi inhibits recombinant 3βHSD activity in vitro and endogenous 3βHSD activity in LNCaP and LAPC4 cells , including conversion of [ ( 3 ) H ] - dehydroepiandrosterone ( DB01708 ) to Δ ( 4 )- androstenedione , androgen receptor nuclear translocation , expression of androgen receptor - responsive genes , and xenograft growth in orchiectomized mice supplemented with DB01708 . Abi also blocks conversion of Δ ( 5 )- DB01524 to testosterone by 3βHSD . Abi inhibits 3βHSD1 and 3βHSD2 enzymatic activity in vitro ; blocks conversion from DB01708 to androstenedione and DB02901 with an IC ( 50 ) value of less than 1 μmol / L in CRPC cell lines ; inhibits androgen receptor nuclear translocation ; expression of O15393 , prostate - specific antigen , and Q13451 ; and decreases CRPC xenograft growth in DB01708 - supplemented mice . CONCLUSIONS : We conclude that abi inhibits 3βHSD - mediated conversion of DB01708 to active androgens in CRPC . This second mode of action might be exploited to reverse resistance to P05093 inhibition at the standard abi dose by dose - escalation or simply by administration with food to increase drug exposure .","Antitumor activity with P05093 blockade indicates that castration - resistant prostate cancer frequently remains hormone driven . DB05812 acetate is a potent , selective , and orally bioavailable small molecule inhibitor of P05093 , an enzyme that catalyzes two key serial reactions ( 17 alpha hydroxylase and 17 , 20 lyase ) in androgen and estrogen biosynthesis . Clinical trials have confirmed that specific inhibition of P05093 is safe and results in clinically important antitumor activity in up to 70 % of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies . These clinical data indicate that castration - resistant prostate cancer frequently remains hormone dependent and has confirmed that this disease should no longer be described as \" hormone resistant or refractory \" . Biomarker studies , including the analysis of ETS gene fusion status , on patients treated with abiraterone acetate may allow enrichment of patients with a sensitive phenotype in future studies of therapeutics targeting P05093 .","___MASK91___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK91___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .","Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK61___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .","P05093 inhibition as a hormonal strategy for prostate cancer . P10275 ( AR ) signaling has a key role in the pathogenesis of prostate cancer . AR gene amplification , AR overexpression , and activating mutations in the AR occur more frequently as castration - resistant prostate cancer ( CRPC ) evolves , with intratumoral androgen levels remaining sufficient for AR activation despite castration . The source of these androgens might be either adrenal or intratumoral . AR signaling , therefore , remains a valid treatment target for patients with CRPC . P05093 is a key enzyme for androgen biosynthesis . The imidazole antifungal agent ketoconazole weakly and nonspecifically inhibits P05093 , but remains unlicensed for this indication . Chemists at the Cancer Research UK Centre for Cancer Therapeutics have designed a novel , selective , irreversible inhibitor of P05093 called abiraterone , which is more than 20 times more potent than ketoconazole . DB05812 acetate , a prodrug , has undergone phase I assessment , and is rapidly progressing from phase II to phase III trials , in view of its high level of antitumor activity . This agent is safe and well tolerated , and activity profiles suggest that approximately 50 % of CRPC remains AR - ligand driven . Other P05093 inhibitors with alternative mechanisms of action , for example VN / 124 - 1 , are in preclinical development . The rationale for and implications of P05093 inhibition and the P05093 - targeting agents in development are discussed in this Review .","Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .","DB05812 in prostate cancer : a new angle to an old problem . DB05812 acetate is an orally administered potent inhibitor of cytochrome P450 , family 17 , subfamily A , polypeptide 1 ( P05093 ) , which is essential for synthesis of testosterone from cholesterol . Although decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer , residual androgens may still be detected in patients treated with luteinizing hormone - releasing hormone agonists or antagonists . Treatment with abiraterone results in rapid , and complete , inhibition of androgen synthesis in the adrenal glands and potentially within the tumor itself . An overall survival benefit of maximal androgen suppression was recently shown in a randomized placebo - controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate - resistant prostate cancer previously treated with docetaxel chemotherapy . DB05812 ' s efficacy shows the importance of androgen signaling in patients with castrate - resistant metastatic disease , with additional confirmation from recent studies of other novel agents such as MDV3100 , an androgen receptor signaling inhibitor . These promising results now pose a new angle to an old problem about hormonal therapy and raise new questions about how resistance develops , how to best sequence therapy , and how to optimize combinations with other emerging novel agents .","Medical strategies for treatment of castration resistant prostate cancer ( CRPC ) docetaxel resistant . Current landscape of treatment of castration - resistant prostate cancer ( CRPC ) has recently changed . DB06772 , a new taxane with potential antineoplastic activity , has been approved by Food and Drug Administration ( FDA ) after docetaxel failure . In a phase III trial , cabazitaxel showed increased overall survival ( OS ) compared with mitoxantrone ( 15 . 1 vs . 12 . 7 mo , HR 0 . 70 , 95 % CI 0 . 59 - 0 . 83 , p < 0 . 0001 ) . Furthermore , chemotherapy is not the only strategy available : several studies have shown as CRPC remains dependent on androgen receptor function for growth . DB05812 acetate , an irreversible inhibitor of P05093 , has also been approved by FDA after docetaxel failure . In a phase III trial comparing abiraterone acetate to placebo , abiraterone showed improvement in OS ( 14 . 8 vs . 10 . 4 mo , HR 0 . 65 , 95 % CI 0 . 54 - 0 . 77 ; p < 0 . 0001 ) . This review will discuss current options and the ongoing trials for second - line treatment of CRPC including chemotherapy , hormonal therapies , antiangiogenetic and immune strategies .","The 5α - androstanedione pathway to dihydrotestosterone in castration - resistant prostate cancer . The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor ( AR ) , as well as the availability of endogenous AR agonists . Originating from the gonads , testosterone is released into circulation and is converted by steroid - 5α - reductase in prostate cancer to 5α - dihydrotestosterone ( DB02901 ) , potently activating AR and driving tumor progression . Advanced prostate cancer is initially treated with gonadal testosterone depletion , which suppresses this cascade of events and typically leads to a treatment response . Eventually , resistance to testosterone deprivation occurs with \" castration - resistant \" prostate cancer ( CRPC ) and is driven by the intratumoral synthesis of DB02901 . The generation of DB02901 occurs in large part from adrenal 19 - carbon precursor steroids , which are dependent on expression of P05093 . Although the path from adrenal precursor steroids to DB02901 was generally thought to require 5α - reduction of testosterone , recent data suggest that it instead involves conversion from Δ - androstenedione by steroid - 5α - reductase isoenzyme - 1 to 5α - androstanedione , followed by subsequent conversion to DB02901 . The 5α - androstanedione pathway to DB02901 therefore bypasses testosterone entirely . DB05812 acetate effectively inhibits P05093 , blocks the synthesis of androgens , and extends the survival of men with CRPC . Further progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate .","Generation and properties of a new human ventral mesencephalic neural stem cell line . Neural stem cells ( NSCs ) are powerful research tools for the design and discovery of new approaches to cell therapy in neurodegenerative diseases like Parkinson ' s disease . Several epigenetic and genetic strategies have been tested for long - term maintenance and expansion of these cells in vitro . Here we report the generation of a new stable cell line of human neural stem cells derived from ventral mesencephalon ( hVM1 ) based on v - myc immortalization . The cells expressed neural stem cell and radial glia markers like nestin , vimentin and 3CB2 under proliferation conditions . After withdrawal of growth factors , proliferation and expression of v - myc were dramatically reduced and the cells differentiated into astrocytes , oligodendrocytes and neurons . hVM1 cells yield a large number of dopaminergic neurons ( about 12 % of total cells are TH + ) after differentiation , which also produce dopamine . In addition to proneural genes ( Q9H2A3 , MASH1 ) , differentiated cells show expression of several genuine mesencephalic dopaminergic markers such as : Q8TE12 , O60663 , P48051 , P00325 , P43354 , O75364 , Q05940 and Q01959 , indicating that they retain their regional identity . Our data indicate that this cell line and its clonal derivatives may constitute good candidates for the study of development and physiology of human dopaminergic neurons in vitro , and to develop tools for Parkinson ' s disease cell replacement preclinical research and drug testing .","Interactions of abiraterone , eplerenone , and prednisolone with wild - type and mutant androgen receptor : a rationale for increasing abiraterone exposure or combining with MDV3100 . Prostate cancer progression can be associated with androgen receptor ( AR ) mutations acquired following treatment with castration and / or an antiandrogen . DB05812 , a rationally designed inhibitor of P05093 recently approved for the treatment of docetaxel - treated castration - resistant prostate cancer ( CRPC ) , is often effective , but requires coadministration with glucocorticoids to curtail side effects . Here , we hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid - induced activation of mutated AR . We found that prednisolone plasma levels in patients with CRPC were sufficiently high to activate mutant AR . P08235 antagonists , such as spironolactone and eplerenone that are used to treat side effects related to mineralocorticoid excess , can also bind to and activate signaling through wild - type or mutant AR . DB05812 inhibited in vitro proliferation and AR - regulated gene expression of AR - positive prostate cancer cells , which could be explained by AR antagonism in addition to inhibition of steroidogenesis . In fact , activation of mutant AR by eplerenone was inhibited by MDV3100 , bicalutamide , or greater concentrations of abiraterone . Therefore , an increase in abiraterone exposure could reverse resistance secondary to activation of AR by residual ligands or coadministered drugs . Together , our findings provide a strong rationale for clinical evaluation of combined P05093 inhibition and AR antagonism .","[ Roles of medical oncologists in the new era of CRPC therapy in Japan ] . Currently , the standard therapy for advanced prostate cancer is endocrine therapy ( luteinizing hormone - releasing hormone [ LH - RH ] agonists alone or LH - RHagonists plus antiandrogens ) . However , most patients eventually become resistant to these therapies as well as castration therapy . New endocrine therapies for castration - resistant prostate cancer ( CRPC ) have been developed . DB05812 , a P05093 inhibitor , and enzalutamide , a novel androgen receptor antagonist , have been shown to improve the overall survival , and they are set to be approved in Japan soon . Moreover , docetaxel and cabazitaxel have been established as first - and second - line chemotherapeutic drugs , respectively . Although there is currently no established molecular target drug for CRPC , some drugs such as cabozantinib seem to be effective , and they may be used in the future . In these situations of new drug development , the contribution of medical oncologists is predictable . While medical oncologists can not play central roles in all aspects of drug therapy for urological malignancies in Japan , they must play roles in certain aspects such as new drug development starting from phase I trials , improving multidisciplinary care for adverse events , and promoting translational research .","Recent progress in pharmaceutical therapies for castration - resistant prostate cancer . Since 2010 , six drugs have been approved for the treatment of castration - resistant prostate cancer , i . e . , P05093 inhibitor DB05812 , androgen receptor antagonist DB08899 , cytotoxic agent DB06772 , vaccine Sipuleucel - T , antibody DB06643 against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin . All these drugs demonstrate improvement on overall survival , expect for DB06643 , which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone - metastasis - free survival . Besides further P05093 inhibitors ( Orteronel , Galeterone , VT - 464 and CFG920 ) , androgen receptor antagonists ( ARN - 509 , ODM - 201 , AZD - 3514 and EZN - 4176 ) and vaccine Prostvac , more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials , including various kinase inhibitors and platinum complexes . Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments . Under these flourishing circumstances , more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients .","DB05812 acetate , a novel adrenal inhibitor in metastatic castration - resistant prostate cancer . The androgen receptor remains the key player in patients with castration - resistant prostate cancer ( CRPC ) . Available agents capable of blocking early adrenal androgen production have limited activity and can lead to significant toxicities . DB05812 acetate , a pregnenolone analog , is a small molecule that irreversibly inhibits P05093 , a rate - limiting enzyme in androgen biosynthesis . Several clinical trials have demonstrated the safety and efficacy of this compound in men with metastatic CRPC . Recently , a randomized phase 3 trial evaluating abiraterone acetate in docetaxel - refractory CRPC patients demonstrated a survival improvement over placebo - treated patients ( 14 . 8 vs 10 . 9 months ; HR 0 . 646 ; P < 0 . 0001 ) . A similar trial in the pre - chemotherapy setting has completed accrual and is undergoing analysis . Here we review the rationale and clinical development of abiraterone acetate in men with CRPC .","Retreatment of men with metastatic castrate - resistant prostate cancer with abiraterone . BACKGROUND : DB05812 acetate ( AA ) , oral P05093 inhibitor , is an active agent in the treatment of metastatic castrate - resistant prostate cancer ( mCRPC ) . METHODS : We ( R . L . A and N . A ) retrospectively evaluated outcome in 12 men who were re - treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre . RESULTS : All men were heavily pre - treated for mCRPC with a median of four prior lines of therapy , one of which was AA ( given either pre - or post - chemotherapy ) . Eleven out of 12 ( 92 % ) men stopped their first treatment course of AA due to progression and one stopped for financial reasons . Seven men had a PSA decrease ≥ 50 % following their first AA treatment , of which three ( 46 % ) had a PSA decrease ≥ 50 % to AA re - treatment . The responses to AA re - treatment were generally short - lived with a median biochemical progression - free survival of 2 . 3 months and median treatment duration of 3 . 2 months . No PSA responses to AA re - treatment were seen in five men who did not have an initial PSA response to AA . CONCLUSIONS : Our data suggest that AA re - challenge may have limited benefit in select men with mCRPC , and warrants further formal research .","Is abiraterone acetate well tolerated and effective in the treatment of castration - resistant prostate cancer ? This Practice Point commentary discusses the findings of the first phase I trial to evaluate abiraterone acetate ( an inhibitor of the androgen - regulating enzyme P05093 ) in the treatment of castration - resistant prostate cancer . This open - label , dose - escalation study by Attard et al . showed that abiraterone was well tolerated but often induced a syndrome of secondary mineralocorticoid excess that improved with eplerenone ( a mineralocorticoid receptor antagonist ) . DB05812 is a potent suppressor of adrenal androgen synthesis , and produced lasting prostate - specific antigen responses in approximately half of the patients . A few patients had partial regression of distant metastases . Although promising , these results should be interpreted with caution owing to the small sample size and because the study was not primarily designed to examine drug efficacy . Multi - institutional , prospective trials should provide additional information on the tolerability and activity of this compound and further define the population most likely to benefit from this endocrine approach .","Hormonal therapy for prostate cancer : toward further unraveling of androgen receptor function . Prostate cancer is a major cause of cancer - related death in men . Prostate cancer is an androgen - responsive tumor and the treatment of advanced prostate cancer involves hormonal therapy . First - line treatment for advanced prostate cancer is androgen deprivation therapy ( ADT ) , usually with agents that suppress gonadotropins through a pituitary mechanism . DB00644 agonists and antagonists both suppress gonadal release of testosterone , although their activity profiles vary . ADT down - regulates androgen receptor ( AR ) transcriptional activity in the tumor but the response in metastatic disease is transient and tumors progress as castration - resistant prostate cancer ( CRPC ) . Although serum testosterone concentrations decline dramatically with ADT , CRPC growth remains largely dependent on AR activity . Secondary hormonal therapies are then often employed to further dampen AR - driven transcription . These secondary hormonal therapies either further deplete adrenal or intratumoral androgen synthesis , or directly and competitively antagonize AR . New hormonal agents with both of these mechanisms are in clinical trials and show promising activity in patients with CRPC . DB05812 acetate is an inhibitor of P05093 , which is an enzyme required for the synthesis of all androgens and estrogens . MDV3100 is an AR antagonist that has a higher affinity for AR than any other AR antagonist in clinic use . In phase I and phase II clinical trials , both agents have significant activity . These agents and the promise of the development of others provide hope that more effective hormonal therapies may soon be offered to patients , which will improve clinical outcomes .","P05093 inhibitors in castration - resistant prostate cancer . The majority of prostate cancer ( PCa ) cases are diagnosed as a localized disease . Definitive treatment , active surveillance or watchful waiting are employed as therapeutic paradigms . The current standard of care for the treatment of metastatic PCa is either medical or surgical castration . Once PCa progresses in spite of castrate androgen levels it is termed ' castration - resistant prostate cancer ' ( CRPC ) . Patients may even exhibit rising PSA levels with possible bone , lymph node or solid organ metastases . In 2010 , the only agent approved for the treatment of CRPC was docetaxel , a chemotherapeutic agent . It is now known that cells from patients with CRPC express androgen receptors ( AR ) and remain continuously influenced by androgens . As such , treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have come to the forefront . The use of cytochrome P450c17 ( P05093 ) inhibitor underlies one of the most recent advances in the treatment of CRPC . DB05812 acetate ( AA ) was the first P05093 inhibitor approved in the United States . This review will discuss CRPC in general with a specific focus on AA and novel P05093 inhibitors . AA clinical trials will be reviewed along with other novel adjunct treatments that may enhance the effectiveness of abiraterone therapy . Furthermore , the most recently identified P05093 inhibitors Orteronel , Galeterone , VT - 464 , and CFG920 will also be explored ."],"string":"[\n \"Use of prednisone with abiraterone acetate in metastatic castration - resistant prostate cancer . DB05812 acetate , a prodrug of the P05093 inhibitor abiraterone that blocks androgen biosynthesis , is approved for treatment of patients with metastatic castration - resistant prostate cancer ( mCRPC ) in combination with prednisone or prednisolone 5 mg twice daily . This review evaluates the basis for the effects of prednisone on mineralocorticoid - related adverse events that arise because of P05093 inhibition with abiraterone . Coadministration with the recommended dose of glucocorticoid compensates for abiraterone - induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone . Consequently , 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate , analogous to use of glucocorticoid replacement therapy for certain endocrine disorders . We searched PubMed to identify safety concerns regarding glucocorticoid use , placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer . In general , glucocorticoid - related adverse events , including bone loss , immunosuppression , hyperglycemia , mood and cognitive alterations , and myopathy , appear dose related and tend to occur at doses and / or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC . Although glucocorticoids are often used to manage tumor - related symptoms or to prevent treatment - related toxicity , available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC . Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone , the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens .\",\n \"New agents and strategies for the hormonal treatment of castration - resistant prostate cancer . IMPORTANCE OF THE FIELD : Hormonal therapy with medical or surgical castration is the mainstay of systemic therapy for advanced prostate cancer . Depletion of gonadal testosterone in circulation is typically initially effective , although responses are transient and metastatic disease progresses as castration - resistant prostate cancer ( CRPC ) . AREAS COVERED IN THIS REVIEW : CRPC is accompanied by a gain of function in the androgen receptor ( AR ) , which may occur at the level of AR itself or through intratumoral repletion of androgens that in turn stimulate AR . Investigational drugs in clinical trials have promising activity in CRPC . DB05812 acetate is a P05093 inhibitor that blocks the synthesis of adrenal androgens . MDV3100 is a nonsteroidal AR antagonist with a greater binding affinity than other AR antagonists currently in clinical use . Insights into the mechanisms of intratumoral steroidogenesis in CRPC have defined other potential targets . Metabolism from DB01708 to testosterone and dihydrotestosterone requires 3 - hydroxyl oxidation and Delta ( 5 ) isomerization to Delta ( 4 ) by 3beta - hydroxysteroid dehydrogenase ( 3betaHSD ) and 17 - keto reduction by 17beta - hydroxysteroid dehydrogenase ( 17betaHSD ) - 3 or - 5 . AR activation in CRPC by intratumoral steroids requires these enzymatic steps . Investigation into specific inhibitors of 3betaHSD and 17betaHSD are required to determine their efficacy and potential roles in the treatment of CPRC . WHAT THE READER WILL GAIN : Readers will gain an understanding of the biology of CRPC , new investigational hormonal agents and novel approaches to the treatment of CRPC . TAKE HOME MESSAGE : Intratumoral androgens drive CRPC progression . New investigational hormonal agents that inhibit intratumoral androgens are highly active in the treatment of CRPC . Alternative strategies hold the promise for the development of other agents with novel mechanisms of action .\",\n \"Transforming growth factor - beta1 induces tumor stroma and reduces tumor infiltrate in cervical cancer . Cervical carcinomas consist of tumor cell nests surrounded by varying amounts of intratumoral stroma containing different quantities and types of immune cells . Besides controlling ( epithelial ) cell growth , the multifunctional cytokine transforming growth factor - beta ( 1 ) ( TGF - beta ( 1 ) ) is involved in the formation of stroma and extracellular matrix ( Q13201 ) and in immunosuppression . Several malignancies are known to be associated with enhanced production of TGF - beta ( 1 ) , repression or mutation of TGF - beta transmembrane receptors , or mutations at the postreceptor intracellular signaling pathway . The aim of our study was to investigate the role of tumor cell - derived TGF - beta ( 1 ) on the amount of intratumoral stroma ; the deposition of collagen IV , fibronectin , and laminin ; and the tumor infiltrate in cervical carcinoma . The expression of TGF - beta ( 1 ) mRNA in 108 paraffin - embedded cervical carcinomas was detected by mRNA in situ hybridization . Immunohistochemistry was used to investigate the amount of tumor stroma and Q13201 proteins and the extent of the tumor infiltrate . P00747 activator inhibitor - 1 ( P05121 ) protein expression in tumor cells was determined to verify the biological activity of TGF - beta ( 1 .) Cytoplasmatic TGF - beta ( 1 ) mRNA expression in tumor cells was significantly correlated with the amount of intratumoral stroma and the deposition of collagen IV . TGF - beta ( 1 ) mRNA expression in every tumor was accompanied by P05121 expression , indicating biological activity of TGF - beta ( 1 ) . An inverse relationship between TGF - beta ( 1 ) mRNA expression in tumor cells and the extent of the tumor infiltrate was demonstrated . Our results indicate that cervical cancer cells affect the amount and the composition of the intratumoral stroma and the tumor infiltrate by the production and secretion of TGF - beta ( 1 ) .\",\n \"Antitumour activity of docetaxel following treatment with the P05093 inhibitor abiraterone : clinical evidence for cross - resistance ? BACKGROUND : DB05812 and docetaxel are both approved treatments for men with metastatic castration - resistant prostate cancer ( mCRPC ) . DB05812 pre - docetaxel is currently undergoing evaluation in a phase III study . In vitro studies indicate that taxanes may act by disrupting androgen receptor signalling . We hypothesised that prior abiraterone exposure would adversely impact docetaxel efficacy . PATIENTS AND METHODS : We retrospectively evaluated activity of docetaxel in mCRPC patients previously treated with abiraterone , using Prostate Cancer Working Group and radiological criteria . RESULTS : Of the 54 patients treated with abiraterone , 35 subsequently received docetaxel . DB01248 resulted in a prostate - specific antigen ( PSA ) decline of ≥ 50 % in nine patients [ 26 % , 95 % confidence interval ( CI ) 13 % to 43 % ] , with a median time to PSA progression of 4 . 6 months ( 95 % CI 4 . 2 % to 5 . 9 % ) . PSA declines ≥ 30 % were achieved by 13 patients ( 37 % , 95 % CI 22 % to 55 % ) . The median overall survival was 12 . 5 months ( 95 % CI 10 . 6 - 19 . 4 ) . All patients who failed to achieve a PSA fall on abiraterone and were deemed abiraterone - refractory were also docetaxel - refractory ( N = 8 ) . In the 24 patients with radiologically evaluable disease , partial responses were reported in four patients ( 11 % ) , none of whom were abiraterone - refractory . CONCLUSION : The activity of docetaxel post - abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone - refractory patients .\",\n \"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK10___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .\",\n \"Effect of dietary NaCl on tyrosine hydroxylase in the superior cervical ganglia of Dahl rats . To investigate the involvement of peripheral catecholamines in the development of Dahl - Iwai salt - sensitive ( Q8IX12 / Eis ) hypertension , we performed immunohistochemical staining of tyrosine hydroxylase ( TH ) in the superior cervical ganglia ( SCG ) of Q8IX12 / Eis rats and Dahl - Iwai salt - resistant ( P30518 / Eis ) rats , and in situ hybridization histochemistry for demonstration of TH mRNA localization in the SCG of these rats . Q8IX12 / Eis and P30518 / Eis rats were fed on a high ( 8 % ) salt diet or on a low ( 0 . 3 % ) salt diet for 4 weeks . Nerve cells in the SCG of Q8IX12 / Eis high salt rats exhibited more intense TH - immunoreactivity ( P < 0 . 01 ) and hybridization signals ( P < 0 . 01 ) than those of the other experimental groups . These findings suggest that activation of peripheral sympathetic nerves may account for hypertension in Q8IX12 / Eis rats on a high salt diet .\",\n \"17 ( E )- picolinylidene androstane derivatives as potential inhibitors of prostate cancer cell growth : antiproliferative activity and molecular docking studies . We report a rapid and efficient synthesis of A - ring modified 17α - picolyl and 17 ( E )- picolinylidene androstane derivatives from dehydroepiandrosterone . Compounds were validated spectroscopically and structurally characterized by X - ray crystallography . Virtual screening by molecular docking against clinical targets of steroidal anticancer drugs ( ERα , AR , P11511 and P05093 ) suggests that 17 ( E )- picolinylidene , but not 17α - picolyl androstanes could specifically interact with P05093 ( 17α - hydroxylase ) with similar geometry and affinity as DB05812 , a 17 - pyridinyl androstane drug clinically used in the treatment of prostate cancer . In addition , several 17 ( E )- picolinylidene androstanes demonstrated selective antiproliferative activity against PC3 prostate cancer cells , which correlates with DB05812 antiproliferative activity and predicted P05093 binding affinities . Based on these preliminary results , 17 ( E )- picolinylidene androstane derivatives could be a promising starting point for the development of new compounds for the treatment of prostate cancer .\",\n \"[ DB05812 acetate ( ZYTIGA ®)- development and literature review ] . DB05812 acetate ( AA ) has been approved in more than 80 countries for the treatment of patients with metastatic castration - resistant prostate cancer ( mCRPC ) . In July 2013 , a marketing approval application for AA was submitted to the Japanese Ministry of Health , Labour , and Welfare . AA is a selective inhibitor of P05093 , a crucial enzyme for androgen biosynthesis . AA exerts its anti - tumor activity by directly inhibiting androgen production at all three sources , i . e . , the testes , adrenal glands , and tumor itself . Data from international phase III studies and phase I and II studies in Japan have indicated that AA improves the overall survival and quality of life ( QoL ) of patients with mCRPC . Herein , we have summarized the development of AA and the results of important international and local clinical trials in Japan . In addition , the effect of food on AA bioavailability , concomitant steroid use , and liver function test abnormalities have been discussed regarding the appropriate use of AA .\",\n \"Highly - selective 4 -( 1 , 2 , 3 - triazole )- based P450c17a 17 , 20 - lyase inhibitors . The orally - active P05093 inhibitor abiraterone acetate ( AA ) decreases adrenal and intratumoral androgen biosynthesis and is an effective agent for the treatment of prostate cancer . DB05812 potently inhibits both reactions catalyzed by P05093 , the 17α - hydroxylase ( hydroxylase ) reaction as well as the 17 , 20 - lyase ( lyase ) transformation . P05093 hydroxylase inhibition prevents the synthesis of adrenal glucocorticoids and causes an accumulation of circulating mineralocorticoids . As a consequence of potent P05093 hydroxylase inhibition ( i . e . , lack of lyase selectivity ) , AA must be co - administered with the cortisol replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome ( MES ) . Herein , we describe rationally - designed , P05093 lyase - selective inhibitors that could prove safer and more effective than abiraterone . Using proprietary methodology , the high - affinity pyridine or imidazole metal - binding group found in current clinical P05093 inhibitors was replaced with novel , less avid , metal - binding groups in concert with potency - enhancing molecular scaffold modifications . This process produced a unique series of P05093 lyase - selective inhibitors that included the oral agent 6 ( VT - 464 ) , now in Phase 2 prostate cancer clinical trials . The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases .\",\n \"Mapping of 13 horse genes by fluorescence in - situ hybridization ( Q5TCZ1 ) and somatic cell hybrid analysis . We report fluorescence in - situ hybridization ( Q5TCZ1 ) and somatic cell hybrid mapping data for 13 different horse genes ( P01160 , P06729 , P10909 , P54108 , P05093 , P02679 , P18510 , P22301 , P45452 , PRM1 , P35354 , P01375 and P04637 ) . Primers for PCR amplification of intronic or untranslated regions were designed from horse - specific DNA or mRNA sequences in GenBank . Two different horse bacterial artificial chromosome ( BAC ) libraries were screened with PCR for clones containing these 13 Type I loci , nine of which were found in the libraries . BAC clones were used as probes in dual colour Q5TCZ1 to confirm their precise chromosomal origin . The remaining four genes were mapped in a somatic cell hybrid panel . All chromosomal assignments except one were in agreement with human - horse ZOO - Q5TCZ1 data and revealed new and more detailed information on the equine comparative map . P10909 was mapped by synteny to ECA2 while human - horse ZOO - Q5TCZ1 data predicted that P10909 would be located on ECA9 . The assignment of P18510 permitted analysis of gene order conservation between HSA2 and ECA15 , which identified that an event of inversion had occurred during the evolution of these two homologous chromosomes .\",\n \"[ Mechanisms of resistance to P05093 inhibitors in castrate resistant prostate cancer ] . INTRODUCTION : DB05812 acetate has increased the overall survival of patients with metastatic castration - resistant prostate cancer . However , despite an initial response to treatment , many patients develop resistance to the drug . In this paper we present different hypotheses that may explain the emergence of resistance . METHOD : This review was conducted from the PubMed database . The most relevant articles were selected and analyzed . RESULTS : The molecular mechanisms of resistance to abiraterone acetate remain largely elusive . We detailed some of them including the reactivation of the androgen receptor through alternative biosynthesis of androgens , over expression or mutation of the androgen receptor gene , or the action of co - activators . The over expression of P05093 or the alteration of other genes ' expression involved in steroidogenesis could also contribute to the resistance . CONCLUSION : Some of the molecular mechanisms involved in the resistance to abiraterone acetate were detailed . Better understanding of these mechanisms is a key step to allow the emergence of new therapeutic options and personalized treatments of castration resistant prostate cancer .\",\n \"Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration - resistant prostate cancer . PURPOSE : DB05812 is the active metabolite of the pro - drug abiraterone acetate ( AA ) and a selective inhibitor of P05093 , a key enzyme in testosterone synthesis , and improves overall survival in postdocetaxel metastatic castration - resistant prostate cancer ( mCRPC ) . This open - label , single - arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval . METHODS : The study was conducted in 33 patients with mCRPC . Patients received AA 1 , 000 mg orally once daily + prednisone 5 mg orally twice daily . Electrocardiograms ( ECGs ) were collected in triplicate using 12 - lead Holter monitoring . Baseline ECGs were obtained on Cycle 1 Day - 1 . Serial ECG recordings and time - matched pharmacokinetic ( PK ) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1 . Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8 . RESULTS : After AA administration , the upper bound of the 2 - sided 90 % confidence interval ( CI ) for the mean baseline - adjusted QTcF change was < 10 ms ; no patients discontinued due to QTc prolongation or adverse events . No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [ estimated slope ( 90 % CI ) : 0 . 0031 ( - 0 . 0040 , 0 . 0102 ) ] . CONCLUSIONS : There is no significant effect of AA plus prednisone on the QT / QTc interval in patients with mCRPC .\",\n \"DB05812 acetate : oral androgen biosynthesis inhibitor for treatment of castration - resistant prostate cancer . Prostate cancer is the second leading cause of cancer death in men in the US and Europe . The treatment of advanced - stage prostate cancer has been androgen deprivation . Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes , but adrenal glands and even prostate cancer tissue continue to produce androgens , which eventually leads to continued prostate cancer growth despite castrate level of androgens . This stage is known as castrate - resistant prostate cancer ( CRPC ) , which continues to be a challenge to treat . Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate - specific antigen levels further , but has not actually translated into life - prolonging options . The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer . Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting . One such agent is abiraterone acetate , which significantly reduces androgen production by blocking the enzyme , cytochrome P450 17 alpha - hydroxylase ( P05093 ) . This has provided physicians with another treatment option for patients with CRPC . The landscape for prostate cancer treatment has changed with the approval of cabazitaxel , sipuleucel - T and abiraterone . Here we provide an overview of abiraterone acetate , its mechanism of action , and its potential place for therapy in CRPC .\",\n \"Synthesis , biological evaluation , and molecular modeling of abiraterone analogues : novel P05093 inhibitors for the treatment of prostate cancer . DB05812 , a steroidal cytochrome P450 17alpha - hydroxylase - 17 , 20 - lyase inhibitor ( P05093 ) , is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen - dependent prostate cancer . Since steroidal compounds often show side effects attributable to their structure , we have tried to replace the sterane scaffold by nonsteroidal core structures . The design and synthesis of 20 new abiraterone mimetics are described . Their activities have been tested with recombinant human P05093 expressed in E . coli . Promising compounds were further evaluated for selectivity against P15538 , P19099 , and the hepatic P08684 . Compounds 19 and 20 showed comparable activity to abiraterone ( IC50 values of 144 and 64 nM vs 72 nM ) and similar or even better selectivity against the other CYP enzymes . Selected compounds were also docked into our homology model , and the same binding modes as for abiraterone were found .\",\n \"Q8IX12 promotes chromatin loading of androgen receptor ( AR ) transcription complex by stabilizing the association between AR and P23769 . P10275 ( AR ) , a ligand - dependent transcription factor , plays a critical role in prostate cancer onset and progression , and its transcriptional function is mediated largely by distinct nuclear receptor co - regulators . Here , we show that cell cycle and apoptosis regulator 1 ( Q8IX12 ) functions as an AR co - activator . Q8IX12 interacted with and enhanced the transcriptional activity of AR . Depletion of Q8IX12 caused reduction in androgen - dependent expression of a subset of AR target genes . We further showed that Q8IX12 is required for recruitment of AR , MED1 and RNA polymerase II to the enhancers of AR target genes and for androgen - induced long - range prostate specific antigen enhancer - promoter interaction . The molecular mechanism underlying Q8IX12 function in AR - mediated transcription involves Q8IX12 - mediated enhanced recruitment of P23769 , a pioneer factor for AR , to AR - binding sites . Q8IX12 stabilized the interaction between AR and P23769 by interacting directly with both proteins , thereby facilitating AR and P23769 occupancy on the enhancers . Furthermore , Q8IX12 depletion inhibited the growth , migration , invasion of prostate cancer cells and reduced the tumorigenicity of prostate cancer cells in vivo . Our results firmly established Q8IX12 as an AR co - activator that plays a key role in AR transcription complex assembly and has an important physiological role in androgen signaling and prostate tumorigenesis .\",\n \"Beyond castration and chemotherapy : novel approaches to targeting androgen - driven pathways . In castrate - resistant prostate cancer , beyond chemotherapy , existing guidelines suggest only supportive care . However , recent evidence suggests that continued targeting of androgen - dependent pathways may be an efficacious approach . Clinical data is now available for two mechanistically distinct agents ( abiraterone and MDV3100 ) that both ultimately target these pathways . DB05812 is a potent and irreversible inhibitor of P05093 , a critical enzyme in androgen biosynthesis . Phase II studies indicate substantial declines in PSA amongst castrate - resistant patients treated with abiraterone , both prior to and following cytotoxic chemotherapy . In contrast to abiraterone , MDV3100 is a direct inhibitor of the androgen receptor , binding the receptor irreversibly with substantially higher affinity as compared to bicalutamide . A recent phase I / II trial of MDV3100 in castrate - resistant prostate cancer demonstrated tolerability of the agent with activity at the lowest dose level . On the basis of these compelling data , both abiraterone and MDV3100 will be examined in the phase III setting .\",\n \"Genetic variants associated with myocardial infarction and the risk factors in Chinese population . BACKGROUND : Recent genome - wide association ( GWA ) studies in Caucasians identified multiple single nucleotide polymorphisms ( SNPs ) associated with coronary artery disease ( CAD ) . The associations of those SNPs with myocardial infarction ( MI ) have not been replicated in Asian populations . Among those previously identified SNPs , we selected nine ( rs10953541 , rs1122608 , rs12190287 , rs12413409 , rs1412444 , rs1746048 , rs3798220 , rs4977574 , rs579459 , in or near genes 7q22 , P01130 , O43680 , P05093 , P38571 , P48061 , P08519 , CDKN2A , P16442 , respectively ) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with MI and MI related risk factors in Chinese population . METHODS AND RESULTS : We conducted a case - control association study on a cohort of 2365 MI patients and 2678 unrelated controls from the Chinese population . Genotyping of 9 SNPs were performed by the TaqMan Real Time PCR method . After age , sex , and BMI adjustment , we observed the SNPs rs12190287 , rs12413409 , rs1412444 , rs1746048 and rs4977574 , were significantly associated with MI in additive models and rs12190287 , rs12413409 , rs4977574 were significantly associated with phenotypes of MI at the same time . We also found three SNPs rs1122608 , rs3798220 and rs579459 were significantly associated with risk factors of MI , although they had no association with MI in Chinese population . CONCLUSION : Results of this study indicate that 5 SNPs were associated with MI and 3 SNPs were associated with associated with lipoprotein levels but not with MI in a Chinese population . The present study supports some CAD - related genes in Caucasian as important genes for MI in a Chinese population .\",\n \"Anti - angiogenic and anti - tumor effects of P50750 - 593 , a potent and selective inhibitor of vascular endothelial growth factor and platelet - derived growth factor receptor tyrosine kinase . We recently reported that P50750 - 593 , a novel imidazo [ 1 , 2 - b ] pyridazine derivative , is a highly potent and selective inhibitor of the vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) receptor tyrosine kinase families . Moreover , P50750 - 593 exhibits a uniquely long - acting inhibitory profile towards P15692 receptor 2 ( P35968 ) and PDGF receptor β ( PDGFRβ ) . In this study , we demonstrated that P50750 - 593 potently inhibits P15692 - and PDGF - stimulated cellular phosphorylation and proliferation of human umbilical vein endothelial cells and human coronary artery smooth muscle cells . P50750 - 593 also potently inhibits P15692 - induced tube formation of endothelial cells co - cultured with fibroblasts . Oral administration of P50750 - 593 exhibited strong anti - tumor effects against various human cancer xenografts along with good tolerability despite a low level of plasma exposure . Even after the blood and tissue concentrations of P50750 - 593 decreased below the detectable limit , a pharmacodynamic marker ( phospho P35968 ) was almost completely suppressed , indicating that its long duration of enzyme inhibition might contribute to the potent activity of P50750 - 593 . Immunohistochemical staining indicated that P50750 - 593 showed anti - proliferative and pro - apoptotic effects on tumors along with a decrease of vessel density and inhibition of pericyte recruitment to microvessels in vivo . Furthermore , dynamic contrast - enhanced magnetic resonance imaging revealed that P50750 - 593 reduced tumor vessel permeability prior to the onset of anti - tumor activity . In conclusion , P50750 - 593 is an extremely potent VEGFR / P09619 kinase inhibitor whose potent anti - angiogenic activity suggests therapeutic potential for the treatment of solid tumors .\",\n \"DB05812 acetate , a first - in - class P05093 inhibitor , establishes a new treatment paradigm in castration - resistant prostate cancer .\",\n \"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .\",\n \"[ DB05812 acetate : a novel therapeutic option in hormone - refractory prostate cancer ] . Until recently , only therapy with docetaxel and prednisone has been shown to prolong survival in men with hormonorefractory metastatic prostate cancer . With approvals of sipuleucel - T , cabazitaxel , and abiraterone acetate , all based on improvement in overall survival , the scenary for management of men with metastatic prostate cancer has dramatically changed . DB05812 acetate was developed to specifically inhibit cytochrome P450 ( CYP ) 17A1 , which is an essential enzyme in the biosynthesis of testosterone . In the phase III , the trial treatment with abiraterone acetate plus prednisone prolongs overall survival relative to prednisone alone in patients with metastatic castration - resistant prostate cancer who have disease progression after treatment with docetaxel and associated with an acceptable tolerability profile , which was generally similar to that of the placebo plus prednisone group . However , adverse events resulting from elevated mineralocorticoid levels because of P05093 inhibition , fluid retention and oedema , hypokalaemia , hypertension occurred in significantly more in abiraterone acetate plus prednisone than in placebo plus prednisone .\",\n \"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK78___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \\\" neurological dose \\\" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .\",\n \"Limited in vitro efficacy of P05093 inhibition on human castration resistant prostate cancer . Although accumulating evidence indicates high expression of P05093 ( P45017A1 ) allows castration resistant prostate cancer ( CRPC ) to maintain high intratumoral androgen levels , the potential P45017A1 activity has not been characterized yet . The aim of this study was to examine the potential P05093 activity including 17α - hydroxylase and 17 , 20 - lyase activities in human CRPC and the effect of a CYP17A inhibitor . We used three human CRPC cell lines : C4 - 2 and C4 - 2AT6 which was established from C4 - 2 under androgen ablation conditions for 6months , and PC3 . To ascertain the potential P05093 activity , we cultured with the steroid precursors : ( 13 ) C -[ 2 , 3 , 4 ]- progesterone ( 13C - Prog ) , and analyzed the sequential biosynthesis ( 13 ) C -[ 2 , 3 , 4 ]- 17 - hydroxyprogesterone ( 13C - 17OHP ) and ( 13 ) C -[ 2 , 3 , 4 ]- androstenedione ( 13C - Adione ) by liquid chromatography / mass spectrometry ( LC / MS / MS ). The C4 - 2AT6 cells showed significantly higher P05093 expression than C4 - 2 cells ( p < 0 . 001 ) . LC / MS / MS analysis enabled us to detect the 13C - 17 - OHP and 13C - A - dione in these cell lines . The concentration ratio of 13C - Adione / 13C - 17OHP ( Adione - 17OHP ratio ) , which is thought to reflect the differences between 17 - hydroxylase and 17 , 20 - lyase activities , was then determined . The Adione - 17OHP ratio in C4 - 2AT6 cells was significantly higher than that of C4 - 2 cells ( p < 0 . 001 ) . DB05812 were able to inhibit the CYP17A activities , although abiraterone did not have anti - proliferative effects on C4 - 2 and C4 - 2AT6 cells at clinically achievable concentrations of < 1000nM in vitro . The present study clearly demonstrates CRPC have the dual activities of P05093 mediated by 17 - hydroxylase activity and 17 , 20 - lyase activity . DB05812 does n ' t have an in vitro anti - proliferative efficacy in CRPC cells , suggesting limited efficacy in vitro .\",\n \"Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate . BACKGROUND : DB05812 acetate ( AA ) , a highly potent P05093 inhibitor , has demonstrated marked clinical benefit in patients with metastatic castration - resistant prostate cancer ( CRPC ) . Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations . The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor ( AR ) activity in prostate cancer ( PC ) cells . METHODS : Fluorescence resonance energy transfer ( FRET ) assay was used to assess the effect of mineralocorticoids on androgen - induced conformational change of the AR . LAPC4 , LNCaP and LN - AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations , including levels measured in the serum of AA - treated patients in a phase I trial . AR - dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells . RESULTS : Corticosterone ( CS ) and deoxycorticosterone ( DOC ) inhibited androgen - induced conformational change of the AR in the FRET assay . CS inhibited AR - dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA - treated patients . DOC inhibited AR transcriptional activity and cell growth at 10 - fold greater concentrations than measured in the serum of AA - treated patients . CONCLUSIONS : Mineralocorticoids directly inhibit androgen - induced conformational change of the AR . CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA . Further investigation of the potential therapeutic implications of mineralocorticoids in AA - treated CRPC patients is warranted .\",\n \"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK73___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .\",\n \"The V2 vasopressin receptor stimulates P27361 / 2 activity independently of heterotrimeric G protein signalling . The V2 vasopressin receptor ( P30518 ) activates the mitogen activated protein kinases ( MAPK ) P27361 / 2 through a mechanism involving the scaffolding protein beta arrestin . Here we report that this activating pathway is independent of G alpha s , G alpha i , G alpha q or G betagamma and that the P30518 - mediated activation of G alpha s inhibits P27361 / 2 activity in a DB02527 / PKA - dependent manner . In the HEK293 cells studied , the beta arrestin - promoted activation was found to dominate over the PKA - mediated inhibition of the pathway , leading to a strong vasopressin - stimulated P27361 / 2 activation . Despite the strong MAPK activation and in contrast with other GPCR , P30518 did not induce any significant increase in DNA synthesis , consistent with the notion that the stable interaction between P30518 and beta arrestin prevents signal propagation to the nucleus . Beta arrestin was found to be essential for the P27361 / 2 activation , indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues . Based on the use of selective pharmacological inhibitors , dominant negative mutants and siRNA , we conclude that the beta arrestin - dependent activation of P27361 / 2 by the P30518 involves c - Src and a metalloproteinase - dependent trans - activation event . These findings demonstrate that beta arrestin is a genuine signalling initiator that can , on its own , engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand .\",\n \"Vascular endothelial growth factor gene polymorphism is associated with calcium oxalate stone disease . Growth factor - related genes regulate cell growth , differentiation and apoptosis in the kidney in response to cellular injury . One of the theories of stone formation is that cellular injury , and thus growth factors , play a role . We therefore investigated the association between growth factor genes and calcium oxalate stone disease . The most frequently seen polymorphism of the vascular endothelial growth factor ( P15692 ) gene is Bst U I C / T , which is located upstream at the - 460th nucleotide . Other growth factor - related gene polymorphisms include the cytochrome P450c17alpha enzyme ( P05093 ) gene MspA I C / T polymorphism at the 5 '- UTR promoter region , the epidermal growth factor receptor ( P00533 ) gene Bsr I polymorphism ( A to T ) at position 2 , 073 , and the insulin - like growth factor - 2 ( IGF - 2 ) gene Apa I A / G at exon 9 . All four polymorphisms were used as genetic markers in this study in the search for an association between stone disease and growth factor related genes . A normal control group of 230 healthy people , and 230 patients with calcium oxalate stone , were examined . The polymorphism was seen following polymerase chain reaction based restriction analysis . The result revealed a significant difference between normal individuals and stone patients ( P = 0 . 0003 , Fisher ' s exact test ) in the distribution of the P15692 gene polymorphism as well as an odds ratio of 1 . 30 ( 95 % confidence interval = 0 . 993 - 1 . 715 ) per copy of the \\\" T \\\" allele . Whereas , the IGF - 2 , P00533 and P05093 gene polymorphisms did not reveal a significant association with stone disease . We conclude that the P15692 gene Bst U I polymorphism is a suitable genetic marker of urolithiasis .\",\n \"Prostate cancer - from steroid transformations to clinical translation . The survival benefit conferred by two hormonal agents in phase III trials has clinically validated the long suspected and now widely recognized phenomenon of castration - resistant prostate cancer ( CRPC ) hormone dependence . DB05812 inhibits steroid 17α - hydroxylase / 17 , 20 - lyase ( P05093 ) and blocks androgen synthesis , whereas enzalutamide directly binds and antagonizes the androgen receptor . Both agents are highly effective against CRPC and significantly prolong survival following docetaxel treatment . However , this clinical validation of the androgen pathway has led to questions regarding the fundamental mechanisms of CRPC , as well as resistance to abiraterone and enzalutamide . Our understanding of the predominant steroid transformation pathways that lead to dihydrotestosterone synthesis in CRPC is evolving . The role of steroidogenesis in the development of resistance to abiraterone and enzalutamide remains uncertain . The specific roles of candidate enzyme targets in the development of resistance to these agents must be defined if we are to identify novel targets for improved pharmacologic therapies .\",\n \"___MASK25___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK25___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK25___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .\",\n \"Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( DB02901 ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .\",\n \"A - ring modified steroidal azoles retaining similar potent and slowly reversible P05093 inhibition as abiraterone . DB05812 acetate is a potent inhibitor of human cytochrome P450c17 ( P05093 , 17α - hydroxylase / 17 , 20 - lyase ) and is clinically used in combination with prednisone for the treatment of castration - resistant prostate cancer . Although many studies have documented the potency of abiraterone ( Abi ) in a variety of in vitro and in vivo systems for several species , the exact potency of Abi for human P05093 enzyme has not yet been determined , and the structural requirements for high - potency steroidal azole inhibitors are not established . We synthesized 4 Abi analogs differing in the A - B ring substitution patterns : 3α - hydroxy - Δ ( 4 )- Abi ( 13 ) , 3 - keto - Δ ( 4 )- Abi ( 11 ) , 3 - keto - 5α - Abi ( 6 ) , and 3α - hydroxy - 5α - Abi ( 5 ) . We measured the spectral binding constants ( Ks ) using purified and modified human P05093 along with the determination constants ( Ki ) applying a native human P05093 enzyme in yeast microsomes for these compounds as well as for ketoconazole . For Abi , 3 - keto - Δ ( 4 )- Abi , 3 - keto - 5α - Abi , and 3α - hydroxy - 5α - Abi , the type 2 spectral changes gave the best fit for a quadratic equation , since in these experiments Ks values were 0 . 1 - 2 . 6nM , much lower than that for ketoconazole and 3α - hydroxy - Δ ( 4 )- Abi ( Ks values were 140 and 1660nM , respectively ) . Inhibition experiments showed mixed inhibition patterns with Ki values of 7 - 80nM . Abi dissociation from the P05093 - Abi complex was incomplete and slow ; the t1 / 2 for dissociation was 1 . 8h , with 55 % of complex remaining after 5h . We conclude that Abi and the 3 related steroidal azoles ( 3 - keto - Δ ( 4 )- Abi , 3 - keto - 5α - Abi , and 3α - hydroxy - 5α - Abi ) , which also mimic natural substrates , are extraordinarily potent inhibitors of human P05093 , whereas the 3α - hydroxy - Δ ( 4 )- Abi is moderately potent and comparable to ketoconazole .\",\n \"Clinical appraisal of abiraterone in the treatment of metastatic prostatic cancer : patient considerations , novel opportunities , and future directions . While androgen - deprivation therapy can induce dramatic clinical responses in advanced and metastatic prostate cancer , refractory disease ( castration - resistant prostate cancer [ CRPC ] ) eventually emerges . In recent years , several studies have demonstrated the importance of residual intratumoral androgens in maintaining androgen receptor ( AR ) transcriptional activity in CRPC . The cytochrome P450 enzyme P05093 is an obligatory step in androgen synthesis , and therefore a critical therapeutic target in CRPC . DB05812 acetate is a selective , irreversible inhibitor of P05093 and can suppress adrenal synthesis of androgen precursors , and possibly in situ steroidogenesis in the tumor microenvironment . In a phase III multicenter study , abiraterone in combination with prednisone improved median overall survival of men with docetaxel - refractory CRPC by 3 . 9 months compared to placebo plus prednisone , and also resulted in higher objective prostate - specific antigen and radiographic response rates . The study led to the FDA approval in April 2011 of abiraterone for treatment of chemotherapy - refractory CRPC patients , validating steroidogenesis and the AR axis in general as therapeutic targets in CRPC . The FDA indication for abiraterone was expanded to all CRPCs in December 2012 , while evaluation in even earlier disease states is ongoing . We propose a comprehensive AR axis - targeting approach via simultaneous , frontline enzymatic blockade of several steroidogenic enzymes ( eg , P05093 and P42330 ) in combination with gonadotropin - releasing hormone analogs and potent , second - generation AR antagonists ( eg , enzalutamide ) in order to improve outcomes in patients with prostate cancer .\",\n \"The AP - 1 family member P01100 blocks transcriptional activity of the nuclear receptor steroidogenic factor 1 . Steroid production in the adrenal zona glomerulosa is under the control of angiotensin II ( Ang II ) , which , upon binding to its receptor , activates protein kinase C ( PKC ) within these cells . PKC is a potent inhibitor of the steroidogenic enzyme P05093 . We have demonstrated that , in the ovary , PKC activates expression of P01100 , a member of the AP - 1 family , and increased expression of this gene is linked to P05093 downregulation . However , the pathway and the molecular mechanism responsible for the inhibitory effect of PKC on P05093 expression are not defined . Herein , we demonstrated that Ang II inhibited P05093 through PKC and P27361 / 2 - activated P01100 and that blocking P01100 expression decreased PKC - mediated inhibition . Although P05093 transcription was activated by the nuclear receptor Q13285 , expression of P01100 resulted in a decrease in Q13285 - mediated gene transcription . P01100 physically interacted with the hinge region of Q13285 and modulated its transactivity , thus preventing binding of cofactors such as SRC1 and CBP , which were necessary to fully activate P05093 transcription . Collectively , these results indicate a new regulatory mechanism for Q13285 transcriptional activity that might influence adrenal zone - specific expression of P05093 , a mechanism that can potentially be applied to other steroidogenic tissues .\",\n \"Novel P05093 inhibitors : synthesis , biological evaluation , structure - activity relationships and modelling of methoxy - and hydroxy - substituted methyleneimidazolyl biphenyls . Recently , the steroidal P05093 inhibitor DB05812 entered phase II clinical trial for the treatment of androgen - dependent prostate cancer . As 17alpha - hydroxylase - 17 , 20 - lyase ( P05093 ) catalyzes the last step in androgen biosynthesis , inhibition of this target should affect not only testicular but also adrenal androgen formation . Therefore P05093 inhibitors should be advantageous over existing therapies , for example with DB00644 analogues . However , steroidal drugs are known for side effects which are due to affinities for steroid receptors . Therefore we decided to synthesize non - steroidal compounds mimicking the natural P05093 substrates pregnenolone and progesterone . The synthesis and biological evaluation of a series of 15 novel and highly active non - steroidal P05093 inhibitors are reported . The compounds were prepared via Suzuki - cross - coupling , Grignard reaction and CDI - assisted S ( N ) t - reaction with imidazole and their inhibitory activity was examined with recombinant human P05093 expressed in Escherichia coli . Promising compounds were further tested for their selectivity against the hepatic enzyme P08684 and the glucocorticoid - forming enzyme P15538 . All compounds turned out to be potent P05093 inhibitors . The most active compounds 7 and 8 were much more active than Ketoconazole showing activity comparable to DB05812 ( IC ( 50 ) values of 90 and 52nM vs . 72nM ) . Most compounds also showed higher selectivities than Ketoconazole , but turned out to be less selective than DB05812 . Docking studies using our P05093 protein model were performed with selected compounds to study the interactions between the inhibitors and the amino acid residues of the active site .\",\n \"Status of the down - regulated canine testis using two different P01148 agonist implants in comparison with the juvenile testis . Testicular function in the dog was down - regulated using two different P01148 agonist implants , with adult and juvenile testes serving as controls . Treatment resulted in an increased percentage of the interstitial area and decreased area of Leydig cell nuclei . Expression of P49675 and the steroidogenic enzymes cytochrome P450 side - chain cleavage enzyme ( P450scc , P05108 ) and cytochrome P450 17α - hydroxylase - 17 , 20 - lyase ( P450c17 , P05093 ) in Leydig cells was blocked at the mRNA and protein level , showing no differences between the two agonists . Staining for androgen receptor ( AR ) by immunohistochemistry was positive in Sertoli , Leydig and peritubular cells and some spermatogonia , with in situ hybridization confirming expression in Sertoli cells . At the mRNA level , expression of AR was not affected ; however , translation was blocked ( reduced percentage of AR - positive Sertoli cells ) , with the number of nuclei in basal position being decreased . In the juvenile testes , mRNA expression of P49675 , P05108 and P05093 was higher compared with the other groups but distinctly lower for the AR . At the protein level , the expression was at the limit of detection for P49675 ; AR - positive Sertoli cells were not detected . Our observations show that the down - regulated testis is different from the juvenile one rather resembling the testicular status in seasonal breeders out of season .\",\n \"DB05812 acetate : targeting persistent androgen dependence in castration - resistant prostate cancer . DB05812 acetate is the first second - line hormonal agent proven to improve survival in metastatic castration - resistant prostate cancer . It selectively inhibits cytochrome P450 17 ( P05093 ) α - hydroxylase and cytochrome17 , 20 ( C17 , 20 ) - lyase , which are enzymes critical for androgen synthesis . DB05812 acetate was initially approved in the United States in 2011 after demonstrating a 4 - month survival benefit in docetaxel - refractory metastatic prostate cancer . The FDA recently expanded its indication for use in the pre - chemotherapy setting after it elicited significant delays in disease progression and a strong trend for increased overall survival in phase III studies . Ongoing investigations of abiraterone are evaluating its efficacy in earlier disease states , exploring its synergy in combination with other therapeutic agents , and assessing the necessity for administration of concurrent steroids and gonadal suppression . The identification and development of predictive biomarkers will optimize the incorporation of abiraterone into the management of advanced prostate cancer .\",\n \"DB05812 acetate : redefining hormone treatment for advanced prostate cancer . Prostate cancer has long since been recognised as being hormonally driven via androgen receptor signalling . DB05812 acetate ( AA ) is a rationally designed P05093 inhibitor that blocks the conversion of androgens from non - gonadal precursors effectively , thus reducing testosterone to undetectable levels . AA has recently been proved to extend survival for men with metastatic castration - resistant prostate cancer who have progressive disease after first - line chemotherapy treatment . In addition , it is currently being tested in a Phase III trial in the pre - chemotherapy setting . This paper will review the preclinical discovery and clinical development of AA and will outline the strategy of parallel translational research .\",\n \"___MASK24___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK24___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK24___ is a promising pharmacological tool in the treatment of renal edema .\",\n \"Genetic polymorphisms of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes in adolescent girls with polycystic ovary syndrome . BACKGROUND : Polycystic ovary syndrome ( PCOS ) , whose genetic basis is not completely well understood , is the most common endocrine disorder in women and it typically develops during adolescence . The aim of this study is to investigate the possible association between single nucleotide polymorphisms ( SNPs ) of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes and PCOS in adolescent girls . METHODS : DNA samples from forty - four adolescent girls with PCOS and 50 healthy controls were analyzed by PCR - RFLP and direct DNA sequencing to determine the genotypic frequency of 17 different polymorphic loci on the P23945 ( A307T , N680S ) , P05093 ( - 34 T / C ) , P04798 ( T6235C ) , Q9HC96 ( 44 , 43 , 19 , 63 ) , P06213 ( exon 17 C / T ) , P05121 ( 4G / 5G ) genes . Genotyping of exon 12 ( six polymorphisms ) and intron 12 ( one polymorphism ) of P06213 gene by direct DNA sequencing was performed for the first time in this study . RESULTS : No significant differences were observed in the genotype and allele distributions of above mentioned polymorphisms between cases and control groups . CONCLUSION : Our data does not support an association between SNPs of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes and susceptibility to PCOS or related traits in Turkish adolescent girls .\",\n \"Androgen synthesis inhibitors in the treatment of castration - resistant prostate cancer . Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer . However , in the majority of patients who develop castration - resistant prostate cancer ( CRPC ) , it is possible to detect persistent activation of the androgen receptor ( AR ) through androgens produced in the adrenal gland or within the tumor itself . DB05812 acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme P05093 with activity as a 17α - hydroxylase and 17 , 20 - lyase . P05093 is necessary for production of nongonadal androgens from cholesterol . Regulatory approval of abiraterone in 2011 , based on a phase III trial showing a significant improvement in overall survival ( OS ) with abiraterone and prednisone versus prednisone , represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC . Inhibition of 17α - hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol - mediated suppression of pituitary adrenocorticotropic hormone ( DB01285 ) , providing a rationale for development of P05093 inhibitors with increased specificity for 17 , 20 - lyase ( orteronel , galeterone and VT - 464 ) that can potentially be administered without exogenous corticosteroids . In this article , we review the development of abiraterone and other P05093 inhibitors ; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality - of - life , potential early predictors of response , and optimal sequencing of abiraterone with respect to other agents ; and results of translational studies providing insights into resistance mechanisms to P05093 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity .\",\n \"Cytochrome P450 17 ( P05093 ) is involved in endometrial cancinogenesis through apoptosis and invasion pathways . Cytochrome P450 17 ( P05093 ) encodes cytochrome P450c17α , an enzyme with 17α - hydroxylase and 17 , 20 - lyase activities involved in estradiol biosynthesis . Here we examine the role of P05093 gene in endometrial carcinogenesis . Immunohistochemistry staining of endometrial carcinoma and corresponding uninvolved tissues showed that P05093 is upregulated in endometrial cancers ( 15 of 24 , 62 . 5 % ) . To understand the functional significance of this upregulation , we silenced P05093 gene by introduction of siRNA into endometrial cancer cell line KLE followed by functional studies . Further , to understand the molecular basis of the role of P05093 , we profiled the expression of key pathway - specific genes and identified several components of the apoptosis and invasion pathways that are potentially regulated by P05093 . Silencing of P05093 caused decreased cell proliferation and induced apoptosis . Significantly , P05093 depletion leads to downregulation of anti - apoptotic genes B cell lymphoma 2 ( Bcl - 2 ) and telomerase reverse transcriptase ( O14746 ) , indicating induced apoptosis . Also , attenuation of P05093 decreased the cellular invasion ability and regulated expression of several invasion pathway components such as melanoma cell adhesion molecule ( P43121 ) , matrix metallopeptidase 2 and 9 ( P08253 and P14780 ) , and tissue inhibitor of metalloproteinase 3 ( P35625 ) . In conclusion , this is the first report documenting that upregulation of P05093 in endometrial cancers play a crucial role in endometrial carcinogenesis by targeting multiple components of apoptosis and invasion pathways . Further studies are required to understand the detailed mechanisms underlying P05093 - mediated regulation of these components .\",\n \"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK41___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .\",\n \"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK15___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .\",\n \"DB05812 inhibits 3β - hydroxysteroid dehydrogenase : a rationale for increasing drug exposure in castration - resistant prostate cancer . PURPOSE : Treatment with abiraterone ( abi ) acetate prolongs survival in castration - resistant prostate cancer ( CRPC ) . Resistance to abi invariably occurs , probably due in part to upregulation of steroidogenic enzymes and / or other mechanisms that sustain dihydrotestosterone ( DB02901 ) synthesis , which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes . On the basis of the 3β - hydroxyl , Δ ( 5 )- structure , we hypothesized that abi also inhibits 3β - hydroxysteroid dehydrogenase / isomerase ( 3βHSD ) , which is absolutely required for DB02901 synthesis in CRPC , regardless of origins or routes of synthesis . EXPERIMENTAL DESIGN : We tested the effects of abi on 3βHSD activity , androgen receptor localization , expression of androgen receptor - responsive genes , and CRPC growth in vivo . RESULTS : Abi inhibits recombinant 3βHSD activity in vitro and endogenous 3βHSD activity in LNCaP and LAPC4 cells , including conversion of [ ( 3 ) H ] - dehydroepiandrosterone ( DB01708 ) to Δ ( 4 )- androstenedione , androgen receptor nuclear translocation , expression of androgen receptor - responsive genes , and xenograft growth in orchiectomized mice supplemented with DB01708 . Abi also blocks conversion of Δ ( 5 )- DB01524 to testosterone by 3βHSD . Abi inhibits 3βHSD1 and 3βHSD2 enzymatic activity in vitro ; blocks conversion from DB01708 to androstenedione and DB02901 with an IC ( 50 ) value of less than 1 μmol / L in CRPC cell lines ; inhibits androgen receptor nuclear translocation ; expression of O15393 , prostate - specific antigen , and Q13451 ; and decreases CRPC xenograft growth in DB01708 - supplemented mice . CONCLUSIONS : We conclude that abi inhibits 3βHSD - mediated conversion of DB01708 to active androgens in CRPC . This second mode of action might be exploited to reverse resistance to P05093 inhibition at the standard abi dose by dose - escalation or simply by administration with food to increase drug exposure .\",\n \"Antitumor activity with P05093 blockade indicates that castration - resistant prostate cancer frequently remains hormone driven . DB05812 acetate is a potent , selective , and orally bioavailable small molecule inhibitor of P05093 , an enzyme that catalyzes two key serial reactions ( 17 alpha hydroxylase and 17 , 20 lyase ) in androgen and estrogen biosynthesis . Clinical trials have confirmed that specific inhibition of P05093 is safe and results in clinically important antitumor activity in up to 70 % of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies . These clinical data indicate that castration - resistant prostate cancer frequently remains hormone dependent and has confirmed that this disease should no longer be described as \\\" hormone resistant or refractory \\\" . Biomarker studies , including the analysis of ETS gene fusion status , on patients treated with abiraterone acetate may allow enrichment of patients with a sensitive phenotype in future studies of therapeutics targeting P05093 .\",\n \"___MASK91___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK91___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .\",\n \"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK61___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .\",\n \"P05093 inhibition as a hormonal strategy for prostate cancer . P10275 ( AR ) signaling has a key role in the pathogenesis of prostate cancer . AR gene amplification , AR overexpression , and activating mutations in the AR occur more frequently as castration - resistant prostate cancer ( CRPC ) evolves , with intratumoral androgen levels remaining sufficient for AR activation despite castration . The source of these androgens might be either adrenal or intratumoral . AR signaling , therefore , remains a valid treatment target for patients with CRPC . P05093 is a key enzyme for androgen biosynthesis . The imidazole antifungal agent ketoconazole weakly and nonspecifically inhibits P05093 , but remains unlicensed for this indication . Chemists at the Cancer Research UK Centre for Cancer Therapeutics have designed a novel , selective , irreversible inhibitor of P05093 called abiraterone , which is more than 20 times more potent than ketoconazole . DB05812 acetate , a prodrug , has undergone phase I assessment , and is rapidly progressing from phase II to phase III trials , in view of its high level of antitumor activity . This agent is safe and well tolerated , and activity profiles suggest that approximately 50 % of CRPC remains AR - ligand driven . Other P05093 inhibitors with alternative mechanisms of action , for example VN / 124 - 1 , are in preclinical development . The rationale for and implications of P05093 inhibition and the P05093 - targeting agents in development are discussed in this Review .\",\n \"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .\",\n \"DB05812 in prostate cancer : a new angle to an old problem . DB05812 acetate is an orally administered potent inhibitor of cytochrome P450 , family 17 , subfamily A , polypeptide 1 ( P05093 ) , which is essential for synthesis of testosterone from cholesterol . Although decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer , residual androgens may still be detected in patients treated with luteinizing hormone - releasing hormone agonists or antagonists . Treatment with abiraterone results in rapid , and complete , inhibition of androgen synthesis in the adrenal glands and potentially within the tumor itself . An overall survival benefit of maximal androgen suppression was recently shown in a randomized placebo - controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate - resistant prostate cancer previously treated with docetaxel chemotherapy . DB05812 ' s efficacy shows the importance of androgen signaling in patients with castrate - resistant metastatic disease , with additional confirmation from recent studies of other novel agents such as MDV3100 , an androgen receptor signaling inhibitor . These promising results now pose a new angle to an old problem about hormonal therapy and raise new questions about how resistance develops , how to best sequence therapy , and how to optimize combinations with other emerging novel agents .\",\n \"Medical strategies for treatment of castration resistant prostate cancer ( CRPC ) docetaxel resistant . Current landscape of treatment of castration - resistant prostate cancer ( CRPC ) has recently changed . DB06772 , a new taxane with potential antineoplastic activity , has been approved by Food and Drug Administration ( FDA ) after docetaxel failure . In a phase III trial , cabazitaxel showed increased overall survival ( OS ) compared with mitoxantrone ( 15 . 1 vs . 12 . 7 mo , HR 0 . 70 , 95 % CI 0 . 59 - 0 . 83 , p < 0 . 0001 ) . Furthermore , chemotherapy is not the only strategy available : several studies have shown as CRPC remains dependent on androgen receptor function for growth . DB05812 acetate , an irreversible inhibitor of P05093 , has also been approved by FDA after docetaxel failure . In a phase III trial comparing abiraterone acetate to placebo , abiraterone showed improvement in OS ( 14 . 8 vs . 10 . 4 mo , HR 0 . 65 , 95 % CI 0 . 54 - 0 . 77 ; p < 0 . 0001 ) . This review will discuss current options and the ongoing trials for second - line treatment of CRPC including chemotherapy , hormonal therapies , antiangiogenetic and immune strategies .\",\n \"The 5α - androstanedione pathway to dihydrotestosterone in castration - resistant prostate cancer . The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor ( AR ) , as well as the availability of endogenous AR agonists . Originating from the gonads , testosterone is released into circulation and is converted by steroid - 5α - reductase in prostate cancer to 5α - dihydrotestosterone ( DB02901 ) , potently activating AR and driving tumor progression . Advanced prostate cancer is initially treated with gonadal testosterone depletion , which suppresses this cascade of events and typically leads to a treatment response . Eventually , resistance to testosterone deprivation occurs with \\\" castration - resistant \\\" prostate cancer ( CRPC ) and is driven by the intratumoral synthesis of DB02901 . The generation of DB02901 occurs in large part from adrenal 19 - carbon precursor steroids , which are dependent on expression of P05093 . Although the path from adrenal precursor steroids to DB02901 was generally thought to require 5α - reduction of testosterone , recent data suggest that it instead involves conversion from Δ - androstenedione by steroid - 5α - reductase isoenzyme - 1 to 5α - androstanedione , followed by subsequent conversion to DB02901 . The 5α - androstanedione pathway to DB02901 therefore bypasses testosterone entirely . DB05812 acetate effectively inhibits P05093 , blocks the synthesis of androgens , and extends the survival of men with CRPC . Further progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate .\",\n \"Generation and properties of a new human ventral mesencephalic neural stem cell line . Neural stem cells ( NSCs ) are powerful research tools for the design and discovery of new approaches to cell therapy in neurodegenerative diseases like Parkinson ' s disease . Several epigenetic and genetic strategies have been tested for long - term maintenance and expansion of these cells in vitro . Here we report the generation of a new stable cell line of human neural stem cells derived from ventral mesencephalon ( hVM1 ) based on v - myc immortalization . The cells expressed neural stem cell and radial glia markers like nestin , vimentin and 3CB2 under proliferation conditions . After withdrawal of growth factors , proliferation and expression of v - myc were dramatically reduced and the cells differentiated into astrocytes , oligodendrocytes and neurons . hVM1 cells yield a large number of dopaminergic neurons ( about 12 % of total cells are TH + ) after differentiation , which also produce dopamine . In addition to proneural genes ( Q9H2A3 , MASH1 ) , differentiated cells show expression of several genuine mesencephalic dopaminergic markers such as : Q8TE12 , O60663 , P48051 , P00325 , P43354 , O75364 , Q05940 and Q01959 , indicating that they retain their regional identity . Our data indicate that this cell line and its clonal derivatives may constitute good candidates for the study of development and physiology of human dopaminergic neurons in vitro , and to develop tools for Parkinson ' s disease cell replacement preclinical research and drug testing .\",\n \"Interactions of abiraterone , eplerenone , and prednisolone with wild - type and mutant androgen receptor : a rationale for increasing abiraterone exposure or combining with MDV3100 . Prostate cancer progression can be associated with androgen receptor ( AR ) mutations acquired following treatment with castration and / or an antiandrogen . DB05812 , a rationally designed inhibitor of P05093 recently approved for the treatment of docetaxel - treated castration - resistant prostate cancer ( CRPC ) , is often effective , but requires coadministration with glucocorticoids to curtail side effects . Here , we hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid - induced activation of mutated AR . We found that prednisolone plasma levels in patients with CRPC were sufficiently high to activate mutant AR . P08235 antagonists , such as spironolactone and eplerenone that are used to treat side effects related to mineralocorticoid excess , can also bind to and activate signaling through wild - type or mutant AR . DB05812 inhibited in vitro proliferation and AR - regulated gene expression of AR - positive prostate cancer cells , which could be explained by AR antagonism in addition to inhibition of steroidogenesis . In fact , activation of mutant AR by eplerenone was inhibited by MDV3100 , bicalutamide , or greater concentrations of abiraterone . Therefore , an increase in abiraterone exposure could reverse resistance secondary to activation of AR by residual ligands or coadministered drugs . Together , our findings provide a strong rationale for clinical evaluation of combined P05093 inhibition and AR antagonism .\",\n \"[ Roles of medical oncologists in the new era of CRPC therapy in Japan ] . Currently , the standard therapy for advanced prostate cancer is endocrine therapy ( luteinizing hormone - releasing hormone [ LH - RH ] agonists alone or LH - RHagonists plus antiandrogens ) . However , most patients eventually become resistant to these therapies as well as castration therapy . New endocrine therapies for castration - resistant prostate cancer ( CRPC ) have been developed . DB05812 , a P05093 inhibitor , and enzalutamide , a novel androgen receptor antagonist , have been shown to improve the overall survival , and they are set to be approved in Japan soon . Moreover , docetaxel and cabazitaxel have been established as first - and second - line chemotherapeutic drugs , respectively . Although there is currently no established molecular target drug for CRPC , some drugs such as cabozantinib seem to be effective , and they may be used in the future . In these situations of new drug development , the contribution of medical oncologists is predictable . While medical oncologists can not play central roles in all aspects of drug therapy for urological malignancies in Japan , they must play roles in certain aspects such as new drug development starting from phase I trials , improving multidisciplinary care for adverse events , and promoting translational research .\",\n \"Recent progress in pharmaceutical therapies for castration - resistant prostate cancer . Since 2010 , six drugs have been approved for the treatment of castration - resistant prostate cancer , i . e . , P05093 inhibitor DB05812 , androgen receptor antagonist DB08899 , cytotoxic agent DB06772 , vaccine Sipuleucel - T , antibody DB06643 against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin . All these drugs demonstrate improvement on overall survival , expect for DB06643 , which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone - metastasis - free survival . Besides further P05093 inhibitors ( Orteronel , Galeterone , VT - 464 and CFG920 ) , androgen receptor antagonists ( ARN - 509 , ODM - 201 , AZD - 3514 and EZN - 4176 ) and vaccine Prostvac , more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials , including various kinase inhibitors and platinum complexes . Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments . Under these flourishing circumstances , more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients .\",\n \"DB05812 acetate , a novel adrenal inhibitor in metastatic castration - resistant prostate cancer . The androgen receptor remains the key player in patients with castration - resistant prostate cancer ( CRPC ) . Available agents capable of blocking early adrenal androgen production have limited activity and can lead to significant toxicities . DB05812 acetate , a pregnenolone analog , is a small molecule that irreversibly inhibits P05093 , a rate - limiting enzyme in androgen biosynthesis . Several clinical trials have demonstrated the safety and efficacy of this compound in men with metastatic CRPC . Recently , a randomized phase 3 trial evaluating abiraterone acetate in docetaxel - refractory CRPC patients demonstrated a survival improvement over placebo - treated patients ( 14 . 8 vs 10 . 9 months ; HR 0 . 646 ; P < 0 . 0001 ) . A similar trial in the pre - chemotherapy setting has completed accrual and is undergoing analysis . Here we review the rationale and clinical development of abiraterone acetate in men with CRPC .\",\n \"Retreatment of men with metastatic castrate - resistant prostate cancer with abiraterone . BACKGROUND : DB05812 acetate ( AA ) , oral P05093 inhibitor , is an active agent in the treatment of metastatic castrate - resistant prostate cancer ( mCRPC ) . METHODS : We ( R . L . A and N . A ) retrospectively evaluated outcome in 12 men who were re - treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre . RESULTS : All men were heavily pre - treated for mCRPC with a median of four prior lines of therapy , one of which was AA ( given either pre - or post - chemotherapy ) . Eleven out of 12 ( 92 % ) men stopped their first treatment course of AA due to progression and one stopped for financial reasons . Seven men had a PSA decrease ≥ 50 % following their first AA treatment , of which three ( 46 % ) had a PSA decrease ≥ 50 % to AA re - treatment . The responses to AA re - treatment were generally short - lived with a median biochemical progression - free survival of 2 . 3 months and median treatment duration of 3 . 2 months . No PSA responses to AA re - treatment were seen in five men who did not have an initial PSA response to AA . CONCLUSIONS : Our data suggest that AA re - challenge may have limited benefit in select men with mCRPC , and warrants further formal research .\",\n \"Is abiraterone acetate well tolerated and effective in the treatment of castration - resistant prostate cancer ? This Practice Point commentary discusses the findings of the first phase I trial to evaluate abiraterone acetate ( an inhibitor of the androgen - regulating enzyme P05093 ) in the treatment of castration - resistant prostate cancer . This open - label , dose - escalation study by Attard et al . showed that abiraterone was well tolerated but often induced a syndrome of secondary mineralocorticoid excess that improved with eplerenone ( a mineralocorticoid receptor antagonist ) . DB05812 is a potent suppressor of adrenal androgen synthesis , and produced lasting prostate - specific antigen responses in approximately half of the patients . A few patients had partial regression of distant metastases . Although promising , these results should be interpreted with caution owing to the small sample size and because the study was not primarily designed to examine drug efficacy . Multi - institutional , prospective trials should provide additional information on the tolerability and activity of this compound and further define the population most likely to benefit from this endocrine approach .\",\n \"Hormonal therapy for prostate cancer : toward further unraveling of androgen receptor function . Prostate cancer is a major cause of cancer - related death in men . Prostate cancer is an androgen - responsive tumor and the treatment of advanced prostate cancer involves hormonal therapy . First - line treatment for advanced prostate cancer is androgen deprivation therapy ( ADT ) , usually with agents that suppress gonadotropins through a pituitary mechanism . DB00644 agonists and antagonists both suppress gonadal release of testosterone , although their activity profiles vary . ADT down - regulates androgen receptor ( AR ) transcriptional activity in the tumor but the response in metastatic disease is transient and tumors progress as castration - resistant prostate cancer ( CRPC ) . Although serum testosterone concentrations decline dramatically with ADT , CRPC growth remains largely dependent on AR activity . Secondary hormonal therapies are then often employed to further dampen AR - driven transcription . These secondary hormonal therapies either further deplete adrenal or intratumoral androgen synthesis , or directly and competitively antagonize AR . New hormonal agents with both of these mechanisms are in clinical trials and show promising activity in patients with CRPC . DB05812 acetate is an inhibitor of P05093 , which is an enzyme required for the synthesis of all androgens and estrogens . MDV3100 is an AR antagonist that has a higher affinity for AR than any other AR antagonist in clinic use . In phase I and phase II clinical trials , both agents have significant activity . These agents and the promise of the development of others provide hope that more effective hormonal therapies may soon be offered to patients , which will improve clinical outcomes .\",\n \"P05093 inhibitors in castration - resistant prostate cancer . The majority of prostate cancer ( PCa ) cases are diagnosed as a localized disease . Definitive treatment , active surveillance or watchful waiting are employed as therapeutic paradigms . The current standard of care for the treatment of metastatic PCa is either medical or surgical castration . Once PCa progresses in spite of castrate androgen levels it is termed ' castration - resistant prostate cancer ' ( CRPC ) . Patients may even exhibit rising PSA levels with possible bone , lymph node or solid organ metastases . In 2010 , the only agent approved for the treatment of CRPC was docetaxel , a chemotherapeutic agent . It is now known that cells from patients with CRPC express androgen receptors ( AR ) and remain continuously influenced by androgens . As such , treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have come to the forefront . The use of cytochrome P450c17 ( P05093 ) inhibitor underlies one of the most recent advances in the treatment of CRPC . DB05812 acetate ( AA ) was the first P05093 inhibitor approved in the United States . This review will discuss CRPC in general with a specific focus on AA and novel P05093 inhibitors . AA clinical trials will be reviewed along with other novel adjunct treatments that may enhance the effectiveness of abiraterone therapy . Furthermore , the most recently identified P05093 inhibitors Orteronel , Galeterone , VT - 464 , and CFG920 will also be explored .\"\n]"},"candidates":{"kind":"list like","value":["___MASK10___","___MASK15___","___MASK24___","___MASK25___","___MASK41___","___MASK61___","___MASK73___","___MASK78___","___MASK91___"],"string":"[\n \"___MASK10___\",\n \"___MASK15___\",\n \"___MASK24___\",\n \"___MASK25___\",\n \"___MASK41___\",\n \"___MASK61___\",\n \"___MASK73___\",\n \"___MASK78___\",\n \"___MASK91___\"\n]"},"answer":{"kind":"string","value":"___MASK10___"},"id":{"kind":"string","value":"MH_train_474"}}},{"rowIdx":475,"cells":{"query":{"kind":"string","value":"interacts_with DB00181?"},"supports":{"kind":"list like","value":["Benzyl isothiocyanate ( BITC ) inhibits migration and invasion of human gastric cancer AGS cells via suppressing P29323 signal pathways . Metastasis suppressors and associated other regulators of cell motility play a critical initial role in tumor invasion and metastases . Benzyl isothiocyanate ( BITC ) is a hydrolysis compound of glucotropaeolin in dietary cruciferous vegetables . BITC has been found to exhibit prevention of cancers in laboratory animals and might also be chemoprotective in humans . Here , the purpose of this study was to investigate the effects of BITC on cell proliferation , migration , invasion and mitogen - activated protein kinase ( MAPK ) pathways of AGS human gastric cancer cells . Wound healing and Boyden chamber ( migration and invasion ) assays demonstrated that BITC exhibited an inhibitory effect on the abilities of migration and invasion in AGS cancer cells . BITC suppressed cell migration and invasion of AGS cells in a dose - dependent manner . Results from Western blotting indicated that BITC exerted an inhibitory effect on the P27361 / 2 , Ras , P62993 , Rho A , P35228 , P35354 for causing the inhibitions of P08253 , - 7 and - 9 then followed by the inhibitions of invasion and migration of AGS cells in vitro . BITC also promoted O14733 , Q99759 , c - jun , P45983 / 2 , P15692 , Sos1 , phosphoinositide 3 - kinase ( PI3K ) , PKC , nuclear factor - kappaB ( NF - κB ) p65 in AGS cells . Results from real - time polymerized chain reaction ( PCR ) showed that BITC inhibited the gene expressions of P08253 ,- 7 - 9 , Q05397 , Q13464 and RhoA after BITC treatment for 24 and 48 hours in AGS cells . Taken together , the finding may provide new mechanisms and functions of BITC , which inhibit migration and invasion of human gastric cancer AGS cells .","Association study of 45 candidate genes in nicotine dependence in Han Chinese . Numerous genetic linkages , association studies have been performed in different ethnic groups and revealed many susceptibility loci and genes for nicotine dependence . However , limited similar researches were performed in Han Chinese . This study was designed to investigate the association of candidate genes with nicotine dependence in Han Chinese . We genotyped 384 SNPs within 45 candidate genes with nicotine dependence in a Han Chinese population consisting 223 high nicotine dependent subjects and 257 low nicotine dependent subjects by employing GoldenGate genotyping assay ( Illumina ) . Following association analysis was performed using PLINK software . Individual SNP - based association analysis revealed that nine SNPs located in P35462 ( rs2630351 ) , P21918 ( rs1967550 ) , Q9Y6R4 ( rs2314378 ) , DDC ( rs11575461 ) , Q05901 ( rs4954 ) , O75899 ( rs2779562 ) , P14416 ( rs11214613 and rs6589377 ) and P43681 ( rs2236196 ) were significantly associated with FTND after correction for multiple testing with the p values from 2 . 59 × 10 (- 7 ) to 9 . 99 × 10 (- 5 ) . Haplotype - based association analysis revealed haplotype G - A - A formed by rs2630351 , rs167771 and rs324032 and haplotype G - G - G - A formed by rs3773678 , rs2630349 , rs2630351 and rs167771 in P35462 ; haplotype of G - A formed by rs2779562 and rs2808566 in O75899 and haplotype of T - T - A - G - A formed by rs6832644 , rs4057797 , rs9764 , rs4552421 and rs10033119 in P25929 are associated with FTND ( p = 3 . 61 × 10 (- 7 )- 8 . 78 × 10 (- 6 ) ) . Our results provided confirmation of the previous findings that P14416 , P35462 , DDC , Q05901 , O75899 and P43681 are associated with nicotine dependence . Furthermore , we for the first time report a significant association between nicotine dependence and P21918 , Q9Y6R4 and P25929 . These findings need independent replication in the future studies .","Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK50___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .","Molecular identification of the human O75899 : cell surface expression and coupling to adenylyl cyclase in the absence of Q9UBS5 . We have identified a gene encoding a GABAB receptor , the human O75899 , located on chromosome 9q22 . 1 , that is distinct from the recently reported rat Q9UBS5 . O75899 structurally resembles Q9UBS5 ( 35 % identity ) , having seven transmembrane domains and a large extracellular region , but differs in having a longer carboxy - terminal tail . O75899 is localized to the cell surface in transfected COS cells , and negatively couples to adenylyl cyclase in response to GABA , baclofen , and 3 - aminopropyl ( methyl ) phosphinic acid in CHO cells lacking Q9UBS5 . DB00181 action is inhibited by the GABABR antagonist , 2 - hydroxysaclofen . The human O75899 and Q9UBS5 genes are differentially expressed in the nervous system , with the greatest difference being detected in the striatum in which Q9UBS5 but not O75899 mRNA transcripts are detected . O75899 and Q9UBS5 mRNAs are also coexpressed in various brain regions such as the Purkinje cell layer of the cerebellum . Identification of a functional homomeric O75899 coupled to adenylyl cyclase suggests that the complexity of GABAB pharmacological data is at least in part due to the presence of more than one receptor and opens avenues for future research leading to an understanding of metabotropic GABA receptor signal transduction mechanisms .","Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK79___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK79___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK79___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK79___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK79___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK79___ increased the protein expression of hepatic P05181 and ___MASK79___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK79___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK79___ and RFP - induced hepatotoxicity .","A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor . Transforming growth factor beta ( TGFbeta ) signal transduction is mediated by two receptor DB00133 / DB00156 kinases acting in series , type II TGFbeta receptor ( P37173 ) phosphorylating type I TGFbeta receptor ( P36897 ) . Because the failure of interaction cloning , thus far , to identify bona fide P36897 substrates might reasonably have been due to the use of inactive P36897 as bait , we sought to identify molecules that interact specifically with active P36897 , employing the triple mutation L193A , P194A , T204D in a yeast two - hybrid system . The DB00149 - Pro substitutions prevent interaction with FK506 - binding protein 12 ( P62942 ) , whose putative function in TGFbeta signaling we have previously disproved ; the charge substitution at Thr204 constitutively activates P36897 . Unlike previous screens using wild - type P36897 , where P62942 predominated , none of the resulting colonies encoded P62942 . A novel protein was identified , P36897 - associated protein - 1 ( TRAP - 1 ) , that interacts in yeast specifically with mutationally activated P36897 , but not wild - type P36897 , P37173 , or irrelevant proteins . In mammalian cells , TRAP - 1 was co - precipitated only by mutationally activated P36897 and ligand - activated P36897 , but not wild - type P36897 in the absence of TGFbeta . The partial TRAP - 1 protein that specifically binds these mutationally and ligand - activated forms of P36897 can inhibit signaling by the native receptor after stimulation with TGFbeta or by the constitutively activated receptor mutation , as measured by a TGFbeta - dependent reporter gene . Thus , TRAP - 1 can distinguish activated forms of the receptor from wild - type receptor in the absence of TGFbeta and may potentially have a functional role in TGFbeta signaling .","[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK47___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .","Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK25___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .","[ Differential gene expression in nasopharyngeal carcinoma cell with reduced and normal expression of 6A8 alpha - mannosidase ] . OBJECTIVE : To detect the differential display of mRNA expression between human nasopharyngeal carcinoma cell CNE - 2L2 with reduced malignancy caused by transduction of a DNA antisense to 6A8 alpha - mannosidase cDNA ( AS cell ) and the wild type cell ( W cell ) . METHODS : Differential display of mRNA expression was analyzed using DNA microarray analysis . The datasets were confirmed by Northern blotting and RT - PCR . RESULTS : Out of the 1069 genes analyzed , 34 genes were up - regulated in AS cells relative to W cells . Conversely , 42 genes were down - regulated . The genes , up - regulation of which might have suppressive effect on tumor malignant behaviors , were P130 mRNA for 130K protein , TGF - betaIIR alpha , Q9UBS5 , P36897 , Q13829 , STANIN , E - CADHERIN , P35221 and 2 , P48378 , TMPO , etc . The genes , down - regulation of which might have suppressive effect on tumor malignant behaviors , were P16070 , Q92597 , P01137 , P46782 , LEGUMAIIN , P35520 , P13987 , P09661 , etc . The microarray datasets were confirmed by Northern blot and RT - PCR analysis . CONCLUSIONS : In comparison to the W cell , AS cell has up - regulation of 34 genes and down - regulation of 42 genes . Changes of the gene expression may play a role in the malignancy reduction of AS cell .","Immunocytochemical localization of Q9UBS5 receptor subunits in the basolateral amygdala . Gamma - aminobutyric acid B ( GABAB ) receptors ( GBRs ) are G - protein - coupled receptors that mediate a slow , prolonged form of inhibition in the basolateral amygdala ( P00519 ) and other brain areas . Recent studies indicate that this receptor is a heterodimer consisting of Q9UBS5 ( GBR1 ) and O75899 subunits . In the present investigation , antibodies to the Q9UBS5 subunit were used to study the neuronal localization of GBRs in the rat P00519 . GBR immunoreactivity was mainly found in spine - sparse interneurons and astrocytes at the light microscopic level . Very few pyramidal neurons exhibited perikaryal staining . Dual - labeling immunofluorescence analysis indicated that each of the four main subpopulations of interneurons exhibited GBR immunoreactivity . Virtually 100 % of large CCK + neurons in the basolateral and lateral nuclei were GBR + . In the basolateral nucleus 72 % of somatostatin ( Q8TE85 ) , 73 % of parvalbumin ( PV ) and 25 % of P01282 positive interneurons were GBR + . In the lateral nucleus 50 % of somatostatin , 30 % of parvalbumin and 27 % of P01282 positive interneurons were GBR + . Electron microscopic ( EM ) analysis revealed that most of the light neuropil staining seen at the light microscopic level was due to the staining of dendritic shafts and spines , most of which probably belonged to spiny pyramidal cells . Very few axon terminals ( Ats ) were GBR + . In summary , this investigation demonstrates that the distal dendrites of pyramidal cells , and varying percentages of each of the four main subpopulations of interneurons in the P00519 , express GBRs . Because previous studies suggest that GBR - mediated inhibition modulates DB01221 - dependent EPSPs in the P00519 , these receptors may play an important role in neuronal plasticity related to emotional learning .","Type B gamma - aminobutyric acid receptors modulate the function of the extracellular Ca2 +- sensing receptor and cell differentiation in murine growth plate chondrocytes . Extracellular calcium - sensing receptors ( CaRs ) and metabotropic or type B gamma - aminobutyric acid receptors ( GABA - B - Rs ) , two closely related members of family C of the G protein - coupled receptor superfamily , dimerize in the formation of signaling and membrane - anchored receptor complexes . We tested whether CaRs and two GABA - B - R subunits ( Q96GN5 and R2 ) are expressed in mouse growth plate chondrocytes ( GPCs ) by PCR and immunocytochemistry and whether interactions between these receptors influence the expression and function of the CaR and extracellular Ca ( 2 +)- mediated cell differentiation . Both CaRs and the Q9UBS5 and - R2 were expressed in the same zones of the growth plate and extensively colocalized in intracellular compartments and on the membranes of cultured GPCs . The Q9UBS5 co - immunoprecipitated with the CaR , confirming a physical interaction between the two receptors in GPCs . In vitro knockout of Q9UBS5 genes , using a Cre - lox recombination strategy , blunted the ability of high extracellular Ca ( 2 +) concentration to activate phospholipase C and P27361 / 2 , suppressed cell proliferation , and enhanced apoptosis in cultured GPCs . In GPCs , in which the Q9UBS5 was acutely knocked down , there was reduced expression of early chondrocyte markers , aggrecan and type II collagen , and increased expression of the late differentiation markers , type X collagen and osteopontin . These results support the idea that physical interactions between CaRs and GABA - B - R1s modulate the growth and differentiation of GPCs , potentially by altering the function of CaRs .","Novel therapy for insulin - dependent diabetes mellitus : infusion of in vitro - generated insulin - secreting cells . P01308 - dependent diabetes mellitus ( IDDM ) is a metabolic disease usually resulting from autoimmune - mediated β - cell destruction requiring lifetime exogenous insulin replacement . Mesenchymal stem cells ( O60682 ) hold promising therapy . We present our experience of treating IDDM with co - infusion of in vitro autologous adipose tissue - derived O60682 - differentiated insulin - secreting cells ( ISC ) with hematopoietic stem cells ( P19526 ) . This was an Institutional Review Board approved prospective non - randomized open - labeled clinical trial after informed consent from ten patients . ISC were differentiated from autologous adipose tissue - derived O60682 and were infused with bone marrow - derived P19526 in portal , thymic circulation by mini - laparotomy and in subcutaneous circulation . Patients were monitored for blood sugar levels , serum C - peptide levels , glycosylated hemoglobin ( Hb1Ac ) and glutamic acid decarboxylase ( Q99259 ) antibodies . P01308 administration was made on sliding scale with an objective of maintaining FBS < 150 mg / dL and PPBS around 200 mg / dL . Mean 3 . 34 mL cell inoculums with 5 . 25 × 10 ( 4 ) cells / μL were infused . No untoward effects were observed . Over a mean follow - up of 31 . 71 months , mean serum C - peptide of 0 . 22 ng / mL before infusion had sustained rise of 0 . 92 ng / mL with decreased exogenous insulin requirement from 63 . 9 international units ( IU ) / day to 38 . 6 IU / day . Improvement in mean Hb1Ac was observed from 10 . 99 to 6 . 72 % . Mean Q99259 antibodies were positive in all patients with mean of 331 . 10 IU / mL , which decreased to mean of 123 IU / mL . Co - infusion of autologous ISC with P19526 represents a viable novel therapeutic option for IDDM .","Puerarin alleviates noise - induced hearing loss via affecting PKCγ and GABAB receptor expression . Noise - induced hearing loss ( NIHL ) often results from prolonged exposure to high levels of noise . Our previous study revealed that during the development of NIHL , the expression of protein kinase C γ subunit ( PKCγ ) and GABAB receptor ( GABABR ) was changed within the cochlear nuclear complex ( CNC ) , suggesting that these molecules might be the potential targets for the treatment of NIHL . As an extending study , here we focused on puerarin , a major isoflavonoid extracted from Pueraria lobota , which has been used in the treatment of cardiovascular and cerebrovascular diseases , and investigated whether it could protect against NIHL by acting on PKCγ and GABABR . Transgenic Q99259 - GFP knock - in mice were subjected to the NIHL model and their auditory functions were evaluated by the auditory brainstem response thresholds and distortion product oto - acoustic emission signals . Our results showed that 200mg / kg puerarin treatment ameliorated the thresholds of auditory brainstem response of NIHL mice significantly . Triple immunofluorescence staining and electron microscopy results revealed that GFP - positive neurons in the superficial layers of CNC expressed both PKCγ and Q9UBS5 , and Q99259 - positive terminals contacted PKCγ - or Q9UBS5 - positive neurons . Immunoblotting and RT - PCR results showed that NIHL increased the expression of PKCγ but decreased that of Q9UBS5 and O75899 at both protein and mRNA levels in the CNC . Puerarin significantly attenuated the increased expression of PKCγ but elevated the reduced expression of Q9UBS5 and O75899 after noise exposure . Thus , we provided the first evidence that puerarin ameliorated the auditory functions of NIHL mice , and this effect may be due to its ability to regulate the expression of PKCγ and GABABR .","P42345 inhibitor RAD001 ( ___MASK54___ ) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c - P00519 protein . Constitutive tyrosine kinase ( TK ) activity of Q92817 P11274 - P00519 fusion protein of chronic myeloid leukemia ( CML ) usurps physiological functions of normal p145 c - P00519 protein . Accordingly , its inhibition by imatinib mesylate ( IM ) lets p145 c - P00519 translocate into the nuclear compartment , which drives cell growth arrest and apoptotic death . Here we show that IM and the mammalian target of rapamycin ( P42345 ) inhibitor RAD001 ( ___MASK54___ ) have additive effects on P11274 - P00519 - expressing cells . Those effects are at least partly conditional upon the enhanced nuclear accumulation of p145 c - P00519 through events encompassing post - translational modifications of p145 c - P00519 ( DB00156 ( 735 ) phosphorylation ) precluding its nuclear export and of 14 - 3 - 3 sigma ( DB00133 ( 186 ) phosphorylation by c - Jun N - terminal kinase [ JNK ] ) promoting p145 c - P00519 nuclear re - import .","Complex formation with the Type B gamma - aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium - sensing receptor . Studies with P29320 - 293 cells and neurons . We co - immunoprecipitated the Ca ( 2 +)- sensing receptor ( CaR ) and type B gamma - aminobutyric acid receptor ( GABA - B - R ) from human embryonic kidney ( P29320 ) - 293 cells expressing these receptors and from brain lysates where both receptors are present . CaRs extensively co - localized with the two subunits of the GABA - B - R ( Q96GN5 and R2 ) in P29320 - 293 cell membranes and intracellular organelles . Coexpressing CaRs and GABA - B - R1s in P29320 - 293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [ Ca ( 2 +) ] ( [ Ca ( 2 +)]( e ) ) . In contrast , coexpressing CaRs and GABA - B - R2s enhanced CaR expression and signaling responses to raising [ Ca ( 2 +)]( e ) . The latter effects of the O75899 on the CaR were blunted by coexpressing the Q9UBS5 . Coexpressing the CaR with Q9UBS5 or R2 enhanced the total cellular and cell surface expression of the Q9UBS5 or R2 , respectively . Studies with truncated CaRs indicated that the N - terminal extracellular domain of the CaR participated in the interaction of the CaR with the Q9UBS5 and R2 . In cultured mouse hippocampal neurons , CaRs co - localized with the Q9UBS5 and R2 . CaRs and GABA - B - R1s also co - immunoprecipitated from brain lysates . The expression of the CaR was increased in lysates from Q9UBS5 knock - out mouse brains and in cultured hippocampal neurons with their Q9UBS5 genes deleted in vitro . Thus , CaRs and GABA - B - R subunits can form heteromeric complexes in cells , and their interactions affect cell surface expression and signaling of CaR , which may contribute to extracellular Ca ( 2 +)- dependent receptor activation in target tissues .","P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK98___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )","Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .","O15105 and protein phosphatase 1alpha are critical determinants in the duration of TGF - beta / P37023 signaling in endothelial cells . BACKGROUND : In endothelial cells ( EC ) , transforming growth factor - beta ( TGF - beta ) can bind to and transduce signals through P37023 and P36897 . The TGF - beta / P36897 and TGF - beta / P37023 pathways have opposite effects on EC behaviour . Besides differential receptor binding , the duration of TGF - beta signaling is an important specificity determinant for signaling responses . TGF - beta / P37023 - induced Q15797 / 5 phosphorylation in ECs occurs transiently . RESULTS : The temporal activation of TGF - beta - induced Q15797 / 5 phosphorylation in ECs was found to be affected by de novo protein synthesis , and P37023 and Q99717 expression levels determined signal strength of TGF - beta / P37023 signaling pathway . O15105 and protein phosphatase 1alpha ( PP1alpha ) mRNA expression levels were found to be specifically upregulated by TGF - beta / P37023 . Ectopic expression of O15105 or PP1alpha potently inhibited TGF - beta / P37023 - induced Q15797 / 5 phosphorylation in ECs . Conversely , siRNA - mediated knockdown of O15105 or PP1alpha enhanced TGF - beta / P37023 - induced signaling responses . PP1alpha interacted with P37023 and this association was further potentiated by O15105 . Dephosphorylation of the P37023 , immunoprecipitated from cell lysates , was attenuated by a specific P50391 inhibitor . CONCLUSION : Our results suggest that upon its induction by the TGF - beta / P37023 pathway , O15105 may recruit PP1alpha to P37023 , and thereby control TGF - beta / P37023 - induced Q15797 / 5 phosphorylation .","aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK22___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .","Molecular and biochemical analysis of calmodulin interactions with the calmodulin - binding domain of plant glutamate decarboxylase . We previously provided what to our knowledge is the first evidence that plant glutamate decarboxylase ( Q99259 ) is a calmodulin ( P62158 ) - binding protein . Here , we studied the Q99259 P62158 - binding domain in detail . A synthetic peptide of 26 amino acids corresponding to this domain forms a stable complex with Ca2 +/ P62158 with a 1 : 1 stoichiometry , and amino acid substitutions suggest that tryptophan - 485 has an indispensable role in P62158 binding . Chemical cross - linking revealed specific P62158 / Q99259 interactions even in the absence of Ca2 + . However , increasing KCI concentrations or deletion of two carboxy - terminal lysines abolished these interactions but had a mild effect on P62158 / Q99259 interactions in the presence of Ca2 + . We conclude that in the presence of Ca ( 2 +)- hydrophobic interactions involving tryptophan - 485 and electrostatic interactions involving the carboxy - terminal lysines mediate P62158 / Q99259 complex formation . By contrast , in the absence of Ca2 + , P62158 / Q99259 interactions are essentially electrostatic and involve the carboxy - terminal lysines . In addition , a tryptophan residue and carboxy - terminal lysines are present in the P62158 - binding domain of an Arabidopsis Q99259 . Finally , we demonstrate that petunia Q99259 activity is stimulated in vitro by Ca2 +/ P62158 . Our study provides a molecular basis for Ca ( 2 +)- dependent P62158 / Q99259 interactions and suggests the possible occurrence of Ca ( 2 +)- independent P62158 / Q99259 interactions .","Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK73___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .","Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK97___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .","Interplay between inhibitory ferric and stimulatory curcumin regulates phosphorylation - dependent human cystic fibrosis transmembrane conductance regulator and ΔF508 activity . Curcumin potentiates cystic fibrosis transmembrane conductance regulator ( P13569 ) activation in an DB00171 - independent but phosphorylation - dependent manner . The underlying molecular mechanisms are unclear . Here , P29320 - 293T cells cultured in an Fe ( 3 +)- containing medium were transiently transfected with P13569 constructs , and the role of the inhibitory Fe ( 3 +) bridge between intracellular loop 3 and the regulatory domain of P13569 in this pathway was investigated . The results showed that ethylenediaminetetraacetic acid ( DB00974 ) stimulated phosphorylation - dependent P13569 activation and the stimulation was suppressed by the deletion of the regulatory domain or the insertion of a C832A mutation that removes the Fe ( 3 +)- binding interface . Furthermore , curcumin potentiation of P13569 was significantly weakened not only by Fe ( 3 +)- insensitive mutations at the interface between the regulatory domain and intracellular loop 3 but also by N - ethylmaleimide or DB00974 pretreatment that removes Fe ( 3 +) . More importantly , potentiation of P13569 was completely suppressed by sufficient Fe ( 3 +) . Finally , the insertion of Fe ( 3 +)- insensitive H950R / S768R increased the curcumin - independent activity of ΔF508 but weakened its curcumin potentiation . Thus , Fe ( 3 +) homeostasis in epithelia may play a critical role in regulating P13569 activity , and targeting Fe ( 3 +)- chelating potentiators may direct new therapies for cystic fibrosis ."],"string":"[\n \"Benzyl isothiocyanate ( BITC ) inhibits migration and invasion of human gastric cancer AGS cells via suppressing P29323 signal pathways . Metastasis suppressors and associated other regulators of cell motility play a critical initial role in tumor invasion and metastases . Benzyl isothiocyanate ( BITC ) is a hydrolysis compound of glucotropaeolin in dietary cruciferous vegetables . BITC has been found to exhibit prevention of cancers in laboratory animals and might also be chemoprotective in humans . Here , the purpose of this study was to investigate the effects of BITC on cell proliferation , migration , invasion and mitogen - activated protein kinase ( MAPK ) pathways of AGS human gastric cancer cells . Wound healing and Boyden chamber ( migration and invasion ) assays demonstrated that BITC exhibited an inhibitory effect on the abilities of migration and invasion in AGS cancer cells . BITC suppressed cell migration and invasion of AGS cells in a dose - dependent manner . Results from Western blotting indicated that BITC exerted an inhibitory effect on the P27361 / 2 , Ras , P62993 , Rho A , P35228 , P35354 for causing the inhibitions of P08253 , - 7 and - 9 then followed by the inhibitions of invasion and migration of AGS cells in vitro . BITC also promoted O14733 , Q99759 , c - jun , P45983 / 2 , P15692 , Sos1 , phosphoinositide 3 - kinase ( PI3K ) , PKC , nuclear factor - kappaB ( NF - κB ) p65 in AGS cells . Results from real - time polymerized chain reaction ( PCR ) showed that BITC inhibited the gene expressions of P08253 ,- 7 - 9 , Q05397 , Q13464 and RhoA after BITC treatment for 24 and 48 hours in AGS cells . Taken together , the finding may provide new mechanisms and functions of BITC , which inhibit migration and invasion of human gastric cancer AGS cells .\",\n \"Association study of 45 candidate genes in nicotine dependence in Han Chinese . Numerous genetic linkages , association studies have been performed in different ethnic groups and revealed many susceptibility loci and genes for nicotine dependence . However , limited similar researches were performed in Han Chinese . This study was designed to investigate the association of candidate genes with nicotine dependence in Han Chinese . We genotyped 384 SNPs within 45 candidate genes with nicotine dependence in a Han Chinese population consisting 223 high nicotine dependent subjects and 257 low nicotine dependent subjects by employing GoldenGate genotyping assay ( Illumina ) . Following association analysis was performed using PLINK software . Individual SNP - based association analysis revealed that nine SNPs located in P35462 ( rs2630351 ) , P21918 ( rs1967550 ) , Q9Y6R4 ( rs2314378 ) , DDC ( rs11575461 ) , Q05901 ( rs4954 ) , O75899 ( rs2779562 ) , P14416 ( rs11214613 and rs6589377 ) and P43681 ( rs2236196 ) were significantly associated with FTND after correction for multiple testing with the p values from 2 . 59 × 10 (- 7 ) to 9 . 99 × 10 (- 5 ) . Haplotype - based association analysis revealed haplotype G - A - A formed by rs2630351 , rs167771 and rs324032 and haplotype G - G - G - A formed by rs3773678 , rs2630349 , rs2630351 and rs167771 in P35462 ; haplotype of G - A formed by rs2779562 and rs2808566 in O75899 and haplotype of T - T - A - G - A formed by rs6832644 , rs4057797 , rs9764 , rs4552421 and rs10033119 in P25929 are associated with FTND ( p = 3 . 61 × 10 (- 7 )- 8 . 78 × 10 (- 6 ) ) . Our results provided confirmation of the previous findings that P14416 , P35462 , DDC , Q05901 , O75899 and P43681 are associated with nicotine dependence . Furthermore , we for the first time report a significant association between nicotine dependence and P21918 , Q9Y6R4 and P25929 . These findings need independent replication in the future studies .\",\n \"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK50___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .\",\n \"Molecular identification of the human O75899 : cell surface expression and coupling to adenylyl cyclase in the absence of Q9UBS5 . We have identified a gene encoding a GABAB receptor , the human O75899 , located on chromosome 9q22 . 1 , that is distinct from the recently reported rat Q9UBS5 . O75899 structurally resembles Q9UBS5 ( 35 % identity ) , having seven transmembrane domains and a large extracellular region , but differs in having a longer carboxy - terminal tail . O75899 is localized to the cell surface in transfected COS cells , and negatively couples to adenylyl cyclase in response to GABA , baclofen , and 3 - aminopropyl ( methyl ) phosphinic acid in CHO cells lacking Q9UBS5 . DB00181 action is inhibited by the GABABR antagonist , 2 - hydroxysaclofen . The human O75899 and Q9UBS5 genes are differentially expressed in the nervous system , with the greatest difference being detected in the striatum in which Q9UBS5 but not O75899 mRNA transcripts are detected . O75899 and Q9UBS5 mRNAs are also coexpressed in various brain regions such as the Purkinje cell layer of the cerebellum . Identification of a functional homomeric O75899 coupled to adenylyl cyclase suggests that the complexity of GABAB pharmacological data is at least in part due to the presence of more than one receptor and opens avenues for future research leading to an understanding of metabotropic GABA receptor signal transduction mechanisms .\",\n \"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK79___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK79___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK79___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK79___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK79___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK79___ increased the protein expression of hepatic P05181 and ___MASK79___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK79___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK79___ and RFP - induced hepatotoxicity .\",\n \"A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor . Transforming growth factor beta ( TGFbeta ) signal transduction is mediated by two receptor DB00133 / DB00156 kinases acting in series , type II TGFbeta receptor ( P37173 ) phosphorylating type I TGFbeta receptor ( P36897 ) . Because the failure of interaction cloning , thus far , to identify bona fide P36897 substrates might reasonably have been due to the use of inactive P36897 as bait , we sought to identify molecules that interact specifically with active P36897 , employing the triple mutation L193A , P194A , T204D in a yeast two - hybrid system . The DB00149 - Pro substitutions prevent interaction with FK506 - binding protein 12 ( P62942 ) , whose putative function in TGFbeta signaling we have previously disproved ; the charge substitution at Thr204 constitutively activates P36897 . Unlike previous screens using wild - type P36897 , where P62942 predominated , none of the resulting colonies encoded P62942 . A novel protein was identified , P36897 - associated protein - 1 ( TRAP - 1 ) , that interacts in yeast specifically with mutationally activated P36897 , but not wild - type P36897 , P37173 , or irrelevant proteins . In mammalian cells , TRAP - 1 was co - precipitated only by mutationally activated P36897 and ligand - activated P36897 , but not wild - type P36897 in the absence of TGFbeta . The partial TRAP - 1 protein that specifically binds these mutationally and ligand - activated forms of P36897 can inhibit signaling by the native receptor after stimulation with TGFbeta or by the constitutively activated receptor mutation , as measured by a TGFbeta - dependent reporter gene . Thus , TRAP - 1 can distinguish activated forms of the receptor from wild - type receptor in the absence of TGFbeta and may potentially have a functional role in TGFbeta signaling .\",\n \"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK47___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .\",\n \"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK25___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .\",\n \"[ Differential gene expression in nasopharyngeal carcinoma cell with reduced and normal expression of 6A8 alpha - mannosidase ] . OBJECTIVE : To detect the differential display of mRNA expression between human nasopharyngeal carcinoma cell CNE - 2L2 with reduced malignancy caused by transduction of a DNA antisense to 6A8 alpha - mannosidase cDNA ( AS cell ) and the wild type cell ( W cell ) . METHODS : Differential display of mRNA expression was analyzed using DNA microarray analysis . The datasets were confirmed by Northern blotting and RT - PCR . RESULTS : Out of the 1069 genes analyzed , 34 genes were up - regulated in AS cells relative to W cells . Conversely , 42 genes were down - regulated . The genes , up - regulation of which might have suppressive effect on tumor malignant behaviors , were P130 mRNA for 130K protein , TGF - betaIIR alpha , Q9UBS5 , P36897 , Q13829 , STANIN , E - CADHERIN , P35221 and 2 , P48378 , TMPO , etc . The genes , down - regulation of which might have suppressive effect on tumor malignant behaviors , were P16070 , Q92597 , P01137 , P46782 , LEGUMAIIN , P35520 , P13987 , P09661 , etc . The microarray datasets were confirmed by Northern blot and RT - PCR analysis . CONCLUSIONS : In comparison to the W cell , AS cell has up - regulation of 34 genes and down - regulation of 42 genes . Changes of the gene expression may play a role in the malignancy reduction of AS cell .\",\n \"Immunocytochemical localization of Q9UBS5 receptor subunits in the basolateral amygdala . Gamma - aminobutyric acid B ( GABAB ) receptors ( GBRs ) are G - protein - coupled receptors that mediate a slow , prolonged form of inhibition in the basolateral amygdala ( P00519 ) and other brain areas . Recent studies indicate that this receptor is a heterodimer consisting of Q9UBS5 ( GBR1 ) and O75899 subunits . In the present investigation , antibodies to the Q9UBS5 subunit were used to study the neuronal localization of GBRs in the rat P00519 . GBR immunoreactivity was mainly found in spine - sparse interneurons and astrocytes at the light microscopic level . Very few pyramidal neurons exhibited perikaryal staining . Dual - labeling immunofluorescence analysis indicated that each of the four main subpopulations of interneurons exhibited GBR immunoreactivity . Virtually 100 % of large CCK + neurons in the basolateral and lateral nuclei were GBR + . In the basolateral nucleus 72 % of somatostatin ( Q8TE85 ) , 73 % of parvalbumin ( PV ) and 25 % of P01282 positive interneurons were GBR + . In the lateral nucleus 50 % of somatostatin , 30 % of parvalbumin and 27 % of P01282 positive interneurons were GBR + . Electron microscopic ( EM ) analysis revealed that most of the light neuropil staining seen at the light microscopic level was due to the staining of dendritic shafts and spines , most of which probably belonged to spiny pyramidal cells . Very few axon terminals ( Ats ) were GBR + . In summary , this investigation demonstrates that the distal dendrites of pyramidal cells , and varying percentages of each of the four main subpopulations of interneurons in the P00519 , express GBRs . Because previous studies suggest that GBR - mediated inhibition modulates DB01221 - dependent EPSPs in the P00519 , these receptors may play an important role in neuronal plasticity related to emotional learning .\",\n \"Type B gamma - aminobutyric acid receptors modulate the function of the extracellular Ca2 +- sensing receptor and cell differentiation in murine growth plate chondrocytes . Extracellular calcium - sensing receptors ( CaRs ) and metabotropic or type B gamma - aminobutyric acid receptors ( GABA - B - Rs ) , two closely related members of family C of the G protein - coupled receptor superfamily , dimerize in the formation of signaling and membrane - anchored receptor complexes . We tested whether CaRs and two GABA - B - R subunits ( Q96GN5 and R2 ) are expressed in mouse growth plate chondrocytes ( GPCs ) by PCR and immunocytochemistry and whether interactions between these receptors influence the expression and function of the CaR and extracellular Ca ( 2 +)- mediated cell differentiation . Both CaRs and the Q9UBS5 and - R2 were expressed in the same zones of the growth plate and extensively colocalized in intracellular compartments and on the membranes of cultured GPCs . The Q9UBS5 co - immunoprecipitated with the CaR , confirming a physical interaction between the two receptors in GPCs . In vitro knockout of Q9UBS5 genes , using a Cre - lox recombination strategy , blunted the ability of high extracellular Ca ( 2 +) concentration to activate phospholipase C and P27361 / 2 , suppressed cell proliferation , and enhanced apoptosis in cultured GPCs . In GPCs , in which the Q9UBS5 was acutely knocked down , there was reduced expression of early chondrocyte markers , aggrecan and type II collagen , and increased expression of the late differentiation markers , type X collagen and osteopontin . These results support the idea that physical interactions between CaRs and GABA - B - R1s modulate the growth and differentiation of GPCs , potentially by altering the function of CaRs .\",\n \"Novel therapy for insulin - dependent diabetes mellitus : infusion of in vitro - generated insulin - secreting cells . P01308 - dependent diabetes mellitus ( IDDM ) is a metabolic disease usually resulting from autoimmune - mediated β - cell destruction requiring lifetime exogenous insulin replacement . Mesenchymal stem cells ( O60682 ) hold promising therapy . We present our experience of treating IDDM with co - infusion of in vitro autologous adipose tissue - derived O60682 - differentiated insulin - secreting cells ( ISC ) with hematopoietic stem cells ( P19526 ) . This was an Institutional Review Board approved prospective non - randomized open - labeled clinical trial after informed consent from ten patients . ISC were differentiated from autologous adipose tissue - derived O60682 and were infused with bone marrow - derived P19526 in portal , thymic circulation by mini - laparotomy and in subcutaneous circulation . Patients were monitored for blood sugar levels , serum C - peptide levels , glycosylated hemoglobin ( Hb1Ac ) and glutamic acid decarboxylase ( Q99259 ) antibodies . P01308 administration was made on sliding scale with an objective of maintaining FBS < 150 mg / dL and PPBS around 200 mg / dL . Mean 3 . 34 mL cell inoculums with 5 . 25 × 10 ( 4 ) cells / μL were infused . No untoward effects were observed . Over a mean follow - up of 31 . 71 months , mean serum C - peptide of 0 . 22 ng / mL before infusion had sustained rise of 0 . 92 ng / mL with decreased exogenous insulin requirement from 63 . 9 international units ( IU ) / day to 38 . 6 IU / day . Improvement in mean Hb1Ac was observed from 10 . 99 to 6 . 72 % . Mean Q99259 antibodies were positive in all patients with mean of 331 . 10 IU / mL , which decreased to mean of 123 IU / mL . Co - infusion of autologous ISC with P19526 represents a viable novel therapeutic option for IDDM .\",\n \"Puerarin alleviates noise - induced hearing loss via affecting PKCγ and GABAB receptor expression . Noise - induced hearing loss ( NIHL ) often results from prolonged exposure to high levels of noise . Our previous study revealed that during the development of NIHL , the expression of protein kinase C γ subunit ( PKCγ ) and GABAB receptor ( GABABR ) was changed within the cochlear nuclear complex ( CNC ) , suggesting that these molecules might be the potential targets for the treatment of NIHL . As an extending study , here we focused on puerarin , a major isoflavonoid extracted from Pueraria lobota , which has been used in the treatment of cardiovascular and cerebrovascular diseases , and investigated whether it could protect against NIHL by acting on PKCγ and GABABR . Transgenic Q99259 - GFP knock - in mice were subjected to the NIHL model and their auditory functions were evaluated by the auditory brainstem response thresholds and distortion product oto - acoustic emission signals . Our results showed that 200mg / kg puerarin treatment ameliorated the thresholds of auditory brainstem response of NIHL mice significantly . Triple immunofluorescence staining and electron microscopy results revealed that GFP - positive neurons in the superficial layers of CNC expressed both PKCγ and Q9UBS5 , and Q99259 - positive terminals contacted PKCγ - or Q9UBS5 - positive neurons . Immunoblotting and RT - PCR results showed that NIHL increased the expression of PKCγ but decreased that of Q9UBS5 and O75899 at both protein and mRNA levels in the CNC . Puerarin significantly attenuated the increased expression of PKCγ but elevated the reduced expression of Q9UBS5 and O75899 after noise exposure . Thus , we provided the first evidence that puerarin ameliorated the auditory functions of NIHL mice , and this effect may be due to its ability to regulate the expression of PKCγ and GABABR .\",\n \"P42345 inhibitor RAD001 ( ___MASK54___ ) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c - P00519 protein . Constitutive tyrosine kinase ( TK ) activity of Q92817 P11274 - P00519 fusion protein of chronic myeloid leukemia ( CML ) usurps physiological functions of normal p145 c - P00519 protein . Accordingly , its inhibition by imatinib mesylate ( IM ) lets p145 c - P00519 translocate into the nuclear compartment , which drives cell growth arrest and apoptotic death . Here we show that IM and the mammalian target of rapamycin ( P42345 ) inhibitor RAD001 ( ___MASK54___ ) have additive effects on P11274 - P00519 - expressing cells . Those effects are at least partly conditional upon the enhanced nuclear accumulation of p145 c - P00519 through events encompassing post - translational modifications of p145 c - P00519 ( DB00156 ( 735 ) phosphorylation ) precluding its nuclear export and of 14 - 3 - 3 sigma ( DB00133 ( 186 ) phosphorylation by c - Jun N - terminal kinase [ JNK ] ) promoting p145 c - P00519 nuclear re - import .\",\n \"Complex formation with the Type B gamma - aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium - sensing receptor . Studies with P29320 - 293 cells and neurons . We co - immunoprecipitated the Ca ( 2 +)- sensing receptor ( CaR ) and type B gamma - aminobutyric acid receptor ( GABA - B - R ) from human embryonic kidney ( P29320 ) - 293 cells expressing these receptors and from brain lysates where both receptors are present . CaRs extensively co - localized with the two subunits of the GABA - B - R ( Q96GN5 and R2 ) in P29320 - 293 cell membranes and intracellular organelles . Coexpressing CaRs and GABA - B - R1s in P29320 - 293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [ Ca ( 2 +) ] ( [ Ca ( 2 +)]( e ) ) . In contrast , coexpressing CaRs and GABA - B - R2s enhanced CaR expression and signaling responses to raising [ Ca ( 2 +)]( e ) . The latter effects of the O75899 on the CaR were blunted by coexpressing the Q9UBS5 . Coexpressing the CaR with Q9UBS5 or R2 enhanced the total cellular and cell surface expression of the Q9UBS5 or R2 , respectively . Studies with truncated CaRs indicated that the N - terminal extracellular domain of the CaR participated in the interaction of the CaR with the Q9UBS5 and R2 . In cultured mouse hippocampal neurons , CaRs co - localized with the Q9UBS5 and R2 . CaRs and GABA - B - R1s also co - immunoprecipitated from brain lysates . The expression of the CaR was increased in lysates from Q9UBS5 knock - out mouse brains and in cultured hippocampal neurons with their Q9UBS5 genes deleted in vitro . Thus , CaRs and GABA - B - R subunits can form heteromeric complexes in cells , and their interactions affect cell surface expression and signaling of CaR , which may contribute to extracellular Ca ( 2 +)- dependent receptor activation in target tissues .\",\n \"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK98___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .\",\n \"O15105 and protein phosphatase 1alpha are critical determinants in the duration of TGF - beta / P37023 signaling in endothelial cells . BACKGROUND : In endothelial cells ( EC ) , transforming growth factor - beta ( TGF - beta ) can bind to and transduce signals through P37023 and P36897 . The TGF - beta / P36897 and TGF - beta / P37023 pathways have opposite effects on EC behaviour . Besides differential receptor binding , the duration of TGF - beta signaling is an important specificity determinant for signaling responses . TGF - beta / P37023 - induced Q15797 / 5 phosphorylation in ECs occurs transiently . RESULTS : The temporal activation of TGF - beta - induced Q15797 / 5 phosphorylation in ECs was found to be affected by de novo protein synthesis , and P37023 and Q99717 expression levels determined signal strength of TGF - beta / P37023 signaling pathway . O15105 and protein phosphatase 1alpha ( PP1alpha ) mRNA expression levels were found to be specifically upregulated by TGF - beta / P37023 . Ectopic expression of O15105 or PP1alpha potently inhibited TGF - beta / P37023 - induced Q15797 / 5 phosphorylation in ECs . Conversely , siRNA - mediated knockdown of O15105 or PP1alpha enhanced TGF - beta / P37023 - induced signaling responses . PP1alpha interacted with P37023 and this association was further potentiated by O15105 . Dephosphorylation of the P37023 , immunoprecipitated from cell lysates , was attenuated by a specific P50391 inhibitor . CONCLUSION : Our results suggest that upon its induction by the TGF - beta / P37023 pathway , O15105 may recruit PP1alpha to P37023 , and thereby control TGF - beta / P37023 - induced Q15797 / 5 phosphorylation .\",\n \"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK22___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .\",\n \"Molecular and biochemical analysis of calmodulin interactions with the calmodulin - binding domain of plant glutamate decarboxylase . We previously provided what to our knowledge is the first evidence that plant glutamate decarboxylase ( Q99259 ) is a calmodulin ( P62158 ) - binding protein . Here , we studied the Q99259 P62158 - binding domain in detail . A synthetic peptide of 26 amino acids corresponding to this domain forms a stable complex with Ca2 +/ P62158 with a 1 : 1 stoichiometry , and amino acid substitutions suggest that tryptophan - 485 has an indispensable role in P62158 binding . Chemical cross - linking revealed specific P62158 / Q99259 interactions even in the absence of Ca2 + . However , increasing KCI concentrations or deletion of two carboxy - terminal lysines abolished these interactions but had a mild effect on P62158 / Q99259 interactions in the presence of Ca2 + . We conclude that in the presence of Ca ( 2 +)- hydrophobic interactions involving tryptophan - 485 and electrostatic interactions involving the carboxy - terminal lysines mediate P62158 / Q99259 complex formation . By contrast , in the absence of Ca2 + , P62158 / Q99259 interactions are essentially electrostatic and involve the carboxy - terminal lysines . In addition , a tryptophan residue and carboxy - terminal lysines are present in the P62158 - binding domain of an Arabidopsis Q99259 . Finally , we demonstrate that petunia Q99259 activity is stimulated in vitro by Ca2 +/ P62158 . Our study provides a molecular basis for Ca ( 2 +)- dependent P62158 / Q99259 interactions and suggests the possible occurrence of Ca ( 2 +)- independent P62158 / Q99259 interactions .\",\n \"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK73___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .\",\n \"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \\\" correctors \\\" such as ___MASK97___ ( VX - 809 ) that improve P13569 maturation and trafficking and \\\" potentiators \\\" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .\",\n \"Interplay between inhibitory ferric and stimulatory curcumin regulates phosphorylation - dependent human cystic fibrosis transmembrane conductance regulator and ΔF508 activity . Curcumin potentiates cystic fibrosis transmembrane conductance regulator ( P13569 ) activation in an DB00171 - independent but phosphorylation - dependent manner . The underlying molecular mechanisms are unclear . Here , P29320 - 293T cells cultured in an Fe ( 3 +)- containing medium were transiently transfected with P13569 constructs , and the role of the inhibitory Fe ( 3 +) bridge between intracellular loop 3 and the regulatory domain of P13569 in this pathway was investigated . The results showed that ethylenediaminetetraacetic acid ( DB00974 ) stimulated phosphorylation - dependent P13569 activation and the stimulation was suppressed by the deletion of the regulatory domain or the insertion of a C832A mutation that removes the Fe ( 3 +)- binding interface . Furthermore , curcumin potentiation of P13569 was significantly weakened not only by Fe ( 3 +)- insensitive mutations at the interface between the regulatory domain and intracellular loop 3 but also by N - ethylmaleimide or DB00974 pretreatment that removes Fe ( 3 +) . More importantly , potentiation of P13569 was completely suppressed by sufficient Fe ( 3 +) . Finally , the insertion of Fe ( 3 +)- insensitive H950R / S768R increased the curcumin - independent activity of ΔF508 but weakened its curcumin potentiation . Thus , Fe ( 3 +) homeostasis in epithelia may play a critical role in regulating P13569 activity , and targeting Fe ( 3 +)- chelating potentiators may direct new therapies for cystic fibrosis .\"\n]"},"candidates":{"kind":"list like","value":["___MASK22___","___MASK25___","___MASK47___","___MASK50___","___MASK54___","___MASK73___","___MASK79___","___MASK97___","___MASK98___"],"string":"[\n \"___MASK22___\",\n \"___MASK25___\",\n \"___MASK47___\",\n \"___MASK50___\",\n \"___MASK54___\",\n \"___MASK73___\",\n \"___MASK79___\",\n \"___MASK97___\",\n \"___MASK98___\"\n]"},"answer":{"kind":"string","value":"___MASK98___"},"id":{"kind":"string","value":"MH_train_475"}}},{"rowIdx":476,"cells":{"query":{"kind":"string","value":"interacts_with DB00112?"},"supports":{"kind":"list like","value":["Suppressive effect of bevacizumab on peritoneal dissemination from gastric cancer in a peritoneal metastasis model . PURPOSE : Vascular endothelial growth factor ( P15692 ) has been reported to enhance vascular permeability and angiogenesis in the abdominal wall , thereby contributing to peritoneal dissemination with malignant ascites . We conducted this experimental study to find out if bevacizumab , a humanized monoclonal antibody against P15692 , had a suppressive effect on peritoneal dissemination from gastric cancer , in an experimental nude mouse model of peritoneal metastasis . METHODS : Each mouse was treated with a single intraperitoneal ( i . p . ) injection of bevacizumab . Five mice were killed , and we measured their body weight , the mean number of tumor nodules , and the volume of ascites . We also extracted retroperitoneal tissues for histological examination , to count the frequency of mitosis , and to calculate the mitotic index . Another five mice were monitored until death , and their mean survival duration was calculated . RESULTS : The volume of ascites and the mitotic index were significantly lower in the therapy group than in the nontherapy group ( P = 0 . 042 and P < 0 . 01 , respectively ) . The survival curve of the therapy group was significantly higher than that of the nontherapy group ( P = 0 . 005 ) . CONCLUSION : DB00112 may suppress peritoneal dissemination from gastric cancer .","[ DB00112 combined with cisplan inhibits malignant ascites production in nude mice bearing transplanted ovary carcinoma with high P15692 expression ] . OBJECTIVE : To establish a nude mouse model of malignant ascites with human ovarian carcinoma cell line OVCAR3 which highly expresses P15692 and evaluate the therapeutic of DB00112 combined with cisplan . METHODS : Forty - eight nude mice with malignant ascites resulting from intraperitoneal transplantation of human ovarian carcinoma cell line OVCAR3 were treated with intraperitoneal injection of DB00112 , cisplan , their combination , and PBS , respectively , to observe the effect on ascites development , P15692 content in the ascites , peritoneal permeability , development of new vessels and number of tumor cells in the ascites . RESULTS : DB00112 obviously inhibited ascites accumulation and peritoneal capillary permeability , reduced P15692 protein level and microvascular density in the tumor tissues and the number of red cells and tumor cells in the malignant ascites , and prolonged the survival of the mice . The combination of DB00112 and cisplan further enhanced the therapeutic efficacy of DB00112 . CONCLUSION : The bio - chemotherapeutic strategy with DB00112 combined with cisplan can be a promising method for treatment of malignant ascites .","Dynamic contrast - enhanced and diffusion Q9BWK5 show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF - 1alpha using PX - 478 . PX - 478 is a new agent known to inhibit the hypoxia - responsive transcription factor , HIF - 1alpha , in experimental tumors . The current study was undertaken in preparation for clinical trials to determine which noninvasive imaging endpoint ( s ) is sensitive to this drug ' s actions . Dynamic contrast - enhanced ( DCE ) and diffusion - weighted ( DW ) magnetic resonance imaging ( Q9BWK5 ) were used to monitor acute effects on tumor hemodynamics and cellularity , respectively . Mice bearing human xenografts were treated either with PX - 478 or vehicle , and imaged over time . DW imaging was performed at three b values to generate apparent diffusion coefficient of water ( ADCw ) maps . For DCE - Q9BWK5 , a macromolecular contrast reagent , BSA - DB00789 , was used to determine vascular permeability and vascular volume fractions . PX - 478 induced a dramatic reduction in tumor blood vessel permeability within 2 hours after treatment , which returned to baseline by 48 hours . The anti - P15692 antibody , DB00112 , reduced both the permeability and vascular volume . PX - 478 had no effect on the perfusion behavior of a drug - resistant tumor system , A - 549 . Tumor cellularity , estimated from ADCw , was significantly decreased 24 and 36 hours after treatment . This is the earliest significant response of ADC to therapy yet reported . Based on these preclinical findings , both of these imaging endpoints will be included in the clinical trial of PX - 478 .","DB00112 immune complexes activate platelets and induce thrombosis in P12318 transgenic mice . BACKGROUND : Treatment with DB00112 has been associated with arterial thromboembolism in colorectal cancer patients . However , the mechanism of this remains poorly understood , and preclinical testing in mice failed to predict thrombosis . OBJECTIVE : We investigated whether thrombosis might be the result of platelet activation mediated via the FcgammaRIIa ( IgG ) receptor - which is not present on mouse platelets - and aimed to identify the functional roles of heparin and platelet surface localization in Bev - induced FcgammaRIIa activation . METHODS AND RESULTS : We found that Bev immune complexes ( IC ) activate platelets via FcgammaRIIa , and therefore attempted to reproduce this finding in vivo using FcgammaRIIa ( hFcR ) transgenic mice . Bev IC were shown to be thrombotic in hFcR mice in the presence of heparin . This activity required the heparin - binding domain of Bev ' s target , vascular endothelial growth factor ( P15692 ) . ___MASK75___ promoted Bev IC deposition on to platelets in a mechanism similar to that observed with antibodies from patients with heparin - induced thrombocytopenia . When sub - active amounts of ADP or thrombin were used to prime platelets ( simulating hypercoagulability in patients ) , Bev IC - induced dense granule release was significantly potentiated , and much lower ( sub - therapeutic ) heparin concentrations were sufficient for Bev IC - induced platelet aggregation . CONCLUSIONS : The prevailing rationale for thrombosis in Bev therapy is that P15692 blockade leads to vascular inflammation and clotting . However , we conclude that Bev can induce platelet aggregation , degranulation and thrombosis through complex formation with P15692 and activation of the platelet FcgammaRIIa receptor , and that this provides a better explanation for the thrombotic events observed in vivo .","Intravitreal DB00112 ( DB00112 (®) ) for Diabetic Retinopathy at 24 - months : The 2008 Juan Verdaguer - Planas Lecture . Diabetic retinopathy ( DR ) remains the major threat to sight in the working age population . Diabetic macular edema ( DME ) is a manifestation of DR that produces loss of central vision . Proliferative diabetic retinopathy ( PDR ) is a major cause of visual loss in diabetic patients . In PDR , the growth of new vessels is thought to occur as a result of vascular endothelial growth factor ( P15692 ) release into the vitreous cavity as a response to ischemia . Furthermore , P15692 increases vessel permeability leading to deposition of proteins in the interstitium that facilitate the process of angiogenesis and macular edema . This review demonstrates multiple benefits of intravitreal bevacizumab ( IVB ) on DR including DME and PDR at 24 months of follow up . The results indicate that IVB injections may have a beneficial effect on macular thickness and visual acuity ( VA ) in diffuse diabetic macular edema . Therefore , in the future this new therapy could replace or complement focal / grid laser photocoagulation in DME . In PDR , this new option could be an adjuvant agent to pan - retina photocoagulation so that more selective therapy may be applied . In addition , we report a series of patients in which tractional retinal detachment developed or progressed after adjuvant preoperative IVB in severe PDR .","Potentiation of anti - angiogenic activity of heparin by blocking the P01008 - interacting pentasaccharide unit and increasing net anionic charge . ___MASK75___ , a potent anticoagulant used for the prevention of venous thromboembolism , has been recognized as a tumor angiogenesis inhibitor . Its limitation in clinical application for cancer therapy , however , arises from its strong anticoagulant activity , which causes associated adverse effects . In this study , we show the structural correlation of LHT7 , a previously developed heparin - based angiogenesis inhibitor , with its influence on P15692 blockade and its decreased anticoagulant activity . LHT7 was characterized as having average seven molecules of sodium taurocholates conjugated to one molecule of low - molecular - weight heparin ( LMWH ) . This study showed that the conjugation of sodium taurocholates selectively blocked interaction with antithrombin III ( P01008 ) while enhancing the binding with P15692 . This resulted in LHT7 to have negligible anticoagulant activity but potent anti - angiogenic activity . Following up on this finding , we showed that the bidirectional effect of sodium taurocholate conjugation was due to its unique structure , that is , the sterane core hindering the P01008 - binding pentasaccharide unit of LMWH with its bulky and rigid structural characteristics while the terminal sulfate group interacts with P15692 to produce stronger binding . In addition , we showed that LHT7 was localized in the tumor , especially on the endothelial cells . One explanation for this might be that LHT7 was delivered to the tumor via platelets .","Antivascular endothelial growth factor for retinopathy of prematurity . PURPOSE OF REVIEW : This review will discuss a potentially more effective treatment for retinopathy of prematurity ( P04000 ) with fewer acute and long - term complications . DB00112 ( bevacizumab ) therapy is a promising anti - vascular endothelial growth factor ( anti - P15692 ) administered directly into the vitreous . RECENT FINDINGS : Recent reports detail the use of DB00112 alone , and in combination with light amplification by stimulated emission of radiation ( LASER ) therapy and vitrectomy , for P04000 stages 3 , 4 , and 5 . Currently , one clinical trial is studying DB00112 alone for acute vision - threatening P04000 stage 3 in zone I and posterior zone II without LASER therapy . Another clinical trial is investigating DB00112 following LASER therapy for recurrent P04000 stages 4 and 5 . SUMMARY : Treatment for P04000 has evolved from later , more destructive ( cryotherapy ) to earlier , less destructive ( LASER therapy ) peripheral retinal ablation . If evidence - based data supports early findings , the use of DB00112 may be recommended without the need for ablative LASER therapy and before retinal detachment develops . DB00112 will be especially useful for P04000 stage 3 cases with hemorrhage decreasing retinal visualization , rigid pupils , intravitreal neovascularization with early or developing ( minimal ) fibrous membranes , or aggressive posterior retinopathy of prematurity ( AP - P04000 ) . These cases all continue to have poor outcomes with LASER therapy .","Ablation of cholesterol biosynthesis in neural stem cells increases their P15692 expression and angiogenesis but causes neuron apoptosis . Although sufficient cholesterol supply is known to be crucial for neurons in the developing mammalian brain , the cholesterol requirement of neural stem and progenitor cells in the embryonic central nervous system has not been addressed . Here we have conditionally ablated the activity of squalene synthase ( P37268 ) , a key enzyme for endogenous cholesterol production , in the neural stem and progenitor cells of the ventricular zone ( VZ ) of the embryonic mouse brain . Mutant embryos exhibited a reduced brain size due to the atrophy of the neuronal layers , and died at birth . Analyses of the E11 . 5 - E15 . 5 dorsal telencephalon and diencephalon revealed that this atrophy was due to massive apoptosis of newborn neurons , implying that this progeny of the P37268 - ablated neural stem and progenitor cells was dependent on endogenous cholesterol biosynthesis for survival . Interestingly , the neural stem and progenitor cells of the VZ , the primary target of P37268 inactivation , did not undergo significant apoptosis . Instead , vascular endothelial growth factor ( P15692 ) expression in these cells was strongly upregulated via a hypoxia - inducible factor - 1 - independent pathway , and angiogenesis in the VZ was increased . Consistent with an increased supply of lipoproteins to these cells , the level of lipid droplets containing triacylglycerides with unsaturated fatty acyl chains was found to be elevated . Our study establishes a direct link between intracellular cholesterol levels , P15692 expression , and angiogenesis . Moreover , our data reveal a hitherto unknown compensatory process by which the neural stem and progenitor cells of the developing mammalian brain evade the detrimental consequences of impaired endogenous cholesterol biosynthesis .","Evaluation of cytotoxic effects of bevacizumab on human corneal cells . PURPOSE : Corneal neovascularization contributes to corneal opacification in inflammatory conditions of the cornea and severely compromises the success of corneal transplantation . Vascular endothelial growth factor ( P15692 ) plays an important role in stimulating and maintaining corneal neovascularization . Anti - P15692 therapy , especially the use of anti - P15692 antibody bevacizumab , has gained popularity in the management of retinal neovascularization and is being used topically for corneal neovascularization . The aim of this study was to investigate the safety profile of bevacizumab on human corneal cell lines . METHODS : Human corneal epithelial and fibroblast cell lines and an umbilical vascular endothelial cell line were treated with increasing doses of bevacizumab . The effect of this treatment on cell viability was assessed by WST - 1 and crystal violet staining assays . Cytotoxicity was also assessed by fluorescent microscopy and flow cytometric evaluation of propidium iodide - stained cells . RESULTS : In the cytotoxicity experiments , there was no difference in cell numbers after 24 - hour exposure compared with control in any of the cell lines at the concentrations tested ( P > 0 . 05 to 0 . 98 ) . CONCLUSION : DB00112 was nontoxic to human corneal epithelial and fibroblast cells at 3 different concentrations .","Evolving role of novel targeted agents in renal cell carcinoma . The treatment of metastatic renal cell carcinoma ( RCC ) has changed dramatically over the past few years . An improved understanding of the biology of RCC has resulted in the development of novel targeted therapeutic agents that have altered the natural history of this disease . In particular , the hypoxia - inducible factor ( HIF ) / vascular endothelial growth factor ( P15692 ) pathway and the mammalian target of rapamycin ( P42345 ) signal transduction pathway have been exploited . DB01268 malate ( Sutent ) , sorafenib tosylate ( Nexavar ) , bevacizumab ( DB00112 ) / interferon alfa , and temsirolimus ( DB06287 ) have improved clinical outcomes in randomized trials by inhibiting these tumorigenic pathways . Combinations and sequences of these agents are being evaluated . Other novel multitargeted tyrosine kinase inhibitors ( pazopanib and axitinib ) and P42345 inhibitors ( everolimus ) are in clinical development . Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC .","Expression and role of P15692 in the adult retinal pigment epithelium . PURPOSE : Despite a lack of active angiogenesis , P15692 is expressed in nearly every adult tissue , and recent evidence suggests that P15692 may serve as a survival factor for both vascular and nonvascular tissues . P15692 blockade is a widely used treatment for neovascular diseases such as wet age - related macular degeneration ( AMD ) . Therefore , it was sought in this study to evaluate the expression and role of endogenous P15692 in Q96AT9 . METHODS : P15692 and P35968 expression in the murine retina were assessed during development . DB00112 was used to neutralize P15692 in ARPE - 19 cells , and the effects on cell survival and apical microvill were assessed by TUNEL and SEM , respectively . P15692 was systemically neutralized in vivo by adenoviral - mediated overexpression of soluble P17948 ( sFlt ) . Q96AT9 and choriocapillaris were analyzed by transmission electron microscopy ( TEM ) . Changes in gene expression were evaluated by quantitative real - time PCR . RESULTS : P15692 expression was detected in the developing Q96AT9 as early as embryonic day ( E ) 9 . 5 , whereas P35968 expression by Q96AT9 began nonuniformly between postnatal ( P ) day 6 . 5 and P8 . 5 . P15692 neutralization in vitro led to increased apoptosis and reduced microvilli density and length . Systemic P15692 neutralization led to transient degenerative changes ; Q96AT9 were vacuolated and separated from photoreceptor outer segments , and choriocapillaris fenestrations were decreased . P15692 levels were elevated in Q96AT9 of Ad - sFlt1 mice at day 4 postinfection , and there was increased expression of the neurotrophic factor CD59a at day 14 . CONCLUSIONS : These results indicate that P15692 plays a critical role in survival and maintenance of Q96AT9 integrity . Potential undesired off - target effects should be considered with chronic use of anti - P15692 agents .","Neuroprotective profile of novel P12931 kinase inhibitors in rodent models of cerebral ischemia . Src kinase signaling has been implicated in multiple mechanisms of ischemic injury , including vascular endothelial growth factor ( P15692 ) - mediated vascular permeability that leads to vasogenic edema , a major clinical complication in stroke and brain trauma . Here we report the effects of two novel Src kinase inhibitors , 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 3 -( 4 - methyl - 1 - piperazinyl ) propoxy ]- 3 - quinolinecarbonitrile ( ___MASK54___ ) and 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 4 -( 4 - methypiperazin - 1 - yl ) but - 1 - ynyl ]- 3 - quinolinecarbonitrile ( SKS - 927 ) , on ischemia - induced brain infarction and short - and long - term neurological deficits . Two well established transient [ transient middle cerebral artery occlusion ( tMCAO ) ] and permanent [ permanent middle cerebral artery occlusion ( pMCAO ) ] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario . Brain penetration of Src inhibitors , their effect on blood - brain barrier integrity and P15692 signaling in human endothelial cells were also evaluated . Our results demonstrate that both agents potently block P15692 - mediated signaling in human endothelial cells , penetrate rat brain upon systemic administration , and inhibit postischemic Src activation and vascular leakage . Treatment with ___MASK54___ or SKS - 927 ( at the doses of 3 - 30 mg / kg i . v . ) resulted in a dose - dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4 - to 6 - h after tMCAO . Src blockade after pMCAO resulted in accelerated improvement in recovery from motor , sensory , and reflex deficits during a long - term ( 3 weeks ) testing period poststroke . These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke .","Anti - P15692 Treatment of Corneal Neovascularization . Vascular endothelial growth factor ( P15692 ) is an angiogenic factor shown to be a critical secreted cytokine in tumorigenesis and retinal neovascularization ( NV ) . Currently , there are two anti - P15692 agents , pegaptanib and ranizumab , approved by the United States Food and Drug Administration ( FDA ) for intravitreal use in the treatment of wet age - related macular degeneration ( AMD ) . DB00112 is FDA - approved for intravenous administration in the treatment of several cancers and is in widespread use , off - label , as an intravitreal injection to treat a variety of retinal pathologies . Animal studies demonstrate the role of P15692 in corneal NV . There are now a number of human case series reporting the use of anti - P15692 agents , primarily bevacizumab , to treat corneal NV . This review summarizes reports to date on the use of anti - P15692 agents in the treatment of corneal NV in humans , noting the limitations of current data and the need for further studies . The experience of one clinician with the use of an anti - P15692 drug in the treatment of active corneal NV is presented .","Vascular endothelial growth factor stimulates organ - specific host matrix metalloproteinase - 9 expression and ovarian cancer invasion . Vascular endothelial growth factor ( P15692 ) and matrix metalloproteinases ( MMP ) regulate each other , contributing to tumor progression . We have previously reported that P14780 induces the release of tumor P15692 , promoting ascites formation in human ovarian carcinoma xenografts . The aim of this study was to investigate whether tumor - derived P15692 regulated the expression of gelatinase by the stroma , influencing the invasive properties of ovarian tumors . Tumor variants derived from 1A9 human ovarian carcinoma , stably expressing P15692 ( 121 ) in the sense ( 1A9 - VS - 1 ) and antisense orientations ( 1A9 - VAS - 3 ) , were used . In vivo , zymographic analysis of tumors from 1A9 - VS - 1 implanted in the peritoneal cavity of nude mice showed higher levels of gelatinases , particularly murine P14780 , indicating that P15692 stimulates host expression of the matrix - degrading enzyme . Murine P14780 expression was also high in the ovaries of mice bearing 1A9 - VS - 1 tumors . The effect on host P14780 activity was organ - specific . The levels of host pro - P14780 in ovaries correlated with the plasma levels of tumor P15692 and with the selective invasion of the ovaries . Induction of host P14780 expression in tumors and ovaries was independent of the site of tumor growth as it was seen in mice carrying both intraperitoneal and subcutaneous tumors . The anti - P15692 antibody bevacizumab ( DB00112 ) inhibited P14780 expression and tumor invasion in the ovaries of mice bearing 1A9 - VS - 1 tumors . These findings point to a complex cross - talk between P15692 and MMPs in the progression of ovarian tumor and suggest the possibility of using P15692 inhibitors to affect MMP - dependent tumor invasion .","Levels of vascular endothelial growth factor and pigment epithelium - derived factor in eyes before and after intravitreal injection of bevacizumab . PURPOSE : DB00112 is a human monoclonal IgG1 antibody that blocks the action of vascular endothelial growth factor ( P15692 ) . The purpose of this study was to determine the level of P15692 and pigment epithelium - derived factor ( P36955 ) in eyes with proliferative diabetic retinopathy ( PDR ) before and after an intravitreal injection of bevacizumab . METHODS : Eleven eyes of ten patients were studied . Patients were included if they had neovascular glaucoma , rubeosis of the iris with PDR , or aggressive PDR . Samples of aqueous humor were collected just before the injection of bevacizumab and the vitrectomy . The concentrations of P15692 and P36955 in the aqueous humor were measured by enzyme - linked immunosorbent assay , and the effects of bevacizumab on PDR were evaluated . RESULTS : The free P15692 concentration before the injection was 676 . 5 +/- 186 . 7 pg / ml ( mean +/- SEM , n = 11 ) . Seven days later , it was significantly reduced to 7 . 1 +/- 7 . 1 pg / ml ( P < 0 . 005 , n = 9 ) . The P36955 concentration before the injection was 2 . 32 +/- 0 . 49 microg / ml ( n = 11 ) , and 7 days later , it was 3 . 23 +/- 0 . 76 microg / ml ( P = 0 . 33 ) . During the vitrectomy , patients had less intraoperative bleeding when the neovascular tissues were cut . CONCLUSIONS : An intravitreal injection of bevacizumab significantly decreased the free P15692 in the aqueous humor by 7 days , indicating that the clinical effects of bevacizumab appear rapidly . However , intravitreal bevacizumab did not affect the level of intraocular P36955 .","[ Intravitreal bevacizumab for neovascular age - related macular degeneration ] . The efficacy and safety of the therapeutic anti - P15692 concept has already been demonstrated for pegaptanib and ranibizumab . DB00112 acts as an antibody against all P15692 isoforms and has been developed for oncological indications with intravenous application . Initial reports on intravitreal administration in patients with neovascular age - related macular disease ( AMD ) have shown beneficial morphological and functional effects . In the meantime , bevacizumab has been used off - label in thousands of patients with AMD . However , data from prospective , controlled , randomized trials on both safety and efficacy are lacking . Herein recent experiences with bevacizumab are summarized and discussed . Furthermore , a web - based platform for online data registration and pooled analyses is presented .","Antitumor activity of bevacizumab in combination with capecitabine and oxaliplatin in human colorectal cancer xenograft models . To understand the mechanisms of the effects of combination treatments , we established animal models showing antitumor activity of bevacizumab as a monotherapy and in combination with capecitabine or capecitabine and oxaliplatin and measured thymidine phosphorylase ( TP ) and vascular endothelial growth factor ( P15692 ) levels . Tumor - inoculated nude mice were treated with bevacizumab , capecitabine , and oxaliplatin , alone or in combination , after tumor growth was confirmed and volume and microvessel density ( P53602 ) in tumors were evaluated . Levels of TP and P15692 in the tumor were examined by ELISA . DB00112 showed significant antitumor activity as a monotherapy in three xenograft models ( COL - 16 - Q86SG6 , COLO 205 and CXF280 ) . The P53602 in tumor tissues treated with bevacizumab was lower than that of the control . Antitumor activity of bevacizumab in combination with capecitabine was significantly higher than that of each agent alone ( COL - 16 - Q86SG6 , COLO 205 ) . Furthermore , the antitumor activity of bevacizumab in combination with capecitabine + oxaliplatin was significantly superior to that of capecitabine + oxaliplatin ( COL - 16 - Q86SG6 ) . TP and P15692 levels were not increased by bevacizumab or capecitabine , respectively , suggesting there are other potentially efficacious mechanisms involved . In the present study we established human colorectal cancer xenograft models which reflect the efficacy of clinical combination therapies , capecitabine + bevacizumab and capecitabine + oxaliplatin + bevacizumab . We will further investigate the mechanisms of the combination therapies using these models .","Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .","Advances in Q9BWK5 assessment of gliomas and response to anti - P15692 therapy . DB00112 is thought to normalize tumor vasculature and restore the blood - brain barrier , decreasing enhancement and peritumoral edema . Conventional measurements of tumor response rely upon dimensions of enhancing tumor . After bevacizumab treatment , glioblastomas are more prone to progress as nonenhancing tumor . The RANO ( Response Assessment in Neuro - Oncology ) criteria for glioma response use fluid - attenuated inversion recovery ( FLAIR ) / P24752 hyperintensity as a surrogate for nonenhancing tumor ; however , nonenhancing tumor can be difficult to differentiate from other causes of FLAIR / P24752 hyperintensity ( e . g . , radiation - induced gliosis ) . Due to these difficulties , recent efforts have been directed toward identifying new biomarkers that either predict treatment response or accurately measure response of both enhancing and nonenhancing tumor shortly after treatment initiation . This will allow for earlier treatment decisions , saving patients from the adverse effects of ineffective therapies while allowing them to try alternative therapies sooner . An active area of research is the use of physiologic imaging , which can potentially detect treatment effects before changes in tumor size are evident .","From the discovery of vascular endothelial growth factor to the introduction of avastin in clinical trials - an interview with Napoleone Ferrara by Domenico Ribatti . Napoleone Ferrara and his colleagues at Genentech were the first to isolate and clone vascular endothelial growth factor ( P15692 ) in 1989 . DB00117 laboratory has investigated many aspects of P15692 biochemistry and molecular biology . In 1993 , Ferrara reported that inhibition of P15692 - induced angiogenesis by specific monoclonal antibodies resulted in dramatic suppression of the growth of a variety of tumors in vivo . These findings provided an important evidence that inhibition of angiogenesis may suppress tumor growth and blocking P15692 action could have therapeutic value for a variety of malignancies . A further development was the design in a rational fashion in 1997 of a humanized anti - P15692 monoclonal antibody ( DB00112 ) , now in clinical trials as a treatment for several solid tumors and also outside of cancer , in the treatment of age - related macular degeneration ( AMD ) . Ferrara ' s work is revolutionizing quality of life for many of the estimated 1 . 2 million individuals in the US who have wet AMD . Upwards of a million AMD patients worldwide have already received anti - P15692 antibody therapy .","The potential role of P15692 - induced vascularisation in the bony repair of injured growth plate cartilage . Growth plate injuries often result in undesirable bony repair causing bone growth defects , for which the underlying mechanisms are unclear . Whilst the key importance of pro - angiogenic vascular endothelial growth factor ( P15692 ) is well - known in bone development and fracture repair , its role during growth plate bony repair remains unexplored . Using a rat tibial growth plate injury repair model with anti - P15692 antibody , DB00112 , as a single i . p . injection ( 2 . 5 mg / kg ) after injury , this study examined the roles of P15692 - driven angiogenesis during growth plate bony repair . Histology analyses observed isolectin - B4 - positive endothelial cells and blood vessel - like structures within the injury site on days 6 and 14 , with anti - P15692 treatment significantly decreasing blood - vessel - like structures within the injury site ( P < 0 . 05 ) . Compared with untreated controls , anti - P15692 treatment resulted in an increase in undifferentiated mesenchymal repair tissue , but decreased bony tissue at the injury site at day 14 ( P < 0 . 01 ) . Consistently , microcomputed tomography analysis of the injury site showed significantly decreased bony repair tissue after treatment ( P < 0 . 01 ) . RT - PCR analyses revealed a significant decrease in osteocalcin ( P < 0 . 01 ) and a decreasing trend in Runx2 expression at the injury site following treatment . Furthermore , growth plate injury - induced reduced tibial lengthening was more pronounced in anti - P15692 - treated injured rats on day 60 , consistent with the observation of a significantly increased height of the hypertrophic zone adjacent to the growth plate injury site ( P < 0 . 05 ) . These results indicate that P15692 is important for angiogenesis and formation of bony repair tissue at the growth plate injury site as well as for endochondral bone lengthening function of the uninjured growth plate .","Smith - Magenis syndrome resulting from a de novo direct insertion of proximal 17q into 17p11 . 2 . We report on a de novo intrachromosomal rearrangement of chromosome 17 in a patient with Smith - Magenis syndrome ( P52788 ) . This 11 - year - old boy had short stature , midfacial hypoplasia , and behavioral problems characteristic of this syndrome . Cytogenetic analysis showed that the proximal long arm of a chromosome 17 ( q11 . 2 - q21 . 3 ) was inserted into its short arm at p11 . 2 , resulting in an apparent deletion of the P52788 critical region [ ins ( 17 )( p11 . 2q11 . 2q21 . 3 ) ] . Fluorescence in situ hybridization studies ( Q5TCZ1 ) demonstrated that the inserted segment included both the P04626 and P10276 loci , and dual color hybridizations defined the insertion as direct , with P04626 located more proximally on the short arm of the der ( 17 ) . The resulting deletion of the short arm included loci c130G3 , D17S258 , FLI , and D17S29 , while the more proximal loci , D17S446 and D17S58 , remained apparently unaffected and in their native locations . The CMT1A locus also remained in its native location on the short arm of the metacentric der ( 17 ) chromosome . A de novo intrachromosomal insertional rearrangement of chromosome 17 in a case of P52788 has not been reported previously and further illustrates the instability of this chromosomal region .","Suppression of melanoma - associated neoangiogenesis by bevacizumab . BACKGROUND : DB00112 , a potent antibody against the vascular endothelial growth factor ( P15692 ) , has been shown to be effective for treatment of colorectal cancer . Recently , high effectiveness of bevacizumab in combination with paclitaxel has been reported in a single metastatic melanoma case . To our knowledge , we demonstrate for the first time the antiangiogenetic effect of bevacizumab in a patient with a vitreous melanoma metastasis . OBSERVATIONS : A 68 - year - old man with a vitreous melanoma metastasis of the left eye was treated with a revitrectomy combined with intravitreal bevacizumab application because of iris neovascularization and progressive epiretinal tumor plaques . Four days after the treatment , the melanoma - associated neovascularization completely disappeared , but it recurred after 6 weeks . Although repetitive administration of local bevacizumab produced the same antiangiogenetic effect , progression of the epiretinal tumor plaques could not be stopped with the local bevacizumab treatment . CONCLUSIONS : Intraocular administration of the anti - P15692 drug bevacizumab causes immediate and complete regression of melanoma - associated angiogenesis . The rationale for the therapeutic strategy in our patient was an elevated level of P15692 in the vitreous cavity . Because we could not demonstrate a direct antiproliferative effect of bevacizumab on melanoma metastasis , bevacizumab seems most promising if evaluated in combination with antiproliferative agents .","___MASK51___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .","A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro . Statins and nitrogenous bisphosphonates ( NBP ) inhibit 3 - hydroxy - 3 - methylglutaryl - coenzyme - A reductase ( P04035 ) and farnesyl diphosphate synthase ( P14324 ) , respectively , leading to depletion of farnesyl diphosphate ( FPP ) and disruption of protein prenylation . P37268 ( P37268 ) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis . Herein , we have identified novel bisphosphonates as potent and specific inhibitors of P37268 , including the tetrasodium salt of 9 - biphenyl - 4 , 8 - dimethyl - nona - 3 , 7 - dienyl - 1 , 1 - bisphosphonic acid ( compound 5 ) . Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells . At high concentrations , lovastatin and zoledronate impaired protein prenylation and decreased cell viability , which limits their potential use for cholesterol depletion . When combined with lovastatin , compound 5 prevented lovastatin - induced FPP depletion and impairment of protein farnesylation . Compound 5 in combination with the NBP zoledronate completely prevented zoledronate - induced impairment of both protein farnesylation and geranylgeranylation . Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone . The combination of an P37268 inhibitor with an P04035 or P14324 inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion .","DB00112 and ovarian cancer . PURPOSE OF REVIEW : Vascular endothelial growth factor ( P15692 ) , one of the major pathways involved in tumor angiogenesis , is often overexpressed in epithelial ovarian cancer ( EOC ) , and therefore an attractive target for therapy . This review aims to evaluate the rationale for targeting angiogenic pathways by the usage of the anti - P15692 agent bevacizumab in EOC . RECENT FINDINGS : DB00112 monotherapy has been shown to be effective in the treatment of EOC with response rate of 16 - 21 % in phase II trials . In phase III trials , patients with advanced EOC who received combination chemotherapy ( paclitaxel + carboplatin ) plus bevacizumab with maintenance bevacizumab had significantly longer progression - free survival than those who received chemotherapy alone , but did not prolong overall survival . The most common grade 3 / 4 adverse events of bevacizumab monotherapy include hypertension and proteinuria , while heavily pretreated patients were at increased risk of bowel perforation . The addition of bevacizumab to the standard chemotherapy in patients with advanced EOC may not be cost - effective . SUMMARY : DB00112 has significant activity and is the most promising drug in EOC . However , understanding of its unique adverse events and identification of predictive biomarkers of bevacizumab response are necessary in order to select patients most likely to benefit from this therapy .","Integrin inhibitor suppresses bevacizumab - induced glioma invasion . Glioblastoma is known to secrete high levels of vascular endothelial growth factor ( P15692 ) , and clinical studies with bevacizumab , a monoclonal antibody to P15692 , have demonstrated convincing therapeutic benefits in glioblastoma patients . However , its induction of invasive proliferation has also been reported . We examined the effects of treatment with cilengitide , an integrin inhibitor , on bevacizumab - induced invasive changes in glioma . U87Δ P00533 cells were stereotactically injected into the brain of nude mice or rats . Five days after tumor implantation , cilengitide and bevacizumab were administered intraperitoneally three times a week . At 18 days after tumor implantation , the brains were removed and observed histopathologically . Next , the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis . DB00112 treatment led to increased cell invasion in spite of decreased angiogenesis . When the rats were treated with a combination of bevacizumab and cilengitide , the depth of tumor invasion was significantly less than with only bevacizumab . Pathway analysis demonstrated the inhibition of invasion - associated genes such as the integrin - mediated cell adhesion pathway in the combination group . This study showed that the combination of bevacizumab with cilengitide exerted its anti - invasive effect . The elucidation of this mechanism might contribute to the treatment of bevacizumab - refractory glioma .","In vivo optical molecular imaging of vascular endothelial growth factor for monitoring cancer treatment . PURPOSE : Vascular endothelial growth factor ( P15692 ) expression is a critical component in tumor growth and metastasis . Capabilities to monitor P15692 expression in vivo can potentially serve as a useful tool for diagnosis , prognosis , treatment planning , monitoring , and research . Here , we present the first report of in vivo hyperspectral molecular imaging strategy capable of monitoring treatment - induced changes in P15692 expression . EXPERIMENTAL DESIGN : P15692 was targeted with an anti - P15692 antibody conjugated with a fluorescent dye and was imaged in vivo using a hyperspectral imaging system . The strategy was validated by quantitatively monitoring P15692 levels in three different tumors as well as following photodynamic treatment . Specificity of the molecular imaging strategy was tested using in vivo competition experiments and mathematically using a quantitative pharmacokinetic model . RESULTS : The molecular imaging strategy successfully imaged P15692 levels quantitatively in three different tumors and showed concordance with results from standard ELISA . Changes in tumoral P15692 concentration following photodynamic treatment and DB00112 treatment were shown . Immunohistochemistry shows that ( a ) the P15692 - specific contrast agent labels both proteoglycan - bound and unbound P15692 in the extracellular space and ( b ) the bound P15692 is released from the extracellular matrix in response to photodynamic therapy . In vivo competition experiments and quantitative pharmacokinetic model - based analysis confirmed the high specificity of the imaging strategy . CONCLUSION : This first report of in vivo quantitative optical molecular imaging - based monitoring of a secreted cytokine in tumors may have implications in providing tools for mechanistic investigations as well as for improved treatment design and merits further investigation .","Cutaneous thrombogenic vasculopathy associated with bevacizumab therapy . DB00112 , a humanized monoclonal antibody against vascular endothelial growth factor ( P15692 ) , is an angiogenesis inhibitor used to treat a variety of cancers , including lung , colon , cervical , ovarian , and renal cancers as well as glioblastoma . A significant adverse effect associated with its use is one of thromboembolic events . We report a case of a 74 - year - old male with diagnosis of glioblastoma multiforme treated with partial resection , radiation , temozolomide , and bevacizumab . He presented to a plastic surgeon with a several week history of asymptomatic crusted hemorrhagic ulcers and purpuric patches on the lower legs shortly following the initiation of bevacizumab . A biopsy showed an occlusive pauci - inflammatory thrombogenic vasculopathy associated with ischemic epidermal and dermal changes and accompanied by extensive vascular C5b - 9 ( complement C5b - 9 membrane attack complex ) deposition . DB00112 has been associated with thrombotic complications including atypical hemolytic uremic syndrome and arterial and venous thrombosis . C5b - 9 may be the factor most important in the mechanism of vascular thrombosis given the extent of deposition in our index case . Thrombotic events in the skin associated with bevacizumab therapy are without precedent and dermatologists should be aware of this potential complication .","Phase I trial of combretastatin A4 phosphate ( DB05284 ) in combination with bevacizumab in patients with advanced cancer . PURPOSE : The vascular disrupting agent ( VDA ) combretastatin A4 phosphate ( DB05284 ) induces significant tumor necrosis as a single agent . Preclinical models have shown that the addition of an anti - P15692 antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity . EXPERIMENTAL DESIGN : Patients with advanced solid malignancies received DB05284 at 45 , 54 , or 63 mg / m ( 2 ) on day 1 , day 8 , and then every 14 days . DB00112 10 mg / kg was given on day 8 and at subsequent cycles four hours after DB05284 . Functional imaging with dynamic contrast enhanced - Q9BWK5 ( DCE - Q9BWK5 ) was conducted at baseline , after DB05284 alone , and after cycle 1 DB05284 + bevacizumab . RESULTS : A total of 63 mg / m ( 2 ) DB05284 + 10 mg / kg bevacizumab q14 is the recommended phase II dose . A total of 15 patients were enrolled . Dose - limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage . Most common toxicities were hypertension , headache , lymphopenia , pruritus , and pyrexia . Asymptomatic electrocardiographic changes were seen in five patients . Nine of 14 patients experienced disease stabilization . A patient with ovarian cancer had a Q8WXI7 response lasting for more than a year . DCE - Q9BWK5 showed statistically significant reductions in tumor perfusion / vascular permeability , which reversed after DB05284 alone but which were sustained following bevacizumab . Circulating P28906 (+) and CD133 (+) bone marrow progenitors increased following DB05284 as did P15692 and granulocyte colony - stimulating factor levels . CONCLUSIONS : DB05284 in combination with bevacizumab appears safe and well tolerated in this dosing schedule . DB05284 induced profound vascular changes , which were maintained by the presence of bevacizumab .","Expression of Q99572 receptor increases in vivo tumor growth . The Q99572 receptor is an DB00171 - gated ion channel known for its cytotoxic activity . However , recent evidence suggests a role for Q99572 in cell proliferation . Here , we found that Q99572 exhibits significant growth - promoting effects in vivo . Human embryonic kidney cells expressing Q99572 exhibited a more tumorigenic and anaplastic phenotype than control cells in vivo , and the growth rate and size of these tumors were significantly reduced by intratumoral injection of the Q99572 inhibitor - oxidized DB00171 . The accelerated growth of Q99572 - expressing tumors was characterized by increased proliferation , reduced apoptosis , and a high level of activated transcription factor O95644 . These tumors also showed a more developed vascular network than control tumors and secreted elevated amounts of P15692 . The growth and neoangiogenesis of Q99572 - expressing tumors was blocked by intratumoral injection of the P15692 - blocking antibody DB00112 ( bevacizumab ) , pharmacologic Q99572 blockade , or Q99572 silencing in vivo . Immunohistochemistry revealed strong Q99572 positivity in several human cancers . Together , our findings provide direct evidence that Q99572 promotes tumor growth in vivo .","Anti - P15692 therapy in pituitary carcinoma . We report the case of a 44 - year - old male patient with an aggressive silent corticotroph cell pituitary adenoma , subtype 2 . In that it progressed to carcinoma despite temozolomide administration , anti - P15692 therapy was begun . Q9BWK5 , PET scan and pathologic analysis were undertaken . After 10 months of anti - P15692 ( bevacizumab ) treatment no progression of the lesion was noted . The tumor was biopsied and morphological analysis showed severe cell injury , vascular abnormalities and fibrosis . DB00112 treatment has continued for additional 16 months to present with stabilization of disease as documented on serial Q9BWK5 and PET scans . This is the first case of a bevacizumab - treated pituitary carcinoma with long - term , now 26 months , control of disease . The present findings are promising in that anti - angiogenic therapy appears to represent a new option in the treatment of aggressive pituitary tumors .","Future directions in vascular endothelial growth factor - targeted therapy for metastatic colorectal cancer . DB00112 , the first approved vascular endothelial growth factor ( P15692 ) - targeted agent for metastatic colorectal cancer , continues to be developed in phase III trials in other tumor types . Its use is being explored not only in advanced disease , but also in earlier - stage disease in the adjuvant setting . Preclinical and clinical research is also addressing several potential strategies for maximizing the benefits of bevacizumab and other P15692 - targeted agents , including ( 1 ) dual inhibition of P15692 and platelet - derived growth factor signaling to target both the endothelial and the pericyte components of tumor vasculature ; ( 2 ) combining P15692 - targeted agents with other targeted agents , such as inhibitors of P04626 or epidermal growth factor receptor signaling , which affect several angiogenic pathways ; and ( 3 ) combining P15692 - targeted agents with low - dose , metronomic chemotherapy . The optimal dose and schedule of P15692 - targeted agents is another unanswered question . Further investigation of the mechanism of action and vascular effects of P15692 - targeted agents in humans will help to address these questions . Mechanistic studies in humans will be aided by the development and validation of surrogate clinical end points such as noninvasive assessment of hemodynamics and vascular changes within tumors , using imaging studies .","AAVrh . 10 - mediated genetic delivery of bevacizumab to the pleura to provide local anti - P15692 to suppress growth of metastatic lung tumors . Vascular endothelial growth factor ( P15692 ) produced by tumor cells has a central role in stimulating angiogenesis required for tumor growth . Humanized monoclonal anti - P15692 antibody ( bevacizumab , DB00112 ) , approved as a treatment for non - squamous , non - small cell lung cancer , requires administration every 3 weeks . We hypothesized that an intrapleural administration of an adeno - associated virus ( AAV ) vector expressing an anti - P15692 antibody equivalent of bevacizumab would result in sustained anti - P15692 localized expression within the lung and suppress metastatic tumor growth . The AAV vector AAVrh . 10alphaVEGF encodes the light chain and heavy chain complementary DNAs of monoclonal antibody A . 4 . 6 . 1 , a murine antibody that specifically recognizes human P15692 with the same antigen - binding site as bevacizumab . A metastatic lung tumor model was established in severe combined immunodeficient mice by intravenous administration of human DU145 prostate carcinoma cells . Intrapleural administration of AAVrh . 10alphaVEGF directed long - term expression of the anti - human P15692 antibody in lung , as shown by sustained , high - level anti - human P15692 titers in lung epithelial lining fluid for 40 weeks , which was the duration of the study . In the AAVrh . 10alphaVEGF - treated animals , tumor growth was significantly suppressed ( P < 0 . 05 ) , the numbers of blood vessels and mitotic nuclei in the tumor was decreased ( P < 0 . 05 ) and there was increased survival ( P < 0 . 05 ) . Thus , intrapleural administration of an AAVrh . 10 vector , encoding the murine monoclonal antibody equivalent of bevacizumab , effectively suppresses the growth of metastatic lung tumors , suggesting AAV - mediated gene transfer to the pleura to deliver bevacizumab locally to the lung as a novel alternative platform to conventional monoclonal antibody therapy .","The role of bevacizumab in the treatment of non - small cell lung cancer : current indications and future developments . The majority of non - small cell lung cancer ( NSCLC ) patients present with advanced disease , and despite the improvement in efficacy and safety outcomes with platinum - based chemotherapy , this standard cytotoxic approach has reached a therapeutic plateau , with the prognosis for this clinical condition remaining poor . Advances in the knowledge of tumor biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment . DB00112 , an anti - growth factor vascular endothelial growth factor ( P15692 ) monoclonal antibody , is the antiangiogenic agent at the most advanced stage of development in the treatment of solid tumors and also in NSCLC treatment . DB00112 , combined with platinum - based chemotherapy , has been demonstrated to improve efficacy outcomes over chemotherapy alone in the treatment of nonsquamous advanced NSCLC in two phase III randomized trials . These represent the first evidence of improvement in treatment outcomes of chemotherapy with targeted therapies in the first - line treatment of advanced NSCLC . Future clinical developments of bevacizumab in NSCLC treatment will include the combination of this agent with other targeted therapies in advanced disease ( especially with erlotinib , an epidermal growth factor receptor tyrosine kinase inhibitor ) and the integration of this agent into combined modality approaches for the treatment of early - stage and locally advanced disease .","DB00112 treatment for human glioblastoma . Can it induce cognitive impairment ? Recent results from 2 double - blind , placebo - controlled phase III trials ( RTOG 0825 ) and ( AVAglio ) for first - line treatment of glioblastoma patients with the P15692 antibody bevacizumab , showed similar results , related to overall and progression - free survival . The RTOG 0825 trial indicated , opposed to the AVAglio trial , that patients treated with bevacizumab showed a decline in global neurocognitive function compared to untreated patients , - a decline that was most obvious after prolonged treatment . At present , there is a considerably controversy related to these observations . In the present work we point at the possibility that bevacizumab treatment of the normal brain can reduce synaptic plasticity in the hippocampus . We believe that such a phenomenon may partly explain the reduced cognitive function observed in patients in the RTOG 0825 trial . Since the same effects were not clearly defined in the AVAglio trial , further studies on putative neurocognitive effects after bevacizumab treatment are warranted .","Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab / DB00112 treatment : the role of CXCL cytokines . The anti - P15692 targeted antibody bevacizumab ( BVZ ) has been approved for treating renal cell carcinomas ( RCCs ) . Although BVZ increases the progression - free survival of patients with metastatic RCC , the effect on overall survival is poor . To gain insight into the limited efficacy of BVZ on overall survival , we analyzed patient samples of RCC for angiogenic factors that may participate in escape from anti - P15692 therapy . Our study shows that the level of vascular endothelial growth factor ( P15692 ) in tumors was increased compared with normal tissue . The level of interleukin - 8 / P10145 , a pro - angiogenic member of the CXCL family of cytokines , was also increased in tumors . These observations gave us a good reason to analyze the combined effects of BVZ and anti - P10145 antibodies on tumor growth . Surprisingly , we report that BVZ accelerates the growth of RCC in nude mice with in vivo selection of tumor cells with an increased growth capacity . Downregulation of receptor tyrosine phosphatase - κ , a phosphatase implicated in P01133 receptor regulation , may partly explain this phenomenon . Modification of the vascular network and development of lymphatic vessels through P49767 production and compensatory production of pro - angiogenic CXCL cytokines were also observed . The apparent normalization of the vascular network prompted us to associate BVZ with the chemotherapeutic agent paclitaxel . While efficient in vitro , paclitaxel did not reverse the anti - P15692 effects in vivo . Anti - P10145 - targeting antibodies were promising as they decreased intra - tumor P15692 production ; decreased the pro - angiogenic CXCL / anti - angiogenic CXCL ratio and did not induce lymphangiogenesis . These observations hold clinical implication as they highlight putative markers implicated in escape from BVZ treatment . They also recommend proceeding with caution in the use of anti - P15692 therapy alone for treatment of RCC .","Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK88___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK88___ .","[ ___MASK64___ sodium ( Photofrin - II ) ] . ___MASK64___ sodium ( ___MASK64___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK64___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .","Synergy of nab - paclitaxel and bevacizumab in eradicating large orthotopic breast tumors and preexisting metastases . INTRODUCTION : Patients with metastatic disease are considered incurable . We previously showed that nabpaclitaxel ( nanoparticle albumin - embedded paclitaxel ) combined with anti - vascular endothelial growth factor A ( P15692 ) antibody , bevacizumab , eradicates orthotopic small - sized breast tumors and metastasis . Here , we assessed this therapy in two models of advanced ( 450 - 600 mm ( 3 ) ) breast tumors and delineated P15692 - dependent mechanisms of tumor resistance . METHODS : Mice with luciferase - tagged advanced MDA - MB - 231 and MDA - MB - 435 tumors were treated with saline , nab - paclitaxel ( 10 or 30 mg / kg ) , bevacizumab ( 4 mg / kg ) , or combined drugs . Lymphatic and lung metastases were measured by luciferase assay . Proinflammatory and survival pathways were measured by ELISA , Western blot and immunohistochemistry . RESULTS : Nab - paclitaxel transiently suppressed primary tumors by 70 % to 90 % but had no effect on metastasis . Coadministration of bevacizumab increased the response rate to 99 % , including 71 % of complete responses in MDA - MB - 231 - bearing mice treated concurrently with 30 mg / kg of nab - paclitaxel . This combinatory regimen significantly reduced or eliminated preexisting lymphatic and distant metastases in MDA - MB - 231 and MDA - MB - 435 models . The mechanism involves paclitaxel - induced NF - κB pathway that upregulates P15692 and other tumor prosurvival proteins . CONCLUSIONS : DB00112 prevents tumor recurrence and metastasis promoted by nab - paclitaxel activation of NF - κB pathway . Combination therapy with high - dosed nab - paclitaxel demonstrates the potential to eradicate advanced primary tumors and preexisting metastases . These findings strongly support translating this regimen into clinics .","Targeted approaches for treating advanced clear cell renal carcinoma . The mainstay of any curative treatment in renal cell carcinoma ( RCC ) is surgery . In the case of metastatic disease at presentation , a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment . Interferon ( IFN ) - a offers in a small but significant percentage of patients advantage in overall survival . Interleukin ( IL ) - 2 - based therapy gives similar survival rates . To date , hormonal therapy and chemotherapy do not have a proven impact on survival . Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel - Lindau ( P40337 ) gene . This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor ( P15692 ) in this highly vascularized tumor . This opens interesting new treatment strategies including blockade of P15692 with the monoclonal antibody bevacizumab ( DB00112 ) and inhibition of P15692 receptor tyrosine kinases with small oral molecules such as sunitinib ( SU11248 , Sutent ) or PTK787 . Likewise , inhibition of the Raf kinase pathway with oral sorafenib ( Bay 43 - 9006 , Nexavar ) or inhibition of the P42345 pathway with intravenous CCI - 779 are under investigation . Preliminary clinical results with all these compounds are promising , and the results of ongoing first - line phase III studies will become available in the next years .","Vascular endothelial growth factor ( P15692 ) as a target of bevacizumab in cancer : from the biology to the clinic . Angiogenesis is important in the growth and progression of solid tumours . The main pro - angiogenic factor , namely vascular endothelial growth factor ( P15692 ) , also known as vascular permeability factor , is a potent angiogenic cytokine that induces mitosis and also regulates the permeability of endothelial cells . The soluble isoform of P15692 is a dimeric glycoprotein of 36 - 46 kDa , induced by hypoxia and oncogenic mutation and it binds to two specific tyrosine - kinase receptors : P15692 - 1 ( flt - 1 ) and P15692 - 2 ( P35968 / flk1 ) . An increase in P15692 expression in tumour tissue or some blood compartments ( i . e . serum or plasma ) has been found in solid and haematological malignancies of various origins and is associated with metastasis formation and poor prognosis . DB00112 , a recombinant humanised monoclonal antibody developed against P15692 , binds to soluble P15692 , preventing receptor binding and inhibiting endothelial cell proliferation and vessel formation . Pre - clinical and clinical studies have shown that bevacizumab alone or in combination with a cytotoxic agent decreases tumour growth and increases median survival time and time to tumour progression . DB00112 is the first anti - angiogenetic treatment approved by the American Food and Drug Administration in the first - line treatment of metastatic colorectal cancer . It has shown preliminary evidence of efficacy for breast , non - small - cell lung , pancreatic , prostate , head and neck and renal cancer as well as haematological malignancies . Common toxicities associated with bevacizumab include hypertension , proteinuria , bleeding episodes and thrombotic events . This review summarises the critical role of P15692 and discusses the data available on bevacizumab , from the humanisation of its parent murine monoclonal antibody ( mAb ) A . 4 . 6 . 1 to its use in cancer clinical trials .","Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK18___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .","Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer . Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer , but the clinical benefits are usually transitory . The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab . For this , angiogenesis - focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control . Reverse transcription - PCR was used for results validation . The insulin growth factor 1 ( DB01277 ) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab . Cixutumumab was used to block DB01277 signaling in vivo . Dual anti - P15692 and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth . Immunohistochemistry measured multivessel density , Akt activation , and cell proliferation , whereas terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling ( TUNEL ) assay measured apoptosis in ovarian cancer xenografts . DB00112 and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway . The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone . In summary , DB01277 activation represents an important mechanism of adaptive escape during anti - P15692 therapy in ovarian cancer . This study provides the rationale for designing bevacizumab - based combination regimens to enhance antitumor activity .","P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .","Current opinion on bevacizumab on endometrial cancer treatment . INTRODUCTION : Advanced or recurrent endometrial cancer is still a challenge for clinicians as it has a poor prognosis despite treatment efforts . Thus , there is an urgent need for new agents with activity in this subset of patients . The increased knowledge of the molecular aspects of endometrial carcinogenesis has led to the development of molecular targeted therapies and in particular anti - angiogenic drugs . One of the most promising of these agents is bevacizumab , a recombinant humanized immunoglobulin monoclonal antibody to P15692 . AREAS COVERED : The objective of this paper is to discuss the role of angiogenesis in endometrial cancer and analyze the rational of bevacizumab use , alone or in combination with other therapies , in endometrial cancer patients . We reviewed the most important preclinical and clinical studies published on this topic up to March 2014 . EXPERT OPINION : DB00112 in combination with others targeted therapies , chemotherapy or radiotherapy demonstrated promising anti - tumor activity . Despite the good oncological outcomes of these recent clinical experiences , caution must be used in light of significant toxicity reported in this subset of heavily pre - treated patients . The identification of biomarkers able to predict either the efficacy or toxicity of anti - angiogenic drugs is a compelling need .","Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .","Identification of microRNAs involved in the modulation of pro - angiogenic factors in atherosclerosis by a polyphenol - rich extract from propolis . New vessel formation plays a critical role in the progression and vulnerability of atherosclerotic lesions . It has been shown that polyphenols from propolis attenuate the progression of atherosclerosis and also exert inhibitory effects on angiogenic factors . However , the mechanisms underlying these effects are not completely understood . Thus , this study aimed to identify microRNAs ( miRNAs ) involved in the modulation of pro - angiogenic factors in the atherosclerotic plaques of P01130 gene knockout mice treated with a polyphenol - rich extract of Chilean propolis . The progression of the atherosclerotic lesions was significantly attenuated in treated mice compared with control mice . Using microarray analysis and a bioinformatic approach , we identified 29 differentially expressed miRNAs . Many of these miRNAs were involved in biological processes associated with angiogenesis , such as the cell cycle , cell migration , cell growth and proliferation . Among them , three miRNAs ( miR - 181a , miR - 106a and miR - 20b ) were over - expressed and inversely related to the expression of Vegfa ( vascular endothelial growth factor A ) and Hif1a ( hypoxia inducible factor 1 alpha ) . In addition , P15692 protein expression was attenuated in histological sections obtained from the aortic sinuses of treated mice . P15692 is a key pro - angiogenic factor in atherosclerotic plaques , and Hif1a , which is expressed in the necrotic nucleus of the atheroma , is its main inducer . We found a correlation between the over - expression of miR - 181a , miR - 106a and miR - 20b and their target genes , Hif1a and Vegfa , which is consistent with attenuation of the atherosclerotic lesion . In conclusion , our data analysis provides evidence that the anti - angiogenic effects of polyphenols from Chilean propolis can be modulated by miRNAs , in particular miR - 181a , miR - 106a and miR - 20b .","Phase I safety and pharmacokinetic study of bevacizumab in Chinese patients with advanced cancer . BACKGROUND : bevacizumab is a humanized recombinant vascular endothelial growth factor ( P15692 ) monoclonal antibody , which specifically binds to P15692 and inhibits tumor cell growth , proliferation and metastasis . We aimed to investigate the safety and pharmacokinetics of bevacizumab in Chinese patients with advanced cancer . METHODS : Thirty - nine Chinese patients with metastatic or relapsed cancers who failed prior therapy were enrolled in this phase I study of bevacizumab . DB00112 was infused by a calculated pump at doses from 5 mg / kg to 15 mg / kg in 90 minutes . Patients underwent serial pharmacokinetic evaluations . Patients that received at least one infusion of bevacizumab were included in the safety study . RESULTS : Thirty - five patients finished all 5 infusions following protocol . One patient withdrew after 3 infusions due to grade 3 proteinuria . Common adverse events possibly related to the study drug were proteinuria ( 17 / 39 , 43 . 6 % ) , hypertension ( 13 / 39 , 33 . 3 % ) , gingival bleeding ( 7 / 39 , 17 . 9 % ) , epistaxis ( 6 / 39 , 15 . 4 % ) , pharyngeal inflammation ( 6 / 39 , 15 . 4 % ) , fatigue ( 6 / 39 , 15 . 4 % ) and stomatitis ( 4 / 39 , 10 . 3 % ) . DB00112 pharmacokinetics was linear within the range of 5 mg / kg q2w -- 10 mg / kg q2w and 15 mg / kg q3w . CL ( clearance ) , Vd ( volume of distribution at elimination ) and Vss ( volume of distribution at steady state ) were similar after single and multiple doses at 5 , 10 and 15 mg / kg . CONCLUSIONS : DB00112 is well tolerated in Chinese patients . No unexpected adverse events were observed . There is no racial difference in the pharmacokinetics .","4 -[ 3 , 5 - Bis ( trimethylsilyl ) benzamido ] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor . 4 -[ 3 , 5 - bis ( trimethylsilyl ) benzamido ] Benzoic acid ( TAC - 101 ) has potent antiproliferative , antiangiogenic , and antitumor effects in vitro and in vivo . These effects might be due to TAC - 101 binding to retinoic acid receptor alpha ( P10276 ) and interfering with the binding of activator protein - 1 ( AP - 1 ) to DNA . However , little is known about the detailed mechanism of TAC - 101 function . We investigated the mechanism of the antiangiogenic effect of TAC - 101 using a rat hepatic metastatic model in vivo and DLD - 1 human colon cancer cells in vitro . Liver metastases were induced by portal injection of Q15293 - 9 rat colonic cancer cells into F344 rats . TAC - 101 ( 8 mg / kg ) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density ( P53602 ) and vascular endothelial growth factor ( P15692 ) . TAC - 101 significantly reduced both P53602 and P15692 expression . Northern blot analysis and ELISA indicated that TAC - 101 efficiently inhibited production of P15692 mRNA and protein in DLD - 1 cells in a time - and dose - dependent manner . These findings suggest that TAC - 101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of P15692 .","Global reported endophthalmitis risk following intravitreal injections of anti - P15692 : a literature review and analysis . PURPOSE : To report on endophthalmitis occurrence and associated risk factors following the intravitreal injection of anti - P15692 agents based on a review of published literature . MATERIALS AND METHODS : A Medline search was performed using the terms \" bevacizumab \" and \" ranibizumab \" . A total of 534 English - language articles of varying design and published from 2006 to November 2013 were analyzed for endophthalmitis occurrence and contributing perioperative factors . RESULTS : A total of 445 , 503 injections were counted . There were 103 cases of postinjection endophthalmitis in 176 , 124 injections ( 0 . 058 % ) with bevacizumab ( DB00112 ) versus 79 cases in 269 , 379 injections ( 0 . 029 % ) with ranibizumab ( Lucentis ) . This difference was due to a significantly higher occurrence of culture - negative endophthalmitis associated with bevacizumab injections . Culture - positive risk was not statistically different between the two drugs . The reported use of postinjection topical antibiotics increased the risk of culture - positive endophthalmitis . No association was found with the use of povidone iodine , a lid speculum , a mask , or an operating room . Streptococcus spp . were the most prevalent causative organism , accounting for nine of 54 ( 17 % ) of all culture - positive cases . CONCLUSION : Reported postinjection endophthalmitis occurred significantly more in patients treated with bevacizumab than those treated with ranibizumab . However , culture - positive occurrence was similar . Despite the potential for contamination at the time of drug compounding , bevacizumab does not appear to confer a higher risk of culture - positive endophthalmitis than ranibizumab . This study also suggests antibiotic use may increase endophthalmitis occurrence .","Preclinical evaluation of holmium - 166 labeled anti - P15692 ( DB00112 ) . Radiolabeled antiangiogenic monoclonal antibodies are potential agents for targeted therapy in specific types of malignancies . In this study , ( 166 ) Ho - DOTA - DB00112 was used in biodistribution studies using single - photon emission computed tomography ( SPECT ) to acquire dosimetric aspects of the radiolabeled antibody in mice . The liver toxicity of the radiolabeled antibody was also determined using serum glutamic pyruvic transaminase , serum glutamic oxaloacetic transaminase and alkaline phosphatase assay 2 - 7 days post - injection . The SPECT biodistribution demonstrated a similar pattern as the other radiolabeled anti - vascular endothelial growth factor A ( P15692 ) immunoconjugates . ( 166 ) Ho - DOTA - DB00112 was revealed as a potential compound for therapy / imaging of P15692 expression in oncology .","[ DB00112 and invasive procedures : practical recommendations ] . As first line chemotherapy DB00112 , associated with a platinum based regime , improves survival in patients with metastatic , non small cell , non epidermoid bronchial carcinoma . Marketing authorization for this indication was obtained in 2007 . This treatment produces specific secondary effects related to its anti - angiogenic action . Physiologically , vascular endothelial growth factor ( P15692 ) is important in the process of scar formation . DB00112 inhibits scar formation and may encourage bleeding . The aim of this article is to analyse the specific risks associated with invasive procedures and to produce practical recommendations . Unfortunately there are few data in the literature . We depend , therefore , principally on studies of neo - adjuvant chemotherapy in metastatic colo - rectal cancer prior to excision of hepatic metastases and on our own experience of excision of pulmonary metastases from solid tumours treated with bevacizumab . We recommend a delay of 2 days between implantation of an intravenous device and the initiation of bevacizumab , a delay of at least 5 weeks between the last injection of bevacizumab and invasive surgery and a delay of 4 weeks between surgery and the initiation of bevacizumab treatment . Obviously , referral to a medico - surgical team experienced in the management of these patients is strongly recommended .","Accomplishments in 2008 in the treatment of advanced metastatic colorectal cancer . Overview of the Disease IncidencePredictive BiomarkersCurrent General Therapy StandardsAccomplishments During the Year Combined Modality Management of Liver MetastasesTreatment of Advanced Disease Equivalence of FOLFOX and CAPOXAddition of DB00112 to Standard ChemotherapyDual P00533 and P15692 InhibitionBevacizumab Upon Progression While on First - Line TherapyBenefit in the Elderly PopulationWhat Needs to be Done Comments on ResearchObstacles to Progress .","Synthesis and evaluation of ( 99m ) Tc chelate - conjugated bevacizumab . Vascular endothelial growth factor ( P15692 ) is one of the classic factors involved in tumor - induced angiognesis in several solid tumors . DB00112 , a monoclonal antibody against P15692 , can be used as an imaging tool in preclinical studies . The aim of this study was to radiolabel DB00112 with ( 99m ) Tc and to evaluate in vivo its imaging properties in an adenocarcinoma animal model . For this purpose , DB00112 was derivatized with Suc - HYNIC as a bifunctional coupling agent . A mixture of Tricine / SnCl ( 2 ). 2H ( 2 ) O was added to DB00112 - HYNIC and radiolabeled with ( 99m ) TcO ( 4 )(-) . The radiochemical stability of the radiolabeled antibody was assessed . Biodistribution and scintigraphy imaging were performed in normal CD1 female mice and in spontaneous adenocarcinoma tumor bearing CD1 mice ( n = 5 ) . We demonstrated that 99mTc - HYNIC - DB00112 was stable . In vivo biodistribution studies revealed that tumor uptake of ( 99m ) Tc - HYNIC - DB00112 was 1 . 37 ± 0 . 51 % and 5 . 33 ± 2 . 13 % at 4 and 24 h postinjection , respectively . Scintigraphy image studies showed tumor selective uptake of ( 99m ) Tc - HYNIC - DB00112 in the tumor - bearing mice . We conclude that ( 99m ) Tc - HYNIC - Bevacizumb has the potential to be used as a tracer for tumor imaging in preclinical studies .","Next generation molecular targeted agents for breast cancer : focus on P00533 and VEGFR pathways . Here we reviewed the recent progress of molecular targeting drugs , including trastuzumab , lapatinib , erlotinib and bevacituzumab . Fortunately , Her - 2 positive cases of metastatic or relapsed cases , those with the worse prognosis , are responsive to trastuzumab - based chemotherapy . ___MASK35___ will likely be effective against trastuzumab - resistant cases and brain metastases . Furthermore , the introduction of bevacituzumab will improve P15692 - VEGFR - associated tumor growth .","[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK43___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .","Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK19___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .","[ Tumor vasculature as a therapeutic target in non - small cell lung cancer ] . Despite developments in conventional ( chemo ) radiotherapy and surgery , survival of non - small cell lung cancer ( NSCLC ) patients remains poor . Treatments with targeted molecular drugs offer novel therapeutic strategies . DB00112 , a recombinant anti - vascular endothelial growth factor ( P15692 ) antibody , is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC . However , a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain . Furthermore , novel agents targeting the pre - existing NSCLC vasculature ( i . e . vascular disrupting agents , VDAs ) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies . Herein , we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC .","Vascular endothelial growth factor in fellow eyes of eyes injected with intravitreal bevacizumab . BACKGROUND : To study the effect on untreated fellow eyes of eyes treated with an intravitreal injection of bevacizumab . METHODS : DB00112 ( 1 . 25 mg / 0 . 05 ml ) was injected into the vitreous cavity of one eye ( the first eye ) as a preoperative adjunctive therapy for proliferative diabetic retinopathy ; vitrectomy was performed 1 week later . Immediately after vitrectomy , bevacizumab ( 1 . 25 mg / 0 . 05 ml ) was injected into the fellow eye ( the second eye ) followed by vitrectomy 1 week later . Aqueous humor samples were obtained from both eyes in five cases just before intravitreal injection of bevacizumab and just before vitrectomy 1 week later . Vascular endothelial growth factor ( P15692 ) concentrations in the aqueous humor were measured by enzyme - linked immunosorbent assay ( ELISA ) . RESULTS : P15692 concentrations in the aqueous humor of the first eyes ranged from 146 to 398 pg / ml ( mean , 302 +/- 100 pg / ml ) before intravitreal injection of bevacizumab ; 1 week later , the P15692 concentrations in the injected eyes were less than 31 pg / ml , the lower limit of the ELISA , in all cases ( p < 0 . 001 ) . The concentrations in the uninjected fellow eyes ranged from 181 to 551 pg / ml ( mean , 382 +/- 119 pg / ml ) . CONCLUSIONS : There seemed to be no or a minimal effect of the intravitreal injections of bevacizumab on the uninjected fellow eyes ."],"string":"[\n \"Suppressive effect of bevacizumab on peritoneal dissemination from gastric cancer in a peritoneal metastasis model . PURPOSE : Vascular endothelial growth factor ( P15692 ) has been reported to enhance vascular permeability and angiogenesis in the abdominal wall , thereby contributing to peritoneal dissemination with malignant ascites . We conducted this experimental study to find out if bevacizumab , a humanized monoclonal antibody against P15692 , had a suppressive effect on peritoneal dissemination from gastric cancer , in an experimental nude mouse model of peritoneal metastasis . METHODS : Each mouse was treated with a single intraperitoneal ( i . p . ) injection of bevacizumab . Five mice were killed , and we measured their body weight , the mean number of tumor nodules , and the volume of ascites . We also extracted retroperitoneal tissues for histological examination , to count the frequency of mitosis , and to calculate the mitotic index . Another five mice were monitored until death , and their mean survival duration was calculated . RESULTS : The volume of ascites and the mitotic index were significantly lower in the therapy group than in the nontherapy group ( P = 0 . 042 and P < 0 . 01 , respectively ) . The survival curve of the therapy group was significantly higher than that of the nontherapy group ( P = 0 . 005 ) . CONCLUSION : DB00112 may suppress peritoneal dissemination from gastric cancer .\",\n \"[ DB00112 combined with cisplan inhibits malignant ascites production in nude mice bearing transplanted ovary carcinoma with high P15692 expression ] . OBJECTIVE : To establish a nude mouse model of malignant ascites with human ovarian carcinoma cell line OVCAR3 which highly expresses P15692 and evaluate the therapeutic of DB00112 combined with cisplan . METHODS : Forty - eight nude mice with malignant ascites resulting from intraperitoneal transplantation of human ovarian carcinoma cell line OVCAR3 were treated with intraperitoneal injection of DB00112 , cisplan , their combination , and PBS , respectively , to observe the effect on ascites development , P15692 content in the ascites , peritoneal permeability , development of new vessels and number of tumor cells in the ascites . RESULTS : DB00112 obviously inhibited ascites accumulation and peritoneal capillary permeability , reduced P15692 protein level and microvascular density in the tumor tissues and the number of red cells and tumor cells in the malignant ascites , and prolonged the survival of the mice . The combination of DB00112 and cisplan further enhanced the therapeutic efficacy of DB00112 . CONCLUSION : The bio - chemotherapeutic strategy with DB00112 combined with cisplan can be a promising method for treatment of malignant ascites .\",\n \"Dynamic contrast - enhanced and diffusion Q9BWK5 show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF - 1alpha using PX - 478 . PX - 478 is a new agent known to inhibit the hypoxia - responsive transcription factor , HIF - 1alpha , in experimental tumors . The current study was undertaken in preparation for clinical trials to determine which noninvasive imaging endpoint ( s ) is sensitive to this drug ' s actions . Dynamic contrast - enhanced ( DCE ) and diffusion - weighted ( DW ) magnetic resonance imaging ( Q9BWK5 ) were used to monitor acute effects on tumor hemodynamics and cellularity , respectively . Mice bearing human xenografts were treated either with PX - 478 or vehicle , and imaged over time . DW imaging was performed at three b values to generate apparent diffusion coefficient of water ( ADCw ) maps . For DCE - Q9BWK5 , a macromolecular contrast reagent , BSA - DB00789 , was used to determine vascular permeability and vascular volume fractions . PX - 478 induced a dramatic reduction in tumor blood vessel permeability within 2 hours after treatment , which returned to baseline by 48 hours . The anti - P15692 antibody , DB00112 , reduced both the permeability and vascular volume . PX - 478 had no effect on the perfusion behavior of a drug - resistant tumor system , A - 549 . Tumor cellularity , estimated from ADCw , was significantly decreased 24 and 36 hours after treatment . This is the earliest significant response of ADC to therapy yet reported . Based on these preclinical findings , both of these imaging endpoints will be included in the clinical trial of PX - 478 .\",\n \"DB00112 immune complexes activate platelets and induce thrombosis in P12318 transgenic mice . BACKGROUND : Treatment with DB00112 has been associated with arterial thromboembolism in colorectal cancer patients . However , the mechanism of this remains poorly understood , and preclinical testing in mice failed to predict thrombosis . OBJECTIVE : We investigated whether thrombosis might be the result of platelet activation mediated via the FcgammaRIIa ( IgG ) receptor - which is not present on mouse platelets - and aimed to identify the functional roles of heparin and platelet surface localization in Bev - induced FcgammaRIIa activation . METHODS AND RESULTS : We found that Bev immune complexes ( IC ) activate platelets via FcgammaRIIa , and therefore attempted to reproduce this finding in vivo using FcgammaRIIa ( hFcR ) transgenic mice . Bev IC were shown to be thrombotic in hFcR mice in the presence of heparin . This activity required the heparin - binding domain of Bev ' s target , vascular endothelial growth factor ( P15692 ) . ___MASK75___ promoted Bev IC deposition on to platelets in a mechanism similar to that observed with antibodies from patients with heparin - induced thrombocytopenia . When sub - active amounts of ADP or thrombin were used to prime platelets ( simulating hypercoagulability in patients ) , Bev IC - induced dense granule release was significantly potentiated , and much lower ( sub - therapeutic ) heparin concentrations were sufficient for Bev IC - induced platelet aggregation . CONCLUSIONS : The prevailing rationale for thrombosis in Bev therapy is that P15692 blockade leads to vascular inflammation and clotting . However , we conclude that Bev can induce platelet aggregation , degranulation and thrombosis through complex formation with P15692 and activation of the platelet FcgammaRIIa receptor , and that this provides a better explanation for the thrombotic events observed in vivo .\",\n \"Intravitreal DB00112 ( DB00112 (®) ) for Diabetic Retinopathy at 24 - months : The 2008 Juan Verdaguer - Planas Lecture . Diabetic retinopathy ( DR ) remains the major threat to sight in the working age population . Diabetic macular edema ( DME ) is a manifestation of DR that produces loss of central vision . Proliferative diabetic retinopathy ( PDR ) is a major cause of visual loss in diabetic patients . In PDR , the growth of new vessels is thought to occur as a result of vascular endothelial growth factor ( P15692 ) release into the vitreous cavity as a response to ischemia . Furthermore , P15692 increases vessel permeability leading to deposition of proteins in the interstitium that facilitate the process of angiogenesis and macular edema . This review demonstrates multiple benefits of intravitreal bevacizumab ( IVB ) on DR including DME and PDR at 24 months of follow up . The results indicate that IVB injections may have a beneficial effect on macular thickness and visual acuity ( VA ) in diffuse diabetic macular edema . Therefore , in the future this new therapy could replace or complement focal / grid laser photocoagulation in DME . In PDR , this new option could be an adjuvant agent to pan - retina photocoagulation so that more selective therapy may be applied . In addition , we report a series of patients in which tractional retinal detachment developed or progressed after adjuvant preoperative IVB in severe PDR .\",\n \"Potentiation of anti - angiogenic activity of heparin by blocking the P01008 - interacting pentasaccharide unit and increasing net anionic charge . ___MASK75___ , a potent anticoagulant used for the prevention of venous thromboembolism , has been recognized as a tumor angiogenesis inhibitor . Its limitation in clinical application for cancer therapy , however , arises from its strong anticoagulant activity , which causes associated adverse effects . In this study , we show the structural correlation of LHT7 , a previously developed heparin - based angiogenesis inhibitor , with its influence on P15692 blockade and its decreased anticoagulant activity . LHT7 was characterized as having average seven molecules of sodium taurocholates conjugated to one molecule of low - molecular - weight heparin ( LMWH ) . This study showed that the conjugation of sodium taurocholates selectively blocked interaction with antithrombin III ( P01008 ) while enhancing the binding with P15692 . This resulted in LHT7 to have negligible anticoagulant activity but potent anti - angiogenic activity . Following up on this finding , we showed that the bidirectional effect of sodium taurocholate conjugation was due to its unique structure , that is , the sterane core hindering the P01008 - binding pentasaccharide unit of LMWH with its bulky and rigid structural characteristics while the terminal sulfate group interacts with P15692 to produce stronger binding . In addition , we showed that LHT7 was localized in the tumor , especially on the endothelial cells . One explanation for this might be that LHT7 was delivered to the tumor via platelets .\",\n \"Antivascular endothelial growth factor for retinopathy of prematurity . PURPOSE OF REVIEW : This review will discuss a potentially more effective treatment for retinopathy of prematurity ( P04000 ) with fewer acute and long - term complications . DB00112 ( bevacizumab ) therapy is a promising anti - vascular endothelial growth factor ( anti - P15692 ) administered directly into the vitreous . RECENT FINDINGS : Recent reports detail the use of DB00112 alone , and in combination with light amplification by stimulated emission of radiation ( LASER ) therapy and vitrectomy , for P04000 stages 3 , 4 , and 5 . Currently , one clinical trial is studying DB00112 alone for acute vision - threatening P04000 stage 3 in zone I and posterior zone II without LASER therapy . Another clinical trial is investigating DB00112 following LASER therapy for recurrent P04000 stages 4 and 5 . SUMMARY : Treatment for P04000 has evolved from later , more destructive ( cryotherapy ) to earlier , less destructive ( LASER therapy ) peripheral retinal ablation . If evidence - based data supports early findings , the use of DB00112 may be recommended without the need for ablative LASER therapy and before retinal detachment develops . DB00112 will be especially useful for P04000 stage 3 cases with hemorrhage decreasing retinal visualization , rigid pupils , intravitreal neovascularization with early or developing ( minimal ) fibrous membranes , or aggressive posterior retinopathy of prematurity ( AP - P04000 ) . These cases all continue to have poor outcomes with LASER therapy .\",\n \"Ablation of cholesterol biosynthesis in neural stem cells increases their P15692 expression and angiogenesis but causes neuron apoptosis . Although sufficient cholesterol supply is known to be crucial for neurons in the developing mammalian brain , the cholesterol requirement of neural stem and progenitor cells in the embryonic central nervous system has not been addressed . Here we have conditionally ablated the activity of squalene synthase ( P37268 ) , a key enzyme for endogenous cholesterol production , in the neural stem and progenitor cells of the ventricular zone ( VZ ) of the embryonic mouse brain . Mutant embryos exhibited a reduced brain size due to the atrophy of the neuronal layers , and died at birth . Analyses of the E11 . 5 - E15 . 5 dorsal telencephalon and diencephalon revealed that this atrophy was due to massive apoptosis of newborn neurons , implying that this progeny of the P37268 - ablated neural stem and progenitor cells was dependent on endogenous cholesterol biosynthesis for survival . Interestingly , the neural stem and progenitor cells of the VZ , the primary target of P37268 inactivation , did not undergo significant apoptosis . Instead , vascular endothelial growth factor ( P15692 ) expression in these cells was strongly upregulated via a hypoxia - inducible factor - 1 - independent pathway , and angiogenesis in the VZ was increased . Consistent with an increased supply of lipoproteins to these cells , the level of lipid droplets containing triacylglycerides with unsaturated fatty acyl chains was found to be elevated . Our study establishes a direct link between intracellular cholesterol levels , P15692 expression , and angiogenesis . Moreover , our data reveal a hitherto unknown compensatory process by which the neural stem and progenitor cells of the developing mammalian brain evade the detrimental consequences of impaired endogenous cholesterol biosynthesis .\",\n \"Evaluation of cytotoxic effects of bevacizumab on human corneal cells . PURPOSE : Corneal neovascularization contributes to corneal opacification in inflammatory conditions of the cornea and severely compromises the success of corneal transplantation . Vascular endothelial growth factor ( P15692 ) plays an important role in stimulating and maintaining corneal neovascularization . Anti - P15692 therapy , especially the use of anti - P15692 antibody bevacizumab , has gained popularity in the management of retinal neovascularization and is being used topically for corneal neovascularization . The aim of this study was to investigate the safety profile of bevacizumab on human corneal cell lines . METHODS : Human corneal epithelial and fibroblast cell lines and an umbilical vascular endothelial cell line were treated with increasing doses of bevacizumab . The effect of this treatment on cell viability was assessed by WST - 1 and crystal violet staining assays . Cytotoxicity was also assessed by fluorescent microscopy and flow cytometric evaluation of propidium iodide - stained cells . RESULTS : In the cytotoxicity experiments , there was no difference in cell numbers after 24 - hour exposure compared with control in any of the cell lines at the concentrations tested ( P > 0 . 05 to 0 . 98 ) . CONCLUSION : DB00112 was nontoxic to human corneal epithelial and fibroblast cells at 3 different concentrations .\",\n \"Evolving role of novel targeted agents in renal cell carcinoma . The treatment of metastatic renal cell carcinoma ( RCC ) has changed dramatically over the past few years . An improved understanding of the biology of RCC has resulted in the development of novel targeted therapeutic agents that have altered the natural history of this disease . In particular , the hypoxia - inducible factor ( HIF ) / vascular endothelial growth factor ( P15692 ) pathway and the mammalian target of rapamycin ( P42345 ) signal transduction pathway have been exploited . DB01268 malate ( Sutent ) , sorafenib tosylate ( Nexavar ) , bevacizumab ( DB00112 ) / interferon alfa , and temsirolimus ( DB06287 ) have improved clinical outcomes in randomized trials by inhibiting these tumorigenic pathways . Combinations and sequences of these agents are being evaluated . Other novel multitargeted tyrosine kinase inhibitors ( pazopanib and axitinib ) and P42345 inhibitors ( everolimus ) are in clinical development . Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC .\",\n \"Expression and role of P15692 in the adult retinal pigment epithelium . PURPOSE : Despite a lack of active angiogenesis , P15692 is expressed in nearly every adult tissue , and recent evidence suggests that P15692 may serve as a survival factor for both vascular and nonvascular tissues . P15692 blockade is a widely used treatment for neovascular diseases such as wet age - related macular degeneration ( AMD ) . Therefore , it was sought in this study to evaluate the expression and role of endogenous P15692 in Q96AT9 . METHODS : P15692 and P35968 expression in the murine retina were assessed during development . DB00112 was used to neutralize P15692 in ARPE - 19 cells , and the effects on cell survival and apical microvill were assessed by TUNEL and SEM , respectively . P15692 was systemically neutralized in vivo by adenoviral - mediated overexpression of soluble P17948 ( sFlt ) . Q96AT9 and choriocapillaris were analyzed by transmission electron microscopy ( TEM ) . Changes in gene expression were evaluated by quantitative real - time PCR . RESULTS : P15692 expression was detected in the developing Q96AT9 as early as embryonic day ( E ) 9 . 5 , whereas P35968 expression by Q96AT9 began nonuniformly between postnatal ( P ) day 6 . 5 and P8 . 5 . P15692 neutralization in vitro led to increased apoptosis and reduced microvilli density and length . Systemic P15692 neutralization led to transient degenerative changes ; Q96AT9 were vacuolated and separated from photoreceptor outer segments , and choriocapillaris fenestrations were decreased . P15692 levels were elevated in Q96AT9 of Ad - sFlt1 mice at day 4 postinfection , and there was increased expression of the neurotrophic factor CD59a at day 14 . CONCLUSIONS : These results indicate that P15692 plays a critical role in survival and maintenance of Q96AT9 integrity . Potential undesired off - target effects should be considered with chronic use of anti - P15692 agents .\",\n \"Neuroprotective profile of novel P12931 kinase inhibitors in rodent models of cerebral ischemia . Src kinase signaling has been implicated in multiple mechanisms of ischemic injury , including vascular endothelial growth factor ( P15692 ) - mediated vascular permeability that leads to vasogenic edema , a major clinical complication in stroke and brain trauma . Here we report the effects of two novel Src kinase inhibitors , 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 3 -( 4 - methyl - 1 - piperazinyl ) propoxy ]- 3 - quinolinecarbonitrile ( ___MASK54___ ) and 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 4 -( 4 - methypiperazin - 1 - yl ) but - 1 - ynyl ]- 3 - quinolinecarbonitrile ( SKS - 927 ) , on ischemia - induced brain infarction and short - and long - term neurological deficits . Two well established transient [ transient middle cerebral artery occlusion ( tMCAO ) ] and permanent [ permanent middle cerebral artery occlusion ( pMCAO ) ] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario . Brain penetration of Src inhibitors , their effect on blood - brain barrier integrity and P15692 signaling in human endothelial cells were also evaluated . Our results demonstrate that both agents potently block P15692 - mediated signaling in human endothelial cells , penetrate rat brain upon systemic administration , and inhibit postischemic Src activation and vascular leakage . Treatment with ___MASK54___ or SKS - 927 ( at the doses of 3 - 30 mg / kg i . v . ) resulted in a dose - dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4 - to 6 - h after tMCAO . Src blockade after pMCAO resulted in accelerated improvement in recovery from motor , sensory , and reflex deficits during a long - term ( 3 weeks ) testing period poststroke . These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke .\",\n \"Anti - P15692 Treatment of Corneal Neovascularization . Vascular endothelial growth factor ( P15692 ) is an angiogenic factor shown to be a critical secreted cytokine in tumorigenesis and retinal neovascularization ( NV ) . Currently , there are two anti - P15692 agents , pegaptanib and ranizumab , approved by the United States Food and Drug Administration ( FDA ) for intravitreal use in the treatment of wet age - related macular degeneration ( AMD ) . DB00112 is FDA - approved for intravenous administration in the treatment of several cancers and is in widespread use , off - label , as an intravitreal injection to treat a variety of retinal pathologies . Animal studies demonstrate the role of P15692 in corneal NV . There are now a number of human case series reporting the use of anti - P15692 agents , primarily bevacizumab , to treat corneal NV . This review summarizes reports to date on the use of anti - P15692 agents in the treatment of corneal NV in humans , noting the limitations of current data and the need for further studies . The experience of one clinician with the use of an anti - P15692 drug in the treatment of active corneal NV is presented .\",\n \"Vascular endothelial growth factor stimulates organ - specific host matrix metalloproteinase - 9 expression and ovarian cancer invasion . Vascular endothelial growth factor ( P15692 ) and matrix metalloproteinases ( MMP ) regulate each other , contributing to tumor progression . We have previously reported that P14780 induces the release of tumor P15692 , promoting ascites formation in human ovarian carcinoma xenografts . The aim of this study was to investigate whether tumor - derived P15692 regulated the expression of gelatinase by the stroma , influencing the invasive properties of ovarian tumors . Tumor variants derived from 1A9 human ovarian carcinoma , stably expressing P15692 ( 121 ) in the sense ( 1A9 - VS - 1 ) and antisense orientations ( 1A9 - VAS - 3 ) , were used . In vivo , zymographic analysis of tumors from 1A9 - VS - 1 implanted in the peritoneal cavity of nude mice showed higher levels of gelatinases , particularly murine P14780 , indicating that P15692 stimulates host expression of the matrix - degrading enzyme . Murine P14780 expression was also high in the ovaries of mice bearing 1A9 - VS - 1 tumors . The effect on host P14780 activity was organ - specific . The levels of host pro - P14780 in ovaries correlated with the plasma levels of tumor P15692 and with the selective invasion of the ovaries . Induction of host P14780 expression in tumors and ovaries was independent of the site of tumor growth as it was seen in mice carrying both intraperitoneal and subcutaneous tumors . The anti - P15692 antibody bevacizumab ( DB00112 ) inhibited P14780 expression and tumor invasion in the ovaries of mice bearing 1A9 - VS - 1 tumors . These findings point to a complex cross - talk between P15692 and MMPs in the progression of ovarian tumor and suggest the possibility of using P15692 inhibitors to affect MMP - dependent tumor invasion .\",\n \"Levels of vascular endothelial growth factor and pigment epithelium - derived factor in eyes before and after intravitreal injection of bevacizumab . PURPOSE : DB00112 is a human monoclonal IgG1 antibody that blocks the action of vascular endothelial growth factor ( P15692 ) . The purpose of this study was to determine the level of P15692 and pigment epithelium - derived factor ( P36955 ) in eyes with proliferative diabetic retinopathy ( PDR ) before and after an intravitreal injection of bevacizumab . METHODS : Eleven eyes of ten patients were studied . Patients were included if they had neovascular glaucoma , rubeosis of the iris with PDR , or aggressive PDR . Samples of aqueous humor were collected just before the injection of bevacizumab and the vitrectomy . The concentrations of P15692 and P36955 in the aqueous humor were measured by enzyme - linked immunosorbent assay , and the effects of bevacizumab on PDR were evaluated . RESULTS : The free P15692 concentration before the injection was 676 . 5 +/- 186 . 7 pg / ml ( mean +/- SEM , n = 11 ) . Seven days later , it was significantly reduced to 7 . 1 +/- 7 . 1 pg / ml ( P < 0 . 005 , n = 9 ) . The P36955 concentration before the injection was 2 . 32 +/- 0 . 49 microg / ml ( n = 11 ) , and 7 days later , it was 3 . 23 +/- 0 . 76 microg / ml ( P = 0 . 33 ) . During the vitrectomy , patients had less intraoperative bleeding when the neovascular tissues were cut . CONCLUSIONS : An intravitreal injection of bevacizumab significantly decreased the free P15692 in the aqueous humor by 7 days , indicating that the clinical effects of bevacizumab appear rapidly . However , intravitreal bevacizumab did not affect the level of intraocular P36955 .\",\n \"[ Intravitreal bevacizumab for neovascular age - related macular degeneration ] . The efficacy and safety of the therapeutic anti - P15692 concept has already been demonstrated for pegaptanib and ranibizumab . DB00112 acts as an antibody against all P15692 isoforms and has been developed for oncological indications with intravenous application . Initial reports on intravitreal administration in patients with neovascular age - related macular disease ( AMD ) have shown beneficial morphological and functional effects . In the meantime , bevacizumab has been used off - label in thousands of patients with AMD . However , data from prospective , controlled , randomized trials on both safety and efficacy are lacking . Herein recent experiences with bevacizumab are summarized and discussed . Furthermore , a web - based platform for online data registration and pooled analyses is presented .\",\n \"Antitumor activity of bevacizumab in combination with capecitabine and oxaliplatin in human colorectal cancer xenograft models . To understand the mechanisms of the effects of combination treatments , we established animal models showing antitumor activity of bevacizumab as a monotherapy and in combination with capecitabine or capecitabine and oxaliplatin and measured thymidine phosphorylase ( TP ) and vascular endothelial growth factor ( P15692 ) levels . Tumor - inoculated nude mice were treated with bevacizumab , capecitabine , and oxaliplatin , alone or in combination , after tumor growth was confirmed and volume and microvessel density ( P53602 ) in tumors were evaluated . Levels of TP and P15692 in the tumor were examined by ELISA . DB00112 showed significant antitumor activity as a monotherapy in three xenograft models ( COL - 16 - Q86SG6 , COLO 205 and CXF280 ) . The P53602 in tumor tissues treated with bevacizumab was lower than that of the control . Antitumor activity of bevacizumab in combination with capecitabine was significantly higher than that of each agent alone ( COL - 16 - Q86SG6 , COLO 205 ) . Furthermore , the antitumor activity of bevacizumab in combination with capecitabine + oxaliplatin was significantly superior to that of capecitabine + oxaliplatin ( COL - 16 - Q86SG6 ) . TP and P15692 levels were not increased by bevacizumab or capecitabine , respectively , suggesting there are other potentially efficacious mechanisms involved . In the present study we established human colorectal cancer xenograft models which reflect the efficacy of clinical combination therapies , capecitabine + bevacizumab and capecitabine + oxaliplatin + bevacizumab . We will further investigate the mechanisms of the combination therapies using these models .\",\n \"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .\",\n \"Advances in Q9BWK5 assessment of gliomas and response to anti - P15692 therapy . DB00112 is thought to normalize tumor vasculature and restore the blood - brain barrier , decreasing enhancement and peritumoral edema . Conventional measurements of tumor response rely upon dimensions of enhancing tumor . After bevacizumab treatment , glioblastomas are more prone to progress as nonenhancing tumor . The RANO ( Response Assessment in Neuro - Oncology ) criteria for glioma response use fluid - attenuated inversion recovery ( FLAIR ) / P24752 hyperintensity as a surrogate for nonenhancing tumor ; however , nonenhancing tumor can be difficult to differentiate from other causes of FLAIR / P24752 hyperintensity ( e . g . , radiation - induced gliosis ) . Due to these difficulties , recent efforts have been directed toward identifying new biomarkers that either predict treatment response or accurately measure response of both enhancing and nonenhancing tumor shortly after treatment initiation . This will allow for earlier treatment decisions , saving patients from the adverse effects of ineffective therapies while allowing them to try alternative therapies sooner . An active area of research is the use of physiologic imaging , which can potentially detect treatment effects before changes in tumor size are evident .\",\n \"From the discovery of vascular endothelial growth factor to the introduction of avastin in clinical trials - an interview with Napoleone Ferrara by Domenico Ribatti . Napoleone Ferrara and his colleagues at Genentech were the first to isolate and clone vascular endothelial growth factor ( P15692 ) in 1989 . DB00117 laboratory has investigated many aspects of P15692 biochemistry and molecular biology . In 1993 , Ferrara reported that inhibition of P15692 - induced angiogenesis by specific monoclonal antibodies resulted in dramatic suppression of the growth of a variety of tumors in vivo . These findings provided an important evidence that inhibition of angiogenesis may suppress tumor growth and blocking P15692 action could have therapeutic value for a variety of malignancies . A further development was the design in a rational fashion in 1997 of a humanized anti - P15692 monoclonal antibody ( DB00112 ) , now in clinical trials as a treatment for several solid tumors and also outside of cancer , in the treatment of age - related macular degeneration ( AMD ) . Ferrara ' s work is revolutionizing quality of life for many of the estimated 1 . 2 million individuals in the US who have wet AMD . Upwards of a million AMD patients worldwide have already received anti - P15692 antibody therapy .\",\n \"The potential role of P15692 - induced vascularisation in the bony repair of injured growth plate cartilage . Growth plate injuries often result in undesirable bony repair causing bone growth defects , for which the underlying mechanisms are unclear . Whilst the key importance of pro - angiogenic vascular endothelial growth factor ( P15692 ) is well - known in bone development and fracture repair , its role during growth plate bony repair remains unexplored . Using a rat tibial growth plate injury repair model with anti - P15692 antibody , DB00112 , as a single i . p . injection ( 2 . 5 mg / kg ) after injury , this study examined the roles of P15692 - driven angiogenesis during growth plate bony repair . Histology analyses observed isolectin - B4 - positive endothelial cells and blood vessel - like structures within the injury site on days 6 and 14 , with anti - P15692 treatment significantly decreasing blood - vessel - like structures within the injury site ( P < 0 . 05 ) . Compared with untreated controls , anti - P15692 treatment resulted in an increase in undifferentiated mesenchymal repair tissue , but decreased bony tissue at the injury site at day 14 ( P < 0 . 01 ) . Consistently , microcomputed tomography analysis of the injury site showed significantly decreased bony repair tissue after treatment ( P < 0 . 01 ) . RT - PCR analyses revealed a significant decrease in osteocalcin ( P < 0 . 01 ) and a decreasing trend in Runx2 expression at the injury site following treatment . Furthermore , growth plate injury - induced reduced tibial lengthening was more pronounced in anti - P15692 - treated injured rats on day 60 , consistent with the observation of a significantly increased height of the hypertrophic zone adjacent to the growth plate injury site ( P < 0 . 05 ) . These results indicate that P15692 is important for angiogenesis and formation of bony repair tissue at the growth plate injury site as well as for endochondral bone lengthening function of the uninjured growth plate .\",\n \"Smith - Magenis syndrome resulting from a de novo direct insertion of proximal 17q into 17p11 . 2 . We report on a de novo intrachromosomal rearrangement of chromosome 17 in a patient with Smith - Magenis syndrome ( P52788 ) . This 11 - year - old boy had short stature , midfacial hypoplasia , and behavioral problems characteristic of this syndrome . Cytogenetic analysis showed that the proximal long arm of a chromosome 17 ( q11 . 2 - q21 . 3 ) was inserted into its short arm at p11 . 2 , resulting in an apparent deletion of the P52788 critical region [ ins ( 17 )( p11 . 2q11 . 2q21 . 3 ) ] . Fluorescence in situ hybridization studies ( Q5TCZ1 ) demonstrated that the inserted segment included both the P04626 and P10276 loci , and dual color hybridizations defined the insertion as direct , with P04626 located more proximally on the short arm of the der ( 17 ) . The resulting deletion of the short arm included loci c130G3 , D17S258 , FLI , and D17S29 , while the more proximal loci , D17S446 and D17S58 , remained apparently unaffected and in their native locations . The CMT1A locus also remained in its native location on the short arm of the metacentric der ( 17 ) chromosome . A de novo intrachromosomal insertional rearrangement of chromosome 17 in a case of P52788 has not been reported previously and further illustrates the instability of this chromosomal region .\",\n \"Suppression of melanoma - associated neoangiogenesis by bevacizumab . BACKGROUND : DB00112 , a potent antibody against the vascular endothelial growth factor ( P15692 ) , has been shown to be effective for treatment of colorectal cancer . Recently , high effectiveness of bevacizumab in combination with paclitaxel has been reported in a single metastatic melanoma case . To our knowledge , we demonstrate for the first time the antiangiogenetic effect of bevacizumab in a patient with a vitreous melanoma metastasis . OBSERVATIONS : A 68 - year - old man with a vitreous melanoma metastasis of the left eye was treated with a revitrectomy combined with intravitreal bevacizumab application because of iris neovascularization and progressive epiretinal tumor plaques . Four days after the treatment , the melanoma - associated neovascularization completely disappeared , but it recurred after 6 weeks . Although repetitive administration of local bevacizumab produced the same antiangiogenetic effect , progression of the epiretinal tumor plaques could not be stopped with the local bevacizumab treatment . CONCLUSIONS : Intraocular administration of the anti - P15692 drug bevacizumab causes immediate and complete regression of melanoma - associated angiogenesis . The rationale for the therapeutic strategy in our patient was an elevated level of P15692 in the vitreous cavity . Because we could not demonstrate a direct antiproliferative effect of bevacizumab on melanoma metastasis , bevacizumab seems most promising if evaluated in combination with antiproliferative agents .\",\n \"___MASK51___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .\",\n \"A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro . Statins and nitrogenous bisphosphonates ( NBP ) inhibit 3 - hydroxy - 3 - methylglutaryl - coenzyme - A reductase ( P04035 ) and farnesyl diphosphate synthase ( P14324 ) , respectively , leading to depletion of farnesyl diphosphate ( FPP ) and disruption of protein prenylation . P37268 ( P37268 ) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis . Herein , we have identified novel bisphosphonates as potent and specific inhibitors of P37268 , including the tetrasodium salt of 9 - biphenyl - 4 , 8 - dimethyl - nona - 3 , 7 - dienyl - 1 , 1 - bisphosphonic acid ( compound 5 ) . Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells . At high concentrations , lovastatin and zoledronate impaired protein prenylation and decreased cell viability , which limits their potential use for cholesterol depletion . When combined with lovastatin , compound 5 prevented lovastatin - induced FPP depletion and impairment of protein farnesylation . Compound 5 in combination with the NBP zoledronate completely prevented zoledronate - induced impairment of both protein farnesylation and geranylgeranylation . Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone . The combination of an P37268 inhibitor with an P04035 or P14324 inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion .\",\n \"DB00112 and ovarian cancer . PURPOSE OF REVIEW : Vascular endothelial growth factor ( P15692 ) , one of the major pathways involved in tumor angiogenesis , is often overexpressed in epithelial ovarian cancer ( EOC ) , and therefore an attractive target for therapy . This review aims to evaluate the rationale for targeting angiogenic pathways by the usage of the anti - P15692 agent bevacizumab in EOC . RECENT FINDINGS : DB00112 monotherapy has been shown to be effective in the treatment of EOC with response rate of 16 - 21 % in phase II trials . In phase III trials , patients with advanced EOC who received combination chemotherapy ( paclitaxel + carboplatin ) plus bevacizumab with maintenance bevacizumab had significantly longer progression - free survival than those who received chemotherapy alone , but did not prolong overall survival . The most common grade 3 / 4 adverse events of bevacizumab monotherapy include hypertension and proteinuria , while heavily pretreated patients were at increased risk of bowel perforation . The addition of bevacizumab to the standard chemotherapy in patients with advanced EOC may not be cost - effective . SUMMARY : DB00112 has significant activity and is the most promising drug in EOC . However , understanding of its unique adverse events and identification of predictive biomarkers of bevacizumab response are necessary in order to select patients most likely to benefit from this therapy .\",\n \"Integrin inhibitor suppresses bevacizumab - induced glioma invasion . Glioblastoma is known to secrete high levels of vascular endothelial growth factor ( P15692 ) , and clinical studies with bevacizumab , a monoclonal antibody to P15692 , have demonstrated convincing therapeutic benefits in glioblastoma patients . However , its induction of invasive proliferation has also been reported . We examined the effects of treatment with cilengitide , an integrin inhibitor , on bevacizumab - induced invasive changes in glioma . U87Δ P00533 cells were stereotactically injected into the brain of nude mice or rats . Five days after tumor implantation , cilengitide and bevacizumab were administered intraperitoneally three times a week . At 18 days after tumor implantation , the brains were removed and observed histopathologically . Next , the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis . DB00112 treatment led to increased cell invasion in spite of decreased angiogenesis . When the rats were treated with a combination of bevacizumab and cilengitide , the depth of tumor invasion was significantly less than with only bevacizumab . Pathway analysis demonstrated the inhibition of invasion - associated genes such as the integrin - mediated cell adhesion pathway in the combination group . This study showed that the combination of bevacizumab with cilengitide exerted its anti - invasive effect . The elucidation of this mechanism might contribute to the treatment of bevacizumab - refractory glioma .\",\n \"In vivo optical molecular imaging of vascular endothelial growth factor for monitoring cancer treatment . PURPOSE : Vascular endothelial growth factor ( P15692 ) expression is a critical component in tumor growth and metastasis . Capabilities to monitor P15692 expression in vivo can potentially serve as a useful tool for diagnosis , prognosis , treatment planning , monitoring , and research . Here , we present the first report of in vivo hyperspectral molecular imaging strategy capable of monitoring treatment - induced changes in P15692 expression . EXPERIMENTAL DESIGN : P15692 was targeted with an anti - P15692 antibody conjugated with a fluorescent dye and was imaged in vivo using a hyperspectral imaging system . The strategy was validated by quantitatively monitoring P15692 levels in three different tumors as well as following photodynamic treatment . Specificity of the molecular imaging strategy was tested using in vivo competition experiments and mathematically using a quantitative pharmacokinetic model . RESULTS : The molecular imaging strategy successfully imaged P15692 levels quantitatively in three different tumors and showed concordance with results from standard ELISA . Changes in tumoral P15692 concentration following photodynamic treatment and DB00112 treatment were shown . Immunohistochemistry shows that ( a ) the P15692 - specific contrast agent labels both proteoglycan - bound and unbound P15692 in the extracellular space and ( b ) the bound P15692 is released from the extracellular matrix in response to photodynamic therapy . In vivo competition experiments and quantitative pharmacokinetic model - based analysis confirmed the high specificity of the imaging strategy . CONCLUSION : This first report of in vivo quantitative optical molecular imaging - based monitoring of a secreted cytokine in tumors may have implications in providing tools for mechanistic investigations as well as for improved treatment design and merits further investigation .\",\n \"Cutaneous thrombogenic vasculopathy associated with bevacizumab therapy . DB00112 , a humanized monoclonal antibody against vascular endothelial growth factor ( P15692 ) , is an angiogenesis inhibitor used to treat a variety of cancers , including lung , colon , cervical , ovarian , and renal cancers as well as glioblastoma . A significant adverse effect associated with its use is one of thromboembolic events . We report a case of a 74 - year - old male with diagnosis of glioblastoma multiforme treated with partial resection , radiation , temozolomide , and bevacizumab . He presented to a plastic surgeon with a several week history of asymptomatic crusted hemorrhagic ulcers and purpuric patches on the lower legs shortly following the initiation of bevacizumab . A biopsy showed an occlusive pauci - inflammatory thrombogenic vasculopathy associated with ischemic epidermal and dermal changes and accompanied by extensive vascular C5b - 9 ( complement C5b - 9 membrane attack complex ) deposition . DB00112 has been associated with thrombotic complications including atypical hemolytic uremic syndrome and arterial and venous thrombosis . C5b - 9 may be the factor most important in the mechanism of vascular thrombosis given the extent of deposition in our index case . Thrombotic events in the skin associated with bevacizumab therapy are without precedent and dermatologists should be aware of this potential complication .\",\n \"Phase I trial of combretastatin A4 phosphate ( DB05284 ) in combination with bevacizumab in patients with advanced cancer . PURPOSE : The vascular disrupting agent ( VDA ) combretastatin A4 phosphate ( DB05284 ) induces significant tumor necrosis as a single agent . Preclinical models have shown that the addition of an anti - P15692 antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity . EXPERIMENTAL DESIGN : Patients with advanced solid malignancies received DB05284 at 45 , 54 , or 63 mg / m ( 2 ) on day 1 , day 8 , and then every 14 days . DB00112 10 mg / kg was given on day 8 and at subsequent cycles four hours after DB05284 . Functional imaging with dynamic contrast enhanced - Q9BWK5 ( DCE - Q9BWK5 ) was conducted at baseline , after DB05284 alone , and after cycle 1 DB05284 + bevacizumab . RESULTS : A total of 63 mg / m ( 2 ) DB05284 + 10 mg / kg bevacizumab q14 is the recommended phase II dose . A total of 15 patients were enrolled . Dose - limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage . Most common toxicities were hypertension , headache , lymphopenia , pruritus , and pyrexia . Asymptomatic electrocardiographic changes were seen in five patients . Nine of 14 patients experienced disease stabilization . A patient with ovarian cancer had a Q8WXI7 response lasting for more than a year . DCE - Q9BWK5 showed statistically significant reductions in tumor perfusion / vascular permeability , which reversed after DB05284 alone but which were sustained following bevacizumab . Circulating P28906 (+) and CD133 (+) bone marrow progenitors increased following DB05284 as did P15692 and granulocyte colony - stimulating factor levels . CONCLUSIONS : DB05284 in combination with bevacizumab appears safe and well tolerated in this dosing schedule . DB05284 induced profound vascular changes , which were maintained by the presence of bevacizumab .\",\n \"Expression of Q99572 receptor increases in vivo tumor growth . The Q99572 receptor is an DB00171 - gated ion channel known for its cytotoxic activity . However , recent evidence suggests a role for Q99572 in cell proliferation . Here , we found that Q99572 exhibits significant growth - promoting effects in vivo . Human embryonic kidney cells expressing Q99572 exhibited a more tumorigenic and anaplastic phenotype than control cells in vivo , and the growth rate and size of these tumors were significantly reduced by intratumoral injection of the Q99572 inhibitor - oxidized DB00171 . The accelerated growth of Q99572 - expressing tumors was characterized by increased proliferation , reduced apoptosis , and a high level of activated transcription factor O95644 . These tumors also showed a more developed vascular network than control tumors and secreted elevated amounts of P15692 . The growth and neoangiogenesis of Q99572 - expressing tumors was blocked by intratumoral injection of the P15692 - blocking antibody DB00112 ( bevacizumab ) , pharmacologic Q99572 blockade , or Q99572 silencing in vivo . Immunohistochemistry revealed strong Q99572 positivity in several human cancers . Together , our findings provide direct evidence that Q99572 promotes tumor growth in vivo .\",\n \"Anti - P15692 therapy in pituitary carcinoma . We report the case of a 44 - year - old male patient with an aggressive silent corticotroph cell pituitary adenoma , subtype 2 . In that it progressed to carcinoma despite temozolomide administration , anti - P15692 therapy was begun . Q9BWK5 , PET scan and pathologic analysis were undertaken . After 10 months of anti - P15692 ( bevacizumab ) treatment no progression of the lesion was noted . The tumor was biopsied and morphological analysis showed severe cell injury , vascular abnormalities and fibrosis . DB00112 treatment has continued for additional 16 months to present with stabilization of disease as documented on serial Q9BWK5 and PET scans . This is the first case of a bevacizumab - treated pituitary carcinoma with long - term , now 26 months , control of disease . The present findings are promising in that anti - angiogenic therapy appears to represent a new option in the treatment of aggressive pituitary tumors .\",\n \"Future directions in vascular endothelial growth factor - targeted therapy for metastatic colorectal cancer . DB00112 , the first approved vascular endothelial growth factor ( P15692 ) - targeted agent for metastatic colorectal cancer , continues to be developed in phase III trials in other tumor types . Its use is being explored not only in advanced disease , but also in earlier - stage disease in the adjuvant setting . Preclinical and clinical research is also addressing several potential strategies for maximizing the benefits of bevacizumab and other P15692 - targeted agents , including ( 1 ) dual inhibition of P15692 and platelet - derived growth factor signaling to target both the endothelial and the pericyte components of tumor vasculature ; ( 2 ) combining P15692 - targeted agents with other targeted agents , such as inhibitors of P04626 or epidermal growth factor receptor signaling , which affect several angiogenic pathways ; and ( 3 ) combining P15692 - targeted agents with low - dose , metronomic chemotherapy . The optimal dose and schedule of P15692 - targeted agents is another unanswered question . Further investigation of the mechanism of action and vascular effects of P15692 - targeted agents in humans will help to address these questions . Mechanistic studies in humans will be aided by the development and validation of surrogate clinical end points such as noninvasive assessment of hemodynamics and vascular changes within tumors , using imaging studies .\",\n \"AAVrh . 10 - mediated genetic delivery of bevacizumab to the pleura to provide local anti - P15692 to suppress growth of metastatic lung tumors . Vascular endothelial growth factor ( P15692 ) produced by tumor cells has a central role in stimulating angiogenesis required for tumor growth . Humanized monoclonal anti - P15692 antibody ( bevacizumab , DB00112 ) , approved as a treatment for non - squamous , non - small cell lung cancer , requires administration every 3 weeks . We hypothesized that an intrapleural administration of an adeno - associated virus ( AAV ) vector expressing an anti - P15692 antibody equivalent of bevacizumab would result in sustained anti - P15692 localized expression within the lung and suppress metastatic tumor growth . The AAV vector AAVrh . 10alphaVEGF encodes the light chain and heavy chain complementary DNAs of monoclonal antibody A . 4 . 6 . 1 , a murine antibody that specifically recognizes human P15692 with the same antigen - binding site as bevacizumab . A metastatic lung tumor model was established in severe combined immunodeficient mice by intravenous administration of human DU145 prostate carcinoma cells . Intrapleural administration of AAVrh . 10alphaVEGF directed long - term expression of the anti - human P15692 antibody in lung , as shown by sustained , high - level anti - human P15692 titers in lung epithelial lining fluid for 40 weeks , which was the duration of the study . In the AAVrh . 10alphaVEGF - treated animals , tumor growth was significantly suppressed ( P < 0 . 05 ) , the numbers of blood vessels and mitotic nuclei in the tumor was decreased ( P < 0 . 05 ) and there was increased survival ( P < 0 . 05 ) . Thus , intrapleural administration of an AAVrh . 10 vector , encoding the murine monoclonal antibody equivalent of bevacizumab , effectively suppresses the growth of metastatic lung tumors , suggesting AAV - mediated gene transfer to the pleura to deliver bevacizumab locally to the lung as a novel alternative platform to conventional monoclonal antibody therapy .\",\n \"The role of bevacizumab in the treatment of non - small cell lung cancer : current indications and future developments . The majority of non - small cell lung cancer ( NSCLC ) patients present with advanced disease , and despite the improvement in efficacy and safety outcomes with platinum - based chemotherapy , this standard cytotoxic approach has reached a therapeutic plateau , with the prognosis for this clinical condition remaining poor . Advances in the knowledge of tumor biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment . DB00112 , an anti - growth factor vascular endothelial growth factor ( P15692 ) monoclonal antibody , is the antiangiogenic agent at the most advanced stage of development in the treatment of solid tumors and also in NSCLC treatment . DB00112 , combined with platinum - based chemotherapy , has been demonstrated to improve efficacy outcomes over chemotherapy alone in the treatment of nonsquamous advanced NSCLC in two phase III randomized trials . These represent the first evidence of improvement in treatment outcomes of chemotherapy with targeted therapies in the first - line treatment of advanced NSCLC . Future clinical developments of bevacizumab in NSCLC treatment will include the combination of this agent with other targeted therapies in advanced disease ( especially with erlotinib , an epidermal growth factor receptor tyrosine kinase inhibitor ) and the integration of this agent into combined modality approaches for the treatment of early - stage and locally advanced disease .\",\n \"DB00112 treatment for human glioblastoma . Can it induce cognitive impairment ? Recent results from 2 double - blind , placebo - controlled phase III trials ( RTOG 0825 ) and ( AVAglio ) for first - line treatment of glioblastoma patients with the P15692 antibody bevacizumab , showed similar results , related to overall and progression - free survival . The RTOG 0825 trial indicated , opposed to the AVAglio trial , that patients treated with bevacizumab showed a decline in global neurocognitive function compared to untreated patients , - a decline that was most obvious after prolonged treatment . At present , there is a considerably controversy related to these observations . In the present work we point at the possibility that bevacizumab treatment of the normal brain can reduce synaptic plasticity in the hippocampus . We believe that such a phenomenon may partly explain the reduced cognitive function observed in patients in the RTOG 0825 trial . Since the same effects were not clearly defined in the AVAglio trial , further studies on putative neurocognitive effects after bevacizumab treatment are warranted .\",\n \"Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab / DB00112 treatment : the role of CXCL cytokines . The anti - P15692 targeted antibody bevacizumab ( BVZ ) has been approved for treating renal cell carcinomas ( RCCs ) . Although BVZ increases the progression - free survival of patients with metastatic RCC , the effect on overall survival is poor . To gain insight into the limited efficacy of BVZ on overall survival , we analyzed patient samples of RCC for angiogenic factors that may participate in escape from anti - P15692 therapy . Our study shows that the level of vascular endothelial growth factor ( P15692 ) in tumors was increased compared with normal tissue . The level of interleukin - 8 / P10145 , a pro - angiogenic member of the CXCL family of cytokines , was also increased in tumors . These observations gave us a good reason to analyze the combined effects of BVZ and anti - P10145 antibodies on tumor growth . Surprisingly , we report that BVZ accelerates the growth of RCC in nude mice with in vivo selection of tumor cells with an increased growth capacity . Downregulation of receptor tyrosine phosphatase - κ , a phosphatase implicated in P01133 receptor regulation , may partly explain this phenomenon . Modification of the vascular network and development of lymphatic vessels through P49767 production and compensatory production of pro - angiogenic CXCL cytokines were also observed . The apparent normalization of the vascular network prompted us to associate BVZ with the chemotherapeutic agent paclitaxel . While efficient in vitro , paclitaxel did not reverse the anti - P15692 effects in vivo . Anti - P10145 - targeting antibodies were promising as they decreased intra - tumor P15692 production ; decreased the pro - angiogenic CXCL / anti - angiogenic CXCL ratio and did not induce lymphangiogenesis . These observations hold clinical implication as they highlight putative markers implicated in escape from BVZ treatment . They also recommend proceeding with caution in the use of anti - P15692 therapy alone for treatment of RCC .\",\n \"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK88___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK88___ .\",\n \"[ ___MASK64___ sodium ( Photofrin - II ) ] . ___MASK64___ sodium ( ___MASK64___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK64___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .\",\n \"Synergy of nab - paclitaxel and bevacizumab in eradicating large orthotopic breast tumors and preexisting metastases . INTRODUCTION : Patients with metastatic disease are considered incurable . We previously showed that nabpaclitaxel ( nanoparticle albumin - embedded paclitaxel ) combined with anti - vascular endothelial growth factor A ( P15692 ) antibody , bevacizumab , eradicates orthotopic small - sized breast tumors and metastasis . Here , we assessed this therapy in two models of advanced ( 450 - 600 mm ( 3 ) ) breast tumors and delineated P15692 - dependent mechanisms of tumor resistance . METHODS : Mice with luciferase - tagged advanced MDA - MB - 231 and MDA - MB - 435 tumors were treated with saline , nab - paclitaxel ( 10 or 30 mg / kg ) , bevacizumab ( 4 mg / kg ) , or combined drugs . Lymphatic and lung metastases were measured by luciferase assay . Proinflammatory and survival pathways were measured by ELISA , Western blot and immunohistochemistry . RESULTS : Nab - paclitaxel transiently suppressed primary tumors by 70 % to 90 % but had no effect on metastasis . Coadministration of bevacizumab increased the response rate to 99 % , including 71 % of complete responses in MDA - MB - 231 - bearing mice treated concurrently with 30 mg / kg of nab - paclitaxel . This combinatory regimen significantly reduced or eliminated preexisting lymphatic and distant metastases in MDA - MB - 231 and MDA - MB - 435 models . The mechanism involves paclitaxel - induced NF - κB pathway that upregulates P15692 and other tumor prosurvival proteins . CONCLUSIONS : DB00112 prevents tumor recurrence and metastasis promoted by nab - paclitaxel activation of NF - κB pathway . Combination therapy with high - dosed nab - paclitaxel demonstrates the potential to eradicate advanced primary tumors and preexisting metastases . These findings strongly support translating this regimen into clinics .\",\n \"Targeted approaches for treating advanced clear cell renal carcinoma . The mainstay of any curative treatment in renal cell carcinoma ( RCC ) is surgery . In the case of metastatic disease at presentation , a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment . Interferon ( IFN ) - a offers in a small but significant percentage of patients advantage in overall survival . Interleukin ( IL ) - 2 - based therapy gives similar survival rates . To date , hormonal therapy and chemotherapy do not have a proven impact on survival . Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel - Lindau ( P40337 ) gene . This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor ( P15692 ) in this highly vascularized tumor . This opens interesting new treatment strategies including blockade of P15692 with the monoclonal antibody bevacizumab ( DB00112 ) and inhibition of P15692 receptor tyrosine kinases with small oral molecules such as sunitinib ( SU11248 , Sutent ) or PTK787 . Likewise , inhibition of the Raf kinase pathway with oral sorafenib ( Bay 43 - 9006 , Nexavar ) or inhibition of the P42345 pathway with intravenous CCI - 779 are under investigation . Preliminary clinical results with all these compounds are promising , and the results of ongoing first - line phase III studies will become available in the next years .\",\n \"Vascular endothelial growth factor ( P15692 ) as a target of bevacizumab in cancer : from the biology to the clinic . Angiogenesis is important in the growth and progression of solid tumours . The main pro - angiogenic factor , namely vascular endothelial growth factor ( P15692 ) , also known as vascular permeability factor , is a potent angiogenic cytokine that induces mitosis and also regulates the permeability of endothelial cells . The soluble isoform of P15692 is a dimeric glycoprotein of 36 - 46 kDa , induced by hypoxia and oncogenic mutation and it binds to two specific tyrosine - kinase receptors : P15692 - 1 ( flt - 1 ) and P15692 - 2 ( P35968 / flk1 ) . An increase in P15692 expression in tumour tissue or some blood compartments ( i . e . serum or plasma ) has been found in solid and haematological malignancies of various origins and is associated with metastasis formation and poor prognosis . DB00112 , a recombinant humanised monoclonal antibody developed against P15692 , binds to soluble P15692 , preventing receptor binding and inhibiting endothelial cell proliferation and vessel formation . Pre - clinical and clinical studies have shown that bevacizumab alone or in combination with a cytotoxic agent decreases tumour growth and increases median survival time and time to tumour progression . DB00112 is the first anti - angiogenetic treatment approved by the American Food and Drug Administration in the first - line treatment of metastatic colorectal cancer . It has shown preliminary evidence of efficacy for breast , non - small - cell lung , pancreatic , prostate , head and neck and renal cancer as well as haematological malignancies . Common toxicities associated with bevacizumab include hypertension , proteinuria , bleeding episodes and thrombotic events . This review summarises the critical role of P15692 and discusses the data available on bevacizumab , from the humanisation of its parent murine monoclonal antibody ( mAb ) A . 4 . 6 . 1 to its use in cancer clinical trials .\",\n \"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK18___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .\",\n \"Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer . Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer , but the clinical benefits are usually transitory . The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab . For this , angiogenesis - focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control . Reverse transcription - PCR was used for results validation . The insulin growth factor 1 ( DB01277 ) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab . Cixutumumab was used to block DB01277 signaling in vivo . Dual anti - P15692 and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth . Immunohistochemistry measured multivessel density , Akt activation , and cell proliferation , whereas terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling ( TUNEL ) assay measured apoptosis in ovarian cancer xenografts . DB00112 and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway . The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone . In summary , DB01277 activation represents an important mechanism of adaptive escape during anti - P15692 therapy in ovarian cancer . This study provides the rationale for designing bevacizumab - based combination regimens to enhance antitumor activity .\",\n \"P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .\",\n \"Current opinion on bevacizumab on endometrial cancer treatment . INTRODUCTION : Advanced or recurrent endometrial cancer is still a challenge for clinicians as it has a poor prognosis despite treatment efforts . Thus , there is an urgent need for new agents with activity in this subset of patients . The increased knowledge of the molecular aspects of endometrial carcinogenesis has led to the development of molecular targeted therapies and in particular anti - angiogenic drugs . One of the most promising of these agents is bevacizumab , a recombinant humanized immunoglobulin monoclonal antibody to P15692 . AREAS COVERED : The objective of this paper is to discuss the role of angiogenesis in endometrial cancer and analyze the rational of bevacizumab use , alone or in combination with other therapies , in endometrial cancer patients . We reviewed the most important preclinical and clinical studies published on this topic up to March 2014 . EXPERT OPINION : DB00112 in combination with others targeted therapies , chemotherapy or radiotherapy demonstrated promising anti - tumor activity . Despite the good oncological outcomes of these recent clinical experiences , caution must be used in light of significant toxicity reported in this subset of heavily pre - treated patients . The identification of biomarkers able to predict either the efficacy or toxicity of anti - angiogenic drugs is a compelling need .\",\n \"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .\",\n \"Identification of microRNAs involved in the modulation of pro - angiogenic factors in atherosclerosis by a polyphenol - rich extract from propolis . New vessel formation plays a critical role in the progression and vulnerability of atherosclerotic lesions . It has been shown that polyphenols from propolis attenuate the progression of atherosclerosis and also exert inhibitory effects on angiogenic factors . However , the mechanisms underlying these effects are not completely understood . Thus , this study aimed to identify microRNAs ( miRNAs ) involved in the modulation of pro - angiogenic factors in the atherosclerotic plaques of P01130 gene knockout mice treated with a polyphenol - rich extract of Chilean propolis . The progression of the atherosclerotic lesions was significantly attenuated in treated mice compared with control mice . Using microarray analysis and a bioinformatic approach , we identified 29 differentially expressed miRNAs . Many of these miRNAs were involved in biological processes associated with angiogenesis , such as the cell cycle , cell migration , cell growth and proliferation . Among them , three miRNAs ( miR - 181a , miR - 106a and miR - 20b ) were over - expressed and inversely related to the expression of Vegfa ( vascular endothelial growth factor A ) and Hif1a ( hypoxia inducible factor 1 alpha ) . In addition , P15692 protein expression was attenuated in histological sections obtained from the aortic sinuses of treated mice . P15692 is a key pro - angiogenic factor in atherosclerotic plaques , and Hif1a , which is expressed in the necrotic nucleus of the atheroma , is its main inducer . We found a correlation between the over - expression of miR - 181a , miR - 106a and miR - 20b and their target genes , Hif1a and Vegfa , which is consistent with attenuation of the atherosclerotic lesion . In conclusion , our data analysis provides evidence that the anti - angiogenic effects of polyphenols from Chilean propolis can be modulated by miRNAs , in particular miR - 181a , miR - 106a and miR - 20b .\",\n \"Phase I safety and pharmacokinetic study of bevacizumab in Chinese patients with advanced cancer . BACKGROUND : bevacizumab is a humanized recombinant vascular endothelial growth factor ( P15692 ) monoclonal antibody , which specifically binds to P15692 and inhibits tumor cell growth , proliferation and metastasis . We aimed to investigate the safety and pharmacokinetics of bevacizumab in Chinese patients with advanced cancer . METHODS : Thirty - nine Chinese patients with metastatic or relapsed cancers who failed prior therapy were enrolled in this phase I study of bevacizumab . DB00112 was infused by a calculated pump at doses from 5 mg / kg to 15 mg / kg in 90 minutes . Patients underwent serial pharmacokinetic evaluations . Patients that received at least one infusion of bevacizumab were included in the safety study . RESULTS : Thirty - five patients finished all 5 infusions following protocol . One patient withdrew after 3 infusions due to grade 3 proteinuria . Common adverse events possibly related to the study drug were proteinuria ( 17 / 39 , 43 . 6 % ) , hypertension ( 13 / 39 , 33 . 3 % ) , gingival bleeding ( 7 / 39 , 17 . 9 % ) , epistaxis ( 6 / 39 , 15 . 4 % ) , pharyngeal inflammation ( 6 / 39 , 15 . 4 % ) , fatigue ( 6 / 39 , 15 . 4 % ) and stomatitis ( 4 / 39 , 10 . 3 % ) . DB00112 pharmacokinetics was linear within the range of 5 mg / kg q2w -- 10 mg / kg q2w and 15 mg / kg q3w . CL ( clearance ) , Vd ( volume of distribution at elimination ) and Vss ( volume of distribution at steady state ) were similar after single and multiple doses at 5 , 10 and 15 mg / kg . CONCLUSIONS : DB00112 is well tolerated in Chinese patients . No unexpected adverse events were observed . There is no racial difference in the pharmacokinetics .\",\n \"4 -[ 3 , 5 - Bis ( trimethylsilyl ) benzamido ] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor . 4 -[ 3 , 5 - bis ( trimethylsilyl ) benzamido ] Benzoic acid ( TAC - 101 ) has potent antiproliferative , antiangiogenic , and antitumor effects in vitro and in vivo . These effects might be due to TAC - 101 binding to retinoic acid receptor alpha ( P10276 ) and interfering with the binding of activator protein - 1 ( AP - 1 ) to DNA . However , little is known about the detailed mechanism of TAC - 101 function . We investigated the mechanism of the antiangiogenic effect of TAC - 101 using a rat hepatic metastatic model in vivo and DLD - 1 human colon cancer cells in vitro . Liver metastases were induced by portal injection of Q15293 - 9 rat colonic cancer cells into F344 rats . TAC - 101 ( 8 mg / kg ) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density ( P53602 ) and vascular endothelial growth factor ( P15692 ) . TAC - 101 significantly reduced both P53602 and P15692 expression . Northern blot analysis and ELISA indicated that TAC - 101 efficiently inhibited production of P15692 mRNA and protein in DLD - 1 cells in a time - and dose - dependent manner . These findings suggest that TAC - 101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of P15692 .\",\n \"Global reported endophthalmitis risk following intravitreal injections of anti - P15692 : a literature review and analysis . PURPOSE : To report on endophthalmitis occurrence and associated risk factors following the intravitreal injection of anti - P15692 agents based on a review of published literature . MATERIALS AND METHODS : A Medline search was performed using the terms \\\" bevacizumab \\\" and \\\" ranibizumab \\\" . A total of 534 English - language articles of varying design and published from 2006 to November 2013 were analyzed for endophthalmitis occurrence and contributing perioperative factors . RESULTS : A total of 445 , 503 injections were counted . There were 103 cases of postinjection endophthalmitis in 176 , 124 injections ( 0 . 058 % ) with bevacizumab ( DB00112 ) versus 79 cases in 269 , 379 injections ( 0 . 029 % ) with ranibizumab ( Lucentis ) . This difference was due to a significantly higher occurrence of culture - negative endophthalmitis associated with bevacizumab injections . Culture - positive risk was not statistically different between the two drugs . The reported use of postinjection topical antibiotics increased the risk of culture - positive endophthalmitis . No association was found with the use of povidone iodine , a lid speculum , a mask , or an operating room . Streptococcus spp . were the most prevalent causative organism , accounting for nine of 54 ( 17 % ) of all culture - positive cases . CONCLUSION : Reported postinjection endophthalmitis occurred significantly more in patients treated with bevacizumab than those treated with ranibizumab . However , culture - positive occurrence was similar . Despite the potential for contamination at the time of drug compounding , bevacizumab does not appear to confer a higher risk of culture - positive endophthalmitis than ranibizumab . This study also suggests antibiotic use may increase endophthalmitis occurrence .\",\n \"Preclinical evaluation of holmium - 166 labeled anti - P15692 ( DB00112 ) . Radiolabeled antiangiogenic monoclonal antibodies are potential agents for targeted therapy in specific types of malignancies . In this study , ( 166 ) Ho - DOTA - DB00112 was used in biodistribution studies using single - photon emission computed tomography ( SPECT ) to acquire dosimetric aspects of the radiolabeled antibody in mice . The liver toxicity of the radiolabeled antibody was also determined using serum glutamic pyruvic transaminase , serum glutamic oxaloacetic transaminase and alkaline phosphatase assay 2 - 7 days post - injection . The SPECT biodistribution demonstrated a similar pattern as the other radiolabeled anti - vascular endothelial growth factor A ( P15692 ) immunoconjugates . ( 166 ) Ho - DOTA - DB00112 was revealed as a potential compound for therapy / imaging of P15692 expression in oncology .\",\n \"[ DB00112 and invasive procedures : practical recommendations ] . As first line chemotherapy DB00112 , associated with a platinum based regime , improves survival in patients with metastatic , non small cell , non epidermoid bronchial carcinoma . Marketing authorization for this indication was obtained in 2007 . This treatment produces specific secondary effects related to its anti - angiogenic action . Physiologically , vascular endothelial growth factor ( P15692 ) is important in the process of scar formation . DB00112 inhibits scar formation and may encourage bleeding . The aim of this article is to analyse the specific risks associated with invasive procedures and to produce practical recommendations . Unfortunately there are few data in the literature . We depend , therefore , principally on studies of neo - adjuvant chemotherapy in metastatic colo - rectal cancer prior to excision of hepatic metastases and on our own experience of excision of pulmonary metastases from solid tumours treated with bevacizumab . We recommend a delay of 2 days between implantation of an intravenous device and the initiation of bevacizumab , a delay of at least 5 weeks between the last injection of bevacizumab and invasive surgery and a delay of 4 weeks between surgery and the initiation of bevacizumab treatment . Obviously , referral to a medico - surgical team experienced in the management of these patients is strongly recommended .\",\n \"Accomplishments in 2008 in the treatment of advanced metastatic colorectal cancer . Overview of the Disease IncidencePredictive BiomarkersCurrent General Therapy StandardsAccomplishments During the Year Combined Modality Management of Liver MetastasesTreatment of Advanced Disease Equivalence of FOLFOX and CAPOXAddition of DB00112 to Standard ChemotherapyDual P00533 and P15692 InhibitionBevacizumab Upon Progression While on First - Line TherapyBenefit in the Elderly PopulationWhat Needs to be Done Comments on ResearchObstacles to Progress .\",\n \"Synthesis and evaluation of ( 99m ) Tc chelate - conjugated bevacizumab . Vascular endothelial growth factor ( P15692 ) is one of the classic factors involved in tumor - induced angiognesis in several solid tumors . DB00112 , a monoclonal antibody against P15692 , can be used as an imaging tool in preclinical studies . The aim of this study was to radiolabel DB00112 with ( 99m ) Tc and to evaluate in vivo its imaging properties in an adenocarcinoma animal model . For this purpose , DB00112 was derivatized with Suc - HYNIC as a bifunctional coupling agent . A mixture of Tricine / SnCl ( 2 ). 2H ( 2 ) O was added to DB00112 - HYNIC and radiolabeled with ( 99m ) TcO ( 4 )(-) . The radiochemical stability of the radiolabeled antibody was assessed . Biodistribution and scintigraphy imaging were performed in normal CD1 female mice and in spontaneous adenocarcinoma tumor bearing CD1 mice ( n = 5 ) . We demonstrated that 99mTc - HYNIC - DB00112 was stable . In vivo biodistribution studies revealed that tumor uptake of ( 99m ) Tc - HYNIC - DB00112 was 1 . 37 ± 0 . 51 % and 5 . 33 ± 2 . 13 % at 4 and 24 h postinjection , respectively . Scintigraphy image studies showed tumor selective uptake of ( 99m ) Tc - HYNIC - DB00112 in the tumor - bearing mice . We conclude that ( 99m ) Tc - HYNIC - Bevacizumb has the potential to be used as a tracer for tumor imaging in preclinical studies .\",\n \"Next generation molecular targeted agents for breast cancer : focus on P00533 and VEGFR pathways . Here we reviewed the recent progress of molecular targeting drugs , including trastuzumab , lapatinib , erlotinib and bevacituzumab . Fortunately , Her - 2 positive cases of metastatic or relapsed cases , those with the worse prognosis , are responsive to trastuzumab - based chemotherapy . ___MASK35___ will likely be effective against trastuzumab - resistant cases and brain metastases . Furthermore , the introduction of bevacituzumab will improve P15692 - VEGFR - associated tumor growth .\",\n \"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK43___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .\",\n \"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK19___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .\",\n \"[ Tumor vasculature as a therapeutic target in non - small cell lung cancer ] . Despite developments in conventional ( chemo ) radiotherapy and surgery , survival of non - small cell lung cancer ( NSCLC ) patients remains poor . Treatments with targeted molecular drugs offer novel therapeutic strategies . DB00112 , a recombinant anti - vascular endothelial growth factor ( P15692 ) antibody , is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC . However , a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain . Furthermore , novel agents targeting the pre - existing NSCLC vasculature ( i . e . vascular disrupting agents , VDAs ) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies . Herein , we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC .\",\n \"Vascular endothelial growth factor in fellow eyes of eyes injected with intravitreal bevacizumab . BACKGROUND : To study the effect on untreated fellow eyes of eyes treated with an intravitreal injection of bevacizumab . METHODS : DB00112 ( 1 . 25 mg / 0 . 05 ml ) was injected into the vitreous cavity of one eye ( the first eye ) as a preoperative adjunctive therapy for proliferative diabetic retinopathy ; vitrectomy was performed 1 week later . Immediately after vitrectomy , bevacizumab ( 1 . 25 mg / 0 . 05 ml ) was injected into the fellow eye ( the second eye ) followed by vitrectomy 1 week later . Aqueous humor samples were obtained from both eyes in five cases just before intravitreal injection of bevacizumab and just before vitrectomy 1 week later . Vascular endothelial growth factor ( P15692 ) concentrations in the aqueous humor were measured by enzyme - linked immunosorbent assay ( ELISA ) . RESULTS : P15692 concentrations in the aqueous humor of the first eyes ranged from 146 to 398 pg / ml ( mean , 302 +/- 100 pg / ml ) before intravitreal injection of bevacizumab ; 1 week later , the P15692 concentrations in the injected eyes were less than 31 pg / ml , the lower limit of the ELISA , in all cases ( p < 0 . 001 ) . The concentrations in the uninjected fellow eyes ranged from 181 to 551 pg / ml ( mean , 382 +/- 119 pg / ml ) . CONCLUSIONS : There seemed to be no or a minimal effect of the intravitreal injections of bevacizumab on the uninjected fellow eyes .\"\n]"},"candidates":{"kind":"list like","value":["___MASK18___","___MASK19___","___MASK35___","___MASK43___","___MASK51___","___MASK54___","___MASK64___","___MASK75___","___MASK88___"],"string":"[\n \"___MASK18___\",\n \"___MASK19___\",\n \"___MASK35___\",\n \"___MASK43___\",\n \"___MASK51___\",\n \"___MASK54___\",\n \"___MASK64___\",\n \"___MASK75___\",\n \"___MASK88___\"\n]"},"answer":{"kind":"string","value":"___MASK18___"},"id":{"kind":"string","value":"MH_train_476"}}},{"rowIdx":477,"cells":{"query":{"kind":"string","value":"interacts_with DB01278?"},"supports":{"kind":"list like","value":["Biomarkers for assessing therapeutic response in bladder cancer . Reliable markers for assessing therapeutic response are needed to select the most effective treatment strategy for bladder cancer patients . We analyzed the role of biomarkers predicting response of non - muscle invasive bladder cancer ( NMIBC ) on BCG induction , and of non - organ confined muscle invasive bladder cancer ( MIBC ) on neoadjuvant chemotherapy . A critical , non - structured review of the literature was conducted . For assessing BCG therapy outcome , measurement of urinary P60568 levels seems to be the most potent marker of all the clinical parameters reviewed . Measurements of urinary interleukins P10145 , Q14116 , and tumour necrosis factor apoptosis - inducing ligand levels seem promising as well . Immunohistochemical markers ( ie , P04637 , Ki - 67 , and Rb ) display contradictory results and seem unsuitable . Gene polymorphisms need to be studied more thoroughly before their clinical relevance can be determined . Regarding assessing and predicting response of MIBC to neoadjuvant chemotherapy , a set of potent markers has been studied . However , no conclusive evidence is yet available on their additional value over the established clinicopathological variables . Prospective trials are needed to validate the clinical benefit of molecular markers to predict response to BCG ( NMIBC ) and neoadjuvant chemotherapy ( MIBC ) before predictive biomarkers can become part of clinical practice .","P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK26___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .","___MASK20___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK20___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .","Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK93___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .","Genomic instability and poor prognosis associated with abnormal P04637 in breast carcinomas . Molecular and immunohistochemical analysis . Alterations of the P04637 gene were analyzed in samples from 87 primary breast cancer patients , using molecular and immunohistochemical approaches . Mutations were detected in 17 % of the samples , using polymerase chain reaction ( PCR ) and constant denaturant gel electrophoresis ( CDGE ) on exons 5 - 8 of the P04637 gene , and were confirmed by sequencing . Abnormal P04637 protein staining was found in 55 % of the primary samples , using the monoclonal P04637 antibody DO7 . A statistically significant association was found between P04637 mutations and abnormal protein staining ( p = 0 . 002 ) . Our results suggest that dysfunction of the P04637 protein is associated with tumor progression , as we found an association between P04637 abnormalities and accumulation of genetic lesions , measured as overall allelic imbalance ( AI ) , homogeneously staining regions ( HSR ) and strong P04626 overexpression . Furthermore , patients with P04637 mutation had a highly elevated risk of dying from breast cancer during the study period ( p < 0 . 001 , RR = 10 . 68 ) at a median follow - up time of 42 months . Abnormal P04637 staining was much more frequent than the mutations , but it was not of prognostic significance , whereas strong staining was an independent prognostic factor . We therefore conclude that loss of functional P04637 leads to genetic instability , resulting in poorer short - term prognosis , and that only strong staining of P04637 , and not abnormal protein staining in general , is of prognostic significance .","Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK82___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .","P10275 - induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53 / p73 - mediated apoptosis in breast carcinomas . P10275 ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR ' s anti - tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 and O15350 , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 are AR - target genes , mediating androgen - induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas .","P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK29___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK29___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .","P10997 - driven metabolic reprogramming induces regression of p53 - deficient tumours in vivo . P04637 is commonly altered in human cancer , and Tp53 reactivation suppresses tumours in vivo in mice ( P04637 and Tp53 are also known as p53 ) . This strategy has proven difficult to implement therapeutically , and here we examine an alternative strategy by manipulating the p53 family members , Tp63 and Tp73 ( also known as p63 and p73 , respectively ) . The acidic transactivation - domain - bearing ( TA ) isoforms of p63 and p73 structurally and functionally resemble p53 , whereas the ΔN isoforms ( lacking the acidic transactivation domain ) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant - negative fashion against p53 , TAp63 and TAp73 to inhibit their tumour - suppressive functions . The p53 family interacts extensively in cellular processes that promote tumour suppression , such as apoptosis and autophagy , thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway . Here we show that deletion of the ΔN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53 - deficient tumours through upregulation of P10997 , the gene that encodes amylin , a 37 - amino - acid peptide co - secreted with insulin by the β cells of the pancreas . We found that P10997 is causally involved in this tumour regression and that amylin functions through the calcitonin receptor ( CalcR ) and receptor activity modifying protein 3 ( O60896 ) to inhibit glycolysis and induce reactive oxygen species and apoptosis . DB01278 , a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes , caused rapid tumour regression in p53 - deficient thymic lymphomas , representing a novel strategy to target p53 - deficient cancers .","E3 ubiquitin ligase Q13049 negatively regulates tumor suppressor p53 to promote tumorigenesis . P04637 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses , including apoptosis , cell cycle arrest and senescence . To ensure its proper levels and functions in cells , p53 is tightly regulated mainly through post - translational modifications , such as ubiquitination . Here , we identified E3 ubiquitin ligase Q13049 as a novel p53 target gene and negative regulator to regulate p53 - mediated stress responses . In response to stress , such as DNA damage , p53 binds to the p53 responsive element in the promoter of the Q13049 gene and transcriptionally induces the expression of Q13049 in cells . In turn , Q13049 interacts with p53 and promotes p53 degradation through ubiquitination . Thus , Q13049 negatively regulates p53 - mediated apoptosis , cell cycle arrest and senescence in response to stress . Q13049 is frequently overexpressed in different types of human tumors . Q13049 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53 - dependent manner . Taken together , our results demonstrated that as a novel p53 target and a novel negative regulator for p53 , Q13049 has an important role in regulation of p53 and p53 - mediated cellular stress responses . Furthermore , our results also revealed that impairing p53 function is a novel mechanism for Q13049 in tumorigenesis .","___MASK45___ for joints and bones . ___MASK45___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK45___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK45___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .","P10997 - leptin coadministration stimulates central histaminergic signaling in rats . Combined amylin + leptin ( Q9BXJ7 + P41159 ) can reduce diet induced obesity and is very effective in combating P41159 resistance . The purpose of this study was to evaluate the effect of Q9BXJ7 + P41159 on central histaminergic signaling in lean and obese rats . Male rats were administered P41159 ( 300 μg / kg / d ) , Q9BXJ7 ( 100 μg / kg / d ) , Q9BXJ7 + P41159 or vehicle ( SAL , 0 . 9 % normal saline ) , via a subcutaneous mini - osmotic pump or single injection ( P41159 , 300 μg / kg and Q9BXJ7 , 100 μg / kg ) for acute studies . Q9BXJ7 + P41159 administration increased expression of histamine H1 receptor ( HIR ) and histidine decarboxylase ( HDC ) mRNA in the hypothalamus . Increased levels of P35367 were seen in arcuate ( Arc ) and ventromedial hypothalamus ( VMH ) as well as the area postrema ( APOS ) and nucleus of solitary tract ( P30990 ) following Q9BXJ7 + P41159 administration . APOS and P30990 also showed expression of immediate early gene c - P01100 in the hindbrain in Q9BXJ7 + P41159 - treated rats . We confirmed previous evidence indicating that Q9BXJ7 + P41159 increased P35610 - 3 protein phosphorylation in Arc and VMH . Finally , by in vivo microdialysis , we observed an increase in methyl P42357 levels in the VMH of Q9BXJ7 , P41159 and Q9BXJ7 + P41159 - treated rats . Taken together , these observations are consistent with an important role that neuronal P42357 may play in mediating the potent effects of Q9BXJ7 + P41159 on food intake and body weight .","Control of the P29323 Q96HU1 kinase cascade by Ras and Raf . Activation of ERKs plays a central part in the control of cell proliferation . In this chapter , we have concentrated on the identification and regulation of the kinases that activate Mek . We have chosen to focus on this area because of the many puzzles associated with it . Key issues for the future are the need to derive methods to determine what contribution each individual activator makes to both the magnitude and duration of Mek activation and understanding the mechanisms of regulation . Furthermore , we have considered the roles of Raf and the other kinases solely as Mek activators ; they may well have other substrates including cdc25A ( Galaktionov et al , 1995 ) , I kappa B ( Li and Sedivy , 1993 ) and P04637 ( Jamal and Ziff , 1995 ) .","Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK36___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .","Pathway based analysis of SNPs with relevance to ___MASK88___ therapy : relation to intratumoral mRNA expression and survival . Genetic factors are thought to play a role in resistance towards chemotherapeutic agents such as 5 - fluorouracil ( ___MASK88___ ) . Approximately 30 genes are directly or indirectly involved in ___MASK88___ metabolism , and genetic variation in any of these may contribute to anti - tumor response . Polymorphisms in these genes were analyzed in relation to tumoral mRNA levels of ___MASK88___ metabolizing genes , response to chemotherapy and survival . A total of 21 genetic variants were studied in 35 breast cancer patients treated with 5 - FluoroUracil , mitomycin ( FUMI ) and in a similar cohort of 90 doxorubicin treated breast cancer patients . Genotype distributions were compared using 109 healthy controls . No significant association was found between any polymorphisms and response to chemotherapy as measured by shrinkage of tumor . However , carriers of 3 copies of the P04818 5 ' UTR repeat had shorter survival than noncarriers ( p = . 048 ) in the FUMI treatment group , but not in the doxorubicin treated group . Carriers of 3 copies of the repeat were also more frequently observed in both patients groups than in healthy controls ( p = . 034 ) . Several highly significant associations were observed between genotypes and expression levels of ___MASK88___ metabolizing genes . A SNP in codon 72 of P04637 was revealed to be a key regulator of ___MASK88___ metabolizing genes such as P00374 and P42898 , constituting 50 % of all significant associations observed after FUMI therapy . These data suggest that 3 copies of the P04818 5 ' UTR repeat may give a treatment specific reduced survival in breast cancer patients , and that P04637 may have a direct , allele specific , role in ___MASK88___ mediated response .","Expression of the calcitonin receptor , calcitonin receptor - like receptor , and receptor activity modifying proteins during osteoclast differentiation . The expressions of the calcitonin receptor ( CTR ) , the calcitonin receptor - like receptor ( CLR ) , the receptor activity - modifying proteins ( RAMP ) 1 - 3 , and of the receptor component protein ( RCP ) have been studied in mouse bone marrow macrophages ( BMM ) during osteoclast differentiation , induced by treatment with P09603 and O14788 . Analyses of mRNA showed that CLR and O60894 - 3 , but not CTR , were expressed in P09603 stimulated BMM . O14788 gradually increased CTR mRNA , transiently enhanced CLR and transiently decreased O60894 mRNA , but did not affect O60895 , O60896 , or RCP mRNA . However , O14788 did not affect protein levels of CLR or O60894 - 3 as assessed by Western blots or FACS analyses , whereas immunocytochemistry showed enhanced CTR protein . Analyses of DB02527 production showed that BMM cells expressed functional receptors for calcitonin gene - related peptide ( P80511 ) , amylin , adrenomedullin , and intermedin , but not for calcitonin and calcitonin receptor stimulating peptide ( CRSP ) , but that O14788 induced the expression of receptors for calcitonin and CRSP as well . P01258 , P80511 , amylin , adrenomedullin , intermedin , and CRSP all down regulated the CTR mRNA , but none of the peptides caused any effects on the expression of CLR or any of the RAMPs . Our data show that BMM cells express receptors for P80511 , amylin , adrenomedullin , and intermedin and that O14788 induces the formation of receptors for calcitonin and CRSP in these cells . We also show , for the first time , that the CTR is not only down regulated by signaling through the CTR but also by the peptides signaling through CLR / RAMPs .","P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK73___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 ."],"string":"[\n \"Biomarkers for assessing therapeutic response in bladder cancer . Reliable markers for assessing therapeutic response are needed to select the most effective treatment strategy for bladder cancer patients . We analyzed the role of biomarkers predicting response of non - muscle invasive bladder cancer ( NMIBC ) on BCG induction , and of non - organ confined muscle invasive bladder cancer ( MIBC ) on neoadjuvant chemotherapy . A critical , non - structured review of the literature was conducted . For assessing BCG therapy outcome , measurement of urinary P60568 levels seems to be the most potent marker of all the clinical parameters reviewed . Measurements of urinary interleukins P10145 , Q14116 , and tumour necrosis factor apoptosis - inducing ligand levels seem promising as well . Immunohistochemical markers ( ie , P04637 , Ki - 67 , and Rb ) display contradictory results and seem unsuitable . Gene polymorphisms need to be studied more thoroughly before their clinical relevance can be determined . Regarding assessing and predicting response of MIBC to neoadjuvant chemotherapy , a set of potent markers has been studied . However , no conclusive evidence is yet available on their additional value over the established clinicopathological variables . Prospective trials are needed to validate the clinical benefit of molecular markers to predict response to BCG ( NMIBC ) and neoadjuvant chemotherapy ( MIBC ) before predictive biomarkers can become part of clinical practice .\",\n \"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK26___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .\",\n \"___MASK20___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK20___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .\",\n \"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK93___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .\",\n \"Genomic instability and poor prognosis associated with abnormal P04637 in breast carcinomas . Molecular and immunohistochemical analysis . Alterations of the P04637 gene were analyzed in samples from 87 primary breast cancer patients , using molecular and immunohistochemical approaches . Mutations were detected in 17 % of the samples , using polymerase chain reaction ( PCR ) and constant denaturant gel electrophoresis ( CDGE ) on exons 5 - 8 of the P04637 gene , and were confirmed by sequencing . Abnormal P04637 protein staining was found in 55 % of the primary samples , using the monoclonal P04637 antibody DO7 . A statistically significant association was found between P04637 mutations and abnormal protein staining ( p = 0 . 002 ) . Our results suggest that dysfunction of the P04637 protein is associated with tumor progression , as we found an association between P04637 abnormalities and accumulation of genetic lesions , measured as overall allelic imbalance ( AI ) , homogeneously staining regions ( HSR ) and strong P04626 overexpression . Furthermore , patients with P04637 mutation had a highly elevated risk of dying from breast cancer during the study period ( p < 0 . 001 , RR = 10 . 68 ) at a median follow - up time of 42 months . Abnormal P04637 staining was much more frequent than the mutations , but it was not of prognostic significance , whereas strong staining was an independent prognostic factor . We therefore conclude that loss of functional P04637 leads to genetic instability , resulting in poorer short - term prognosis , and that only strong staining of P04637 , and not abnormal protein staining in general , is of prognostic significance .\",\n \"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK82___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .\",\n \"P10275 - induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53 / p73 - mediated apoptosis in breast carcinomas . P10275 ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR ' s anti - tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 and O15350 , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 are AR - target genes , mediating androgen - induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas .\",\n \"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK29___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK29___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .\",\n \"P10997 - driven metabolic reprogramming induces regression of p53 - deficient tumours in vivo . P04637 is commonly altered in human cancer , and Tp53 reactivation suppresses tumours in vivo in mice ( P04637 and Tp53 are also known as p53 ) . This strategy has proven difficult to implement therapeutically , and here we examine an alternative strategy by manipulating the p53 family members , Tp63 and Tp73 ( also known as p63 and p73 , respectively ) . The acidic transactivation - domain - bearing ( TA ) isoforms of p63 and p73 structurally and functionally resemble p53 , whereas the ΔN isoforms ( lacking the acidic transactivation domain ) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant - negative fashion against p53 , TAp63 and TAp73 to inhibit their tumour - suppressive functions . The p53 family interacts extensively in cellular processes that promote tumour suppression , such as apoptosis and autophagy , thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway . Here we show that deletion of the ΔN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53 - deficient tumours through upregulation of P10997 , the gene that encodes amylin , a 37 - amino - acid peptide co - secreted with insulin by the β cells of the pancreas . We found that P10997 is causally involved in this tumour regression and that amylin functions through the calcitonin receptor ( CalcR ) and receptor activity modifying protein 3 ( O60896 ) to inhibit glycolysis and induce reactive oxygen species and apoptosis . DB01278 , a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes , caused rapid tumour regression in p53 - deficient thymic lymphomas , representing a novel strategy to target p53 - deficient cancers .\",\n \"E3 ubiquitin ligase Q13049 negatively regulates tumor suppressor p53 to promote tumorigenesis . P04637 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses , including apoptosis , cell cycle arrest and senescence . To ensure its proper levels and functions in cells , p53 is tightly regulated mainly through post - translational modifications , such as ubiquitination . Here , we identified E3 ubiquitin ligase Q13049 as a novel p53 target gene and negative regulator to regulate p53 - mediated stress responses . In response to stress , such as DNA damage , p53 binds to the p53 responsive element in the promoter of the Q13049 gene and transcriptionally induces the expression of Q13049 in cells . In turn , Q13049 interacts with p53 and promotes p53 degradation through ubiquitination . Thus , Q13049 negatively regulates p53 - mediated apoptosis , cell cycle arrest and senescence in response to stress . Q13049 is frequently overexpressed in different types of human tumors . Q13049 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53 - dependent manner . Taken together , our results demonstrated that as a novel p53 target and a novel negative regulator for p53 , Q13049 has an important role in regulation of p53 and p53 - mediated cellular stress responses . Furthermore , our results also revealed that impairing p53 function is a novel mechanism for Q13049 in tumorigenesis .\",\n \"___MASK45___ for joints and bones . ___MASK45___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK45___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK45___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .\",\n \"P10997 - leptin coadministration stimulates central histaminergic signaling in rats . Combined amylin + leptin ( Q9BXJ7 + P41159 ) can reduce diet induced obesity and is very effective in combating P41159 resistance . The purpose of this study was to evaluate the effect of Q9BXJ7 + P41159 on central histaminergic signaling in lean and obese rats . Male rats were administered P41159 ( 300 μg / kg / d ) , Q9BXJ7 ( 100 μg / kg / d ) , Q9BXJ7 + P41159 or vehicle ( SAL , 0 . 9 % normal saline ) , via a subcutaneous mini - osmotic pump or single injection ( P41159 , 300 μg / kg and Q9BXJ7 , 100 μg / kg ) for acute studies . Q9BXJ7 + P41159 administration increased expression of histamine H1 receptor ( HIR ) and histidine decarboxylase ( HDC ) mRNA in the hypothalamus . Increased levels of P35367 were seen in arcuate ( Arc ) and ventromedial hypothalamus ( VMH ) as well as the area postrema ( APOS ) and nucleus of solitary tract ( P30990 ) following Q9BXJ7 + P41159 administration . APOS and P30990 also showed expression of immediate early gene c - P01100 in the hindbrain in Q9BXJ7 + P41159 - treated rats . We confirmed previous evidence indicating that Q9BXJ7 + P41159 increased P35610 - 3 protein phosphorylation in Arc and VMH . Finally , by in vivo microdialysis , we observed an increase in methyl P42357 levels in the VMH of Q9BXJ7 , P41159 and Q9BXJ7 + P41159 - treated rats . Taken together , these observations are consistent with an important role that neuronal P42357 may play in mediating the potent effects of Q9BXJ7 + P41159 on food intake and body weight .\",\n \"Control of the P29323 Q96HU1 kinase cascade by Ras and Raf . Activation of ERKs plays a central part in the control of cell proliferation . In this chapter , we have concentrated on the identification and regulation of the kinases that activate Mek . We have chosen to focus on this area because of the many puzzles associated with it . Key issues for the future are the need to derive methods to determine what contribution each individual activator makes to both the magnitude and duration of Mek activation and understanding the mechanisms of regulation . Furthermore , we have considered the roles of Raf and the other kinases solely as Mek activators ; they may well have other substrates including cdc25A ( Galaktionov et al , 1995 ) , I kappa B ( Li and Sedivy , 1993 ) and P04637 ( Jamal and Ziff , 1995 ) .\",\n \"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK36___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .\",\n \"Pathway based analysis of SNPs with relevance to ___MASK88___ therapy : relation to intratumoral mRNA expression and survival . Genetic factors are thought to play a role in resistance towards chemotherapeutic agents such as 5 - fluorouracil ( ___MASK88___ ) . Approximately 30 genes are directly or indirectly involved in ___MASK88___ metabolism , and genetic variation in any of these may contribute to anti - tumor response . Polymorphisms in these genes were analyzed in relation to tumoral mRNA levels of ___MASK88___ metabolizing genes , response to chemotherapy and survival . A total of 21 genetic variants were studied in 35 breast cancer patients treated with 5 - FluoroUracil , mitomycin ( FUMI ) and in a similar cohort of 90 doxorubicin treated breast cancer patients . Genotype distributions were compared using 109 healthy controls . No significant association was found between any polymorphisms and response to chemotherapy as measured by shrinkage of tumor . However , carriers of 3 copies of the P04818 5 ' UTR repeat had shorter survival than noncarriers ( p = . 048 ) in the FUMI treatment group , but not in the doxorubicin treated group . Carriers of 3 copies of the repeat were also more frequently observed in both patients groups than in healthy controls ( p = . 034 ) . Several highly significant associations were observed between genotypes and expression levels of ___MASK88___ metabolizing genes . A SNP in codon 72 of P04637 was revealed to be a key regulator of ___MASK88___ metabolizing genes such as P00374 and P42898 , constituting 50 % of all significant associations observed after FUMI therapy . These data suggest that 3 copies of the P04818 5 ' UTR repeat may give a treatment specific reduced survival in breast cancer patients , and that P04637 may have a direct , allele specific , role in ___MASK88___ mediated response .\",\n \"Expression of the calcitonin receptor , calcitonin receptor - like receptor , and receptor activity modifying proteins during osteoclast differentiation . The expressions of the calcitonin receptor ( CTR ) , the calcitonin receptor - like receptor ( CLR ) , the receptor activity - modifying proteins ( RAMP ) 1 - 3 , and of the receptor component protein ( RCP ) have been studied in mouse bone marrow macrophages ( BMM ) during osteoclast differentiation , induced by treatment with P09603 and O14788 . Analyses of mRNA showed that CLR and O60894 - 3 , but not CTR , were expressed in P09603 stimulated BMM . O14788 gradually increased CTR mRNA , transiently enhanced CLR and transiently decreased O60894 mRNA , but did not affect O60895 , O60896 , or RCP mRNA . However , O14788 did not affect protein levels of CLR or O60894 - 3 as assessed by Western blots or FACS analyses , whereas immunocytochemistry showed enhanced CTR protein . Analyses of DB02527 production showed that BMM cells expressed functional receptors for calcitonin gene - related peptide ( P80511 ) , amylin , adrenomedullin , and intermedin , but not for calcitonin and calcitonin receptor stimulating peptide ( CRSP ) , but that O14788 induced the expression of receptors for calcitonin and CRSP as well . P01258 , P80511 , amylin , adrenomedullin , intermedin , and CRSP all down regulated the CTR mRNA , but none of the peptides caused any effects on the expression of CLR or any of the RAMPs . Our data show that BMM cells express receptors for P80511 , amylin , adrenomedullin , and intermedin and that O14788 induces the formation of receptors for calcitonin and CRSP in these cells . We also show , for the first time , that the CTR is not only down regulated by signaling through the CTR but also by the peptides signaling through CLR / RAMPs .\",\n \"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK73___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .\"\n]"},"candidates":{"kind":"list like","value":["___MASK20___","___MASK26___","___MASK29___","___MASK36___","___MASK45___","___MASK73___","___MASK82___","___MASK88___","___MASK93___"],"string":"[\n \"___MASK20___\",\n \"___MASK26___\",\n \"___MASK29___\",\n \"___MASK36___\",\n \"___MASK45___\",\n \"___MASK73___\",\n \"___MASK82___\",\n \"___MASK88___\",\n \"___MASK93___\"\n]"},"answer":{"kind":"string","value":"___MASK29___"},"id":{"kind":"string","value":"MH_train_477"}}},{"rowIdx":478,"cells":{"query":{"kind":"string","value":"interacts_with DB01257?"},"supports":{"kind":"list like","value":["DB01257 in renal transplantation . Antibody - mediated rejection , be it acute , subacute or chronic , is currently recognized as the major cause of graft loss in kidney transplant recipients . Anti - HLA donor - specific antibodies are deleterious to the graft fate whether they pre - exist to the transplantation or appear in the course of transplantation . The role of complement is therefore prominent in most instances . As well , the role of complement activation is crucial in the recurrence of atypical hemolytic uremic syndrome post - transplantation ( aHUS ) as well as following ischemia - reperfusion injury leading to delayed graft function . DB01257 , a fully humanized monoclonal antibody directed against the P01031 component of the complement cascade is efficient in chronically and safely blocking complement activation for example in paroxysmal nocturnal hemoglobinuria . In the setting of kidney transplantation , there is convincing but still limited evidence that eculizumab is efficient in preventing both acute and chronic antibody - mediated rejection in highly sensitized recipients requiring desensitization before getting a living donor kidney transplant . Studies are currently ongoing to determine its efficacy and safety in P16442 incompatible transplantation , in the prevention of acute and chronic rejection either with a living or a deceased donor kidney as well as in the prevention of delayed graft function . Similar to its efficacy in aHUS on native kidneys , eculizumab prevents or treats recurrence after kidney transplantation . There is still a lot of research to be performed in order to determine precisely the exact indications and the length of treatment with this very active but also very expensive drug that will undoubtedly revolutionize the current management of patients with donor specific antibodies ( DSAs ) and at risk of HUS recurrence .","Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK63___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK63___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK63___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK63___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK63___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK63___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK63___ .","The role of complement inhibition in PNH . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare , chronic , debilitating , acquired disorder that most frequently presents in early adulthood and usually continues throughout the life of a patient . PNH results in the death of approximately half of affected individuals , mainly through thrombotic complications , and until recently had no specific therapy . In 2007 eculizumab , an anti - complement antibody targeting the P01031 complement component was approved for PNH by both the US Food and Drug Administration ( FDA ) and the European Medicines Agency ( EMEA ) . DB01257 is very effective in the treatment of intravascular hemolysis and all its sequelae , which include most of the symptoms and complications of PNH . DB01257 has revolutionized our approach to hemolytic PNH and as it markedly reduces the principal complications of PNH , namely thrombosis and renal failure , should have a significant impact on survival . However , the development of eculizumab presents new challenges in PNH , such as how to avoid complications of therapy , how to overcome some of the problems associated with treatment and who to select for treatment , as only a proportion of patients with a PNH clone will benefit . This article will review the evidence behind the use of eculizumab in PNH , the effect it will have on the complications of the disease , the most appropriate selection of patients for therapy , the optimal management and the potential complications of the therapy .","Severe atypical HUS caused by P08603 S1191L -- case presentation and review of treatment options . Atypical hemolytic uremic syndrome ( aHUS ) has been associated with defective regulation of the alternative complement pathway . Although the use of plasma therapy is recommended , there is little consensus on the optimal treatment regimen . The outcome in many cases remains poor despite an improvement in our understanding of the pathology of aHUS . We have followed a female patient with aHUS associated with heterozygous complement Factor H ( P08603 ) mutation ( S1191L ) over a period of 15 years . She has been plasma dependent since infancy and has subsequently progressed to end stage kidney disease ( ESKD ) requiring dialysis treatment . Despite ESKD she still depends on regular plasma infusions to prevent thrombocytopenia . The long - term treatment plan for this patient is challenging . Renal transplantation in patients with the S1191L mutation of the P08603 gene carries a high risk of failure due to recurrence of aHUS in the renal graft . Thus , the only available curative treatment seems to be combined liver - kidney transplantation , covered by intensive plasma therapy , which comes with a high risk of morbidity and mortality . Antibodies against key activating components of the complement cascade may provide a promising alternative therapeutic strategy in the future . DB01257 , a monoclonal humanized anti - P01031 antibody , has recently been shown to be effective and well - tolerated in patients with paroxysmal nocturnal hemoglobinuria by preventing complement - mediated lysis of affected erythrocytes . Treatment of our patient with eculizumab is supported by recent reports on its successful use in two ( pediatric and adult ) patients with complement - based aHUS .","Successful management of obstructive jaundice due to gallstones with eculizumab in a patient with paroxysmal nocturnal hemoglobinuria . Paroxysmal nocturnal hemoglobinuria ( PNH ) makes patients susceptible to intravascular hemolysis and thrombosis , and it can be life - threatening in stressful situations . DB01257 , a humanized monoclonal antibody that inhibits the complement protein P01031 , has been evaluated as a novel therapy for PNH . We herein describe the case of a 59 - year - old Japanese woman with classic PNH , who had been successfully treated with eculizumab , but who later developed acute cholecystitis / cholangitis from gallstones . Although the severe obstructive jaundice requiring endoscopic therapy following cholecystectomy was complicated , critical intravascular hemolysis and thrombosis were not observed . Therefore , utilizing eculizumab during the peri - operative management of PNH patients should be carefully taken into consideration .","Conformationally altered hyaluronan restricts complement classical pathway activation by binding to C1q , C1r , C1s , P06681 , P01031 and P02748 , and suppresses Q9NZC7 expression in prostate DU145 cells . Linear non - sulfated hyaluronan ( HA ) does not bind complement proteins yet inhibits their hemolytic function . We have previously induced the complement inhibitory function of HA by heat treatment . However , heated HA readily loses its anti - complementary activity probably due to instantaneous interchain re - association . Here , HA solutions were heated and then freeze - dried . Compared to native HA , heated / freeze - dried HA stably restricted serum complement - mediated hemolysis via the classical pathway , in which serum C1 hemolytic function and P01024 activation were blocked . Also , treated HA had a significantly increased binding of component C1q , C1r , C1s , P06681 , P01031 , P02748 , P , D and H . Further , when HA was gel - fractionated by electrophoresis and then freeze - dried , its anti - complementary activity was stably induced . Both native and heated / freeze - dried HA stimulated P29323 phosphorylation in prostate DU145 cells . However , treated HA suppressed the expression of tumor suppressors Q9NZC7 and WOX2 . Together , HA with an altered conformation stabilizes its inhibition and binding of complement proteins . It may recognize cell surface receptors differently from native HA , thereby differentially regulating the expression of cellular proteins .","The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab . Paroxysmal nocturnal hemoglobinuria is a rare disorder of hemopoietic stem cells . Affected individuals have a triad of clinical associations - intravascular hemolysis , an increased risk of thromboembolism , and bone marrow failure . Most of the symptoms experienced in this disease occur due to the absence of complement regulatory proteins on the surface of the red blood cells . Complement activation is thus not checked and causes destruction of these cells . DB01257 is a monoclonal antibody treatment which specifically binds to the complement protein P01031 , preventing its cleavage , and so halts the complement cascade and prevents the formation of the terminal complement proteins . DB01257 prevents intravascular hemolysis , stabilizes hemoglobin levels , reduces or stops the need for blood transfusions , and improves fatigue and patient quality of life as well as reducing pulmonary hypertension , decreasing the risk of thrombosis and protecting against worsening renal function . It is not a curative therapy but has a great benefit on those with this rare debilitating condition .","DB01257 : DB01257 , h5G1 . 1 , long - acting anti - P01031 monoclonal antibody 5G1 - 1 , long - acting anti - P01031 monoclonal antibody DB01257 .","Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK43___ and Tissue P00747 Activator in Occluded Arteries .","Hyperhemolysis syndrome in anemia of chronic disease . BACKGROUND : Occasional cases of delayed hemolytic transfusion reaction ( P10275 ) demonstrate severe and persistent hemolysis and are referred to as hyperhemolysis syndrome . This syndrome usually occurs in patients with sickle cell disease and possibly thalassemia who receive multiple transfusions . There are few such clinical reports in patients without hemoglobinopathies . CASE REPORT : A 67 - year - old woman with anemia and a history of four previous transfusions was admitted with shortness of breath and a hematocrit ( Hct ) level of 27 percent . The patient was group O with a negative antibody screen . She received 1 unit of electronically cross - matched red blood cells ( RBCs ) and was discharged . Thirteen days later she returned to hospital with weakness and a Hct level of 23 percent . The antibody screen now demonstrated anti - K alloantibody . The direct antigloblulin test ( Q01959 ) was positive with both anti - immunoglobulin G and anti - complement ( P01024 ) . Anti - K was recovered in the eluate . The previously transfused RBC unit was positive for presence of the K antigen . The patient ' s RBCs were negative for the presence of K antigen . Other laboratory data confirmed ongoing hemolysis , and a diagnosis of P10275 was made . She continued to display findings of active hemolysis for 9 more weeks requiring 19 units of RBCs . Thirty - four days after the original transfusion , her Q01959 remained positive and both the plasma sample and a RBC eluate demonstrated anti - K . CONCLUSION : The delayed hemolytic transfusion reaction with hyperhemolysis can occur among patients without hemoglobinopathies .","Role of Q14116 in overt pain - like behaviour in mice . There are evidences that targeting Q14116 might be beneficial to inhibit inflammatory symptoms , including hypernociception ( decrease in nociceptive threshold ) . The mechanism of Q14116 mechanical hypernociception depends on endothelin in rats and mice . However , the role of Q14116 in overt pain - like behaviour remains undetermined . Therefore , we addressed the role of Q14116 in writhing response induced by intraperitoneal ( i . p . ) injection of phenyl - p - benzoquinone ( PBQ ) and acetic acid in mice . Firstly , it was detected that PBQ and acetic acid i . p . injection induced a dose - dependent number of writhes in Balb / c mice . Subsequently , it was observed that the PBQ - but not the acetic acid - induced writhes were diminished in Q14116 deficient ( ( -/- ) ) mice . Therefore , considering that P01579 , endothelin and prostanoids mediate Q14116 - induced mechanical hypernociception , we also investigated the role of these mediators in the same model of writhing response in which Q14116 participates . It was noticed that PBQ - induced writhes were diminished in P01579 (-/-) mice and by the treatment with ___MASK85___ ( mixed endothelin P25101 / ETB receptor antagonist ) , BQ 123 ( cyclo [ DTrp - DAsp - Pro - DVal - DB00149 ] , selective endothelin P25101 receptor antagonist ) , BQ 788 ( N - cys - 2 , 6 dimethylpiperidinocarbonyl - l - methylleucyl - d - 1 - methoxycarboyl - d - norleucine , selective endothelin ETB receptor antagonist ) or indomethacin ( cycloxigenase inhibitor ) . Thus , Q14116 , P01579 , endothelin acting on endothelin P25101 and ETB receptors , and prostanoids mediate PBQ - induced writhing response in mice . To conclude , these results further advance the understanding of the physiopathology of overt pain - like behaviour , and suggest for the first time a role for Q14116 in writhing response in mice .","DB01257 for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas - kidney transplantation -- a case report . A 34 - year - old female recipient of a simultaneous pancreas - kidney transplant presented 7 days posttransplant with acute renal allograft dysfunction , thrombocytopenia , and microangiopathic hemolytic anemia . Renal biopsy revealed acute antibody - mediated rejection ( AMR ) and acute thrombotic microangiopathy ( TMA ) . Clinical and laboratory manifestations , which had only partly responded to treatment with daily plasma exchange and intravenous immunoglobulin , resolved rapidly and completely to eculizumab ( Soliris , Alexion Pharmaceuticals , Inc . , Cheshire , Conn ) , a complement factor P01031 antibody . De novo posttransplant TMA is a rare and serious complication that can lead to graft loss in up to one third of cases . This is the first report of successful treatment of de novo TMA with eculizumab , which has previously shown benefit in recurrent atypical hemolytic uremic syndrome as well as in refractory acute AMR . Targeted complement inhibition offers the promise of a safe and effective therapeutic strategy in de novo TMA , especially in light of recent evidence suggesting that genetic mutations in complement regulatory proteins may predispose transplant recipients to this serious disease .","Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .","DB01257 treatment of acute antibody - mediated rejection in renal transplantation : case reports . The occurrence of acute antibody - mediated rejection ( AMR ) , especially in more severe cases , continues to be associated with a poor prognosis for implant survival . Here , we have reported the results of treatment of two patients who developed AMR associated with thrombotic microangiopathy immediately after transplantation . We used a single dose of eculizumab at an early stage jointly with conventional modalities of steroid boluses , plasmapheresis , intravenous immunoglobulin , and rituximab . In both cases , the clinical course was favorable . DB01257 , a monoclonal antibody with a high affinity for complement protein P01031 , prevents generation of the final membrane attack complex , blocking this cascade . To date , there are a few reports of the usefulness of eculizumab in AMR . DB01257 can help to stop endothelial damage , especially in severe cases that show a risk of progression to cortical necrosis , by providing a therapeutic window until the other modalities begin to control the immune response . In our experience , the use of eculizumab can be beneficial in the treatment of AMR .","[ Paroxysmal nocturnal hemoglobinuria therapy with eculizumab : Spanish experience ] . BACKGROUND AND OBJECTIVES : Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare acquired clonal disease characterized by complement - mediated hemolysis , bone marrow failure and thrombosis . DB01257 is a humanized monoclonal antibody that blocks the cytolytic component of the complement system by binding to complement P01031 . MATERIAL AND METHODS : We report the results of eculizumab treatment in 25 PNH patients from different centers in Spain . Statistical analysis was perfomed with a SPSS v15 . 0 software . RESULTS : Fifty - eight per cent of the patients achieved transfusional independence after a median of 14 months . Transfusion requirements were reduced in 60 % of the remaining cases . Fatigue resolved in 96 % of the patients and smooth muscle dystony - related symptoms in all cases . A single case of treatment - related infection was observed . CONCLUSIONS : DB01257 controls effectively hemolysis and greatly improves clinical symptoms . The drug is safe and well tolerated , without significant adverse effects except meningococcal infection . Patients with suboptimal response to treatment must be assessed for bone marrow insufficiency and extravascular haemolysis .","Complement in lupus nephritis : the good , the bad , and the unknown . The complement system consists of 3 pathways and more than 30 proteins , including those with biological activity that directly or indirectly mediate the effects of this system , plus a set of regulatory proteins necessary to prevent injudicious complement activation on host tissue . The role for complement in the pathogenesis of systemic lupus erythematosus ( SLE ) is paradoxic . On one hand , the complement system appears to have protective features in that hereditary homozygous deficiencies of classic pathway components are associated with an increased risk for SLE . On the other hand , immune complex - mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathologic features that are logical consequences of complement activation . By using accurate mouse models of SLE , we have gained remarkable insights into pathogenic features likely relevant to the human disease , and the ability to test potential therapies , some of which have made it to standard clinical use . Studies in genetically altered mice and using recombinant protein inhibitors of complement have confirmed what was believed but unproven - early complement proteins C1q and C4 are protective whereas complement activation later in the pathways is proinflammatory and deleterious . Two complement inhibitors , soluble complement receptor 1 ( TP10 , Avant Immunotherapeutics , Needham , MA ) and a monoclonal anti - P01031 antibody ( DB01257 , Alexion Pharmaceuticals , Inc . , Cheshire , CT ) have been shown to inhibit complement safely and now are being investigated in a variety of clinical conditions . Although these and others earlier in their clinical development hold promise to be used therapeutically in lupus nephritis , this optimism must be tempered by the fact that the clinical trials to prove this remain fraught with obstacles .","[ DB01257 in paroxysmal nocturnal hemoglobinuria ] . Paroxysmal nocturnal hemoglobinuria is a rare acquired clonal of the hematopoietic stem cell due to acquired mutation of the P37287 gene . This results in the lack of two P06744 - anchored membrane proteins involved in the inhibition of complement attack , thus explaining red cells hemolysis . The development of an anti - P01031 monoclonal antibody ( eculizumab ) had profoundly modified the treatment of the the hemolytic form of the disease .","DB01257 and recurrent P01024 glomerulonephritis . BACKGROUND : Hyperactivity of the alternative complement pathway is the principle defect in P01024 glomerulopathies ( C3G ) . DB01257 , a monoclonal antibody that binds P01031 to prevent formation of the membrane attack complex , has been shown to be beneficial in some patients with this disease . METHODS : In this open - label , proof - of - concept efficacy - and - safety study , a patient with the initial diagnosis of dense deposit disease ( DDD ) and allograft recurrence of P01024 glomerulonephritis ( C3GN ) was treated with eculizumab every other week for 1 year . The patient had pathological evidence of C3GN and proteinuria > 1 g / day at enrollment . He underwent graft biopsy before enrollment and repeat biopsy at 6 and 12 months . RESULTS : Although no mutations were identified in complement genes , functional studies were positive for P01024 nephritic factors and elevated levels of soluble membrane attack complex ( sMAC ) . On therapy , sMAC levels normalized and although proteinuria initially decreased , it increased reaching pre - treatment levels at 12 months . Although serum creatinine remained stable , repeat allograft biopsies showed progression of disease . CONCLUSIONS : Clinical and histopathologic data suggest a partial response to eculizumab in this patient . While eculizumab blocked activation of the terminal complement cascade , persistent dysregulation of the alternative pathway remained , indicating eculizumab alone can not control disease in this patient . Additional research is required to identify effective anticomplement therapy for this group of C3G patients .","Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab . In paroxysmal nocturnal hemoglobinuria ( PNH ) hemolytic anemia is due mainly to deficiency of the complement regulator P13987 on the surface of red blood cells ( RBCs ) . DB01257 , an antibody that targets complement fraction 5 ( P01031 ) , has proven highly effective in abolishing complement - mediated intravascular hemolysis in PNH ; however , the hematologic benefit varies considerably among patients . In the aim to understand the basis for this variable response , we have investigated by flow cytometry the binding of complement fraction 3 ( P01024 ) on RBCs from PNH patients before and during eculizumab treatment . There was no evidence of P01024 on RBCs of untreated PNH patients ; by contrast , in all patients on eculizumab ( n = 41 ) a substantial fraction of RBCs had P01024 bound on their surface , and this was entirely restricted to RBCs with the PNH phenotype ( P13987 (-) ) . The proportion of P01024 (+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab . In 3 patients in whom ( 51 ) Cr labeling of RBCs was carried out while on eculizumab , we have demonstrated reduced RBC half - life in vivo , with excess ( 51 ) Cr uptake in spleen and in liver . Binding of P01024 by PNH RBCs may constitute an additional disease mechanism in PNH , strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis .","DB01257 treatment modifies the immune profile of PNH patients . Paroxysmal Nocturnal Haemoglobinuria ( PNH ) is due to pathological expansion of a stem progenitor bearing a somatic mutation of P37287 gene involved in the biosynthesis of the glycosyl - phosphatidyl - inositol ( P06744 ) anchor . Numerous data suggest a role for immune - mediated mechanisms in the selection / expansion of P06744 - defective clone . Haemolytic anaemia in PNH is dependent on the effect of complement against P06744 - defective red cells . DB01257 , an anti - P01031 monoclonal antibody , is dramatically effective in controlling haemolysis and thrombosis , in reducing fatigue and in improving quality of life of patients . However , this therapy presents new challenges that need to be properly faced . Here , we report the decrease in B , Natural Killer ( NK ) and regulatory T cells ( Treg ) , an altered cytokine profile of invariant - NKT cells ( NKTi ) and the increasing of P61073 ( P61073 ) receptor in PNH patients before the DB01257 therapy . Treatment significantly affects some of these alterations : after DB01257 , the number of B lymphocytes , the cytokine secretion of NKTi and P61073 expression on CD8 T cells became similar to healthy donors . No effects were observed on NK and Treg . The amplitude of the P06744 - defective compartment remained unchanged .","Paroxysmal nocturnal hemoglobinuria from bench to bedside . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare hematologic disease that presents with protean manifestations . Clinical and laboratory investigation over the past 25 years has uncovered most of the basic science underpinnings of PNH and has led to the development of a highly effective targeted therapy . PNH originates from a multipotent hematopoietic stem cell ( P19526 ) that acquires a somatic mutation in a gene called phosphatidylinositol glycan anchor biosynthesis , class A ( P37287 ) . The P37287 gene is required for the first step in glycosylphosphatidylinositol ( P06744 ) anchor biosynthesis . Failure to synthesize P06744 anchors leads to an absence of all proteins that utilize P06744 to attach to the plasma membrane . Two P06744 - anchor proteins , P08174 and P13987 , are complement regulatory proteins ; their absence on the surface of PNH cells leads to complement - mediated hemolysis . The release of free hemoglobin leads to scavenging of nitric oxide and contributes to many clinical manifestations , including esophageal spasm , fatigue , and possibly thrombosis . Aerolysin is a pore - forming toxin that binds P06744 - anchored proteins and kills normal cells , but not PNH cells . A fluorescinated aerolysin variant ( FLAER ) binds P06744 - anchor and serves as a novel reagent diagnosing PNH . DB01257 , a humanized monoclonal antibody against P01031 , is the first effective drug therapy for PNH .","Activated factor B ( Bb ) of the alternative pathway of complement activation cleaves and activates plasminogen . Activated Factor B ( Bb ) , the central serine esterase of the alternative pathway of complement activation , exhibits restricted substrate specificity in the complement system for P01024 and P01031 . The results presented here indicate that Bb can cleave and activate plasminogen in an experimental system containing purified plasminogen and Bb ; complement cellular intermediate bearing the Bb - enzyme ; or cobra venom factor - stabilized Bb - enzyme ( CVF , Bb ) . Cleavage of plasminogen by Factor Bb generated 2 disulfide - linked polypeptides with apparent m . w . of 64 , 000 and 25 , 000 to 32 , 000 ( SDS - PAGE ) . Complement cellular intermediates containing the C3b , Bb - enzyme cleave 40 to 80 % of 4 . 5 micrograms of 125I - labeled plasminogen during 30 min of incubation at 37 degrees C ; native Factor B was inactive ; and anti - Factor Blg inhibited by 100 % the plasminogen cleavage mediated by complement cellular intermediates bearing the Bb - enzyme . Fibrinolytic activity was detected in plasminogen activator ( PA ) assays when purified plasminogen and 125I - labeled fibrin tubes were incubated with Bb , CVF , Bb , or complement cellular intermediates bearing the C3b , Bb - enzyme : 10 micrograms Bb released 40 to 65 % of the 125I - fibrin released by 5 micrograms urokinase in 4 hr at 37 degrees C . P00747 activator activity of the C3b , Bb - enzyme was found to be regulated in serum . At dilutions of Q6T4R5 1 : 50 , the PA - activity of 1 . 6 micrograms Bb was 100 % inhibited , and at a 1 : 250 dilution , 50 % inhibition was observed . This report describes a novel activity for the Bb - enzyme , which constitutes the P01024 / P01031 - convertase of the alternative pathway of complement activation .","[ HIV - 1 neuropathogenesis : therapeutic strategies against neuronal loss induced by gp120 / Tat glycoprotein in the central nervous system ] . Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors ( P61073 , P49238 and CR5 ) produces proinflammatory cytokine release by infected cells , increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species ( ROS ) that eventually damage the neuron . Moreover , the neurotoxin Tat produces dendritic loss by interacting with the low - density lipoprotein receptor ( Q14764 ) and also overstimulates N - methyl D - aspartate receptors ( DB01221 ) . Furthermore , the aberrant interaction of glycoprotein gp120 with the P61073 chemokine receptor causes caspase - 3 - dependent apoptosis ( ceramide is also released ) activating apoptotic proteins ( p53 and retinoblastoma ) , which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS . Similarly , gliosis / microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid ( P13500 and fractalkine , among others ) contribute to the neuropathogenesis of HIV - 1 . P37840 and beta amyloid deposits have also been detected in post mortem brains of seropositives patients . In addition , there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system ; such as osteopontin , Q86VB7 and fractalkine , among others . Lastly , clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins ( P49841 ) , microglial activation inhibitors ( minocycline ) , antioxidants ( selegiline ) or trophic factors ( DB01277 , growth hormone or erythropoietin ) . These trials have shown that their treatments are beneficial and complementary to treat complications of HIV / AIDS .","Novel future therapeutic options in myasthenia gravis . BACKGROUND : Myasthenia Gravis ( MG ) is an autoimmune disease caused by complement - fixing antibodies against the acetylcholine receptors ( AChR ) . Antigen - specific P01730 + T cells , Tregs and Th17 + are also necessary . Consequently , antibodies , B cells , molecules associated with signalling pathways on T helper cells , cytokines and complement are targets for more specific treatment options . OBJECTIVES : Because available immunosuppressive therapies cause unacceptable side effects after long - term use or are not always effective in inducing remission , novel biological agents directed against the following targets might be options for future therapies in MG : 1 ) T cell Intracellular Signaling Pathways associated with T cell activation , such as monoclonal antibodies against P31358 , Interleukin 2 - receptor ( P60568 R ) , co - stimulatory molecules or compounds inhibiting Janus tyrosine kinases P23458 , P52333 ; 2 ) B cells , against key B cell - surface molecules or trophic factors B cell activation factor ( Q9Y275 ) and a proliferating inducing ligand ( APRIL ) ; 3 ) Complement , against P01024 or P01031 that intercept membranolytic attack complex formation ; 4 ) Cytokines and cytokine receptors , including P05231 , Q16552 , the p40 subunit of IL12 / 1L - 23 , and GM - P04141 ; and 5 ) Lymphocyte migration molecules . Construction of recombinant AChR antibodies that block the binding of the pathogenic antibodies , can be a future molecular tool . CONCLUSION : New biological agents are in the offing for future therapies in MG . Their efficacy needs to be secured with vigorously controlled clinical trials and weighted against excessive cost and rare complications .","5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK30___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .","Effects of membrane attack complex of complement on apoptosis in experimental autoimmune encephalomyelitis . Complement activation is involved in the initiation of inflammation and antibody - mediated demyelination in experimental autoimmune encephalomyelitis ( EAE ) . We investigated the role of MAC in apoptosis in myelin - induced EAE in complement P01031 - deficient ( P01031 - d ) and P01031 - sufficient ( P01031 - s ) mice . The number of apoptotic cells assessed by TUNEL assay was significantly increased in P01031 - d mice during clinical recovery as compared with P01031 - s mice . Most of the apoptotic cells were lymphocytes , monocytes , and oligodendrocytes . DNA microarray was performed using total RNA extracted from spinal cords . Genes expressed higher in P01031 - s included members of the caspase ( caspase 6 , 7 ) , P01375 and TNFR families ( P26842 , P48023 , lymphotoxin - beta R ) and survivin . These results indicate that P01031 and possibly MAC may be required for the limitation of inflammatory response within the central nervous system .","DB01257 in neonatal hemolytic uremic syndrome with homozygous factor H deficiency . BACKGROUND : Neonatal atypical hemolytic uremic syndrome ( aHUS ) is a rare but severe disease that is mainly due to methylmalonic aciduria or genetic complement abnormalities . Traditional management of aHUS includes plasma infusion / exchange , but in small or unstable infants , plasma exchange can be challenging because of high extracorporeal volume and difficulty to obtain an adequate venous access . The P01031 complement blocker eculizumab has become a cornerstone of first - line management of aHUS due to complement deregulation in older patients . However , little data are available on its use in neonatal aHUS . CASE - DIAGNOSIS / TREATMENT : We report on an 11 - day - old neonate with severe aHUS ( myocardial impairment , respiratory failure , acute kidney disease requiring hemodiafiltration ) due to homozygous factor - H deficiency . She received early treatment with eculizumab as first - line therapy and completely recovered within 5 days . A second dose of eculizumab was administered 7 days after the first infusion , followed by a dose every 2 weeks for 2 months and then every 3 weeks , at the same dosage ( 300 mg ) . With more than 24 months of follow - up , renal function remains normal . CONCLUSIONS : We report on the long - term efficacy and safety of eculizumab as first - line therapy in neonatal aHUS . However its use still requires optimization in terms of indications and administration ( frequency , dosage ) .","DB01257 : safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic - uremic syndrome : case report . In a recent study , eculizumab , a humanized monoclonal antibody which targets complement factor P01031 , appeared to resolve hemolysis and thrombocytopenia leading to recovery of renal function in a transplant patient during an episode of an atypical hemolytic uremic syndrome . We report the efficacy of eculizumab in a patient who presented with a recurrence of atypical hemolytic syndrome at 3 years after renal transplantation . After 17 months of eculizumab treatment , and without concomitant plasma therapy , renal function was maintained , the need for blood transfusions reduced , and acute thrombotic microangiopathy and hemolysis controlled . These data suggested that eculizumab should be considered to be a permanent treatment for this patient .","Aspergillus Niger peritonitis in a peritoneal dialysis patient treated with eculizumab . The complement system plays a vital role in preventing life - threatening infections by ensuring optimal functioning of the host immune system . Its dysregulation has been implicated in causing glomerular , hematological , and transplant - related disorders . DB01257 a novel monoclonal antibody against complement component P01031 has emerged in the recent past as the standard of care offering an effective rescue and maintenance therapy against many of these disorders . Its use has been associated with increased risk of infections predominantly with encapsulated organisms . There is no data in the literature on its effects in end - stage kidney disease ( ESKD ) or dialysis patients . We describe here a very rare case of Aspergillus Niger peritonitis in an ESKD patient on peritoneal dialysis ( PD ) receiving maintenance eculizumab therapy for atypical hemolytic uremic syndrome . Given that murine models with the same defect as that induced by eculizumab is vulnerable to invasive Aspergillosis , it is suggested that the fungal peritonitis in this patient was the result of the eculizumab therapy .","DB01257 in anti - factor h antibodies associated with atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a life - threatening multisystemic condition often leading to end - stage renal failure . It results from an increased activation of the alternative pathway of the complement system due to mutations of genes coding for inhibitors of this pathway or from autoantibodies directed against them . DB01257 is a monoclonal antibody directed against complement component P01031 and inhibiting the activation of the effector limb of the complement system . Its efficacy has already been demonstrated in aHUS . The present article reports for the first time the use of eculizumab in a patient presenting with aHUS associated with circulating anti - complement Factor H autoantibodies and complicated by cardiac and neurologic symptoms . Our observation highlights the efficacy of eculizumab in this form of aHUS not only on renal symptoms but also on the extrarenal symptoms . It also suggests that eculizumab should be used very promptly after aHUS presentation to prevent life - threatening complications and to reduce the risk of chronic disabilities . To obtain a complete inhibition of the effector limb activation , the advised dosage must be respected . After this initial therapy in the autoimmune aHUS form , a long - term immunosuppressive treatment should be considered , to prevent relapses by reducing anti - complement Factor H autoantibody plasma levels .","Efficacy of P01375 gene - transduced tumor cells in treatment of established in vivo tumor . The therapeutic effect of P01375 gene - transduced mouse fibrosarcoma cells ( Meth - A : P01031 ) on pre - inoculated parental cells ( Meth - A : M0 ) was studied . Subcutaneous ( s . c . ) transplantation of M0 cells into one flank of syngeneic BALB / c mice was followed by s . c . injection of irradiated MO or P01031 into the opposite flank 1 week later . The initial M0 tumor ( T - MO ) completely regressed in P01031 - vaccinated mice , whereas in M0 - vaccinated mice continuous growth of T - M0 was observed . When a similar experiment was carried out in SCID mice , no regression of T - MO was observed , suggesting that the tumor regression in BALB / c mice was not due to direct anti - tumor activity of P01375 secreted from P01031 , but to systemic immunity . Regression of the rechallenged M0 tumor was observed in mice which had shown T - MO regression by P01031 vaccination , but rechallenged Colon 26 cells ( syngeneic to BALB / c mice ) continued to grow , indicating a specific immunity to Meth - A cells ) . The systemic immunity evoked in P01031 - vaccinated mice was directly demonstrated by enhanced killer activities of Q96QP1 and CTL with a proliferation of T - cell population in their splenocytes . Abrogation of the therapeutic effect of P01031 vaccination with anti - Thy 1 and anti - Lyt 2 also demonstrates the involvement of cellular immunity in tumor regression .","Managing a pregnant patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare clonal stem cell disorder , which affects women of child - bearing age . PNH is associated with thrombotic complications , which are the main causes of morbidity and mortality . Management of a pregnant woman with PNH remains a challenge due to high incidence of thrombotic complications and the difficulty of differentiating a PNH crisis from the complications of pregnancy . PNH is associated with an increased rate of premature labor and fetal loss . DB01257 , a humanized monoclonal antibody directed against the terminal complement protein P01031 , has revolutionized treatment of PNH . However , the role of eculizumab in pregnancy is unclear . We review the current strategies for the management of pregnant women with PNH , underline the controversies and present our recommendations .","Adaptive mutations in a human immunodeficiency virus type 1 envelope protein with a truncated V3 loop restore function by improving interactions with P01730 . We previously reported that a human immunodeficiency virus type 1 ( HIV - 1 ) clade B envelope protein with a severely truncated V3 loop regained function after passage in tissue culture . The adapted virus , termed Q96RJ0 , retained the V3 truncation , was exquisitely sensitive to neutralization by the P01730 binding site monoclonal antibody b12 and by HIV - positive human sera , used P51681 to enter cells , and was completely resistant to small molecule P51681 antagonists . To examine the mechanistic basis for these properties , we singly and in combination introduced each of the 5 mutations from the adapted clone Q96RJ0 into the unadapted envelope . We found that single amino acid changes in the P01024 region , the V3 loop , and in the fusion peptide were responsible for imparting near - normal levels of envelope function to Q96RJ0 . T342A , which resulted in the loss of a highly conserved glycosylation site in P01024 , played the primary role . The adaptive amino acid changes had no impact on P51681 antagonist resistance but made virus more sensitive to neutralization by antibodies to the P01730 binding site , modestly enhanced affinity for P01730 , and made Q96RJ0 more responsive to P01730 binding . Specifically , Q96RJ0 was triggered by soluble P01730 more readily than the parental Env and , unlike the parental Env , could mediate entry on cells that express low levels of P01730 . In contrast , Q96RJ0 interacted with P51681 less efficiently and was highly sensitive to antibodies that bind to the P51681 N terminus and ECL2 . Therefore , enhanced utilization of P01730 is one mechanism by which HIV - 1 can overcome mutations in the V3 region that negatively affect P51681 interactions .","Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK16___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .","Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) in childhood is a rare disease associated with high morbidity and mortality . Most cases progress to end - stage renal failure . In approximately 50 % of affected patients , mutations in genes encoding complement proteins are causative of the impairment in the regulation of the complement alternative pathway . This leads to deficient host cell protection and inappropriate complement activation on platelets and endothelial cells , particularly in the kidneys . P08603 ( FH ) heterozygosity induces unregulated activation of the membrane attack complex ( MAC ) C5b - 9 . Present therapeutic strategies for aHUS include lifelong plasmapheresis and renal dialysis . Unfortunately , kidney transplantation is frequently an unsatisfactory intervention due to the high rate of post - transplantation HUS recurrence , particularly in patients with FH mutation . Combined liver - kidney transplantation is also associated with poor outcome , mostly as a result of premature liver failure secondary to uncontrolled complement activation . DB01257 is a complement P01031 antibody that inhibits complement factor 5a ( C5a ) and the formation of the MAC . Thus , this antibody may be a promising new agent for patients with an aHUS undergoing kidney transplantation . We present the first case of a young patient with aHUS who received eculizumab as prophylactic treatment prior to a successful kidney transplantation .","Screening of high - affinity scFvs from a ribosome displayed library using BIAcore biosensor . An experimental protocol was developed to screen high - affinity single - chain Fv antibody fragments ( scFvs ) from a Xanthomonas axonopodis pv . citri ( Xac ) immunized ribosome display library using BIAcore biosensor . The screening methods involved immobilizing antigen [ lipopolysaccharides ( LPS ) of Xac ] on sensor chip Q9Y251 and then unpurified expression products of scFvs flowing over the immobilized sensor chip . The affinity - improved scFvs were selected based on dissociation rate constants ( k ( d ) ) . Thirty - five enzyme - linked immunosorbent assay - positive scFvs were analyzed by BIAcore , and three of those ( scFv A1 , B2 , and P01031 ) with lower k ( d ) were screened . To demonstrate the accuracy of the screening method , the three scFvs were expressed in Escherichia coli HB2151 and purified . The purified scFvs were subsequently further identified according to association rate and affinity constants . The results showed that the three scFvs ( A1 , B2 , and P01031 ) had high affinity for LPS of Xac ( 3 . 51 x 10 (- 11 ) , 1 . 13 x 10 (- 10 ) , 5 . 06 x 10 (- 10 ) M , respectively ) . Furthermore , the scFv B2 was highly specific for LPS of Xac and had no any cross - reactions with bovine serum albumin and LPS from Xac - related bacteria . This provided evidence that the information from the BIAcore screening assay could be accurate .","Treatment of a patient with classical paroxysmal nocturnal hemoglobinuria and Budd - Chiari syndrome , with complement inhibitor eculizumab : Case Report . Background . Paroxysmal nocturnal haemoglobinuria ( PNH ) is a rare acquired clonal disorder of hematopoietic stem cells involving all blood cells . Erythrocytes have increased susceptibility to complement - mediated haemolysis . Thrombosis is the leading cause of mortality and follows episodes of acute hemolysis . DB01257 , a monoclonal antibody blocking activation of complement P01031 is currently used in the treatment of PNH . Recent results demonstrated that eculizumab effectively reduces thrombosis . Description of case . We present a 30 - year - old male patient admitted with abdominal and lumbar pain . Thorough investigation revealed severe hemolytic anemia requiring transfusions and hepatosplenomegaly . Imaging findings were compatible with a Budd - Chiari syndrome . Flow cytometry confirmed the PNH diagnosis . Due to refractory ascites he underwent a transjugular intrahepatic portal - systemic shunt ( TIPS ) and eculizumab administration was started . Results . He has already completed three years of eculizumab treatment and he is transfusion independent . There is also a significant reduction in fatigue with improvement in his quality of life . Doppler scans of his TIPS persistently show it to be patent . Conclusions . Classical PNH patients with thrombosis and severe intravascular hemolysis are particularly challenging to manage . For these patients , eculizumab is a reasonable therapeutic option , expecting that by decreasing the risk for thrombosis , life expectancy may be increased .","Laboratory tests for paroxysmal nocturnal hemoglobinuria . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare hematological disorder that is often suspected in a patient presenting with non - immune hemolytic anemia associated with pancytopenia or venous thrombosis . This disorder is a consequence of acquired somatic mutations in the phosphatidylinositol glycan class A ( P37287 ) gene in the hematopoietic stem cells ( P19526 ) of patients . The presence of these mutations leads to production of blood cells with decreased glycosyl phosphatidylinositol - anchored cell surface proteins , making red blood cells derived from the clone more sensitive to complement mediated hemolysis . The diagnosis of PNH may be difficult in some cases due a low proportion of PNH cells in the blood and occasionally due to difficulties in selecting the most appropriate diagnostic studies . The latest generation of tests allow for detection of very small populations of PNH cells , for following the natural course and response to therapy of the disease , and for helping to decide when to initiate therapy with monoclonal antibody targeting the terminal complement protein P01031 ( DB01257 ) , anticoagulation , and in some cases allogeneic P19526 transplant . In this article , we review the different diagnostic tests available to clinicians for PNH diagnosis .","Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK30___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .","Anti - complement therapy for glomerular diseases . A major shift in our understanding of glomerular diseases is the focus on which components of the complement pathway are involved in mediating kidney injury . For example , the membranoproliferative glomerulonephritis lesion is no longer classified solely by ultrastructural findings on biopsy and is now divided into immune - complex - mediated lesions vs complement - mediated lesions . In turn , this emphasis on complement leads to interest in therapies that target complement as potential disease - modifying agents . DB01257 , the first available anti - complement therapy , blocks at the level of P01031 and has revolutionized the treatment of atypical hemolytic uremic syndrome . Whether this agent will work equally well for the far more heterogeneous entities of P01024 glomerulonephritis and dense deposit disease remains unclear . Instead , newer agents that target P01024 may turn out to be the most effective and specific therapy for these P01024 glomerulopathies .","The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK46___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .","DB01257 in acute recurrence of thrombotic microangiopathy after renal transplantation . Renal thrombotic microangiopathy ( TMA ) is a severe complication of systemic lupus erythematosus ( SLE ) , which is associated with the presence of antiphospholipid ( aPL ) antibodies . In its most fulminant form , TMA leads to a rapid and irreversible end - stage renal failure . DB01257 , an anti - P01031 monoclonal antibody , is a novel therapy of choice for patients with paroxysmal nocturnal hemoglobinuria ( PNH ) and atypical hemolytic uremic syndrome . Here , we report the case of a 27 - year - old woman , known for SLE and end - stage renal disease due to fulminant TMA . Both aPL antibodies and antinucleosome antibodies were positive . The patient underwent a living - related kidney transplantation with immediate production of urine . Although serum creatinine was remaining high , a graft biopsy , performed on day 6 , demonstrated a TMA recurrence . Despite a treatment with plasma exchange , the situation got worse and dialysis was started . DB01257 treatment was subsequently administered and renal function improved rapidly . Three months after transplantation , serum creatinine was at 100 μmol / L , without proteinuria . This case illustrates the benefit of eculizumab therapy in a fulminant recurrence of TMA after kidney transplantation , resistant to classical therapy .","Complement inhibitor eculizumab in atypical hemolytic uremic syndrome . BACKGROUND AND OBJECTIVES : Atypical hemolytic uremic syndrome ( aHUS ) is associated with a congenital or acquired dysregulation of the complement alternative pathway that leads to continuous complement activation on host cells causing inflammation and damage . DB01257 , a humanized mAb against complement protein P01031 , inhibits activation of the terminal complement pathway . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS : We report an adolescent with relapsing unclassified aHUS . On admission , a high plasma creatinine level indicated a poor prognosis , and hemodialysis had to be started . Plasma exchanges were initially effective against the microangiopathic hemolytic activity and allowed a temporary improvement of renal function with termination of hemodialysis after 7 wk . Subsequently , plasma exchanges ( three times per week ) failed to prevent ongoing aHUS activity and progressive renal failure . After 12 wk , aHUS treatment was switched to eculizumab . RESULTS : DB01257 was effective in terminating the microangiopathic hemolytic process in two aHUS relapses ; however , after normalization of complement activity , aHUS recurred and ultimately led to anuric end - stage renal failure . CONCLUSIONS : In this patient , complement inhibition by eculizumab temporarily terminated the microangiopathic hemolytic activity . Nevertheless , renal damage as a result of preceding and subsequent aHUS activity resulted in end - stage renal failure ; therefore , therapeutic success may depend on early administration of eculizumab . The optimal duration of treatment may be variable and remains to be determined .","Blockade of alternative complement pathway in dense deposit disease . A patient aged 17 with dense deposit disease associated with complement activation , circulating P01024 Nef , and Factor H mutation presented with nephrotic syndrome and hypertension . Steroid therapy , plasma exchange , and rituximab failed to improve proteinuria and hypertension despite a normalization of the circulating sC5b9 complex . DB01257 , a monoclonal antibody directed against P01031 , was used to block the terminal product of the complement cascade . The dose was adapted to achieve a CH50 below 10 % , but proteinuria and blood pressure were not improved after 3 months of treatment .","Pyrogenic signaling via vagal afferents : what stimulates their receptors ? Although there is good evidence that pyrogenic messages may be conveyed from the periphery to the brain via vagal afferents , the exact nature of the factors that activate their sensory terminals is unclear . Since IL - 1beta and DB00917 have established roles in fever production and since their receptors have been identified on or near vagal nerves , they are potential candidate mediators . A difficulty , however , is that ( 1 ) IL - 1beta is not expressed constitutively in mononuclear phagocytes , their presumed cell source upon stimulation by exogenous pyrogens , e . g . endotoxin , and ( 2 ) similarly , the isoform of the enzyme that selectively mediates the production and release of DB00917 by endotoxin - stimulated macrophages , P35354 , is also not constitutively expressed in these cells . Since the transcription and translation of these factors significantly lags the onset of fever induced by endotoxin administered intravenously , in particular , it is possible that a secondary , quickly - acting mediator evoked in almost immediate reaction to the presence of endotoxin excites , directly or indirectly , the sensory neurons . We have evidence that the complement component P01031 contributes importantly to the initiation of the febrile response to endotoxin . This article briefly reviews the prevailing concepts of pyrogen sensing and signaling , examines their shortcomings particularly in terms of the temporal discrepancy between the very rapid onset of the febrile response to intravenously administered endotoxin and the significant delay in the elaboration of the putative mediators of fever , and presents newer data that may help to integrate the various preposed mechanisms .","Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a P08603 mutation . Kidney transplant in patients with atypical hemolytic uremic syndrome ( aHUS ) is associated with a poor outcome because of recurrent disease , especially in patients known to have a factor H mutation . Long - term prophylactic plasma exchange and combined liver - kidney transplant have prevented graft loss caused by recurrence . However , the mortality associated with liver transplant is not negligible , and prophylactic plasma exchange requires permanent vascular access and regular hospitalization and exposes the patient to potential allergic reactions to plasma . DB01257 is a high - affinity humanized monoclonal antibody that binds to P01031 and thus prevents generation of C5a and the membrane attack complex . We report the case of a 17 - year - old girl with aHUS associated with a mutation in the gene for complement factor H ( P08603 ; c . 3572C > T , Ser1191Leu ) who was highly dependent on plasma exchange . Because of severe allergic reactions to plasma after the third renal graft , eculizumab was introduced in place of plasma exchange without problems . This and other reports suggest that the promise of complement inhibitors in the management of aHUS is going to be fulfilled .","___MASK88___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .","Activation of cellular invasion by trefoil peptides and src is mediated by cyclooxygenase - and thromboxane A2 receptor - dependent signaling pathways . We have investigated the possible functional relationships between cellular invasion pathways induced by trefoil factors ( TFFs ) , src , and the cyclooxygenases P23219 and P35354 . Pharmacological inhibitors of the Rho small GTPase ( P01024 exoenzyme ) , phospholipase C ( U - 73122 ) , cyclooxygenases ( SC - 560 , NS - 398 ) , and the thromboxane A2 receptor ( P21731 ) antagonist SQ - 295 completely abolished invasion induced by intestinal trefoil factor , pS2 , and src in kidney and colonic epithelial cells MDCKts . src and PCmsrc . In contrast , invasion was induced by the P21731 mimetic U - 46619 , constitutively activated forms of the heterotrimeric G - proteins Galphaq ( AGalphaq ) , Galpha12 , Galpha13 ( AGalpha12 / 13 ) , which are signaling elements downstream of P21731 . Ectopic overexpression of pS2 cDNA and protein in MDCKts . src - pS2 cells and human colorectal cancer cells HCT8 / S11 - pS2 initiate distinct invasion signals that are Rho independent and P36551 and P21731 dependent . We detected a marked induction of P35354 protein and accumulation of the stable PGH2 / TXA2 metabolite TXB2 in the conditioned medium from cells transformed by src . This led to activation of the P21731 - dependent invasion pathway , which is monitored via a Rho - and Galpha12 / Galpha13 - independent mechanism using the Galphaq / PKC signaling cascade . These findings identify a new intracrine / paracrine loop that can be monitored by TFFs and src in inflammatory diseases and progression of colorectal cancers .","DB01257 therapy for atypical haemolytic uraemic syndrome due to a gain - of - function mutation of complement factor B . BACKGROUND : Atypical haemolytic uraemic syndrome ( aHUS ) is caused by dysregulated complement activation . A humanised anti - P01031 monoclonal antibody has recently become available for treatment of this condition CASE - DIAGNOSIS / TREATMENT : We present the first description of an infant with an activating mutation of complement factor B successfully treated with eculizumab . On standard doses she had evidence of ongoing P01031 cleavage despite a good clinical response . CONCLUSIONS : DB01257 is effective therapy for aHUS associated with factor B mutations , but recommended doses may not be adequate for all patients .","N - aryl - N '- benzylpiperazines as potential antipsychotic agents . N1 -( 2 - Alkoxyphenyl ) piperazines additionally containing an N4 - benzyl group bearing alcohol , amide , imide , or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response ( CAR ) test predictive of clinical antipsychotic activity and in in vitro receptor - binding assays . Certain of the compounds display high affinity for the D2 , P08908 , and alpha 1 - adrenergic receptors . Structures bearing acyclic amide , lactam , and imide functionalities display good biological activity , with a preference for the 1 , 3 - disubstituted phenyl ring relative to the 1 , 4 - and 1 , 2 - congeners ( 7 vs 10 and 12 ) . Every possible position of hydantoin attachment was investigated ( e . g . , substitution at N1 , N3 , and P01031 ) . The hydantoin involving attachment to N1 ( 24 ) was found to have good biological activity , whereas those hydantoins with attachment to N3 or P01031 ( 22 , 23 , and 25 ) were inactive . Several of the smaller acetylated derivatives ( 30 and 33 ) have fair in vivo activity , which was lost in the case of the larger benzoyl analog 31 . DB03419 congener 34 had modest affinity for the D2 receptor ( 65 nM ) as well as excellent in vivo activity . Benzylamino compounds display ( viz . 27 and 35 - 38 ) moderate CAR activity but have surprising receptor affinity , often greater than those of comparable structures bearing a carbonyl ( 36 vs 7 ) . Benzyl and benzhydryl alcohol compounds 40 - 48 are more active than amino structures 27 and 35 - 38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and P08908 receptor binding .","Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK88___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK88___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK88___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .","Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK20___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .","Clinical grand rounds : atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a rare , lifethreatening , chronic , genetic disease of uncontrolled alternative pathway complement activation . The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged . Regardless of the cause of aHUS , with or without a demonstrated mutation or autoantibody , blockade of terminal complement activation through P01031 is of high interest as a mechanism to ameliorate the disease . DB01257 , an existing monoclonal antibody directed against P01031 with high affinity , prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b - 9 , by blocking P01031 cleavage . We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS .","Mycobacteria - primed macrophages and dendritic cells induce an up - regulation of complement C5a anaphylatoxin receptor ( CD88 ) in CD3 + murine T cells . Complement C5a anaphylatoxin is a potent activator of macrophages , neutrophils , and dendritic cells ( DC ) and binds the C5a receptor ( P21730 ; CD88 ) . Although C5a is chemotactic for T cells , expression of P21730 on murine T cells has been disputed . We report here that naïve , Con A - activated , and cytokine ( IL - 12 , Q14116 ) - stimulated murine CD3 + T cells from three strains of mice [ C57Bl / 6 , B10 . nSn ( P01031 +/+ ) , B10 . on ( P01031 -/- ) ] lacked P21730 , as evaluated by immunophenotyping with an anti - P21730 mAb . Ligation of CD3 induced a modest up - regulation with 3 % of CD3 + T cells expressing cell surface P21730 . T cells primed by P25054 differentiate into effector T cells . Activation of mycobacteria [ bacillus Calmette - Guerin ( BCG ) ] - sensitized T cells through MHC II and TCR interactions via BCG - infected macrophages enhanced the expression of P21730 with approximately 14 % of CD3 + T cells positive for P21730 . Comparable expression was found in P01031 +/+ as well as P01031 -/- strains of mice ( 14 % and 15 % , respectively ) . Furthermore , anti - CD3 - activated T cells were primed by BCG - infected DC , and a larger proportion of the primed T cells expressed P21730 ( 30 - 40 % ) . Finally , mice infected with BCG showed significant numbers of CD3 + T cells expressing P21730 in the spleens during infection . As P25054 , such as macrophages and DC , can secrete P01031 and cleave P01031 to C5a and C5b through a peptidase , we suggest that macrophage and DC - T cell interactions can up - regulate P21730 on T cells through MHC II - TCR and provide a C5a peptide for additional local activation of T cells via P21730 .","Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK48___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .","Efficacy of eculizumab in a patient with factor - H - associated atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a rare , chronic , life - threatening disease due to complement dysregulation . The use of early - onset plasma therapy is recommended , but optimal long - term treatment regimen is not well defined . DB01257 , a monoclonal humanized anti - P01031 antibody , has shown success in patients with aHUS . We report a 7 - year - old girl with aHUS associated with factor H mutations successfully treated with eculizumab . Weekly plasma infusion ( PI ) of 25 - 30 ml / kg with short - term intensified PI during aHUS exacerbations was effective for 4 . 3 years . Progressive mild renal failure ( stage 2 ) was attributed to chronic glomerular lesions . Subsequently , she exhibited aHUS exacerbation unresponsive to intensified PI . DB01257 was initiated at 600 mg , resulting in immediate and complete inhibition of terminal complement activation . During the week following treatment , we observed a complete reversal of aHUS activity . She has been receiving 600 mg eculizumab every 2 weeks for the last 12 months . She had no aHUS exacerbation , and serum creatinine level returned to normal . In this patient , eculizumab led to control of PI - resistant aHUS exacerbation and chronic microangiopathic hemolytic activity . Clinical trials are ongoing to assess the safety and efficacy of this drug in the management of aHUS .","DB01257 for the treatment of preeclampsia / HELLP syndrome . Severe preeclampsia with hemolysis , elevated liver enzymes and low platelets ( HELLP ) syndrome is a leading cause of maternal and neonatal morbidity and mortality worldwide . Occurrence at an extremely premature gestational age is most challenging as there are dichotomous imperatives : delivery as definitive therapy for maternal health vs . prolongation of pregnancy to avoid prematurity and associated morbidities . We describe a patient presenting with severe preeclampsia / HELLP syndrome at 26 weeks gestation that was treated with DB01257 , a targeted inhibitor of complement protein P01031 , which resulted in marked clinical improvement and complete normalization of lab parameters . Pregnancy was prolonged 17 days , likely resulting in a reduction of neonatal morbidity with its associated short and long - term health care costs . Successful use of DB01257 in this case suggests that complement inhibition may be an effective treatment strategy for severe preeclampsia / HELLP syndrome ."],"string":"[\n \"DB01257 in renal transplantation . Antibody - mediated rejection , be it acute , subacute or chronic , is currently recognized as the major cause of graft loss in kidney transplant recipients . Anti - HLA donor - specific antibodies are deleterious to the graft fate whether they pre - exist to the transplantation or appear in the course of transplantation . The role of complement is therefore prominent in most instances . As well , the role of complement activation is crucial in the recurrence of atypical hemolytic uremic syndrome post - transplantation ( aHUS ) as well as following ischemia - reperfusion injury leading to delayed graft function . DB01257 , a fully humanized monoclonal antibody directed against the P01031 component of the complement cascade is efficient in chronically and safely blocking complement activation for example in paroxysmal nocturnal hemoglobinuria . In the setting of kidney transplantation , there is convincing but still limited evidence that eculizumab is efficient in preventing both acute and chronic antibody - mediated rejection in highly sensitized recipients requiring desensitization before getting a living donor kidney transplant . Studies are currently ongoing to determine its efficacy and safety in P16442 incompatible transplantation , in the prevention of acute and chronic rejection either with a living or a deceased donor kidney as well as in the prevention of delayed graft function . Similar to its efficacy in aHUS on native kidneys , eculizumab prevents or treats recurrence after kidney transplantation . There is still a lot of research to be performed in order to determine precisely the exact indications and the length of treatment with this very active but also very expensive drug that will undoubtedly revolutionize the current management of patients with donor specific antibodies ( DSAs ) and at risk of HUS recurrence .\",\n \"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK63___ and its - in terms of P36551 - inhibition - \\\" inactive \\\" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK63___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK63___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK63___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK63___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK63___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK63___ .\",\n \"The role of complement inhibition in PNH . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare , chronic , debilitating , acquired disorder that most frequently presents in early adulthood and usually continues throughout the life of a patient . PNH results in the death of approximately half of affected individuals , mainly through thrombotic complications , and until recently had no specific therapy . In 2007 eculizumab , an anti - complement antibody targeting the P01031 complement component was approved for PNH by both the US Food and Drug Administration ( FDA ) and the European Medicines Agency ( EMEA ) . DB01257 is very effective in the treatment of intravascular hemolysis and all its sequelae , which include most of the symptoms and complications of PNH . DB01257 has revolutionized our approach to hemolytic PNH and as it markedly reduces the principal complications of PNH , namely thrombosis and renal failure , should have a significant impact on survival . However , the development of eculizumab presents new challenges in PNH , such as how to avoid complications of therapy , how to overcome some of the problems associated with treatment and who to select for treatment , as only a proportion of patients with a PNH clone will benefit . This article will review the evidence behind the use of eculizumab in PNH , the effect it will have on the complications of the disease , the most appropriate selection of patients for therapy , the optimal management and the potential complications of the therapy .\",\n \"Severe atypical HUS caused by P08603 S1191L -- case presentation and review of treatment options . Atypical hemolytic uremic syndrome ( aHUS ) has been associated with defective regulation of the alternative complement pathway . Although the use of plasma therapy is recommended , there is little consensus on the optimal treatment regimen . The outcome in many cases remains poor despite an improvement in our understanding of the pathology of aHUS . We have followed a female patient with aHUS associated with heterozygous complement Factor H ( P08603 ) mutation ( S1191L ) over a period of 15 years . She has been plasma dependent since infancy and has subsequently progressed to end stage kidney disease ( ESKD ) requiring dialysis treatment . Despite ESKD she still depends on regular plasma infusions to prevent thrombocytopenia . The long - term treatment plan for this patient is challenging . Renal transplantation in patients with the S1191L mutation of the P08603 gene carries a high risk of failure due to recurrence of aHUS in the renal graft . Thus , the only available curative treatment seems to be combined liver - kidney transplantation , covered by intensive plasma therapy , which comes with a high risk of morbidity and mortality . Antibodies against key activating components of the complement cascade may provide a promising alternative therapeutic strategy in the future . DB01257 , a monoclonal humanized anti - P01031 antibody , has recently been shown to be effective and well - tolerated in patients with paroxysmal nocturnal hemoglobinuria by preventing complement - mediated lysis of affected erythrocytes . Treatment of our patient with eculizumab is supported by recent reports on its successful use in two ( pediatric and adult ) patients with complement - based aHUS .\",\n \"Successful management of obstructive jaundice due to gallstones with eculizumab in a patient with paroxysmal nocturnal hemoglobinuria . Paroxysmal nocturnal hemoglobinuria ( PNH ) makes patients susceptible to intravascular hemolysis and thrombosis , and it can be life - threatening in stressful situations . DB01257 , a humanized monoclonal antibody that inhibits the complement protein P01031 , has been evaluated as a novel therapy for PNH . We herein describe the case of a 59 - year - old Japanese woman with classic PNH , who had been successfully treated with eculizumab , but who later developed acute cholecystitis / cholangitis from gallstones . Although the severe obstructive jaundice requiring endoscopic therapy following cholecystectomy was complicated , critical intravascular hemolysis and thrombosis were not observed . Therefore , utilizing eculizumab during the peri - operative management of PNH patients should be carefully taken into consideration .\",\n \"Conformationally altered hyaluronan restricts complement classical pathway activation by binding to C1q , C1r , C1s , P06681 , P01031 and P02748 , and suppresses Q9NZC7 expression in prostate DU145 cells . Linear non - sulfated hyaluronan ( HA ) does not bind complement proteins yet inhibits their hemolytic function . We have previously induced the complement inhibitory function of HA by heat treatment . However , heated HA readily loses its anti - complementary activity probably due to instantaneous interchain re - association . Here , HA solutions were heated and then freeze - dried . Compared to native HA , heated / freeze - dried HA stably restricted serum complement - mediated hemolysis via the classical pathway , in which serum C1 hemolytic function and P01024 activation were blocked . Also , treated HA had a significantly increased binding of component C1q , C1r , C1s , P06681 , P01031 , P02748 , P , D and H . Further , when HA was gel - fractionated by electrophoresis and then freeze - dried , its anti - complementary activity was stably induced . Both native and heated / freeze - dried HA stimulated P29323 phosphorylation in prostate DU145 cells . However , treated HA suppressed the expression of tumor suppressors Q9NZC7 and WOX2 . Together , HA with an altered conformation stabilizes its inhibition and binding of complement proteins . It may recognize cell surface receptors differently from native HA , thereby differentially regulating the expression of cellular proteins .\",\n \"The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab . Paroxysmal nocturnal hemoglobinuria is a rare disorder of hemopoietic stem cells . Affected individuals have a triad of clinical associations - intravascular hemolysis , an increased risk of thromboembolism , and bone marrow failure . Most of the symptoms experienced in this disease occur due to the absence of complement regulatory proteins on the surface of the red blood cells . Complement activation is thus not checked and causes destruction of these cells . DB01257 is a monoclonal antibody treatment which specifically binds to the complement protein P01031 , preventing its cleavage , and so halts the complement cascade and prevents the formation of the terminal complement proteins . DB01257 prevents intravascular hemolysis , stabilizes hemoglobin levels , reduces or stops the need for blood transfusions , and improves fatigue and patient quality of life as well as reducing pulmonary hypertension , decreasing the risk of thrombosis and protecting against worsening renal function . It is not a curative therapy but has a great benefit on those with this rare debilitating condition .\",\n \"DB01257 : DB01257 , h5G1 . 1 , long - acting anti - P01031 monoclonal antibody 5G1 - 1 , long - acting anti - P01031 monoclonal antibody DB01257 .\",\n \"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK43___ and Tissue P00747 Activator in Occluded Arteries .\",\n \"Hyperhemolysis syndrome in anemia of chronic disease . BACKGROUND : Occasional cases of delayed hemolytic transfusion reaction ( P10275 ) demonstrate severe and persistent hemolysis and are referred to as hyperhemolysis syndrome . This syndrome usually occurs in patients with sickle cell disease and possibly thalassemia who receive multiple transfusions . There are few such clinical reports in patients without hemoglobinopathies . CASE REPORT : A 67 - year - old woman with anemia and a history of four previous transfusions was admitted with shortness of breath and a hematocrit ( Hct ) level of 27 percent . The patient was group O with a negative antibody screen . She received 1 unit of electronically cross - matched red blood cells ( RBCs ) and was discharged . Thirteen days later she returned to hospital with weakness and a Hct level of 23 percent . The antibody screen now demonstrated anti - K alloantibody . The direct antigloblulin test ( Q01959 ) was positive with both anti - immunoglobulin G and anti - complement ( P01024 ) . Anti - K was recovered in the eluate . The previously transfused RBC unit was positive for presence of the K antigen . The patient ' s RBCs were negative for the presence of K antigen . Other laboratory data confirmed ongoing hemolysis , and a diagnosis of P10275 was made . She continued to display findings of active hemolysis for 9 more weeks requiring 19 units of RBCs . Thirty - four days after the original transfusion , her Q01959 remained positive and both the plasma sample and a RBC eluate demonstrated anti - K . CONCLUSION : The delayed hemolytic transfusion reaction with hyperhemolysis can occur among patients without hemoglobinopathies .\",\n \"Role of Q14116 in overt pain - like behaviour in mice . There are evidences that targeting Q14116 might be beneficial to inhibit inflammatory symptoms , including hypernociception ( decrease in nociceptive threshold ) . The mechanism of Q14116 mechanical hypernociception depends on endothelin in rats and mice . However , the role of Q14116 in overt pain - like behaviour remains undetermined . Therefore , we addressed the role of Q14116 in writhing response induced by intraperitoneal ( i . p . ) injection of phenyl - p - benzoquinone ( PBQ ) and acetic acid in mice . Firstly , it was detected that PBQ and acetic acid i . p . injection induced a dose - dependent number of writhes in Balb / c mice . Subsequently , it was observed that the PBQ - but not the acetic acid - induced writhes were diminished in Q14116 deficient ( ( -/- ) ) mice . Therefore , considering that P01579 , endothelin and prostanoids mediate Q14116 - induced mechanical hypernociception , we also investigated the role of these mediators in the same model of writhing response in which Q14116 participates . It was noticed that PBQ - induced writhes were diminished in P01579 (-/-) mice and by the treatment with ___MASK85___ ( mixed endothelin P25101 / ETB receptor antagonist ) , BQ 123 ( cyclo [ DTrp - DAsp - Pro - DVal - DB00149 ] , selective endothelin P25101 receptor antagonist ) , BQ 788 ( N - cys - 2 , 6 dimethylpiperidinocarbonyl - l - methylleucyl - d - 1 - methoxycarboyl - d - norleucine , selective endothelin ETB receptor antagonist ) or indomethacin ( cycloxigenase inhibitor ) . Thus , Q14116 , P01579 , endothelin acting on endothelin P25101 and ETB receptors , and prostanoids mediate PBQ - induced writhing response in mice . To conclude , these results further advance the understanding of the physiopathology of overt pain - like behaviour , and suggest for the first time a role for Q14116 in writhing response in mice .\",\n \"DB01257 for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas - kidney transplantation -- a case report . A 34 - year - old female recipient of a simultaneous pancreas - kidney transplant presented 7 days posttransplant with acute renal allograft dysfunction , thrombocytopenia , and microangiopathic hemolytic anemia . Renal biopsy revealed acute antibody - mediated rejection ( AMR ) and acute thrombotic microangiopathy ( TMA ) . Clinical and laboratory manifestations , which had only partly responded to treatment with daily plasma exchange and intravenous immunoglobulin , resolved rapidly and completely to eculizumab ( Soliris , Alexion Pharmaceuticals , Inc . , Cheshire , Conn ) , a complement factor P01031 antibody . De novo posttransplant TMA is a rare and serious complication that can lead to graft loss in up to one third of cases . This is the first report of successful treatment of de novo TMA with eculizumab , which has previously shown benefit in recurrent atypical hemolytic uremic syndrome as well as in refractory acute AMR . Targeted complement inhibition offers the promise of a safe and effective therapeutic strategy in de novo TMA , especially in light of recent evidence suggesting that genetic mutations in complement regulatory proteins may predispose transplant recipients to this serious disease .\",\n \"Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .\",\n \"DB01257 treatment of acute antibody - mediated rejection in renal transplantation : case reports . The occurrence of acute antibody - mediated rejection ( AMR ) , especially in more severe cases , continues to be associated with a poor prognosis for implant survival . Here , we have reported the results of treatment of two patients who developed AMR associated with thrombotic microangiopathy immediately after transplantation . We used a single dose of eculizumab at an early stage jointly with conventional modalities of steroid boluses , plasmapheresis , intravenous immunoglobulin , and rituximab . In both cases , the clinical course was favorable . DB01257 , a monoclonal antibody with a high affinity for complement protein P01031 , prevents generation of the final membrane attack complex , blocking this cascade . To date , there are a few reports of the usefulness of eculizumab in AMR . DB01257 can help to stop endothelial damage , especially in severe cases that show a risk of progression to cortical necrosis , by providing a therapeutic window until the other modalities begin to control the immune response . In our experience , the use of eculizumab can be beneficial in the treatment of AMR .\",\n \"[ Paroxysmal nocturnal hemoglobinuria therapy with eculizumab : Spanish experience ] . BACKGROUND AND OBJECTIVES : Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare acquired clonal disease characterized by complement - mediated hemolysis , bone marrow failure and thrombosis . DB01257 is a humanized monoclonal antibody that blocks the cytolytic component of the complement system by binding to complement P01031 . MATERIAL AND METHODS : We report the results of eculizumab treatment in 25 PNH patients from different centers in Spain . Statistical analysis was perfomed with a SPSS v15 . 0 software . RESULTS : Fifty - eight per cent of the patients achieved transfusional independence after a median of 14 months . Transfusion requirements were reduced in 60 % of the remaining cases . Fatigue resolved in 96 % of the patients and smooth muscle dystony - related symptoms in all cases . A single case of treatment - related infection was observed . CONCLUSIONS : DB01257 controls effectively hemolysis and greatly improves clinical symptoms . The drug is safe and well tolerated , without significant adverse effects except meningococcal infection . Patients with suboptimal response to treatment must be assessed for bone marrow insufficiency and extravascular haemolysis .\",\n \"Complement in lupus nephritis : the good , the bad , and the unknown . The complement system consists of 3 pathways and more than 30 proteins , including those with biological activity that directly or indirectly mediate the effects of this system , plus a set of regulatory proteins necessary to prevent injudicious complement activation on host tissue . The role for complement in the pathogenesis of systemic lupus erythematosus ( SLE ) is paradoxic . On one hand , the complement system appears to have protective features in that hereditary homozygous deficiencies of classic pathway components are associated with an increased risk for SLE . On the other hand , immune complex - mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathologic features that are logical consequences of complement activation . By using accurate mouse models of SLE , we have gained remarkable insights into pathogenic features likely relevant to the human disease , and the ability to test potential therapies , some of which have made it to standard clinical use . Studies in genetically altered mice and using recombinant protein inhibitors of complement have confirmed what was believed but unproven - early complement proteins C1q and C4 are protective whereas complement activation later in the pathways is proinflammatory and deleterious . Two complement inhibitors , soluble complement receptor 1 ( TP10 , Avant Immunotherapeutics , Needham , MA ) and a monoclonal anti - P01031 antibody ( DB01257 , Alexion Pharmaceuticals , Inc . , Cheshire , CT ) have been shown to inhibit complement safely and now are being investigated in a variety of clinical conditions . Although these and others earlier in their clinical development hold promise to be used therapeutically in lupus nephritis , this optimism must be tempered by the fact that the clinical trials to prove this remain fraught with obstacles .\",\n \"[ DB01257 in paroxysmal nocturnal hemoglobinuria ] . Paroxysmal nocturnal hemoglobinuria is a rare acquired clonal of the hematopoietic stem cell due to acquired mutation of the P37287 gene . This results in the lack of two P06744 - anchored membrane proteins involved in the inhibition of complement attack , thus explaining red cells hemolysis . The development of an anti - P01031 monoclonal antibody ( eculizumab ) had profoundly modified the treatment of the the hemolytic form of the disease .\",\n \"DB01257 and recurrent P01024 glomerulonephritis . BACKGROUND : Hyperactivity of the alternative complement pathway is the principle defect in P01024 glomerulopathies ( C3G ) . DB01257 , a monoclonal antibody that binds P01031 to prevent formation of the membrane attack complex , has been shown to be beneficial in some patients with this disease . METHODS : In this open - label , proof - of - concept efficacy - and - safety study , a patient with the initial diagnosis of dense deposit disease ( DDD ) and allograft recurrence of P01024 glomerulonephritis ( C3GN ) was treated with eculizumab every other week for 1 year . The patient had pathological evidence of C3GN and proteinuria > 1 g / day at enrollment . He underwent graft biopsy before enrollment and repeat biopsy at 6 and 12 months . RESULTS : Although no mutations were identified in complement genes , functional studies were positive for P01024 nephritic factors and elevated levels of soluble membrane attack complex ( sMAC ) . On therapy , sMAC levels normalized and although proteinuria initially decreased , it increased reaching pre - treatment levels at 12 months . Although serum creatinine remained stable , repeat allograft biopsies showed progression of disease . CONCLUSIONS : Clinical and histopathologic data suggest a partial response to eculizumab in this patient . While eculizumab blocked activation of the terminal complement cascade , persistent dysregulation of the alternative pathway remained , indicating eculizumab alone can not control disease in this patient . Additional research is required to identify effective anticomplement therapy for this group of C3G patients .\",\n \"Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab . In paroxysmal nocturnal hemoglobinuria ( PNH ) hemolytic anemia is due mainly to deficiency of the complement regulator P13987 on the surface of red blood cells ( RBCs ) . DB01257 , an antibody that targets complement fraction 5 ( P01031 ) , has proven highly effective in abolishing complement - mediated intravascular hemolysis in PNH ; however , the hematologic benefit varies considerably among patients . In the aim to understand the basis for this variable response , we have investigated by flow cytometry the binding of complement fraction 3 ( P01024 ) on RBCs from PNH patients before and during eculizumab treatment . There was no evidence of P01024 on RBCs of untreated PNH patients ; by contrast , in all patients on eculizumab ( n = 41 ) a substantial fraction of RBCs had P01024 bound on their surface , and this was entirely restricted to RBCs with the PNH phenotype ( P13987 (-) ) . The proportion of P01024 (+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab . In 3 patients in whom ( 51 ) Cr labeling of RBCs was carried out while on eculizumab , we have demonstrated reduced RBC half - life in vivo , with excess ( 51 ) Cr uptake in spleen and in liver . Binding of P01024 by PNH RBCs may constitute an additional disease mechanism in PNH , strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis .\",\n \"DB01257 treatment modifies the immune profile of PNH patients . Paroxysmal Nocturnal Haemoglobinuria ( PNH ) is due to pathological expansion of a stem progenitor bearing a somatic mutation of P37287 gene involved in the biosynthesis of the glycosyl - phosphatidyl - inositol ( P06744 ) anchor . Numerous data suggest a role for immune - mediated mechanisms in the selection / expansion of P06744 - defective clone . Haemolytic anaemia in PNH is dependent on the effect of complement against P06744 - defective red cells . DB01257 , an anti - P01031 monoclonal antibody , is dramatically effective in controlling haemolysis and thrombosis , in reducing fatigue and in improving quality of life of patients . However , this therapy presents new challenges that need to be properly faced . Here , we report the decrease in B , Natural Killer ( NK ) and regulatory T cells ( Treg ) , an altered cytokine profile of invariant - NKT cells ( NKTi ) and the increasing of P61073 ( P61073 ) receptor in PNH patients before the DB01257 therapy . Treatment significantly affects some of these alterations : after DB01257 , the number of B lymphocytes , the cytokine secretion of NKTi and P61073 expression on CD8 T cells became similar to healthy donors . No effects were observed on NK and Treg . The amplitude of the P06744 - defective compartment remained unchanged .\",\n \"Paroxysmal nocturnal hemoglobinuria from bench to bedside . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare hematologic disease that presents with protean manifestations . Clinical and laboratory investigation over the past 25 years has uncovered most of the basic science underpinnings of PNH and has led to the development of a highly effective targeted therapy . PNH originates from a multipotent hematopoietic stem cell ( P19526 ) that acquires a somatic mutation in a gene called phosphatidylinositol glycan anchor biosynthesis , class A ( P37287 ) . The P37287 gene is required for the first step in glycosylphosphatidylinositol ( P06744 ) anchor biosynthesis . Failure to synthesize P06744 anchors leads to an absence of all proteins that utilize P06744 to attach to the plasma membrane . Two P06744 - anchor proteins , P08174 and P13987 , are complement regulatory proteins ; their absence on the surface of PNH cells leads to complement - mediated hemolysis . The release of free hemoglobin leads to scavenging of nitric oxide and contributes to many clinical manifestations , including esophageal spasm , fatigue , and possibly thrombosis . Aerolysin is a pore - forming toxin that binds P06744 - anchored proteins and kills normal cells , but not PNH cells . A fluorescinated aerolysin variant ( FLAER ) binds P06744 - anchor and serves as a novel reagent diagnosing PNH . DB01257 , a humanized monoclonal antibody against P01031 , is the first effective drug therapy for PNH .\",\n \"Activated factor B ( Bb ) of the alternative pathway of complement activation cleaves and activates plasminogen . Activated Factor B ( Bb ) , the central serine esterase of the alternative pathway of complement activation , exhibits restricted substrate specificity in the complement system for P01024 and P01031 . The results presented here indicate that Bb can cleave and activate plasminogen in an experimental system containing purified plasminogen and Bb ; complement cellular intermediate bearing the Bb - enzyme ; or cobra venom factor - stabilized Bb - enzyme ( CVF , Bb ) . Cleavage of plasminogen by Factor Bb generated 2 disulfide - linked polypeptides with apparent m . w . of 64 , 000 and 25 , 000 to 32 , 000 ( SDS - PAGE ) . Complement cellular intermediates containing the C3b , Bb - enzyme cleave 40 to 80 % of 4 . 5 micrograms of 125I - labeled plasminogen during 30 min of incubation at 37 degrees C ; native Factor B was inactive ; and anti - Factor Blg inhibited by 100 % the plasminogen cleavage mediated by complement cellular intermediates bearing the Bb - enzyme . Fibrinolytic activity was detected in plasminogen activator ( PA ) assays when purified plasminogen and 125I - labeled fibrin tubes were incubated with Bb , CVF , Bb , or complement cellular intermediates bearing the C3b , Bb - enzyme : 10 micrograms Bb released 40 to 65 % of the 125I - fibrin released by 5 micrograms urokinase in 4 hr at 37 degrees C . P00747 activator activity of the C3b , Bb - enzyme was found to be regulated in serum . At dilutions of Q6T4R5 1 : 50 , the PA - activity of 1 . 6 micrograms Bb was 100 % inhibited , and at a 1 : 250 dilution , 50 % inhibition was observed . This report describes a novel activity for the Bb - enzyme , which constitutes the P01024 / P01031 - convertase of the alternative pathway of complement activation .\",\n \"[ HIV - 1 neuropathogenesis : therapeutic strategies against neuronal loss induced by gp120 / Tat glycoprotein in the central nervous system ] . Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors ( P61073 , P49238 and CR5 ) produces proinflammatory cytokine release by infected cells , increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species ( ROS ) that eventually damage the neuron . Moreover , the neurotoxin Tat produces dendritic loss by interacting with the low - density lipoprotein receptor ( Q14764 ) and also overstimulates N - methyl D - aspartate receptors ( DB01221 ) . Furthermore , the aberrant interaction of glycoprotein gp120 with the P61073 chemokine receptor causes caspase - 3 - dependent apoptosis ( ceramide is also released ) activating apoptotic proteins ( p53 and retinoblastoma ) , which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS . Similarly , gliosis / microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid ( P13500 and fractalkine , among others ) contribute to the neuropathogenesis of HIV - 1 . P37840 and beta amyloid deposits have also been detected in post mortem brains of seropositives patients . In addition , there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system ; such as osteopontin , Q86VB7 and fractalkine , among others . Lastly , clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins ( P49841 ) , microglial activation inhibitors ( minocycline ) , antioxidants ( selegiline ) or trophic factors ( DB01277 , growth hormone or erythropoietin ) . These trials have shown that their treatments are beneficial and complementary to treat complications of HIV / AIDS .\",\n \"Novel future therapeutic options in myasthenia gravis . BACKGROUND : Myasthenia Gravis ( MG ) is an autoimmune disease caused by complement - fixing antibodies against the acetylcholine receptors ( AChR ) . Antigen - specific P01730 + T cells , Tregs and Th17 + are also necessary . Consequently , antibodies , B cells , molecules associated with signalling pathways on T helper cells , cytokines and complement are targets for more specific treatment options . OBJECTIVES : Because available immunosuppressive therapies cause unacceptable side effects after long - term use or are not always effective in inducing remission , novel biological agents directed against the following targets might be options for future therapies in MG : 1 ) T cell Intracellular Signaling Pathways associated with T cell activation , such as monoclonal antibodies against P31358 , Interleukin 2 - receptor ( P60568 R ) , co - stimulatory molecules or compounds inhibiting Janus tyrosine kinases P23458 , P52333 ; 2 ) B cells , against key B cell - surface molecules or trophic factors B cell activation factor ( Q9Y275 ) and a proliferating inducing ligand ( APRIL ) ; 3 ) Complement , against P01024 or P01031 that intercept membranolytic attack complex formation ; 4 ) Cytokines and cytokine receptors , including P05231 , Q16552 , the p40 subunit of IL12 / 1L - 23 , and GM - P04141 ; and 5 ) Lymphocyte migration molecules . Construction of recombinant AChR antibodies that block the binding of the pathogenic antibodies , can be a future molecular tool . CONCLUSION : New biological agents are in the offing for future therapies in MG . Their efficacy needs to be secured with vigorously controlled clinical trials and weighted against excessive cost and rare complications .\",\n \"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK30___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .\",\n \"Effects of membrane attack complex of complement on apoptosis in experimental autoimmune encephalomyelitis . Complement activation is involved in the initiation of inflammation and antibody - mediated demyelination in experimental autoimmune encephalomyelitis ( EAE ) . We investigated the role of MAC in apoptosis in myelin - induced EAE in complement P01031 - deficient ( P01031 - d ) and P01031 - sufficient ( P01031 - s ) mice . The number of apoptotic cells assessed by TUNEL assay was significantly increased in P01031 - d mice during clinical recovery as compared with P01031 - s mice . Most of the apoptotic cells were lymphocytes , monocytes , and oligodendrocytes . DNA microarray was performed using total RNA extracted from spinal cords . Genes expressed higher in P01031 - s included members of the caspase ( caspase 6 , 7 ) , P01375 and TNFR families ( P26842 , P48023 , lymphotoxin - beta R ) and survivin . These results indicate that P01031 and possibly MAC may be required for the limitation of inflammatory response within the central nervous system .\",\n \"DB01257 in neonatal hemolytic uremic syndrome with homozygous factor H deficiency . BACKGROUND : Neonatal atypical hemolytic uremic syndrome ( aHUS ) is a rare but severe disease that is mainly due to methylmalonic aciduria or genetic complement abnormalities . Traditional management of aHUS includes plasma infusion / exchange , but in small or unstable infants , plasma exchange can be challenging because of high extracorporeal volume and difficulty to obtain an adequate venous access . The P01031 complement blocker eculizumab has become a cornerstone of first - line management of aHUS due to complement deregulation in older patients . However , little data are available on its use in neonatal aHUS . CASE - DIAGNOSIS / TREATMENT : We report on an 11 - day - old neonate with severe aHUS ( myocardial impairment , respiratory failure , acute kidney disease requiring hemodiafiltration ) due to homozygous factor - H deficiency . She received early treatment with eculizumab as first - line therapy and completely recovered within 5 days . A second dose of eculizumab was administered 7 days after the first infusion , followed by a dose every 2 weeks for 2 months and then every 3 weeks , at the same dosage ( 300 mg ) . With more than 24 months of follow - up , renal function remains normal . CONCLUSIONS : We report on the long - term efficacy and safety of eculizumab as first - line therapy in neonatal aHUS . However its use still requires optimization in terms of indications and administration ( frequency , dosage ) .\",\n \"DB01257 : safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic - uremic syndrome : case report . In a recent study , eculizumab , a humanized monoclonal antibody which targets complement factor P01031 , appeared to resolve hemolysis and thrombocytopenia leading to recovery of renal function in a transplant patient during an episode of an atypical hemolytic uremic syndrome . We report the efficacy of eculizumab in a patient who presented with a recurrence of atypical hemolytic syndrome at 3 years after renal transplantation . After 17 months of eculizumab treatment , and without concomitant plasma therapy , renal function was maintained , the need for blood transfusions reduced , and acute thrombotic microangiopathy and hemolysis controlled . These data suggested that eculizumab should be considered to be a permanent treatment for this patient .\",\n \"Aspergillus Niger peritonitis in a peritoneal dialysis patient treated with eculizumab . The complement system plays a vital role in preventing life - threatening infections by ensuring optimal functioning of the host immune system . Its dysregulation has been implicated in causing glomerular , hematological , and transplant - related disorders . DB01257 a novel monoclonal antibody against complement component P01031 has emerged in the recent past as the standard of care offering an effective rescue and maintenance therapy against many of these disorders . Its use has been associated with increased risk of infections predominantly with encapsulated organisms . There is no data in the literature on its effects in end - stage kidney disease ( ESKD ) or dialysis patients . We describe here a very rare case of Aspergillus Niger peritonitis in an ESKD patient on peritoneal dialysis ( PD ) receiving maintenance eculizumab therapy for atypical hemolytic uremic syndrome . Given that murine models with the same defect as that induced by eculizumab is vulnerable to invasive Aspergillosis , it is suggested that the fungal peritonitis in this patient was the result of the eculizumab therapy .\",\n \"DB01257 in anti - factor h antibodies associated with atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a life - threatening multisystemic condition often leading to end - stage renal failure . It results from an increased activation of the alternative pathway of the complement system due to mutations of genes coding for inhibitors of this pathway or from autoantibodies directed against them . DB01257 is a monoclonal antibody directed against complement component P01031 and inhibiting the activation of the effector limb of the complement system . Its efficacy has already been demonstrated in aHUS . The present article reports for the first time the use of eculizumab in a patient presenting with aHUS associated with circulating anti - complement Factor H autoantibodies and complicated by cardiac and neurologic symptoms . Our observation highlights the efficacy of eculizumab in this form of aHUS not only on renal symptoms but also on the extrarenal symptoms . It also suggests that eculizumab should be used very promptly after aHUS presentation to prevent life - threatening complications and to reduce the risk of chronic disabilities . To obtain a complete inhibition of the effector limb activation , the advised dosage must be respected . After this initial therapy in the autoimmune aHUS form , a long - term immunosuppressive treatment should be considered , to prevent relapses by reducing anti - complement Factor H autoantibody plasma levels .\",\n \"Efficacy of P01375 gene - transduced tumor cells in treatment of established in vivo tumor . The therapeutic effect of P01375 gene - transduced mouse fibrosarcoma cells ( Meth - A : P01031 ) on pre - inoculated parental cells ( Meth - A : M0 ) was studied . Subcutaneous ( s . c . ) transplantation of M0 cells into one flank of syngeneic BALB / c mice was followed by s . c . injection of irradiated MO or P01031 into the opposite flank 1 week later . The initial M0 tumor ( T - MO ) completely regressed in P01031 - vaccinated mice , whereas in M0 - vaccinated mice continuous growth of T - M0 was observed . When a similar experiment was carried out in SCID mice , no regression of T - MO was observed , suggesting that the tumor regression in BALB / c mice was not due to direct anti - tumor activity of P01375 secreted from P01031 , but to systemic immunity . Regression of the rechallenged M0 tumor was observed in mice which had shown T - MO regression by P01031 vaccination , but rechallenged Colon 26 cells ( syngeneic to BALB / c mice ) continued to grow , indicating a specific immunity to Meth - A cells ) . The systemic immunity evoked in P01031 - vaccinated mice was directly demonstrated by enhanced killer activities of Q96QP1 and CTL with a proliferation of T - cell population in their splenocytes . Abrogation of the therapeutic effect of P01031 vaccination with anti - Thy 1 and anti - Lyt 2 also demonstrates the involvement of cellular immunity in tumor regression .\",\n \"Managing a pregnant patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare clonal stem cell disorder , which affects women of child - bearing age . PNH is associated with thrombotic complications , which are the main causes of morbidity and mortality . Management of a pregnant woman with PNH remains a challenge due to high incidence of thrombotic complications and the difficulty of differentiating a PNH crisis from the complications of pregnancy . PNH is associated with an increased rate of premature labor and fetal loss . DB01257 , a humanized monoclonal antibody directed against the terminal complement protein P01031 , has revolutionized treatment of PNH . However , the role of eculizumab in pregnancy is unclear . We review the current strategies for the management of pregnant women with PNH , underline the controversies and present our recommendations .\",\n \"Adaptive mutations in a human immunodeficiency virus type 1 envelope protein with a truncated V3 loop restore function by improving interactions with P01730 . We previously reported that a human immunodeficiency virus type 1 ( HIV - 1 ) clade B envelope protein with a severely truncated V3 loop regained function after passage in tissue culture . The adapted virus , termed Q96RJ0 , retained the V3 truncation , was exquisitely sensitive to neutralization by the P01730 binding site monoclonal antibody b12 and by HIV - positive human sera , used P51681 to enter cells , and was completely resistant to small molecule P51681 antagonists . To examine the mechanistic basis for these properties , we singly and in combination introduced each of the 5 mutations from the adapted clone Q96RJ0 into the unadapted envelope . We found that single amino acid changes in the P01024 region , the V3 loop , and in the fusion peptide were responsible for imparting near - normal levels of envelope function to Q96RJ0 . T342A , which resulted in the loss of a highly conserved glycosylation site in P01024 , played the primary role . The adaptive amino acid changes had no impact on P51681 antagonist resistance but made virus more sensitive to neutralization by antibodies to the P01730 binding site , modestly enhanced affinity for P01730 , and made Q96RJ0 more responsive to P01730 binding . Specifically , Q96RJ0 was triggered by soluble P01730 more readily than the parental Env and , unlike the parental Env , could mediate entry on cells that express low levels of P01730 . In contrast , Q96RJ0 interacted with P51681 less efficiently and was highly sensitive to antibodies that bind to the P51681 N terminus and ECL2 . Therefore , enhanced utilization of P01730 is one mechanism by which HIV - 1 can overcome mutations in the V3 region that negatively affect P51681 interactions .\",\n \"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK16___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .\",\n \"Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) in childhood is a rare disease associated with high morbidity and mortality . Most cases progress to end - stage renal failure . In approximately 50 % of affected patients , mutations in genes encoding complement proteins are causative of the impairment in the regulation of the complement alternative pathway . This leads to deficient host cell protection and inappropriate complement activation on platelets and endothelial cells , particularly in the kidneys . P08603 ( FH ) heterozygosity induces unregulated activation of the membrane attack complex ( MAC ) C5b - 9 . Present therapeutic strategies for aHUS include lifelong plasmapheresis and renal dialysis . Unfortunately , kidney transplantation is frequently an unsatisfactory intervention due to the high rate of post - transplantation HUS recurrence , particularly in patients with FH mutation . Combined liver - kidney transplantation is also associated with poor outcome , mostly as a result of premature liver failure secondary to uncontrolled complement activation . DB01257 is a complement P01031 antibody that inhibits complement factor 5a ( C5a ) and the formation of the MAC . Thus , this antibody may be a promising new agent for patients with an aHUS undergoing kidney transplantation . We present the first case of a young patient with aHUS who received eculizumab as prophylactic treatment prior to a successful kidney transplantation .\",\n \"Screening of high - affinity scFvs from a ribosome displayed library using BIAcore biosensor . An experimental protocol was developed to screen high - affinity single - chain Fv antibody fragments ( scFvs ) from a Xanthomonas axonopodis pv . citri ( Xac ) immunized ribosome display library using BIAcore biosensor . The screening methods involved immobilizing antigen [ lipopolysaccharides ( LPS ) of Xac ] on sensor chip Q9Y251 and then unpurified expression products of scFvs flowing over the immobilized sensor chip . The affinity - improved scFvs were selected based on dissociation rate constants ( k ( d ) ) . Thirty - five enzyme - linked immunosorbent assay - positive scFvs were analyzed by BIAcore , and three of those ( scFv A1 , B2 , and P01031 ) with lower k ( d ) were screened . To demonstrate the accuracy of the screening method , the three scFvs were expressed in Escherichia coli HB2151 and purified . The purified scFvs were subsequently further identified according to association rate and affinity constants . The results showed that the three scFvs ( A1 , B2 , and P01031 ) had high affinity for LPS of Xac ( 3 . 51 x 10 (- 11 ) , 1 . 13 x 10 (- 10 ) , 5 . 06 x 10 (- 10 ) M , respectively ) . Furthermore , the scFv B2 was highly specific for LPS of Xac and had no any cross - reactions with bovine serum albumin and LPS from Xac - related bacteria . This provided evidence that the information from the BIAcore screening assay could be accurate .\",\n \"Treatment of a patient with classical paroxysmal nocturnal hemoglobinuria and Budd - Chiari syndrome , with complement inhibitor eculizumab : Case Report . Background . Paroxysmal nocturnal haemoglobinuria ( PNH ) is a rare acquired clonal disorder of hematopoietic stem cells involving all blood cells . Erythrocytes have increased susceptibility to complement - mediated haemolysis . Thrombosis is the leading cause of mortality and follows episodes of acute hemolysis . DB01257 , a monoclonal antibody blocking activation of complement P01031 is currently used in the treatment of PNH . Recent results demonstrated that eculizumab effectively reduces thrombosis . Description of case . We present a 30 - year - old male patient admitted with abdominal and lumbar pain . Thorough investigation revealed severe hemolytic anemia requiring transfusions and hepatosplenomegaly . Imaging findings were compatible with a Budd - Chiari syndrome . Flow cytometry confirmed the PNH diagnosis . Due to refractory ascites he underwent a transjugular intrahepatic portal - systemic shunt ( TIPS ) and eculizumab administration was started . Results . He has already completed three years of eculizumab treatment and he is transfusion independent . There is also a significant reduction in fatigue with improvement in his quality of life . Doppler scans of his TIPS persistently show it to be patent . Conclusions . Classical PNH patients with thrombosis and severe intravascular hemolysis are particularly challenging to manage . For these patients , eculizumab is a reasonable therapeutic option , expecting that by decreasing the risk for thrombosis , life expectancy may be increased .\",\n \"Laboratory tests for paroxysmal nocturnal hemoglobinuria . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare hematological disorder that is often suspected in a patient presenting with non - immune hemolytic anemia associated with pancytopenia or venous thrombosis . This disorder is a consequence of acquired somatic mutations in the phosphatidylinositol glycan class A ( P37287 ) gene in the hematopoietic stem cells ( P19526 ) of patients . The presence of these mutations leads to production of blood cells with decreased glycosyl phosphatidylinositol - anchored cell surface proteins , making red blood cells derived from the clone more sensitive to complement mediated hemolysis . The diagnosis of PNH may be difficult in some cases due a low proportion of PNH cells in the blood and occasionally due to difficulties in selecting the most appropriate diagnostic studies . The latest generation of tests allow for detection of very small populations of PNH cells , for following the natural course and response to therapy of the disease , and for helping to decide when to initiate therapy with monoclonal antibody targeting the terminal complement protein P01031 ( DB01257 ) , anticoagulation , and in some cases allogeneic P19526 transplant . In this article , we review the different diagnostic tests available to clinicians for PNH diagnosis .\",\n \"Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK30___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .\",\n \"Anti - complement therapy for glomerular diseases . A major shift in our understanding of glomerular diseases is the focus on which components of the complement pathway are involved in mediating kidney injury . For example , the membranoproliferative glomerulonephritis lesion is no longer classified solely by ultrastructural findings on biopsy and is now divided into immune - complex - mediated lesions vs complement - mediated lesions . In turn , this emphasis on complement leads to interest in therapies that target complement as potential disease - modifying agents . DB01257 , the first available anti - complement therapy , blocks at the level of P01031 and has revolutionized the treatment of atypical hemolytic uremic syndrome . Whether this agent will work equally well for the far more heterogeneous entities of P01024 glomerulonephritis and dense deposit disease remains unclear . Instead , newer agents that target P01024 may turn out to be the most effective and specific therapy for these P01024 glomerulopathies .\",\n \"The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK46___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .\",\n \"DB01257 in acute recurrence of thrombotic microangiopathy after renal transplantation . Renal thrombotic microangiopathy ( TMA ) is a severe complication of systemic lupus erythematosus ( SLE ) , which is associated with the presence of antiphospholipid ( aPL ) antibodies . In its most fulminant form , TMA leads to a rapid and irreversible end - stage renal failure . DB01257 , an anti - P01031 monoclonal antibody , is a novel therapy of choice for patients with paroxysmal nocturnal hemoglobinuria ( PNH ) and atypical hemolytic uremic syndrome . Here , we report the case of a 27 - year - old woman , known for SLE and end - stage renal disease due to fulminant TMA . Both aPL antibodies and antinucleosome antibodies were positive . The patient underwent a living - related kidney transplantation with immediate production of urine . Although serum creatinine was remaining high , a graft biopsy , performed on day 6 , demonstrated a TMA recurrence . Despite a treatment with plasma exchange , the situation got worse and dialysis was started . DB01257 treatment was subsequently administered and renal function improved rapidly . Three months after transplantation , serum creatinine was at 100 μmol / L , without proteinuria . This case illustrates the benefit of eculizumab therapy in a fulminant recurrence of TMA after kidney transplantation , resistant to classical therapy .\",\n \"Complement inhibitor eculizumab in atypical hemolytic uremic syndrome . BACKGROUND AND OBJECTIVES : Atypical hemolytic uremic syndrome ( aHUS ) is associated with a congenital or acquired dysregulation of the complement alternative pathway that leads to continuous complement activation on host cells causing inflammation and damage . DB01257 , a humanized mAb against complement protein P01031 , inhibits activation of the terminal complement pathway . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS : We report an adolescent with relapsing unclassified aHUS . On admission , a high plasma creatinine level indicated a poor prognosis , and hemodialysis had to be started . Plasma exchanges were initially effective against the microangiopathic hemolytic activity and allowed a temporary improvement of renal function with termination of hemodialysis after 7 wk . Subsequently , plasma exchanges ( three times per week ) failed to prevent ongoing aHUS activity and progressive renal failure . After 12 wk , aHUS treatment was switched to eculizumab . RESULTS : DB01257 was effective in terminating the microangiopathic hemolytic process in two aHUS relapses ; however , after normalization of complement activity , aHUS recurred and ultimately led to anuric end - stage renal failure . CONCLUSIONS : In this patient , complement inhibition by eculizumab temporarily terminated the microangiopathic hemolytic activity . Nevertheless , renal damage as a result of preceding and subsequent aHUS activity resulted in end - stage renal failure ; therefore , therapeutic success may depend on early administration of eculizumab . The optimal duration of treatment may be variable and remains to be determined .\",\n \"Blockade of alternative complement pathway in dense deposit disease . A patient aged 17 with dense deposit disease associated with complement activation , circulating P01024 Nef , and Factor H mutation presented with nephrotic syndrome and hypertension . Steroid therapy , plasma exchange , and rituximab failed to improve proteinuria and hypertension despite a normalization of the circulating sC5b9 complex . DB01257 , a monoclonal antibody directed against P01031 , was used to block the terminal product of the complement cascade . The dose was adapted to achieve a CH50 below 10 % , but proteinuria and blood pressure were not improved after 3 months of treatment .\",\n \"Pyrogenic signaling via vagal afferents : what stimulates their receptors ? Although there is good evidence that pyrogenic messages may be conveyed from the periphery to the brain via vagal afferents , the exact nature of the factors that activate their sensory terminals is unclear . Since IL - 1beta and DB00917 have established roles in fever production and since their receptors have been identified on or near vagal nerves , they are potential candidate mediators . A difficulty , however , is that ( 1 ) IL - 1beta is not expressed constitutively in mononuclear phagocytes , their presumed cell source upon stimulation by exogenous pyrogens , e . g . endotoxin , and ( 2 ) similarly , the isoform of the enzyme that selectively mediates the production and release of DB00917 by endotoxin - stimulated macrophages , P35354 , is also not constitutively expressed in these cells . Since the transcription and translation of these factors significantly lags the onset of fever induced by endotoxin administered intravenously , in particular , it is possible that a secondary , quickly - acting mediator evoked in almost immediate reaction to the presence of endotoxin excites , directly or indirectly , the sensory neurons . We have evidence that the complement component P01031 contributes importantly to the initiation of the febrile response to endotoxin . This article briefly reviews the prevailing concepts of pyrogen sensing and signaling , examines their shortcomings particularly in terms of the temporal discrepancy between the very rapid onset of the febrile response to intravenously administered endotoxin and the significant delay in the elaboration of the putative mediators of fever , and presents newer data that may help to integrate the various preposed mechanisms .\",\n \"Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a P08603 mutation . Kidney transplant in patients with atypical hemolytic uremic syndrome ( aHUS ) is associated with a poor outcome because of recurrent disease , especially in patients known to have a factor H mutation . Long - term prophylactic plasma exchange and combined liver - kidney transplant have prevented graft loss caused by recurrence . However , the mortality associated with liver transplant is not negligible , and prophylactic plasma exchange requires permanent vascular access and regular hospitalization and exposes the patient to potential allergic reactions to plasma . DB01257 is a high - affinity humanized monoclonal antibody that binds to P01031 and thus prevents generation of C5a and the membrane attack complex . We report the case of a 17 - year - old girl with aHUS associated with a mutation in the gene for complement factor H ( P08603 ; c . 3572C > T , Ser1191Leu ) who was highly dependent on plasma exchange . Because of severe allergic reactions to plasma after the third renal graft , eculizumab was introduced in place of plasma exchange without problems . This and other reports suggest that the promise of complement inhibitors in the management of aHUS is going to be fulfilled .\",\n \"___MASK88___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .\",\n \"Activation of cellular invasion by trefoil peptides and src is mediated by cyclooxygenase - and thromboxane A2 receptor - dependent signaling pathways . We have investigated the possible functional relationships between cellular invasion pathways induced by trefoil factors ( TFFs ) , src , and the cyclooxygenases P23219 and P35354 . Pharmacological inhibitors of the Rho small GTPase ( P01024 exoenzyme ) , phospholipase C ( U - 73122 ) , cyclooxygenases ( SC - 560 , NS - 398 ) , and the thromboxane A2 receptor ( P21731 ) antagonist SQ - 295 completely abolished invasion induced by intestinal trefoil factor , pS2 , and src in kidney and colonic epithelial cells MDCKts . src and PCmsrc . In contrast , invasion was induced by the P21731 mimetic U - 46619 , constitutively activated forms of the heterotrimeric G - proteins Galphaq ( AGalphaq ) , Galpha12 , Galpha13 ( AGalpha12 / 13 ) , which are signaling elements downstream of P21731 . Ectopic overexpression of pS2 cDNA and protein in MDCKts . src - pS2 cells and human colorectal cancer cells HCT8 / S11 - pS2 initiate distinct invasion signals that are Rho independent and P36551 and P21731 dependent . We detected a marked induction of P35354 protein and accumulation of the stable PGH2 / TXA2 metabolite TXB2 in the conditioned medium from cells transformed by src . This led to activation of the P21731 - dependent invasion pathway , which is monitored via a Rho - and Galpha12 / Galpha13 - independent mechanism using the Galphaq / PKC signaling cascade . These findings identify a new intracrine / paracrine loop that can be monitored by TFFs and src in inflammatory diseases and progression of colorectal cancers .\",\n \"DB01257 therapy for atypical haemolytic uraemic syndrome due to a gain - of - function mutation of complement factor B . BACKGROUND : Atypical haemolytic uraemic syndrome ( aHUS ) is caused by dysregulated complement activation . A humanised anti - P01031 monoclonal antibody has recently become available for treatment of this condition CASE - DIAGNOSIS / TREATMENT : We present the first description of an infant with an activating mutation of complement factor B successfully treated with eculizumab . On standard doses she had evidence of ongoing P01031 cleavage despite a good clinical response . CONCLUSIONS : DB01257 is effective therapy for aHUS associated with factor B mutations , but recommended doses may not be adequate for all patients .\",\n \"N - aryl - N '- benzylpiperazines as potential antipsychotic agents . N1 -( 2 - Alkoxyphenyl ) piperazines additionally containing an N4 - benzyl group bearing alcohol , amide , imide , or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response ( CAR ) test predictive of clinical antipsychotic activity and in in vitro receptor - binding assays . Certain of the compounds display high affinity for the D2 , P08908 , and alpha 1 - adrenergic receptors . Structures bearing acyclic amide , lactam , and imide functionalities display good biological activity , with a preference for the 1 , 3 - disubstituted phenyl ring relative to the 1 , 4 - and 1 , 2 - congeners ( 7 vs 10 and 12 ) . Every possible position of hydantoin attachment was investigated ( e . g . , substitution at N1 , N3 , and P01031 ) . The hydantoin involving attachment to N1 ( 24 ) was found to have good biological activity , whereas those hydantoins with attachment to N3 or P01031 ( 22 , 23 , and 25 ) were inactive . Several of the smaller acetylated derivatives ( 30 and 33 ) have fair in vivo activity , which was lost in the case of the larger benzoyl analog 31 . DB03419 congener 34 had modest affinity for the D2 receptor ( 65 nM ) as well as excellent in vivo activity . Benzylamino compounds display ( viz . 27 and 35 - 38 ) moderate CAR activity but have surprising receptor affinity , often greater than those of comparable structures bearing a carbonyl ( 36 vs 7 ) . Benzyl and benzhydryl alcohol compounds 40 - 48 are more active than amino structures 27 and 35 - 38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and P08908 receptor binding .\",\n \"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK88___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK88___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK88___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .\",\n \"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK20___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .\",\n \"Clinical grand rounds : atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a rare , lifethreatening , chronic , genetic disease of uncontrolled alternative pathway complement activation . The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged . Regardless of the cause of aHUS , with or without a demonstrated mutation or autoantibody , blockade of terminal complement activation through P01031 is of high interest as a mechanism to ameliorate the disease . DB01257 , an existing monoclonal antibody directed against P01031 with high affinity , prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b - 9 , by blocking P01031 cleavage . We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS .\",\n \"Mycobacteria - primed macrophages and dendritic cells induce an up - regulation of complement C5a anaphylatoxin receptor ( CD88 ) in CD3 + murine T cells . Complement C5a anaphylatoxin is a potent activator of macrophages , neutrophils , and dendritic cells ( DC ) and binds the C5a receptor ( P21730 ; CD88 ) . Although C5a is chemotactic for T cells , expression of P21730 on murine T cells has been disputed . We report here that naïve , Con A - activated , and cytokine ( IL - 12 , Q14116 ) - stimulated murine CD3 + T cells from three strains of mice [ C57Bl / 6 , B10 . nSn ( P01031 +/+ ) , B10 . on ( P01031 -/- ) ] lacked P21730 , as evaluated by immunophenotyping with an anti - P21730 mAb . Ligation of CD3 induced a modest up - regulation with 3 % of CD3 + T cells expressing cell surface P21730 . T cells primed by P25054 differentiate into effector T cells . Activation of mycobacteria [ bacillus Calmette - Guerin ( BCG ) ] - sensitized T cells through MHC II and TCR interactions via BCG - infected macrophages enhanced the expression of P21730 with approximately 14 % of CD3 + T cells positive for P21730 . Comparable expression was found in P01031 +/+ as well as P01031 -/- strains of mice ( 14 % and 15 % , respectively ) . Furthermore , anti - CD3 - activated T cells were primed by BCG - infected DC , and a larger proportion of the primed T cells expressed P21730 ( 30 - 40 % ) . Finally , mice infected with BCG showed significant numbers of CD3 + T cells expressing P21730 in the spleens during infection . As P25054 , such as macrophages and DC , can secrete P01031 and cleave P01031 to C5a and C5b through a peptidase , we suggest that macrophage and DC - T cell interactions can up - regulate P21730 on T cells through MHC II - TCR and provide a C5a peptide for additional local activation of T cells via P21730 .\",\n \"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK48___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .\",\n \"Efficacy of eculizumab in a patient with factor - H - associated atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a rare , chronic , life - threatening disease due to complement dysregulation . The use of early - onset plasma therapy is recommended , but optimal long - term treatment regimen is not well defined . DB01257 , a monoclonal humanized anti - P01031 antibody , has shown success in patients with aHUS . We report a 7 - year - old girl with aHUS associated with factor H mutations successfully treated with eculizumab . Weekly plasma infusion ( PI ) of 25 - 30 ml / kg with short - term intensified PI during aHUS exacerbations was effective for 4 . 3 years . Progressive mild renal failure ( stage 2 ) was attributed to chronic glomerular lesions . Subsequently , she exhibited aHUS exacerbation unresponsive to intensified PI . DB01257 was initiated at 600 mg , resulting in immediate and complete inhibition of terminal complement activation . During the week following treatment , we observed a complete reversal of aHUS activity . She has been receiving 600 mg eculizumab every 2 weeks for the last 12 months . She had no aHUS exacerbation , and serum creatinine level returned to normal . In this patient , eculizumab led to control of PI - resistant aHUS exacerbation and chronic microangiopathic hemolytic activity . Clinical trials are ongoing to assess the safety and efficacy of this drug in the management of aHUS .\",\n \"DB01257 for the treatment of preeclampsia / HELLP syndrome . Severe preeclampsia with hemolysis , elevated liver enzymes and low platelets ( HELLP ) syndrome is a leading cause of maternal and neonatal morbidity and mortality worldwide . Occurrence at an extremely premature gestational age is most challenging as there are dichotomous imperatives : delivery as definitive therapy for maternal health vs . prolongation of pregnancy to avoid prematurity and associated morbidities . We describe a patient presenting with severe preeclampsia / HELLP syndrome at 26 weeks gestation that was treated with DB01257 , a targeted inhibitor of complement protein P01031 , which resulted in marked clinical improvement and complete normalization of lab parameters . Pregnancy was prolonged 17 days , likely resulting in a reduction of neonatal morbidity with its associated short and long - term health care costs . Successful use of DB01257 in this case suggests that complement inhibition may be an effective treatment strategy for severe preeclampsia / HELLP syndrome .\"\n]"},"candidates":{"kind":"list like","value":["___MASK16___","___MASK20___","___MASK30___","___MASK43___","___MASK46___","___MASK48___","___MASK63___","___MASK85___","___MASK88___"],"string":"[\n \"___MASK16___\",\n \"___MASK20___\",\n \"___MASK30___\",\n \"___MASK43___\",\n \"___MASK46___\",\n \"___MASK48___\",\n \"___MASK63___\",\n \"___MASK85___\",\n \"___MASK88___\"\n]"},"answer":{"kind":"string","value":"___MASK46___"},"id":{"kind":"string","value":"MH_train_478"}}},{"rowIdx":479,"cells":{"query":{"kind":"string","value":"interacts_with DB01268?"},"supports":{"kind":"list like","value":["P84022 linker phosphorylation attenuates P84022 transcriptional activity and TGF - β1 / P84022 - induced epithelial - mesenchymal transition in renal epithelial cells . Transforming growth factor - β1 ( TGF - β1 ) has a distinct role in renal fibrosis associated with epithelial - mesenchymal transition ( EMT ) of the renal tubules and synthesis of extracellular matrix . P84022 plays an essential role in fibrosis initiated by EMT . Phosphorylation of P84022 in the C - terminal SSXS motif by type I TGF - β receptor kinase is essential for mediating TGF - β response . P84022 activity is also regulated by phosphorylation in the linker region . However , the functional role of P84022 linker phosphorylation is not well characterized . We now show that P84022 EPSM mutant , which mutated the four phosphorylation sites in the linker region , markedly enhanced TGF - β1 - induced EMT of P84022 - deficient primary renal tubular epithelial cells , whereas P84022 3S - A mutant , which mutated the C - terminal phosphorylation sites , was unable to induce EMT in response to TGF - β1 . Furthermore , immunoblotting and RT - PCR analysis showed a marked induction of fibrogenic gene expression with a significant reduction in P12830 in P52789 human renal epithelial cells expressing P84022 EPSM . TGF - β1 could not induce the expression of α - SMA , vimentin , fibronectin and P05121 or reduce the expression of P12830 in P52789 cells expressing P84022 3S - A in response to TGF - β1 . Our results suggest that P84022 linker phosphorylation has a negative regulatory role on P84022 transcriptional activity and TGF - β1 / P84022 - induced renal EMT . Elucidation of mechanism regulating the P84022 linker phosphorylation can provide a new strategy to control renal fibrosis .","The role of P10721 in the management of patients with gastrointestinal stromal tumors . In recent years , immunohistochemical staining for P10721 ( CD117 ) has become integral to the diagnosis of gastrointestinal stromal tumors ( GISTs ) , nearly 90 % of which harbor activating mutations in the P10721 receptor tyrosine kinase gene . Approximately 80 % of patients with metastatic GIST show at least some clinical response to the targeted small molecule P10721 inhibitor imatinib . The response to imatinib is closely correlated with the presence and type of P10721 mutation . GISTs with the most common P10721 exon 11 mutations have the highest response rate by far , whereas GISTs lacking mutations in P10721 or the alternative receptor tyrosine kinase P16234 show much lower rates of response to imatinib . Less than 5 % of GISTs are P10721 - immunonegative ; and many of these tumors have activating mutations of P16234 , some of which are also inhibited by imatinib . Most patients who initially respond to imatinib become resistant and eventually progress , which coincides with the selection of imatinib - resistant secondary P10721 mutations in the kinase domain . DB01268 has recently been approved for patients with GIST , principally those who fail imatinib therapy ; and additional small molecule inhibitors are in the pipeline . It is becoming evident that alternative approaches to direct P10721 inhibition will be required for long - term survival of patients with advanced GISTs . This review examines the role of P10721 in the diagnosis and management of patients with GIST .","Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK45___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .","Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .","No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK67___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK67___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK67___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK67___ among adults with ADHD .","Complementary and alternative medicine use and quality of life in patients with primary brain tumors . This study explored the use of complementary and alternative medicine ( P62158 ) approaches and their relationship with demographic and disease characteristics and quality of life ( QOL ) in the primary brain tumor ( P10721 ) population . One hundred one P10721 patients were enrolled in this study . The results showed that 34 % of patients reported using P62158 . Forty - one percent reported using more than one type of P62158 . The average cost of each P62158 used per month was 69 dollars , with 20 % of patients spending more than 100 dollars per month . The majority ( 74 % ) reported that their physicians were unaware of their use of P62158 . Data analysis found a higher performance status to be the only factor significantly related to use of P62158 therapy ( P < 0 . 005 ) . There was no difference in patient report of QOL between users and nonusers of P62158 therapies . The high number of patients who do not report P62158 use has potential implications for evaluation of symptoms and response to therapy in this population . This may be especially relevant in those patients with higher functional status participating in clinical trials .","P01308 reverses growth hormone - induced homologous desensitization . Growth hormone ( GH ) is secreted in a pulsatile pattern to promote body growth and metabolism . GH exerts its function by activating several signaling pathways , including O60674 / P35610 and MEK / P29323 . P27361 / 2 activation by GH plays important roles in gene expression , cell proliferation , and growth . We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure , a second GH exposure induces P42229 phosphorylation but not P27361 / 2 phosphorylation ( Ji , S . , Frank , S . J . , and Messina , J . L . ( 2002 ) J . Biol . Chem . 277 , 28384 - 28393 ) . In this study the mechanisms underlying GH - induced homologous desensitization were investigated . A second GH exposure activated the signaling intermediates upstream of MEK / P29323 , including O60674 , Ras , and P04049 . This correlated with recovery of P10912 levels , but was insufficient for GH - induced phosphorylation of Q02750 / 2 and P27361 / 2 . P01308 restored the ability of a second GH exposure to induce phosphorylation of Q02750 / 2 and P27361 / 2 without altering P10912 levels or GH - induced phosphorylation / activation of O60674 and P04049 . GH and insulin synergized in promoting cell proliferation . Further investigation suggested that insulin increased the amount of MEK bound to Q8IVT5 ( kinase suppressor of Ras ) and restored GH - induced tyrosine phosphorylation of Q8IVT5 . Previous GH exposure also induced desensitization of P42224 and P40763 phosphorylation , but this desensitization was not reversed by insulin . Thus , insulin - regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal , physiologic pulse of GH .","DB01268 induced pyoderma gangrenosum - like ulcerations . Pyoderma gangrenosum is a non - infectious neutro ? philic skin disease commonly associated with underlying systemic diseases . Histopathological and laboratory diagnostics are unspecific in the majority of the cases and the diagnosis is made in accordance with the clinical picture . Here , we report the case of a 69 - year old man with progredient pyoderma gangrenosum - like ulcerations under treatment with sunitinib due to hepatocellular carcinoma . A conventional ulcer therapy did not lead to a regression of the lesions . Solely cessation of sunitinib therapy resulted in an improvement of the ulcerations . DB01268 is a multikinase inhibitor that targets the PDGF - α - and ? β - , P15692 - 1 - 3 - , P10721 - , P36888 - , P09603 - and P07949 - receptor , thereby impairing tumour proliferation , pathological angiogenesis and metastasation . Here , we demonstrate that pyoderma gangrenosum - like ulcers may represent a serious side effect of sunitinib - based anti - cancer treatment .","Association of Ang - 2 with integrin beta 2 controls Ang - 2 / DB00102 - dependent upregulation of human peripheral blood monocyte fibrinolysis . O15123 ( Ang - 2 ) , an angiogenic factor that is generally considered an autocrine factor for endothelial cells was shown in a previous study to upregulate peripheral blood monocyte fibrinolysis in concert with platelet - derived growth factor - BB ( DB00102 ) . This upregulation of fibrinolysis was demonstrated to be due to upregulation of elements of the matrix metalloproteinase and serine protease fibrinolytic pathways . The manner in which Ang - 2 interacts with monocytes was not elucidated though no expression of the angiopoietin receptor tyrosine kinase Tie - 2 was found for monocytes . In this study Ang - 2 was found to bind to integrin beta ( 2 ) , and functional inhibition of integrin beta ( 2 ) eliminated Ang - 2 / DB00102 - mediated upregulation of monocyte fibrin invasion . Additionally , integrin beta ( 2 ) blockade significantly inhibited the Ang - 2 / DB00102 based increase in matrix metalloproteinase - 9 ( P14780 ) and membrane type - 1 - MMP ( P50281 ) . Furthermore , Ang - 2 / DB00102 - upregulated urokinase plasminogen - activator receptor ( Q03405 ) was shown to be associated in complexes with integrin beta ( 2 ) . In addition , Ang - 2 was shown to upregulate P09619 expression in monocytes . Therefore several components of the mechanism via which the novel interaction of Ang - 2 and DB00102 with monocytes occurs have been identified .","The role of vascular endothelial growth factor and matrix metalloproteinases in canine lymphoma : in vivo and in vitro study . BACKGROUND : Canine lymphoma represents the most frequent haematopoietic cancer and it shares some similarities with human non - Hodgkin lymphoma . Matrix metalloproteinases ( MMPs ) and vascular endothelial growth factor ( P15692 ) play a coordinated role during invasion and proliferation of malignant cells ; however , little is known about their role in canine haematologic malignancies . The aim of this study was to investigate the mRNA and protein expression of P15692 and the most relevant MMPs in canine lymphoma . Lymph node aspirates from 26 B - cell and 21 T - cell lymphomas were collected . The protein expression levels of P14780 , P08253 and P15692 were evaluated by immunocytochemistry , and the mRNA levels of P08253 , P14780 , P50281 , P01033 , P16035 , O95980 , P15692 and P15692 - 164 were measured using quantitative RT - PCR . RESULTS : P50281 , P01033 and O95980 mRNA levels were significantly higher in T - cell lymphomas than in B - cell lymphomas . Higher mRNA and protein levels of P14780 and P15692 were observed in T - cell lymphomas than in B - cell lymphomas and healthy control lymph nodes . A positive correlation was found between P14780 and P15692 in T - cell lymphomas . Moreover , P14780 , P50281 , P01033 and P15692 were expressed at the highest levels in high - grade T - cell lymphomas . CONCLUSIONS : This study provides new information on the expression of different MMPs and P15692 in canine lymphoma , suggesting a possible correlation between different MMPs and P15692 , immunophenotype and prognosis .","___MASK99___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK99___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .","Gastrointestinal stromal tumors : a review of case reports , diagnosis , treatment , and future directions . Gastrointestinal stromal tumor ( GIST ) is a nonepithelial , mesenchymal tumor first described by Mazur and Clark in 1983 . Since then , its molecular biology has been studied in great detail . Special interest in the role of tyrosine kinase in its regulation has been the target by different drug research . Mutation in c - kit exons 9 , 11 , 13 , 17 and P16234 mutation in exons 12 , 14 , 18 are responsible for activation of gene signaling system resulting in uncontrolled phosphorylation and tissue growth . However , 5 to 15 % of GISTs does not harbor these mutations , which raises additional questions in another alternate signaling pathway mutation yet to be discovered . Diagnosis of GISTs relies heavily on P10721 / CD117 immunohistochemical staining , which can detect most GISTs except for a few 3 % to 5 % that harbors P16234 mutation . Newer staining against PKC theta and DOG - 1 genes showed promising results but are not readily available . Clinical manifestation of GISTs is broad and highly dependent on tumor size . Surgery still remains the first - line treatment for GISTs . The advancement of molecular biology has revolutionized the availability of newer drugs , Imatinib and DB01268 . Together with its advancement is the occurrence of Imatinib / DB01268 drug resistance . With this , newer monoclonal antibody drugs are being developed and are undergoing clinical trials to hopefully improve survival in patients with GISTs .","Gene profiling in Pap - cell smears of high - risk human papillomavirus - positive squamous cervical carcinoma . OBJECTIVE : The purpose of the study was to investigate benign and malignant squamous cervical cells obtained by cervical swabs with regard to differentially expressed genes and gene expression profiling , in order to evaluate the biological behavior and clinical outcome of cervical malignancies . METHODS : Cervical squamous cells from six women with high - risk human papillomavirus positive [ HR - HPV (+) ] cervical carcinoma and from six HPV - negative women with normal ectocervical cells were analyzed by cDNA array . RESULTS : cDNA over - expression of several genes such as MET ( c - met ) , Nm23 - H1 ( P15531 ) , P00533 , P21802 , Nm23 - H2 ( P22392 ) , P04626 ( c - erbB - 2 ) , cyclin - dependent kinase inhibitor 4 ( CDKN2A , P42771 ) , cytokeratin 8 ( P05787 ) , P01116 ( K - ras ) , P17948 , KGF ( P21781 ) , P10415 - like 2 protein ( Q92843 ) , Q15303 , P04198 ( N - myc ) , cyclin D1 ( P24385 ) , P10721 ( c - kit ) , secreted phosphoprotein 1 ( P10451 ) and P42224 , was significant in cervical squamous cell carcinoma ( CSCC ) . Gene expression was downregulated for 13 genes in CSCC , such as interleukin 1 alpha ( P01583 ) , the transforming growth factor receptor beta superfamily ( TGFbeta ; P01137 ) , some members of the insulin - like growth factor binding proteins ( IGFBPs ) and the integrin family ( P23229 , P05556 ) . CONCLUSION : This study was focused on the gene expression profiling of HR - HPV (-) and ( + ) cervical squamous cells and CSCC obtained by cytobrush . We observed gene expression patterns and signaling pathways that permit the investigator to distinguish between benign squamous cervical cells and CSCC with and without HPV infection .","[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK94___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .","Raddeanin A , a triterpenoid saponin isolated from Anemone raddeana , suppresses the angiogenesis and growth of human colorectal tumor by inhibiting P35968 signaling . Raddeanin A ( RA ) is an active triterpenoid saponin from a traditional Chinese medicinal herb , Anemone raddeana Regel . It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells . However , whether RA can inhibit angiogenesis , an essential step in cancer development , remains unknown . In this study , we found that RA could significantly inhibit human umbilical vein endothelial cell ( HUVEC ) proliferation , motility , migration , and tube formation . RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane ( P62158 ) , restrained the trunk angiogenesis in zebrafish , and suppressed angiogenesis and growth of human HCT - 15 colorectal cancer xenograft in mice . Western blot assay showed that RA suppressed P15692 - induced phosphorylation of P35968 and its downstream protein kinases including PLCγ1 , O60674 , Q05397 , Src , and Akt . Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the DB00171 binding pocket of P35968 kinase domain . Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis , demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy .","Prognostic role of Q01094 and members of the CDKN2A network in gastrointestinal stromal tumors . PURPOSE : The aim of the current study was to examine the prognostic relevance of the CDKN2A tumor suppressor pathway in gastrointestinal stromal tumors ( GIST ) . EXPERIMENTAL DESIGN : We determined the mRNA expression of p1 ( INK4A ) , p14 ( Q8N726 ) , P11802 , P06400 , Q00987 , P04637 , and Q01094 by quantitative reverse transcription - PCR in 38 cases of GISTs and correlated the findings with clinicopathologic factors , including mutation analysis of P10721 and P16234 . RESULTS : The k - means cluster analysis yielded three prognostic subgroups of GISTs with distinct mRNA expression patterns of the CDKN2A pathway . GISTs with low mRNA expression of the CDKN2A transcripts p16 ( INK4A ) and p14 ( Q8N726 ) but high mRNA expression of P11802 , P06400 , Q00987 , P04637 , and Q01094 were associated with aggressive clinical behavior and unfavorable prognosis , whereas GISTs with a low mRNA expression of P11802 , P06400 , Q00987 , P04637 , and Q01094 were not . GISTs with a moderate to high mRNA expression of all examined genes also seemed to be associated with unfavorable prognosis . Regarding mutation analysis , we found significant differences in the P10721 / P16234 genotype among the three clusters . Univariate analysis revealed high expression of Q01094 to be associated with mitotic count , proliferation rate , P10721 mutation , and aggressive clinical behavior . These findings on mRNA level could be confirmed by immunohistochemistry . CONCLUSION : Our findings implicate differential regulation schemes of the CDKN2A tumor suppressor pathway converging to up - regulation of Q01094 as the critical link to increased cell proliferation and adverse prognosis of GISTs .","Pharmacological management of gastrointestinal stromal tumours : an update on the role of sunitinib . The efficacy and tolerability of the receptor tyrosine kinase inhibitor , sunitinib malate , have been demonstrated in phase I - III clinical trials of patients with imatinib - resistant or imatinib - intolerant gastrointestinal stromal tumours ( GIST ) as well as in a worldwide expanded - access study and in a continuous daily dosing ( CDD ) trial . Tumour genotype may have a significant influence on the activity of sunitinib in patients with imatinib - resistant GIST . DB01268 activity was observed across different GIST genotypes and particularly in patients with wild - type and P10721 exon 9 mutations ( all relatively resistant to standard - dose imatinib ) and in patients with secondary P10721 exons 13 and 14 mutations . Adverse events with sunitinib were generally mild to moderate and easily managed by dose reduction , dose interruption or standard supportive measures . Treatment discontinuation can be avoided in most patients by close monitoring before and during treatment with appropriate adverse event management as necessary . The correlation between treatment exposure and clinical response is prompting the search for new approaches to treatment optimisation to ensure that patients derive maximum benefit from sunitinib therapy , including dose adjustments based on blood testing to ensure optimal drug exposure , and the use of the alternative CDD regimen to avoid treatment interruption .","New paradigms in gastrointestinal stromal tumour management . BACKGROUND : Targeted agents have improved the prognosis for patients with advanced gastrointestinal stromal tumours ( GISTs ) . Many patients exhibit intolerance or resistance to first - line therapy with imatinib mesylate . DB01268 malate is approved multinationally for the treatment of advanced imatinib - refractory GIST . DESIGN : This article reviews responses to imatinib and sunitinib reported in clinical trials in advanced GIST and discusses the effect of mutational status on treatment responses ; therapeutic developments in GIST treatment are also reviewed . RESULTS : Imatinib 400 mg / day has shown efficacy for first - line treatment of advanced GIST , particularly in patients with P10721 exon 11 mutations . DB01268 50 mg / day ( Schedule 4 / 2 ) has demonstrated effectiveness and tolerability in imatinib - refractory GIST , including patients who would be excluded from clinical trials . DB01268 is associated with longer median overall survival in patients with primary P10721 exon 9 mutations and wild - type GIST compared with P10721 exon 11 mutations in a retrospective study . Ongoing studies , including imatinib in the adjuvant setting and the use of targeted agents in sequence or in combination , will further refine the therapeutic pathway for advanced GIST . CONCLUSIONS : The availability of targeted therapies and greater knowledge of the effect of mutational status on patient responses will assist in optimising outcomes in advanced GIST .","Molecular target modulation , imaging , and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure . PURPOSE : To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor ( GIST ) patients after imatinib failure , in addition to assessing the safety and pharmacokinetics ( PK ) of different dose schedules . EXPERIMENTAL DESIGN : In this open - label , dose - ranging , phase I / II study , 97 patients with metastatic imatinib - resistant / intolerant GIST received sunitinib at doses of 25 , 50 , or 75 mg / d on one of three schedules . Serial tumor imaging was done using computed tomography and [ 18F ] fluoro - 2 - deoxy - d - glucose positron emission tomography scanning . PK and cell proliferation and P10721 phosphorylation status in tumor biopsies were also analyzed . RESULTS : Clinical benefit was observed in 52 patients ( 54 % : 7 objective partial responses , 45 stable disease > or = 6 months ) . Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [ 18F ] fluoro - 2 - deoxy - d - glucose positron emission tomography . DB01268 treatment was associated with reduced tumor cell proliferation by > 25 % in 52 % of cases analyzed and reduced levels of phospho - P10721 in tumor biopsies ( indicating target modulation ) . The recommended dose schedule was 50 mg / d for 4 weeks followed by 2 weeks off treatment . On the 50 - mg dose across all schedules , 79 % of PK - evaluable patients achieved total drug trough concentrations above the target concentration ( 50 ng / mL ) within 14 days of dosing . In addition , adverse events were generally mild to moderate in severity . CONCLUSION : Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of P10721 in GIST following imatinib failure , illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy .","___MASK46___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .","DB01268 induces P60484 expression and inhibits P09619 signaling and migration of medulloblastoma cells . We previously showed that inhibition of the platelet - derived growth factor receptor ( P09619 ) blocks the survival and migration of medulloblastoma cells . Identification of in vitro P09619 - targeting pharmacologic agents that are suitable for preclinical testing in medulloblastoma models in vivo will be critical for efficiently translating these agents to clinical investigation in children with medulloblastoma . In this study , we investigated whether the multi - tyrosine kinase inhibitor sunitinib , effectively inhibits P09619 signaling required for medulloblastoma cell migration . Daoy and D556 human medulloblastoma cells pre - treated for 1 h with 0 . 2 μM sunitinib demonstrated induction of P60484 expression and significant inhibition of P09619 signaling activity and transactivation of P00533 , in a DB01367 - independent manner , in response to DB00102 stimulation . DB01268 pre - treatment markedly reduced medulloblastoma cell migration in response to both DB00102 and 10 % serum at 4 and 24 h after treatment . Pre - treatment with sunitinib for 1 h also resulted in detachment and decreased viability of D556 , but not Daoy , cells and only after 48 h following treatment . However , sunitinib did not induce apoptosis in either cell line at any time point , indicating that the anti - migratory effects of sunitinib were not due to impeding cell survival . DB01268 similarly inhibited P09619 signaling and migration of primary murine Smo / Smo medulloblastoma cells , suggesting that the Smo / Smo mouse is an appropriate model for preclinical testing of sunitinib . These results indicate that sunitinib may be an important pharmacologic agent for the treatment of invasive medulloblastoma , particularly given evidence of its ability to cross the blood - brain barrier to target tumor cells , and thus warrants further in vivo testing for confirmation of efficacy .","Indicators for the exposure assessment of transformation products of organic micropollutants . Environmental transformation products of organic micropollutants have the potential to be similarly or even more mobile , persistent , ortoxic than their parent compounds . They should , therefore , be included in chemical hazard and risk assessment procedures as well as in the assessment of soil and water quality . To fulfill this requirement most efficiently , screening approaches that select relevant transformation products for detailed assessment are needed . This paper presents two process - based multimedia , multispecies models that allow us to quantitatively estimate the environmental fate of transformation products . The resulting exposure patterns are assessed with two indicators : joint persistence ( JP ) , which describes the temporal extent of environmental exposure to a parent compound and its transformation products , and the predicted relative aquatic concentrations ( P31749 ) , which estimate the relative concentrations of parent compounds and their transformation products in surface water bodies . As a case study , JP and P31749 are calculated for 16 pesticides and their relevant transformation products . The results for the JP indicator confirm the importance of considering transformation products in the assessment of overall persistence ; for example , in the context of P10721 assessments . Comparison of P31749 results with monitoring data on herbicides and their transformation products shows the suitability of our approach for estimating relative concentrations in surface water , and as a consequence , its usefulness in identifying transformation products for future water quality monitoring programs . Transformation products of triketones and other highly used acidic herbicides are specifically identified as targets .","Expression and mutational status of treatment - relevant targets and key oncogenes in 123 malignant salivary gland tumours . BACKGROUND : Malignant tumours of the salivary glands ( MSGT ) are rare and pleomorphic entities . Patients with advanced disease may benefit from targeted therapy ; however , specific targets for optimising and personalising treatments are yet to be identified . DESIGN : Immunohistochemistry for C - P10721 , P00533 , P04626 , P15941 , phospho - P42345 , androgen / estrogens / progesterone receptors and Ki67 was carried out and evaluated in terms of progression - free and overall survival . High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology . RESULTS : Several therapy leads were identified , including high levels of P04626 and androgen receptors in salivary duct carcinomas , C - P10721 in myoepithelial carcinomas and P00533 in mucoepidermoid carcinomas . Recurrent mutations involving downstream elements of the P00533 pathway were found in P01112 , notably in tumours with a myoepithelial component , and in other key oncogenes ( P01116 / P01111 / PI3KCA / P15056 / MAP2K ) . On the other hand , < 1 % of samples had P00533 or P04626 mutations . CONCLUSION : Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads . Genotyping results suggest activation downstream of P00533 in 18 of the 107 samples that could be associated with low efficacy of P00533 inhibitors . Other molecules , such as PI3K / MEK or P42345 inhibitors , may have anti - tumour activity in this subgroup . The high mutation rate in P01112 highlights a novel key oncogenic event in MSGT .","DB11588 donors or heme oxygenase - 1 ( P09601 ) overexpression blocks interleukin - 18 - mediated NF - kappaB - P60484 - dependent human cardiac endothelial cell death . The objective of this study was to determine whether heme oxygenase - 1 ( P09601 ) or heme metabolites exert cytoprotective effects on interleukin - 18 - mediated endothelial cell ( EC ) death . Treatment with interleukin ( IL ) - 18 increased NF - kappaB activation and P60484 induction , suppressed Akt activation , and stimulated EC death . While ectopic expression of p65 enhanced P60484 transcription , adenoviral transduction of dnIkappaB - alpha , dnp65 , or dnIKKbeta was inhibitory . Furthermore , Q14116 suppressed P09601 mRNA expression via enhanced mRNA degradation . Overexpression of P09601 , treatment with P09601 inducer hemin , or the CO donor cobalt ( III ) protoporphyrin IX all reversed Q14116 - mediated NF - kappaB activation , P60484 induction , Akt suppression , and EC death . Furthermore , hemin induced P09601 expression , and P09601 knockdown , P09601 inhibition , or CO scavengers all reversed the prosurvival effects of hemin . In addition , the CO donors CORM - 1 and CORM - 3 and the heme metabolites biliverdin and bilirubin attenuated Q14116 - induced EC death via a similar signaling pathway . Q14116 induced p38alpha MAPK activation , and suppressed p38beta isoform expression . While p38alpha knockdown attenuated , p38beta knockdown potentiated Q14116 - mediated EC death . DB03404 and P09601 reversed Q14116 - mediated p38alpha induction and restored p38beta levels . These results demonstrate that Q14116 suppresses P09601 expression and induces EC death . P09601 overexpression , P09601 induction , or treatment with heme metabolites all reverse Q14116 - mediated p38alpha MAPK and NF - kappaB activation , P60484 induction , Akt suppression , and EC death . Thus , P09601 inducers and CO donors may have the therapeutic potential to effectively block Q14116 signaling and reduce Q14116 - dependent vascular injury and inflammation .","Small in - frame deletion in the epidermal growth factor receptor as a target for DB05294 . DB05294 is an inhibitor of vascular endothelial growth factor receptor - 2 ( P35968 / P35968 ) tyrosine kinase , with additional activity against epidermal growth factor receptor ( P00533 ) tyrosine kinase . DB05294 inhibits angiogenesis and growth of a wide range of tumor models in vivo . Gefitinib ( \" ___MASK62___ \" ) is a selective P00533 tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation . Here , the ability of gefitinib and DB05294 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro , and a strong correlation was noted between the IC ( 50 ) values of gefitinib and DB05294 ( r = 0 . 79 ) . No correlation was observed between the sensitivity to DB05294 and the level of P00533 or VEGFR expression . The NSCLC cell line PC - 9 was seen to be hypersensitive to gefitinib and DB05294 , and a small ( 15 - bp ) in - frame deletion of an DB00171 - binding site ( exon 19 ) in the P00533 was detected ( delE746 - A750 - type deletion ) . To clarify the involvement of the deletional mutation of P00533 in the cellular sensitivity to DB05294 , we examined the effect of this agent on HEK293 stable transfectants expressing deletional P00533 that designed as the same deletion site observed in PC - 9 cells ( 293 - pDelta15 ) . These cells exhibited a 60 - fold higher sensitivity to DB05294 compared with transfectants expressing wild - type P00533 . DB05294 inhibited the phosphorylation of the mutant P00533 by 10 - fold compared with cells with wild - type P00533 . In conclusion , the findings suggested that a small in - frame deletion in the P00533 increased the cellular sensitivity to DB05294 .","Estradiol increases cell growth in human astrocytoma cell lines through ERα activation and its interaction with Q15788 and Q9Y6Q9 coactivators . Estradiol ( E2 ) regulates several cellular functions through the interaction with estrogen receptor subtypes , ERα and ERβ , which present different functional and regulation properties . ER subtypes have been identified in human astrocytomas , the most common and aggressive primary brain tumors . We studied the role of ER subtypes in cell growth of two human astrocytoma cell lines derived from tumors of different evolution grades : U373 and D54 ( grades III and IV , respectively ) . E2 significantly increased the number of cells in both lines and the co - administration with an ER antagonist ( ICI 182 , 780 ) significantly blocked E2 effects . ERα was the predominant subtype in both cell lines . E2 and ICI 182 , 780 down - regulated ERα expression . The number of U373 and D54 cells significantly increased after PPT ( ERα agonist ) treatment but not after DPN ( ERβ agonist ) one . To determine the role of Q15788 and Q9Y6Q9 coactivators in ERα induced cell growth , we silenced them with RNA interference . Coactivator silencing blocked the increase in cell number induced by PPT . The content of proteins involved in proliferation and metastasis was also determined after PPT treatment . Western blot analysis showed that in U373 cells the content of PR isoforms ( PR - A and PR - B ) , P00533 , P15692 and cyclin D1 increased after PPT treatment while in D54 cells only the content of P00533 was increased . Our results demonstrate that E2 induces cell growth of human astrocytoma cell lines through ERα and its interaction with Q15788 and Q9Y6Q9 and also suggest differential roles of ERα on cell growth depending on astrocytoma grade .","Efficacy and safety of sunitinib in Chinese patients with imatinib - resistant or - intolerant gastrointestinal stromal tumors . AIMS : To assess the efficacy and safety of sunitinib in Chinese patients with imatinib - resistant or - intolerant gastrointestinal stromal tumors ( GISTs ) , and evaluate the impact of genotype on sunitinib efficacy . MATERIALS & METHODS : In a single - arm retrospective study , 55 patients with recurrent or metastatic GISTs who were resistant or intolerant to prior imatinib treatment received sunitinib for at least one treatment cycle . RESULTS : The median progression - free survival was 35 weeks ( 95 % CI : 24 . 6 - 45 . 4 ) in patients who received sunitinib 37 . 5 mg / day as a continuous daily dose versus 30 weeks ( 95 % CI : 12 . 8 - 47 . 2 ) in those who received sunitinib 50 mg / day as a 4 - weeks - on , 2 - weeks - off ( 4 / 2 ) schedule ( p = 0 . 707 ) . The median overall survival of all patients was 86 weeks ( 95 % CI : 75 . 0 - 97 . 0 ) . Patients with P10721 exon 9 mutations had a significantly longer progression - free survival compared with those with P10721 exon 11 mutations and patients with wild - type GISTs ( p = 0 . 022 ) . DB01268 therapy was well tolerated , with most adverse events rated as grade 1 or 2 in severity . The sunitinib 37 . 5 mg / day continuous daily dose schedule was better tolerated by Chinese GIST patients than the 50 mg / day 4 / 2 schedule . CONCLUSION : DB01268 was effective and well tolerated in Chinese patients with imatinib - resistant or - intolerant GISTs . Patients with P10721 exon 9 mutations showed the best efficacy . A 37 . 5 mg / day continuous daily dose sunitinib dosing schedule appears to be the optimal choice for Chinese patients due to a decreased incidence of adverse events .","P40763 signaling is induced by intercellular adhesion in squamous cell carcinoma cells . The signal transducer and activator of transcription - 3 ( P40763 ) frequently activated during tumor progression has been linked to enhanced cell growth . In squamous cell carcinoma of the head and neck ( HNSCC ) , P40763 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways . In the present study , we have examined the potential mechanism by which cell - cell contact initiates P40763 activation . Using a panel of HNSCC cell lines , Ca (+ 2 )- dependent cell - cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of P40763 - Y705 and P42224 - Y701 . This intercellular adhesion - induced P40763 activation was mediated by JAK and Src signaling and partially by P00533 signaling . In addition , immunolocalization studies revealed initial formation of phosphorylated P40763 - Y705 at nascent P12830 cell junctions with eventual translocation to the nucleus in cell aggregates . Adhesion - mediated P35610 activation in monolayer and cell aggregate cultures required functional P12830 . These results indicate that , in HNSCC cells , cadherin - mediated intercellular adhesion induces P35610 signaling that may modulate cell survival and resistance to apoptosis during tumor progression .","Tyrosine kinases as targets in cancer therapy - successes and failures . Protein kinases play a crucial role in signal transduction and also in cellular proliferation , differentiation and various regulatory mechanisms . The inhibition of growth - related kinases , especially tyrosine kinases , might therefore provide new therapies for diseases such as cancer . Due to the enormous progress that has been made in the past few years in the identification of the human genome , in molecular and cell biology technologies , in structural biology and in bioinformatics , the number of receptor and non - receptor tyrosine kinases that have been identified as valuable molecular targets has greatly increased . Currently , more than 20 different tyrosine kinase targets are under evaluation in drug discovery projects in oncology . The progress made in the crystallisation of protein kinases , in most cases complexed with DB00171 - site - directed inhibitors , has confirmed that the ATPbinding domain of tyrosine kinases is an attractive target for rational drug design ; more than 20 DB00171 - competitive , low molecular weight inhibitors are in various phases of clinical evaluation . Meanwhile , clinical proof - of - concept ( POC ) has been achieved with several antibodies and small molecules targeted against tyrosine kinases . With Herceptin , Glivec and ___MASK62___ ( registered in Japan ) , the first kinase drugs have entered the market . This review describes the preclinical and clinical status of low molecular weight drugs targeted against different tyrosine kinases ( e . g . , epidermal growth factor receptor [ P00533 ] , vascular endothelial growth factor receptor [ VEGFR ] , platelet - derived growth factor receptor [ P09619 ] , Kit , Fms - like tyrosine kinase [ Flt ] - 3 ) , briefly describes new targets , and provides a critical analysis of the current situation in the area of tyrosine kinase inhibitors .","___MASK46___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK46___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .","DB01268 acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma . DB01268 is a broad - spectrum small - molecule inhibitor of receptor tyrosine kinases ( RTK ) that serves as the present standard of care for first - line therapy of advanced clear cell renal cell carcinoma ( ccRCC ) . A full understanding of the targets and mechanism of action of sunitinib in ccRCC treatment remains incomplete . In this study , we evaluated several tumor cell and endothelial targets of sunitinib and investigated which RTK ( s ) may specifically contribute to its therapeutic effects . Microarray expression profiling and Western blot analysis revealed that among known sunitinib targets , only platelet - derived growth factor receptor - beta and vascular endothelial growth factor receptor - 2 ( P35968 ) were overexpressed in ccRCCs relative to normal tissues . DB01268 was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations ( approximately 0 . 1 micromol / L ) that inhibit RTK targets . In contrast , sunitinib inhibited endothelial cell proliferation and motility at the same concentrations by suppressing P35968 signaling . Moreover , whereas sunitinib inhibited the growth of ccRCC xenograft tumors and decreased tumor microvessel density as soon as 12 hours after treatment , sunitinib showed no significant effects on tumor cell proliferation or apoptosis up to 72 hours after treatment . Our findings indicate that sunitinib inhibits ccRCC growth primarily through an antiangiogenic mechanism and not through direct targeting of ccRCC tumor cells .","P50281 as a downstream target of P11274 - P00519 / P00519 interactor 1 signaling : polarized distribution and involvement in P11274 - P00519 - stimulated leukemic cell migration .","DB01268 : a newly approved small - molecule inhibitor of angiogenesis . The advent of targeted therapies has allowed treatment to be directed at signaling pathways integral to tumor growth and survival . DB01268 ( SU11248 , sunitinib malate ; Pfizer Inc . , New York , NY , USA ) is a novel oral small - molecule multitargeted receptor tyrosine kinase inhibitor that has demonstrated direct antitumor activity and antiangiogenic action . It targets the vascular endothelial growth factor receptor ( VEGFR ) , platelet derived growth factor receptor ( P09619 ) , stem - cell factor receptor and Fms - like tyrosine kinase receptor 3 receptor tyrosine - kinases . In January 2006 , sunitinib malate was granted approval by the U . S . Food and Drug Administration for the treatment of gastrointestinal stromal tumor after disease progression on , or intolerance to , imatinib mesylate , as well as for the treatment of metastatic renal cell cancer . This review will discuss the development of sunitinib , particularly in acute myeloid leukemia , imatinib - resistant gastrointestinal stromal tumors and renal cell cancer . The review will also discuss ongoing trials with sunitinib in other malignancies such as neuroendocrine tumors and breast cancer , as well as its potential future development in combination therapy with other agents and in other malignancies .","DB01268 in malignant melanoma : a treatment option only for P10721 - mutated patients ? DB01268 has previously been reported to be potentially effective in the treatment of malignant melanomas expressing c - P10721 . Here we report on the case of a 77 - year - old gentleman affected by a metastatic clear cell carcinoma of the kidney and a metastatic malignant melanoma with liver and lung metastases . Despite the negativity for CD117 and the absence of P10721 amplification or mutations in the melanoma specimen , he achieved a partial response both in the lungs and in the liver while on sunitinib ( 50 mg once / day , 4 weeks on / 2 weeks off ) for the treatment of kidney cancer . To our knowledge , this represents the first evidence of sunitinib activity in P10721 wild - type melanoma . Further studies should be performed to confirm these preliminary data .","The retinoid signalling molecule , O95361 , is repressed during squamous cell carcinoma skin carcinogenesis in vivo and reduces skin cancer cell migration in vitro . Retinoid therapy is used for chemo - prevention in immuno - suppressed patients at high risk of developing skin cancer . The retinoid signalling molecule , tripartite motif protein 16 ( O95361 ) , is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid - sensitive neuroblastoma . We sought to determine the role of O95361 in skin squamous cell carcinoma ( SCC ) pathogenesis . We have shown that O95361 expression was markedly reduced during the histological progression from normal skin to actinic keratosis and SCC . SCC cell lines exhibited lower cytoplasmic and nuclear O95361 expression compared with primary human keratinocyte ( PHK ) cells due to reduced O95361 protein stability . Overexpressed O95361 translocated to the nucleus , inducing growth arrest and cell differentiation . In SCC cells , O95361 bound to and down regulated nuclear Q01094 , this is required for cell replication . Retinoid treatment increased nuclear O95361 expression in retinoid - sensitive PHK cells , but not in retinoid - resistant SCC cells . Overexpression of O95361 reduced SCC cell migration , which required the C - terminal P07949 finger protein ( RFP ) - like domain of O95361 . The mesenchymal intermediate filament protein , vimentin , was directly bound and down - regulated by O95361 and was required for O95361 - reduced cell migration . Taken together , our data suggest that loss of O95361 expression plays an important role in the development of cutaneous SCC and is a determinant of retinoid sensitivity .","DB01268 malate in solitary fibrous tumor ( P51668 ) . BACKGROUND : To report on sunitinib activity in a retrospective series of 35 solitary fibrous tumor ( P51668 ) treated at a single institution . PATIENTS AND METHODS : From April 2008 , 35 patients with progressive advanced P51668 ( male / female : 20 / 15 ; mean age : 58 years ; meningeal / extrameningeal : 6 / 29 ; locally advanced / metastatic : 15 / 20 ; prior chemotherapy : 25 ) were treated , on an individual use basis , with continuous - dosing sunitinib 37 . 5 mg / day . P09619 ( P09619 ) and vascular endothelial growth factor receptor 2 ( P35968 ) status were assessed by immunohistochemistry and , in a subgroup of patients , by real time PCR . RESULTS : Thirty - one patients were assessable for response by RECIST ( one early death ; three early interruptions ) . Best responses were 2 partial response ( PR ) , 16 stable disease , 13 progressive disease . A < 30 % decrease in size was observed in three patients . Fourteen of 29 patients assessable by Choi criteria had a PR . Median progression - free survival by RECIST was 6 months ( range 1 - 22 ) . In two of six patients , resistance to sunitinib was overcome by increasing sunitinib to 50 mg / day . P09619 and / or P35968 were positive in all cases and not predictive of response ; a less aggressive morphology corresponded to an increased response rate ( 53 % PR by Choi in the malignant P51668 , 20 % PR in the pleomorphic / dedifferentiated P51668 ) . CONCLUSIONS : DB01268 is active in P51668 . Response can be long - lasting .","Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma . BACKGROUND : Coactivation of tyrosine kinase limits the efficacy of tyrosine kinase inhibitors . We hypothesized that a strategic combination therapy could overcome tyrosine kinase coactivation and compensatory oncogenic signaling in patients with adrenocortical carcinoma ( ACC ) . METHODS : We profiled 88 tyrosine kinases before and after treatment with sunitinib in H295R and SW13 ACC cells . The effects of monotherapy and strategic combination regimens were determined by the 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 5 -( 3 - carboxymethoxyphenyl )- 2 -( 4 - sulfophenyl )- 2H - tetrazolium ( ie , MTS ) assay . RESULTS : The minimum inhibitory concentrations ( IC ( min ) ) of sunitinib quenched its primary targets : P36888 , P35968 , and P07949 . In contrast , P29323 , P08631 , Chk2 , P07947 , CREB , MEK , MSK , p38 , P09769 , and P30530 were hyperactivated . Monotherapy with sunitinib or PD98059 at their IC ( min ) reduced proliferation by 23 % and 19 % , respectively , in H295R cells and by 25 % and 24 % , respectively , in SW13 cells . DB01268 and PD98059 in combination decreased proliferation by 68 % and 64 % in H295R and in SW13 cells , respectively ( P < . 05 versus monotherapy ) . The effects of combination treatment exceeded the sum of the effects observed with each individual agent alone . CONCLUSION : We describe the first preclinical model to develop strategic combination therapy to overcome tyrosine kinase coactivation in ACC . Because many tyrosine kinase inhibitors are readily available , this model can be immediately tested in clinical trials for patients with advanced ACC .","Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK36___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .","DB01268 : bridging present and future cancer treatment . Tyrosine kinase receptors ( RTKs ) are a heterogeneous group of transmembrane proteins involved in signal transduction . These receptors are expressed in many different cells and regulate cellular growth , differentiation and angiogenesis . Overexpression and / or the structural alteration of different RTKs classes are generally associated to cancer and , when RTKs - mediated signal transduction pathways are abnormally activated , generate cancer growth , angiogenesis and metastatization . Therapeutic intervention targeting RTKs concerns antagonist drugs as little molecules or monoclonal antibodies . DB01268 malate is a little molecule able to block intracellular tyrosine kinase domain of RTKs , which has both direct anticancer and antiangiogenetic activity . DB01268 targets selectively vascular endothelial growth factor , P10721 , Flt3 and platelet - derived growth factor receptors and the receptor encoded by the ret proto - oncogene . This drug is used in the treatment of gastrointestinal stromal cancer ( GIST ) resistant to imatinib and metastatic renal cell carcinoma ( RCC ) . In this review , we report preclinical data of sunitinib , even about synergism with chemotherapy and radiotherapy , data relative to phase III trials of sunitinib in the treatment of GIST and RCC , and we try to plan what will be future applications of sunitinib in different types of cancer , even in association to chemotherapy , radiotherapy and monoclonal antibodies .","DB01268 in metastatic thymic carcinomas : laboratory findings and initial clinical experience . BACKGROUND : Thymic carcinoma ( TC ) is a rare aggressive tumour . Median survival with current treatments is only 2 years . DB01268 is a multi - targeted tyrosine kinase inhibitor that has shown benefit in various other cancers . METHODS : Laboratory analyses of snap - frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases ( RTKs ) in TC samples . On the basis of molecular analyses showing activation of multiple RTKs in their tumour , four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols . RESULTS : RTK analysis in three of the patients showed activation of multiple RTKs , including platelet - derived growth factor - beta and vascular endothelial growth factor 3 . Mutations of P00533 , c - P10721 , P01116 , and P15056 genes were not found . Administration of sunitinib yielded a partial remission ( lasting 2 to 18 + months ) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in DB09150 - PET in another one . The overall survival with sunitinib treatment ranges from 4 to 40 + months . Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re - administration of sunitinib . CONCLUSIONS : DB01268 is an active treatment for metastatic TC . A panel of molecular analyses may be warranted for optimal patient selection .","Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .","Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .","Reinvestigation of carrier transport properties in liquid crystalline 2 - phenylbenzothiazole derivatives . We have reinvestigated the charge carrier transport properties in a liquid crystal of 2 -( 4 '- heptyloxyphenyl )- 6 - dodecylthiobenzothiazole ( 7O - P10721 - P28222 ) , for which the electronic conduction was first established in rodlike liquid crystals and for which the highest hole mobility in the smectic A ( SmA ) phase ever achieved was reported . We found that 7O - P10721 - P28222 exhibited three crystal phases , one of which appeared in a limited temperature range of 10 degrees just below the phase transition temperature from the SmA phase . In this crystal phase , nondispersive transient photohole currents were observed in time - of - flight experiments , and its hole mobility was determined to be 8 x 10 (- 3 ) cm ( 2 )/ Vs , slightly higher than that reported previously in the SmA phase . For the SmA phase , however , the hole mobility was 1 x 10 (- 4 ) cm ( 2 )/ Vs . Furthermore , we established the electron transport in the SmA phase of purified 7O - P10721 - P28222 , whose mobility was the same as the hole mobility in that phase . In order to confirm generality of the new findings in 7O - P10721 - P28222 , we investigated the carrier transport properties of its derivative having a short hydrocarbon chain , 2 -( 4 '- heptyloxyphenyl )- 6 - butylthiobenzothiazole ( 7O - P10721 - S4 ) , and obtained comparable results . The present results correct a mistake in the previous report and give an idea of what a typical mobility in the SmA phase is . On the basis of these results , we discuss what determines the charge carrier mobility in smectic mesophases .","Ligand - dependent platelet - derived growth factor receptor ( P09619 ) - alpha activation sensitizes rare lung cancer and sarcoma cells to P09619 kinase inhibitors . Platelet - derived growth factor ( PDGF ) receptors ( P09619 ) and their ligands play critical roles in several human malignancies . DB01268 is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor , c - P10721 , and P09619 , and has shown clinical activity in various solid tumors . Activation of P09619 signaling has been described in gastrointestinal stromal tumors ( P16234 mutations ) as well as in chronic myeloid leukemia ( P11274 - P16234 translocation ) , and sunitinib can yield clinical benefit in both settings . However , the discovery of P09619 activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti - P09619 therapies , such as sunitinib . Using a high - throughput cancer cell line screening platform , we found that only 2 of 637 tested human tumor - derived cell lines show significant sensitivity to single - agent sunitinib exposure . These two cell lines [ a non - small - cell lung cancer ( NSCLC ) and a rhabdomyosarcoma ] showed expression of highly phosphorylated P16234 . In the sunitinib - sensitive adenosquamous NSCLC cell line , P16234 expression was associated with focal PFGRA gene amplification , which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens . Moreover , in this NSCLC cell line , focal amplification of the gene encoding the P09619 ligand Q9NRA1 was also detected , and silencing P16234 or Q9NRA1 expression by RNA interference inhibited proliferation . A similar codependency on P16234 and Q9NRA1 was observed in the sunitinib - sensitive rhabdomyosarcoma cell line . These findings suggest that , in addition to gastrointestinal stromal tumors , rare tumors that show Q9NRA1 - mediated P16234 activation may also be clinically responsive to pharmacologic P16234 or Q9NRA1 inhibition .","Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors . BACKGROUND : Myelosuppression has been observed with several multikinase angiogenesis inhibitors in clinical studies , although the frequency and severity varies among the different agents . Inhibitors targeting vascular endothelial growth factor receptor ( VEGFR ) often inhibit other kinases , which may contribute to their adverse - event profiles . METHODS : Kinase selectivity of pazopanib , sorafenib , and sunitinib was evaluated in a panel of 242 kinases . Cellular potency was measured using autophosphorylation assays . Effect on human bone marrow progenitor growth in the presence of multiple growth factors was evaluated and correlated with the kinase selectivity . RESULTS : DB01268 inhibited more kinases than pazopanib and sorafenib , at potencies within 10 - fold of P35968 . All three compounds potently inhibited P35968 , platelet - derived growth factor receptor - beta and c - Kit , However , pazopanib was less active against Flt - 3 in both kinase and cellular assays . The inhibitory properties of pazopanib , sorafenib , and sunitinib were dependent on the growth factor used to initiate bone marrow colony formation . Addition of stem cell factor and / or Flt - 3 ligand with granulocyte - macrophage colony stimulating factor resulted in significant shifts in potency for sorafenib and sunitinib but less so for pazopanib . CONCLUSION : Activity against c - kit and Flt - 3 by multikinase angiogenesis inhibitors provide a potential explanation for the differences in myelosuppression observed with these agents in patients .","Plasma biomarkers correlating with clinical outcome in a phase II study of sorafenib in advanced NSCLC . We investigated the relationship between plasma protein biomarker concentrations and clinical outcomes in 52 patients with relapsed / refractory advanced non - small cell lung cancer ( NSCLC ) treated with 400 ~ mg bid sorafenib in a phase II trial . Blood samples were collected at baseline , on day 15 of cycle 1 ( C1D15 ) , and on day 1 of cycle 3 ( C3D1 ) , and plasma concentrations of total P15692 , P15692 - 165 , soluble ( s ) P35968 , DB00102 , sPDGFR - β , sEGFR , sHER - 2 , uPA , P05121 , Q03405 , P01033 , and circulating Ras P38936 were assayed by ELISA . Elevated baseline P15692 , P15692 - 165 , DB00102 , Ras P38936 , and P01033 concentrations were associated with poorer patient outcomes ( shorter overall survival [ OS ] and / or progression - free survival [ PFS ] ) . During treatment , the mean concentrations of sVEGFR - 2 , DB00102 , sPDGFR - β , P01033 , Q03405 , and P05121 decreased , while the mean sEGFR concentration increased . Increases in P15692 , P15692 - 165 , DB00102 , and P01033 during treatment were associated with better outcomes ( longer OS and / or PFS ) , whereas increases in plasma Ras P38936 during treatment were associated with shorter PFS . The associations between baseline concentrations and / or pharmacodynamic changes in plasma proteins and clinical outcomes in NSCLC patients treated with sorafenib suggest that these biomarkers may have a prognostic role and / or predict the efficacy of sorafenib in patients with NSCLC .","Recent advances in the treatment of gastrointestinal stromal tumors . Constitutively activating mutations in the P10721 and platelet - derived growth factor receptor α ( P16234 ) RTKs play a crucial role in the biology of gastrointestinal stromal tumors ( GISTs ) , and this disease has served as an effective model for targeting gain - of - function kinase mutations in cancer . Imatinib has entered the clinical arena in the last decade and substantially improved the outcome in these formerly untreatable cancers . However , most advanced GISTs responding to imatinib progress within 2 - 3 years due to heterogeneous subclones harboring a range of imatinib - resistant secondary P10721 mutations . DB01268 , and more recently , regorafenib , have obtained US Food and Drug Administration approval for the treatment of GISTs after imatinib failure , and thus expanded the treatment options in resistant disease . Within this framework , we present an evaluation of current GIST management , emphasizing the most recent advances in the field together with a discussion on future steps to be taken in refractory disease .","Differential radiosensitisation by ZD1839 ( ___MASK62___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK62___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .","DB01268 in the treatment of advanced solid tumors . DB01268 is an oral multikinase inhibitor that blocks the vascular endothelial growth factor receptor ( VEGFR ) , platelet - derived growth factor receptor ( P09619 ) alpha and beta , c - kit , and other receptors . These attributes have proven to be efficacious in the treatment of metastatic renal cell carcinoma ( RCC ) , unresectable gastrointestinal stromal tumors ( GIST ) , and well - differentiated advanced pancreatic neuroendocrine tumors ( PNET ) . Though activity has been reported in other tumor types , phase III trials have not yet demonstrated improved survival outcomes in these cancers . Most side effects including hypertension , hand - foot syndrome , and diarrhea are generally well manageable . This review will detail the preclinical data leading up to the results of the pivotal phase III clinical trials that have led to the widespread use of sunitinib in advanced RCC , GIST , and PNET .","Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients . PURPOSE : To investigate the angiogenic changes in primary tumor tissue of renal cell carcinoma ( RCC ) patients treated with P15692 - targeted therapy . EXPERIMENTAL DESIGN : Phase II trials of P15692 pathway - targeted therapy given before cytoreductive surgery were carried out with metastatic RCC patients with the primary tumor in situ to investigate the necessity of nephrectomy . Primary tumor tissues were obtained and assessed for angiogenesis parameters . Results were compared with similar analyses on untreated tumors . RESULTS : DB01268 or bevacizumab pretreatment resulted in a significant reduction of microvessel density in the primary tumor . Also , an increase in vascular pericyte coverage was found in sunitinib - pretreated tumors , consistent with efficient angiogenesis inhibition . Expression of several key regulators of angiogenesis was found to be suppressed in pretreated tissues , among which P17948 and P35968 , angiopoietin - 1 and angiopoietin - 2 and platelet - derived growth factor - B . In addition , apoptosis in tumor and endothelial cells was induced . Interestingly , in sunitinib - pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed , which was not the case in bevacizumab - pretreated tumors . A positive correlation with the interval between halting the therapy and surgery was found , suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment . CONCLUSION : This study describes , for the first time , the angiostatic response in human primary renal cancers at the tissue level upon treatment with P15692 - targeted therapy . Discontinuation of treatment with tyrosine kinase inhibitors leads to accelerated endothelial cell proliferation . The results of this study contribute important data to the ongoing discussion on the discontinuation of treatment with kinase inhibitors .","A curated database of miRNA mediated feed - forward loops involving MYC as master regulator . BACKGROUND : The MYC transcription factors are known to be involved in the biology of many human cancer types . But little is known about the Myc / microRNAs cooperation in the regulation of genes at the transcriptional and post - transcriptional level . METHODOLOGY / PRINCIPAL FINDINGS : Employing independent databases with experimentally validated data , we identified several mixed microRNA / Transcription Factor Feed - Forward Loops regulated by Myc and characterized completely by experimentally supported regulatory interactions , in human . We then studied the statistical and functional properties of these circuits and discussed in more detail a few interesting examples involving Q01094 , P60484 , P06400 and P15692 . CONCLUSIONS / SIGNIFICANCE : We have assembled and characterized a catalogue of human mixed Transcription Factor / microRNA Feed - Forward Loops , having Myc as master regulator and completely defined by experimentally verified regulatory interactions .","Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .","Induction of high mobility group box 1 release from serotonin - stimulated human umbilical vein endothelial cells . High mobility group box 1 ( P09429 ) is a non - histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis . The P09429 functions as a potent proinflammatory cytokine in the extracellular spaces . Recently , P09429 has been implicated in the progression of atherosclerosis . However , the association between P09429 and the development of atherosclerosis is poorly understood . Therefore , we examined whether serotonin ( 5 - HT ) , a key factor involved in the development of atherosclerosis , induced P09429 release in human umbilical vein endothelial cells ( HUVECs ) . We found that 5 - HT induced the release of P09429 but not of P27361 / 2 and JNK from HUVECs via the 5 - HT receptor ( P28222 ) / p38 mitogen - activated protein kinase ( MAPK ) signaling pathway . The p38MAPK inhibitor SB203580 and the P28222 antagonist GR55526 markedly inhibited P09429 release from 5 - HT - stimulated HUVECs . The vascular endothelial growth factor ( P15692 ) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis . We found that P09429 induced P15692 production in macrophage - like RAW264 . 7 cells . P09429 induced the activation of p38MAPK , P27361 / 2 and Akt . The P19957 - kinase inhibitor LY294002 significantly inhibited P15692 production in P09429 - stimulated macrophages , while other kinase inhibitors did not . These results suggest that P09429 release may contribute as a risk factor in the development and progression of atherosclerosis .","In vivo antitumor and antimetastatic activity of sunitinib in preclinical neuroblastoma mouse model . Neuroblastoma ( NB ) is one of the most common pediatric solid tumors originating from the neural crest lineage . Despite intensive treatment protocols including megatherapy with hematopoietic stem cell transplantation , the prognosis of NB patients remains poor . More effective therapeutics are required . High vascularity has been described as a feature of aggressive , widely disseminated NB . Our previous work demonstrated the overexpression of vascular endothelial growth factor ( P15692 ) in NB , and we showed that an anti - P15692 receptor ( P35968 ) antibody could induce sustained NB tumor suppression and regression . DB01268 is a kinase inhibitor targeting platelet - derived growth factor receptors and VEGFRs and , therefore , a promising antiangiogenic agent . In this study , we investigated the antitumor activity of sunitinib and its synergistic cytotoxicity with conventional ( cyclophosphamide ) and novel ( rapamycin ) therapies . Both NB cell lines and tumor - initiating cells from patient tumor samples were used in our in vitro and in vivo models for these drug testing . We show that sunitinib inhibits tumor cell proliferation and phosphorylation of VEGFRs . It also inhibits tumor growth , angiogenesis , and metastasis in tumor xenograft models . Low - dose sunitinib ( 20 mg / kg ) demonstrates synergistic cytotoxicity with an P42345 inhibitor , rapamycin , which is more effective than the traditional chemotherapeutic drug , cyclophosphamide . These preclinical studies provide the evidence of antitumor activity of sunitinib both in the early stage of tumor formation and in the progressive metastatic disease . These studies also provide the framework for clinical trial of sunitinib , alone and in combination with conventional and novel therapies to increase efficacy and improve patient outcome in NB .","Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK3___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK3___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK3___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .","17 ___MASK87___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .","Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki - 1 renal cell carcinoma . BACKGROUND : DB01268 ( VEGFR / P09619 inhibitor ) and everolimus ( P42345 inhibitor ) are both approved for advanced renal cell carcinoma ( RCC ) as first - line and second - line therapy , respectively . In the clinics , sunitinib treatment is limited by the emergence of acquired resistance , leading to a switch to second - line treatment at progression , often based on everolimus . No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression . Such strategy is expected to delay the emergence of acquired resistance and improve tumour control . The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus . METHODS : In human Caki - 1 RCC xenograft model , sunitinib was alternated with everolimus every week , every 2 weeks , or every 3 weeks . Effects on necrosis , hypoxia , angiogenesis , and EMT status were assessed by immunohisochemistry and immunofluorescence . RESULTS : DB01268 and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies . In each group of treatment , tumour growth control was associated with inhibition of P42345 pathway and changes from a mesenchymal towards an epithelial phenotype , with a decrease in vimentin and an increase in P12830 expression . The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects , leading to tumour necrosis . CONCLUSIONS : In summary , our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent .","Inhibition of cerebrovascular raf activation attenuates cerebral blood flow and prevents upregulation of contractile receptors after subarachnoid hemorrhage . BACKGROUND : Late cerebral ischemia carries high morbidity and mortality after subarachnoid hemorrhage ( Q53FZ2 ) due to reduced cerebral blood flow ( Q03701 ) and the subsequent cerebral ischemia which is associated with upregulation of contractile receptors in the vascular smooth muscle cells ( SMC ) via activation of mitogen - activated protein kinase ( MAPK ) of the extracellular signal - regulated kinase ( P29323 ) 1 / 2 signal pathway . We hypothesize that Q53FZ2 initiates cerebrovascular P27361 / 2 activation , resulting in receptor upregulation . The raf inhibitor will inhibit the molecular events upstream P27361 / 2 and may provide a therapeutic window for treatment of cerebral ischemia after Q53FZ2 . RESULTS : Here we demonstrate that Q53FZ2 increases the phosphorylation level of P27361 / 2 in cerebral vessels and reduces the neurology score in rats in additional with the Q03701 measured by an autoradiographic method . The intracisternal administration of SB - 386023 - b , a specific inhibitor of raf , given 6 h after Q53FZ2 , aborts the receptor changes and protects the brain from the development of late cerebral ischemia at 48 h . This is accompanied by reduced phosphorylation of P27361 / 2 in cerebrovascular SMC . Q53FZ2 per se enhances contractile responses to endothelin - 1 ( ET - 1 ) , 5 - carboxamidotryptamine ( 5 - CT ) and angiotensin II ( Ang II ) , upregulates ETB , P28222 and AT1 receptor mRNA and protein levels . Treatment with SB - 386023 - b given as late as at 6 h but not at 12 h after the Q53FZ2 significantly decreased the receptor upregulation , the reduction in Q03701 and the neurology score . CONCLUSION : These results provide evidence for a role of the P27361 / 2 pathway in regulation of expression of cerebrovascular SMC receptors . It is suggested that raf inhibition may reduce late cerebral ischemia after Q53FZ2 and provides a realistic time window for therapy .","The 4q12 amplicon in malignant peripheral nerve sheath tumors : consequences on gene expression and implications for sunitinib treatment . BACKGROUND : Malignant peripheral nerve sheath tumors ( MPNST ) are highly aggressive tumors which originate from Schwann cells and develop in about 10 % of neurofibromatosis type 1 ( P21359 ) patients . The five year survival rate is poor and more effective therapies are needed . DB01268 is a drug targeting receptor tyrosine kinases ( RTK ) like PDGFRalpha , c - Kit and P35968 . These genes are structurally related and cluster on chromosomal segment 4q12 . METHODOLOGY / PRINCIPAL FINDINGS : Here we characterize this region by multiplex ligation - dependent probe amplification ( MLPA ) in MPNST . Our probe set encompasses the 3 adjacent RTK genes ( P16234 , P10721 , P35968 ) and 6 flanking genes . We found amplification of several genes within this region in a subset of MPNST and MPNST cell lines . Transcript and protein expression of P16234 matched well with its increased copy number suggesting a central role of P16234 within the amplicon . Studying the effect of sunitinib on 5 MPNST cell lines revealed that cell line S462 harboring the 4q12 amplicon was extremely sensitive to the drug with an IC50 below 1 . 0 microM . Moreover , sunitinib induced apoptosis and prevented PDGF - AA induced signaling via PDGFRalpha as determined by western blotting . Co - expression of P15692 and its receptor P35968 ( P35968 ) was present in MPNST cell lines suggesting an autocrine loop . We show that P15692 triggered signal transduction via the MAPK pathway , which could be blocked by sunitinib . CONCLUSIONS / SIGNIFICANCE : Since multiple receptors targeted by sunitinib are expressed or over - expressed by MPNST cells sunitinib appears as an attractive drug for treatment of MPNST patients . Presence of the 4q12 amplicon and subsequent over - expression of P16234 might serve as predictive markers for efficacy of sunitinib .","Real - time US versus CT determination of pubic arch interference for brachytherapy . PURPOSE : Part 1 , to determine whether transrectal ultrasonography ( US ) enables accurate determination of pubic arch interference ( P05121 ) for prostate brachytherapy ( P10721 ) ; part 2 , to compare the accuracy of transrectal US with that of computed tomography ( CT ) for P05121 determination ; and part 3 , to determine the cost savings of P05121 determination with transrectal US versus that with CT . MATERIALS AND METHODS : Part 1 : The pubic arch was identified intraoperatively with transrectal US and compared with attempted needle passage ( 14 patients ) . Part 2 : Planning CT with the patient supine was compared with planning transrectal US with patients in the dorsal lithotomy position ( nine patients ) . Part 3 : Cost savings were calculated for P05121 determination with transrectal US versus that with CT ( 32 patients per group ) . RESULTS : Part 1 : Transrectal US accurately showed the pubic arch relative to the prostate . Part 2 : CT resulted in P05121 overestimation by 11 . 8 mm . Part 3 : Cost savings with transrectal US were $ 1 , 465 per patient . CONCLUSION : Transrectal US P05121 determination is easily performed , intraoperatively useful , and accurate . CT can result in P05121 overestimation . Reducing direct CT costs and the indirect costs of unnecessary hormonal therapy for false - positive P05121 will reduce expense and improve patient care . Transrectal US should replace CT for P05121 determination .","Combined targeted therapies in non - small cell lung cancer : a winner strategy ? PURPOSE OF REVIEW : Current treatment modalities provide limited improvement in the natural course of lung cancer , and prognosis remains poor . Lung cancer is a malignancy with great molecular heterogeneity . The complexity of the signalling process leading to cancer cell proliferation and to the neoplastic phenotype supports the necessity of interfering at different stages to avoid cancer cell resistance to therapy . RECENT FINDINGS : Use of several agents with multiple growth factor receptor or intracellular targets has shown encouraging results in phase I and II clinical trials in non - small cell lung cancer . DB05294 is a dual epidermal growth factor receptor and vascular endothelial growth factor receptor 2 small - molecule tyrosine kinase inhibitor ; sorafenib is an oral kinase inhibitor of P04049 and is also active against vascular endothelial growth factor receptors 2 and 3 , platelet - derived growth factor receptor beta , and c - P10721 . DB01268 is a vascular endothelial growth factor receptor 1 , 2 , and 3 , c - P10721 , and platelet - derived growth factor receptor alpha and beta tyrosine kinase inhibitor . SUMMARY : Combined use of epidermal growth factor receptor - tyrosine kinase inhibitor erlotinib and the humanized vascular endothelial growth factor receptor monoclonal antibody bevacizumab in advanced , chemotherapy - refractory non - small cell lung cancer has shown promising results ."],"string":"[\n \"P84022 linker phosphorylation attenuates P84022 transcriptional activity and TGF - β1 / P84022 - induced epithelial - mesenchymal transition in renal epithelial cells . Transforming growth factor - β1 ( TGF - β1 ) has a distinct role in renal fibrosis associated with epithelial - mesenchymal transition ( EMT ) of the renal tubules and synthesis of extracellular matrix . P84022 plays an essential role in fibrosis initiated by EMT . Phosphorylation of P84022 in the C - terminal SSXS motif by type I TGF - β receptor kinase is essential for mediating TGF - β response . P84022 activity is also regulated by phosphorylation in the linker region . However , the functional role of P84022 linker phosphorylation is not well characterized . We now show that P84022 EPSM mutant , which mutated the four phosphorylation sites in the linker region , markedly enhanced TGF - β1 - induced EMT of P84022 - deficient primary renal tubular epithelial cells , whereas P84022 3S - A mutant , which mutated the C - terminal phosphorylation sites , was unable to induce EMT in response to TGF - β1 . Furthermore , immunoblotting and RT - PCR analysis showed a marked induction of fibrogenic gene expression with a significant reduction in P12830 in P52789 human renal epithelial cells expressing P84022 EPSM . TGF - β1 could not induce the expression of α - SMA , vimentin , fibronectin and P05121 or reduce the expression of P12830 in P52789 cells expressing P84022 3S - A in response to TGF - β1 . Our results suggest that P84022 linker phosphorylation has a negative regulatory role on P84022 transcriptional activity and TGF - β1 / P84022 - induced renal EMT . Elucidation of mechanism regulating the P84022 linker phosphorylation can provide a new strategy to control renal fibrosis .\",\n \"The role of P10721 in the management of patients with gastrointestinal stromal tumors . In recent years , immunohistochemical staining for P10721 ( CD117 ) has become integral to the diagnosis of gastrointestinal stromal tumors ( GISTs ) , nearly 90 % of which harbor activating mutations in the P10721 receptor tyrosine kinase gene . Approximately 80 % of patients with metastatic GIST show at least some clinical response to the targeted small molecule P10721 inhibitor imatinib . The response to imatinib is closely correlated with the presence and type of P10721 mutation . GISTs with the most common P10721 exon 11 mutations have the highest response rate by far , whereas GISTs lacking mutations in P10721 or the alternative receptor tyrosine kinase P16234 show much lower rates of response to imatinib . Less than 5 % of GISTs are P10721 - immunonegative ; and many of these tumors have activating mutations of P16234 , some of which are also inhibited by imatinib . Most patients who initially respond to imatinib become resistant and eventually progress , which coincides with the selection of imatinib - resistant secondary P10721 mutations in the kinase domain . DB01268 has recently been approved for patients with GIST , principally those who fail imatinib therapy ; and additional small molecule inhibitors are in the pipeline . It is becoming evident that alternative approaches to direct P10721 inhibition will be required for long - term survival of patients with advanced GISTs . This review examines the role of P10721 in the diagnosis and management of patients with GIST .\",\n \"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK45___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .\",\n \"Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .\",\n \"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK67___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK67___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK67___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK67___ among adults with ADHD .\",\n \"Complementary and alternative medicine use and quality of life in patients with primary brain tumors . This study explored the use of complementary and alternative medicine ( P62158 ) approaches and their relationship with demographic and disease characteristics and quality of life ( QOL ) in the primary brain tumor ( P10721 ) population . One hundred one P10721 patients were enrolled in this study . The results showed that 34 % of patients reported using P62158 . Forty - one percent reported using more than one type of P62158 . The average cost of each P62158 used per month was 69 dollars , with 20 % of patients spending more than 100 dollars per month . The majority ( 74 % ) reported that their physicians were unaware of their use of P62158 . Data analysis found a higher performance status to be the only factor significantly related to use of P62158 therapy ( P < 0 . 005 ) . There was no difference in patient report of QOL between users and nonusers of P62158 therapies . The high number of patients who do not report P62158 use has potential implications for evaluation of symptoms and response to therapy in this population . This may be especially relevant in those patients with higher functional status participating in clinical trials .\",\n \"P01308 reverses growth hormone - induced homologous desensitization . Growth hormone ( GH ) is secreted in a pulsatile pattern to promote body growth and metabolism . GH exerts its function by activating several signaling pathways , including O60674 / P35610 and MEK / P29323 . P27361 / 2 activation by GH plays important roles in gene expression , cell proliferation , and growth . We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure , a second GH exposure induces P42229 phosphorylation but not P27361 / 2 phosphorylation ( Ji , S . , Frank , S . J . , and Messina , J . L . ( 2002 ) J . Biol . Chem . 277 , 28384 - 28393 ) . In this study the mechanisms underlying GH - induced homologous desensitization were investigated . A second GH exposure activated the signaling intermediates upstream of MEK / P29323 , including O60674 , Ras , and P04049 . This correlated with recovery of P10912 levels , but was insufficient for GH - induced phosphorylation of Q02750 / 2 and P27361 / 2 . P01308 restored the ability of a second GH exposure to induce phosphorylation of Q02750 / 2 and P27361 / 2 without altering P10912 levels or GH - induced phosphorylation / activation of O60674 and P04049 . GH and insulin synergized in promoting cell proliferation . Further investigation suggested that insulin increased the amount of MEK bound to Q8IVT5 ( kinase suppressor of Ras ) and restored GH - induced tyrosine phosphorylation of Q8IVT5 . Previous GH exposure also induced desensitization of P42224 and P40763 phosphorylation , but this desensitization was not reversed by insulin . Thus , insulin - regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal , physiologic pulse of GH .\",\n \"DB01268 induced pyoderma gangrenosum - like ulcerations . Pyoderma gangrenosum is a non - infectious neutro ? philic skin disease commonly associated with underlying systemic diseases . Histopathological and laboratory diagnostics are unspecific in the majority of the cases and the diagnosis is made in accordance with the clinical picture . Here , we report the case of a 69 - year old man with progredient pyoderma gangrenosum - like ulcerations under treatment with sunitinib due to hepatocellular carcinoma . A conventional ulcer therapy did not lead to a regression of the lesions . Solely cessation of sunitinib therapy resulted in an improvement of the ulcerations . DB01268 is a multikinase inhibitor that targets the PDGF - α - and ? β - , P15692 - 1 - 3 - , P10721 - , P36888 - , P09603 - and P07949 - receptor , thereby impairing tumour proliferation , pathological angiogenesis and metastasation . Here , we demonstrate that pyoderma gangrenosum - like ulcers may represent a serious side effect of sunitinib - based anti - cancer treatment .\",\n \"Association of Ang - 2 with integrin beta 2 controls Ang - 2 / DB00102 - dependent upregulation of human peripheral blood monocyte fibrinolysis . O15123 ( Ang - 2 ) , an angiogenic factor that is generally considered an autocrine factor for endothelial cells was shown in a previous study to upregulate peripheral blood monocyte fibrinolysis in concert with platelet - derived growth factor - BB ( DB00102 ) . This upregulation of fibrinolysis was demonstrated to be due to upregulation of elements of the matrix metalloproteinase and serine protease fibrinolytic pathways . The manner in which Ang - 2 interacts with monocytes was not elucidated though no expression of the angiopoietin receptor tyrosine kinase Tie - 2 was found for monocytes . In this study Ang - 2 was found to bind to integrin beta ( 2 ) , and functional inhibition of integrin beta ( 2 ) eliminated Ang - 2 / DB00102 - mediated upregulation of monocyte fibrin invasion . Additionally , integrin beta ( 2 ) blockade significantly inhibited the Ang - 2 / DB00102 based increase in matrix metalloproteinase - 9 ( P14780 ) and membrane type - 1 - MMP ( P50281 ) . Furthermore , Ang - 2 / DB00102 - upregulated urokinase plasminogen - activator receptor ( Q03405 ) was shown to be associated in complexes with integrin beta ( 2 ) . In addition , Ang - 2 was shown to upregulate P09619 expression in monocytes . Therefore several components of the mechanism via which the novel interaction of Ang - 2 and DB00102 with monocytes occurs have been identified .\",\n \"The role of vascular endothelial growth factor and matrix metalloproteinases in canine lymphoma : in vivo and in vitro study . BACKGROUND : Canine lymphoma represents the most frequent haematopoietic cancer and it shares some similarities with human non - Hodgkin lymphoma . Matrix metalloproteinases ( MMPs ) and vascular endothelial growth factor ( P15692 ) play a coordinated role during invasion and proliferation of malignant cells ; however , little is known about their role in canine haematologic malignancies . The aim of this study was to investigate the mRNA and protein expression of P15692 and the most relevant MMPs in canine lymphoma . Lymph node aspirates from 26 B - cell and 21 T - cell lymphomas were collected . The protein expression levels of P14780 , P08253 and P15692 were evaluated by immunocytochemistry , and the mRNA levels of P08253 , P14780 , P50281 , P01033 , P16035 , O95980 , P15692 and P15692 - 164 were measured using quantitative RT - PCR . RESULTS : P50281 , P01033 and O95980 mRNA levels were significantly higher in T - cell lymphomas than in B - cell lymphomas . Higher mRNA and protein levels of P14780 and P15692 were observed in T - cell lymphomas than in B - cell lymphomas and healthy control lymph nodes . A positive correlation was found between P14780 and P15692 in T - cell lymphomas . Moreover , P14780 , P50281 , P01033 and P15692 were expressed at the highest levels in high - grade T - cell lymphomas . CONCLUSIONS : This study provides new information on the expression of different MMPs and P15692 in canine lymphoma , suggesting a possible correlation between different MMPs and P15692 , immunophenotype and prognosis .\",\n \"___MASK99___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK99___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .\",\n \"Gastrointestinal stromal tumors : a review of case reports , diagnosis , treatment , and future directions . Gastrointestinal stromal tumor ( GIST ) is a nonepithelial , mesenchymal tumor first described by Mazur and Clark in 1983 . Since then , its molecular biology has been studied in great detail . Special interest in the role of tyrosine kinase in its regulation has been the target by different drug research . Mutation in c - kit exons 9 , 11 , 13 , 17 and P16234 mutation in exons 12 , 14 , 18 are responsible for activation of gene signaling system resulting in uncontrolled phosphorylation and tissue growth . However , 5 to 15 % of GISTs does not harbor these mutations , which raises additional questions in another alternate signaling pathway mutation yet to be discovered . Diagnosis of GISTs relies heavily on P10721 / CD117 immunohistochemical staining , which can detect most GISTs except for a few 3 % to 5 % that harbors P16234 mutation . Newer staining against PKC theta and DOG - 1 genes showed promising results but are not readily available . Clinical manifestation of GISTs is broad and highly dependent on tumor size . Surgery still remains the first - line treatment for GISTs . The advancement of molecular biology has revolutionized the availability of newer drugs , Imatinib and DB01268 . Together with its advancement is the occurrence of Imatinib / DB01268 drug resistance . With this , newer monoclonal antibody drugs are being developed and are undergoing clinical trials to hopefully improve survival in patients with GISTs .\",\n \"Gene profiling in Pap - cell smears of high - risk human papillomavirus - positive squamous cervical carcinoma . OBJECTIVE : The purpose of the study was to investigate benign and malignant squamous cervical cells obtained by cervical swabs with regard to differentially expressed genes and gene expression profiling , in order to evaluate the biological behavior and clinical outcome of cervical malignancies . METHODS : Cervical squamous cells from six women with high - risk human papillomavirus positive [ HR - HPV (+) ] cervical carcinoma and from six HPV - negative women with normal ectocervical cells were analyzed by cDNA array . RESULTS : cDNA over - expression of several genes such as MET ( c - met ) , Nm23 - H1 ( P15531 ) , P00533 , P21802 , Nm23 - H2 ( P22392 ) , P04626 ( c - erbB - 2 ) , cyclin - dependent kinase inhibitor 4 ( CDKN2A , P42771 ) , cytokeratin 8 ( P05787 ) , P01116 ( K - ras ) , P17948 , KGF ( P21781 ) , P10415 - like 2 protein ( Q92843 ) , Q15303 , P04198 ( N - myc ) , cyclin D1 ( P24385 ) , P10721 ( c - kit ) , secreted phosphoprotein 1 ( P10451 ) and P42224 , was significant in cervical squamous cell carcinoma ( CSCC ) . Gene expression was downregulated for 13 genes in CSCC , such as interleukin 1 alpha ( P01583 ) , the transforming growth factor receptor beta superfamily ( TGFbeta ; P01137 ) , some members of the insulin - like growth factor binding proteins ( IGFBPs ) and the integrin family ( P23229 , P05556 ) . CONCLUSION : This study was focused on the gene expression profiling of HR - HPV (-) and ( + ) cervical squamous cells and CSCC obtained by cytobrush . We observed gene expression patterns and signaling pathways that permit the investigator to distinguish between benign squamous cervical cells and CSCC with and without HPV infection .\",\n \"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK94___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .\",\n \"Raddeanin A , a triterpenoid saponin isolated from Anemone raddeana , suppresses the angiogenesis and growth of human colorectal tumor by inhibiting P35968 signaling . Raddeanin A ( RA ) is an active triterpenoid saponin from a traditional Chinese medicinal herb , Anemone raddeana Regel . It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells . However , whether RA can inhibit angiogenesis , an essential step in cancer development , remains unknown . In this study , we found that RA could significantly inhibit human umbilical vein endothelial cell ( HUVEC ) proliferation , motility , migration , and tube formation . RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane ( P62158 ) , restrained the trunk angiogenesis in zebrafish , and suppressed angiogenesis and growth of human HCT - 15 colorectal cancer xenograft in mice . Western blot assay showed that RA suppressed P15692 - induced phosphorylation of P35968 and its downstream protein kinases including PLCγ1 , O60674 , Q05397 , Src , and Akt . Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the DB00171 binding pocket of P35968 kinase domain . Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis , demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy .\",\n \"Prognostic role of Q01094 and members of the CDKN2A network in gastrointestinal stromal tumors . PURPOSE : The aim of the current study was to examine the prognostic relevance of the CDKN2A tumor suppressor pathway in gastrointestinal stromal tumors ( GIST ) . EXPERIMENTAL DESIGN : We determined the mRNA expression of p1 ( INK4A ) , p14 ( Q8N726 ) , P11802 , P06400 , Q00987 , P04637 , and Q01094 by quantitative reverse transcription - PCR in 38 cases of GISTs and correlated the findings with clinicopathologic factors , including mutation analysis of P10721 and P16234 . RESULTS : The k - means cluster analysis yielded three prognostic subgroups of GISTs with distinct mRNA expression patterns of the CDKN2A pathway . GISTs with low mRNA expression of the CDKN2A transcripts p16 ( INK4A ) and p14 ( Q8N726 ) but high mRNA expression of P11802 , P06400 , Q00987 , P04637 , and Q01094 were associated with aggressive clinical behavior and unfavorable prognosis , whereas GISTs with a low mRNA expression of P11802 , P06400 , Q00987 , P04637 , and Q01094 were not . GISTs with a moderate to high mRNA expression of all examined genes also seemed to be associated with unfavorable prognosis . Regarding mutation analysis , we found significant differences in the P10721 / P16234 genotype among the three clusters . Univariate analysis revealed high expression of Q01094 to be associated with mitotic count , proliferation rate , P10721 mutation , and aggressive clinical behavior . These findings on mRNA level could be confirmed by immunohistochemistry . CONCLUSION : Our findings implicate differential regulation schemes of the CDKN2A tumor suppressor pathway converging to up - regulation of Q01094 as the critical link to increased cell proliferation and adverse prognosis of GISTs .\",\n \"Pharmacological management of gastrointestinal stromal tumours : an update on the role of sunitinib . The efficacy and tolerability of the receptor tyrosine kinase inhibitor , sunitinib malate , have been demonstrated in phase I - III clinical trials of patients with imatinib - resistant or imatinib - intolerant gastrointestinal stromal tumours ( GIST ) as well as in a worldwide expanded - access study and in a continuous daily dosing ( CDD ) trial . Tumour genotype may have a significant influence on the activity of sunitinib in patients with imatinib - resistant GIST . DB01268 activity was observed across different GIST genotypes and particularly in patients with wild - type and P10721 exon 9 mutations ( all relatively resistant to standard - dose imatinib ) and in patients with secondary P10721 exons 13 and 14 mutations . Adverse events with sunitinib were generally mild to moderate and easily managed by dose reduction , dose interruption or standard supportive measures . Treatment discontinuation can be avoided in most patients by close monitoring before and during treatment with appropriate adverse event management as necessary . The correlation between treatment exposure and clinical response is prompting the search for new approaches to treatment optimisation to ensure that patients derive maximum benefit from sunitinib therapy , including dose adjustments based on blood testing to ensure optimal drug exposure , and the use of the alternative CDD regimen to avoid treatment interruption .\",\n \"New paradigms in gastrointestinal stromal tumour management . BACKGROUND : Targeted agents have improved the prognosis for patients with advanced gastrointestinal stromal tumours ( GISTs ) . Many patients exhibit intolerance or resistance to first - line therapy with imatinib mesylate . DB01268 malate is approved multinationally for the treatment of advanced imatinib - refractory GIST . DESIGN : This article reviews responses to imatinib and sunitinib reported in clinical trials in advanced GIST and discusses the effect of mutational status on treatment responses ; therapeutic developments in GIST treatment are also reviewed . RESULTS : Imatinib 400 mg / day has shown efficacy for first - line treatment of advanced GIST , particularly in patients with P10721 exon 11 mutations . DB01268 50 mg / day ( Schedule 4 / 2 ) has demonstrated effectiveness and tolerability in imatinib - refractory GIST , including patients who would be excluded from clinical trials . DB01268 is associated with longer median overall survival in patients with primary P10721 exon 9 mutations and wild - type GIST compared with P10721 exon 11 mutations in a retrospective study . Ongoing studies , including imatinib in the adjuvant setting and the use of targeted agents in sequence or in combination , will further refine the therapeutic pathway for advanced GIST . CONCLUSIONS : The availability of targeted therapies and greater knowledge of the effect of mutational status on patient responses will assist in optimising outcomes in advanced GIST .\",\n \"Molecular target modulation , imaging , and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure . PURPOSE : To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor ( GIST ) patients after imatinib failure , in addition to assessing the safety and pharmacokinetics ( PK ) of different dose schedules . EXPERIMENTAL DESIGN : In this open - label , dose - ranging , phase I / II study , 97 patients with metastatic imatinib - resistant / intolerant GIST received sunitinib at doses of 25 , 50 , or 75 mg / d on one of three schedules . Serial tumor imaging was done using computed tomography and [ 18F ] fluoro - 2 - deoxy - d - glucose positron emission tomography scanning . PK and cell proliferation and P10721 phosphorylation status in tumor biopsies were also analyzed . RESULTS : Clinical benefit was observed in 52 patients ( 54 % : 7 objective partial responses , 45 stable disease > or = 6 months ) . Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [ 18F ] fluoro - 2 - deoxy - d - glucose positron emission tomography . DB01268 treatment was associated with reduced tumor cell proliferation by > 25 % in 52 % of cases analyzed and reduced levels of phospho - P10721 in tumor biopsies ( indicating target modulation ) . The recommended dose schedule was 50 mg / d for 4 weeks followed by 2 weeks off treatment . On the 50 - mg dose across all schedules , 79 % of PK - evaluable patients achieved total drug trough concentrations above the target concentration ( 50 ng / mL ) within 14 days of dosing . In addition , adverse events were generally mild to moderate in severity . CONCLUSION : Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of P10721 in GIST following imatinib failure , illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy .\",\n \"___MASK46___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .\",\n \"DB01268 induces P60484 expression and inhibits P09619 signaling and migration of medulloblastoma cells . We previously showed that inhibition of the platelet - derived growth factor receptor ( P09619 ) blocks the survival and migration of medulloblastoma cells . Identification of in vitro P09619 - targeting pharmacologic agents that are suitable for preclinical testing in medulloblastoma models in vivo will be critical for efficiently translating these agents to clinical investigation in children with medulloblastoma . In this study , we investigated whether the multi - tyrosine kinase inhibitor sunitinib , effectively inhibits P09619 signaling required for medulloblastoma cell migration . Daoy and D556 human medulloblastoma cells pre - treated for 1 h with 0 . 2 μM sunitinib demonstrated induction of P60484 expression and significant inhibition of P09619 signaling activity and transactivation of P00533 , in a DB01367 - independent manner , in response to DB00102 stimulation . DB01268 pre - treatment markedly reduced medulloblastoma cell migration in response to both DB00102 and 10 % serum at 4 and 24 h after treatment . Pre - treatment with sunitinib for 1 h also resulted in detachment and decreased viability of D556 , but not Daoy , cells and only after 48 h following treatment . However , sunitinib did not induce apoptosis in either cell line at any time point , indicating that the anti - migratory effects of sunitinib were not due to impeding cell survival . DB01268 similarly inhibited P09619 signaling and migration of primary murine Smo / Smo medulloblastoma cells , suggesting that the Smo / Smo mouse is an appropriate model for preclinical testing of sunitinib . These results indicate that sunitinib may be an important pharmacologic agent for the treatment of invasive medulloblastoma , particularly given evidence of its ability to cross the blood - brain barrier to target tumor cells , and thus warrants further in vivo testing for confirmation of efficacy .\",\n \"Indicators for the exposure assessment of transformation products of organic micropollutants . Environmental transformation products of organic micropollutants have the potential to be similarly or even more mobile , persistent , ortoxic than their parent compounds . They should , therefore , be included in chemical hazard and risk assessment procedures as well as in the assessment of soil and water quality . To fulfill this requirement most efficiently , screening approaches that select relevant transformation products for detailed assessment are needed . This paper presents two process - based multimedia , multispecies models that allow us to quantitatively estimate the environmental fate of transformation products . The resulting exposure patterns are assessed with two indicators : joint persistence ( JP ) , which describes the temporal extent of environmental exposure to a parent compound and its transformation products , and the predicted relative aquatic concentrations ( P31749 ) , which estimate the relative concentrations of parent compounds and their transformation products in surface water bodies . As a case study , JP and P31749 are calculated for 16 pesticides and their relevant transformation products . The results for the JP indicator confirm the importance of considering transformation products in the assessment of overall persistence ; for example , in the context of P10721 assessments . Comparison of P31749 results with monitoring data on herbicides and their transformation products shows the suitability of our approach for estimating relative concentrations in surface water , and as a consequence , its usefulness in identifying transformation products for future water quality monitoring programs . Transformation products of triketones and other highly used acidic herbicides are specifically identified as targets .\",\n \"Expression and mutational status of treatment - relevant targets and key oncogenes in 123 malignant salivary gland tumours . BACKGROUND : Malignant tumours of the salivary glands ( MSGT ) are rare and pleomorphic entities . Patients with advanced disease may benefit from targeted therapy ; however , specific targets for optimising and personalising treatments are yet to be identified . DESIGN : Immunohistochemistry for C - P10721 , P00533 , P04626 , P15941 , phospho - P42345 , androgen / estrogens / progesterone receptors and Ki67 was carried out and evaluated in terms of progression - free and overall survival . High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology . RESULTS : Several therapy leads were identified , including high levels of P04626 and androgen receptors in salivary duct carcinomas , C - P10721 in myoepithelial carcinomas and P00533 in mucoepidermoid carcinomas . Recurrent mutations involving downstream elements of the P00533 pathway were found in P01112 , notably in tumours with a myoepithelial component , and in other key oncogenes ( P01116 / P01111 / PI3KCA / P15056 / MAP2K ) . On the other hand , < 1 % of samples had P00533 or P04626 mutations . CONCLUSION : Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads . Genotyping results suggest activation downstream of P00533 in 18 of the 107 samples that could be associated with low efficacy of P00533 inhibitors . Other molecules , such as PI3K / MEK or P42345 inhibitors , may have anti - tumour activity in this subgroup . The high mutation rate in P01112 highlights a novel key oncogenic event in MSGT .\",\n \"DB11588 donors or heme oxygenase - 1 ( P09601 ) overexpression blocks interleukin - 18 - mediated NF - kappaB - P60484 - dependent human cardiac endothelial cell death . The objective of this study was to determine whether heme oxygenase - 1 ( P09601 ) or heme metabolites exert cytoprotective effects on interleukin - 18 - mediated endothelial cell ( EC ) death . Treatment with interleukin ( IL ) - 18 increased NF - kappaB activation and P60484 induction , suppressed Akt activation , and stimulated EC death . While ectopic expression of p65 enhanced P60484 transcription , adenoviral transduction of dnIkappaB - alpha , dnp65 , or dnIKKbeta was inhibitory . Furthermore , Q14116 suppressed P09601 mRNA expression via enhanced mRNA degradation . Overexpression of P09601 , treatment with P09601 inducer hemin , or the CO donor cobalt ( III ) protoporphyrin IX all reversed Q14116 - mediated NF - kappaB activation , P60484 induction , Akt suppression , and EC death . Furthermore , hemin induced P09601 expression , and P09601 knockdown , P09601 inhibition , or CO scavengers all reversed the prosurvival effects of hemin . In addition , the CO donors CORM - 1 and CORM - 3 and the heme metabolites biliverdin and bilirubin attenuated Q14116 - induced EC death via a similar signaling pathway . Q14116 induced p38alpha MAPK activation , and suppressed p38beta isoform expression . While p38alpha knockdown attenuated , p38beta knockdown potentiated Q14116 - mediated EC death . DB03404 and P09601 reversed Q14116 - mediated p38alpha induction and restored p38beta levels . These results demonstrate that Q14116 suppresses P09601 expression and induces EC death . P09601 overexpression , P09601 induction , or treatment with heme metabolites all reverse Q14116 - mediated p38alpha MAPK and NF - kappaB activation , P60484 induction , Akt suppression , and EC death . Thus , P09601 inducers and CO donors may have the therapeutic potential to effectively block Q14116 signaling and reduce Q14116 - dependent vascular injury and inflammation .\",\n \"Small in - frame deletion in the epidermal growth factor receptor as a target for DB05294 . DB05294 is an inhibitor of vascular endothelial growth factor receptor - 2 ( P35968 / P35968 ) tyrosine kinase , with additional activity against epidermal growth factor receptor ( P00533 ) tyrosine kinase . DB05294 inhibits angiogenesis and growth of a wide range of tumor models in vivo . Gefitinib ( \\\" ___MASK62___ \\\" ) is a selective P00533 tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation . Here , the ability of gefitinib and DB05294 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro , and a strong correlation was noted between the IC ( 50 ) values of gefitinib and DB05294 ( r = 0 . 79 ) . No correlation was observed between the sensitivity to DB05294 and the level of P00533 or VEGFR expression . The NSCLC cell line PC - 9 was seen to be hypersensitive to gefitinib and DB05294 , and a small ( 15 - bp ) in - frame deletion of an DB00171 - binding site ( exon 19 ) in the P00533 was detected ( delE746 - A750 - type deletion ) . To clarify the involvement of the deletional mutation of P00533 in the cellular sensitivity to DB05294 , we examined the effect of this agent on HEK293 stable transfectants expressing deletional P00533 that designed as the same deletion site observed in PC - 9 cells ( 293 - pDelta15 ) . These cells exhibited a 60 - fold higher sensitivity to DB05294 compared with transfectants expressing wild - type P00533 . DB05294 inhibited the phosphorylation of the mutant P00533 by 10 - fold compared with cells with wild - type P00533 . In conclusion , the findings suggested that a small in - frame deletion in the P00533 increased the cellular sensitivity to DB05294 .\",\n \"Estradiol increases cell growth in human astrocytoma cell lines through ERα activation and its interaction with Q15788 and Q9Y6Q9 coactivators . Estradiol ( E2 ) regulates several cellular functions through the interaction with estrogen receptor subtypes , ERα and ERβ , which present different functional and regulation properties . ER subtypes have been identified in human astrocytomas , the most common and aggressive primary brain tumors . We studied the role of ER subtypes in cell growth of two human astrocytoma cell lines derived from tumors of different evolution grades : U373 and D54 ( grades III and IV , respectively ) . E2 significantly increased the number of cells in both lines and the co - administration with an ER antagonist ( ICI 182 , 780 ) significantly blocked E2 effects . ERα was the predominant subtype in both cell lines . E2 and ICI 182 , 780 down - regulated ERα expression . The number of U373 and D54 cells significantly increased after PPT ( ERα agonist ) treatment but not after DPN ( ERβ agonist ) one . To determine the role of Q15788 and Q9Y6Q9 coactivators in ERα induced cell growth , we silenced them with RNA interference . Coactivator silencing blocked the increase in cell number induced by PPT . The content of proteins involved in proliferation and metastasis was also determined after PPT treatment . Western blot analysis showed that in U373 cells the content of PR isoforms ( PR - A and PR - B ) , P00533 , P15692 and cyclin D1 increased after PPT treatment while in D54 cells only the content of P00533 was increased . Our results demonstrate that E2 induces cell growth of human astrocytoma cell lines through ERα and its interaction with Q15788 and Q9Y6Q9 and also suggest differential roles of ERα on cell growth depending on astrocytoma grade .\",\n \"Efficacy and safety of sunitinib in Chinese patients with imatinib - resistant or - intolerant gastrointestinal stromal tumors . AIMS : To assess the efficacy and safety of sunitinib in Chinese patients with imatinib - resistant or - intolerant gastrointestinal stromal tumors ( GISTs ) , and evaluate the impact of genotype on sunitinib efficacy . MATERIALS & METHODS : In a single - arm retrospective study , 55 patients with recurrent or metastatic GISTs who were resistant or intolerant to prior imatinib treatment received sunitinib for at least one treatment cycle . RESULTS : The median progression - free survival was 35 weeks ( 95 % CI : 24 . 6 - 45 . 4 ) in patients who received sunitinib 37 . 5 mg / day as a continuous daily dose versus 30 weeks ( 95 % CI : 12 . 8 - 47 . 2 ) in those who received sunitinib 50 mg / day as a 4 - weeks - on , 2 - weeks - off ( 4 / 2 ) schedule ( p = 0 . 707 ) . The median overall survival of all patients was 86 weeks ( 95 % CI : 75 . 0 - 97 . 0 ) . Patients with P10721 exon 9 mutations had a significantly longer progression - free survival compared with those with P10721 exon 11 mutations and patients with wild - type GISTs ( p = 0 . 022 ) . DB01268 therapy was well tolerated , with most adverse events rated as grade 1 or 2 in severity . The sunitinib 37 . 5 mg / day continuous daily dose schedule was better tolerated by Chinese GIST patients than the 50 mg / day 4 / 2 schedule . CONCLUSION : DB01268 was effective and well tolerated in Chinese patients with imatinib - resistant or - intolerant GISTs . Patients with P10721 exon 9 mutations showed the best efficacy . A 37 . 5 mg / day continuous daily dose sunitinib dosing schedule appears to be the optimal choice for Chinese patients due to a decreased incidence of adverse events .\",\n \"P40763 signaling is induced by intercellular adhesion in squamous cell carcinoma cells . The signal transducer and activator of transcription - 3 ( P40763 ) frequently activated during tumor progression has been linked to enhanced cell growth . In squamous cell carcinoma of the head and neck ( HNSCC ) , P40763 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways . In the present study , we have examined the potential mechanism by which cell - cell contact initiates P40763 activation . Using a panel of HNSCC cell lines , Ca (+ 2 )- dependent cell - cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of P40763 - Y705 and P42224 - Y701 . This intercellular adhesion - induced P40763 activation was mediated by JAK and Src signaling and partially by P00533 signaling . In addition , immunolocalization studies revealed initial formation of phosphorylated P40763 - Y705 at nascent P12830 cell junctions with eventual translocation to the nucleus in cell aggregates . Adhesion - mediated P35610 activation in monolayer and cell aggregate cultures required functional P12830 . These results indicate that , in HNSCC cells , cadherin - mediated intercellular adhesion induces P35610 signaling that may modulate cell survival and resistance to apoptosis during tumor progression .\",\n \"Tyrosine kinases as targets in cancer therapy - successes and failures . Protein kinases play a crucial role in signal transduction and also in cellular proliferation , differentiation and various regulatory mechanisms . The inhibition of growth - related kinases , especially tyrosine kinases , might therefore provide new therapies for diseases such as cancer . Due to the enormous progress that has been made in the past few years in the identification of the human genome , in molecular and cell biology technologies , in structural biology and in bioinformatics , the number of receptor and non - receptor tyrosine kinases that have been identified as valuable molecular targets has greatly increased . Currently , more than 20 different tyrosine kinase targets are under evaluation in drug discovery projects in oncology . The progress made in the crystallisation of protein kinases , in most cases complexed with DB00171 - site - directed inhibitors , has confirmed that the ATPbinding domain of tyrosine kinases is an attractive target for rational drug design ; more than 20 DB00171 - competitive , low molecular weight inhibitors are in various phases of clinical evaluation . Meanwhile , clinical proof - of - concept ( POC ) has been achieved with several antibodies and small molecules targeted against tyrosine kinases . With Herceptin , Glivec and ___MASK62___ ( registered in Japan ) , the first kinase drugs have entered the market . This review describes the preclinical and clinical status of low molecular weight drugs targeted against different tyrosine kinases ( e . g . , epidermal growth factor receptor [ P00533 ] , vascular endothelial growth factor receptor [ VEGFR ] , platelet - derived growth factor receptor [ P09619 ] , Kit , Fms - like tyrosine kinase [ Flt ] - 3 ) , briefly describes new targets , and provides a critical analysis of the current situation in the area of tyrosine kinase inhibitors .\",\n \"___MASK46___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK46___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .\",\n \"DB01268 acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma . DB01268 is a broad - spectrum small - molecule inhibitor of receptor tyrosine kinases ( RTK ) that serves as the present standard of care for first - line therapy of advanced clear cell renal cell carcinoma ( ccRCC ) . A full understanding of the targets and mechanism of action of sunitinib in ccRCC treatment remains incomplete . In this study , we evaluated several tumor cell and endothelial targets of sunitinib and investigated which RTK ( s ) may specifically contribute to its therapeutic effects . Microarray expression profiling and Western blot analysis revealed that among known sunitinib targets , only platelet - derived growth factor receptor - beta and vascular endothelial growth factor receptor - 2 ( P35968 ) were overexpressed in ccRCCs relative to normal tissues . DB01268 was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations ( approximately 0 . 1 micromol / L ) that inhibit RTK targets . In contrast , sunitinib inhibited endothelial cell proliferation and motility at the same concentrations by suppressing P35968 signaling . Moreover , whereas sunitinib inhibited the growth of ccRCC xenograft tumors and decreased tumor microvessel density as soon as 12 hours after treatment , sunitinib showed no significant effects on tumor cell proliferation or apoptosis up to 72 hours after treatment . Our findings indicate that sunitinib inhibits ccRCC growth primarily through an antiangiogenic mechanism and not through direct targeting of ccRCC tumor cells .\",\n \"P50281 as a downstream target of P11274 - P00519 / P00519 interactor 1 signaling : polarized distribution and involvement in P11274 - P00519 - stimulated leukemic cell migration .\",\n \"DB01268 : a newly approved small - molecule inhibitor of angiogenesis . The advent of targeted therapies has allowed treatment to be directed at signaling pathways integral to tumor growth and survival . DB01268 ( SU11248 , sunitinib malate ; Pfizer Inc . , New York , NY , USA ) is a novel oral small - molecule multitargeted receptor tyrosine kinase inhibitor that has demonstrated direct antitumor activity and antiangiogenic action . It targets the vascular endothelial growth factor receptor ( VEGFR ) , platelet derived growth factor receptor ( P09619 ) , stem - cell factor receptor and Fms - like tyrosine kinase receptor 3 receptor tyrosine - kinases . In January 2006 , sunitinib malate was granted approval by the U . S . Food and Drug Administration for the treatment of gastrointestinal stromal tumor after disease progression on , or intolerance to , imatinib mesylate , as well as for the treatment of metastatic renal cell cancer . This review will discuss the development of sunitinib , particularly in acute myeloid leukemia , imatinib - resistant gastrointestinal stromal tumors and renal cell cancer . The review will also discuss ongoing trials with sunitinib in other malignancies such as neuroendocrine tumors and breast cancer , as well as its potential future development in combination therapy with other agents and in other malignancies .\",\n \"DB01268 in malignant melanoma : a treatment option only for P10721 - mutated patients ? DB01268 has previously been reported to be potentially effective in the treatment of malignant melanomas expressing c - P10721 . Here we report on the case of a 77 - year - old gentleman affected by a metastatic clear cell carcinoma of the kidney and a metastatic malignant melanoma with liver and lung metastases . Despite the negativity for CD117 and the absence of P10721 amplification or mutations in the melanoma specimen , he achieved a partial response both in the lungs and in the liver while on sunitinib ( 50 mg once / day , 4 weeks on / 2 weeks off ) for the treatment of kidney cancer . To our knowledge , this represents the first evidence of sunitinib activity in P10721 wild - type melanoma . Further studies should be performed to confirm these preliminary data .\",\n \"The retinoid signalling molecule , O95361 , is repressed during squamous cell carcinoma skin carcinogenesis in vivo and reduces skin cancer cell migration in vitro . Retinoid therapy is used for chemo - prevention in immuno - suppressed patients at high risk of developing skin cancer . The retinoid signalling molecule , tripartite motif protein 16 ( O95361 ) , is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid - sensitive neuroblastoma . We sought to determine the role of O95361 in skin squamous cell carcinoma ( SCC ) pathogenesis . We have shown that O95361 expression was markedly reduced during the histological progression from normal skin to actinic keratosis and SCC . SCC cell lines exhibited lower cytoplasmic and nuclear O95361 expression compared with primary human keratinocyte ( PHK ) cells due to reduced O95361 protein stability . Overexpressed O95361 translocated to the nucleus , inducing growth arrest and cell differentiation . In SCC cells , O95361 bound to and down regulated nuclear Q01094 , this is required for cell replication . Retinoid treatment increased nuclear O95361 expression in retinoid - sensitive PHK cells , but not in retinoid - resistant SCC cells . Overexpression of O95361 reduced SCC cell migration , which required the C - terminal P07949 finger protein ( RFP ) - like domain of O95361 . The mesenchymal intermediate filament protein , vimentin , was directly bound and down - regulated by O95361 and was required for O95361 - reduced cell migration . Taken together , our data suggest that loss of O95361 expression plays an important role in the development of cutaneous SCC and is a determinant of retinoid sensitivity .\",\n \"DB01268 malate in solitary fibrous tumor ( P51668 ) . BACKGROUND : To report on sunitinib activity in a retrospective series of 35 solitary fibrous tumor ( P51668 ) treated at a single institution . PATIENTS AND METHODS : From April 2008 , 35 patients with progressive advanced P51668 ( male / female : 20 / 15 ; mean age : 58 years ; meningeal / extrameningeal : 6 / 29 ; locally advanced / metastatic : 15 / 20 ; prior chemotherapy : 25 ) were treated , on an individual use basis , with continuous - dosing sunitinib 37 . 5 mg / day . P09619 ( P09619 ) and vascular endothelial growth factor receptor 2 ( P35968 ) status were assessed by immunohistochemistry and , in a subgroup of patients , by real time PCR . RESULTS : Thirty - one patients were assessable for response by RECIST ( one early death ; three early interruptions ) . Best responses were 2 partial response ( PR ) , 16 stable disease , 13 progressive disease . A < 30 % decrease in size was observed in three patients . Fourteen of 29 patients assessable by Choi criteria had a PR . Median progression - free survival by RECIST was 6 months ( range 1 - 22 ) . In two of six patients , resistance to sunitinib was overcome by increasing sunitinib to 50 mg / day . P09619 and / or P35968 were positive in all cases and not predictive of response ; a less aggressive morphology corresponded to an increased response rate ( 53 % PR by Choi in the malignant P51668 , 20 % PR in the pleomorphic / dedifferentiated P51668 ) . CONCLUSIONS : DB01268 is active in P51668 . Response can be long - lasting .\",\n \"Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma . BACKGROUND : Coactivation of tyrosine kinase limits the efficacy of tyrosine kinase inhibitors . We hypothesized that a strategic combination therapy could overcome tyrosine kinase coactivation and compensatory oncogenic signaling in patients with adrenocortical carcinoma ( ACC ) . METHODS : We profiled 88 tyrosine kinases before and after treatment with sunitinib in H295R and SW13 ACC cells . The effects of monotherapy and strategic combination regimens were determined by the 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 5 -( 3 - carboxymethoxyphenyl )- 2 -( 4 - sulfophenyl )- 2H - tetrazolium ( ie , MTS ) assay . RESULTS : The minimum inhibitory concentrations ( IC ( min ) ) of sunitinib quenched its primary targets : P36888 , P35968 , and P07949 . In contrast , P29323 , P08631 , Chk2 , P07947 , CREB , MEK , MSK , p38 , P09769 , and P30530 were hyperactivated . Monotherapy with sunitinib or PD98059 at their IC ( min ) reduced proliferation by 23 % and 19 % , respectively , in H295R cells and by 25 % and 24 % , respectively , in SW13 cells . DB01268 and PD98059 in combination decreased proliferation by 68 % and 64 % in H295R and in SW13 cells , respectively ( P < . 05 versus monotherapy ) . The effects of combination treatment exceeded the sum of the effects observed with each individual agent alone . CONCLUSION : We describe the first preclinical model to develop strategic combination therapy to overcome tyrosine kinase coactivation in ACC . Because many tyrosine kinase inhibitors are readily available , this model can be immediately tested in clinical trials for patients with advanced ACC .\",\n \"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK36___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .\",\n \"DB01268 : bridging present and future cancer treatment . Tyrosine kinase receptors ( RTKs ) are a heterogeneous group of transmembrane proteins involved in signal transduction . These receptors are expressed in many different cells and regulate cellular growth , differentiation and angiogenesis . Overexpression and / or the structural alteration of different RTKs classes are generally associated to cancer and , when RTKs - mediated signal transduction pathways are abnormally activated , generate cancer growth , angiogenesis and metastatization . Therapeutic intervention targeting RTKs concerns antagonist drugs as little molecules or monoclonal antibodies . DB01268 malate is a little molecule able to block intracellular tyrosine kinase domain of RTKs , which has both direct anticancer and antiangiogenetic activity . DB01268 targets selectively vascular endothelial growth factor , P10721 , Flt3 and platelet - derived growth factor receptors and the receptor encoded by the ret proto - oncogene . This drug is used in the treatment of gastrointestinal stromal cancer ( GIST ) resistant to imatinib and metastatic renal cell carcinoma ( RCC ) . In this review , we report preclinical data of sunitinib , even about synergism with chemotherapy and radiotherapy , data relative to phase III trials of sunitinib in the treatment of GIST and RCC , and we try to plan what will be future applications of sunitinib in different types of cancer , even in association to chemotherapy , radiotherapy and monoclonal antibodies .\",\n \"DB01268 in metastatic thymic carcinomas : laboratory findings and initial clinical experience . BACKGROUND : Thymic carcinoma ( TC ) is a rare aggressive tumour . Median survival with current treatments is only 2 years . DB01268 is a multi - targeted tyrosine kinase inhibitor that has shown benefit in various other cancers . METHODS : Laboratory analyses of snap - frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases ( RTKs ) in TC samples . On the basis of molecular analyses showing activation of multiple RTKs in their tumour , four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols . RESULTS : RTK analysis in three of the patients showed activation of multiple RTKs , including platelet - derived growth factor - beta and vascular endothelial growth factor 3 . Mutations of P00533 , c - P10721 , P01116 , and P15056 genes were not found . Administration of sunitinib yielded a partial remission ( lasting 2 to 18 + months ) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in DB09150 - PET in another one . The overall survival with sunitinib treatment ranges from 4 to 40 + months . Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re - administration of sunitinib . CONCLUSIONS : DB01268 is an active treatment for metastatic TC . A panel of molecular analyses may be warranted for optimal patient selection .\",\n \"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .\",\n \"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .\",\n \"Reinvestigation of carrier transport properties in liquid crystalline 2 - phenylbenzothiazole derivatives . We have reinvestigated the charge carrier transport properties in a liquid crystal of 2 -( 4 '- heptyloxyphenyl )- 6 - dodecylthiobenzothiazole ( 7O - P10721 - P28222 ) , for which the electronic conduction was first established in rodlike liquid crystals and for which the highest hole mobility in the smectic A ( SmA ) phase ever achieved was reported . We found that 7O - P10721 - P28222 exhibited three crystal phases , one of which appeared in a limited temperature range of 10 degrees just below the phase transition temperature from the SmA phase . In this crystal phase , nondispersive transient photohole currents were observed in time - of - flight experiments , and its hole mobility was determined to be 8 x 10 (- 3 ) cm ( 2 )/ Vs , slightly higher than that reported previously in the SmA phase . For the SmA phase , however , the hole mobility was 1 x 10 (- 4 ) cm ( 2 )/ Vs . Furthermore , we established the electron transport in the SmA phase of purified 7O - P10721 - P28222 , whose mobility was the same as the hole mobility in that phase . In order to confirm generality of the new findings in 7O - P10721 - P28222 , we investigated the carrier transport properties of its derivative having a short hydrocarbon chain , 2 -( 4 '- heptyloxyphenyl )- 6 - butylthiobenzothiazole ( 7O - P10721 - S4 ) , and obtained comparable results . The present results correct a mistake in the previous report and give an idea of what a typical mobility in the SmA phase is . On the basis of these results , we discuss what determines the charge carrier mobility in smectic mesophases .\",\n \"Ligand - dependent platelet - derived growth factor receptor ( P09619 ) - alpha activation sensitizes rare lung cancer and sarcoma cells to P09619 kinase inhibitors . Platelet - derived growth factor ( PDGF ) receptors ( P09619 ) and their ligands play critical roles in several human malignancies . DB01268 is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor , c - P10721 , and P09619 , and has shown clinical activity in various solid tumors . Activation of P09619 signaling has been described in gastrointestinal stromal tumors ( P16234 mutations ) as well as in chronic myeloid leukemia ( P11274 - P16234 translocation ) , and sunitinib can yield clinical benefit in both settings . However , the discovery of P09619 activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti - P09619 therapies , such as sunitinib . Using a high - throughput cancer cell line screening platform , we found that only 2 of 637 tested human tumor - derived cell lines show significant sensitivity to single - agent sunitinib exposure . These two cell lines [ a non - small - cell lung cancer ( NSCLC ) and a rhabdomyosarcoma ] showed expression of highly phosphorylated P16234 . In the sunitinib - sensitive adenosquamous NSCLC cell line , P16234 expression was associated with focal PFGRA gene amplification , which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens . Moreover , in this NSCLC cell line , focal amplification of the gene encoding the P09619 ligand Q9NRA1 was also detected , and silencing P16234 or Q9NRA1 expression by RNA interference inhibited proliferation . A similar codependency on P16234 and Q9NRA1 was observed in the sunitinib - sensitive rhabdomyosarcoma cell line . These findings suggest that , in addition to gastrointestinal stromal tumors , rare tumors that show Q9NRA1 - mediated P16234 activation may also be clinically responsive to pharmacologic P16234 or Q9NRA1 inhibition .\",\n \"Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors . BACKGROUND : Myelosuppression has been observed with several multikinase angiogenesis inhibitors in clinical studies , although the frequency and severity varies among the different agents . Inhibitors targeting vascular endothelial growth factor receptor ( VEGFR ) often inhibit other kinases , which may contribute to their adverse - event profiles . METHODS : Kinase selectivity of pazopanib , sorafenib , and sunitinib was evaluated in a panel of 242 kinases . Cellular potency was measured using autophosphorylation assays . Effect on human bone marrow progenitor growth in the presence of multiple growth factors was evaluated and correlated with the kinase selectivity . RESULTS : DB01268 inhibited more kinases than pazopanib and sorafenib , at potencies within 10 - fold of P35968 . All three compounds potently inhibited P35968 , platelet - derived growth factor receptor - beta and c - Kit , However , pazopanib was less active against Flt - 3 in both kinase and cellular assays . The inhibitory properties of pazopanib , sorafenib , and sunitinib were dependent on the growth factor used to initiate bone marrow colony formation . Addition of stem cell factor and / or Flt - 3 ligand with granulocyte - macrophage colony stimulating factor resulted in significant shifts in potency for sorafenib and sunitinib but less so for pazopanib . CONCLUSION : Activity against c - kit and Flt - 3 by multikinase angiogenesis inhibitors provide a potential explanation for the differences in myelosuppression observed with these agents in patients .\",\n \"Plasma biomarkers correlating with clinical outcome in a phase II study of sorafenib in advanced NSCLC . We investigated the relationship between plasma protein biomarker concentrations and clinical outcomes in 52 patients with relapsed / refractory advanced non - small cell lung cancer ( NSCLC ) treated with 400 ~ mg bid sorafenib in a phase II trial . Blood samples were collected at baseline , on day 15 of cycle 1 ( C1D15 ) , and on day 1 of cycle 3 ( C3D1 ) , and plasma concentrations of total P15692 , P15692 - 165 , soluble ( s ) P35968 , DB00102 , sPDGFR - β , sEGFR , sHER - 2 , uPA , P05121 , Q03405 , P01033 , and circulating Ras P38936 were assayed by ELISA . Elevated baseline P15692 , P15692 - 165 , DB00102 , Ras P38936 , and P01033 concentrations were associated with poorer patient outcomes ( shorter overall survival [ OS ] and / or progression - free survival [ PFS ] ) . During treatment , the mean concentrations of sVEGFR - 2 , DB00102 , sPDGFR - β , P01033 , Q03405 , and P05121 decreased , while the mean sEGFR concentration increased . Increases in P15692 , P15692 - 165 , DB00102 , and P01033 during treatment were associated with better outcomes ( longer OS and / or PFS ) , whereas increases in plasma Ras P38936 during treatment were associated with shorter PFS . The associations between baseline concentrations and / or pharmacodynamic changes in plasma proteins and clinical outcomes in NSCLC patients treated with sorafenib suggest that these biomarkers may have a prognostic role and / or predict the efficacy of sorafenib in patients with NSCLC .\",\n \"Recent advances in the treatment of gastrointestinal stromal tumors . Constitutively activating mutations in the P10721 and platelet - derived growth factor receptor α ( P16234 ) RTKs play a crucial role in the biology of gastrointestinal stromal tumors ( GISTs ) , and this disease has served as an effective model for targeting gain - of - function kinase mutations in cancer . Imatinib has entered the clinical arena in the last decade and substantially improved the outcome in these formerly untreatable cancers . However , most advanced GISTs responding to imatinib progress within 2 - 3 years due to heterogeneous subclones harboring a range of imatinib - resistant secondary P10721 mutations . DB01268 , and more recently , regorafenib , have obtained US Food and Drug Administration approval for the treatment of GISTs after imatinib failure , and thus expanded the treatment options in resistant disease . Within this framework , we present an evaluation of current GIST management , emphasizing the most recent advances in the field together with a discussion on future steps to be taken in refractory disease .\",\n \"Differential radiosensitisation by ZD1839 ( ___MASK62___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK62___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .\",\n \"DB01268 in the treatment of advanced solid tumors . DB01268 is an oral multikinase inhibitor that blocks the vascular endothelial growth factor receptor ( VEGFR ) , platelet - derived growth factor receptor ( P09619 ) alpha and beta , c - kit , and other receptors . These attributes have proven to be efficacious in the treatment of metastatic renal cell carcinoma ( RCC ) , unresectable gastrointestinal stromal tumors ( GIST ) , and well - differentiated advanced pancreatic neuroendocrine tumors ( PNET ) . Though activity has been reported in other tumor types , phase III trials have not yet demonstrated improved survival outcomes in these cancers . Most side effects including hypertension , hand - foot syndrome , and diarrhea are generally well manageable . This review will detail the preclinical data leading up to the results of the pivotal phase III clinical trials that have led to the widespread use of sunitinib in advanced RCC , GIST , and PNET .\",\n \"Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients . PURPOSE : To investigate the angiogenic changes in primary tumor tissue of renal cell carcinoma ( RCC ) patients treated with P15692 - targeted therapy . EXPERIMENTAL DESIGN : Phase II trials of P15692 pathway - targeted therapy given before cytoreductive surgery were carried out with metastatic RCC patients with the primary tumor in situ to investigate the necessity of nephrectomy . Primary tumor tissues were obtained and assessed for angiogenesis parameters . Results were compared with similar analyses on untreated tumors . RESULTS : DB01268 or bevacizumab pretreatment resulted in a significant reduction of microvessel density in the primary tumor . Also , an increase in vascular pericyte coverage was found in sunitinib - pretreated tumors , consistent with efficient angiogenesis inhibition . Expression of several key regulators of angiogenesis was found to be suppressed in pretreated tissues , among which P17948 and P35968 , angiopoietin - 1 and angiopoietin - 2 and platelet - derived growth factor - B . In addition , apoptosis in tumor and endothelial cells was induced . Interestingly , in sunitinib - pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed , which was not the case in bevacizumab - pretreated tumors . A positive correlation with the interval between halting the therapy and surgery was found , suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment . CONCLUSION : This study describes , for the first time , the angiostatic response in human primary renal cancers at the tissue level upon treatment with P15692 - targeted therapy . Discontinuation of treatment with tyrosine kinase inhibitors leads to accelerated endothelial cell proliferation . The results of this study contribute important data to the ongoing discussion on the discontinuation of treatment with kinase inhibitors .\",\n \"A curated database of miRNA mediated feed - forward loops involving MYC as master regulator . BACKGROUND : The MYC transcription factors are known to be involved in the biology of many human cancer types . But little is known about the Myc / microRNAs cooperation in the regulation of genes at the transcriptional and post - transcriptional level . METHODOLOGY / PRINCIPAL FINDINGS : Employing independent databases with experimentally validated data , we identified several mixed microRNA / Transcription Factor Feed - Forward Loops regulated by Myc and characterized completely by experimentally supported regulatory interactions , in human . We then studied the statistical and functional properties of these circuits and discussed in more detail a few interesting examples involving Q01094 , P60484 , P06400 and P15692 . CONCLUSIONS / SIGNIFICANCE : We have assembled and characterized a catalogue of human mixed Transcription Factor / microRNA Feed - Forward Loops , having Myc as master regulator and completely defined by experimentally verified regulatory interactions .\",\n \"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .\",\n \"Induction of high mobility group box 1 release from serotonin - stimulated human umbilical vein endothelial cells . High mobility group box 1 ( P09429 ) is a non - histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis . The P09429 functions as a potent proinflammatory cytokine in the extracellular spaces . Recently , P09429 has been implicated in the progression of atherosclerosis . However , the association between P09429 and the development of atherosclerosis is poorly understood . Therefore , we examined whether serotonin ( 5 - HT ) , a key factor involved in the development of atherosclerosis , induced P09429 release in human umbilical vein endothelial cells ( HUVECs ) . We found that 5 - HT induced the release of P09429 but not of P27361 / 2 and JNK from HUVECs via the 5 - HT receptor ( P28222 ) / p38 mitogen - activated protein kinase ( MAPK ) signaling pathway . The p38MAPK inhibitor SB203580 and the P28222 antagonist GR55526 markedly inhibited P09429 release from 5 - HT - stimulated HUVECs . The vascular endothelial growth factor ( P15692 ) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis . We found that P09429 induced P15692 production in macrophage - like RAW264 . 7 cells . P09429 induced the activation of p38MAPK , P27361 / 2 and Akt . The P19957 - kinase inhibitor LY294002 significantly inhibited P15692 production in P09429 - stimulated macrophages , while other kinase inhibitors did not . These results suggest that P09429 release may contribute as a risk factor in the development and progression of atherosclerosis .\",\n \"In vivo antitumor and antimetastatic activity of sunitinib in preclinical neuroblastoma mouse model . Neuroblastoma ( NB ) is one of the most common pediatric solid tumors originating from the neural crest lineage . Despite intensive treatment protocols including megatherapy with hematopoietic stem cell transplantation , the prognosis of NB patients remains poor . More effective therapeutics are required . High vascularity has been described as a feature of aggressive , widely disseminated NB . Our previous work demonstrated the overexpression of vascular endothelial growth factor ( P15692 ) in NB , and we showed that an anti - P15692 receptor ( P35968 ) antibody could induce sustained NB tumor suppression and regression . DB01268 is a kinase inhibitor targeting platelet - derived growth factor receptors and VEGFRs and , therefore , a promising antiangiogenic agent . In this study , we investigated the antitumor activity of sunitinib and its synergistic cytotoxicity with conventional ( cyclophosphamide ) and novel ( rapamycin ) therapies . Both NB cell lines and tumor - initiating cells from patient tumor samples were used in our in vitro and in vivo models for these drug testing . We show that sunitinib inhibits tumor cell proliferation and phosphorylation of VEGFRs . It also inhibits tumor growth , angiogenesis , and metastasis in tumor xenograft models . Low - dose sunitinib ( 20 mg / kg ) demonstrates synergistic cytotoxicity with an P42345 inhibitor , rapamycin , which is more effective than the traditional chemotherapeutic drug , cyclophosphamide . These preclinical studies provide the evidence of antitumor activity of sunitinib both in the early stage of tumor formation and in the progressive metastatic disease . These studies also provide the framework for clinical trial of sunitinib , alone and in combination with conventional and novel therapies to increase efficacy and improve patient outcome in NB .\",\n \"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK3___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK3___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK3___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .\",\n \"17 ___MASK87___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .\",\n \"Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki - 1 renal cell carcinoma . BACKGROUND : DB01268 ( VEGFR / P09619 inhibitor ) and everolimus ( P42345 inhibitor ) are both approved for advanced renal cell carcinoma ( RCC ) as first - line and second - line therapy , respectively . In the clinics , sunitinib treatment is limited by the emergence of acquired resistance , leading to a switch to second - line treatment at progression , often based on everolimus . No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression . Such strategy is expected to delay the emergence of acquired resistance and improve tumour control . The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus . METHODS : In human Caki - 1 RCC xenograft model , sunitinib was alternated with everolimus every week , every 2 weeks , or every 3 weeks . Effects on necrosis , hypoxia , angiogenesis , and EMT status were assessed by immunohisochemistry and immunofluorescence . RESULTS : DB01268 and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies . In each group of treatment , tumour growth control was associated with inhibition of P42345 pathway and changes from a mesenchymal towards an epithelial phenotype , with a decrease in vimentin and an increase in P12830 expression . The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects , leading to tumour necrosis . CONCLUSIONS : In summary , our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent .\",\n \"Inhibition of cerebrovascular raf activation attenuates cerebral blood flow and prevents upregulation of contractile receptors after subarachnoid hemorrhage . BACKGROUND : Late cerebral ischemia carries high morbidity and mortality after subarachnoid hemorrhage ( Q53FZ2 ) due to reduced cerebral blood flow ( Q03701 ) and the subsequent cerebral ischemia which is associated with upregulation of contractile receptors in the vascular smooth muscle cells ( SMC ) via activation of mitogen - activated protein kinase ( MAPK ) of the extracellular signal - regulated kinase ( P29323 ) 1 / 2 signal pathway . We hypothesize that Q53FZ2 initiates cerebrovascular P27361 / 2 activation , resulting in receptor upregulation . The raf inhibitor will inhibit the molecular events upstream P27361 / 2 and may provide a therapeutic window for treatment of cerebral ischemia after Q53FZ2 . RESULTS : Here we demonstrate that Q53FZ2 increases the phosphorylation level of P27361 / 2 in cerebral vessels and reduces the neurology score in rats in additional with the Q03701 measured by an autoradiographic method . The intracisternal administration of SB - 386023 - b , a specific inhibitor of raf , given 6 h after Q53FZ2 , aborts the receptor changes and protects the brain from the development of late cerebral ischemia at 48 h . This is accompanied by reduced phosphorylation of P27361 / 2 in cerebrovascular SMC . Q53FZ2 per se enhances contractile responses to endothelin - 1 ( ET - 1 ) , 5 - carboxamidotryptamine ( 5 - CT ) and angiotensin II ( Ang II ) , upregulates ETB , P28222 and AT1 receptor mRNA and protein levels . Treatment with SB - 386023 - b given as late as at 6 h but not at 12 h after the Q53FZ2 significantly decreased the receptor upregulation , the reduction in Q03701 and the neurology score . CONCLUSION : These results provide evidence for a role of the P27361 / 2 pathway in regulation of expression of cerebrovascular SMC receptors . It is suggested that raf inhibition may reduce late cerebral ischemia after Q53FZ2 and provides a realistic time window for therapy .\",\n \"The 4q12 amplicon in malignant peripheral nerve sheath tumors : consequences on gene expression and implications for sunitinib treatment . BACKGROUND : Malignant peripheral nerve sheath tumors ( MPNST ) are highly aggressive tumors which originate from Schwann cells and develop in about 10 % of neurofibromatosis type 1 ( P21359 ) patients . The five year survival rate is poor and more effective therapies are needed . DB01268 is a drug targeting receptor tyrosine kinases ( RTK ) like PDGFRalpha , c - Kit and P35968 . These genes are structurally related and cluster on chromosomal segment 4q12 . METHODOLOGY / PRINCIPAL FINDINGS : Here we characterize this region by multiplex ligation - dependent probe amplification ( MLPA ) in MPNST . Our probe set encompasses the 3 adjacent RTK genes ( P16234 , P10721 , P35968 ) and 6 flanking genes . We found amplification of several genes within this region in a subset of MPNST and MPNST cell lines . Transcript and protein expression of P16234 matched well with its increased copy number suggesting a central role of P16234 within the amplicon . Studying the effect of sunitinib on 5 MPNST cell lines revealed that cell line S462 harboring the 4q12 amplicon was extremely sensitive to the drug with an IC50 below 1 . 0 microM . Moreover , sunitinib induced apoptosis and prevented PDGF - AA induced signaling via PDGFRalpha as determined by western blotting . Co - expression of P15692 and its receptor P35968 ( P35968 ) was present in MPNST cell lines suggesting an autocrine loop . We show that P15692 triggered signal transduction via the MAPK pathway , which could be blocked by sunitinib . CONCLUSIONS / SIGNIFICANCE : Since multiple receptors targeted by sunitinib are expressed or over - expressed by MPNST cells sunitinib appears as an attractive drug for treatment of MPNST patients . Presence of the 4q12 amplicon and subsequent over - expression of P16234 might serve as predictive markers for efficacy of sunitinib .\",\n \"Real - time US versus CT determination of pubic arch interference for brachytherapy . PURPOSE : Part 1 , to determine whether transrectal ultrasonography ( US ) enables accurate determination of pubic arch interference ( P05121 ) for prostate brachytherapy ( P10721 ) ; part 2 , to compare the accuracy of transrectal US with that of computed tomography ( CT ) for P05121 determination ; and part 3 , to determine the cost savings of P05121 determination with transrectal US versus that with CT . MATERIALS AND METHODS : Part 1 : The pubic arch was identified intraoperatively with transrectal US and compared with attempted needle passage ( 14 patients ) . Part 2 : Planning CT with the patient supine was compared with planning transrectal US with patients in the dorsal lithotomy position ( nine patients ) . Part 3 : Cost savings were calculated for P05121 determination with transrectal US versus that with CT ( 32 patients per group ) . RESULTS : Part 1 : Transrectal US accurately showed the pubic arch relative to the prostate . Part 2 : CT resulted in P05121 overestimation by 11 . 8 mm . Part 3 : Cost savings with transrectal US were $ 1 , 465 per patient . CONCLUSION : Transrectal US P05121 determination is easily performed , intraoperatively useful , and accurate . CT can result in P05121 overestimation . Reducing direct CT costs and the indirect costs of unnecessary hormonal therapy for false - positive P05121 will reduce expense and improve patient care . Transrectal US should replace CT for P05121 determination .\",\n \"Combined targeted therapies in non - small cell lung cancer : a winner strategy ? PURPOSE OF REVIEW : Current treatment modalities provide limited improvement in the natural course of lung cancer , and prognosis remains poor . Lung cancer is a malignancy with great molecular heterogeneity . The complexity of the signalling process leading to cancer cell proliferation and to the neoplastic phenotype supports the necessity of interfering at different stages to avoid cancer cell resistance to therapy . RECENT FINDINGS : Use of several agents with multiple growth factor receptor or intracellular targets has shown encouraging results in phase I and II clinical trials in non - small cell lung cancer . DB05294 is a dual epidermal growth factor receptor and vascular endothelial growth factor receptor 2 small - molecule tyrosine kinase inhibitor ; sorafenib is an oral kinase inhibitor of P04049 and is also active against vascular endothelial growth factor receptors 2 and 3 , platelet - derived growth factor receptor beta , and c - P10721 . DB01268 is a vascular endothelial growth factor receptor 1 , 2 , and 3 , c - P10721 , and platelet - derived growth factor receptor alpha and beta tyrosine kinase inhibitor . SUMMARY : Combined use of epidermal growth factor receptor - tyrosine kinase inhibitor erlotinib and the humanized vascular endothelial growth factor receptor monoclonal antibody bevacizumab in advanced , chemotherapy - refractory non - small cell lung cancer has shown promising results .\"\n]"},"candidates":{"kind":"list like","value":["___MASK36___","___MASK3___","___MASK45___","___MASK46___","___MASK62___","___MASK67___","___MASK87___","___MASK94___","___MASK99___"],"string":"[\n \"___MASK36___\",\n \"___MASK3___\",\n \"___MASK45___\",\n \"___MASK46___\",\n \"___MASK62___\",\n \"___MASK67___\",\n \"___MASK87___\",\n \"___MASK94___\",\n \"___MASK99___\"\n]"},"answer":{"kind":"string","value":"___MASK3___"},"id":{"kind":"string","value":"MH_train_479"}}},{"rowIdx":480,"cells":{"query":{"kind":"string","value":"interacts_with DB01240?"},"supports":{"kind":"list like","value":["The anticoagulant effect of PGI2S and tPA in transgenic umbilical vein endothelial cells is linked to up - regulation of PKA and PKC . The selection of vascular grafts for coronary artery bypass surgery is crucial for a positive outcome . This study aimed to establish a novel line of vascular endothelial cells with a potent anticoagulant effect . A lentiviral vector was used to stably transfect human umbilical vein endothelial cells ( HUVECs ) with PGI2S alone ( HUVEC - PGI2S ) or both PGI2S and tPA ( HUVEC - PGI2S - tPA ) . Both HUVEC - PGI2S and HUVEC - PGI2S - tPA cells over - expressing PGI2S and tPA were compared to mock - transfected cells . The enzyme - linked immuno sorbent assay ( ELISAs ) demonstrated that the anticoagulation components , P01008 and P00747 , were up - regulated and coagulation factor FVIII was down - regulated in both cell lines . QRT - PCR and western blotting demonstrated the vasodilation and platelet disaggregation proteins PKA , PKC , and P43119 were up - regulated in both cell lines , but MAPK expression was not altered in either cell line . However , cell viability and colony formation assays and cell cycle analysis demonstrated that both cell lines had a lower rate of cell growth and induced P55008 phase arrest . HUVEC - PGI2S and HUVEC - PGI2S - tPA cells have a potent anticoagulant effect and their use in vascular heterografts may decrease the risk of thrombosis .","Inhibition of myoblast migration by prostacyclin is associated with enhanced cell fusion . Satellite cells are stem cells that are critical for the formation and growth of skeletal muscle during myogenesis . To differentiate and fuse , proliferating satellite cells or myoblasts must migrate and establish stable cell - cell contacts . However , the factors that regulate myoblast migration and fusion are not understood completely . We have identified DB01240 as a novel regulator of myogenesis in vitro . DB01240 is a member of the family of prostaglandins ( PG ) , autocrine / paracrine signaling molecules synthesized via the cyclooxygenase - 1 and - 2 pathways . Primary mouse muscle cells both secrete DB01240 and express the P43119 , IP , at various stages of myogenesis . Using genetic and pharmacological approaches , we show that DB01240 is a negative regulator of myoblast migration that also enhances cell fusion . Thus , DB01240 may act as a \" brake \" on migrating cells to facilitate cell - cell contact and fusion . Together , our results highlight the importance of the balance between positive and negative regulators in cell migration and myogenesis . This work may have implications for migration of other populations of adult stem cells and / or cells that undergo fusion .","Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats . OBJECTIVE : The aim of this study was to evaluate the possible role of prostacyclin ( DB01240 ) in the pathogenesis of hypertension in spontaneously hypertensive rats ( SHR ) . METHODS : Measurement of mRNA and protein levels of PGH synthase ( PGHS ) - 1 , DB01240 synthase and the P43119 , in the thoracic aorta was performed in SHR aged 5 , 10 , 20 , and 40 weeks old and in age - matched normotensive Wistar - Kyoto ( WKY ) rats with a competitive polymerase chain reaction method and immunoblotting . Aortic production of 6 - keto - PGF1 alpha , the main metabolite of DB01240 , was also measured . RESULTS : Compared with age - matched WKY rats , P23219 mRNA and protein levels in the thoracic aorta of SHR increased with age , reaching three - and twofold higher than WKY rats at 40 weeks old , respectively . DB01240 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old . In contrast , P43119 mRNA levels in SHR were consistently lower than in WKY rats at all ages . CONCLUSIONS : These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites , including PGH2 and DB01240 . They also suggest that the decreased expression of P43119 mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR .","The ' allosteric modulator ' P35240 - 202676 disrupts G protein - coupled receptor function via sulphydryl - sensitive mechanisms . 1 . Previous studies suggest that the thiadiazole compound P35240 - 202676 ( N -( 2 , 3 - diphenyl - 1 , 2 , 4 - thiadiazol - 5 -( 2H )- ylidene ) methanamine ) acts as an allosteric modulator of a variety of structurally distinct G protein - coupled receptors ( GPCRs ) . It was postulated that P35240 - 202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family . The molecular mechanisms of such a promiscuous action , however , remain obscure . 2 . To clarify the mechanism of P35240 - 202676 action , we used the functional approach of [ 35S ] GTPgammaS autoradiography with rat brain cryostat sections together with classical membrane [ 35S ] GTPgammaS binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi - family of G proteins . 3 . We found that in the absence of dithiotreitol ( DTT ) , P35240 - 202676 ( 10 (- 7 )- 10 (- 5 ) M ) elicits nonspecific effects in the [ 35S ] GTPgammaS - based G protein activation assays , thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor - mediated G protein activity . Such a nonspecific behaviour was fully reversed upon addition of DTT ( 1 mM ) , revealing thiol - based mechanism of action . 4 . In routine incubations containing DTT , P35240 - 202676 had no effect on receptor - driven G protein activity , as assessed for adenosine A1 , alpha2 - adrenergic , cannabinoid P21554 , lysophosphatidic acid Q92633 , muscarinic M2 / M4 , purinergic Q9H244 or sphingosine 1 - phosphate receptors , suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function . 5 . 1H NMR analysis indicated that P35240 - 202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue . 6 . We conclude that P35240 - 202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms .","Thiazolidinedione drugs down - regulate P61073 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor gamma - dependent manner . Peroxisome proliferator activated receptor ( Q07869 ) gamma is a nuclear receptor involved primarily in lipid and glucose metabolism . PPARgamma is also expressed in several cancer types , and has been suggested to play a role in tumor progression . PPARgamma agonists have been shown to reduce the growth of colorectal carcinoma cells in culture and in xenograft models . Furthermore , the PPARgamma agonist thiazolidinedione has been shown to reduce metastasis in a murine model of rectal cancer . Since the chemokine receptor P61073 has emerged as an important player in tumorigenesis , particularly in the process of metastasis , we sought to determine if PPARgamma agonists might act in part by reducing P61073 expression . We found that rosiglitazone , a thiazolidinedione PPARgamma agonist used primarily in the treatment of type 2 diabetes , significantly reduced cell - surface expression of P61073 protein on HT - 29 human colorectal carcinoma cells . This effect occurred at concentrations as low as 1 nM , and was first evident after 8 h of drug exposure . P61073 mRNA was also down - regulated after treatment with rosiglitazone , indicating that the effect occurs at the level of transcription . Four other thiazolidinedione compounds ( ciglitazone , pioglitazone , troglitazone , and MCC555 ) also significantly reduced P61073 expression . To confirm the involvement of PPARgamma in thiazolidinedione - induced P61073 down - regulation , we used PPARgamma antagonists GW9662 and T0070907 , both of which completely blocked the effect of rosiglitazone on P61073 expression . Furthermore , HT - 29 cells in which PPARgamma expression was reduced using shRNA were less responsive to rosiglitazone . In conclusion , we have shown that thiazolidinedione compounds reduce P61073 mRNA and cell - surface protein expression in a PPARgamma - dependent manner .","Activation of a TGF - beta - specific multistep gene expression program in mature macrophages requires glucocorticoid - mediated surface expression of TGF - beta receptor II . Alternatively activated ( M2 ) macrophages regulate steady state - , cancer - , and inflammation - related tissue remodeling . They are induced by Th2 - cytokines and glucocorticoids ( GC ) . The responsiveness of mature macrophages to TGF - beta , a cytokine involved in inflammation , cancer , and atherosclerosis , is currently controversial . Recently , we demonstrated that Q9NRM6 is up - regulated in human monocyte - derived macrophages differentiated in the presence of Th2 cytokines P05112 and TGF - beta1 . In this study , we show that mature human macrophages differentiated in the presence of P05112 , and dexamethasone ( M2 ( P05112 / GC ) ) but not M2 ( P05112 ) responds to TGF - beta1 which induced a gene expression program comprising 111 genes including transcriptional / signaling regulators ( Q02535 and Q08116 ) , immune modulators ( P20292 and Q9NRM6 ) and atherosclerosis - related genes ( P20292 , P41146 , P02654 , P02655 , and P02649 ) . Analysis of molecular mechanism underlying GC / TGF - beta cooperation revealed that surface expression of TGF - betaRII was high in M2 ( GC ) and M2 ( P05112 / GC ) , but absent from M2 ( P05112 ) , whereas the expression of TGF - betaRI / II mRNA , TGF - betaRII total protein , and surface expression of TGF - betaRIII were unchanged . GC dexamethasone was essential for increased surface expression of functional TGF - betaRII because its effect was observed also in combination with P35225 , P09603 , and GM - P04141 . Prolonged Q15796 - mediated signaling observed in TGF - beta1 - treated M2 ( P05112 / GC ) was due to insufficient activity of negative feedback mechanism what can be explained by up - regulation of Q96EB6 , a negative regulator of O15105 , and the retention of TGF - betaRII complex on the cell surface . In summary , mature human M2 macrophages made permissive to TGF - beta by GC - induced surface expression of TGF - betaRII activate in response to TGF - beta1 , a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion .","Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .","P43119 up - regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1 / 2 pathway . DB01240 ( P06744 ) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven - transmembrane G protein - coupled receptor ( IP receptor ) . Recent studies have ascertained a role for prostanoid - receptor signaling in angiogenesis . In this study we examined the temporal - spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes . Quantitative RT - PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle . Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity . Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle . To explore the role of the IP receptor in glandular epithelial cells , we used the Ishikawa endometrial epithelial cell line . Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost ( a P06744 analog ) rapidly activated P27361 / 2 signaling and induced the expression of proangiogenic genes , basic fibroblast growth factor , angiopoietin - 1 , and angiopoietin - 2 , in an epidermal growth factor receptor ( P00533 ) - dependent manner . Furthermore , P00533 colocalized with IP receptor in the glandular epithelial compartment . These data suggest that P06744 - IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the P00533 .","Cyclooxygenase inhibition abrogates aeroallergen - induced immune tolerance by suppressing prostaglandin I2 receptor signaling . BACKGROUND : The prevalence of allergic diseases has doubled in developed countries in the past several decades . Cyclooxygenase ( P36551 ) - inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses . However , whether P36551 inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known . OBJECTIVE : To determine the role of the P36551 pathway and prostaglandin I2 ( DB01240 ) signaling through the P43119 ( IP ) in aeroallergen - induced immune tolerance . METHODS : Wild - type ( WT ) BALB / c mice and IP knockout mice were aerosolized with ovalbumin ( OVA ) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA / alum . The P36551 inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase . Two weeks after sensitization , the mice were challenged with OVA aerosols . Mouse bronchoalveolar lavage fluid was harvested for cell counts and TH2 cytokine measurements . RESULTS : WT mice treated with indomethacin had greater numbers of total cells , eosinophils , and lymphocytes , and increased P05113 and P35225 protein expression in BAL fluid compared to vehicle - treated mice . Similarly , IP knockout mice had augmented inflammation and TH2 cytokine responses compared to WT mice . In contrast , the DB01240 analog cicaprost attenuated the anti - tolerance effect of P36551 inhibition . CONCLUSION : P36551 inhibition abrogated immune tolerance by suppressing DB01240 IP signaling , suggesting that DB01240 signaling promotes immune tolerance and that clinical use of P36551 - inhibiting drugs may increase the risk of developing allergic diseases .","Microarray analyses of the effects of NF - kappaB or PI3K pathway inhibitors on the LPS - induced gene expression profile in RAW264 . 7 cells : synergistic effects of rapamycin on LPS - induced P14780 - overexpression . Lipopolysaccharide ( LPS ) activates a broad range of signalling pathways including mainly NF - kappaB and the MAPK cascade , but recent evidence suggests that LPS stimulation also activates the PI3K pathway . To unravel the specific roles of both pathways in LPS signalling and gene expression profiling , we investigated the effects of different inhibitors of NF - kappaB ( BAY 11 - 7082 ) , PI3K ( wortmannin and LY294002 ) but also of P42345 ( rapamycin ) , a kinase acting downstream of PI3K / Akt , in LPS - stimulated RAW264 . 7 macrophages , analyzing their effects on the LPS - induced gene expression profile using a low density DNA microarray designed to monitor the expression of pro - inflammatory genes . After statistical and hierarchical cluster analyses , we determined five clusters of genes differentially affected by the four inhibitors used . In the fifth cluster corresponding to genes upregulated by LPS and mainly affected by BAY 11 - 7082 , the gene encoding P14780 displayed a particular expression profile , since rapamycin drastically enhanced the LPS - induced upregulation at both the mRNA and protein levels . ___MASK91___ also enhanced the LPS - induced NF - kappaB transactivation as determined by a reporter assay , phosphorylation of the p38 and Erk1 / 2 MAPKs , and counteracted Q07869 activity . These results suggest that P42345 could negatively regulate the effects of LPS on the NF - kappaB and MAPK pathways . We also performed real - time RT - PCR assays on mmp9 expression using rosiglitazone ( agonist of PPARgamma ) , PD98059 ( inhibitor of Erk 1 / 2 ) and SB203580 ( inhibitor of p38 ( MAPK ) ) , that were able to counteract the rapamycin mediated overexpression of mmp9 in response to LPS . Our results suggest a new pathway involving P42345 for regulating specifically mmp9 in LPS - stimulated RAW264 . 7 cells .","P12644 modulates fibroblast growth factor - mediated induction of proximal and distal lung differentiation in mouse embryonic tracheal epithelium in mesenchyme - free culture . Lung morphogenesis and differentiation require interaction between the epithelium and mesenchyme , which is mediated by diffusible molecules such as fibroblast growth factors ( FGFs ) , bone morphogenetic protein 4 ( P12644 ) , and Shh . We have used mesenchyme - free culture to study the effects of these molecules on lung epithelial differentiation . We have tested the individual abilities of P05230 , P09038 , P21781 , P31371 , O15520 , and O76093 , as well as P12644 and Shh to promote growth and specify distal lung differentiation in mouse tracheal epithelium . The different FGFs exhibited distinct abilities to induce epithelial growth and the expression of the distal lung epithelial marker , surfactant protein C ( P11686 ) , although all FGFs were able to induce expression of P12644 . Tracheal epithelium treated with O15520 showed little growth and failed to express P11686 as measured by whole - mount in situ hybridization and quantitative real - time polymerase chain reaction . P05230 treatment resulted in the strongest induction of P11686 . Treatment with P12644 inhibited epithelial growth and differentiation and antagonized the stimulatory effects of P05230 . In contrast , inhibition of endogenous P12644 signaling with Q13253 protein did not inhibit growth or expression of P11686 but did increase the expression of the proximal lung markers P11684 and Q92949 . Expression of Shh was not affected by any of the conditions tested . These results suggest that P12644 does not signal epithelial cells to adopt a distal fate but may regulate the expansion of proximal epithelial cells in the lung .","Human prostacyclin platelet receptors in diabetes mellitus . Conflicting data have been reported about the impaired sensitivity to the inhibitory effect of prostacyclin ( DB01240 ) in platelets from patients with diabetes . In the present paper we investigated binding of and sensitivity to DB01240 of platelets from insulin dependent ( IDDM ) ( n = 9 ) , non insulin dependent ( NIDDM ) ( n = 8 ) diabetics and two groups of ten healthy subjects of equivalent age in relation to platelet lipidic content . Platelet sensitivity to DB01240 ( DB01240 IC50 ) was found not significantly changed in diabetics as compared to controls ; similarly , no significant differences of the number of high affinity receptors for DB01240 in platelets from patients with IDDM and NIDDM were observed . Platelet sensitivity to DB01240 and DB01240 receptors were found to be significantly related to platelet cholesterol content ( r = 0 . 89 , p less than 0 . 001 and r = - 0 . 80 , p less than 0 . 001 respectively ) . In conclusion platelet P43119 changes are not detectable in diabetics in good metabolic control , but could take place when platelet lipid composition is altered .","Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension . Q16647 ( PGIS ) is the final committed enzyme in the metabolic pathway leading to prostacyclin ( DB01240 ) production . Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels , but the importance of this deficiency for lung vascular remodeling remains unclear . We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension . To study this hypothesis , transgenic mice were created with selective pulmonary PGIS overexpression using a construct of the 3 . 7 - kb human surfactant protein - C ( P11686 ) promoter and the rat PGIS cDNA . Transgenic mice ( Tg + ) and nontransgenic littermates ( Tg - ) were subjected to a simulated altitude of 17 , 000 ft for 5 weeks , and right ventricular systolic pressure ( RVSP ) was measured . Histology was performed on the lungs . The Tg + mice produced 2 - fold more pulmonary 6 - keto prostaglandin F1alpha ( PGF1alpha ) levels than did Tg - mice . After exposure to chronic hypobaric hypoxia , Tg + mice have lower RVSP than do Tg - mice . Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg + mice in comparison with vessel wall hypertrophy in the Tg - mice . These studies demonstrate that Tg + mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia . We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia . This has important implications for the pathogenesis and treatment of severe pulmonary hypertension .","Is transforming growth factor - β signaling activated in human hypertrophied prostate treated by 5 - alpha reductase inhibitor ? BACKGROUND AND AIM : It is well known that androgen deprivation relates to penile fibrosis , so we hypothesize that long - term treatment with 5 - alphareductase inhibitors ( 5ARIs ) may increase the risk of fibrosis of prostate . PATIENTS AND METHODS : Thirty - two BPH patients who underwent transurethral resection of the prostate were enrolled . The patients were divided into two groups : group one , 16 patients underwent TURP who had been treated with tamsulosin for 2 years ; group two , 16 patients underwent TURP who had been treated with combination of tamsulosin and dutasteride for at least 1 year . We evaluated the expressions of P29475 , P35228 , P29474 , TGF - β1 , TGF - β2 , phosphorylated - Q15796 / 3 ( p - Q15796 / 3 ) , P12830 , P19022 , and α - smooth muscle actin in the resected prostate tissues by western blotting , and the TGF - β concentration was determined by ELISA kit . RESULTS : The expressions of 3 isoforms of NOS were significantly increased in group 2 except of P29474 in lateral prostate , and the expressions of TGF - β1 , TGF - β2 , and p - Q15796 / 3 increased about 2 - fold compared with group 1 . In group 2 , the P12830 expression decreased while P19022 expression increased significantly . CONCLUSIONS : The overexpression of P29475 may contribute to prostate smooth muscle relaxation ; however , long - time treatment with 5 Q9Y4X5 increases the risk of fibrosis of prostate .","Non - prostanoid prostacyclin mimetics . 6 . Derivatives of 2 -[ 3 -[ 2 -( 4 , 5 - Diphenyl - 2 - oxazolyl ) ethyl ] phenoxy ] acetic acid modified beta - to the oxazole ring . 2 -[ 3 -[ 2 -( 4 , 5 - Diphenyl - 2 - oxazolyl ) ethyl ] phenoxy ] acetic acid , 1 , has been described as a non - prostanoid DB01240 mimetic that demonstrates anti - thrombotic properties of long duration in animal models of thrombosis . The effects of substitution and modification of the carbon beta - to the oxazole heterocycle of 1 were examined and equated with the potency of the compounds as inhibitors of ADP - induced human platelet aggregation in vitro . Potency was sensitive to both the size of the substituent and the identity of the beta - atom . The carbamates 13c - e demonstrated IC50 ' s of 0 . 28 - 0 . 36 microM and were significantly more potent than the progenitor 1 , IC50 = 1 . 2 microM . The ethyl carbamate 13c displaced [ 3H ] - iloprost from platelet membranes in a concentration - dependent fashion that was half maximal at 20 nM , which compares with IC50 ' s of 171 nM for 1 and 39 nM or unlabelled iloprost . Carbamate 13c stimulated platelet adenylate cyclase but the maximal effect was less than that observed for DB01240 , identifying 13c as a partial agonist at the platelet P43119 .","Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .","Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK87___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .","Estrogen protects the heart from ischemia - reperfusion injury via P35354 - derived DB01240 . There is an accumulating body of data to suggest that estrogen mediates its cardioprotective effects via cyclooxygenase activation and synthesis of prostaglandins ( PG ) , specifically DB01240 . We hypothesized that inhibition of P35354 would prevent estrogen ' s cardioprotective effects after myocardial ischemia - reperfusion . Acute treatment with 17beta - estradiol ( E2 ; 20 microg / rabbit ) increased P35354 protein expression and activity in the myocardium . To determine the effects of P35354 inhibition on infarct size after E2 treatment , New Zealand white rabbits were anesthetized and administered the P35354 inhibitor nimesulide ( 5 mg / kg ) or vehicle intravenously 30 minutes before an intravenous injection of E2 . Thirty minutes after estrogen treatment , the coronary artery was occluded for 30 minutes followed by 4 hours of reperfusion . E2 significantly decreased infarct size as a percent of area at risk when compared to vehicle ( 18 . 9 +/- 3 . 1 versus 47 . 0 +/- 4 . 1 ; P < 0 . 001 ) . Pretreatment with nimesulide nullified the infarct size sparing effect of E2 ( 55 . 8 +/- 5 . 6 ) . Treatment with the P43119 antagonist RO3244794 also abolished the protective effects of E2 ( 45 . 3 +/- 4 . 5 ) . The results indicate that estrogen protects the myocardium from ischemia - reperfusion injury through increased production of P35354 - derived DB01240 . The data indicate that selective P35354 inhibitors might counteract the potential cytoprotective effects of estrogen in premenopausal or postmenopausal women .","Altered expression of inflammation - related genes in human carotid atherosclerotic plaques . OBJECTIVE : Inflammation is a pivotal process in atherosclerosis development and progression , but the underlying molecular mechanisms remain largely obscure . We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis . METHODS : We studied 11 human carotid plaques , their respective adjacent regions and 7 control arteries from different subjects . Expression of 92 genes was studied by TaqMan low - density array human inflammation panel . Human aortic endothelial and smooth muscle cells were used for in vitro experiments . RESULTS : The mRNA levels of 44 / 92 genes ( 48 % ) differed significantly between the tissues examined ( 13 up - regulated and 31 down - regulated ) . Dysregulated genes encode molecules belonging to different functional classes although most of them encode enzymes involved in the eicosanoid synthesis pathway . The expression of Q16647 and P43119 genes was decreased in human aortic endothelial and smooth muscle cells stimulated with oxLDL and P01375 - α . CONCLUSIONS : This study not only reveals several dysregulated genes in human lesions but also focuses the role played by the genes involved in the eicosanoid synthesis pathway during atherosclerotic development . The decrease of Q16647 and P43119 expression after oxLDL treatment mirrors the decreased mRNA levels in atherosclerotic lesions versus control arteries , which suggests that oxidation is important for Q16647 and P43119 regulation in human vessel cells during atherosclerosis development .","P15692 expression is augmented by hypoxia ‑ induced PGIS in human fibroblasts . Q16647 ( PGIS or Q16647 ) is an enzyme that catalyses the conversion of prostaglandin H2 ( PGH2 ) to prostaglandin I2 ( DB01240 ) . DB01240 promotes cancer growth by activating peroxisome proliferator - activated receptor δ ( PPARδ ) , and increases the expression levels of the pro - angiogenic factor vascular endothelial growth factor ( P15692 ) . We found that the expression of the PGIS gene was enhanced in WI - 38 , TIG - 3 - 20 and HEL human lung fibroblast cells and two cancer cell lines ( NB - 1 and G361 ) under hypoxic conditions . The main localization of PGIS changed from the cytoplasm to the nucleus by hypoxia in WI - 38 cells . The induced PGIS had an enzymatic activity since the intracellular level of 6 - keto - prostaglandin , a useful marker of DB01240 biosynthesis in vivo , was increased with the increasing levels of PGIS . Expression of P15692 was increased in parallel with PGIS induction under hypoxic conditions . PGIS knockdown resulted in the decreased expression of P15692 mRNA . Since P15692 is a known PPARδ target gene , we examined the effects of siRNAs targeting PPARδ on the expression of P15692 under hypoxic conditions . Knockdown of PPARδ suppressed the expression of P15692 under hypoxic conditions in WI - 38 cells . These findings suggest that PGIS is induced by hypoxia and regulates the expression of P15692 in fibroblasts . Fibroblasts in the hypoxic area of tumors may have an important role in tumor growth and angiogenesis .","Developmental regulation of prostacyclin synthase and prostacyclin receptors in the ovine uterus and conceptus during the peri - implantation period . This study documents the expression of prostacyclin ( DB01240 ) synthase ( Q16647 ) and DB01240 receptors in the trophoblast and uterus of the ewe at the time of maternal recognition of pregnancy ( i . e . days 7 , 9 , 12 , 14 and 17 ) . The membrane receptor for DB01240 ( P43119 ) and the nuclear receptors , i . e . peroxisome proliferator - activated receptors ( Q07869 ) and their heterodimer partners the retinoid X receptors ( RXR ) , were analysed . In the endometrium , Q16647 transcript and protein were expressed at day 9 of pregnancy and levels declined from days 12 to 17 . Immunohistochemistry and in situ hybridization indicated that Q16647 was mainly located in the luminal epithelium of the endometrium . Endometrial P43119 , Q07869 , P37231 and P48443 expression was regulated during the peri - implantation period whereas Q03181 , P19793 and P28702 were consistently expressed . In the trophoblast , Q16647 transcript levels rose as development progressed and peaked at day 17 . P43119 and Q07869 transcripts peaked before day 12 and then declined and became nearly undetectable by day 17 , whereas Q03181 and P37231 transcript levels rose steadily from days 12 to 17 . Because the PPARs and the RXRs display different expression profiles , we suggest that different heterodimers may form and support distinct functions as development proceeds . Our results also underline the importance of Q16647 and Q03181 in the trophoblast and P43119 in the uterus , suggesting that DB01240 is of both uterine and trophoblastic origin and is involved in a complex signalling pathway at around the time of implantation in the ewe .","Identification of the prostacyclin receptor by use of [ 15 - 3H1 ] 19 -( 3 - azidophenyl )- 20 - norisocarbacyclin , an irreversible specific photoaffinity probe . The prostaglandin I ( DB01240 ) receptor of mouse mastocytoma P - 815 cells was characterized by photo - affinity labeling with the stable DB01240 analogue [ 15 - 3H1 ] - 19 -( 3 - azidophenyl )- 20 - norisocarbacyclin ( [ 3H ] APNIC ) used as a potential photoaffinity probe for the receptor . [ 3H ] APNIC bound to the mastocytoma membrane with high affinity and in a saturable manner . Scatchard plot analysis indicated a single binding site with a Kd of 4 . 7 nM and a Bmax of 0 . 58 pmol / mg protein . The binding of [ 3H ] APNIC was dose dependently inhibited by APNIC and iloprost , another stable DB01240 agonist , and to a much lesser extent by DB00917 . The binding of the radioligand showed sensitivity to the guanine nucleotide guanosine 5 '- O -( 3 - thio - triphosphate ) ( GTP gamma S ) . Photolysis of [ 3H ] APNIC - prelabeled membranes resulted in incorporation of radiolabel into a protein of approximately 43 kDa . Photolabeling was inhibited by DB01240 agonists and other prostaglandins with specificity for the P43119 and was modulated by GTP gamma S . A protein of approximately 45 kDa was also labeled by [ 3H ] APNIC in the membrane of porcine platelets , membranes that are known to be abundant in DB01240 receptors . These results demonstrate that [ 3H ] APNIC specifically labels a protein that may represent the P43119 and that this radioprobe will be a useful reagent for further characterization and purification of the P43119 .","Recombinational and physical mapping of the locus for primary open - angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open - angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile - onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA1 / D1S210 and NGA5 loci . These loci are 2 . 8 Mb apart on a 4 . 7 - Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G - band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . Our results provide a basis to identify the Q99972 gene .","Impairment of breast cancer cell invasion by P35354 - specific inhibitor NS398 : roles of P61073 and of uPA system . Inhibition of cyclooxygenase - 2 ( P35354 ) is known to impair cancer cell metastatic behaviour , but the mechanisms involved largely remain elusive . We aimed to analyse whether the antimetastatic effect of P35354 inhibition in breast cancer cells could be explained by variations in the expression levels of chemokine receptor P61073 , vascular endothelium growth factor ( P15692 ) and Q96NZ9 / Q03405 components of the urokinase plasminogen activator system ( Q03405 ) . Breast cancer cell line MDA - MB - 231 was exposed to P35354 - specific inhibitor NS398 . Experimental data were assessed using Matrigel invasion tests , qRT - PCR , ELISA , flow cytometry and MTT test . Exposure to NS398 had no major effect on cell viability , apoptosis or P15692 production . Cell invasion was significantly decreased with reductions ranging from of 3 . 6 % with 10 μM NS398 to 81 . 04 % with 100 μM NS398 . P61073 membrane expression was significantly reduced by 18 % ( P < 0 . 05 ) when cells were treated with 100 μM of NS398 for 72 h . Q96NZ9 mRNA levels were significantly reduced to 78 and 63 % after treatment with 10 μM NS398 for 48 and 72 h , respectively ( P < 0 . 05 ) . Q03405 mRNA levels also decreased with mild NS398 concentrations , reaching the lowest level of 56 % with 50 μM of NS398 for 48 h ( P < 0 . 05 ) . With NS398 higher concentrations , Q03405 and Q96NZ9 expression levels increased . According to our results , impairment of expression of P61073 , Q96NZ9 and Q03405 differentially contribute to the antimetastatic effect of P35354 inhibitors depending on drug concentration .","P43119 induces P42224 and P40763 phosphorylations in human erythroleukemia cells : a mechanism requiring PTX - insensitive G proteins , P29323 and JNK . The ability of the human prostacyclin receptor ( hIP ) to regulate the activities of signal transducers and activators of transcription ( STATs ) has not yet been documented . In the present study , we have delineated the mechanism by which hIP induces P40763 phosphorylations in human erythroleukemia ( HEL ) cells . Stimulation of endogenous hIP by its specific agonist , cicaprost , resulted in P40763 Tyr705 and Ser727 phosphorylations in a time - and concentration - dependent manner . Cicaprost - induced P40763 Tyr705 and Ser727 phosphorylations were resistant to pertussis toxin ( PTX ) treatment , suggesting that these responses were mediated through PTX - insensitive G proteins . In addition , extracellular signal - regulated kinase ( P29323 ) and c - Jun N - terminal kinase ( JNK ) , but not p38 MAPK , were shown to be phosphorylated by cicaprost in a time - and concentration - dependent manner via PTX - insensitive G proteins . The levels of the interaction between P40763 , P29323 and JNK were enhanced by cicaprost treatment . The involvement of P04049 , Q02750 / 2 and JNK in cicaprost - induced phosphorylations of P40763 was illustrated by the use of their selective inhibitors . In contrast , p38 MAPK did not appear to be required . Similar observations were obtained with P42224 upon stimulation by cicaprost . Taken together , these results demonstrate for the first time that hIP activation by cicaprost can lead to P42224 and P40763 phosphorylations via signaling pathways involving PTX - insensitive G proteins , P29323 and JNK .","[ Moclobemide ( ___MASK35___ ) , the first P21397 - inhibitor : really something new ? ] .","Dehydration activates an NF - kappaB - driven , P35354 - dependent survival mechanism in renal medullary interstitial cells . Renal prostaglandin ( PG ) synthesis is mediated by cyclooxygenase - 1 and - 2 ( P23219 and P35354 ) . After dehydration , the maintenance of normal renal function becomes particularly dependent upon PG synthesis . The present studies were designed to examine the potential link between medullary P23219 and P35354 expression in hypertonic stress . In response to water deprivation , P35354 , but not P23219 , mRNA levels increase significantly in the renal medulla , specifically in renal medullary interstitial cells ( RMICs ) . DB09145 deprivation also increases renal NF - kappaB - driven reporter expression in transgenic mice . NF - kappaB activity and P35354 expression could be induced in cultured RMICs with hypertonic sodium chloride and mannitol , but not urea . RMIC P35354 expression was also induced by driving NF - kappaB activation with a constitutively active O15111 alpha ( IKKalpha ) . Conversely , introduction of a dominant - negative IkappaB mutant reduced P35354 expression after hypertonicity or IKKalpha induction . RMICs failed to survive hypertonicity when P35354 was downregulated using a P35354 - selective antisense or blocked with the selective nonsteroidal anti - inflammatory drug ( NSAID ) SC58236 , reagents that did not affect cell survival in isotonic media . In rabbits treated with SC58236 , water deprivation induced apoptosis of medullary interstitial cells in the renal papilla . These results demonstrate that water deprivation and hypertonicity activate NF - kappaB . The consequent increase in P35354 expression favors RMIC survival in hypertonic conditions . Inhibition of RMIC P35354 could contribute to NSAID - induced papillary injury .","DB05229 sodium , a stable prostacyclin analogue , elicits dilation of isolated porcine retinal arterioles : roles of P29474 and potassium channels . PURPOSE : DB01240 ( DB01240 ) is usually described as an endoEDRFsthelium - derived relaxing factor , but the vasoreactivity to DB01240 in the retinal arterioles and the underlying mechanisms are not fully understood . We examined the effects of DB01240 on the retinal microcirculation using beraprost sodium ( BPS ) , a stable DB01240 analogue , and the signaling mechanisms involved in this vasomotor activity . METHODS : Porcine retinal arterioles were isolated , cannulated , and pressurized without flow in vitro . Video microscopic techniques recorded the diametric responses to BPS . RESULTS : DB05229 sodium elicited dose - dependent ( 0 . 1 pM - 0 . 1 μM ) vasodilation of the retinal arterioles that was abolished by the P43119 ( IP ) antagonist CAY10441 . DB05229 sodium - induced vasodilation decreased by 50 % after the endothelium was removed and was inhibited by the nitric oxide ( NO ) synthase inhibitor N ( G )- nitro - L - arginine methyl ester ( L - NAME ) comparable with denudation . Inhibition of soluble guanylyl cyclase by 1H - 1 , 2 , 4 - oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) and blockage of protein kinase A ( PKA ) by Rp - 8 - Br - cAMPS were comparable to L - NAME . DB05229 sodium - induced vasodilation was also inhibited by the nonselective potassium channel inhibitor , tetraethylammonium , and the adenosine triphosphate - sensitive potassium ( KATP ) channel blocker , glibenclamide . Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ . CONCLUSIONS : DB05229 sodium , a stable DB01240 analogue , causes vasodilation of the retinal arterioles mediated via the IP receptor . The current findings suggest that BPS elicits endothelium - dependent and - independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle , respectively .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","Identification of antithrombin - modulating genes . Role of O95461 , a gene encoding a bifunctional glycosyltransferase , in the secretion of proteins ? The haemostatic relevance of antithrombin together with the low genetic variability of P01008 , and the high heritability of plasma levels encourage the search for modulating genes . We used a hypothesis - free approach to identify these genes , evaluating associations between plasma antithrombin and 307 , 984 polymorphisms in the GAIT study ( 352 individuals from 21 Spanish families ) . Despite no SNP reaching the genome wide significance threshold , we verified milder positive associations in 307 blood donors from a different cohort . This validation study suggested O95461 , a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin - like linear polysaccharides , as a potential modulator of antithrombin based on the significant association of one SNPs , rs762057 , with anti - FXa activity , particularly after adjustment for age , sex and P01008 rs2227589 genotype , all factors influencing antithrombin levels ( p = 0 . 02 ) . Additional results sustained this association . O95461 silencing inHepG2 and P29320 - EBNA cells did not affect P01008 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention . Milder effects were observed on α1 - antitrypsin , prothrombin and transferrin . Our study suggests O95461 as the first known modifier of plasma antithrombin , and proposes a new role for O95461 in modulating extracellular secretion of certain glycoproteins .","___MASK100___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .","A surface plasmon resonance - based solution affinity assay for heparan sulfate - binding proteins . A surface plasmon resonance - based solution affinity assay is described for measuring the K ( d ) of binding of heparin / heparan sulfate - binding proteins with a variety of ligands . The assay involves the passage of a pre - equilibrated solution of protein and ligand over a sensor chip onto which heparin has been immobilised . DB01109 sensor chips prepared by four different methods , including biotin - streptavidin affinity capture and direct covalent attachment to the chip surface , were successfully used in the assay and gave similar K ( d ) values . The assay is applicable to a wide variety of heparin / HS - binding proteins of diverse structure and function ( e . g . , P05230 , P09038 , P15692 , P10145 , P80075 , P01008 , P02776 ) and to ligands of varying molecular weight and degree of sulfation ( e . g . , heparin , DB05808 , sucrose octasulfate , naphthalene trisulfonate ) and is thus well suited for the rapid screening of ligands in drug discovery applications .","Hypoxia - inducible vascular endothelial growth factor gene therapy using the oxygen - dependent degradation domain in myocardial ischemia . PURPOSE : A hypoxia - inducible P15692 expression system with the oxygen - dependent degradation ( Q8TAX0 ) domain was constructed and tested to be used in gene therapy for ischemic myocardial disease . METHODS : Luciferase and P15692 expression vector systems were constructed with or without the Q8TAX0 domain : pEpo - SV - Luc ( or pEpo - SV - P15692 ) and pEpo - SV - Luc - Q8TAX0 ( or pEpo - SV - P15692 - Q8TAX0 ) . In vitro gene expression efficiency of each vector type was evaluated in P29320 293 cells under both hypoxic and normoxic conditions . The amount of P15692 protein was estimated by ELISA . The P15692 expression vectors with or without the Q8TAX0 domain were injected into ischemic rat myocardium . Fibrosis , neovascularization , and cardiomyocyte apoptosis were assessed using Masson ' s trichrome staining , α - smooth muscle actin ( α - SMA ) immunostaining , and the TUNEL assay , respectively . RESULTS : The plasmid vectors containing Q8TAX0 significantly improved the expression level of P15692 protein in hypoxic conditions . The enhancement of P15692 protein production was attributed to increased protein stability due to oxygen deficiency . In a rat model of myocardial ischemia , the pEpo - SV - P15692 - Q8TAX0 group exhibited less myocardial fibrosis , higher microvessel density , and less cardiomyocyte apoptosis compared to the control groups ( saline and pEpo - SV - P15692 treatments ) . CONCLUSION : An Q8TAX0 - mediated P15692 expression system that facilitates P15692 - production under hypoxia may be useful in the treatment of ischemic heart disease .","___MASK6___ block of cloned human T - type voltage - gated calcium channels . ___MASK6___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .","Evidence for distinct prostaglandin I2 and D2 receptors in human platelets . Incubation of human platelet - rich plasma with prostaglandin I2 ( DB01240 ) , results in a marked increase in adenosine 3 ': 5 '- monophosphate ( DB02527 ) that persists for at least 60 min . The persistent stimulation of DB02527 levels by DB01240 can be rapidly reversed by the addition of either prostaglandin E1 or E2 ( PGE1 , DB00917 ) , but not by prostaglandin D2 ( PGD2 ) . Studies of agonist - specific desensitization of DB02527 accumulation show that PGE1 or DB00917 can desensitize for subsequent PGE or DB01240 activation , and that subthreshold levels of DB01240 desensitize for subsequent PGE1 stimulation . PGD2 desensitizes for consequent PGD2 activation , but not for PGE1 , DB00917 or DB01240 , and PGE compounds and DB01240 do not desensitize for subsequent PGD2 activation . Agonist - specific desensitization for DB01240 is not dependent on DB02527 accumulation , but appears to be a consequence of receptor occupation . Support of the desensitization experiments was obtained through the use of the prostaglandin antagonist N - 0164 [ sodium - p - benzyl - 4 -[- oxo - 2 -( 4 - chlorobenzyl )- 3 - phenyl - propyl ] phenyl phosphonate ) . This compound proved to be a potent antagonist of PGD2 and a weak antagonist of DB01240 - stimulated DB02527 accumulation . These data indicate that human platelets have distinct pharmacological receptors for both DB01240 and PGD2 , and that PGE compounds may actually interact with a P43119 .","DB01088 has potent anti - inflammatory properties on human monocyte - derived dendritic cells . BACKGROUND : The stable prostaglandin I2 analogue ( iloprost ) iloprost has been shown to inhibit allergic airway inflammation in mice by modulating the function of myeloid dendritic cells ( DCs ) . OBJECTIVE : The aim of the current study was to investigate the biological activity of iloprost on human monocyte - derived DCs . METHODS : I prostanoid ( IP ) receptor expression was analysed by RT - PCR . Cytokine secretion by DCs and P01730 + T cells was measured by ELISA . The expression of the transcription factor FoxP3 after co - culture of DCs with P01730 + CD45RA + T cells was analysed by flow cytometry . RESULTS : Human monocyte - derived DCs were found to express mRNA specific for the P43119 IP , and stimulation with iloprost resulted in increased cyclic AMP levels in both immature DCs ( iDCs ) and mature DCs ( mDCs ) . Moreover , iloprost dose dependently inhibited the secretion of P01375 , P05231 , P10145 and IL - 12p70 in mDCs , while it enhanced P22301 production . Changes in cytokine secretion were paralleled by an altered T - cell priming capacity of DCs : in co - culture experiments of iloprost - treated mDC and naïve CD45RA + T cells , an induction of regulatory T cells could be observed , as demonstrated by increased intracellular FoxP3 expression and P22301 production . Additionally , iloprost inhibited the MIP - 3beta - induced migration of mDCs . CONCLUSION : In summary , our results provide evidence that iloprost profoundly affects the function of human myeloid DCs . Therefore , iloprost might also be a new therapeutical option for the treatment of asthma in humans .","Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK37___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .","DB01240 ( P06744 ) receptor binding and cyclic AMP synthesis activities of PGI1 analogues , SM - 10906 and its methyl ester , SM - 10902 , in mastocytoma P - 815 cells . The prostacyclin I1 ( PGI1 ) analogue , SM - 10906 and its methyl ester , SM - 10902 , have been compared with the DB01240 analogue , iloprost , with respect to binding to the P43119 , stimulation of adenylate cyclase activity and inhibition of thrombin - induced Ca2 + mobilization in mastocytoma P - 815 cells . SM - 10906 displaced [ 3H ] iloprost binding to the membrane fraction , the IC50 value being 100 nM , but showed very low affinity for the prostaglandin E ( PGE ) receptor . SM - 10906 dose - dependently stimulated GTP - dependent adenylate cyclase activity in the membrane fraction , the EC50 value being 35 nM . Furthermore , SM - 10906 prevented a thrombin - induced increase in the intracellular Ca2 + concentration , the IC50 value being 300 nM . These IC50 and EC50 values are much lower than those of SM - 10902 . These results demonstrate that SM - 10906 , a stable PGI1 derivative , is an agonist for the [ 3H ] iloprost - binding ( DB01240 ) receptor , and that it prevents thrombin - induced Ca2 + mobilization through stimulation of the adenylate cyclase system in mastocytoma cells . On the other hand , a methyl ester derivative of PGI1 , SM - 10902 , was inactive in the binding assay , but it seems to be a partial agonist for adenylate cyclase activity [ corrected ] .","___MASK15___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .","A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK71___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .","Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK34___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK34___ who were treated with a single dose of mifepristone .","A lung - specific neo - antigen elicits specific CD8 + T cell tolerance with preserved P01730 + T cell reactivity . Implications for immune - mediated lung disease . The A / Japan / 57 influenza hemagglutinin ( HA ) was expressed in BALB / c mice under the transcriptional control of the surfactant protein C ( P11686 ) promoter , resulting in expression of HA in type II alveolar epithelial cells , as well as low level variable expression in other tissues , including the thymus in some of the founder lines . Transgenic animals were able to recover from infection with A / Japan / 57 influenza , and they were able to mount antibody responses to A / Japan / 57 HA in titers similar to wild type . We therefore tested their P01730 + T lymphocyte responses to HA and found them to be similar to wild type responses . However , CD8 + T cells from A / Japan / 57 - infected transgenic animals were unable to express cytolytic activity against target cells expressing the A / Japan / 57 HA . The CD8 + T cell tolerance was also extremely specific , since transgenics immunized with an influenza strain containing a single amino acid substitution in a dominant HA epitope were able to mount full cytolytic responses to that epitope , but not the wild - type epitope . Adoptive transfer of CD8 + T cell clones into transgenic animals resulted extensive interstitial pneumonitis that was antigen - specific and associated with significant morbidity and mortality . We conclude that a lung - specific transgene may lead to specific CD8 + T cell tolerance , with P01730 + T cell and B cell reactivity to the antigen , and that P01730 + T cell reactivity may remain intact to an antigen expressed in the thymus , even when CD8 + T cell tolerance exists . This observation may have profound implications concerning immune - mediated lung diseases , particularly those mediated by P01730 + T cells .","Surfactin exhibits neuroprotective effects by inhibiting amyloid β - mediated microglial activation . Microglial - mediated neuroinflammation and neurotoxicity contribute to the pathogenesis of neurodegenerative diseases including Alzheimer ' s disease ; therefore , control of microglial activation and subsequent suppression of neurotoxic pro - inflammatory molecules could provide a potential therapeutic approach for the treatment of such diseases . In this study , we investigated the effects of surfactin , a surfactant from Bacillus subtilis , on oligomeric amyloid β ( Aβ ) - induced microglial activation and neurotoxicity . Surfactin significantly suppressed expression of P14780 , P35228 and P35354 , as well as production of ROS , NO , DB00917 , P01375 - α , IL - 1β , P05231 and P13500 in Aβ - stimulated BV - 2 microglial cells . Moreover , surfactin markedly inhibited Aβ - induced nuclear translocation and activation of NF - κB as well as phosphorylation of JNK and p38 MAPK . Furthermore , surfactin protected hippocampal HT22 cells from indirect neuronal toxicity mediated by Aβ - treated microglial cells , but had no effect on Aβ - induced direct toxicity to HT22 cells . These results suggest that surfactin impairs the Aβ - induced inflammatory response of microglial cells and confers protection against indirect neurotoxicity to hippocampal cells . Our findings indicate that surfactin may have therapeutic potential for ameliorating Alzheimer ' s disease as well as other neurodegenerative disorders which involve neuroinflammation .","High - dose aspirin in dogs increases vascular resistance with limited additional anti - platelet effect when combined with potent Q9H244 inhibition . INTRODUCTION : With the arrival of the potent Q9H244 antagonists , ticagrelor and prasugrel , the need for co - treatment with aspirin in acute coronary syndromes must be re - examined . This study assessed whether high - dose aspirin : a ) provides additional anti - platelet efficacy , assessed in vivo and ex vivo , when combined with Q9H244 inhibition ; and / or b ) has a negative effect on vascular function . MATERIALS AND METHODS : Using an anaesthetized dog model of thrombosis , the effects of aspirin ( 50mg / kg ) in addition to clopidogrel and ticagrelor were evaluated at two levels of Q9H244 inhibition , maximal ( ≥ 96 % ) and sub - maximal ( ~ 80 % ) , as assessed by ex vivo ADP - induced whole blood impedence aggregometry . RESULTS : In the absence of aspirin , maximal and sub - maximal Q9H244 inhibition inhibited arachidonic acid - induced platelet aggregation by approximately 80 % and 24 % , respectively , without affecting platelet TXA2 formation . During maximal Q9H244 inhibition , aspirin provided less additional inhibition of ex vivo arachidonic acid - and collagen - induced platelet aggregation , as compared with sub - maximal Q9H244 inhibition , without additional anti - thrombotic effect in vivo . DB00945 significantly decreased in vivo DB01240 production ( 27 % ) and increased vascular resistance ( 16 % ) , independently of Q9H244 antagonism . CONCLUSION : In the dog , Q9H244 antagonists inhibit TXA2 - mediated platelet - aggregation independently of aspirin . DB00945 provides less additional anti - platelet effects during maximal compared with sub - maximal Q9H244 inhibition but increases vascular resistance .","Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40 - fold ) in high - responding opossums , but moderately elevated ( 6 - fold ) in low - responding opossums after they had consumed a high - cholesterol and high - fat diet for 24 wk . In both high - and low - responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2 - fold ) , esterified cholesterol ( 11 - fold ) , and triglycerides ( 2 - fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 gene and downregulation of the Q02318 , Q9H221 , and P21439 genes . Genes involved in inflammation ( P01375 , P19838 , and P35354 ) and in oxidative stress ( P13498 and P14598 ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 ) and collagen genes ( Col1A1 , Col3A1 , and Col4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high - responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis .","Differential activation of Gi and Gs proteins by E - and I - type prostaglandins in membranes from the human erythroleukaemia cell line , HEL . The group of prostaglandin ( PG ) E2 - and prostacyclin receptors consists of different subtypes , which exhibit different affinities for prostaglandins and synthetic analogues . DB00917 activities the E - type PG receptor subtypes EP1 , EP2 and EP3 , whereas the DB00917 analogue , sulprostone , binds only to the EP1 and EP3 receptor subtypes . The stable DB01240 analogues , iloprost and cicaprost , both activate the P43119 ( IP ) and iloprost , additionally , bind to the EP1 subtype . Using these subtype - selective PG receptor agonists , we studied the interaction of PG receptor subtypes with Gs and Gi - type heterotrimeric guanine nucleotide - binding proteins ( G proteins ) in membranes from the human erythroleukaemia cell line , HEL . Sulprostone stimulated high - affinity GTPase in HEL membranes in a pertussis toxin ( PTX ) - sensitive manner . In contrast , the stimulations induced by DB00917 , iloprost and cicaprost were only partially inhibited by PTX . DB00917 , sulprostone , iloprost and cicaprost stimulated cholera toxin - catalysed ADP - ribosylation as well as labelling with GTP azidoanilide of membrane proteins comigrating with immunologically identified Gi protein alpha subunits . Furthermore , DB00917 , iloprost and cicaprost enhanced GTP azidoanilide - labelling of Gs protein alpha subunits , whereas sulprostone did not . We suggest that in HEL cells ( 1 ) EP1 and EP3 receptor subtypes activate P55008 proteins , that ( 2 ) the EP2 receptor subtype activates Gs proteins and that ( 3 ) the IP receptor activates both Gi and Gs proteins .","Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .","___MASK71___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .","Altered expression of beta - catenin , P12830 , cycloxygenase - 2 , and p53 protein by ovine intestinal adenocarcinoma cells . Around 1 . 6 % of sheep in New Zealand develop small - intestinal adenocarcinomas . These neoplasms typically develop widespread metastases . The common development of these neoplasms and their subsequent behavior suggests that sheep could be a useful animal model of human colonic cancer . However , for an animal model of human disease to be relevant , similar genetic mutations should be present . Genetic mutations within human colonic cancers frequently result in expression of cycloxygenase - 2 ( P35354 ) , loss of membranous expression of beta - catenin and P12830 , and accumulation of p53 protein within the neoplastic cells . Immunohistochemistry was used to investigate the presence of these 4 proteins within 26 ovine intestinal adenocarcinomas . Loss of membranous beta - catenin reactivity was observed in 14 of 26 ovine intestinal adenocarcinomas ( 54 % ) . The loss of membranous beta - catenin reactivity was accompanied by cytoplasmic and nuclear reactivity in 2 neoplasms . Loss of P12830 was observed within 8 of 26 neoplasms ( 31 % ) . Neoplastic cell expression of P35354 was observed in 12 of 26 neoplasms ( 46 % ) , whereas cells within 3 of 26 neoplasms ( 11 % ) contained visible p53 protein . In conclusion , all 4 proteins that commonly have altered expression in human colonic cancers were also altered in a proportion of the ovine intestinal adenocarcinomas . These results provide additional evidence that sheep could be useful for the study of human colonic cancer .","P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .","DB01240 - deficient mice develop ischemic renal disorders , including nephrosclerosis and renal infarction . BACKGROUND : DB01240 ( DB01240 ) is a short - lived endogenous inhibitor of platelet aggregation and a potent vasodilator and regulator of the growth of vascular smooth muscle cells . To study the role of DB01240 in the vascular system in vivo , DB01240 - deficient ( PGID ) mice were established by genetic disruption of the DB01240 synthase gene . METHODS AND RESULTS : DB01240 synthase - null mice were generated by replacing the exons of DB01240 synthase gene that encodes for the catalytic site of the enzyme with a neomycin resistance gene . In these mice , DB01240 levels in the plasma , kidneys , and lungs were reduced , whereas thromboxane and prostaglandin E2 levels became elevated . Blood pressure and the amounts of urea nitrogen and creatinine in plasma of the PGID mice were significantly higher than those of wild - type mice ( P < 0 . 05 ) . They developed progressive morphological abnormalities in the kidneys , accompanied by atrophy , surface irregularity , fibrosis , cyst , arterial sclerosis , and hypertrophy of vessel walls . Thickening of the thoracic aortic media and adventitia were observed in aged PGID mice . Importantly , these phenotypes have not been reported in P43119 - deficient mice . CONCLUSIONS : DB01240 deficiency resulted in the development of vascular disorders with the thickening of vascular walls and interstitial fibrosis , especially in mouse kidneys . The findings demonstrated in vivo that DB01240 is important in the homeostasis of blood vessels . Our established PGID mice are useful for studies on the initiation and development of vascular diseases , such as ischemic renal disorders with arterial sclerosis and infarction , and also for studies on the novel signaling pathway of DB01240 .","DB01240 - IP signaling and prostaglandin E2 - EP2 / EP4 signaling both mediate joint inflammation in mouse collagen - induced arthritis . Prostaglandin ( PG ) I2 ( prostacyclin [ P06744 ] ) and DB00917 are abundantly present in the synovial fluid of rheumatoid arthritis ( RA ) patients . Although the role of DB00917 in RA has been well studied , how much DB01240 contributes to RA is little known . To examine this issue , we backcrossed mice lacking the P43119 ( IP ) to the DBA / 1J strain and subjected them to collagen - induced arthritis ( CIA ) . IP - deficient ( IP -/- ) mice exhibited significant reduction in arthritic scores compared with wild - type ( WT ) mice , despite anti - collagen antibody production and complement activation similar to WT mice . IP -/- mice also showed significant reduction in contents of proinflammatory cytokines , such as interleukin ( IL ) - 6 in arthritic paws . Consistently , the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced P05231 production and induced expression of other arthritis - related genes . On the other hand , loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA . However , a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4 . Our results show significant roles of both DB01240 - IP and DB00917 - EP2 / EP4 signaling in the development of CIA , and suggest that inhibition of DB00917 synthesis alone may not be sufficient for suppression of RA symptoms .","___MASK91___ induces Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells promoting a new immunoregulatory pathway . Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells ( DCs ) may cause anergy in P01730 (+) CD45RO (+) CD25 (+) T cells transforming them into regulatory T cells ( Tregs ) . Here , we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients . Forty renal transplant patients with biopsy - proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction . At conversion and 2 years thereafter , we measured the rapamycin effects on circulating DCs ( BDCA1 / Q8WTT0 and Q8NHJ6 / Q8N423 expression ) , P01730 (+)/ CD25 ( high )/ Foxp3 (+) Tregs , CD8 (+)/ P10747 (-) T cells , and the Th1 / Th2 balance in graft biopsies . In rapamycin - treated patients , peripheral Q8WTT0 (+) cells were significantly increased along with Q8NHJ6 / Q8N423 (+) DCs . The number of circulating P01730 (+)/ CD25 ( high )/ Foxp3 (+)/ P16410 (+) Tregs , CD8 (+) P10747 (-) T cells , and P17693 serum levels were higher in the rapamycin - treated group . The number of Q8NHJ6 / Q8N423 (+) Q8WTT0 (+) DC was directly and significantly correlated with circulating Tregs and CD8 (+) P10747 (-) T cells . Q8NHJ6 / Q8N423 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin - treated patients . Thus , rapamycin induces the upregulation of Q8NHJ6 and Q8N423 on the DC surface , and this effect is associated with an increase in the number of Tregs and expansion of the CD8 (+) P10747 (-) T cell population . This suggests that P42345 inhibition may promote a novel immunoregulatory pathway .","Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP . Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the renin - angiotensin - aldosterone system ; however , the sensing mechanism remains elusive . Here we investigated the role of DB01240 in renovascular hypertension in vivo , employing mice lacking the P43119 ( IP -/- mice ) . In WT mice with a two - kidney , one - clip model of renovascular hypertension , the BP was significantly elevated . The increase in BP in IP -/- mice , however , was significantly lower than that in WT mice . Similarly , the increases in plasma renin activity , renal renin mRNA , and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP -/- mice than in WT mice . All these parameters were measured in mice lacking the four DB00917 receptor subtypes individually , and we found that these mice had similar responses to WT mice . DB01240 is produced by P35354 and a selective inhibitor of this enzyme , SC - 58125 , also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis , but these effects were absent in IP -/- mice . When the renin - angiotensin - aldosterone system was activated by salt depletion , SC - 58125 blunted the response in WT mice but not in IP -/- mice . These results indicate that DB01240 derived from P35354 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo .","DB00184 induces cell proliferation , invasion and epithelial - mesenchymal transition in a variety of human cancer cell lines . Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer ( NSCLC ) . DB00184 , an active component of cigarettes , has been found to induce proliferation of lung cancer cell lines . In addition , nicotine can induce angiogenesis and confer resistance to apoptosis . All these events are mediated through the nicotinic acetylcholine receptors ( nAChRs ) on lung cancer cells . In this study , we demonstrate that nicotine can promote anchorage - independent growth in NSCLCs . In addition , nicotine also induces morphological changes characteristic of a migratory , invasive phenotype in NSCLCs on collagen gel . These morphological changes were similar to those induced by the promigratory growth factor P15692 . The proinvasive effects of nicotine were mediated by alpha7 - nAChRs on NSCLCs . RT - PCR analysis showed that the alpha7 - nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines . DB00184 was found to promote proliferation and invasion in human breast cancer . The proinvasive effects of nicotine were mediated via a nAChR , Src and calcium - dependent signaling pathway in breast cancer cells . In a similar fashion , nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells . Most importantly , nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition ( EMT ) , characterized by reduction of epithelial markers like P12830 expression , ZO - 1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells . Therefore , it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers .","P35354 - derived prostacyclin modulates vascular remodeling . Suppression of prostacyclin ( DB01240 ) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase ( P36551 ) - 2 inhibitors . Herein , we examine if P35354 - derived DB01240 might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity . Deletion of the P43119 ( IP ) or suppression of DB01240 with the selective P35354 inhibitor , nimesulide , both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow - induced vascular remodeling . Moreover , nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild - type mice . Generation of both thromboxane ( Tx ) A2 and the isoprostane , 8 , 12 - iso iPF ( 2alpha )- VI , are increased in the setting of flow reduction and the latter increases further on administration of nimesulide . Deletion of the TxA2 receptor ( TP ) reduces the hyperplastic response to nimesulide and carotid ligation , despite further augmentation of TP ligand production . Suppression of P35354 - derived DB01240 or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress . Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of P35354 .","Effect of prostaglandins and thromboxane A2 on the contractility of rabbit splenic capsular smooth muscle . The effect of various prostaglandins ( PGs ) and a thromboxane A2 ( TXA2 ) - generating system on the contractility of rabbit splenic capsular smooth muscle has been investigated . DB01240 as well as higher concentrations of PGE1 and 5 , 6 beta - dihydro - DB01240 inhibit noradrenaline - induced contractions of the smooth muscle preparation . The TXA2 - generating system and high concentrations of PGD2 , on the other hand , increase the contractions . The results support the concept that the hypothetical P43119 on the smooth muscle of the rabbit splenic capsule resembles , in its specificity , the P43119 on platelets ."],"string":"[\n \"The anticoagulant effect of PGI2S and tPA in transgenic umbilical vein endothelial cells is linked to up - regulation of PKA and PKC . The selection of vascular grafts for coronary artery bypass surgery is crucial for a positive outcome . This study aimed to establish a novel line of vascular endothelial cells with a potent anticoagulant effect . A lentiviral vector was used to stably transfect human umbilical vein endothelial cells ( HUVECs ) with PGI2S alone ( HUVEC - PGI2S ) or both PGI2S and tPA ( HUVEC - PGI2S - tPA ) . Both HUVEC - PGI2S and HUVEC - PGI2S - tPA cells over - expressing PGI2S and tPA were compared to mock - transfected cells . The enzyme - linked immuno sorbent assay ( ELISAs ) demonstrated that the anticoagulation components , P01008 and P00747 , were up - regulated and coagulation factor FVIII was down - regulated in both cell lines . QRT - PCR and western blotting demonstrated the vasodilation and platelet disaggregation proteins PKA , PKC , and P43119 were up - regulated in both cell lines , but MAPK expression was not altered in either cell line . However , cell viability and colony formation assays and cell cycle analysis demonstrated that both cell lines had a lower rate of cell growth and induced P55008 phase arrest . HUVEC - PGI2S and HUVEC - PGI2S - tPA cells have a potent anticoagulant effect and their use in vascular heterografts may decrease the risk of thrombosis .\",\n \"Inhibition of myoblast migration by prostacyclin is associated with enhanced cell fusion . Satellite cells are stem cells that are critical for the formation and growth of skeletal muscle during myogenesis . To differentiate and fuse , proliferating satellite cells or myoblasts must migrate and establish stable cell - cell contacts . However , the factors that regulate myoblast migration and fusion are not understood completely . We have identified DB01240 as a novel regulator of myogenesis in vitro . DB01240 is a member of the family of prostaglandins ( PG ) , autocrine / paracrine signaling molecules synthesized via the cyclooxygenase - 1 and - 2 pathways . Primary mouse muscle cells both secrete DB01240 and express the P43119 , IP , at various stages of myogenesis . Using genetic and pharmacological approaches , we show that DB01240 is a negative regulator of myoblast migration that also enhances cell fusion . Thus , DB01240 may act as a \\\" brake \\\" on migrating cells to facilitate cell - cell contact and fusion . Together , our results highlight the importance of the balance between positive and negative regulators in cell migration and myogenesis . This work may have implications for migration of other populations of adult stem cells and / or cells that undergo fusion .\",\n \"Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats . OBJECTIVE : The aim of this study was to evaluate the possible role of prostacyclin ( DB01240 ) in the pathogenesis of hypertension in spontaneously hypertensive rats ( SHR ) . METHODS : Measurement of mRNA and protein levels of PGH synthase ( PGHS ) - 1 , DB01240 synthase and the P43119 , in the thoracic aorta was performed in SHR aged 5 , 10 , 20 , and 40 weeks old and in age - matched normotensive Wistar - Kyoto ( WKY ) rats with a competitive polymerase chain reaction method and immunoblotting . Aortic production of 6 - keto - PGF1 alpha , the main metabolite of DB01240 , was also measured . RESULTS : Compared with age - matched WKY rats , P23219 mRNA and protein levels in the thoracic aorta of SHR increased with age , reaching three - and twofold higher than WKY rats at 40 weeks old , respectively . DB01240 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old . In contrast , P43119 mRNA levels in SHR were consistently lower than in WKY rats at all ages . CONCLUSIONS : These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites , including PGH2 and DB01240 . They also suggest that the decreased expression of P43119 mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR .\",\n \"The ' allosteric modulator ' P35240 - 202676 disrupts G protein - coupled receptor function via sulphydryl - sensitive mechanisms . 1 . Previous studies suggest that the thiadiazole compound P35240 - 202676 ( N -( 2 , 3 - diphenyl - 1 , 2 , 4 - thiadiazol - 5 -( 2H )- ylidene ) methanamine ) acts as an allosteric modulator of a variety of structurally distinct G protein - coupled receptors ( GPCRs ) . It was postulated that P35240 - 202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family . The molecular mechanisms of such a promiscuous action , however , remain obscure . 2 . To clarify the mechanism of P35240 - 202676 action , we used the functional approach of [ 35S ] GTPgammaS autoradiography with rat brain cryostat sections together with classical membrane [ 35S ] GTPgammaS binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi - family of G proteins . 3 . We found that in the absence of dithiotreitol ( DTT ) , P35240 - 202676 ( 10 (- 7 )- 10 (- 5 ) M ) elicits nonspecific effects in the [ 35S ] GTPgammaS - based G protein activation assays , thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor - mediated G protein activity . Such a nonspecific behaviour was fully reversed upon addition of DTT ( 1 mM ) , revealing thiol - based mechanism of action . 4 . In routine incubations containing DTT , P35240 - 202676 had no effect on receptor - driven G protein activity , as assessed for adenosine A1 , alpha2 - adrenergic , cannabinoid P21554 , lysophosphatidic acid Q92633 , muscarinic M2 / M4 , purinergic Q9H244 or sphingosine 1 - phosphate receptors , suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function . 5 . 1H NMR analysis indicated that P35240 - 202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue . 6 . We conclude that P35240 - 202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms .\",\n \"Thiazolidinedione drugs down - regulate P61073 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor gamma - dependent manner . Peroxisome proliferator activated receptor ( Q07869 ) gamma is a nuclear receptor involved primarily in lipid and glucose metabolism . PPARgamma is also expressed in several cancer types , and has been suggested to play a role in tumor progression . PPARgamma agonists have been shown to reduce the growth of colorectal carcinoma cells in culture and in xenograft models . Furthermore , the PPARgamma agonist thiazolidinedione has been shown to reduce metastasis in a murine model of rectal cancer . Since the chemokine receptor P61073 has emerged as an important player in tumorigenesis , particularly in the process of metastasis , we sought to determine if PPARgamma agonists might act in part by reducing P61073 expression . We found that rosiglitazone , a thiazolidinedione PPARgamma agonist used primarily in the treatment of type 2 diabetes , significantly reduced cell - surface expression of P61073 protein on HT - 29 human colorectal carcinoma cells . This effect occurred at concentrations as low as 1 nM , and was first evident after 8 h of drug exposure . P61073 mRNA was also down - regulated after treatment with rosiglitazone , indicating that the effect occurs at the level of transcription . Four other thiazolidinedione compounds ( ciglitazone , pioglitazone , troglitazone , and MCC555 ) also significantly reduced P61073 expression . To confirm the involvement of PPARgamma in thiazolidinedione - induced P61073 down - regulation , we used PPARgamma antagonists GW9662 and T0070907 , both of which completely blocked the effect of rosiglitazone on P61073 expression . Furthermore , HT - 29 cells in which PPARgamma expression was reduced using shRNA were less responsive to rosiglitazone . In conclusion , we have shown that thiazolidinedione compounds reduce P61073 mRNA and cell - surface protein expression in a PPARgamma - dependent manner .\",\n \"Activation of a TGF - beta - specific multistep gene expression program in mature macrophages requires glucocorticoid - mediated surface expression of TGF - beta receptor II . Alternatively activated ( M2 ) macrophages regulate steady state - , cancer - , and inflammation - related tissue remodeling . They are induced by Th2 - cytokines and glucocorticoids ( GC ) . The responsiveness of mature macrophages to TGF - beta , a cytokine involved in inflammation , cancer , and atherosclerosis , is currently controversial . Recently , we demonstrated that Q9NRM6 is up - regulated in human monocyte - derived macrophages differentiated in the presence of Th2 cytokines P05112 and TGF - beta1 . In this study , we show that mature human macrophages differentiated in the presence of P05112 , and dexamethasone ( M2 ( P05112 / GC ) ) but not M2 ( P05112 ) responds to TGF - beta1 which induced a gene expression program comprising 111 genes including transcriptional / signaling regulators ( Q02535 and Q08116 ) , immune modulators ( P20292 and Q9NRM6 ) and atherosclerosis - related genes ( P20292 , P41146 , P02654 , P02655 , and P02649 ) . Analysis of molecular mechanism underlying GC / TGF - beta cooperation revealed that surface expression of TGF - betaRII was high in M2 ( GC ) and M2 ( P05112 / GC ) , but absent from M2 ( P05112 ) , whereas the expression of TGF - betaRI / II mRNA , TGF - betaRII total protein , and surface expression of TGF - betaRIII were unchanged . GC dexamethasone was essential for increased surface expression of functional TGF - betaRII because its effect was observed also in combination with P35225 , P09603 , and GM - P04141 . Prolonged Q15796 - mediated signaling observed in TGF - beta1 - treated M2 ( P05112 / GC ) was due to insufficient activity of negative feedback mechanism what can be explained by up - regulation of Q96EB6 , a negative regulator of O15105 , and the retention of TGF - betaRII complex on the cell surface . In summary , mature human M2 macrophages made permissive to TGF - beta by GC - induced surface expression of TGF - betaRII activate in response to TGF - beta1 , a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion .\",\n \"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .\",\n \"P43119 up - regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1 / 2 pathway . DB01240 ( P06744 ) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven - transmembrane G protein - coupled receptor ( IP receptor ) . Recent studies have ascertained a role for prostanoid - receptor signaling in angiogenesis . In this study we examined the temporal - spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes . Quantitative RT - PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle . Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity . Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle . To explore the role of the IP receptor in glandular epithelial cells , we used the Ishikawa endometrial epithelial cell line . Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost ( a P06744 analog ) rapidly activated P27361 / 2 signaling and induced the expression of proangiogenic genes , basic fibroblast growth factor , angiopoietin - 1 , and angiopoietin - 2 , in an epidermal growth factor receptor ( P00533 ) - dependent manner . Furthermore , P00533 colocalized with IP receptor in the glandular epithelial compartment . These data suggest that P06744 - IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the P00533 .\",\n \"Cyclooxygenase inhibition abrogates aeroallergen - induced immune tolerance by suppressing prostaglandin I2 receptor signaling . BACKGROUND : The prevalence of allergic diseases has doubled in developed countries in the past several decades . Cyclooxygenase ( P36551 ) - inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses . However , whether P36551 inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known . OBJECTIVE : To determine the role of the P36551 pathway and prostaglandin I2 ( DB01240 ) signaling through the P43119 ( IP ) in aeroallergen - induced immune tolerance . METHODS : Wild - type ( WT ) BALB / c mice and IP knockout mice were aerosolized with ovalbumin ( OVA ) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA / alum . The P36551 inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase . Two weeks after sensitization , the mice were challenged with OVA aerosols . Mouse bronchoalveolar lavage fluid was harvested for cell counts and TH2 cytokine measurements . RESULTS : WT mice treated with indomethacin had greater numbers of total cells , eosinophils , and lymphocytes , and increased P05113 and P35225 protein expression in BAL fluid compared to vehicle - treated mice . Similarly , IP knockout mice had augmented inflammation and TH2 cytokine responses compared to WT mice . In contrast , the DB01240 analog cicaprost attenuated the anti - tolerance effect of P36551 inhibition . CONCLUSION : P36551 inhibition abrogated immune tolerance by suppressing DB01240 IP signaling , suggesting that DB01240 signaling promotes immune tolerance and that clinical use of P36551 - inhibiting drugs may increase the risk of developing allergic diseases .\",\n \"Microarray analyses of the effects of NF - kappaB or PI3K pathway inhibitors on the LPS - induced gene expression profile in RAW264 . 7 cells : synergistic effects of rapamycin on LPS - induced P14780 - overexpression . Lipopolysaccharide ( LPS ) activates a broad range of signalling pathways including mainly NF - kappaB and the MAPK cascade , but recent evidence suggests that LPS stimulation also activates the PI3K pathway . To unravel the specific roles of both pathways in LPS signalling and gene expression profiling , we investigated the effects of different inhibitors of NF - kappaB ( BAY 11 - 7082 ) , PI3K ( wortmannin and LY294002 ) but also of P42345 ( rapamycin ) , a kinase acting downstream of PI3K / Akt , in LPS - stimulated RAW264 . 7 macrophages , analyzing their effects on the LPS - induced gene expression profile using a low density DNA microarray designed to monitor the expression of pro - inflammatory genes . After statistical and hierarchical cluster analyses , we determined five clusters of genes differentially affected by the four inhibitors used . In the fifth cluster corresponding to genes upregulated by LPS and mainly affected by BAY 11 - 7082 , the gene encoding P14780 displayed a particular expression profile , since rapamycin drastically enhanced the LPS - induced upregulation at both the mRNA and protein levels . ___MASK91___ also enhanced the LPS - induced NF - kappaB transactivation as determined by a reporter assay , phosphorylation of the p38 and Erk1 / 2 MAPKs , and counteracted Q07869 activity . These results suggest that P42345 could negatively regulate the effects of LPS on the NF - kappaB and MAPK pathways . We also performed real - time RT - PCR assays on mmp9 expression using rosiglitazone ( agonist of PPARgamma ) , PD98059 ( inhibitor of Erk 1 / 2 ) and SB203580 ( inhibitor of p38 ( MAPK ) ) , that were able to counteract the rapamycin mediated overexpression of mmp9 in response to LPS . Our results suggest a new pathway involving P42345 for regulating specifically mmp9 in LPS - stimulated RAW264 . 7 cells .\",\n \"P12644 modulates fibroblast growth factor - mediated induction of proximal and distal lung differentiation in mouse embryonic tracheal epithelium in mesenchyme - free culture . Lung morphogenesis and differentiation require interaction between the epithelium and mesenchyme , which is mediated by diffusible molecules such as fibroblast growth factors ( FGFs ) , bone morphogenetic protein 4 ( P12644 ) , and Shh . We have used mesenchyme - free culture to study the effects of these molecules on lung epithelial differentiation . We have tested the individual abilities of P05230 , P09038 , P21781 , P31371 , O15520 , and O76093 , as well as P12644 and Shh to promote growth and specify distal lung differentiation in mouse tracheal epithelium . The different FGFs exhibited distinct abilities to induce epithelial growth and the expression of the distal lung epithelial marker , surfactant protein C ( P11686 ) , although all FGFs were able to induce expression of P12644 . Tracheal epithelium treated with O15520 showed little growth and failed to express P11686 as measured by whole - mount in situ hybridization and quantitative real - time polymerase chain reaction . P05230 treatment resulted in the strongest induction of P11686 . Treatment with P12644 inhibited epithelial growth and differentiation and antagonized the stimulatory effects of P05230 . In contrast , inhibition of endogenous P12644 signaling with Q13253 protein did not inhibit growth or expression of P11686 but did increase the expression of the proximal lung markers P11684 and Q92949 . Expression of Shh was not affected by any of the conditions tested . These results suggest that P12644 does not signal epithelial cells to adopt a distal fate but may regulate the expansion of proximal epithelial cells in the lung .\",\n \"Human prostacyclin platelet receptors in diabetes mellitus . Conflicting data have been reported about the impaired sensitivity to the inhibitory effect of prostacyclin ( DB01240 ) in platelets from patients with diabetes . In the present paper we investigated binding of and sensitivity to DB01240 of platelets from insulin dependent ( IDDM ) ( n = 9 ) , non insulin dependent ( NIDDM ) ( n = 8 ) diabetics and two groups of ten healthy subjects of equivalent age in relation to platelet lipidic content . Platelet sensitivity to DB01240 ( DB01240 IC50 ) was found not significantly changed in diabetics as compared to controls ; similarly , no significant differences of the number of high affinity receptors for DB01240 in platelets from patients with IDDM and NIDDM were observed . Platelet sensitivity to DB01240 and DB01240 receptors were found to be significantly related to platelet cholesterol content ( r = 0 . 89 , p less than 0 . 001 and r = - 0 . 80 , p less than 0 . 001 respectively ) . In conclusion platelet P43119 changes are not detectable in diabetics in good metabolic control , but could take place when platelet lipid composition is altered .\",\n \"Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension . Q16647 ( PGIS ) is the final committed enzyme in the metabolic pathway leading to prostacyclin ( DB01240 ) production . Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels , but the importance of this deficiency for lung vascular remodeling remains unclear . We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension . To study this hypothesis , transgenic mice were created with selective pulmonary PGIS overexpression using a construct of the 3 . 7 - kb human surfactant protein - C ( P11686 ) promoter and the rat PGIS cDNA . Transgenic mice ( Tg + ) and nontransgenic littermates ( Tg - ) were subjected to a simulated altitude of 17 , 000 ft for 5 weeks , and right ventricular systolic pressure ( RVSP ) was measured . Histology was performed on the lungs . The Tg + mice produced 2 - fold more pulmonary 6 - keto prostaglandin F1alpha ( PGF1alpha ) levels than did Tg - mice . After exposure to chronic hypobaric hypoxia , Tg + mice have lower RVSP than do Tg - mice . Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg + mice in comparison with vessel wall hypertrophy in the Tg - mice . These studies demonstrate that Tg + mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia . We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia . This has important implications for the pathogenesis and treatment of severe pulmonary hypertension .\",\n \"Is transforming growth factor - β signaling activated in human hypertrophied prostate treated by 5 - alpha reductase inhibitor ? BACKGROUND AND AIM : It is well known that androgen deprivation relates to penile fibrosis , so we hypothesize that long - term treatment with 5 - alphareductase inhibitors ( 5ARIs ) may increase the risk of fibrosis of prostate . PATIENTS AND METHODS : Thirty - two BPH patients who underwent transurethral resection of the prostate were enrolled . The patients were divided into two groups : group one , 16 patients underwent TURP who had been treated with tamsulosin for 2 years ; group two , 16 patients underwent TURP who had been treated with combination of tamsulosin and dutasteride for at least 1 year . We evaluated the expressions of P29475 , P35228 , P29474 , TGF - β1 , TGF - β2 , phosphorylated - Q15796 / 3 ( p - Q15796 / 3 ) , P12830 , P19022 , and α - smooth muscle actin in the resected prostate tissues by western blotting , and the TGF - β concentration was determined by ELISA kit . RESULTS : The expressions of 3 isoforms of NOS were significantly increased in group 2 except of P29474 in lateral prostate , and the expressions of TGF - β1 , TGF - β2 , and p - Q15796 / 3 increased about 2 - fold compared with group 1 . In group 2 , the P12830 expression decreased while P19022 expression increased significantly . CONCLUSIONS : The overexpression of P29475 may contribute to prostate smooth muscle relaxation ; however , long - time treatment with 5 Q9Y4X5 increases the risk of fibrosis of prostate .\",\n \"Non - prostanoid prostacyclin mimetics . 6 . Derivatives of 2 -[ 3 -[ 2 -( 4 , 5 - Diphenyl - 2 - oxazolyl ) ethyl ] phenoxy ] acetic acid modified beta - to the oxazole ring . 2 -[ 3 -[ 2 -( 4 , 5 - Diphenyl - 2 - oxazolyl ) ethyl ] phenoxy ] acetic acid , 1 , has been described as a non - prostanoid DB01240 mimetic that demonstrates anti - thrombotic properties of long duration in animal models of thrombosis . The effects of substitution and modification of the carbon beta - to the oxazole heterocycle of 1 were examined and equated with the potency of the compounds as inhibitors of ADP - induced human platelet aggregation in vitro . Potency was sensitive to both the size of the substituent and the identity of the beta - atom . The carbamates 13c - e demonstrated IC50 ' s of 0 . 28 - 0 . 36 microM and were significantly more potent than the progenitor 1 , IC50 = 1 . 2 microM . The ethyl carbamate 13c displaced [ 3H ] - iloprost from platelet membranes in a concentration - dependent fashion that was half maximal at 20 nM , which compares with IC50 ' s of 171 nM for 1 and 39 nM or unlabelled iloprost . Carbamate 13c stimulated platelet adenylate cyclase but the maximal effect was less than that observed for DB01240 , identifying 13c as a partial agonist at the platelet P43119 .\",\n \"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .\",\n \"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK87___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .\",\n \"Estrogen protects the heart from ischemia - reperfusion injury via P35354 - derived DB01240 . There is an accumulating body of data to suggest that estrogen mediates its cardioprotective effects via cyclooxygenase activation and synthesis of prostaglandins ( PG ) , specifically DB01240 . We hypothesized that inhibition of P35354 would prevent estrogen ' s cardioprotective effects after myocardial ischemia - reperfusion . Acute treatment with 17beta - estradiol ( E2 ; 20 microg / rabbit ) increased P35354 protein expression and activity in the myocardium . To determine the effects of P35354 inhibition on infarct size after E2 treatment , New Zealand white rabbits were anesthetized and administered the P35354 inhibitor nimesulide ( 5 mg / kg ) or vehicle intravenously 30 minutes before an intravenous injection of E2 . Thirty minutes after estrogen treatment , the coronary artery was occluded for 30 minutes followed by 4 hours of reperfusion . E2 significantly decreased infarct size as a percent of area at risk when compared to vehicle ( 18 . 9 +/- 3 . 1 versus 47 . 0 +/- 4 . 1 ; P < 0 . 001 ) . Pretreatment with nimesulide nullified the infarct size sparing effect of E2 ( 55 . 8 +/- 5 . 6 ) . Treatment with the P43119 antagonist RO3244794 also abolished the protective effects of E2 ( 45 . 3 +/- 4 . 5 ) . The results indicate that estrogen protects the myocardium from ischemia - reperfusion injury through increased production of P35354 - derived DB01240 . The data indicate that selective P35354 inhibitors might counteract the potential cytoprotective effects of estrogen in premenopausal or postmenopausal women .\",\n \"Altered expression of inflammation - related genes in human carotid atherosclerotic plaques . OBJECTIVE : Inflammation is a pivotal process in atherosclerosis development and progression , but the underlying molecular mechanisms remain largely obscure . We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis . METHODS : We studied 11 human carotid plaques , their respective adjacent regions and 7 control arteries from different subjects . Expression of 92 genes was studied by TaqMan low - density array human inflammation panel . Human aortic endothelial and smooth muscle cells were used for in vitro experiments . RESULTS : The mRNA levels of 44 / 92 genes ( 48 % ) differed significantly between the tissues examined ( 13 up - regulated and 31 down - regulated ) . Dysregulated genes encode molecules belonging to different functional classes although most of them encode enzymes involved in the eicosanoid synthesis pathway . The expression of Q16647 and P43119 genes was decreased in human aortic endothelial and smooth muscle cells stimulated with oxLDL and P01375 - α . CONCLUSIONS : This study not only reveals several dysregulated genes in human lesions but also focuses the role played by the genes involved in the eicosanoid synthesis pathway during atherosclerotic development . The decrease of Q16647 and P43119 expression after oxLDL treatment mirrors the decreased mRNA levels in atherosclerotic lesions versus control arteries , which suggests that oxidation is important for Q16647 and P43119 regulation in human vessel cells during atherosclerosis development .\",\n \"P15692 expression is augmented by hypoxia ‑ induced PGIS in human fibroblasts . Q16647 ( PGIS or Q16647 ) is an enzyme that catalyses the conversion of prostaglandin H2 ( PGH2 ) to prostaglandin I2 ( DB01240 ) . DB01240 promotes cancer growth by activating peroxisome proliferator - activated receptor δ ( PPARδ ) , and increases the expression levels of the pro - angiogenic factor vascular endothelial growth factor ( P15692 ) . We found that the expression of the PGIS gene was enhanced in WI - 38 , TIG - 3 - 20 and HEL human lung fibroblast cells and two cancer cell lines ( NB - 1 and G361 ) under hypoxic conditions . The main localization of PGIS changed from the cytoplasm to the nucleus by hypoxia in WI - 38 cells . The induced PGIS had an enzymatic activity since the intracellular level of 6 - keto - prostaglandin , a useful marker of DB01240 biosynthesis in vivo , was increased with the increasing levels of PGIS . Expression of P15692 was increased in parallel with PGIS induction under hypoxic conditions . PGIS knockdown resulted in the decreased expression of P15692 mRNA . Since P15692 is a known PPARδ target gene , we examined the effects of siRNAs targeting PPARδ on the expression of P15692 under hypoxic conditions . Knockdown of PPARδ suppressed the expression of P15692 under hypoxic conditions in WI - 38 cells . These findings suggest that PGIS is induced by hypoxia and regulates the expression of P15692 in fibroblasts . Fibroblasts in the hypoxic area of tumors may have an important role in tumor growth and angiogenesis .\",\n \"Developmental regulation of prostacyclin synthase and prostacyclin receptors in the ovine uterus and conceptus during the peri - implantation period . This study documents the expression of prostacyclin ( DB01240 ) synthase ( Q16647 ) and DB01240 receptors in the trophoblast and uterus of the ewe at the time of maternal recognition of pregnancy ( i . e . days 7 , 9 , 12 , 14 and 17 ) . The membrane receptor for DB01240 ( P43119 ) and the nuclear receptors , i . e . peroxisome proliferator - activated receptors ( Q07869 ) and their heterodimer partners the retinoid X receptors ( RXR ) , were analysed . In the endometrium , Q16647 transcript and protein were expressed at day 9 of pregnancy and levels declined from days 12 to 17 . Immunohistochemistry and in situ hybridization indicated that Q16647 was mainly located in the luminal epithelium of the endometrium . Endometrial P43119 , Q07869 , P37231 and P48443 expression was regulated during the peri - implantation period whereas Q03181 , P19793 and P28702 were consistently expressed . In the trophoblast , Q16647 transcript levels rose as development progressed and peaked at day 17 . P43119 and Q07869 transcripts peaked before day 12 and then declined and became nearly undetectable by day 17 , whereas Q03181 and P37231 transcript levels rose steadily from days 12 to 17 . Because the PPARs and the RXRs display different expression profiles , we suggest that different heterodimers may form and support distinct functions as development proceeds . Our results also underline the importance of Q16647 and Q03181 in the trophoblast and P43119 in the uterus , suggesting that DB01240 is of both uterine and trophoblastic origin and is involved in a complex signalling pathway at around the time of implantation in the ewe .\",\n \"Identification of the prostacyclin receptor by use of [ 15 - 3H1 ] 19 -( 3 - azidophenyl )- 20 - norisocarbacyclin , an irreversible specific photoaffinity probe . The prostaglandin I ( DB01240 ) receptor of mouse mastocytoma P - 815 cells was characterized by photo - affinity labeling with the stable DB01240 analogue [ 15 - 3H1 ] - 19 -( 3 - azidophenyl )- 20 - norisocarbacyclin ( [ 3H ] APNIC ) used as a potential photoaffinity probe for the receptor . [ 3H ] APNIC bound to the mastocytoma membrane with high affinity and in a saturable manner . Scatchard plot analysis indicated a single binding site with a Kd of 4 . 7 nM and a Bmax of 0 . 58 pmol / mg protein . The binding of [ 3H ] APNIC was dose dependently inhibited by APNIC and iloprost , another stable DB01240 agonist , and to a much lesser extent by DB00917 . The binding of the radioligand showed sensitivity to the guanine nucleotide guanosine 5 '- O -( 3 - thio - triphosphate ) ( GTP gamma S ) . Photolysis of [ 3H ] APNIC - prelabeled membranes resulted in incorporation of radiolabel into a protein of approximately 43 kDa . Photolabeling was inhibited by DB01240 agonists and other prostaglandins with specificity for the P43119 and was modulated by GTP gamma S . A protein of approximately 45 kDa was also labeled by [ 3H ] APNIC in the membrane of porcine platelets , membranes that are known to be abundant in DB01240 receptors . These results demonstrate that [ 3H ] APNIC specifically labels a protein that may represent the P43119 and that this radioprobe will be a useful reagent for further characterization and purification of the P43119 .\",\n \"Recombinational and physical mapping of the locus for primary open - angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open - angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile - onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA1 / D1S210 and NGA5 loci . These loci are 2 . 8 Mb apart on a 4 . 7 - Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G - band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . Our results provide a basis to identify the Q99972 gene .\",\n \"Impairment of breast cancer cell invasion by P35354 - specific inhibitor NS398 : roles of P61073 and of uPA system . Inhibition of cyclooxygenase - 2 ( P35354 ) is known to impair cancer cell metastatic behaviour , but the mechanisms involved largely remain elusive . We aimed to analyse whether the antimetastatic effect of P35354 inhibition in breast cancer cells could be explained by variations in the expression levels of chemokine receptor P61073 , vascular endothelium growth factor ( P15692 ) and Q96NZ9 / Q03405 components of the urokinase plasminogen activator system ( Q03405 ) . Breast cancer cell line MDA - MB - 231 was exposed to P35354 - specific inhibitor NS398 . Experimental data were assessed using Matrigel invasion tests , qRT - PCR , ELISA , flow cytometry and MTT test . Exposure to NS398 had no major effect on cell viability , apoptosis or P15692 production . Cell invasion was significantly decreased with reductions ranging from of 3 . 6 % with 10 μM NS398 to 81 . 04 % with 100 μM NS398 . P61073 membrane expression was significantly reduced by 18 % ( P < 0 . 05 ) when cells were treated with 100 μM of NS398 for 72 h . Q96NZ9 mRNA levels were significantly reduced to 78 and 63 % after treatment with 10 μM NS398 for 48 and 72 h , respectively ( P < 0 . 05 ) . Q03405 mRNA levels also decreased with mild NS398 concentrations , reaching the lowest level of 56 % with 50 μM of NS398 for 48 h ( P < 0 . 05 ) . With NS398 higher concentrations , Q03405 and Q96NZ9 expression levels increased . According to our results , impairment of expression of P61073 , Q96NZ9 and Q03405 differentially contribute to the antimetastatic effect of P35354 inhibitors depending on drug concentration .\",\n \"P43119 induces P42224 and P40763 phosphorylations in human erythroleukemia cells : a mechanism requiring PTX - insensitive G proteins , P29323 and JNK . The ability of the human prostacyclin receptor ( hIP ) to regulate the activities of signal transducers and activators of transcription ( STATs ) has not yet been documented . In the present study , we have delineated the mechanism by which hIP induces P40763 phosphorylations in human erythroleukemia ( HEL ) cells . Stimulation of endogenous hIP by its specific agonist , cicaprost , resulted in P40763 Tyr705 and Ser727 phosphorylations in a time - and concentration - dependent manner . Cicaprost - induced P40763 Tyr705 and Ser727 phosphorylations were resistant to pertussis toxin ( PTX ) treatment , suggesting that these responses were mediated through PTX - insensitive G proteins . In addition , extracellular signal - regulated kinase ( P29323 ) and c - Jun N - terminal kinase ( JNK ) , but not p38 MAPK , were shown to be phosphorylated by cicaprost in a time - and concentration - dependent manner via PTX - insensitive G proteins . The levels of the interaction between P40763 , P29323 and JNK were enhanced by cicaprost treatment . The involvement of P04049 , Q02750 / 2 and JNK in cicaprost - induced phosphorylations of P40763 was illustrated by the use of their selective inhibitors . In contrast , p38 MAPK did not appear to be required . Similar observations were obtained with P42224 upon stimulation by cicaprost . Taken together , these results demonstrate for the first time that hIP activation by cicaprost can lead to P42224 and P40763 phosphorylations via signaling pathways involving PTX - insensitive G proteins , P29323 and JNK .\",\n \"[ Moclobemide ( ___MASK35___ ) , the first P21397 - inhibitor : really something new ? ] .\",\n \"Dehydration activates an NF - kappaB - driven , P35354 - dependent survival mechanism in renal medullary interstitial cells . Renal prostaglandin ( PG ) synthesis is mediated by cyclooxygenase - 1 and - 2 ( P23219 and P35354 ) . After dehydration , the maintenance of normal renal function becomes particularly dependent upon PG synthesis . The present studies were designed to examine the potential link between medullary P23219 and P35354 expression in hypertonic stress . In response to water deprivation , P35354 , but not P23219 , mRNA levels increase significantly in the renal medulla , specifically in renal medullary interstitial cells ( RMICs ) . DB09145 deprivation also increases renal NF - kappaB - driven reporter expression in transgenic mice . NF - kappaB activity and P35354 expression could be induced in cultured RMICs with hypertonic sodium chloride and mannitol , but not urea . RMIC P35354 expression was also induced by driving NF - kappaB activation with a constitutively active O15111 alpha ( IKKalpha ) . Conversely , introduction of a dominant - negative IkappaB mutant reduced P35354 expression after hypertonicity or IKKalpha induction . RMICs failed to survive hypertonicity when P35354 was downregulated using a P35354 - selective antisense or blocked with the selective nonsteroidal anti - inflammatory drug ( NSAID ) SC58236 , reagents that did not affect cell survival in isotonic media . In rabbits treated with SC58236 , water deprivation induced apoptosis of medullary interstitial cells in the renal papilla . These results demonstrate that water deprivation and hypertonicity activate NF - kappaB . The consequent increase in P35354 expression favors RMIC survival in hypertonic conditions . Inhibition of RMIC P35354 could contribute to NSAID - induced papillary injury .\",\n \"DB05229 sodium , a stable prostacyclin analogue , elicits dilation of isolated porcine retinal arterioles : roles of P29474 and potassium channels . PURPOSE : DB01240 ( DB01240 ) is usually described as an endoEDRFsthelium - derived relaxing factor , but the vasoreactivity to DB01240 in the retinal arterioles and the underlying mechanisms are not fully understood . We examined the effects of DB01240 on the retinal microcirculation using beraprost sodium ( BPS ) , a stable DB01240 analogue , and the signaling mechanisms involved in this vasomotor activity . METHODS : Porcine retinal arterioles were isolated , cannulated , and pressurized without flow in vitro . Video microscopic techniques recorded the diametric responses to BPS . RESULTS : DB05229 sodium elicited dose - dependent ( 0 . 1 pM - 0 . 1 μM ) vasodilation of the retinal arterioles that was abolished by the P43119 ( IP ) antagonist CAY10441 . DB05229 sodium - induced vasodilation decreased by 50 % after the endothelium was removed and was inhibited by the nitric oxide ( NO ) synthase inhibitor N ( G )- nitro - L - arginine methyl ester ( L - NAME ) comparable with denudation . Inhibition of soluble guanylyl cyclase by 1H - 1 , 2 , 4 - oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) and blockage of protein kinase A ( PKA ) by Rp - 8 - Br - cAMPS were comparable to L - NAME . DB05229 sodium - induced vasodilation was also inhibited by the nonselective potassium channel inhibitor , tetraethylammonium , and the adenosine triphosphate - sensitive potassium ( KATP ) channel blocker , glibenclamide . Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ . CONCLUSIONS : DB05229 sodium , a stable DB01240 analogue , causes vasodilation of the retinal arterioles mediated via the IP receptor . The current findings suggest that BPS elicits endothelium - dependent and - independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle , respectively .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"Identification of antithrombin - modulating genes . Role of O95461 , a gene encoding a bifunctional glycosyltransferase , in the secretion of proteins ? The haemostatic relevance of antithrombin together with the low genetic variability of P01008 , and the high heritability of plasma levels encourage the search for modulating genes . We used a hypothesis - free approach to identify these genes , evaluating associations between plasma antithrombin and 307 , 984 polymorphisms in the GAIT study ( 352 individuals from 21 Spanish families ) . Despite no SNP reaching the genome wide significance threshold , we verified milder positive associations in 307 blood donors from a different cohort . This validation study suggested O95461 , a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin - like linear polysaccharides , as a potential modulator of antithrombin based on the significant association of one SNPs , rs762057 , with anti - FXa activity , particularly after adjustment for age , sex and P01008 rs2227589 genotype , all factors influencing antithrombin levels ( p = 0 . 02 ) . Additional results sustained this association . O95461 silencing inHepG2 and P29320 - EBNA cells did not affect P01008 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention . Milder effects were observed on α1 - antitrypsin , prothrombin and transferrin . Our study suggests O95461 as the first known modifier of plasma antithrombin , and proposes a new role for O95461 in modulating extracellular secretion of certain glycoproteins .\",\n \"___MASK100___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .\",\n \"A surface plasmon resonance - based solution affinity assay for heparan sulfate - binding proteins . A surface plasmon resonance - based solution affinity assay is described for measuring the K ( d ) of binding of heparin / heparan sulfate - binding proteins with a variety of ligands . The assay involves the passage of a pre - equilibrated solution of protein and ligand over a sensor chip onto which heparin has been immobilised . DB01109 sensor chips prepared by four different methods , including biotin - streptavidin affinity capture and direct covalent attachment to the chip surface , were successfully used in the assay and gave similar K ( d ) values . The assay is applicable to a wide variety of heparin / HS - binding proteins of diverse structure and function ( e . g . , P05230 , P09038 , P15692 , P10145 , P80075 , P01008 , P02776 ) and to ligands of varying molecular weight and degree of sulfation ( e . g . , heparin , DB05808 , sucrose octasulfate , naphthalene trisulfonate ) and is thus well suited for the rapid screening of ligands in drug discovery applications .\",\n \"Hypoxia - inducible vascular endothelial growth factor gene therapy using the oxygen - dependent degradation domain in myocardial ischemia . PURPOSE : A hypoxia - inducible P15692 expression system with the oxygen - dependent degradation ( Q8TAX0 ) domain was constructed and tested to be used in gene therapy for ischemic myocardial disease . METHODS : Luciferase and P15692 expression vector systems were constructed with or without the Q8TAX0 domain : pEpo - SV - Luc ( or pEpo - SV - P15692 ) and pEpo - SV - Luc - Q8TAX0 ( or pEpo - SV - P15692 - Q8TAX0 ) . In vitro gene expression efficiency of each vector type was evaluated in P29320 293 cells under both hypoxic and normoxic conditions . The amount of P15692 protein was estimated by ELISA . The P15692 expression vectors with or without the Q8TAX0 domain were injected into ischemic rat myocardium . Fibrosis , neovascularization , and cardiomyocyte apoptosis were assessed using Masson ' s trichrome staining , α - smooth muscle actin ( α - SMA ) immunostaining , and the TUNEL assay , respectively . RESULTS : The plasmid vectors containing Q8TAX0 significantly improved the expression level of P15692 protein in hypoxic conditions . The enhancement of P15692 protein production was attributed to increased protein stability due to oxygen deficiency . In a rat model of myocardial ischemia , the pEpo - SV - P15692 - Q8TAX0 group exhibited less myocardial fibrosis , higher microvessel density , and less cardiomyocyte apoptosis compared to the control groups ( saline and pEpo - SV - P15692 treatments ) . CONCLUSION : An Q8TAX0 - mediated P15692 expression system that facilitates P15692 - production under hypoxia may be useful in the treatment of ischemic heart disease .\",\n \"___MASK6___ block of cloned human T - type voltage - gated calcium channels . ___MASK6___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .\",\n \"Evidence for distinct prostaglandin I2 and D2 receptors in human platelets . Incubation of human platelet - rich plasma with prostaglandin I2 ( DB01240 ) , results in a marked increase in adenosine 3 ': 5 '- monophosphate ( DB02527 ) that persists for at least 60 min . The persistent stimulation of DB02527 levels by DB01240 can be rapidly reversed by the addition of either prostaglandin E1 or E2 ( PGE1 , DB00917 ) , but not by prostaglandin D2 ( PGD2 ) . Studies of agonist - specific desensitization of DB02527 accumulation show that PGE1 or DB00917 can desensitize for subsequent PGE or DB01240 activation , and that subthreshold levels of DB01240 desensitize for subsequent PGE1 stimulation . PGD2 desensitizes for consequent PGD2 activation , but not for PGE1 , DB00917 or DB01240 , and PGE compounds and DB01240 do not desensitize for subsequent PGD2 activation . Agonist - specific desensitization for DB01240 is not dependent on DB02527 accumulation , but appears to be a consequence of receptor occupation . Support of the desensitization experiments was obtained through the use of the prostaglandin antagonist N - 0164 [ sodium - p - benzyl - 4 -[- oxo - 2 -( 4 - chlorobenzyl )- 3 - phenyl - propyl ] phenyl phosphonate ) . This compound proved to be a potent antagonist of PGD2 and a weak antagonist of DB01240 - stimulated DB02527 accumulation . These data indicate that human platelets have distinct pharmacological receptors for both DB01240 and PGD2 , and that PGE compounds may actually interact with a P43119 .\",\n \"DB01088 has potent anti - inflammatory properties on human monocyte - derived dendritic cells . BACKGROUND : The stable prostaglandin I2 analogue ( iloprost ) iloprost has been shown to inhibit allergic airway inflammation in mice by modulating the function of myeloid dendritic cells ( DCs ) . OBJECTIVE : The aim of the current study was to investigate the biological activity of iloprost on human monocyte - derived DCs . METHODS : I prostanoid ( IP ) receptor expression was analysed by RT - PCR . Cytokine secretion by DCs and P01730 + T cells was measured by ELISA . The expression of the transcription factor FoxP3 after co - culture of DCs with P01730 + CD45RA + T cells was analysed by flow cytometry . RESULTS : Human monocyte - derived DCs were found to express mRNA specific for the P43119 IP , and stimulation with iloprost resulted in increased cyclic AMP levels in both immature DCs ( iDCs ) and mature DCs ( mDCs ) . Moreover , iloprost dose dependently inhibited the secretion of P01375 , P05231 , P10145 and IL - 12p70 in mDCs , while it enhanced P22301 production . Changes in cytokine secretion were paralleled by an altered T - cell priming capacity of DCs : in co - culture experiments of iloprost - treated mDC and naïve CD45RA + T cells , an induction of regulatory T cells could be observed , as demonstrated by increased intracellular FoxP3 expression and P22301 production . Additionally , iloprost inhibited the MIP - 3beta - induced migration of mDCs . CONCLUSION : In summary , our results provide evidence that iloprost profoundly affects the function of human myeloid DCs . Therefore , iloprost might also be a new therapeutical option for the treatment of asthma in humans .\",\n \"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK37___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .\",\n \"DB01240 ( P06744 ) receptor binding and cyclic AMP synthesis activities of PGI1 analogues , SM - 10906 and its methyl ester , SM - 10902 , in mastocytoma P - 815 cells . The prostacyclin I1 ( PGI1 ) analogue , SM - 10906 and its methyl ester , SM - 10902 , have been compared with the DB01240 analogue , iloprost , with respect to binding to the P43119 , stimulation of adenylate cyclase activity and inhibition of thrombin - induced Ca2 + mobilization in mastocytoma P - 815 cells . SM - 10906 displaced [ 3H ] iloprost binding to the membrane fraction , the IC50 value being 100 nM , but showed very low affinity for the prostaglandin E ( PGE ) receptor . SM - 10906 dose - dependently stimulated GTP - dependent adenylate cyclase activity in the membrane fraction , the EC50 value being 35 nM . Furthermore , SM - 10906 prevented a thrombin - induced increase in the intracellular Ca2 + concentration , the IC50 value being 300 nM . These IC50 and EC50 values are much lower than those of SM - 10902 . These results demonstrate that SM - 10906 , a stable PGI1 derivative , is an agonist for the [ 3H ] iloprost - binding ( DB01240 ) receptor , and that it prevents thrombin - induced Ca2 + mobilization through stimulation of the adenylate cyclase system in mastocytoma cells . On the other hand , a methyl ester derivative of PGI1 , SM - 10902 , was inactive in the binding assay , but it seems to be a partial agonist for adenylate cyclase activity [ corrected ] .\",\n \"___MASK15___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .\",\n \"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK71___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .\",\n \"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK34___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK34___ who were treated with a single dose of mifepristone .\",\n \"A lung - specific neo - antigen elicits specific CD8 + T cell tolerance with preserved P01730 + T cell reactivity . Implications for immune - mediated lung disease . The A / Japan / 57 influenza hemagglutinin ( HA ) was expressed in BALB / c mice under the transcriptional control of the surfactant protein C ( P11686 ) promoter , resulting in expression of HA in type II alveolar epithelial cells , as well as low level variable expression in other tissues , including the thymus in some of the founder lines . Transgenic animals were able to recover from infection with A / Japan / 57 influenza , and they were able to mount antibody responses to A / Japan / 57 HA in titers similar to wild type . We therefore tested their P01730 + T lymphocyte responses to HA and found them to be similar to wild type responses . However , CD8 + T cells from A / Japan / 57 - infected transgenic animals were unable to express cytolytic activity against target cells expressing the A / Japan / 57 HA . The CD8 + T cell tolerance was also extremely specific , since transgenics immunized with an influenza strain containing a single amino acid substitution in a dominant HA epitope were able to mount full cytolytic responses to that epitope , but not the wild - type epitope . Adoptive transfer of CD8 + T cell clones into transgenic animals resulted extensive interstitial pneumonitis that was antigen - specific and associated with significant morbidity and mortality . We conclude that a lung - specific transgene may lead to specific CD8 + T cell tolerance , with P01730 + T cell and B cell reactivity to the antigen , and that P01730 + T cell reactivity may remain intact to an antigen expressed in the thymus , even when CD8 + T cell tolerance exists . This observation may have profound implications concerning immune - mediated lung diseases , particularly those mediated by P01730 + T cells .\",\n \"Surfactin exhibits neuroprotective effects by inhibiting amyloid β - mediated microglial activation . Microglial - mediated neuroinflammation and neurotoxicity contribute to the pathogenesis of neurodegenerative diseases including Alzheimer ' s disease ; therefore , control of microglial activation and subsequent suppression of neurotoxic pro - inflammatory molecules could provide a potential therapeutic approach for the treatment of such diseases . In this study , we investigated the effects of surfactin , a surfactant from Bacillus subtilis , on oligomeric amyloid β ( Aβ ) - induced microglial activation and neurotoxicity . Surfactin significantly suppressed expression of P14780 , P35228 and P35354 , as well as production of ROS , NO , DB00917 , P01375 - α , IL - 1β , P05231 and P13500 in Aβ - stimulated BV - 2 microglial cells . Moreover , surfactin markedly inhibited Aβ - induced nuclear translocation and activation of NF - κB as well as phosphorylation of JNK and p38 MAPK . Furthermore , surfactin protected hippocampal HT22 cells from indirect neuronal toxicity mediated by Aβ - treated microglial cells , but had no effect on Aβ - induced direct toxicity to HT22 cells . These results suggest that surfactin impairs the Aβ - induced inflammatory response of microglial cells and confers protection against indirect neurotoxicity to hippocampal cells . Our findings indicate that surfactin may have therapeutic potential for ameliorating Alzheimer ' s disease as well as other neurodegenerative disorders which involve neuroinflammation .\",\n \"High - dose aspirin in dogs increases vascular resistance with limited additional anti - platelet effect when combined with potent Q9H244 inhibition . INTRODUCTION : With the arrival of the potent Q9H244 antagonists , ticagrelor and prasugrel , the need for co - treatment with aspirin in acute coronary syndromes must be re - examined . This study assessed whether high - dose aspirin : a ) provides additional anti - platelet efficacy , assessed in vivo and ex vivo , when combined with Q9H244 inhibition ; and / or b ) has a negative effect on vascular function . MATERIALS AND METHODS : Using an anaesthetized dog model of thrombosis , the effects of aspirin ( 50mg / kg ) in addition to clopidogrel and ticagrelor were evaluated at two levels of Q9H244 inhibition , maximal ( ≥ 96 % ) and sub - maximal ( ~ 80 % ) , as assessed by ex vivo ADP - induced whole blood impedence aggregometry . RESULTS : In the absence of aspirin , maximal and sub - maximal Q9H244 inhibition inhibited arachidonic acid - induced platelet aggregation by approximately 80 % and 24 % , respectively , without affecting platelet TXA2 formation . During maximal Q9H244 inhibition , aspirin provided less additional inhibition of ex vivo arachidonic acid - and collagen - induced platelet aggregation , as compared with sub - maximal Q9H244 inhibition , without additional anti - thrombotic effect in vivo . DB00945 significantly decreased in vivo DB01240 production ( 27 % ) and increased vascular resistance ( 16 % ) , independently of Q9H244 antagonism . CONCLUSION : In the dog , Q9H244 antagonists inhibit TXA2 - mediated platelet - aggregation independently of aspirin . DB00945 provides less additional anti - platelet effects during maximal compared with sub - maximal Q9H244 inhibition but increases vascular resistance .\",\n \"Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40 - fold ) in high - responding opossums , but moderately elevated ( 6 - fold ) in low - responding opossums after they had consumed a high - cholesterol and high - fat diet for 24 wk . In both high - and low - responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2 - fold ) , esterified cholesterol ( 11 - fold ) , and triglycerides ( 2 - fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 gene and downregulation of the Q02318 , Q9H221 , and P21439 genes . Genes involved in inflammation ( P01375 , P19838 , and P35354 ) and in oxidative stress ( P13498 and P14598 ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 ) and collagen genes ( Col1A1 , Col3A1 , and Col4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high - responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis .\",\n \"Differential activation of Gi and Gs proteins by E - and I - type prostaglandins in membranes from the human erythroleukaemia cell line , HEL . The group of prostaglandin ( PG ) E2 - and prostacyclin receptors consists of different subtypes , which exhibit different affinities for prostaglandins and synthetic analogues . DB00917 activities the E - type PG receptor subtypes EP1 , EP2 and EP3 , whereas the DB00917 analogue , sulprostone , binds only to the EP1 and EP3 receptor subtypes . The stable DB01240 analogues , iloprost and cicaprost , both activate the P43119 ( IP ) and iloprost , additionally , bind to the EP1 subtype . Using these subtype - selective PG receptor agonists , we studied the interaction of PG receptor subtypes with Gs and Gi - type heterotrimeric guanine nucleotide - binding proteins ( G proteins ) in membranes from the human erythroleukaemia cell line , HEL . Sulprostone stimulated high - affinity GTPase in HEL membranes in a pertussis toxin ( PTX ) - sensitive manner . In contrast , the stimulations induced by DB00917 , iloprost and cicaprost were only partially inhibited by PTX . DB00917 , sulprostone , iloprost and cicaprost stimulated cholera toxin - catalysed ADP - ribosylation as well as labelling with GTP azidoanilide of membrane proteins comigrating with immunologically identified Gi protein alpha subunits . Furthermore , DB00917 , iloprost and cicaprost enhanced GTP azidoanilide - labelling of Gs protein alpha subunits , whereas sulprostone did not . We suggest that in HEL cells ( 1 ) EP1 and EP3 receptor subtypes activate P55008 proteins , that ( 2 ) the EP2 receptor subtype activates Gs proteins and that ( 3 ) the IP receptor activates both Gi and Gs proteins .\",\n \"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .\",\n \"___MASK71___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .\",\n \"Altered expression of beta - catenin , P12830 , cycloxygenase - 2 , and p53 protein by ovine intestinal adenocarcinoma cells . Around 1 . 6 % of sheep in New Zealand develop small - intestinal adenocarcinomas . These neoplasms typically develop widespread metastases . The common development of these neoplasms and their subsequent behavior suggests that sheep could be a useful animal model of human colonic cancer . However , for an animal model of human disease to be relevant , similar genetic mutations should be present . Genetic mutations within human colonic cancers frequently result in expression of cycloxygenase - 2 ( P35354 ) , loss of membranous expression of beta - catenin and P12830 , and accumulation of p53 protein within the neoplastic cells . Immunohistochemistry was used to investigate the presence of these 4 proteins within 26 ovine intestinal adenocarcinomas . Loss of membranous beta - catenin reactivity was observed in 14 of 26 ovine intestinal adenocarcinomas ( 54 % ) . The loss of membranous beta - catenin reactivity was accompanied by cytoplasmic and nuclear reactivity in 2 neoplasms . Loss of P12830 was observed within 8 of 26 neoplasms ( 31 % ) . Neoplastic cell expression of P35354 was observed in 12 of 26 neoplasms ( 46 % ) , whereas cells within 3 of 26 neoplasms ( 11 % ) contained visible p53 protein . In conclusion , all 4 proteins that commonly have altered expression in human colonic cancers were also altered in a proportion of the ovine intestinal adenocarcinomas . These results provide additional evidence that sheep could be useful for the study of human colonic cancer .\",\n \"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .\",\n \"DB01240 - deficient mice develop ischemic renal disorders , including nephrosclerosis and renal infarction . BACKGROUND : DB01240 ( DB01240 ) is a short - lived endogenous inhibitor of platelet aggregation and a potent vasodilator and regulator of the growth of vascular smooth muscle cells . To study the role of DB01240 in the vascular system in vivo , DB01240 - deficient ( PGID ) mice were established by genetic disruption of the DB01240 synthase gene . METHODS AND RESULTS : DB01240 synthase - null mice were generated by replacing the exons of DB01240 synthase gene that encodes for the catalytic site of the enzyme with a neomycin resistance gene . In these mice , DB01240 levels in the plasma , kidneys , and lungs were reduced , whereas thromboxane and prostaglandin E2 levels became elevated . Blood pressure and the amounts of urea nitrogen and creatinine in plasma of the PGID mice were significantly higher than those of wild - type mice ( P < 0 . 05 ) . They developed progressive morphological abnormalities in the kidneys , accompanied by atrophy , surface irregularity , fibrosis , cyst , arterial sclerosis , and hypertrophy of vessel walls . Thickening of the thoracic aortic media and adventitia were observed in aged PGID mice . Importantly , these phenotypes have not been reported in P43119 - deficient mice . CONCLUSIONS : DB01240 deficiency resulted in the development of vascular disorders with the thickening of vascular walls and interstitial fibrosis , especially in mouse kidneys . The findings demonstrated in vivo that DB01240 is important in the homeostasis of blood vessels . Our established PGID mice are useful for studies on the initiation and development of vascular diseases , such as ischemic renal disorders with arterial sclerosis and infarction , and also for studies on the novel signaling pathway of DB01240 .\",\n \"DB01240 - IP signaling and prostaglandin E2 - EP2 / EP4 signaling both mediate joint inflammation in mouse collagen - induced arthritis . Prostaglandin ( PG ) I2 ( prostacyclin [ P06744 ] ) and DB00917 are abundantly present in the synovial fluid of rheumatoid arthritis ( RA ) patients . Although the role of DB00917 in RA has been well studied , how much DB01240 contributes to RA is little known . To examine this issue , we backcrossed mice lacking the P43119 ( IP ) to the DBA / 1J strain and subjected them to collagen - induced arthritis ( CIA ) . IP - deficient ( IP -/- ) mice exhibited significant reduction in arthritic scores compared with wild - type ( WT ) mice , despite anti - collagen antibody production and complement activation similar to WT mice . IP -/- mice also showed significant reduction in contents of proinflammatory cytokines , such as interleukin ( IL ) - 6 in arthritic paws . Consistently , the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced P05231 production and induced expression of other arthritis - related genes . On the other hand , loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA . However , a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4 . Our results show significant roles of both DB01240 - IP and DB00917 - EP2 / EP4 signaling in the development of CIA , and suggest that inhibition of DB00917 synthesis alone may not be sufficient for suppression of RA symptoms .\",\n \"___MASK91___ induces Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells promoting a new immunoregulatory pathway . Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells ( DCs ) may cause anergy in P01730 (+) CD45RO (+) CD25 (+) T cells transforming them into regulatory T cells ( Tregs ) . Here , we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients . Forty renal transplant patients with biopsy - proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction . At conversion and 2 years thereafter , we measured the rapamycin effects on circulating DCs ( BDCA1 / Q8WTT0 and Q8NHJ6 / Q8N423 expression ) , P01730 (+)/ CD25 ( high )/ Foxp3 (+) Tregs , CD8 (+)/ P10747 (-) T cells , and the Th1 / Th2 balance in graft biopsies . In rapamycin - treated patients , peripheral Q8WTT0 (+) cells were significantly increased along with Q8NHJ6 / Q8N423 (+) DCs . The number of circulating P01730 (+)/ CD25 ( high )/ Foxp3 (+)/ P16410 (+) Tregs , CD8 (+) P10747 (-) T cells , and P17693 serum levels were higher in the rapamycin - treated group . The number of Q8NHJ6 / Q8N423 (+) Q8WTT0 (+) DC was directly and significantly correlated with circulating Tregs and CD8 (+) P10747 (-) T cells . Q8NHJ6 / Q8N423 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin - treated patients . Thus , rapamycin induces the upregulation of Q8NHJ6 and Q8N423 on the DC surface , and this effect is associated with an increase in the number of Tregs and expansion of the CD8 (+) P10747 (-) T cell population . This suggests that P42345 inhibition may promote a novel immunoregulatory pathway .\",\n \"Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP . Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the renin - angiotensin - aldosterone system ; however , the sensing mechanism remains elusive . Here we investigated the role of DB01240 in renovascular hypertension in vivo , employing mice lacking the P43119 ( IP -/- mice ) . In WT mice with a two - kidney , one - clip model of renovascular hypertension , the BP was significantly elevated . The increase in BP in IP -/- mice , however , was significantly lower than that in WT mice . Similarly , the increases in plasma renin activity , renal renin mRNA , and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP -/- mice than in WT mice . All these parameters were measured in mice lacking the four DB00917 receptor subtypes individually , and we found that these mice had similar responses to WT mice . DB01240 is produced by P35354 and a selective inhibitor of this enzyme , SC - 58125 , also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis , but these effects were absent in IP -/- mice . When the renin - angiotensin - aldosterone system was activated by salt depletion , SC - 58125 blunted the response in WT mice but not in IP -/- mice . These results indicate that DB01240 derived from P35354 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo .\",\n \"DB00184 induces cell proliferation , invasion and epithelial - mesenchymal transition in a variety of human cancer cell lines . Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer ( NSCLC ) . DB00184 , an active component of cigarettes , has been found to induce proliferation of lung cancer cell lines . In addition , nicotine can induce angiogenesis and confer resistance to apoptosis . All these events are mediated through the nicotinic acetylcholine receptors ( nAChRs ) on lung cancer cells . In this study , we demonstrate that nicotine can promote anchorage - independent growth in NSCLCs . In addition , nicotine also induces morphological changes characteristic of a migratory , invasive phenotype in NSCLCs on collagen gel . These morphological changes were similar to those induced by the promigratory growth factor P15692 . The proinvasive effects of nicotine were mediated by alpha7 - nAChRs on NSCLCs . RT - PCR analysis showed that the alpha7 - nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines . DB00184 was found to promote proliferation and invasion in human breast cancer . The proinvasive effects of nicotine were mediated via a nAChR , Src and calcium - dependent signaling pathway in breast cancer cells . In a similar fashion , nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells . Most importantly , nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition ( EMT ) , characterized by reduction of epithelial markers like P12830 expression , ZO - 1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells . Therefore , it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers .\",\n \"P35354 - derived prostacyclin modulates vascular remodeling . Suppression of prostacyclin ( DB01240 ) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase ( P36551 ) - 2 inhibitors . Herein , we examine if P35354 - derived DB01240 might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity . Deletion of the P43119 ( IP ) or suppression of DB01240 with the selective P35354 inhibitor , nimesulide , both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow - induced vascular remodeling . Moreover , nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild - type mice . Generation of both thromboxane ( Tx ) A2 and the isoprostane , 8 , 12 - iso iPF ( 2alpha )- VI , are increased in the setting of flow reduction and the latter increases further on administration of nimesulide . Deletion of the TxA2 receptor ( TP ) reduces the hyperplastic response to nimesulide and carotid ligation , despite further augmentation of TP ligand production . Suppression of P35354 - derived DB01240 or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress . Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of P35354 .\",\n \"Effect of prostaglandins and thromboxane A2 on the contractility of rabbit splenic capsular smooth muscle . The effect of various prostaglandins ( PGs ) and a thromboxane A2 ( TXA2 ) - generating system on the contractility of rabbit splenic capsular smooth muscle has been investigated . DB01240 as well as higher concentrations of PGE1 and 5 , 6 beta - dihydro - DB01240 inhibit noradrenaline - induced contractions of the smooth muscle preparation . The TXA2 - generating system and high concentrations of PGD2 , on the other hand , increase the contractions . The results support the concept that the hypothetical P43119 on the smooth muscle of the rabbit splenic capsule resembles , in its specificity , the P43119 on platelets .\"\n]"},"candidates":{"kind":"list like","value":["___MASK100___","___MASK15___","___MASK34___","___MASK35___","___MASK37___","___MASK6___","___MASK71___","___MASK87___","___MASK91___"],"string":"[\n \"___MASK100___\",\n \"___MASK15___\",\n \"___MASK34___\",\n \"___MASK35___\",\n \"___MASK37___\",\n \"___MASK6___\",\n \"___MASK71___\",\n \"___MASK87___\",\n \"___MASK91___\"\n]"},"answer":{"kind":"string","value":"___MASK87___"},"id":{"kind":"string","value":"MH_train_480"}}},{"rowIdx":481,"cells":{"query":{"kind":"string","value":"interacts_with DB08875?"},"supports":{"kind":"list like","value":["Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral / derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non - human primates . Cross species polymerase chain reaction ( CS - PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB @ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR - RFLP ) or by direct sequencing . At seventeen of the eighteen PCR - RFLPs , non - human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR - RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3 ' untranslated region ( UTR ) of the P14416 gene illustrate this point .","Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK75___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .","Identification of new candidate therapeutic target genes in triple - negative breast cancer . Triple - negative breast cancer ( TNBC ) is a subgroup of breast cancer that is negative for estrogen and progesterone receptor and P04626 protein expression . It is characterized by its aggressive behavior and by the lack of targeted therapies . To identify new therapeutic targets in TNBC , we used real - time quantitative RT - PCR to analyze 63 TNBC samples in terms of their mRNA expression of 26 genes coding for the major proteins currently targeted by drugs used to treat other cancers or undergoing clinical trials in breast cancer . Six of the 26 genes tested ( P15692 , P12931 , P09874 , Q05397 , P04049 , and P22607 ) were significantly upregulated in 13 % to 46 % of the TNBCs . None of the 6 genes was specifically upregulated in the TNBCs compared with 3 other classical breast tumor subtypes . No association was observed between overexpression of these 6 genes ( except for P22607 ) and P42336 mutation status . These results confirm the interest of targeting P15692 and P09874 in ongoing clinical trials in TNBC patients and also identify new target genes ( P12931 , Q05397 , P04049 , and P22607 ) . Clinical trials could be initiated easily with existing drugs . Our results also suggest that these target genes might serve as predictive biomarkers of the TNBC treatment response .","Increased expression of hypoxia - inducible factor - 1alpha , p48 , and the Notch signaling cascade during acute pancreatitis in mice . Acute pancreatitis ( AP ) is a complex disease that may be linked to acinar cell apoptosis and inadequate acinar cell replacement . Differentiation of acinar cells is regulated by p48 , a DNA binding subunit of the transcription factor PTF1 , and the Notch signaling pathway . Acinar cell apoptosis is triggered by oxygen deprivation , ie , hypoxia , by activation of hypoxia inducible factor - 1alpha ( HIF - 1alpha ) . The aim of this study was to characterize by Northern blot analyses expression of HIF - 1alpha , HIF - 1alpha - inducible genes ( P11166 , P15692 , p53 ) , p48 , and genes involved in the Notch signaling pathway ( Notch - 1 , Dll1 , P02753 - Jk , DB09106 - 1 ) during cerulein - induced AP in mice . Maximal expression of HIF - 1alpha , HIF - 1alpha - inducible genes , p48 , and Notch signaling genes occurred 8 - 12 hours after induction of AP . Maximal expression of p53 occurred 12 - 48 hours after induction of AP . These findings demonstrate that multiple pancreatic genes are activated acutely during AP that support pancreatic cell replenishment , regulation of expression of acinar cell - specific genes , and apoptosis .","Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK90___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .","Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries . BACKGROUND : Atherosclerosis affects aorta , coronary , carotid , and iliac arteries most frequently than any other body vessel . There may be common molecular pathways sustaining this process . Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis . RESULTS : We used DNA microarrays and meta - analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression . We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis . Caveolae and JAK / P35610 pathways , and P06702 / P05109 interacting proteins are certainly involved in the development of vascular disease . We found that the system of caveolae is directly connected with genes that respond to hormone receptors , and indirectly with the apoptosis pathway . Cytokines , chemokines and growth factors released in the blood flux were investigated in parallel . High levels of RANTES , IL - 1ra , MIP - 1 alpha , MIP - 1 beta , P60568 , P05112 , P05113 , P05231 , P13232 , Q16552 , DB00102 , P15692 and P01579 were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels . CONCLUSION : The pattern of cytokine and P06702 / P05109 up - regulation characterizes atherosclerosis as a proinflammatory disorder . Activation of the JAK / P35610 pathway is confirmed by the up - regulation of P05231 , P42224 , Q00978 and Q13651 genes in coronary and carotid plaques . The functional network constructed in our research is an evidence of the central role of P35610 protein and the caveolae system to contribute to preserve the plaque . Moreover , Cav - 1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype .","Response to DB08875 in patients with P07949 fusion - positive lung adenocarcinomas . The discovery of P07949 fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes . In an unselected population of non - small cell lung carcinomas ( NSCLCs ) , P07949 fusions are present in 1 % to 2 % of cases . This incidence increases substantially , however , in never - smokers with lung adenocarcinomas that lack other known driver oncogenes . Although preclinical data provide experimental support for the use of P07949 inhibitors in the treatment of P07949 fusion - positive tumors , clinical data on response are lacking . We report preliminary data for the first three patients treated with the P07949 inhibitor cabozantinib on a prospective phase II trial for patients with P07949 fusion - positive NSCLCs ( NCT01639508 ) . Confirmed partial responses were observed in 2 patients , including one harboring a novel Q9UPN9 - P07949 fusion . A third patient with a P33176 - P07949 fusion has had prolonged stable disease approaching 8 months ( 31 weeks ) . All three patients remain progression - free on treatment .","Endothelial progenitor cells in relation to endothelin - 1 and endothelin receptor blockade : a randomized , controlled trial . AIMS : Endothelial progenitor cells ( EPC ) represent an endogenous repair mechanism involving rendothelialization and neoangiogenesis . Patients with both diabetes and vascular disease have low numbers of circulating EPC . The endothelium - derived peptide , endothelin - 1 ( ET - 1 ) , is increased in patients with type 2 diabetes and vascular complications and has been suggested to contribute to endothelial dysfunction . Therefore , we investigated the relation between EPC and plasma ET - 1 and the effect of dual ET - 1 receptor antagonist treatment . METHODS : In this double blind study patients with type 2 diabetes mellitus and microalbuminuria were randomized to treatment with the dual P25101 / ETB receptor antagonist ___MASK7___ treatment ( 125mg bid ; n = 17 ) or placebo ( n = 19 ) for four weeks . Different EPC subpopulations were enumerated by flow cytometry using triple staining ( P28906 , CD133 , P35968 ) at baseline at the end of treatment . Viability was assessed by 7AAD and Annexin - V - staining . RESULTS : Baseline ET - 1 levels correlated significantly with P02741 levels . Patients with ET - 1 levels above the median value had higher levels of P28906 (+) CD133 (+) and P28906 (+) P35968 (+) EPC . There was no difference in P28906 (+) and P28906 (+) CD133 (+) P35968 (+) cells , markers of EPC apoptosis or circulating markers of endothelial damage between patients with ET - 1 levels below or above the median . Four week treatment with ___MASK7___ did not change EPC levels . CONCLUSION : Among patients with type 2 diabetes and vascular disease , high plasma levels of ET - 1 are associated with higher number of EPC . The recruitment of EPC does not seem to be regulated via ET - 1 receptor activation since treatment with a dual ET - 1 receptor blocker did not affect circulating EPC numbers .","Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK25___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .","DB08875 : a MET , P07949 , and P35968 tyrosine kinase inhibitor . DB08875 is a receptor tyrosine kinase inhibitor with activity against MET , P35968 , P36888 , c - P10721 , and P07949 . Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies . Of note , cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET . Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer ( P04629 ) , NSCLC , breast , ovarian , pancreatic , and prostate cancer . In P04629 , gain of function mutations of P07949 are central for tumorigenesis . Hereditary forms of P04629 ( MEN II ) are caused by germline mutations of P07949 , in sporadic P04629 in up to 50 % of cases P07949 mutations occur . Additionally , activating molecular changes in VEGFR and MET pathways have also been implicated in P04629 progression . Clinical responses with cabozantinib in P04629 could be observed in early clinical trials , and following confirmation of clinical benefit in a randomized phase III trial , cabozantinib gained FDA approval for first - line treatment of advanced P04629 in 2012 . In prostate cancer models , MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis . A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer . Therefore , randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients .","Regulation of mammalian cell cycle progression in the regenerating liver . The process of cell division in mammalian cells is orchestrated by cell - cycle - dependent oscillations of cyclin protein levels . P12004 levels are controlled by redundant transcriptional , post - translational and degradation feedback loops . How each of these separate loops contributes to the regulation of the key cell cycle events and to the connection between the P55008 - S transition and the subsequent mitotic events is under investigation . Here , we present an integrated computational model of the mammalian cell cycle based on the sequential activation of cyclins . We validate the model against experimental data on liver cells ( hepatocytes ) , which undergo one or two rounds of synchronous circadian - clock gated cell divisions during liver regeneration , after partial hepatectomy ( PH ) . The model exhibits bandpass filter properties that allow the system to ignore strong but transient , or sustained but weak damages after PH . Bifurcation analysis of the model suggests two different threshold mechanisms for the progression of the cell through mitosis . These results are coherent with the notion that the mitotic exit in mammalian cells is bistable , and suggests that Cdc20 homologue 1 ( Cdh1 ) is an important regulator of mitosis . Regulation by Cdh1 also explains the observed G2 / M phase prolongation after hepatocyte growth factor ( P14210 ) stimulation during S phase .","Immunological assessment of cryotherapy in breast cancer patients . BACKGROUND : In murine studies , cryotherapy has induced antitumor immune responses associated with the rejection of tumors . However , the effects of freezing - induced immunomodulation in breast cancer ( BC ) patients remain unclear . MATERIALS AND METHODS : Ten BC patients were prospectively divided into two groups : 1 ) cryotherapy followed by surgical excision and 2 ) surgical excision - alone . The cytokine profiles of plasma and peripheral blood mononuclear cells ( PBMCs ) were analyzed using flow cytometry following in vitro stimulation with the 30 - mer P15941 peptide . RESULTS : No differences in the percentages of interferon - γ ( IFN - γ ) - producing cluster of differentiation ( CD ) 4 (+) or CD8 (+) T cells and the plasma levels of IFN - γ , interleukin - 1β ( IL - 1β ) , P60568 , P05112 , P05113 , P05231 , P10145 , P22301 , IL - 12p70 , tumor necrosis factor - α ( P01375 - α ) and P01375 - β were observed between these 2 groups , and PBMCs were not significantly altered . CONCLUSION : Alternations to the type 1 and 2 helper cytokine profiles were not detected in vitro in BC patients treated with cryotherapy - alone .","A novel tumor necrosis factor - responsive transcription factor which recognizes a regulatory element in hemopoietic growth factor genes . A conserved DNA sequence element , termed cytokine 1 ( P04264 ) , is found in the promoter regions of many hemopoietic growth factor ( P14210 ) genes . Mutational analyses and modification interference experiments show that this sequence specifically binds a nuclear transcription factor , NF - GMa , which is a protein with a molecular mass of 43 kilodaltons . It interacts with different affinities with the P04264 - like sequence from a number of P14210 genes , including granulocyte macrophage colony - stimulating factor ( GM - P04141 ) , granulocyte ( G ) - P04141 , interleukin 3 ( P08700 ) , and P05113 . We show here that the level of NF - GMa binding is induced in embryonic fibroblasts by tumor necrosis factor - alpha ( P01375 ) treatment and that the P04264 sequence from the G - P04141 gene is a P01375 - responsive enhancer in these cells . The NF - GMa protein is distinct from another P01375 - responsive transcription factor , NF - kappa B , by several criteria . Firstly , several NF - kappa B - binding sites , although having sequence similarity with the P04264 sequence , can not compete efficiently for NF - GMa binding to P04264 . Secondly , the P04264 sequence from both G - P04141 and GM - P04141 does not respond to phorbol ester treatment as would an NF - kappa B - binding element . These results demonstrate that NF - GMa is a novel transcription factor inducible by P01375 and binds to a common element in P14210 gene promoters .","Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib - pairs in 64 sib - ships from families ascertained by early - onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib - pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation .","Notch4 - induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through P02753 - Jkappa . Notch proteins comprise a family of transmembrane receptors . Ligand activation of Notch releases the intracellular domain of the receptor that translocates to the nucleus and regulates transcription through the DNA - binding protein P02753 - Jkappa . Previously , it has been shown that the Notch4 intracellular region ( N4IC ) can inhibit endothelial sprouting and angiogenesis . Here , N4IC deletion mutants were assessed for their ability to inhibit human microvascular endothelial cell ( HMEC ) sprouting with the use of a quantitative endothelial sprouting assay . Deletion of the ankyrin repeats , but not the RAM ( P02753 - Jkappa associated module ) domain or C - terminal region ( CT ) , abrogated the inhibition of fibroblast growth factor 2 ( P09038 ) - and vascular endothelial growth factor ( P15692 ) - induced sprouting by Notch4 , whereas the ankyrin repeats alone partially blocked sprouting . The ankyrin repeats were also the only domain required for up - regulation of P02753 - Jkappa - dependent gene expression . Interestingly , enforced expression of the ankyrin domain alone was sufficient to up - regulate some , but not all , P02753 - Jkappa - dependent genes . Although N4IC reduced P15692 receptor - 2 ( P35968 ) and vascular endothelial ( VE ) - cadherin expression , neither of these events is necessary and sufficient to explain N4IC - mediated inhibition of sprouting . A constitutively active P02753 - Jkappa mutant significantly inhibited HMEC sprouting but not as strongly as N4IC . Thus , Notch4 - induced inhibition of sprouting requires the ankyrin repeats and appears to involve P02753 - Jkappa - dependent and - independent signaling .","Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK39___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .","Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK25___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .","Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .","DB08875 ( DB05153 ) , a novel MET and P35968 inhibitor , simultaneously suppresses metastasis , angiogenesis , and tumor growth . The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor ( P14210 ) is important for cell growth , survival , and motility and is functionally linked to the signaling pathway of P15692 , which is widely recognized as a key effector in angiogenesis and cancer progression . Dysregulation of the MET / P15692 axis is found in a number of human malignancies and has been associated with tumorigenesis . DB08875 ( DB05153 ) is a small - molecule kinase inhibitor with potent activity toward MET and P15692 receptor 2 ( P35968 ) , as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology , including P07949 , P10721 , P30530 , and P36888 . Treatment with cabozantinib inhibited MET and P35968 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro . In mouse models , cabozantinib dramatically altered tumor pathology , resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose - dependent inhibition of tumor growth in breast , lung , and glioma tumor models . Importantly , treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis , which has been observed with inhibitors of P15692 signaling that do not target MET . Collectively , these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling .","Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF - α / P15692 / Rho - GTPases : pivotal role of P35610 - 3 . Our previous studies have shown that benzyl isothiocyanate ( BITC ) suppresses pancreatic tumor growth by inhibiting P35610 - 3 ; however , the exact mechanism of tumor growth suppression was not clear . Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis . Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken - Chorioallantoic membrane . Furthermore , BITC blocks the migration and invasion of BxPC - 3 and PanC - 1 pancreatic cancer cells in a dose dependant manner . Moreover , secretion of P15692 and P08253 in normoxic and hypoxic BxPC - 3 and PanC - 1 cells was significantly suppressed by BITC . Both P15692 and P08253 play a critical role in angiogenesis and metastasis . Our results reveal that BITC significantly suppresses the phosphorylation of P35968 ( DB00135 - 1175 ) , and expression of HIF - α . Rho - GTPases , which are regulated by P15692 play a crucial role in pancreatic cancer progression . BITC treatment reduced the expression of RhoC whereas up - regulated the expression of tumor suppressor RhoB . P35610 - 3 over - expression or P05231 treatment significantly induced HIF - 1α and P15692 expression ; however , BITC substantially suppressed P35610 - 3 as well as P35610 - 3 - induced HIF - 1α and P15692 expression . Finally , in vivo tumor growth and matrigel - plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC , indicating reduced tumor angiogenesis . Immunoblotting of BITC treated tumors show reduced expression of P35610 - 3 phosphorylation ( DB00135 - 705 ) , HIF - α , P35968 , P15692 , P08253 , CD31 and RhoC . Taken together , our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through P35610 - 3 - dependant pathway .","Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK25___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .","Serum levels of antibodies to thyroid peroxidase correlate with quantitative descriptors of thyroid ultrasound images in patients with breast cancer . The aim of the study was to compare the structural changes in ultrasound image of the thyroid tissue in 12 women with breast cancer ( BC ) and 8 women with colorectal cancer ( CC ) . MATLAB software was used to analyse the digitised images . As quantitative descriptors of thyroid ultrasound images ( QDTI ) were used raw grey scale values of individual image pixels ( RAW ) and the optimal one - dimensional discriminative texture features ( F2 , F6 , P08709 ) . The possible relations between QDTI and thyroid laboratory parameters were tested . In the BC group serum levels of antibodies to thyroid peroxidase negatively correlated with feature RAW ( multiple regression , beta coefficient - 0 . 75 , p = 0 . 004 ) and positively with feature F2 ( multiple regression , beta coefficient 1 . 44 , p = 0 . 04 ) . In the BC group RAW negatively correlated with serum levels of tumour marker P15941 ( Pearson ' s correlation coefficient , r =- 0 . 714 , p = 0 . 00917 ) . No such correlations were found in CC group . The correlations between QDTI and serum levels of antibodies to thyroid peroxidase in patients with BC show that the positivity of antibodies to thyroid peroxidase is probably accompanied with structural changes in the thyroid tissue .","Pharmacogenetics in chemotherapy of colorectal cancer . Although in recent years , chemotherapeutic options for colorectal carcinoma have expanded , overall response rates are still too low , with high rates of toxicity . Pharmacogenetics aim at predicting both treatment response and adverse effects in individual patients . This review describes the current knowledge of pharmacogenetic markers in the systemic treatment of colorectal cancer . P22309 * 28 leads to reduced conjugation of SN - 38 , the active metabolite of irinotecan , resulting in an increased rate of adverse effects , especially neutropenia . To a lesser extent , increased DB00544 toxicity is predicted by Q12882 * 2A . A variable number of tandem repeats polymorphism in the thymidylate synthase enhancer region , in combination with a single nucleotide polymorphism C > G , may predict poorer response to DB00544 . Efficacy of oxaliplatin is influenced by polymorphisms in components of DNA repair systems , such as P07992 and P18887 . Polymorphic changes in the endothelial growth factor receptor probably predict cetuximab efficacy . Furthermore , the antibody - depended cell - mediated cytotoxic effect of cetuximab may be reduced by polymorphisms in the immunoglobin G fragment C receptors . DB00112 efficacy is suspected to be influenced by polymorphisms in the P15692 gene and the hypoxia inducible factor 1alpha gene . Although the interpretation of pharmacogenetic studies is complicated , results imply a promising way of pretreatment prediction of chemotherapy efficacy and toxicity .","Targeting MET and vascular endothelial growth factor receptor signaling in castration - resistant prostate cancer . Effective management of bone metastases in men with castration - resistant prostate cancer ( CRPC ) remains an important unmet medical need . MET and vascular endothelial growth factor receptor ( VEGFR ) are rational targets for intervention in CRPC . Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival . DB08875 is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and P35968 . A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans , bone turnover markers , and pain response , but with significant adverse events leading to dose reduction and treatment discontinuation . Lower doses of cabozantinib retain high levels of activity with less toxicity . Ongoing phase III clinical trials will define the role of cabozantinib in CRPC . We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date .","Targetting esophageal and gastric cancers with monoclonal antibodies . Target therapies and notably monoclonal antibodies are currently being considered for esophageal , gastric , and gastroesophageal junction cancers . P00533 was found to be overexpressed in 60 - 86 % of gastric or gastroesophageal tumors and in 50 - 70 % of esophageal cancers . Cetuximab was shown to be a radiosensitizing agent in the treatment of ENT neoplasia . These results led to several phase II encouraging therapeutic trials evaluating the combination of cetuximab with radiochemotherapy in locally advanced esophageal cancers . Numerous encouraging phase II trials evaluating cetuximab combined with chemotherapy in patients with gastric adenocarcinoma or gastroesophageal junction cancer were reported . These promising results are still to be confirmed by the ongoing phase III trials . Several studies reported P04626 overexpression in gastric cancer ( 7 - 34 % ) , which appeared to be associated with poorer prognosis . ___MASK21___ is a monoclonal antibody directed against the extracellular P04626 domain . The international phase III trial known as ToGA ( ___MASK21___ for Gastric Cancer ) aimed to determine the clinical efficacy and acceptable toxicity profile of trastuzumab in combination with first - line chemotherapy in P04626 - overexpressing gastric or gastroesophageal cancer . Angiogenesis is an essential step in the initial phase of tumorigenesis , and it is normally absent from healthy tissues except for particular physiological situations , such as wound healing . P15692 plays a role in endothelial growth and angiogenesis . DB00112 , a humanized monoclonal anti - P15692 antibody , is currently being studied for gastric cancer . The phase III AVAGAST study , evaluating bevacizumab in association with chemotherapy in advanced gastric adenocarcinoma , did not achieve its primary aim of improved OS in bevacizumab - treated patients .","Suppression of proliferation and migration in highly - metastatic lung cancer cells as well as tumor growth by a new synthesized compound TBrC and its molecular mechanisms of action . To develop new anticancer agents has been considered as a useful and necessary strategy to suppress highly - metastatic lung cancer , the leading cause of cancer - related deaths in the world . In this study , we synthesized a new compound ethyl 6 - bromocoumarin - 3 - carboxylyl L - theanine ( TBrC ) and studied the anticancer activity of TBrC and its molecular mechanisms of action . Our results show that TBrC remarkably inhibits the proliferation and migration in highly - metastatic lung cancer cells by inducing apoptosis and cell cycle arrest as well as regulating related protein expressions . Further study indicated that TBrC not only enhances the protein levels of Bax , cytosolic cytochrome c , caspase - 3 and P09874 but also reduces the protein expressions of Bcl - 2 , cyclin D1 , P17948 and NF - κB as well as inhibits the phosphorylation and expressions of P35968 and Akt in the cancer cells . More importantly , TBrC displays strong suppression of highly - metastatic tumor growth and reduces the tumor weight by 61 . 6 % in tumor - bearing mice without toxicity to the mice . Our results suggest that TBrC suppresses the proliferation and migration of lung cancer cells via VEGFR - Akt - NF - κB signaling pathways ; TBrC may have a wide therapeutic and / or adjuvant therapeutic application in the treatment of lung cancer .","Targeted therapy in gastric cancer . Gastric cancer is often diagnosed at an advanced stage . Although chemotherapy prolongs survival and improves quality of life , the survival of gastric cancer patients with advanced disease is short . Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis , new targeted treatment options have become available for gastric cancer patients . ___MASK21___ , an antibody targeted to HER - 2 , was shown to improve survival of advanced gastric cancer patients harboring HER - 2 overexpression due to gene amplification in their tumor cells , and is currently also explored in adjuvant and neoadjuvant settings . Another agent with promising results in clinical trials is ramucirumab , an antibody targeting P35968 . No clear survival benefit , however , were experienced with agents targeting P00533 ( cetuximab , panitumumab ) , P15692 ( bevacizumab ) , or P42345 ( everolimus ) . Drugs targeting c - MET / P14210 are currently under investigation in biomarker - selected cohorts , with promising results in early clinical trials . This review will summarize the current status of targeted treatment options in gastric cancer .","Adeno - associated virus - mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs . We have previously shown that VEGF165 gene delivery into ischemic skeletal muscle exerts not only proangiogenic , but also remarkable antiapoptotic and proregenerative activity . The aim of this study was to determine whether recombinant adeno - associated virus ( rAAV ) - mediated gene delivery of VEGF165 into cardiac muscle , during acute myocardial infarction , exerts a protective effect to promote long - term functional recovery . Acute infarction of the anterior LV wall was induced in 12 chronically instrumented dogs by permanent occlusion of the LAD coronary artery . Four hours after occlusion , rAAV - VEGF165 or rAAV - LacZ ( n = 6 each ; 5x10 ( 12 ) viral particles per animal ) was directly injected with an echo - guided needle into the dysfunctional cardiac wall . LV and arterial pressure , dP / dtmax , and ejection fraction were not significantly different between the two groups over time . In contrast , in the infarcted region , at four weeks after infarction , fractional shortening was 75 +/- 18 % and - 3 +/- 15 % of baseline and length - pressure area was 54 +/- 15 % and 0 . 8 +/- 15 % of baseline in VEGF165 versus LacZ , respectively ( P < 0 . 05 ) . Histological analysis of the border regions showed a marked increase in the number of alpha - SMA - positive arterioles ( 68 +/- 2 . 8 versus 100 +/- 3 . 8 vessels per microscopic field in LacZ and VEGF165 group , respectively ; P < 0 . 05 ) . In both groups , the receptor P35968 was diffusely expressed on the surviving cardiomyocytes and , consistently , myocardial viability was significantly improved in the VEGF165 - treated group , with several troponin T - expressing cardiomyocytes displaying nuclear positivity for the proliferation marker P12004 . Altogether , our results indicate that VEGF165 gene delivery exerts a marked beneficial action by enhancing both arteriologenesis and cardiomyocyte viability in infarcted myocardium .","Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK94___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .","DB08875 and prostate cancer : inhibiting seed and disrupting soil ? Treatment with cabozantinib , an inhibitor of MET and P35968 signaling , has demonstrated clinical benefit in early trials in men with metastatic prostate cancer . Preclinical evidence suggests that cabozantinib can kill cancer cell seeds while disrupting angiogenesis and stromal cells in the metastatic soil .","Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .","Rare mutations in non - small - cell lung cancer . In the last decade , new insights in molecular biology have changed the therapeutic landscape of non - small - cell lung cancer . Since 2004 , when activating mutations of the P00533 were firstly identified , several genetic aberrations have been discovered , mainly in adenocarcinoma . P00533 mutations are a relatively frequent event in non - small - cell lung cancer , generally consisting of exon 19 deletion or exon 21 substitution . In adenocarcinoma , additional rare mutations are detectable in the P00533 gene , as well as in other genes , including Q9UM73 , P08922 , P07949 , P04626 and P15056 . Recent studies in squamous cell carcinoma identified P04637 as the most frequent mutation , followed by additional more rare mutations , including PI3KCA , P60484 , Q16832 and FGFR . The aim of the present review is to analyze the potential prognostic and predictive role of rare mutations .","A phase I study of cabozantinib ( DB05153 ) in patients with differentiated thyroid cancer . BACKGROUND : DB08875 targets tyrosine kinases including MET , vascular endothelial growth factor ( P15692 ) receptor 2 , and rearranged during transfection ( P07949 ) . Differentiated thyroid cancer ( DTC ) is a tumor type that may be sensitive to cabozantinib . Therefore , we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC . METHODS : This single - arm open - label phase I trial assessed the safety , tolerability , and antitumor activity of cabozantinib in DTC patients taking part in a drug - drug interaction study . Adult patients with histologically confirmed metastatic or surgically unresectable DTC ( including papillary , follicular , or Hürthle cell ) were enrolled . Patients received daily oral dosing of 140 mg cabozantinib . Safety was assessed by evaluation of adverse events ( AEs ) , vital signs , electrocardiograms , laboratory tests , and concomitant medications . Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors ( RECIST ) v1 . 0 . RESULTS : The study enrolled 15 patients who had failed standard radioactive iodine therapy . Patients had received a median of two prior systemic agents , and 11 patients ( 73 % ) had previously received at least one P15692 pathway inhibiting therapy . Common AEs included diarrhea , nausea , fatigue , and decreased appetite . Partial response was reported in eight patients ( 53 % ) . Median progression - free survival and median overall survival were not reached . CONCLUSIONS : DB08875 demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients . The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC .","DB08875 overcomes crizotinib resistance in P08922 fusion - positive cancer . PURPOSE : P08922 rearrangement leads to constitutive P08922 activation with potent transforming activity . In an ongoing phase I trial , the Q9UM73 tyrosine kinase inhibitor ( TKI ) crizotinib shows remarkable initial responses in patients with non - small cell lung cancer ( NSCLC ) harboring P08922 fusions ; however , cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in P08922 . Thus , understanding the crizotinib - resistance mechanisms in P08922 - rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required . EXPERIMENTAL DESIGN : The sensitivity of P04233 - P08922 - transformed Ba / P13726 cells to multiple Q9UM73 inhibitors was examined . Acquired P08922 inhibitor - resistant mutations in P04233 - P08922 fusion were screened by N - ethyl - N - nitrosourea mutagenesis with Ba / P13726 cells . To overcome the resistance mutation , we performed high - throughput drug screening with small - molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials . The effect of the identified drug was assessed in the P04233 - P08922 - mutant Ba / P13726 cells and crizotinib - resistant patient - derived cancer cells ( MGH047 ) harboring G2032R - mutated P04233 - P08922 . RESULTS : We identified multiple novel crizotinib - resistance mutations in the P08922 kinase domain , including the G2032R mutation . As the result of high - throughput drug screening , we found that the cMET / P07949 / VEGFR inhibitor cabozantinib ( DB05153 ) effectively inhibited the survival of P04233 - P08922 wild - type ( WT ) and resistant mutants harboring Ba / P13726 and MGH047 cells . Furthermore , cabozantinib could overcome all the resistance by all newly identified secondary mutations . CONCLUSIONS : We developed a comprehensive model of acquired resistance to P08922 inhibitors in NSCLC with P08922 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance .","Serum hepcidin levels and reticulocyte hemoglobin concentrations as indicators of the iron status of peritoneal dialysis patients . P81172 is the key mediator of renal anemia , and reliable measurement of serum hepcidin levels has been made possible by the ProteinChip system . We therefore investigated the iron status and serum hepcidin levels of peritoneal dialysis ( PD ) patients who had not received frequent doses of an erythrocytosis - stimulating agent ( Q14254 ) and had not received iron therapy . In addition to the usual iron parameters , the iron status of erythrocytes can be determined by measuring reticulocyte hemoglobin ( P07949 - He ) . The mean serum hepcidin level of the PD patients ( n = 52 ) was 80 . 7 ng / mL . Their serum hepcidin levels were significantly positively correlated with their serum ferritin levels and transferrin saturation ( TSAT ) levels , but no correlations were found between their serum hepcidin levels and P07949 - He levels , thereby suggesting that hepcidin has no effect on the iron dynamics of reticulocytes . Since low serum levels of CRP and P05231 , biomarkers of inflammation , were not correlated with the serum hepcidin levels , there is likely to be a threshold for induction of hepcidin expression by inflammation .","Antipruritic activity of the kappa - opioid receptor agonist , P04629 - 820 . The effects of the kappa - opioid receptor agonist , P04629 - 820 , (-)- 17 -( cyclopropylmethyl )- 3 , 14beta - dihydroxy - 4 , 5alpha - epoxy - 6beta - [ N - methyl - trans - 3 -( 3 - furyl ) acrylamido ] morphinan hydrochloride , on the itch sensation were compared with those of histamine H1 receptor antagonists , using the mouse pruritogen - induced scratching model . Peroral administration of P04629 - 820 reduced the numbers of DB05875 - or histamine - induced scratches dose dependently . No obvious suppression of the spontaneous locomotor activity was observed at the doses used for the experiments , indicating that the inhibition of scratches was not due to the effect on general behavior . Furthermore , the scratching inhibitory activity of P04629 - 820 was dose dependently antagonized by the specific kappa - opioid receptor antagonist , nor - binaltorphimine , suggesting that the inhibitory activity was mediated via kappa - opioid receptors . P35367 antagonists , chlorpheniramine and ketotifen , did not inhibit DB05875 - induced scratches , or did so only partially . Both antihistamines inhibited the histamine - induced scratches completely . These results suggest that P04629 - 820 has antipruritic activity which is mediated by kappa - opioid receptors , and is effective in both antihistamine - sensitive and - resistant pruritus .","DB08875 inhibits prostate cancer growth and prevents tumor - induced bone lesions . PURPOSE : DB08875 , an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor ( MET ) and P15692 receptor 2 ( P35968 ) , induces resolution of bone scan lesions in men with castration - resistant prostate cancer bone metastases . The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect , an indirect effect through modulating bone , or both . EXPERIMENTAL DESIGN : Using human prostate cancer xenograft studies in mice , we determined the impact of cabozantinib on tumor growth in soft tissue and bone . In vitro studies with cabozantinib were performed using ( i ) prostate cancer cell lines to evaluate its impact on cell growth , invasive ability , and MET and ( ii ) osteoblast cell lines to evaluate its impact on viability and differentiation and P35968 . RESULTS : DB08875 inhibited progression of multiple prostate cancer cell lines ( Ace - 1 , C4 - 2B , and LuCaP 35 ) in bone metastatic and soft tissue murine models of prostate cancer , except for PC - 3 prostate cancer cells in which it inhibited only subcutaneous growth . DB08875 directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro . DB08875 had a dose - dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo . It blocked MET and P35968 phosphorylation in prostate cancer cells and osteoblast - like cells , respectively . CONCLUSION : These data indicate that cabozantinib has direct antitumor activity , and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy .","Activation and translocation of PKCdelta is necessary for P15692 - induced P29323 activation through P35968 in HEK293T cells . P15692 - P35968 / Flk - 1 signal utilizes the phospholipase C - gamma - protein kinase C ( PKC ) - Raf - MEK - P29323 pathway as the major signaling pathway to induce gene expression and P47712 phosphorylation . However , the spatio - temporal activation of a specific PKC isoform induced by P15692 - P35968 signal has not been clarified . We used HEK293T ( human embryonic kidney ) cells expressing transiently P35968 to examine the activation mechanism of PKC . PKC specific inhibitors and human PKCdelta knock - down using siRNA method showed that PKCdelta played an important role in P15692 - P35968 - induced P29323 activation . P29966 ( P29966 ) translocates from the plasma membrane to the cytoplasm depending upon phosphorylation by PKC . Translocation of P29966 - GFP induced by P15692 - P35968 stimulus was blocked by rottlerin , a PKCdelta specific inhibitor , or human PKCdelta siRNA . P15692 - P35968 stimulation did not induce P29323 phosphorylation in human PKCdelta - knockdown HEK293T cells , but co - expression of rat PKCdelta - GFP recovered the P29323 phosphorylation . Y311 / 332F mutant of rat PKCdelta - GFP which can not be activated by tyrosine - phosphorylation but activated by DAG recovered the P29323 phosphorylation , while C1B - deletion mutant of rat PKCdelta - GFP , which can be activated by tyrosine - phosphorylation but not by DAG , failed to recover the P29323 phosphorylation in human PKCdelta - knockdown HEK293T cell . These results indicate that PKCdelta is involved in P15692 - P35968 - induced P29323 activation via C1B domain .","[ Study of the expression of neural stem cell markers in neuroblastoma tumor samples and correlation with prognostic factors ] . INTRODUCTION : The existence of cancer stem cells ( CSC ) in neuroblastoma ( NB ) has been associated with the development of metastasis , resistance to chemotherapy and recurrence . Our objective is to analyze the expression of proliferation and differentiation markers of neural progenitor cells in NB samples , and to correlate this expression with clinical variables such as histology , genetics and response to conventional therapy . MATERIAL AND METHODS : We performed a retrospective - experimental study with neuroblastoma samples obtained from biopsies or tumor resections between 2010 - 2012 in our Hospital . Fluorescence immunohistochemistry was used to analyze the expression of the different markers : P16070 , P04233 , CD133 , tyrosine hydroxylase , endothelin receptors type A ( P25101 ) and B ( ETB ) , p75 , nestina y and Phox2b , all of them related to neural stem cell biology . The level of expression of the markers was then correlated with clinical variables . RESULTS : P48681 expression was positive in 72 . 2 % of samples and P25101 in 66 . 7 % . Q99453 and P04233 expression were lower , being positive in less than 30 % . The markers P16070 , ETB and Q99453 were expressed in more aggressive tumors . P25101 expression correlated significantly with unfavorable histology tumors ( p = 0 . 01 ) , N - myc amplification ( p = 0 . 05 ) and recurrence / progression ( p = 0 . 05 ) . CONCLUSION : The expression of P16070 , ETB and P25101 was associated with more aggressive tumors and poor prognostic factors . These markers are in the membrane of neural stem cells and may be useful to identify and isolate by flow cytometry CSCs of NB for the study of new therapeutic targets .","Noncatalytic function of P27361 / 2 can promote Raf / MEK / P29323 - mediated growth arrest signaling . Kinase activity is known as the key biochemical property of MAPKs . Here , we report that P27361 / 2 also utilizes its noncatalytic function to mediate certain signal transductions . Sustained activation of the Raf / MEK / P29323 pathway induces growth arrest , accompanied by changes in cell cycle regulators ( decreased retinoblastoma phosphorylation , Q01094 down - regulation , and / or P38936 ( CIP1 ) up - regulation ) and cell type - specific changes in morphology and expression of c - Myc or P07949 in the human tumor lines LNCaP , U251 , and TT . Ablation of P27361 / 2 by RNA interference abrogated all these effects . However , active site - disabled P29323 mutants ( P27361 - K71R , P28482 - K52R , and P28482 - D147A ) , which competitively inhibit activation of endogenous P27361 / 2 , could not block Raf / MEK - induced growth arrest as well as changes in the cell cycle regulators , although they effectively blocked phosphorylation of the P27361 / 2 catalytic activity readouts , p90 ( RSK ) and ELK1 , as well as the cell type - specific changes . Because this indicated a potential noncatalytic P27361 / 2 function , we generated stable lines of the tumor cells in which both P27361 and P28482 were significantly knocked down , and we further investigated the possibility using rat - derived kinase - deficient P29323 mutants ( P28482 - K52R and P28482 - T183A / Y185F ) that were not targeted by human small hairpin RNA . Indeed , P28482 - K52R selectively restored Raf - induced growth inhibitory signaling in P27361 / 2 - depleted cells , as manifested by regained cellular ability to undergo growth arrest and to control the cell cycle regulators without affecting c - Myc and morphology . However , P28482 - T183A / Y185F was less effective , indicating the requirement of TEY site phosphorylation . Our study suggests that functions of P27361 / 2 other than its \" canonical \" kinase activity are also involved in the pathway - mediated growth arrest signaling .","SAR131675 , a potent and selective P35916 - TK inhibitor with antilymphangiogenic , antitumoral , and antimetastatic activities . SAR131675 is a potent and selective P35916 inhibitor . It inhibited P35916 tyrosine kinase activity and P35916 autophosphorylation in P29320 cells with IC ( 50 ) values of 20 and 45 nmol / L , respectively . SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells , induced by the P35916 ligands P49767 and O43915 , with an IC ( 50 ) of about 20 nmol / L . SAR131675 was found to be highly selective for P35916 versus 107 receptors , enzymes , ion channels , and 65 kinases . However , it was moderately active on P35968 with a P35916 / P35968 ratio of about 10 . SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells , further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent . SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models , including mammary 4T1 carcinoma and Q13546 . Tag2 tumors . Interestingly , it significantly reduced lymph node invasion and lung metastasis , showing its antilymphangiogenic activity in vivo . Moreover , treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis . Tumor - associated macrophages ( TAM ) play an important role in tumor growth and metastasis . The expression of P35916 on TAMs has been recently described . F4 / 80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors . Taken together , SAR131675 is the first highly specific P35916 - TK inhibitor described to date , displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion .","Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK7___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK7___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .","Antagonism of endothelin action normalizes altered levels of P15692 and its signaling in the brain of stroke - prone spontaneously hypertensive rat . Stroke - prone spontaneously hypertensive rats ( SHRSP ) often suffer from spontaneous stroke , in part , due to abnormalities in the cerebrovasculature . Here , we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age - dependent stages of hypertension . The profile of P15692 and its receptor , Flk - 1 , was dependent on age and stage of hypertension ( i . e . , down regulated at pre - hypertensive and malignant hypertensive stages , but up regulated at typical hypertensive stage ) , while that of its downstream components , pAkt and P29474 , were down regulated in a time - dependent manner in the frontal cortex of SHRSP compared to age - matched genetic control , normotensive WKY rats . On the other hand , the expression of endothelin - 1 and its type A receptor ( endothelin P25101 receptor ) were up regulated , depending on age and stage of hypertension . In contrast , levels of endothelin type B receptor were down regulated . The regional cerebral blood flow decreased during the development of malignant hypertension . Thus , subsequent experiments were designed to investigate whether endothelin - 1 receptor antagonism , using endothelin - A /- B dual receptor antagonist SB209670 , could normalize the molecular profile of these factors in SHRSP brain . Interestingly , blockage of endothelin - 1 receptor restored to normal , levels of cerebral endothelin - 1 , endothelin P25101 receptor and endothelin ETB receptor ; P15692 and Flk - 1 ; endothelial nitric oxide synthase ( P29474 ) and pAkt , in SHRSP , compared to age - matched WKY . Endothelin receptor blocker might be important to prevent the progression in the defect in P15692 and its angiogenic signaling cascade in the pathogenesis of hypertension - induced vascular remodeling in frontal cortex of SHRSP rats .","Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer . Medullary thyroid cancer is an uncommon malignancy for which until recently little effective treatment existed . It is often characterized by mutation and overexpression of the receptor tyrosine kinases P07949 ( rearranged during transfection ) , P35968 ( vascular endothelial growth factor receptor 2 ) and MET ( mesenchymal - epithelial transition factor ) , which make attractive targets for drug development . DB08875 is an orally bioavailable tyrosine kinase inhibitor which blocks MET , VEGRF2 and P07949 , and has shown considerable activity in medullary thyroid cancer in a Phase III trial , including in heavily pretreated patients . Its novel combination of vascular endothelial growth factor and MET inhibition is believed to address the MET escape pathway , which is thought to be the cause of nonsustained tumor responses resulting from inhibition of vascular endothelial growth factor alone .","Characterization and binding activity of the chondroitin / dermatan sulfate chain from Endocan , a soluble endothelial proteoglycan . Endocan is a recently identified soluble chondroitin / dermatan sulfate ( CS / DS ) proteoglycan . Synthesized by endothelial cells , it has been found to be over - expressed in the vasculature surrounding a number of tumors , and by promoting growth factor mitogenic activities , hepatocyte growth factor / scatter factor ( P14210 / SF ) in particular , it supports cellular proliferation . In this work , we characterized the glycosaminoglycan ( GAG ) chain of Endocan , purified either from the naturally producing human umbilical vein endothelial cells ( HUVEC ) or from a recombinant over - expression system in human embryonic kidney cells ( P29320 ) . Compositional analysis using different chondroitinases as well as nuclear magnetic resonance studies revealed that the GAG chains from both sources share many characteristics , with the exception of size ( 15 and 40 kDa , respectively , for HUVEC and P29320 - 293 cells ) . The DS - specific , IdoA - containing disaccharides contribute 30 % of the chain ( 15 % of which are 2 - O - sulfated ) and are mostly clustered in tetra - ( 35 % ) , hexa - ( 12 % ) , and octa - ( 5 % ) saccharide domains . Highly sulfated D , E , and B disaccharide units ( HexA2S - GalNAc6S , HexA - GalNAc4S6S , and HexA2S - GalNAc4S ) were also detected in significant amounts in both chains and may account for the P14210 / SF - binding activity of the CS / DS . This work establishes that P29320 - 293 cells can be engineered to provide a valuable source of Endocan with authentic CS / DS chains , enabling the purification of sufficient amounts for structural and / or binding analysis and providing a possible model of Endocan CS / DS chain organization .","P01138 - withdrawal induces apoptosis in pancreatic beta cells in vitro . AIMS / HYPOTHESIS : Using primary cultures of human pancreatic islets , purified human pancreatic beta cells and the mouse beta TC6 - P08709 cell line , we analysed the expression of nerve growth factor , ( P01138 / P01138 ) receptors in beta cells . To investigate whether P01138 could sub - serve an autocrine antiapoptotic role in beta cells , we studied the effects of P01138 withdrawal using a neutralizing monoclonal anti - P01138 antibody . METHODS : The expression of P01138 and P01138 receptors ( gp140 ( P04629 ) and p75 ( NTR ) ) were analysed by RT - PCR and immunofluorescence . Pulse - chase experiments and beta cell / PC12 co - cultures were used to investigate P01138 production and secretion from beta cells . Possible apoptosis induced by P01138 withdrawal was monitored by phosphatidylserine translocation , nucleosomal formation , DNA laddering and FACS analysis . Involvement of transcription / translation mechanisms were investigated as well as the gp140 ( P04629 ) required . Finally , signal transduction pathways typically involved in apoptotic mechanisms were analysed by western blot analysis . RESULTS : We show that P01138 and both P01138 receptors , gp140 ( P04629 ) and p75 ( NTR ) are expressed in beta cells where P01138 is produced and secreted in a biologically active form . P01138 - withdrawal induces beta - cell transcription / translation independent apoptosis but mediated by gp140 ( P04629 ) . Analysis of signal transduction pathways revealed that P01138 withdrawal inhibits the P19957 - K , protein kinase B ( AKT ) , Bad survival pathway and activates c - Jun kinase ( JNK ) whereas ERKs and p38 mitogen - activated protein kinase ( MAPK ) are not affected . Moreover , Bcl - XL , but not Bcl - 2 protein expression are reduced . CONCLUSION / INTERPRETATION : We suggest that the integrity of the P01138 / P08138 system and P01138 bioavailability participate in controlling beta - cell survival in culture which represents a key issue for improving possibilities for transplantations in the treatment of diabetes .","DB08875 suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of P35968 and MET . PURPOSE : MET signaling has been suggested a potential role in hepatocellular carcinoma ( HCC ) and associated with prometastasis during antiangiogenesis therapy . We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC . Antitumor effects of cabozantinib , a dual inhibitor of MET and P35968 , were examined in cultured HCC cells as well as in vivo models . EXPERIMENTAL DESIGN : Total MET and phosphorylated MET ( p - MET ) were measured in 29 resected HCC specimens , and correlated with response to sorafenib as postoperative adjuvant therapy . In the second set of experiments using cultured HCC cells , and mouse xenograft and metastatic models , effects of cabozantinib were examined . RESULTS : High level of p - MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy . In cultured HCC cells that expressed p - MET , cabozantinib inhibited the activity of MET and its downstream effectors , leading to P55008 - phase arrest . DB08875 inhibited tumor growth in p - MET - positive and p - MET - negative HCC by decreasing angiogenesis , inhibiting proliferation , and promoting apoptosis , but it exhibited more profound efficacy in p - MET - positive HCC xenografts . DB08875 blocked the hepatocyte growth factor ( P14210 ) - stimulated MET pathway and inhibited the migration and invasion of the HCC cells . Notably , cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model . CONCLUSIONS : Patients with HCC with high level of p - MET are associated with resistance to adjuvant sorafenib treatment . The dual blockade of P35968 and MET by cabozantinib has significant antitumor activities in HCC , and the activation of MET in HCC may be a promising efficacy - predicting biomarker . Clin Cancer Res ; 20 ( 11 ) ; 2959 - 70 . © 2014 AACR .","Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .","DB08875 : a review of its use in patients with medullary thyroid cancer . DB08875 ( Cometriq (®) ) is an orally administered small molecule inhibitor of multiple tyrosine kinase receptors , including those involved in the pathogenesis of medullary thyroid cancer ( P04629 ) [ i . e . rearranged during transfection ( P07949 ) , MET and vascular endothelial growth factor receptor ( VEGFR ) - 2 ] . DB08875 is indicated for the treatment of adults with progressive , unresectable locally advanced ( in the EU ) or metastatic ( in the EU and USA ) P04629 . Compared with placebo , cabozantinib significantly prolonged progression - free survival , reflecting a 72 % reduction in the risk of disease progression or death , in patients with unresectable , locally advanced or metastatic P04629 participating in a multinational , phase III study . A significantly higher proportion of patients receiving cabozantinib than those receiving placebo achieved an objective response or disease stabilization ( i . e . a complete or partial response , or stable disease ) . The overall survival benefit with cabozantinib is as yet unclear , with no significant benefit observed in two interim analyses ( one prespecified , and one unplanned and conducted at the request of the US FDA ) . The tolerability profile of oral cabozantinib is typical for a small molecule targeting the VEGFR and other tyrosine kinase - mediated pathways , with adverse events associated with the inhibition of the P15692 pathway ( e . g . gastrointestinal perforation , haemorrhage , hypertension and venous thrombosis ) reported in the phase III study . Treatment - emergent adverse events were generally managed with supportive therapy , dose reductions and / or dose interruptions . Although final overall survival data are awaited , current evidence suggests cabozantinib to be a valuable treatment option for adults with progressive , unresectable locally advanced or metastatic P04629 .","Expressed luciferase viability assay ( ELVA ) for the measurement of cell growth and viability . An expressed luciferase viability assay ( ELVA ) has been developed for cell viability and cell number based on detecting the expression of luciferase transfected into the cells . Stable transfectants were produced that expressed luciferase constitutively . Like many endogenous enzymes , luciferase is rapidly degraded following cell death , so that the enzyme can be used as a measure of cell viability . A modified luciferase assay was used in which the reagents were added directly to the cells in a microplate . The main advantages compared to other cell viability assays are the wide dynamic range , high sensitivity , low background , and the absence of any requirement to wash or harvest the cells . Stable transfectants of three factor - dependent cell lines ( B13 , Ba / P13726 and CTLL ) were produced and used in cytokine assays . Three strategies of selection after electroporation were tested : ( 1 ) using a plasmid containing both the genes encoding firefly luciferase and a selectable marker ( neo ) , ( 2 ) cotransfection of a plasmid containing luciferase and a plasmid containing a selectable marker ( puromycin resistance ) , and ( 3 ) cotransfection of a plasmid containing luciferase and a plasmid containing the human IL - 5Ralpha - chain , and selecting in P05113 . This latter strategy produces an P05113 responsive cell line expressing luciferase in a single step without the need for antibiotic selection .","A dose - ranging study of cabozantinib in men with castration - resistant prostate cancer and bone metastases . BACKGROUND : DB08875 is an oral MET / P35968 inhibitor . A recent phase II study of cabozantinib ( 100 mg daily ) showed improved bone scans in subjects with metastatic castration - resistant prostate cancer ( mCRPC ) , but adverse events ( AE ) caused frequent dose reductions . This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses . EXPERIMENTAL DESIGN : An adaptive design was used to determine the lowest active daily dose among 60 , 40 , and 20 mg . The primary endpoint was week 6 bone scan response , defined as ≥ 30 % decrease in bone scan lesion area . The secondary endpoint was change in circulating tumor cells ( CTC ) . RESULTS : Among 11 evaluable subjects enrolled at 40 mg , there were 9 partial responses ( PR ) , 1 complete response , and 1 stable disease ( SD ) . Of 10 subjects subsequently enrolled at 20 mg , there were 1 PR , 5 SDs , and 4 with progressive disease . Among 13 subjects enrolled on the 40 mg expansion cohort , there were 6 PRs and 7 SDs . No subjects required dose reduction or treatment interruption at 6 or 12 weeks ; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks . At 40 mg , median treatment duration was 27 weeks . 58 % of subjects with ≥ 5 CTCs / 7 . 5 mL at baseline converted to < 5 . CONCLUSIONS : DB08875 40 mg daily was associated with a high rate of bone scan response . DB08875 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily . These observations informed the design of phase III studies of cabozantinib in mCRPC .","Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .","DB08875 for the treatment of advanced medullary thyroid cancer . INTRODUCTION : Patients with advanced medullary thyroid cancer ( P04629 ) have poor prognoses and limited treatment options . Improved knowledge about molecular aberrations associated with P04629 and the availability of novel targeted tyrosine kinase inhibitors ( TKIs ) have led to new potential treatment modalities . DB08875 is an oral multitargeted TKI with activity against multiple receptors including P07949 , vascular endothelial growth factor receptor type 2 ( P35968 ) , and MET that has been evaluated in P04629 in the preclinical and clinical arenas . METHODS : This article reviews unmet clinical needs in advanced P04629 . The authors consider novel agents that have been studied in P04629 , with a focus on the investigational agent cabozantinib . Up - to - date clinical data of cabozantinib in P04629 are discussed . RESULTS : Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression - free survival in patients with progressive P04629 . These findings indicate that cabozantinib may be an effective therapy in advanced P04629 . No improvement in overall survival has been demonstrated but data are not mature . CONCLUSION : DB08875 may be an effective treatment option for patients with advanced P04629 and is worthy of further evaluation .","Effects of ellagic Acid on angiogenic factors in prostate cancer cells . BACKGROUND : Several natural antioxidants , including ellagic acid ( EA ) , have been reported to have chemotherapeutic activity in vivo and in vitro settings . Cytochrome P450 ( CYP ) activity and synthesis of both epoxyeicosatrienoic acids ( EETs ) and 20 - hydroxy - 5 , 8 , 11 , 14 - eicosatetraenoic acid ( 20 - HETE ) , together with vascular endothelial growth factor ( P15692 ) and heme oxygenase system ( HO ) have emerged as important modulators of tumor growth and metastasis . METHODS : The anti - angiogenic effects of EA were investigated in the human prostatic cancer cell line LnCap . P09601 , P30519 , P51589 and soluble epoxyde hydrolase ( sEH ) expressions were evaluated by western blotting . Levels of P15692 and osteoprotegerin ( O00300 ) were determined in the culture supernatant using an ELISA assay , while CYP mRNAs were determined by qRT - PCR . RESULTS : EA treatment induced a significant decrease ( p < 0 . 05 ) in P09601 , P30519 and P51589 expression , and in P15692 and O00300 levels . Similarly P51589 , P78329 and CYPA22 mRNAs were significantly ( p < 0 . 05 ) down - regulated by EA treatment . The decrease in P51589 mRNA was associated with an increase in sEH expression . CONCLUSIONS : RESULTS reported in the present study highlighted the ability of EA to modulate a new pathway , in addition to anti - proliferative and pro - differentiation properties , via a mechanism that involves a decrease in eicosanoid synthesis and a down - regulation of the HO system in prostate cancer .","DB08875 ( DB05153 ) for the treatment of locally advanced or metastatic progressive medullary thyroid cancer . DB08875 ( DB05153 ) is an oral multiple receptor tyrosine kinase inhibitor manufactured by Exelixis Inc . , CA , USA . It mainly inhibits three tyrosine kinase receptors : MET , P35968 and P07949 . In both preclinical and clinical studies it has been shown to inhibit tumor angiogenesis , invasiveness and metastases . The most frequent side effects are fatigue , diarrhea , decreased appetite , nausea , weight loss and palmar - plantar erythrodysesthesia . A Phase III clinical trial ( EXAM study ) of DB05153 versus placebo in advanced and progressive medullary thyroid cancer showed a 28 versus 0 % overall response rate and a progression - free survival of 11 . 2 versus 4 . 0 months ( hazard ratio : 0 . 28 ; 95 % CI : 0 . 19 - 0 . 40 ; p < 0 . 0001 ) in patients treated with cabozantinib and placebo , respectively . The drug has been approved by the US FDA for the treatment of advanced / progressive metastatic medullary thyroid cancer in the USA . The P15941 is now evaluating its approval in Europe .","Liver regeneration induced by a designer human P05231 / sIL - 6R fusion protein reverses severe hepatocellular injury . The cytokine P05231 plays a significant role in liver regeneration in conjunction with additional growth factors ( P14210 , P01375 , and TGF - alpha ) . Many P05231 effects depend on a naturally occurring soluble P05231 receptor ( sIL - 6R ) . Here , the chimeric protein hyper - P05231 , constructed from the human P05231 protein fused to a truncated form of its receptor , was found to have superagonistic P05231 properties , and as such , enhanced liver cell regeneration . Hyper - P05231 reversed the state of hepatotoxicity and enhanced the survival rates of rats suffering from fulminant hepatic failure after D - galactosamine administration . The hyper - P05231 protein has a significant potential for use in the treatment of severe human liver diseases .","P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK17___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .","Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK84___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .","DB08875 inhibits growth of androgen - sensitive and castration - resistant prostate cancer and affects bone remodeling . DB08875 is an inhibitor of multiple receptor tyrosine kinases , including MET and P35968 . In a phase II clinical trial in advanced prostate cancer ( PCa ) , cabozantinib treatment improved bone scans in 68 % of evaluable patients . Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone - sensitive and castration - resistant PCa in preclinical models while delineating its effects on tumor and bone . Using immunohistochemistry and tissue microarrays containing normal prostate , primary PCa , and soft tissue and bone metastases , our data show that levels of MET , P - MET , and P35968 are increasing during PCa progression . Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases . To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen - sensitive LuCaP 23 . 1 and castration - resistant C4 - 2B PCa tumors . In vivo , cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors . Furthermore , cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume . In summary , the expression pattern of cabozantinib targets in primary and castration - resistant metastatic PCa , and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease .","DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .","Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK21___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK21___ is also being investigated as part of triplet drug regimens . ___MASK21___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .","A new cell culture - based assay quantifies vitamin K 2 , 3 - epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol - driven Q9BQB6 assay . BACKGROUND : ___MASK25___ directly inhibits the vitamin K 2 , 3 - epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) - driven vitamin K 2 , 3 - epoxide reductase ( Q9BQB6 ) assay . ___MASK25___ inhibits wild - type Q9BQB6 function by the DTT - Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance - associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture - based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild - type and variant Q9BQB6 proteins . METHODS : Human coagulation factor ( F ) IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild - type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : ___MASK25___ dose - response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild - type , Val29Leu , Val45Ala and Leu128Arg variants . The corresponding calculated IC50 values were 24 . 7 , 136 . 4 , 152 . 0 and 1226 . 4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild - type Q9BQB6 . Ranked IC50 values from the cell culture - based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation - associated warfarin resistance ."],"string":"[\n \"Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral / derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non - human primates . Cross species polymerase chain reaction ( CS - PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB @ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR - RFLP ) or by direct sequencing . At seventeen of the eighteen PCR - RFLPs , non - human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR - RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3 ' untranslated region ( UTR ) of the P14416 gene illustrate this point .\",\n \"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK75___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .\",\n \"Identification of new candidate therapeutic target genes in triple - negative breast cancer . Triple - negative breast cancer ( TNBC ) is a subgroup of breast cancer that is negative for estrogen and progesterone receptor and P04626 protein expression . It is characterized by its aggressive behavior and by the lack of targeted therapies . To identify new therapeutic targets in TNBC , we used real - time quantitative RT - PCR to analyze 63 TNBC samples in terms of their mRNA expression of 26 genes coding for the major proteins currently targeted by drugs used to treat other cancers or undergoing clinical trials in breast cancer . Six of the 26 genes tested ( P15692 , P12931 , P09874 , Q05397 , P04049 , and P22607 ) were significantly upregulated in 13 % to 46 % of the TNBCs . None of the 6 genes was specifically upregulated in the TNBCs compared with 3 other classical breast tumor subtypes . No association was observed between overexpression of these 6 genes ( except for P22607 ) and P42336 mutation status . These results confirm the interest of targeting P15692 and P09874 in ongoing clinical trials in TNBC patients and also identify new target genes ( P12931 , Q05397 , P04049 , and P22607 ) . Clinical trials could be initiated easily with existing drugs . Our results also suggest that these target genes might serve as predictive biomarkers of the TNBC treatment response .\",\n \"Increased expression of hypoxia - inducible factor - 1alpha , p48 , and the Notch signaling cascade during acute pancreatitis in mice . Acute pancreatitis ( AP ) is a complex disease that may be linked to acinar cell apoptosis and inadequate acinar cell replacement . Differentiation of acinar cells is regulated by p48 , a DNA binding subunit of the transcription factor PTF1 , and the Notch signaling pathway . Acinar cell apoptosis is triggered by oxygen deprivation , ie , hypoxia , by activation of hypoxia inducible factor - 1alpha ( HIF - 1alpha ) . The aim of this study was to characterize by Northern blot analyses expression of HIF - 1alpha , HIF - 1alpha - inducible genes ( P11166 , P15692 , p53 ) , p48 , and genes involved in the Notch signaling pathway ( Notch - 1 , Dll1 , P02753 - Jk , DB09106 - 1 ) during cerulein - induced AP in mice . Maximal expression of HIF - 1alpha , HIF - 1alpha - inducible genes , p48 , and Notch signaling genes occurred 8 - 12 hours after induction of AP . Maximal expression of p53 occurred 12 - 48 hours after induction of AP . These findings demonstrate that multiple pancreatic genes are activated acutely during AP that support pancreatic cell replenishment , regulation of expression of acinar cell - specific genes , and apoptosis .\",\n \"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK90___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .\",\n \"Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries . BACKGROUND : Atherosclerosis affects aorta , coronary , carotid , and iliac arteries most frequently than any other body vessel . There may be common molecular pathways sustaining this process . Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis . RESULTS : We used DNA microarrays and meta - analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression . We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis . Caveolae and JAK / P35610 pathways , and P06702 / P05109 interacting proteins are certainly involved in the development of vascular disease . We found that the system of caveolae is directly connected with genes that respond to hormone receptors , and indirectly with the apoptosis pathway . Cytokines , chemokines and growth factors released in the blood flux were investigated in parallel . High levels of RANTES , IL - 1ra , MIP - 1 alpha , MIP - 1 beta , P60568 , P05112 , P05113 , P05231 , P13232 , Q16552 , DB00102 , P15692 and P01579 were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels . CONCLUSION : The pattern of cytokine and P06702 / P05109 up - regulation characterizes atherosclerosis as a proinflammatory disorder . Activation of the JAK / P35610 pathway is confirmed by the up - regulation of P05231 , P42224 , Q00978 and Q13651 genes in coronary and carotid plaques . The functional network constructed in our research is an evidence of the central role of P35610 protein and the caveolae system to contribute to preserve the plaque . Moreover , Cav - 1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype .\",\n \"Response to DB08875 in patients with P07949 fusion - positive lung adenocarcinomas . The discovery of P07949 fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes . In an unselected population of non - small cell lung carcinomas ( NSCLCs ) , P07949 fusions are present in 1 % to 2 % of cases . This incidence increases substantially , however , in never - smokers with lung adenocarcinomas that lack other known driver oncogenes . Although preclinical data provide experimental support for the use of P07949 inhibitors in the treatment of P07949 fusion - positive tumors , clinical data on response are lacking . We report preliminary data for the first three patients treated with the P07949 inhibitor cabozantinib on a prospective phase II trial for patients with P07949 fusion - positive NSCLCs ( NCT01639508 ) . Confirmed partial responses were observed in 2 patients , including one harboring a novel Q9UPN9 - P07949 fusion . A third patient with a P33176 - P07949 fusion has had prolonged stable disease approaching 8 months ( 31 weeks ) . All three patients remain progression - free on treatment .\",\n \"Endothelial progenitor cells in relation to endothelin - 1 and endothelin receptor blockade : a randomized , controlled trial . AIMS : Endothelial progenitor cells ( EPC ) represent an endogenous repair mechanism involving rendothelialization and neoangiogenesis . Patients with both diabetes and vascular disease have low numbers of circulating EPC . The endothelium - derived peptide , endothelin - 1 ( ET - 1 ) , is increased in patients with type 2 diabetes and vascular complications and has been suggested to contribute to endothelial dysfunction . Therefore , we investigated the relation between EPC and plasma ET - 1 and the effect of dual ET - 1 receptor antagonist treatment . METHODS : In this double blind study patients with type 2 diabetes mellitus and microalbuminuria were randomized to treatment with the dual P25101 / ETB receptor antagonist ___MASK7___ treatment ( 125mg bid ; n = 17 ) or placebo ( n = 19 ) for four weeks . Different EPC subpopulations were enumerated by flow cytometry using triple staining ( P28906 , CD133 , P35968 ) at baseline at the end of treatment . Viability was assessed by 7AAD and Annexin - V - staining . RESULTS : Baseline ET - 1 levels correlated significantly with P02741 levels . Patients with ET - 1 levels above the median value had higher levels of P28906 (+) CD133 (+) and P28906 (+) P35968 (+) EPC . There was no difference in P28906 (+) and P28906 (+) CD133 (+) P35968 (+) cells , markers of EPC apoptosis or circulating markers of endothelial damage between patients with ET - 1 levels below or above the median . Four week treatment with ___MASK7___ did not change EPC levels . CONCLUSION : Among patients with type 2 diabetes and vascular disease , high plasma levels of ET - 1 are associated with higher number of EPC . The recruitment of EPC does not seem to be regulated via ET - 1 receptor activation since treatment with a dual ET - 1 receptor blocker did not affect circulating EPC numbers .\",\n \"Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK25___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .\",\n \"DB08875 : a MET , P07949 , and P35968 tyrosine kinase inhibitor . DB08875 is a receptor tyrosine kinase inhibitor with activity against MET , P35968 , P36888 , c - P10721 , and P07949 . Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies . Of note , cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET . Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer ( P04629 ) , NSCLC , breast , ovarian , pancreatic , and prostate cancer . In P04629 , gain of function mutations of P07949 are central for tumorigenesis . Hereditary forms of P04629 ( MEN II ) are caused by germline mutations of P07949 , in sporadic P04629 in up to 50 % of cases P07949 mutations occur . Additionally , activating molecular changes in VEGFR and MET pathways have also been implicated in P04629 progression . Clinical responses with cabozantinib in P04629 could be observed in early clinical trials , and following confirmation of clinical benefit in a randomized phase III trial , cabozantinib gained FDA approval for first - line treatment of advanced P04629 in 2012 . In prostate cancer models , MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis . A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer . Therefore , randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients .\",\n \"Regulation of mammalian cell cycle progression in the regenerating liver . The process of cell division in mammalian cells is orchestrated by cell - cycle - dependent oscillations of cyclin protein levels . P12004 levels are controlled by redundant transcriptional , post - translational and degradation feedback loops . How each of these separate loops contributes to the regulation of the key cell cycle events and to the connection between the P55008 - S transition and the subsequent mitotic events is under investigation . Here , we present an integrated computational model of the mammalian cell cycle based on the sequential activation of cyclins . We validate the model against experimental data on liver cells ( hepatocytes ) , which undergo one or two rounds of synchronous circadian - clock gated cell divisions during liver regeneration , after partial hepatectomy ( PH ) . The model exhibits bandpass filter properties that allow the system to ignore strong but transient , or sustained but weak damages after PH . Bifurcation analysis of the model suggests two different threshold mechanisms for the progression of the cell through mitosis . These results are coherent with the notion that the mitotic exit in mammalian cells is bistable , and suggests that Cdc20 homologue 1 ( Cdh1 ) is an important regulator of mitosis . Regulation by Cdh1 also explains the observed G2 / M phase prolongation after hepatocyte growth factor ( P14210 ) stimulation during S phase .\",\n \"Immunological assessment of cryotherapy in breast cancer patients . BACKGROUND : In murine studies , cryotherapy has induced antitumor immune responses associated with the rejection of tumors . However , the effects of freezing - induced immunomodulation in breast cancer ( BC ) patients remain unclear . MATERIALS AND METHODS : Ten BC patients were prospectively divided into two groups : 1 ) cryotherapy followed by surgical excision and 2 ) surgical excision - alone . The cytokine profiles of plasma and peripheral blood mononuclear cells ( PBMCs ) were analyzed using flow cytometry following in vitro stimulation with the 30 - mer P15941 peptide . RESULTS : No differences in the percentages of interferon - γ ( IFN - γ ) - producing cluster of differentiation ( CD ) 4 (+) or CD8 (+) T cells and the plasma levels of IFN - γ , interleukin - 1β ( IL - 1β ) , P60568 , P05112 , P05113 , P05231 , P10145 , P22301 , IL - 12p70 , tumor necrosis factor - α ( P01375 - α ) and P01375 - β were observed between these 2 groups , and PBMCs were not significantly altered . CONCLUSION : Alternations to the type 1 and 2 helper cytokine profiles were not detected in vitro in BC patients treated with cryotherapy - alone .\",\n \"A novel tumor necrosis factor - responsive transcription factor which recognizes a regulatory element in hemopoietic growth factor genes . A conserved DNA sequence element , termed cytokine 1 ( P04264 ) , is found in the promoter regions of many hemopoietic growth factor ( P14210 ) genes . Mutational analyses and modification interference experiments show that this sequence specifically binds a nuclear transcription factor , NF - GMa , which is a protein with a molecular mass of 43 kilodaltons . It interacts with different affinities with the P04264 - like sequence from a number of P14210 genes , including granulocyte macrophage colony - stimulating factor ( GM - P04141 ) , granulocyte ( G ) - P04141 , interleukin 3 ( P08700 ) , and P05113 . We show here that the level of NF - GMa binding is induced in embryonic fibroblasts by tumor necrosis factor - alpha ( P01375 ) treatment and that the P04264 sequence from the G - P04141 gene is a P01375 - responsive enhancer in these cells . The NF - GMa protein is distinct from another P01375 - responsive transcription factor , NF - kappa B , by several criteria . Firstly , several NF - kappa B - binding sites , although having sequence similarity with the P04264 sequence , can not compete efficiently for NF - GMa binding to P04264 . Secondly , the P04264 sequence from both G - P04141 and GM - P04141 does not respond to phorbol ester treatment as would an NF - kappa B - binding element . These results demonstrate that NF - GMa is a novel transcription factor inducible by P01375 and binds to a common element in P14210 gene promoters .\",\n \"Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib - pairs in 64 sib - ships from families ascertained by early - onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib - pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation .\",\n \"Notch4 - induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through P02753 - Jkappa . Notch proteins comprise a family of transmembrane receptors . Ligand activation of Notch releases the intracellular domain of the receptor that translocates to the nucleus and regulates transcription through the DNA - binding protein P02753 - Jkappa . Previously , it has been shown that the Notch4 intracellular region ( N4IC ) can inhibit endothelial sprouting and angiogenesis . Here , N4IC deletion mutants were assessed for their ability to inhibit human microvascular endothelial cell ( HMEC ) sprouting with the use of a quantitative endothelial sprouting assay . Deletion of the ankyrin repeats , but not the RAM ( P02753 - Jkappa associated module ) domain or C - terminal region ( CT ) , abrogated the inhibition of fibroblast growth factor 2 ( P09038 ) - and vascular endothelial growth factor ( P15692 ) - induced sprouting by Notch4 , whereas the ankyrin repeats alone partially blocked sprouting . The ankyrin repeats were also the only domain required for up - regulation of P02753 - Jkappa - dependent gene expression . Interestingly , enforced expression of the ankyrin domain alone was sufficient to up - regulate some , but not all , P02753 - Jkappa - dependent genes . Although N4IC reduced P15692 receptor - 2 ( P35968 ) and vascular endothelial ( VE ) - cadherin expression , neither of these events is necessary and sufficient to explain N4IC - mediated inhibition of sprouting . A constitutively active P02753 - Jkappa mutant significantly inhibited HMEC sprouting but not as strongly as N4IC . Thus , Notch4 - induced inhibition of sprouting requires the ankyrin repeats and appears to involve P02753 - Jkappa - dependent and - independent signaling .\",\n \"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK39___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .\",\n \"Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK25___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .\",\n \"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .\",\n \"DB08875 ( DB05153 ) , a novel MET and P35968 inhibitor , simultaneously suppresses metastasis , angiogenesis , and tumor growth . The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor ( P14210 ) is important for cell growth , survival , and motility and is functionally linked to the signaling pathway of P15692 , which is widely recognized as a key effector in angiogenesis and cancer progression . Dysregulation of the MET / P15692 axis is found in a number of human malignancies and has been associated with tumorigenesis . DB08875 ( DB05153 ) is a small - molecule kinase inhibitor with potent activity toward MET and P15692 receptor 2 ( P35968 ) , as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology , including P07949 , P10721 , P30530 , and P36888 . Treatment with cabozantinib inhibited MET and P35968 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro . In mouse models , cabozantinib dramatically altered tumor pathology , resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose - dependent inhibition of tumor growth in breast , lung , and glioma tumor models . Importantly , treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis , which has been observed with inhibitors of P15692 signaling that do not target MET . Collectively , these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling .\",\n \"Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF - α / P15692 / Rho - GTPases : pivotal role of P35610 - 3 . Our previous studies have shown that benzyl isothiocyanate ( BITC ) suppresses pancreatic tumor growth by inhibiting P35610 - 3 ; however , the exact mechanism of tumor growth suppression was not clear . Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis . Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken - Chorioallantoic membrane . Furthermore , BITC blocks the migration and invasion of BxPC - 3 and PanC - 1 pancreatic cancer cells in a dose dependant manner . Moreover , secretion of P15692 and P08253 in normoxic and hypoxic BxPC - 3 and PanC - 1 cells was significantly suppressed by BITC . Both P15692 and P08253 play a critical role in angiogenesis and metastasis . Our results reveal that BITC significantly suppresses the phosphorylation of P35968 ( DB00135 - 1175 ) , and expression of HIF - α . Rho - GTPases , which are regulated by P15692 play a crucial role in pancreatic cancer progression . BITC treatment reduced the expression of RhoC whereas up - regulated the expression of tumor suppressor RhoB . P35610 - 3 over - expression or P05231 treatment significantly induced HIF - 1α and P15692 expression ; however , BITC substantially suppressed P35610 - 3 as well as P35610 - 3 - induced HIF - 1α and P15692 expression . Finally , in vivo tumor growth and matrigel - plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC , indicating reduced tumor angiogenesis . Immunoblotting of BITC treated tumors show reduced expression of P35610 - 3 phosphorylation ( DB00135 - 705 ) , HIF - α , P35968 , P15692 , P08253 , CD31 and RhoC . Taken together , our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through P35610 - 3 - dependant pathway .\",\n \"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK25___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .\",\n \"Serum levels of antibodies to thyroid peroxidase correlate with quantitative descriptors of thyroid ultrasound images in patients with breast cancer . The aim of the study was to compare the structural changes in ultrasound image of the thyroid tissue in 12 women with breast cancer ( BC ) and 8 women with colorectal cancer ( CC ) . MATLAB software was used to analyse the digitised images . As quantitative descriptors of thyroid ultrasound images ( QDTI ) were used raw grey scale values of individual image pixels ( RAW ) and the optimal one - dimensional discriminative texture features ( F2 , F6 , P08709 ) . The possible relations between QDTI and thyroid laboratory parameters were tested . In the BC group serum levels of antibodies to thyroid peroxidase negatively correlated with feature RAW ( multiple regression , beta coefficient - 0 . 75 , p = 0 . 004 ) and positively with feature F2 ( multiple regression , beta coefficient 1 . 44 , p = 0 . 04 ) . In the BC group RAW negatively correlated with serum levels of tumour marker P15941 ( Pearson ' s correlation coefficient , r =- 0 . 714 , p = 0 . 00917 ) . No such correlations were found in CC group . The correlations between QDTI and serum levels of antibodies to thyroid peroxidase in patients with BC show that the positivity of antibodies to thyroid peroxidase is probably accompanied with structural changes in the thyroid tissue .\",\n \"Pharmacogenetics in chemotherapy of colorectal cancer . Although in recent years , chemotherapeutic options for colorectal carcinoma have expanded , overall response rates are still too low , with high rates of toxicity . Pharmacogenetics aim at predicting both treatment response and adverse effects in individual patients . This review describes the current knowledge of pharmacogenetic markers in the systemic treatment of colorectal cancer . P22309 * 28 leads to reduced conjugation of SN - 38 , the active metabolite of irinotecan , resulting in an increased rate of adverse effects , especially neutropenia . To a lesser extent , increased DB00544 toxicity is predicted by Q12882 * 2A . A variable number of tandem repeats polymorphism in the thymidylate synthase enhancer region , in combination with a single nucleotide polymorphism C > G , may predict poorer response to DB00544 . Efficacy of oxaliplatin is influenced by polymorphisms in components of DNA repair systems , such as P07992 and P18887 . Polymorphic changes in the endothelial growth factor receptor probably predict cetuximab efficacy . Furthermore , the antibody - depended cell - mediated cytotoxic effect of cetuximab may be reduced by polymorphisms in the immunoglobin G fragment C receptors . DB00112 efficacy is suspected to be influenced by polymorphisms in the P15692 gene and the hypoxia inducible factor 1alpha gene . Although the interpretation of pharmacogenetic studies is complicated , results imply a promising way of pretreatment prediction of chemotherapy efficacy and toxicity .\",\n \"Targeting MET and vascular endothelial growth factor receptor signaling in castration - resistant prostate cancer . Effective management of bone metastases in men with castration - resistant prostate cancer ( CRPC ) remains an important unmet medical need . MET and vascular endothelial growth factor receptor ( VEGFR ) are rational targets for intervention in CRPC . Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival . DB08875 is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and P35968 . A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans , bone turnover markers , and pain response , but with significant adverse events leading to dose reduction and treatment discontinuation . Lower doses of cabozantinib retain high levels of activity with less toxicity . Ongoing phase III clinical trials will define the role of cabozantinib in CRPC . We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date .\",\n \"Targetting esophageal and gastric cancers with monoclonal antibodies . Target therapies and notably monoclonal antibodies are currently being considered for esophageal , gastric , and gastroesophageal junction cancers . P00533 was found to be overexpressed in 60 - 86 % of gastric or gastroesophageal tumors and in 50 - 70 % of esophageal cancers . Cetuximab was shown to be a radiosensitizing agent in the treatment of ENT neoplasia . These results led to several phase II encouraging therapeutic trials evaluating the combination of cetuximab with radiochemotherapy in locally advanced esophageal cancers . Numerous encouraging phase II trials evaluating cetuximab combined with chemotherapy in patients with gastric adenocarcinoma or gastroesophageal junction cancer were reported . These promising results are still to be confirmed by the ongoing phase III trials . Several studies reported P04626 overexpression in gastric cancer ( 7 - 34 % ) , which appeared to be associated with poorer prognosis . ___MASK21___ is a monoclonal antibody directed against the extracellular P04626 domain . The international phase III trial known as ToGA ( ___MASK21___ for Gastric Cancer ) aimed to determine the clinical efficacy and acceptable toxicity profile of trastuzumab in combination with first - line chemotherapy in P04626 - overexpressing gastric or gastroesophageal cancer . Angiogenesis is an essential step in the initial phase of tumorigenesis , and it is normally absent from healthy tissues except for particular physiological situations , such as wound healing . P15692 plays a role in endothelial growth and angiogenesis . DB00112 , a humanized monoclonal anti - P15692 antibody , is currently being studied for gastric cancer . The phase III AVAGAST study , evaluating bevacizumab in association with chemotherapy in advanced gastric adenocarcinoma , did not achieve its primary aim of improved OS in bevacizumab - treated patients .\",\n \"Suppression of proliferation and migration in highly - metastatic lung cancer cells as well as tumor growth by a new synthesized compound TBrC and its molecular mechanisms of action . To develop new anticancer agents has been considered as a useful and necessary strategy to suppress highly - metastatic lung cancer , the leading cause of cancer - related deaths in the world . In this study , we synthesized a new compound ethyl 6 - bromocoumarin - 3 - carboxylyl L - theanine ( TBrC ) and studied the anticancer activity of TBrC and its molecular mechanisms of action . Our results show that TBrC remarkably inhibits the proliferation and migration in highly - metastatic lung cancer cells by inducing apoptosis and cell cycle arrest as well as regulating related protein expressions . Further study indicated that TBrC not only enhances the protein levels of Bax , cytosolic cytochrome c , caspase - 3 and P09874 but also reduces the protein expressions of Bcl - 2 , cyclin D1 , P17948 and NF - κB as well as inhibits the phosphorylation and expressions of P35968 and Akt in the cancer cells . More importantly , TBrC displays strong suppression of highly - metastatic tumor growth and reduces the tumor weight by 61 . 6 % in tumor - bearing mice without toxicity to the mice . Our results suggest that TBrC suppresses the proliferation and migration of lung cancer cells via VEGFR - Akt - NF - κB signaling pathways ; TBrC may have a wide therapeutic and / or adjuvant therapeutic application in the treatment of lung cancer .\",\n \"Targeted therapy in gastric cancer . Gastric cancer is often diagnosed at an advanced stage . Although chemotherapy prolongs survival and improves quality of life , the survival of gastric cancer patients with advanced disease is short . Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis , new targeted treatment options have become available for gastric cancer patients . ___MASK21___ , an antibody targeted to HER - 2 , was shown to improve survival of advanced gastric cancer patients harboring HER - 2 overexpression due to gene amplification in their tumor cells , and is currently also explored in adjuvant and neoadjuvant settings . Another agent with promising results in clinical trials is ramucirumab , an antibody targeting P35968 . No clear survival benefit , however , were experienced with agents targeting P00533 ( cetuximab , panitumumab ) , P15692 ( bevacizumab ) , or P42345 ( everolimus ) . Drugs targeting c - MET / P14210 are currently under investigation in biomarker - selected cohorts , with promising results in early clinical trials . This review will summarize the current status of targeted treatment options in gastric cancer .\",\n \"Adeno - associated virus - mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs . We have previously shown that VEGF165 gene delivery into ischemic skeletal muscle exerts not only proangiogenic , but also remarkable antiapoptotic and proregenerative activity . The aim of this study was to determine whether recombinant adeno - associated virus ( rAAV ) - mediated gene delivery of VEGF165 into cardiac muscle , during acute myocardial infarction , exerts a protective effect to promote long - term functional recovery . Acute infarction of the anterior LV wall was induced in 12 chronically instrumented dogs by permanent occlusion of the LAD coronary artery . Four hours after occlusion , rAAV - VEGF165 or rAAV - LacZ ( n = 6 each ; 5x10 ( 12 ) viral particles per animal ) was directly injected with an echo - guided needle into the dysfunctional cardiac wall . LV and arterial pressure , dP / dtmax , and ejection fraction were not significantly different between the two groups over time . In contrast , in the infarcted region , at four weeks after infarction , fractional shortening was 75 +/- 18 % and - 3 +/- 15 % of baseline and length - pressure area was 54 +/- 15 % and 0 . 8 +/- 15 % of baseline in VEGF165 versus LacZ , respectively ( P < 0 . 05 ) . Histological analysis of the border regions showed a marked increase in the number of alpha - SMA - positive arterioles ( 68 +/- 2 . 8 versus 100 +/- 3 . 8 vessels per microscopic field in LacZ and VEGF165 group , respectively ; P < 0 . 05 ) . In both groups , the receptor P35968 was diffusely expressed on the surviving cardiomyocytes and , consistently , myocardial viability was significantly improved in the VEGF165 - treated group , with several troponin T - expressing cardiomyocytes displaying nuclear positivity for the proliferation marker P12004 . Altogether , our results indicate that VEGF165 gene delivery exerts a marked beneficial action by enhancing both arteriologenesis and cardiomyocyte viability in infarcted myocardium .\",\n \"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK94___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .\",\n \"DB08875 and prostate cancer : inhibiting seed and disrupting soil ? Treatment with cabozantinib , an inhibitor of MET and P35968 signaling , has demonstrated clinical benefit in early trials in men with metastatic prostate cancer . Preclinical evidence suggests that cabozantinib can kill cancer cell seeds while disrupting angiogenesis and stromal cells in the metastatic soil .\",\n \"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .\",\n \"Rare mutations in non - small - cell lung cancer . In the last decade , new insights in molecular biology have changed the therapeutic landscape of non - small - cell lung cancer . Since 2004 , when activating mutations of the P00533 were firstly identified , several genetic aberrations have been discovered , mainly in adenocarcinoma . P00533 mutations are a relatively frequent event in non - small - cell lung cancer , generally consisting of exon 19 deletion or exon 21 substitution . In adenocarcinoma , additional rare mutations are detectable in the P00533 gene , as well as in other genes , including Q9UM73 , P08922 , P07949 , P04626 and P15056 . Recent studies in squamous cell carcinoma identified P04637 as the most frequent mutation , followed by additional more rare mutations , including PI3KCA , P60484 , Q16832 and FGFR . The aim of the present review is to analyze the potential prognostic and predictive role of rare mutations .\",\n \"A phase I study of cabozantinib ( DB05153 ) in patients with differentiated thyroid cancer . BACKGROUND : DB08875 targets tyrosine kinases including MET , vascular endothelial growth factor ( P15692 ) receptor 2 , and rearranged during transfection ( P07949 ) . Differentiated thyroid cancer ( DTC ) is a tumor type that may be sensitive to cabozantinib . Therefore , we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC . METHODS : This single - arm open - label phase I trial assessed the safety , tolerability , and antitumor activity of cabozantinib in DTC patients taking part in a drug - drug interaction study . Adult patients with histologically confirmed metastatic or surgically unresectable DTC ( including papillary , follicular , or Hürthle cell ) were enrolled . Patients received daily oral dosing of 140 mg cabozantinib . Safety was assessed by evaluation of adverse events ( AEs ) , vital signs , electrocardiograms , laboratory tests , and concomitant medications . Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors ( RECIST ) v1 . 0 . RESULTS : The study enrolled 15 patients who had failed standard radioactive iodine therapy . Patients had received a median of two prior systemic agents , and 11 patients ( 73 % ) had previously received at least one P15692 pathway inhibiting therapy . Common AEs included diarrhea , nausea , fatigue , and decreased appetite . Partial response was reported in eight patients ( 53 % ) . Median progression - free survival and median overall survival were not reached . CONCLUSIONS : DB08875 demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients . The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC .\",\n \"DB08875 overcomes crizotinib resistance in P08922 fusion - positive cancer . PURPOSE : P08922 rearrangement leads to constitutive P08922 activation with potent transforming activity . In an ongoing phase I trial , the Q9UM73 tyrosine kinase inhibitor ( TKI ) crizotinib shows remarkable initial responses in patients with non - small cell lung cancer ( NSCLC ) harboring P08922 fusions ; however , cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in P08922 . Thus , understanding the crizotinib - resistance mechanisms in P08922 - rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required . EXPERIMENTAL DESIGN : The sensitivity of P04233 - P08922 - transformed Ba / P13726 cells to multiple Q9UM73 inhibitors was examined . Acquired P08922 inhibitor - resistant mutations in P04233 - P08922 fusion were screened by N - ethyl - N - nitrosourea mutagenesis with Ba / P13726 cells . To overcome the resistance mutation , we performed high - throughput drug screening with small - molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials . The effect of the identified drug was assessed in the P04233 - P08922 - mutant Ba / P13726 cells and crizotinib - resistant patient - derived cancer cells ( MGH047 ) harboring G2032R - mutated P04233 - P08922 . RESULTS : We identified multiple novel crizotinib - resistance mutations in the P08922 kinase domain , including the G2032R mutation . As the result of high - throughput drug screening , we found that the cMET / P07949 / VEGFR inhibitor cabozantinib ( DB05153 ) effectively inhibited the survival of P04233 - P08922 wild - type ( WT ) and resistant mutants harboring Ba / P13726 and MGH047 cells . Furthermore , cabozantinib could overcome all the resistance by all newly identified secondary mutations . CONCLUSIONS : We developed a comprehensive model of acquired resistance to P08922 inhibitors in NSCLC with P08922 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance .\",\n \"Serum hepcidin levels and reticulocyte hemoglobin concentrations as indicators of the iron status of peritoneal dialysis patients . P81172 is the key mediator of renal anemia , and reliable measurement of serum hepcidin levels has been made possible by the ProteinChip system . We therefore investigated the iron status and serum hepcidin levels of peritoneal dialysis ( PD ) patients who had not received frequent doses of an erythrocytosis - stimulating agent ( Q14254 ) and had not received iron therapy . In addition to the usual iron parameters , the iron status of erythrocytes can be determined by measuring reticulocyte hemoglobin ( P07949 - He ) . The mean serum hepcidin level of the PD patients ( n = 52 ) was 80 . 7 ng / mL . Their serum hepcidin levels were significantly positively correlated with their serum ferritin levels and transferrin saturation ( TSAT ) levels , but no correlations were found between their serum hepcidin levels and P07949 - He levels , thereby suggesting that hepcidin has no effect on the iron dynamics of reticulocytes . Since low serum levels of CRP and P05231 , biomarkers of inflammation , were not correlated with the serum hepcidin levels , there is likely to be a threshold for induction of hepcidin expression by inflammation .\",\n \"Antipruritic activity of the kappa - opioid receptor agonist , P04629 - 820 . The effects of the kappa - opioid receptor agonist , P04629 - 820 , (-)- 17 -( cyclopropylmethyl )- 3 , 14beta - dihydroxy - 4 , 5alpha - epoxy - 6beta - [ N - methyl - trans - 3 -( 3 - furyl ) acrylamido ] morphinan hydrochloride , on the itch sensation were compared with those of histamine H1 receptor antagonists , using the mouse pruritogen - induced scratching model . Peroral administration of P04629 - 820 reduced the numbers of DB05875 - or histamine - induced scratches dose dependently . No obvious suppression of the spontaneous locomotor activity was observed at the doses used for the experiments , indicating that the inhibition of scratches was not due to the effect on general behavior . Furthermore , the scratching inhibitory activity of P04629 - 820 was dose dependently antagonized by the specific kappa - opioid receptor antagonist , nor - binaltorphimine , suggesting that the inhibitory activity was mediated via kappa - opioid receptors . P35367 antagonists , chlorpheniramine and ketotifen , did not inhibit DB05875 - induced scratches , or did so only partially . Both antihistamines inhibited the histamine - induced scratches completely . These results suggest that P04629 - 820 has antipruritic activity which is mediated by kappa - opioid receptors , and is effective in both antihistamine - sensitive and - resistant pruritus .\",\n \"DB08875 inhibits prostate cancer growth and prevents tumor - induced bone lesions . PURPOSE : DB08875 , an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor ( MET ) and P15692 receptor 2 ( P35968 ) , induces resolution of bone scan lesions in men with castration - resistant prostate cancer bone metastases . The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect , an indirect effect through modulating bone , or both . EXPERIMENTAL DESIGN : Using human prostate cancer xenograft studies in mice , we determined the impact of cabozantinib on tumor growth in soft tissue and bone . In vitro studies with cabozantinib were performed using ( i ) prostate cancer cell lines to evaluate its impact on cell growth , invasive ability , and MET and ( ii ) osteoblast cell lines to evaluate its impact on viability and differentiation and P35968 . RESULTS : DB08875 inhibited progression of multiple prostate cancer cell lines ( Ace - 1 , C4 - 2B , and LuCaP 35 ) in bone metastatic and soft tissue murine models of prostate cancer , except for PC - 3 prostate cancer cells in which it inhibited only subcutaneous growth . DB08875 directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro . DB08875 had a dose - dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo . It blocked MET and P35968 phosphorylation in prostate cancer cells and osteoblast - like cells , respectively . CONCLUSION : These data indicate that cabozantinib has direct antitumor activity , and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy .\",\n \"Activation and translocation of PKCdelta is necessary for P15692 - induced P29323 activation through P35968 in HEK293T cells . P15692 - P35968 / Flk - 1 signal utilizes the phospholipase C - gamma - protein kinase C ( PKC ) - Raf - MEK - P29323 pathway as the major signaling pathway to induce gene expression and P47712 phosphorylation . However , the spatio - temporal activation of a specific PKC isoform induced by P15692 - P35968 signal has not been clarified . We used HEK293T ( human embryonic kidney ) cells expressing transiently P35968 to examine the activation mechanism of PKC . PKC specific inhibitors and human PKCdelta knock - down using siRNA method showed that PKCdelta played an important role in P15692 - P35968 - induced P29323 activation . P29966 ( P29966 ) translocates from the plasma membrane to the cytoplasm depending upon phosphorylation by PKC . Translocation of P29966 - GFP induced by P15692 - P35968 stimulus was blocked by rottlerin , a PKCdelta specific inhibitor , or human PKCdelta siRNA . P15692 - P35968 stimulation did not induce P29323 phosphorylation in human PKCdelta - knockdown HEK293T cells , but co - expression of rat PKCdelta - GFP recovered the P29323 phosphorylation . Y311 / 332F mutant of rat PKCdelta - GFP which can not be activated by tyrosine - phosphorylation but activated by DAG recovered the P29323 phosphorylation , while C1B - deletion mutant of rat PKCdelta - GFP , which can be activated by tyrosine - phosphorylation but not by DAG , failed to recover the P29323 phosphorylation in human PKCdelta - knockdown HEK293T cell . These results indicate that PKCdelta is involved in P15692 - P35968 - induced P29323 activation via C1B domain .\",\n \"[ Study of the expression of neural stem cell markers in neuroblastoma tumor samples and correlation with prognostic factors ] . INTRODUCTION : The existence of cancer stem cells ( CSC ) in neuroblastoma ( NB ) has been associated with the development of metastasis , resistance to chemotherapy and recurrence . Our objective is to analyze the expression of proliferation and differentiation markers of neural progenitor cells in NB samples , and to correlate this expression with clinical variables such as histology , genetics and response to conventional therapy . MATERIAL AND METHODS : We performed a retrospective - experimental study with neuroblastoma samples obtained from biopsies or tumor resections between 2010 - 2012 in our Hospital . Fluorescence immunohistochemistry was used to analyze the expression of the different markers : P16070 , P04233 , CD133 , tyrosine hydroxylase , endothelin receptors type A ( P25101 ) and B ( ETB ) , p75 , nestina y and Phox2b , all of them related to neural stem cell biology . The level of expression of the markers was then correlated with clinical variables . RESULTS : P48681 expression was positive in 72 . 2 % of samples and P25101 in 66 . 7 % . Q99453 and P04233 expression were lower , being positive in less than 30 % . The markers P16070 , ETB and Q99453 were expressed in more aggressive tumors . P25101 expression correlated significantly with unfavorable histology tumors ( p = 0 . 01 ) , N - myc amplification ( p = 0 . 05 ) and recurrence / progression ( p = 0 . 05 ) . CONCLUSION : The expression of P16070 , ETB and P25101 was associated with more aggressive tumors and poor prognostic factors . These markers are in the membrane of neural stem cells and may be useful to identify and isolate by flow cytometry CSCs of NB for the study of new therapeutic targets .\",\n \"Noncatalytic function of P27361 / 2 can promote Raf / MEK / P29323 - mediated growth arrest signaling . Kinase activity is known as the key biochemical property of MAPKs . Here , we report that P27361 / 2 also utilizes its noncatalytic function to mediate certain signal transductions . Sustained activation of the Raf / MEK / P29323 pathway induces growth arrest , accompanied by changes in cell cycle regulators ( decreased retinoblastoma phosphorylation , Q01094 down - regulation , and / or P38936 ( CIP1 ) up - regulation ) and cell type - specific changes in morphology and expression of c - Myc or P07949 in the human tumor lines LNCaP , U251 , and TT . Ablation of P27361 / 2 by RNA interference abrogated all these effects . However , active site - disabled P29323 mutants ( P27361 - K71R , P28482 - K52R , and P28482 - D147A ) , which competitively inhibit activation of endogenous P27361 / 2 , could not block Raf / MEK - induced growth arrest as well as changes in the cell cycle regulators , although they effectively blocked phosphorylation of the P27361 / 2 catalytic activity readouts , p90 ( RSK ) and ELK1 , as well as the cell type - specific changes . Because this indicated a potential noncatalytic P27361 / 2 function , we generated stable lines of the tumor cells in which both P27361 and P28482 were significantly knocked down , and we further investigated the possibility using rat - derived kinase - deficient P29323 mutants ( P28482 - K52R and P28482 - T183A / Y185F ) that were not targeted by human small hairpin RNA . Indeed , P28482 - K52R selectively restored Raf - induced growth inhibitory signaling in P27361 / 2 - depleted cells , as manifested by regained cellular ability to undergo growth arrest and to control the cell cycle regulators without affecting c - Myc and morphology . However , P28482 - T183A / Y185F was less effective , indicating the requirement of TEY site phosphorylation . Our study suggests that functions of P27361 / 2 other than its \\\" canonical \\\" kinase activity are also involved in the pathway - mediated growth arrest signaling .\",\n \"SAR131675 , a potent and selective P35916 - TK inhibitor with antilymphangiogenic , antitumoral , and antimetastatic activities . SAR131675 is a potent and selective P35916 inhibitor . It inhibited P35916 tyrosine kinase activity and P35916 autophosphorylation in P29320 cells with IC ( 50 ) values of 20 and 45 nmol / L , respectively . SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells , induced by the P35916 ligands P49767 and O43915 , with an IC ( 50 ) of about 20 nmol / L . SAR131675 was found to be highly selective for P35916 versus 107 receptors , enzymes , ion channels , and 65 kinases . However , it was moderately active on P35968 with a P35916 / P35968 ratio of about 10 . SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells , further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent . SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models , including mammary 4T1 carcinoma and Q13546 . Tag2 tumors . Interestingly , it significantly reduced lymph node invasion and lung metastasis , showing its antilymphangiogenic activity in vivo . Moreover , treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis . Tumor - associated macrophages ( TAM ) play an important role in tumor growth and metastasis . The expression of P35916 on TAMs has been recently described . F4 / 80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors . Taken together , SAR131675 is the first highly specific P35916 - TK inhibitor described to date , displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion .\",\n \"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK7___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK7___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .\",\n \"Antagonism of endothelin action normalizes altered levels of P15692 and its signaling in the brain of stroke - prone spontaneously hypertensive rat . Stroke - prone spontaneously hypertensive rats ( SHRSP ) often suffer from spontaneous stroke , in part , due to abnormalities in the cerebrovasculature . Here , we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age - dependent stages of hypertension . The profile of P15692 and its receptor , Flk - 1 , was dependent on age and stage of hypertension ( i . e . , down regulated at pre - hypertensive and malignant hypertensive stages , but up regulated at typical hypertensive stage ) , while that of its downstream components , pAkt and P29474 , were down regulated in a time - dependent manner in the frontal cortex of SHRSP compared to age - matched genetic control , normotensive WKY rats . On the other hand , the expression of endothelin - 1 and its type A receptor ( endothelin P25101 receptor ) were up regulated , depending on age and stage of hypertension . In contrast , levels of endothelin type B receptor were down regulated . The regional cerebral blood flow decreased during the development of malignant hypertension . Thus , subsequent experiments were designed to investigate whether endothelin - 1 receptor antagonism , using endothelin - A /- B dual receptor antagonist SB209670 , could normalize the molecular profile of these factors in SHRSP brain . Interestingly , blockage of endothelin - 1 receptor restored to normal , levels of cerebral endothelin - 1 , endothelin P25101 receptor and endothelin ETB receptor ; P15692 and Flk - 1 ; endothelial nitric oxide synthase ( P29474 ) and pAkt , in SHRSP , compared to age - matched WKY . Endothelin receptor blocker might be important to prevent the progression in the defect in P15692 and its angiogenic signaling cascade in the pathogenesis of hypertension - induced vascular remodeling in frontal cortex of SHRSP rats .\",\n \"Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer . Medullary thyroid cancer is an uncommon malignancy for which until recently little effective treatment existed . It is often characterized by mutation and overexpression of the receptor tyrosine kinases P07949 ( rearranged during transfection ) , P35968 ( vascular endothelial growth factor receptor 2 ) and MET ( mesenchymal - epithelial transition factor ) , which make attractive targets for drug development . DB08875 is an orally bioavailable tyrosine kinase inhibitor which blocks MET , VEGRF2 and P07949 , and has shown considerable activity in medullary thyroid cancer in a Phase III trial , including in heavily pretreated patients . Its novel combination of vascular endothelial growth factor and MET inhibition is believed to address the MET escape pathway , which is thought to be the cause of nonsustained tumor responses resulting from inhibition of vascular endothelial growth factor alone .\",\n \"Characterization and binding activity of the chondroitin / dermatan sulfate chain from Endocan , a soluble endothelial proteoglycan . Endocan is a recently identified soluble chondroitin / dermatan sulfate ( CS / DS ) proteoglycan . Synthesized by endothelial cells , it has been found to be over - expressed in the vasculature surrounding a number of tumors , and by promoting growth factor mitogenic activities , hepatocyte growth factor / scatter factor ( P14210 / SF ) in particular , it supports cellular proliferation . In this work , we characterized the glycosaminoglycan ( GAG ) chain of Endocan , purified either from the naturally producing human umbilical vein endothelial cells ( HUVEC ) or from a recombinant over - expression system in human embryonic kidney cells ( P29320 ) . Compositional analysis using different chondroitinases as well as nuclear magnetic resonance studies revealed that the GAG chains from both sources share many characteristics , with the exception of size ( 15 and 40 kDa , respectively , for HUVEC and P29320 - 293 cells ) . The DS - specific , IdoA - containing disaccharides contribute 30 % of the chain ( 15 % of which are 2 - O - sulfated ) and are mostly clustered in tetra - ( 35 % ) , hexa - ( 12 % ) , and octa - ( 5 % ) saccharide domains . Highly sulfated D , E , and B disaccharide units ( HexA2S - GalNAc6S , HexA - GalNAc4S6S , and HexA2S - GalNAc4S ) were also detected in significant amounts in both chains and may account for the P14210 / SF - binding activity of the CS / DS . This work establishes that P29320 - 293 cells can be engineered to provide a valuable source of Endocan with authentic CS / DS chains , enabling the purification of sufficient amounts for structural and / or binding analysis and providing a possible model of Endocan CS / DS chain organization .\",\n \"P01138 - withdrawal induces apoptosis in pancreatic beta cells in vitro . AIMS / HYPOTHESIS : Using primary cultures of human pancreatic islets , purified human pancreatic beta cells and the mouse beta TC6 - P08709 cell line , we analysed the expression of nerve growth factor , ( P01138 / P01138 ) receptors in beta cells . To investigate whether P01138 could sub - serve an autocrine antiapoptotic role in beta cells , we studied the effects of P01138 withdrawal using a neutralizing monoclonal anti - P01138 antibody . METHODS : The expression of P01138 and P01138 receptors ( gp140 ( P04629 ) and p75 ( NTR ) ) were analysed by RT - PCR and immunofluorescence . Pulse - chase experiments and beta cell / PC12 co - cultures were used to investigate P01138 production and secretion from beta cells . Possible apoptosis induced by P01138 withdrawal was monitored by phosphatidylserine translocation , nucleosomal formation , DNA laddering and FACS analysis . Involvement of transcription / translation mechanisms were investigated as well as the gp140 ( P04629 ) required . Finally , signal transduction pathways typically involved in apoptotic mechanisms were analysed by western blot analysis . RESULTS : We show that P01138 and both P01138 receptors , gp140 ( P04629 ) and p75 ( NTR ) are expressed in beta cells where P01138 is produced and secreted in a biologically active form . P01138 - withdrawal induces beta - cell transcription / translation independent apoptosis but mediated by gp140 ( P04629 ) . Analysis of signal transduction pathways revealed that P01138 withdrawal inhibits the P19957 - K , protein kinase B ( AKT ) , Bad survival pathway and activates c - Jun kinase ( JNK ) whereas ERKs and p38 mitogen - activated protein kinase ( MAPK ) are not affected . Moreover , Bcl - XL , but not Bcl - 2 protein expression are reduced . CONCLUSION / INTERPRETATION : We suggest that the integrity of the P01138 / P08138 system and P01138 bioavailability participate in controlling beta - cell survival in culture which represents a key issue for improving possibilities for transplantations in the treatment of diabetes .\",\n \"DB08875 suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of P35968 and MET . PURPOSE : MET signaling has been suggested a potential role in hepatocellular carcinoma ( HCC ) and associated with prometastasis during antiangiogenesis therapy . We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC . Antitumor effects of cabozantinib , a dual inhibitor of MET and P35968 , were examined in cultured HCC cells as well as in vivo models . EXPERIMENTAL DESIGN : Total MET and phosphorylated MET ( p - MET ) were measured in 29 resected HCC specimens , and correlated with response to sorafenib as postoperative adjuvant therapy . In the second set of experiments using cultured HCC cells , and mouse xenograft and metastatic models , effects of cabozantinib were examined . RESULTS : High level of p - MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy . In cultured HCC cells that expressed p - MET , cabozantinib inhibited the activity of MET and its downstream effectors , leading to P55008 - phase arrest . DB08875 inhibited tumor growth in p - MET - positive and p - MET - negative HCC by decreasing angiogenesis , inhibiting proliferation , and promoting apoptosis , but it exhibited more profound efficacy in p - MET - positive HCC xenografts . DB08875 blocked the hepatocyte growth factor ( P14210 ) - stimulated MET pathway and inhibited the migration and invasion of the HCC cells . Notably , cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model . CONCLUSIONS : Patients with HCC with high level of p - MET are associated with resistance to adjuvant sorafenib treatment . The dual blockade of P35968 and MET by cabozantinib has significant antitumor activities in HCC , and the activation of MET in HCC may be a promising efficacy - predicting biomarker . Clin Cancer Res ; 20 ( 11 ) ; 2959 - 70 . © 2014 AACR .\",\n \"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .\",\n \"DB08875 : a review of its use in patients with medullary thyroid cancer . DB08875 ( Cometriq (®) ) is an orally administered small molecule inhibitor of multiple tyrosine kinase receptors , including those involved in the pathogenesis of medullary thyroid cancer ( P04629 ) [ i . e . rearranged during transfection ( P07949 ) , MET and vascular endothelial growth factor receptor ( VEGFR ) - 2 ] . DB08875 is indicated for the treatment of adults with progressive , unresectable locally advanced ( in the EU ) or metastatic ( in the EU and USA ) P04629 . Compared with placebo , cabozantinib significantly prolonged progression - free survival , reflecting a 72 % reduction in the risk of disease progression or death , in patients with unresectable , locally advanced or metastatic P04629 participating in a multinational , phase III study . A significantly higher proportion of patients receiving cabozantinib than those receiving placebo achieved an objective response or disease stabilization ( i . e . a complete or partial response , or stable disease ) . The overall survival benefit with cabozantinib is as yet unclear , with no significant benefit observed in two interim analyses ( one prespecified , and one unplanned and conducted at the request of the US FDA ) . The tolerability profile of oral cabozantinib is typical for a small molecule targeting the VEGFR and other tyrosine kinase - mediated pathways , with adverse events associated with the inhibition of the P15692 pathway ( e . g . gastrointestinal perforation , haemorrhage , hypertension and venous thrombosis ) reported in the phase III study . Treatment - emergent adverse events were generally managed with supportive therapy , dose reductions and / or dose interruptions . Although final overall survival data are awaited , current evidence suggests cabozantinib to be a valuable treatment option for adults with progressive , unresectable locally advanced or metastatic P04629 .\",\n \"Expressed luciferase viability assay ( ELVA ) for the measurement of cell growth and viability . An expressed luciferase viability assay ( ELVA ) has been developed for cell viability and cell number based on detecting the expression of luciferase transfected into the cells . Stable transfectants were produced that expressed luciferase constitutively . Like many endogenous enzymes , luciferase is rapidly degraded following cell death , so that the enzyme can be used as a measure of cell viability . A modified luciferase assay was used in which the reagents were added directly to the cells in a microplate . The main advantages compared to other cell viability assays are the wide dynamic range , high sensitivity , low background , and the absence of any requirement to wash or harvest the cells . Stable transfectants of three factor - dependent cell lines ( B13 , Ba / P13726 and CTLL ) were produced and used in cytokine assays . Three strategies of selection after electroporation were tested : ( 1 ) using a plasmid containing both the genes encoding firefly luciferase and a selectable marker ( neo ) , ( 2 ) cotransfection of a plasmid containing luciferase and a plasmid containing a selectable marker ( puromycin resistance ) , and ( 3 ) cotransfection of a plasmid containing luciferase and a plasmid containing the human IL - 5Ralpha - chain , and selecting in P05113 . This latter strategy produces an P05113 responsive cell line expressing luciferase in a single step without the need for antibiotic selection .\",\n \"A dose - ranging study of cabozantinib in men with castration - resistant prostate cancer and bone metastases . BACKGROUND : DB08875 is an oral MET / P35968 inhibitor . A recent phase II study of cabozantinib ( 100 mg daily ) showed improved bone scans in subjects with metastatic castration - resistant prostate cancer ( mCRPC ) , but adverse events ( AE ) caused frequent dose reductions . This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses . EXPERIMENTAL DESIGN : An adaptive design was used to determine the lowest active daily dose among 60 , 40 , and 20 mg . The primary endpoint was week 6 bone scan response , defined as ≥ 30 % decrease in bone scan lesion area . The secondary endpoint was change in circulating tumor cells ( CTC ) . RESULTS : Among 11 evaluable subjects enrolled at 40 mg , there were 9 partial responses ( PR ) , 1 complete response , and 1 stable disease ( SD ) . Of 10 subjects subsequently enrolled at 20 mg , there were 1 PR , 5 SDs , and 4 with progressive disease . Among 13 subjects enrolled on the 40 mg expansion cohort , there were 6 PRs and 7 SDs . No subjects required dose reduction or treatment interruption at 6 or 12 weeks ; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks . At 40 mg , median treatment duration was 27 weeks . 58 % of subjects with ≥ 5 CTCs / 7 . 5 mL at baseline converted to < 5 . CONCLUSIONS : DB08875 40 mg daily was associated with a high rate of bone scan response . DB08875 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily . These observations informed the design of phase III studies of cabozantinib in mCRPC .\",\n \"Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .\",\n \"DB08875 for the treatment of advanced medullary thyroid cancer . INTRODUCTION : Patients with advanced medullary thyroid cancer ( P04629 ) have poor prognoses and limited treatment options . Improved knowledge about molecular aberrations associated with P04629 and the availability of novel targeted tyrosine kinase inhibitors ( TKIs ) have led to new potential treatment modalities . DB08875 is an oral multitargeted TKI with activity against multiple receptors including P07949 , vascular endothelial growth factor receptor type 2 ( P35968 ) , and MET that has been evaluated in P04629 in the preclinical and clinical arenas . METHODS : This article reviews unmet clinical needs in advanced P04629 . The authors consider novel agents that have been studied in P04629 , with a focus on the investigational agent cabozantinib . Up - to - date clinical data of cabozantinib in P04629 are discussed . RESULTS : Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression - free survival in patients with progressive P04629 . These findings indicate that cabozantinib may be an effective therapy in advanced P04629 . No improvement in overall survival has been demonstrated but data are not mature . CONCLUSION : DB08875 may be an effective treatment option for patients with advanced P04629 and is worthy of further evaluation .\",\n \"Effects of ellagic Acid on angiogenic factors in prostate cancer cells . BACKGROUND : Several natural antioxidants , including ellagic acid ( EA ) , have been reported to have chemotherapeutic activity in vivo and in vitro settings . Cytochrome P450 ( CYP ) activity and synthesis of both epoxyeicosatrienoic acids ( EETs ) and 20 - hydroxy - 5 , 8 , 11 , 14 - eicosatetraenoic acid ( 20 - HETE ) , together with vascular endothelial growth factor ( P15692 ) and heme oxygenase system ( HO ) have emerged as important modulators of tumor growth and metastasis . METHODS : The anti - angiogenic effects of EA were investigated in the human prostatic cancer cell line LnCap . P09601 , P30519 , P51589 and soluble epoxyde hydrolase ( sEH ) expressions were evaluated by western blotting . Levels of P15692 and osteoprotegerin ( O00300 ) were determined in the culture supernatant using an ELISA assay , while CYP mRNAs were determined by qRT - PCR . RESULTS : EA treatment induced a significant decrease ( p < 0 . 05 ) in P09601 , P30519 and P51589 expression , and in P15692 and O00300 levels . Similarly P51589 , P78329 and CYPA22 mRNAs were significantly ( p < 0 . 05 ) down - regulated by EA treatment . The decrease in P51589 mRNA was associated with an increase in sEH expression . CONCLUSIONS : RESULTS reported in the present study highlighted the ability of EA to modulate a new pathway , in addition to anti - proliferative and pro - differentiation properties , via a mechanism that involves a decrease in eicosanoid synthesis and a down - regulation of the HO system in prostate cancer .\",\n \"DB08875 ( DB05153 ) for the treatment of locally advanced or metastatic progressive medullary thyroid cancer . DB08875 ( DB05153 ) is an oral multiple receptor tyrosine kinase inhibitor manufactured by Exelixis Inc . , CA , USA . It mainly inhibits three tyrosine kinase receptors : MET , P35968 and P07949 . In both preclinical and clinical studies it has been shown to inhibit tumor angiogenesis , invasiveness and metastases . The most frequent side effects are fatigue , diarrhea , decreased appetite , nausea , weight loss and palmar - plantar erythrodysesthesia . A Phase III clinical trial ( EXAM study ) of DB05153 versus placebo in advanced and progressive medullary thyroid cancer showed a 28 versus 0 % overall response rate and a progression - free survival of 11 . 2 versus 4 . 0 months ( hazard ratio : 0 . 28 ; 95 % CI : 0 . 19 - 0 . 40 ; p < 0 . 0001 ) in patients treated with cabozantinib and placebo , respectively . The drug has been approved by the US FDA for the treatment of advanced / progressive metastatic medullary thyroid cancer in the USA . The P15941 is now evaluating its approval in Europe .\",\n \"Liver regeneration induced by a designer human P05231 / sIL - 6R fusion protein reverses severe hepatocellular injury . The cytokine P05231 plays a significant role in liver regeneration in conjunction with additional growth factors ( P14210 , P01375 , and TGF - alpha ) . Many P05231 effects depend on a naturally occurring soluble P05231 receptor ( sIL - 6R ) . Here , the chimeric protein hyper - P05231 , constructed from the human P05231 protein fused to a truncated form of its receptor , was found to have superagonistic P05231 properties , and as such , enhanced liver cell regeneration . Hyper - P05231 reversed the state of hepatotoxicity and enhanced the survival rates of rats suffering from fulminant hepatic failure after D - galactosamine administration . The hyper - P05231 protein has a significant potential for use in the treatment of severe human liver diseases .\",\n \"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK17___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .\",\n \"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK84___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .\",\n \"DB08875 inhibits growth of androgen - sensitive and castration - resistant prostate cancer and affects bone remodeling . DB08875 is an inhibitor of multiple receptor tyrosine kinases , including MET and P35968 . In a phase II clinical trial in advanced prostate cancer ( PCa ) , cabozantinib treatment improved bone scans in 68 % of evaluable patients . Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone - sensitive and castration - resistant PCa in preclinical models while delineating its effects on tumor and bone . Using immunohistochemistry and tissue microarrays containing normal prostate , primary PCa , and soft tissue and bone metastases , our data show that levels of MET , P - MET , and P35968 are increasing during PCa progression . Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases . To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen - sensitive LuCaP 23 . 1 and castration - resistant C4 - 2B PCa tumors . In vivo , cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors . Furthermore , cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume . In summary , the expression pattern of cabozantinib targets in primary and castration - resistant metastatic PCa , and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease .\",\n \"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .\",\n \"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK21___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK21___ is also being investigated as part of triplet drug regimens . ___MASK21___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .\",\n \"A new cell culture - based assay quantifies vitamin K 2 , 3 - epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol - driven Q9BQB6 assay . BACKGROUND : ___MASK25___ directly inhibits the vitamin K 2 , 3 - epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) - driven vitamin K 2 , 3 - epoxide reductase ( Q9BQB6 ) assay . ___MASK25___ inhibits wild - type Q9BQB6 function by the DTT - Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance - associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture - based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild - type and variant Q9BQB6 proteins . METHODS : Human coagulation factor ( F ) IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild - type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : ___MASK25___ dose - response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild - type , Val29Leu , Val45Ala and Leu128Arg variants . The corresponding calculated IC50 values were 24 . 7 , 136 . 4 , 152 . 0 and 1226 . 4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild - type Q9BQB6 . Ranked IC50 values from the cell culture - based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation - associated warfarin resistance .\"\n]"},"candidates":{"kind":"list like","value":["___MASK17___","___MASK21___","___MASK25___","___MASK39___","___MASK75___","___MASK7___","___MASK84___","___MASK90___","___MASK94___"],"string":"[\n \"___MASK17___\",\n \"___MASK21___\",\n \"___MASK25___\",\n \"___MASK39___\",\n \"___MASK75___\",\n \"___MASK7___\",\n \"___MASK84___\",\n \"___MASK90___\",\n \"___MASK94___\"\n]"},"answer":{"kind":"string","value":"___MASK7___"},"id":{"kind":"string","value":"MH_train_481"}}},{"rowIdx":482,"cells":{"query":{"kind":"string","value":"interacts_with DB00998?"},"supports":{"kind":"list like","value":["5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .","MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .","[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK28___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .","A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .","Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK55___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK55___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .","___MASK57___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK57___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .","DB00998 Vernalis . Vanguard ( now Vernalis ) has developed frovatriptan , a selective P28222 / 1D partial agonist licensed from GlaxoSmithKline as a potential treatment for migraine [ 188478 ] , [ 194382 ] , [ 377863 ] .","Pharmacokinetic evaluation of frovatriptan . INTRODUCTION : Migraine is the most common painful neurological disorder , affecting 13 % of the general population . Triptans represent a powerful pharmacological tool in acute migraine treatment , however , a significant portion of treated patients can not have access to this class due to possible adverse affects . Today , a total of seven DB00669 molecules are available , representing a commonly prescribed migraine treatment . Although there is a need of extensive use of triptans , only 25 % of migraine patients are using triptans . AREAS COVERED : This review includes triptans and evidence for the use of frovatriptan . A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan , considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches . The data were obtained by searching the following key words in MEDLINE : pharmacokinetic , pharmacodynamic , triptans , frovatriptan , migraine , menstrual migraine , relatively to the period 1988 - 2011 . EXPERT OPINION : DB00998 has been developed in order to improve safety and efficacy of triptans . It shows a favorable tolerability and efficacy profile , limited to 24 / 48 - h headache recurrence , when compared with other triptans . Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans . In fact , among triptans , frovatriptan showed the highest potency at the P28222 receptor ( 8 . 2 ) and the longer half - life ( 26 h ) . These parameters determine the clinical properties of frovatriptan ; in particular the lowest rate of headache recurrence in comparison with other triptans .","Activation of the JAK / P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK / P35610 pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 (- 6 ) M ) resulted in time - dependent activation ( approximately 2 - fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10 (- 9 )- 10 (- 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 pathway . Treatment with the 5 - Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5 - HT . Treatment of streptozotocin - induced diabetic rats with ketanserin ( 5 mg . kg - 1 . day - 1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium - denuded thoracic aorta in vivo . 5 - HT ( 10 (- 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 , P23458 , and P42224 via the 5 - Q13049 receptors in a reactive oxygen species - independent manner under both normal and high glucose conditions .","Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .","___MASK15___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK15___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .","___MASK12___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK12___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .","Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK47___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .","Involvement of P28222 receptors in DB00669 - induced contractile responses in guinea - pig isolated iliac artery . Using a series of triptans we characterized in vitro the 5 - hydroxytryptamine ( 5 - HT ) receptor that mediates the contraction in guinea - pig iliac arteries moderately precontracted by prostaglandin F2alpha ( PGF2alpha ) . Additionally , we investigated by reverse - transcriptase polymerase chain reaction ( RT - PCR ) which DB00669 - sensitive receptor is present in this tissue . DB00998 , zolmitriptan , rizatriptan , naratriptan , sumatriptan , and almotriptan contracted guinea - pig iliac arteries with pD2 values of 7 . 52 +/- 0 . 04 , 6 . 72 +/- 0 . 03 , 6 . 38 +/- 0 . 06 , 6 . 22 +/- 0 . 05 , 5 . 86 +/- 0 . 05 and 5 . 26 +/- 0 . 04 respectively . For comparison , the pD2 values for 5 - HT and 5 - carboxamidotryptamine ( 5 - CT ) were 7 . 52 +/- 0 . 02 and 7 . 55 +/- 0 . 03 respectively . In contrast to all other triptans tested , the concentration - response curve for eletriptan was biphasic ( first phase : 0 . 01 - 3 microM , pD2 approximately 6 . 6 ; second phase : > or = 10 microM ) . Contractions to 5 - HT , 5 - CT , frovatriptan , zolmitriptan , rizatriptan , naratriptan , sumatriptan , almotriptan , and eletriptan ( first phase ) were antagonized by the P28222 / 1D receptor antagonist GR127935 ( 10 nM ) and the P28222 receptor antagonist SB216641 ( 10 nM ) . RT - PCR studies in guinea - pig iliac arteries showed a strong signal for the P28222 receptor while expression of P28221 and P30939 receptors was not detected in any sample . The present results demonstrate that DB00669 - induced contraction in guinea - pig iliac arteries is mediated by the P28222 receptor . The guinea - pig iliac artery may be used as a convenient in vitro model to study the ( cardio ) vascular side - effect potential of anti - migraine drugs of the DB00669 family .","Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .","Meta - analysis of oral DB00669 therapy for migraine : number needed to treat and relative cost to achieve relief within 2 hours . OBJECTIVE : To determine the cost - effectiveness of the P28222 / 1D agonists , or triptans , in the acute treatment of migraine . METHODS : To determine the cost - effectiveness of the triptans , a meta - analysis was conducted of the efficacy data from 27 oral DB00669 trials , using the endpoint of \" pain - free \" status within 2 hours after initial dosing as the indicator of efficacy . Efficacy data were used to determine the number needed to treat ( Q13423 ) to achieve pain - free status in 1 patient within 2 hours postdose and then applied the per - dose costs for each DB00669 to the Q13423 values . RESULTS : Rizatriptan 10 mg and almotriptan 12 . 5 mg were the most cost - effective of the triptans , costing $ 48 . 34 and $ 48 . 57 US dollars , respectively , to achieve pain - free status in 1 patient within 2 hours postdose . DB00998 2 . 5 mg was the most costly , with a cost - effective ratio of $ 162 . 49 US dollars . All other triptans fell between these extremes : zolmitriptan 5 mg ( $ 65 . 18 US dollars ) , sumatriptan 100 mg ( $ 70 . 83 US dollars ) , sumatriptan 50 mg ( $ 75 . 67 US dollars ) , zolmitriptan 2 . 5 mg ( $ 78 . 74 US dollars ) , and naratriptan 2 . 5 mg ( $ 141 . 43 US dollars ) , in decreasing order of cost - effectiveness . CONCLUSION : Using an Q13423 analysis , the least - costly drugs to achieve migraine cure within 2 hours are rizatriptan 10 mg and almotriptan 12 . 5 mg . From a population health perspective , the lower acquisition cost of almotriptan 12 . 5 mg allows for effective treatment of more patients than rizatriptan 10 mg for no additional medication cost .","Deliberate self - harm is associated with allelic variation in the tryptophan hydroxylase gene ( P17752 A779C ) , but not with polymorphisms in five other serotonergic genes . BACKGROUND : There is a heritable component to suicidal behaviour , encouraging the search for the associated risk alleles . Given the putative role of the 5 - HT ( 5 - hydroxytryptamine ; serotonin ) system in suicidal behaviour , serotonergic genes are leading candidates . In particular , several studies have reported an association with variants in the tryptophan hydroxylase ( P17752 ) gene . METHOD : We studied six serotonergic gene polymorphisms in a well - characterized sample of 129 deliberate self - harm subjects and 329 comparison subjects . The polymorphisms were P17752 ( A779C ) , 5 - HT transporter ( 5 - HTT , LPR S / L ) , monoamine oxidase A ( P21397 G941T ) , P28222 receptor ( P28222 G861C ) , 5 - Q13049 receptor ( P28223 T102C ) , and P28335 receptor ( P28335 Cys23Ser ) . Genotyping was done using polymerase chain reaction ( PCR ) - based assays . The primary analyses compared allele and genotype frequencies between cases and controls . There were a limited number of planned secondary analyses within the deliberate self - harm group . RESULTS : The P17752 A779 allele was more common in deliberate self - harm subjects than in controls ( OR 1 . 38 , 95 % CI 1 . 02 - 1 . 88 ; P = 0 . 03 ) . None of the other polymorphisms was associated with deliberate self - harm . Within the deliberate self - harm group there were no associations with impulsivity , suicide risk , lifetime history of depression , or family history of deliberate self - harm . CONCLUSIONS : Our data extend the evidence that allelic variation in the P17752 gene is a risk factor for deliberate self - harm . No evidence was found to implicate the other polymorphisms .","DB00998 : a selective type 1B / 1D serotonin receptor agonist for the treatment of migraine headache . DB00998 belongs to an innovative family of compounds aimed at breaking through the long - standing barrier of migraine headache understanding and treatment . While a typology of headaches has been recognized for some time , and a number of therapies have been introduced for reduction of headache pain and duration , the causes of migraine remain a subject of debate . Those prone to attacks continue to endure them and suffer the related symptoms such as nausea and disorientation . DB00998 , like all the triptans , acts by inducing vasoconstriction of the meningeal arteries . It has been shown in pharmacological tests to act selectively as a potent agonist of serotonin P28222 / 1D receptors . DB00998 has been well tolerated in humans and efficacious in reducing headache pain and duration in clinical trials , which have also indicated that dose adjustments for age or gender are not necessary for the drug . Patients have found the use of frovatriptan acceptable over the long - term , and overall a low - incidence of adverse effects has been reported . Though not a prophylactic , frovatriptan has demonstrated the potential to significantly improve the therapeutic approaches to the treatment of migraine .","The efficacy and tolerability of frovatriptan and dexketoprofen for the treatment of acute migraine attacks . DB00998 is a DB00669 characterized by a high affinity for P28222 / 1D receptors and a long half - life contributing to a more sustained and prolonged action than other triptans . DB09214 is a nonsteroidal anti - inflammatory drug with a relatively short half - life and rapid onset of action , blocking the action of cyclo - oxygenase , which is involved in prostaglandins ' production , thus reducing inflammation and pain . Both drugs have been successfully employed as monotherapies for the treatment of acute migraine attacks . The combination of these two drugs ( frovatriptan 2 . 5 mg plus dexketoprofen 25 or 37 . 5 mg ) has been tested in migraine sufferers , showing a rapid and good initial efficacy , with 2 - h pain free rates of 51 % , and a high persistence in the 48 - h following the onset of pain : recurrence occurred in only 29 % of attacks and sustained pain free rates were 43 % at 24 - and 33 % at 48 - h .","Disabling the mitotic spindle and tumor growth by targeting a cavity - induced allosteric site of survivin . Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis . Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy . P00533 and Her / neu - transformed human tumors in particular exhibit high levels of survivin . The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein . We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces . P28222 , a lead compound identified in the screen , can bind to the survivin protein at the intended target site . Moreover , P28222 alters spindle formation , causing mitotic arrest and cell death , and inhibits tumor growth in vitro and in vivo . Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity . Thus , the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers .","Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .","Desmopressin ( ___MASK10___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK10___ ) also has strong vasodilatory effects . ___MASK10___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK10___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK10___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK10___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK10___ - induced vasodilation .","DB00998 , a P28222 / 1D receptor agonist for migraine . DB00998 is one of the most recent serotonin receptor agonists to receive FDA , approved labelling for use in the acute management of migraine with or without aura in adults . The mechanism of action of frovatriptan is thought to be similar to that of a serotonin agonist . However , frovatriptan has distinctive pharmacokinetic and pharmacologic properties , chiefly , a high affinity for serotonin receptors 1B and 1D and a long elimination half - life ; frovatriptan was shown to be more selective for cerebral than coronary arteries , a property which makes frovatriptan more favourable in patients at risk of coronary artery disease . Additionally , frovatriptan has a half - life of approximately 25 h , substantially longer than that of any other agent within its class . This property makes frovatriptan suitable for patients who typically suffer migraines of long duration and / or those who suffer migraine recurrence . The efficacy of frovatriptan in the treatment of acute migraine was demonstrated in five double - blind , randomised , placebo - controlled trials . At 2h , headache response rates for frovatriptan 2 . 5 mg ranged from 38 to 40 % compared to 22 - 35 % for placebo . Headache recurrence for frovatriptan 2 . 5 mg at 24h ranged from 9 to 14 % compared with 18 % in placebo subjects . DB00998 has no clinically significant pharmacokinetic interactions with drugs used for migraine prophylaxis or with commonly prescribed medications . Adverse effects of frovatriptan including dizziness , paresthesia , dry mouth , fatigue and flushing were generally mild and well tolerated . Given the fact that patient response to serotonin agonists is individualised , and selecting an effective agent may involve trial and error , frovatriptan is a welcome alternative in the acute management of migraine .","___MASK42___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK42___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK42___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK42___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK42___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .","Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK24___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK24___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .","DB00998 . black triangle DB00998 , a new serotonin receptor agonist developed for the acute treatment of migraine , has high affinity for serotonin P28222 and P28221 receptor subtypes and is a potent stimulator of contraction in human basilar arteries . black triangle A long terminal elimination half - life ( approximately 26 hours ) is a distinctive pharmacokinetic feature of frovatriptan which appears to be independent of dose , age , gender and renal function . black triangle A single oral dose of frovatriptan 2 . 5mg was effective in the acute treatment of migraine providing meaningful relief within 2 hours to approximately twice as many recipients as placebo in clinical trials . black triangle Consistent relief of migraine symptoms was achieved in patients who treated a number of consecutive attacks with frovatriptan and the incidence of 24 - hour migraine recurrence was reduced . black triangle DB00998 was well tolerated in clinical trials , with the overall incidence of adverse events occurring with frovatriptan 2 . 5mg only slightly higher than that reported with placebo . Mild to moderate fatigue , nausea and paraesthesia were the most commonly reported drug - related adverse events .","A review of the use of frovatriptan in the treatment of menstrually related migraine . Menstrual migraine ( MM ) is a highly prevalent condition associated with considerable disability . Migraine attacks occur exclusively around the menstrual period in approximately 10 % of women with migraine , that is , pure menstrual migraine , while at least 50 % of them also experience migraine at other times of the month , that is , menstrually related migraine ( MRM ) . The therapeutic approach to patients with MRM is based on treatment of the attack , or prophylactic strategies . Triptans are recommended as first - line treatments for moderate to severe migraine attacks , including MM . DB00998 is one of the newest triptans . Its high affinity for P28222 / 1D receptors and long half - life contribute to its distinctive clinical effect , characterized by a more sustained and prolonged effect than other triptans . Indeed , frovatriptan proved to be effective in treating the acute attack , but was particularly effective in the short - term preventive therapy of MM . In addition , frovatriptan is one of the safest triptans , with the lowest risk of treatment - emergent adverse events . Following extensive evidence from randomized pharmacological trials , frovatriptan has now gained a grade A recommendation from the guidelines for short - term prophylaxis of MM . Recent post - hoc analyses of direct comparative trials also suggest that frovatriptan might have an important role in the acute treatment of MRM . In these studies , frovatriptan showed pain relief and pain - free rates similar to those of zolmitriptan , rizatriptan , and almotriptan , but with significantly lower recurrence rates . More well - designed , randomized , prospective studies , specifically enrolling women with MM , will be needed in the near future to confirm the efficacy of frovatriptan in this migraine subtype .","Fluorescence energy transfer analysis of calmodulin - peptide complexes . The interactions between calmodulin and the tryptophan residues of synthetic peptides corresponding to the calmodulin binding domains of skeletal muscle myosin light - chain kinase and the plasma membrane calcium pump were examined . The single tryptophan residue contained in each peptide became relatively immobilized and inaccessible to iodide ion upon binding to calmodulin , indicating that the indole side chain was inserted into a hydrophobic cleft in the surface of calmodulin . Fluorescence energy transfer from peptidyl tryptophan residues to an AEDANS moiety attached to cysteine - 26 of spinach calmodulin was measured . Included in these analyses was a tryptophan - containing peptide analog of the calmodulin binding domain of neuromodulin . These data indicated that the indole ring of each peptide inserted 32 - 35 A away from cysteine - 26 and may therefore interact with the carboxyl - terminal lobe of P62158 in its \" bent \" conformation [ Persechini & Kretsinger ( 1988a ) J . Cardiovasc . Pharmacol . 12 ( Suppl 5 ) , S1 - P28222 ; Ikura et al . ( 1992 ) Science 256 , 632 - 638 ; Vorherr et al . ( 1992 ) Eur . J . Biochem . 204 , 931 - 937 ] . The interchange of tryptophan - 3 and phenylalanine - 21 of the calcium pump peptide increased the efficiency of energy transfer to the AEDANS - moiety approximately 12 - fold , reducing the calculated distance to 20 A . These data suggest that phenylalanine - 21 of the calcium pump peptide interacts with the hydrophobic cleft in the amino - terminal lobe of P62158 .","P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 ."],"string":"[\n \"5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .\",\n \"MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .\",\n \"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK28___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .\",\n \"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .\",\n \"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK55___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK55___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .\",\n \"___MASK57___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK57___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .\",\n \"DB00998 Vernalis . Vanguard ( now Vernalis ) has developed frovatriptan , a selective P28222 / 1D partial agonist licensed from GlaxoSmithKline as a potential treatment for migraine [ 188478 ] , [ 194382 ] , [ 377863 ] .\",\n \"Pharmacokinetic evaluation of frovatriptan . INTRODUCTION : Migraine is the most common painful neurological disorder , affecting 13 % of the general population . Triptans represent a powerful pharmacological tool in acute migraine treatment , however , a significant portion of treated patients can not have access to this class due to possible adverse affects . Today , a total of seven DB00669 molecules are available , representing a commonly prescribed migraine treatment . Although there is a need of extensive use of triptans , only 25 % of migraine patients are using triptans . AREAS COVERED : This review includes triptans and evidence for the use of frovatriptan . A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan , considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches . The data were obtained by searching the following key words in MEDLINE : pharmacokinetic , pharmacodynamic , triptans , frovatriptan , migraine , menstrual migraine , relatively to the period 1988 - 2011 . EXPERT OPINION : DB00998 has been developed in order to improve safety and efficacy of triptans . It shows a favorable tolerability and efficacy profile , limited to 24 / 48 - h headache recurrence , when compared with other triptans . Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans . In fact , among triptans , frovatriptan showed the highest potency at the P28222 receptor ( 8 . 2 ) and the longer half - life ( 26 h ) . These parameters determine the clinical properties of frovatriptan ; in particular the lowest rate of headache recurrence in comparison with other triptans .\",\n \"Activation of the JAK / P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK / P35610 pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 (- 6 ) M ) resulted in time - dependent activation ( approximately 2 - fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10 (- 9 )- 10 (- 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 pathway . Treatment with the 5 - Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5 - HT . Treatment of streptozotocin - induced diabetic rats with ketanserin ( 5 mg . kg - 1 . day - 1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium - denuded thoracic aorta in vivo . 5 - HT ( 10 (- 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 , P23458 , and P42224 via the 5 - Q13049 receptors in a reactive oxygen species - independent manner under both normal and high glucose conditions .\",\n \"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .\",\n \"___MASK15___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK15___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .\",\n \"___MASK12___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK12___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .\",\n \"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK47___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .\",\n \"Involvement of P28222 receptors in DB00669 - induced contractile responses in guinea - pig isolated iliac artery . Using a series of triptans we characterized in vitro the 5 - hydroxytryptamine ( 5 - HT ) receptor that mediates the contraction in guinea - pig iliac arteries moderately precontracted by prostaglandin F2alpha ( PGF2alpha ) . Additionally , we investigated by reverse - transcriptase polymerase chain reaction ( RT - PCR ) which DB00669 - sensitive receptor is present in this tissue . DB00998 , zolmitriptan , rizatriptan , naratriptan , sumatriptan , and almotriptan contracted guinea - pig iliac arteries with pD2 values of 7 . 52 +/- 0 . 04 , 6 . 72 +/- 0 . 03 , 6 . 38 +/- 0 . 06 , 6 . 22 +/- 0 . 05 , 5 . 86 +/- 0 . 05 and 5 . 26 +/- 0 . 04 respectively . For comparison , the pD2 values for 5 - HT and 5 - carboxamidotryptamine ( 5 - CT ) were 7 . 52 +/- 0 . 02 and 7 . 55 +/- 0 . 03 respectively . In contrast to all other triptans tested , the concentration - response curve for eletriptan was biphasic ( first phase : 0 . 01 - 3 microM , pD2 approximately 6 . 6 ; second phase : > or = 10 microM ) . Contractions to 5 - HT , 5 - CT , frovatriptan , zolmitriptan , rizatriptan , naratriptan , sumatriptan , almotriptan , and eletriptan ( first phase ) were antagonized by the P28222 / 1D receptor antagonist GR127935 ( 10 nM ) and the P28222 receptor antagonist SB216641 ( 10 nM ) . RT - PCR studies in guinea - pig iliac arteries showed a strong signal for the P28222 receptor while expression of P28221 and P30939 receptors was not detected in any sample . The present results demonstrate that DB00669 - induced contraction in guinea - pig iliac arteries is mediated by the P28222 receptor . The guinea - pig iliac artery may be used as a convenient in vitro model to study the ( cardio ) vascular side - effect potential of anti - migraine drugs of the DB00669 family .\",\n \"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .\",\n \"Meta - analysis of oral DB00669 therapy for migraine : number needed to treat and relative cost to achieve relief within 2 hours . OBJECTIVE : To determine the cost - effectiveness of the P28222 / 1D agonists , or triptans , in the acute treatment of migraine . METHODS : To determine the cost - effectiveness of the triptans , a meta - analysis was conducted of the efficacy data from 27 oral DB00669 trials , using the endpoint of \\\" pain - free \\\" status within 2 hours after initial dosing as the indicator of efficacy . Efficacy data were used to determine the number needed to treat ( Q13423 ) to achieve pain - free status in 1 patient within 2 hours postdose and then applied the per - dose costs for each DB00669 to the Q13423 values . RESULTS : Rizatriptan 10 mg and almotriptan 12 . 5 mg were the most cost - effective of the triptans , costing $ 48 . 34 and $ 48 . 57 US dollars , respectively , to achieve pain - free status in 1 patient within 2 hours postdose . DB00998 2 . 5 mg was the most costly , with a cost - effective ratio of $ 162 . 49 US dollars . All other triptans fell between these extremes : zolmitriptan 5 mg ( $ 65 . 18 US dollars ) , sumatriptan 100 mg ( $ 70 . 83 US dollars ) , sumatriptan 50 mg ( $ 75 . 67 US dollars ) , zolmitriptan 2 . 5 mg ( $ 78 . 74 US dollars ) , and naratriptan 2 . 5 mg ( $ 141 . 43 US dollars ) , in decreasing order of cost - effectiveness . CONCLUSION : Using an Q13423 analysis , the least - costly drugs to achieve migraine cure within 2 hours are rizatriptan 10 mg and almotriptan 12 . 5 mg . From a population health perspective , the lower acquisition cost of almotriptan 12 . 5 mg allows for effective treatment of more patients than rizatriptan 10 mg for no additional medication cost .\",\n \"Deliberate self - harm is associated with allelic variation in the tryptophan hydroxylase gene ( P17752 A779C ) , but not with polymorphisms in five other serotonergic genes . BACKGROUND : There is a heritable component to suicidal behaviour , encouraging the search for the associated risk alleles . Given the putative role of the 5 - HT ( 5 - hydroxytryptamine ; serotonin ) system in suicidal behaviour , serotonergic genes are leading candidates . In particular , several studies have reported an association with variants in the tryptophan hydroxylase ( P17752 ) gene . METHOD : We studied six serotonergic gene polymorphisms in a well - characterized sample of 129 deliberate self - harm subjects and 329 comparison subjects . The polymorphisms were P17752 ( A779C ) , 5 - HT transporter ( 5 - HTT , LPR S / L ) , monoamine oxidase A ( P21397 G941T ) , P28222 receptor ( P28222 G861C ) , 5 - Q13049 receptor ( P28223 T102C ) , and P28335 receptor ( P28335 Cys23Ser ) . Genotyping was done using polymerase chain reaction ( PCR ) - based assays . The primary analyses compared allele and genotype frequencies between cases and controls . There were a limited number of planned secondary analyses within the deliberate self - harm group . RESULTS : The P17752 A779 allele was more common in deliberate self - harm subjects than in controls ( OR 1 . 38 , 95 % CI 1 . 02 - 1 . 88 ; P = 0 . 03 ) . None of the other polymorphisms was associated with deliberate self - harm . Within the deliberate self - harm group there were no associations with impulsivity , suicide risk , lifetime history of depression , or family history of deliberate self - harm . CONCLUSIONS : Our data extend the evidence that allelic variation in the P17752 gene is a risk factor for deliberate self - harm . No evidence was found to implicate the other polymorphisms .\",\n \"DB00998 : a selective type 1B / 1D serotonin receptor agonist for the treatment of migraine headache . DB00998 belongs to an innovative family of compounds aimed at breaking through the long - standing barrier of migraine headache understanding and treatment . While a typology of headaches has been recognized for some time , and a number of therapies have been introduced for reduction of headache pain and duration , the causes of migraine remain a subject of debate . Those prone to attacks continue to endure them and suffer the related symptoms such as nausea and disorientation . DB00998 , like all the triptans , acts by inducing vasoconstriction of the meningeal arteries . It has been shown in pharmacological tests to act selectively as a potent agonist of serotonin P28222 / 1D receptors . DB00998 has been well tolerated in humans and efficacious in reducing headache pain and duration in clinical trials , which have also indicated that dose adjustments for age or gender are not necessary for the drug . Patients have found the use of frovatriptan acceptable over the long - term , and overall a low - incidence of adverse effects has been reported . Though not a prophylactic , frovatriptan has demonstrated the potential to significantly improve the therapeutic approaches to the treatment of migraine .\",\n \"The efficacy and tolerability of frovatriptan and dexketoprofen for the treatment of acute migraine attacks . DB00998 is a DB00669 characterized by a high affinity for P28222 / 1D receptors and a long half - life contributing to a more sustained and prolonged action than other triptans . DB09214 is a nonsteroidal anti - inflammatory drug with a relatively short half - life and rapid onset of action , blocking the action of cyclo - oxygenase , which is involved in prostaglandins ' production , thus reducing inflammation and pain . Both drugs have been successfully employed as monotherapies for the treatment of acute migraine attacks . The combination of these two drugs ( frovatriptan 2 . 5 mg plus dexketoprofen 25 or 37 . 5 mg ) has been tested in migraine sufferers , showing a rapid and good initial efficacy , with 2 - h pain free rates of 51 % , and a high persistence in the 48 - h following the onset of pain : recurrence occurred in only 29 % of attacks and sustained pain free rates were 43 % at 24 - and 33 % at 48 - h .\",\n \"Disabling the mitotic spindle and tumor growth by targeting a cavity - induced allosteric site of survivin . Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis . Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy . P00533 and Her / neu - transformed human tumors in particular exhibit high levels of survivin . The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein . We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces . P28222 , a lead compound identified in the screen , can bind to the survivin protein at the intended target site . Moreover , P28222 alters spindle formation , causing mitotic arrest and cell death , and inhibits tumor growth in vitro and in vivo . Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity . Thus , the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers .\",\n \"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .\",\n \"Desmopressin ( ___MASK10___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK10___ ) also has strong vasodilatory effects . ___MASK10___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK10___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK10___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK10___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK10___ - induced vasodilation .\",\n \"DB00998 , a P28222 / 1D receptor agonist for migraine . DB00998 is one of the most recent serotonin receptor agonists to receive FDA , approved labelling for use in the acute management of migraine with or without aura in adults . The mechanism of action of frovatriptan is thought to be similar to that of a serotonin agonist . However , frovatriptan has distinctive pharmacokinetic and pharmacologic properties , chiefly , a high affinity for serotonin receptors 1B and 1D and a long elimination half - life ; frovatriptan was shown to be more selective for cerebral than coronary arteries , a property which makes frovatriptan more favourable in patients at risk of coronary artery disease . Additionally , frovatriptan has a half - life of approximately 25 h , substantially longer than that of any other agent within its class . This property makes frovatriptan suitable for patients who typically suffer migraines of long duration and / or those who suffer migraine recurrence . The efficacy of frovatriptan in the treatment of acute migraine was demonstrated in five double - blind , randomised , placebo - controlled trials . At 2h , headache response rates for frovatriptan 2 . 5 mg ranged from 38 to 40 % compared to 22 - 35 % for placebo . Headache recurrence for frovatriptan 2 . 5 mg at 24h ranged from 9 to 14 % compared with 18 % in placebo subjects . DB00998 has no clinically significant pharmacokinetic interactions with drugs used for migraine prophylaxis or with commonly prescribed medications . Adverse effects of frovatriptan including dizziness , paresthesia , dry mouth , fatigue and flushing were generally mild and well tolerated . Given the fact that patient response to serotonin agonists is individualised , and selecting an effective agent may involve trial and error , frovatriptan is a welcome alternative in the acute management of migraine .\",\n \"___MASK42___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK42___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK42___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK42___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK42___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .\",\n \"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK24___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK24___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .\",\n \"DB00998 . black triangle DB00998 , a new serotonin receptor agonist developed for the acute treatment of migraine , has high affinity for serotonin P28222 and P28221 receptor subtypes and is a potent stimulator of contraction in human basilar arteries . black triangle A long terminal elimination half - life ( approximately 26 hours ) is a distinctive pharmacokinetic feature of frovatriptan which appears to be independent of dose , age , gender and renal function . black triangle A single oral dose of frovatriptan 2 . 5mg was effective in the acute treatment of migraine providing meaningful relief within 2 hours to approximately twice as many recipients as placebo in clinical trials . black triangle Consistent relief of migraine symptoms was achieved in patients who treated a number of consecutive attacks with frovatriptan and the incidence of 24 - hour migraine recurrence was reduced . black triangle DB00998 was well tolerated in clinical trials , with the overall incidence of adverse events occurring with frovatriptan 2 . 5mg only slightly higher than that reported with placebo . Mild to moderate fatigue , nausea and paraesthesia were the most commonly reported drug - related adverse events .\",\n \"A review of the use of frovatriptan in the treatment of menstrually related migraine . Menstrual migraine ( MM ) is a highly prevalent condition associated with considerable disability . Migraine attacks occur exclusively around the menstrual period in approximately 10 % of women with migraine , that is , pure menstrual migraine , while at least 50 % of them also experience migraine at other times of the month , that is , menstrually related migraine ( MRM ) . The therapeutic approach to patients with MRM is based on treatment of the attack , or prophylactic strategies . Triptans are recommended as first - line treatments for moderate to severe migraine attacks , including MM . DB00998 is one of the newest triptans . Its high affinity for P28222 / 1D receptors and long half - life contribute to its distinctive clinical effect , characterized by a more sustained and prolonged effect than other triptans . Indeed , frovatriptan proved to be effective in treating the acute attack , but was particularly effective in the short - term preventive therapy of MM . In addition , frovatriptan is one of the safest triptans , with the lowest risk of treatment - emergent adverse events . Following extensive evidence from randomized pharmacological trials , frovatriptan has now gained a grade A recommendation from the guidelines for short - term prophylaxis of MM . Recent post - hoc analyses of direct comparative trials also suggest that frovatriptan might have an important role in the acute treatment of MRM . In these studies , frovatriptan showed pain relief and pain - free rates similar to those of zolmitriptan , rizatriptan , and almotriptan , but with significantly lower recurrence rates . More well - designed , randomized , prospective studies , specifically enrolling women with MM , will be needed in the near future to confirm the efficacy of frovatriptan in this migraine subtype .\",\n \"Fluorescence energy transfer analysis of calmodulin - peptide complexes . The interactions between calmodulin and the tryptophan residues of synthetic peptides corresponding to the calmodulin binding domains of skeletal muscle myosin light - chain kinase and the plasma membrane calcium pump were examined . The single tryptophan residue contained in each peptide became relatively immobilized and inaccessible to iodide ion upon binding to calmodulin , indicating that the indole side chain was inserted into a hydrophobic cleft in the surface of calmodulin . Fluorescence energy transfer from peptidyl tryptophan residues to an AEDANS moiety attached to cysteine - 26 of spinach calmodulin was measured . Included in these analyses was a tryptophan - containing peptide analog of the calmodulin binding domain of neuromodulin . These data indicated that the indole ring of each peptide inserted 32 - 35 A away from cysteine - 26 and may therefore interact with the carboxyl - terminal lobe of P62158 in its \\\" bent \\\" conformation [ Persechini & Kretsinger ( 1988a ) J . Cardiovasc . Pharmacol . 12 ( Suppl 5 ) , S1 - P28222 ; Ikura et al . ( 1992 ) Science 256 , 632 - 638 ; Vorherr et al . ( 1992 ) Eur . J . Biochem . 204 , 931 - 937 ] . The interchange of tryptophan - 3 and phenylalanine - 21 of the calcium pump peptide increased the efficiency of energy transfer to the AEDANS - moiety approximately 12 - fold , reducing the calculated distance to 20 A . These data suggest that phenylalanine - 21 of the calcium pump peptide interacts with the hydrophobic cleft in the amino - terminal lobe of P62158 .\",\n \"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .\"\n]"},"candidates":{"kind":"list like","value":["___MASK10___","___MASK12___","___MASK15___","___MASK24___","___MASK28___","___MASK42___","___MASK47___","___MASK55___","___MASK57___"],"string":"[\n \"___MASK10___\",\n \"___MASK12___\",\n \"___MASK15___\",\n \"___MASK24___\",\n \"___MASK28___\",\n \"___MASK42___\",\n \"___MASK47___\",\n \"___MASK55___\",\n \"___MASK57___\"\n]"},"answer":{"kind":"string","value":"___MASK28___"},"id":{"kind":"string","value":"MH_train_482"}}},{"rowIdx":483,"cells":{"query":{"kind":"string","value":"interacts_with DB00216?"},"supports":{"kind":"list like","value":["DB00216 Pfizer . Pfizer has developed and launched eletriptan , a P28222 / 1D agonist , for the potential treatment of migraine with and without aura . DB00216 has 6 - fold greater affinity for the P28221 receptor than sumatriptan , and a 3 - fold greater affinity for the P28222 receptor [ 249570 ] . DB00216 pharmacology has also been evaluated in vitro in comparison with zolmitriptan ( AstraZeneca plc ) and naratriptan ( GlaxoSmithKline plc ) [ 290116 ] .","P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .","P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .","P00734 haplotype associated with kidney stone disease in Northeastern Thai patients . OBJECTIVE : To evaluate genetic variations associated with kidney stone disease in Northeastern Thai patients . METHODS : Altogether , 67 single nucleotide polymorphisms ( SNP ) distributed within 8 candidate genes , namely P04155 , P05109 , P06702 , P80511 , P02760 , P10451 , P07911 , and F2 , which encode stone inhibitor proteins , including trefoil factor 1 , calgranulin ( A , B , and C ) , bikunin , osteopontin , tamm - Horsfall protein , and prothrombin , respectively , were initially genotyped in 112 individuals each and in additional subjects to consist of 164 patients and 216 control subjects in total . RESULTS : We found that minor allele and homozygous genotype frequencies of 8 of 10 SNPs distributed within the F2 gene were significantly higher in the control group than in the patient group . Two F2 haplotypes were found to be dually associated with kidney stone risk , one ( TGCCGCCGCG ) with increased disease risk and the other ( CGTTCCGCTA ) with decreased disease risk . However , these 2 haplotypes were associated with the disease risks in only the female , not the male , group . CONCLUSIONS : The results of our study indicate that genetic variation of F2 is associated with kidney stone risk in Northeastern Thai female patients .","Characterization and localization of the rabbit ocular calcitonin gene - related peptide ( P80511 ) - receptor component protein ( RCP ) . PURPOSE : To determine whether the calcitonin gene - related peptide ( P80511 ) receptor component protein ( RCP ) , a novel signal transduction molecule , is required for P80511 signaling in the eye and to determine potential ocular sites of P80511 action . METHODS : The cDNA for the rabbit ocular RCP homologue was cloned using a combination of reverse transcription - polymerase chain reaction ( RT - PCR ) and rapid amplification of cDNA ends ( RACE ) . Function of the rabbit ocular RCP was assessed using a sensitive oocyte - based assay , which utilizes the protein kinase A ( PKA ) - sensitive cystic fibrosis transmembrane conductance regulator ( P13569 ) as a sensor of DB02527 formation . RCP expression in the rabbit eye was localized using immunohistochemistry . RESULTS : A 2063 - bp cDNA for the rabbit ocular RCP was cloned and sequenced . Expression of the rabbit RCP cDNA confers P80511 responsiveness in a sensitive oocyte - based assay . Antisense oligonucleotides made to the ocular RCP abolishes P80511 responsiveness of ciliary body and iris mRNA in the oocyte - P13569 assay . Localization of RCP protein in the rabbit eye using immunohistochemistry demonstrated RCP immunoreactivity in the ciliary body and iris blood vessels , as well as in layers of the ciliary epithelium . CONCLUSIONS : The rabbit ocular RCP appears to be required for signal transduction at ocular P80511 receptors and is localized to sites previously reported to bind P80511 , which affect intraocular pressure and neurogenic inflammation .","Candidate gene studies of ADHD : a meta - analytic review . Quantitative genetic studies ( i . e . , twin and adoption studies ) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder ( ADHD ) . Over the past 15 years , considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD . The first aim of the present study was to conduct a comprehensive meta - analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies . The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results . Significant associations were identified for several candidate genes including Q01959 , P21917 , P21918 , P31645 , P28222 , and P60880 . Further , significant heterogeneity was observed for the associations between ADHD and Q01959 , P21917 , P21918 , P09172 , P08913 , P31645 , Q8IWU9 , P21397 , and P60880 , suggesting that future studies should explore potential moderators of these associations ( e . g . , ADHD subtype diagnoses , gender , exposure to environmental risk factors ) . We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD .","Efficacy , safety and tolerability of oral eletriptan in the acute treatment of migraine : results of a phase III , multicentre , placebo - controlled study across three attacks . The efficacy , safety and tolerability of the P28222 / D receptor agonist eletriptan ( 40 mg and 80 mg ) in acute treatment of migraine was evaluated in a multinational , randomized , double - blind , parallel - group , placebo - controlled , three - attack study treating 1153 patients . In the initial attack , significantly more eletriptan patients reported headache relief and complete pain relief at 2 h vs . placebo ( 40 mg 62 % and 32 % , 80 mg 65 % and 34 % , placebo 19 % and 3 % ; P < 0 . 0001 ) . Headache relief occurred faster after eletriptan , with more patients at both doses reporting relief 30 min ( P < 0 . 01 ) and 1 h ( P < 0 . 0001 ) after treatment than after placebo . There was a significantly lower recurrence rate with eletriptan 80 mg compared with placebo ( P < 0 . 01 ) . Adverse events for all treatments were generally mild or moderate and self - limiting . DB00216 40 mg and eletriptan 80 mg both appear to be effective and well - tolerated acute migraine treatments .","Characterisation of the contractile activity of eletriptan at the canine vascular P28222 receptor . The functional activity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1 H - indole ) at the contractile serotonin ( 5 - hydroxytryptamine ; 5 - HT ) ' 1B - like ' receptor in dog isolated saphenous vein and basilar artery was investigated . DB00216 , like 5 - HT and sumatriptan potently contracted saphenous vein ( pEC50 : 6 . 3 , 6 . 9 and 6 . 1 , respectively ) and basilar artery ( pEC50 7 . 2 , 7 . 5 and 6 . 8 , respectively ) . The maximum responses evoked by eletriptan was , unlike sumatriptan , significantly lower than that to 5 - HT ( intrinsic activity saphenous vein : eletriptan 0 . 57 , 5 - HT 1 . 0 , sumatriptan 0 . 85 ; basilar artery : eletriptan 0 . 77 , 5 - HT 0 . 98 , sumatriptan 0 . 89 ) . Contractions evoked by eletriptan were antagonised by the P28222 / 1D receptor antagonist GR125743 ( N - [ 4 - methoxy - 3 - ( 4 - methyl piperazin - 1 - yl ) phenyl ] - 3 - methyl - 4 -( 4 - pyridyl ) benzamide ) with pA2 values of 9 . 1 in saphenous vein and 9 . 4 in basilar artery . Affinity estimates ( pKA ) for 5 - HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6 . 6 and 6 . 3 , respectively , compared to the apparent equilibrium dissociation constant ( pKp ) for eletriptan of 6 . 8 . The rank order of relative intrinsic efficacies ( epsilon ) was 5 - HT > sumatriptan > eletriptan . Thus , eletriptan required greater receptor occupancy ( 4 . 4 - fold ) to evoke an equivalent contraction to 5 - HT and sumatriptan in dog isolated saphenous vein . These data demonstrate that eletriptan is a potent partial agonist at the canine vascular P28222 receptor .","Serotonergic stimulation of corticotropin - releasing hormone and pro - opiomelanocortin gene expression . The neurotransmitter serotonin ( 5 - HT ) stimulates adrenocorticotropic hormone ( DB01285 ) secretion from the anterior pituitary gland via activation of central 5 - HT1 and 5 - HT2 receptors . The effect of 5 - HT is predominantly indirect and may be mediated via release of hypothalamic corticotropin - releasing hormone ( P06850 ) . We therefore investigated the possible involvement of P06850 in the serotonergic stimulation of DB01285 secretion in male rats . Increased neuronal 5 - HT content induced by systemic administration of the precursor 5 - hydroxytryptophan ( 5 - HTP ) in combination with the 5 - HT reuptake inhibitor fluoxetine raised P06850 mRNA expression in the paraventricular nucleus ( PVN ) by 64 % , increased pro - opiomelanocortin ( P01189 ) mRNA in the anterior pituitary lobe by 17 % and stimulated DB01285 secretion five - fold . Central administration of 5 - HT agonists specific to P08908 , P28222 , 5 - Q13049 or P28335 receptors increased P06850 mRNA in the PVN by 15 - 50 % , P01189 mRNA in the anterior pituitary by 15 - 27 % and DB01285 secretion three - to five - fold , whereas a specific 5 - Q9H205 agonist had no effect . Systemic administration of a specific anti - P06850 antiserum inhibited the DB01285 response to 5 - HTP and fluoxetine and prevented the 5 - HTP and fluoxetine - induced P01189 mRNA response in the anterior pituitary lobe . Central or systemic infusion of 5 - HT increased DB01285 secretion seven - and eight - fold , respectively . Systemic pretreatment with the anti - P06850 antiserum reduced the DB01285 responses to 5 - HT by 80 % and 64 % , respectively . It is concluded that 5 - HT via activation of P08908 , 5 - Q13049 , P28335 and possibly also P28222 receptors increases the synthesis of P06850 in the PVN and P01189 in the anterior pituitary lobe , which results in increased DB01285 secretion . Furthermore , the results indicate that P06850 is an important mediator of the DB01285 response to 5 - HT .","Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .","___MASK55___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .","Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK81___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .","___MASK66___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .","Fluorescence energy transfer analysis of calmodulin - peptide complexes . The interactions between calmodulin and the tryptophan residues of synthetic peptides corresponding to the calmodulin binding domains of skeletal muscle myosin light - chain kinase and the plasma membrane calcium pump were examined . The single tryptophan residue contained in each peptide became relatively immobilized and inaccessible to iodide ion upon binding to calmodulin , indicating that the indole side chain was inserted into a hydrophobic cleft in the surface of calmodulin . Fluorescence energy transfer from peptidyl tryptophan residues to an AEDANS moiety attached to cysteine - 26 of spinach calmodulin was measured . Included in these analyses was a tryptophan - containing peptide analog of the calmodulin binding domain of neuromodulin . These data indicated that the indole ring of each peptide inserted 32 - 35 A away from cysteine - 26 and may therefore interact with the carboxyl - terminal lobe of P62158 in its \" bent \" conformation [ Persechini & Kretsinger ( 1988a ) J . Cardiovasc . Pharmacol . 12 ( Suppl 5 ) , S1 - P28222 ; Ikura et al . ( 1992 ) Science 256 , 632 - 638 ; Vorherr et al . ( 1992 ) Eur . J . Biochem . 204 , 931 - 937 ] . The interchange of tryptophan - 3 and phenylalanine - 21 of the calcium pump peptide increased the efficiency of energy transfer to the AEDANS - moiety approximately 12 - fold , reducing the calculated distance to 20 A . These data suggest that phenylalanine - 21 of the calcium pump peptide interacts with the hydrophobic cleft in the amino - terminal lobe of P62158 .","Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK12___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .","DB09280 - ___MASK68___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .","A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma . Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis . Consistent heterogeneity in chromosome number was found , and most cell lines showed a near - triploid chromosome complement . Several cell lines showed deletions of the P04637 ( alias p53 ) , CDKN2A ( alias p16 ) , and P40337 genes . Multiplex fluorescence in situ hybridization ( M - Q5TCZ1 ) analysis revealed chromosome 3 translocated to several other partners chromosomes , as well as breakage events commonly affecting chromosomes 1 , 5 , 8 , 10 , and 17 . The most common abnormality detected with comparative genomic hybridization ( CGH ) was deletions of chromosome 3p , with loss of the Q9NS23 , P49789 , and p44S10 loci frequently involved . CGH gain of 5q showed overrepresentation of the P18146 and P07333 genes . Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the P00533 , O15164 , and P35250 genes . Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of P11802 and SAS loci . M - Q5TCZ1 revealed several other recurrent translocations , and CGH findings included loss of 9p , 14q , and 18q and gain of 8q , 12 , and 20 . Further genomic microarray changes included loss of Q13126 , IGH @ , P28222 , and Q13485 ( previously Q13485 ) and gains of MYC and P11387 . An excellent correlation was observed between the genomic array and Q5TCZ1 data , demonstrating that this technique is effective and accurate . The aberrations detected here may reflect important pathways in renal cancer pathogenesis .","Effects of eletriptan on the peptidergic innervation of the cerebral dura mater and trigeminal ganglion , and on the expression of c - fos and c - jun in the trigeminal complex of the rat in an experimental migraine model . Nociceptive axons and terminals in the supratentorial cerebral dura mater display an intense calcitonin gene - related peptide ( P80511 ) immunoreactivity . In an experimental migraine model , it has been shown that electrical stimulation of the rat trigeminal ganglion induced an increase in the lengths of P80511 - immunoreactive axons , increased size and number of pleomorphic axonal varicosities in the dura mater , and an increased number of c - jun and c - fos protein - expressing nerve cells in the trigeminal complex . We demonstrate the effect of the highly specific and moderately lipophilic serotonin agonist eletriptan ( Pfizer ) which prevents the effects of electrical stimulation in the dura mater . DB00216 also affected the caudal trigeminal complex ; it markedly reduced the numbers of the oncoprotein - expressing cells , mainly after stimulation and to some extent also in nonstimulated animals . DB00216 also affected expression of P80511 in perikarya of trigeminal ganglion cells , insofar as the number of small nerve cells exhibiting a compact P80511 immunoreaction was decreased to one quarter of the original value . In all these respects , eletriptan acted in a similar way to sumatriptan , with the notable exception that eletriptan also blocked the stimulation - induced effects in the nucleus caudalis trigemini and the upper cervical spinal cord ( trigeminal complex ) , whereas sumatriptan did not . It is concluded that eletriptan , acting on perikarya and both the peripheral and the central axon terminals of primary sensory neurons , exerts its antimigraine effect by an agonist action on P28222 / 1D receptors throughout the entire trigeminal system , probably by passing the blood - brain - barrier because of its lipophilic character .","[ ___MASK53___ : A new drug of B - cell malignancies ] . ___MASK53___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK53___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK53___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .","P01258 gene - related peptide - like immunoreactivity and its relation with neurotensin - and corticotropin - releasing hormone - like immunoreactive neurons in the bed nuclei of the stria terminalis in the rat . The distribution of calcitonin gene - related peptide ( P80511 ) - like immunoreactive ( LI ) nerve cells and terminals ( BST ) was studied in the rat . Only the fusiform nucleus was found to consistently contain P80511 - LI neurons . The CRGP - LI terminals had a wide distribution in the BST , being most numerous in the oval and the fusiform nuclei . In the oval nucleus the P80511 - LI terminals formed characteristic \" baskets . \" Since the oval nucleus was known to be studded with neurotensin ( NT ) - and corticotropin - releasing hormone ( P06850 ) - LI neurons , the relationship of the P80511 - LI nerves to NT - and P06850 - LI neurons was investigated by means of a double immunostaining technique . A part of the P80511 - LI baskets were found to contain NT - or P80511 - LI neurons . The possible involvement of the P80511 / NT or P06850 relationship in reciprocal connection between the BST and the parabrachial nucleus and in cardiovascular regulation is discussed .","___MASK59___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK59___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .","Characterisation of the 5 - HT receptor binding profile of eletriptan and kinetics of [ 3H ] eletriptan binding at human P28222 and P28221 receptors . The affinity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1H - indole ) for a range of 5 - HT receptors was compared to values obtained for other P28222 / 1D receptor agonists known to be effective in the treatment of migraine . DB00216 , like sumatriptan , zolmitriptan , naratriptan and rizatriptan had highest affinity for the human P28222 , P28221 and putative 5 - ht1f receptor . Kinetic studies comparing the binding of [ 3H ] eletriptan and [ 3H ] sumatriptan to the human recombinant P28222 and P28221 receptors expressed in HeLa cells revealed that both radioligands bound with high specificity ( > 90 % ) and reached equilibrium within 10 - 15 min . However , [ 3H ] eletriptan had over 6 - fold higher affinity than [ 3H ] sumatriptan at the P28221 receptor ( K ( D ) ) : 0 . 92 and 6 . 58 nM , respectively ) and over 3 - fold higher affinity than [ 3H ] sumatriptan at the P28222 receptor ( K ( D ) : 3 . 14 and 11 . 07 nM , respectively ) . Association and dissociation rates for both radioligands could only be accurately determined at the P28221 receptor and then only at 4 degrees C . At this temperature , [ 3H ] eletriptan had a significantly ( P < 0 . 05 ) faster association rate ( K ( on ) 0 . 249 min (- 1 ) nM (- 1 ) ) than [ 3H ] sumatriptan ( K ( on ) 0 . 024 min (- 1 ) nM (- 1 ) ) and a significantly ( P < 0 . 05 ) slower off - rate ( K ( off ) 0 . 027 min (- 1 ) compared to 0 . 037 min (- 1 ) for [ 3H ] sumatriptan ) . These data indicate that eletriptan is a potent ligand at the human P28222 , P28221 , and 5 - ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache .","Emergence of motor circuit activity . In the developing nervous system , ordered neuronal activity patterns can occur even in the absence of sensory input and to investigate how these arise , we have used the model system of the embryonic chicken spinal motor circuit , focusing on motor neurons of the lateral motor column ( O15467 ) . At the earliest stages of their molecular differentiation , we can detect differences between medial and lateral O15467 neurons in terms of expression of neurotransmitter receptor subunits , including P30532 , P36544 , Q12879 , P39086 , P08908 and P28222 , as well as the Q9H2X9 transporter . Using patch - clamp recordings we also demonstrate that medial and lateral O15467 motor neurons have subtly different activity patterns that reflect the differential expression of neurotransmitter receptor subunits . Using a combination of patch - clamp recordings in single neurons and calcium - imaging of motor neuron populations , we demonstrate that inhibition of nicotinic , muscarinic or GABA - ergic activity , has profound effects of motor circuit activity during the initial stages of neuromuscular junction formation . Finally , by analysing the activity of large populations of motor neurons at different developmental stages , we show that the asynchronous , disordered neuronal activity that occurs at early stages of circuit formation develops into organised , synchronous activity evident at the stage of O15467 neuron muscle innervation . In light of the considerable diversity of neurotransmitter receptor expression , activity patterns in the O15467 are surprisingly similar between neuronal types , however the emergence of patterned activity , in conjunction with the differential expression of transmitter systems likely leads to the development of near - mature patterns of locomotor activity by perinatal ages .","Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK15___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .","A DNA hypermethylation profile reveals new potential biomarkers for prostate cancer diagnosis and prognosis . BACKGROUND : DNA hypermethylation has emerged as a novel molecular biomarker for the evaluation of prostate cancer diagnosis and prognosis . Defining the specific gene hypermethylation profile for prostate cancer could involve groups of genes that specifically discriminate patients with indolent and aggressive tumors . METHODS : Genome - wide methylation analysis was performed on 83 tumor and 10 normal prostate samples using the GoldenGate Methylation Cancer Panel I ( Illumina , Inc . ) . All clinical stages of disease were considered . RESULTS : We found 41 genes hypermethylated in more than 20 % of the tumors analyzed ( P < 0 . 01 ) . Of these , we newly identified P28161 and P01210 as being genes that are hypermethylated in prostate cancer and that were simultaneously methylated in 40 . 9 % of the tumors analyzed . We also identified panels of genes that are more frequently methylated in tumor samples with clinico - pathological indicators of poor prognosis : a high Gleason score , elevated Ki - 67 , and advanced disease . Of these , we found simultaneous hypermethylation of P13569 and P28222 to be common in patients with a high Gleason score and high Ki - 67 levels ; this might indicate the population at higher risk of therapeutic failure . The DNA hypermethylation profile was associated with cancer - specific mortality ( log - rank test , P = 0 . 007 ) and biochemical recurrence - free survival ( log - rank test , P = 0 . 0008 ) . CONCLUSIONS : Our findings strongly indicate that epigenetic silencing of P28161 and P01210 is a common event in prostate cancer that could be used as a molecular marker for prostate cancer diagnosis . In addition , simultaneous P28222 and P13569 hypermethylation could help discriminate aggressive from indolent prostate tumors .","Porcine carotid vascular effects of eletriptan ( UK - 116 , 044 ) : a new P28222 / 1D receptor agonist with anti - migraine activity . It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine . Indeed , a number of acutely acting anti - migraine drugs , including the ergot alkaloids and sumatriptan , constrict porcine carotid arteriovenous anastomoses . In this study , using pentobarbital anaesthetised pigs , we investigated the effects of eletriptan , a close structural analogue of sumatriptan , on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient ( capillary ) fractions . DB00216 ( 10 , 30 , 100 , 300 and 1000 microg kg (- 1 ) , i . v . ) decreased the total carotid blood flow , exclusively by decreasing cephalic arteriovenous anastomotic blood flow ; nutrient blood flow , particularly to the ear , skin and fat , was significantly increased . The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50 % ( ED50 ) were , respectively , 117 +/- 21 microg kg (- 1 ) ( 251 +/- 45 nmol kg (- 1 ) ) and 184 +/- 42 microg kg (- 1 ) ( 396 +/- 91 nmol kg (- 1 ) ) ; the highest dose caused reductions of 84 +/- 3 % and 77 +/- 4 % , respectively . The eletriptan - induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective P28222 / 1D receptor antagonist GR127935 ( 0 . 5 mg kg (- 1 ) ) . On the basis of these results , we conclude that ( 1 ) the eletriptan - induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by P28222 / 1D receptors , and ( 2 ) eletriptan should be effective in aborting migraine headache . Clinical studies have already demonstrated its therapeutic action in migraine patients .","Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis . OBJECTIVE : The accumulation of advanced glycation end products ( AGEs ) , P80511 , and high mobility group box chromosomal protein 1 has been associated with joint inflammation in rheumatoid arthritis ( RA ) . This study was undertaken to determine the induction of the receptor for these proteins , termed receptor for AGEs ( RAGE ) , in synovial tissue ( ST ) macrophages from RA patients . METHODS : RAGE and P34810 expression in ST were determined by 2 - color immunofluorescence labeling . Cell surface and messenger RNA ( mRNA ) expression of RAGE were examined by flow cytometry and reverse transcriptase - polymerase chain reaction ( PCR ) or real - time PCR , respectively . RESULTS : P34810 + lining macrophages , like the vasculature , expressed high levels of RAGE in inflamed ST from RA patients . RAGE mRNA expression was significantly higher in RA ST than in ST from patients with osteoarthritis . RAGE mRNA levels were significantly higher in ST macrophages and normal endothelial cells than in ST P01730 + T cells and synovial fibroblasts stimulated with tumor necrosis factor alpha and interleukin - 1beta ( IL - 1beta ) . Cell surface RAGE was highly induced on normal monocytes after a 24 - hour incubation with a 20 % concentration of RA ST cell culture supernatants . RAGE mRNA expression in adherent monocytes was augmented by various cytokines , most potently by IL - 1beta . CONCLUSION : These results indicate that RAGE overexpression in lining macrophages may be induced , at least in part , by cytokines such as IL - 1 , leading to the amplification of inflammatory responses mediated by RAGE ligands that are abundant in RA joints .","Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .","Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK43___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK43___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK43___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK43___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK43___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively ."],"string":"[\n \"DB00216 Pfizer . Pfizer has developed and launched eletriptan , a P28222 / 1D agonist , for the potential treatment of migraine with and without aura . DB00216 has 6 - fold greater affinity for the P28221 receptor than sumatriptan , and a 3 - fold greater affinity for the P28222 receptor [ 249570 ] . DB00216 pharmacology has also been evaluated in vitro in comparison with zolmitriptan ( AstraZeneca plc ) and naratriptan ( GlaxoSmithKline plc ) [ 290116 ] .\",\n \"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \\\" normal \\\" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .\",\n \"P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .\",\n \"P00734 haplotype associated with kidney stone disease in Northeastern Thai patients . OBJECTIVE : To evaluate genetic variations associated with kidney stone disease in Northeastern Thai patients . METHODS : Altogether , 67 single nucleotide polymorphisms ( SNP ) distributed within 8 candidate genes , namely P04155 , P05109 , P06702 , P80511 , P02760 , P10451 , P07911 , and F2 , which encode stone inhibitor proteins , including trefoil factor 1 , calgranulin ( A , B , and C ) , bikunin , osteopontin , tamm - Horsfall protein , and prothrombin , respectively , were initially genotyped in 112 individuals each and in additional subjects to consist of 164 patients and 216 control subjects in total . RESULTS : We found that minor allele and homozygous genotype frequencies of 8 of 10 SNPs distributed within the F2 gene were significantly higher in the control group than in the patient group . Two F2 haplotypes were found to be dually associated with kidney stone risk , one ( TGCCGCCGCG ) with increased disease risk and the other ( CGTTCCGCTA ) with decreased disease risk . However , these 2 haplotypes were associated with the disease risks in only the female , not the male , group . CONCLUSIONS : The results of our study indicate that genetic variation of F2 is associated with kidney stone risk in Northeastern Thai female patients .\",\n \"Characterization and localization of the rabbit ocular calcitonin gene - related peptide ( P80511 ) - receptor component protein ( RCP ) . PURPOSE : To determine whether the calcitonin gene - related peptide ( P80511 ) receptor component protein ( RCP ) , a novel signal transduction molecule , is required for P80511 signaling in the eye and to determine potential ocular sites of P80511 action . METHODS : The cDNA for the rabbit ocular RCP homologue was cloned using a combination of reverse transcription - polymerase chain reaction ( RT - PCR ) and rapid amplification of cDNA ends ( RACE ) . Function of the rabbit ocular RCP was assessed using a sensitive oocyte - based assay , which utilizes the protein kinase A ( PKA ) - sensitive cystic fibrosis transmembrane conductance regulator ( P13569 ) as a sensor of DB02527 formation . RCP expression in the rabbit eye was localized using immunohistochemistry . RESULTS : A 2063 - bp cDNA for the rabbit ocular RCP was cloned and sequenced . Expression of the rabbit RCP cDNA confers P80511 responsiveness in a sensitive oocyte - based assay . Antisense oligonucleotides made to the ocular RCP abolishes P80511 responsiveness of ciliary body and iris mRNA in the oocyte - P13569 assay . Localization of RCP protein in the rabbit eye using immunohistochemistry demonstrated RCP immunoreactivity in the ciliary body and iris blood vessels , as well as in layers of the ciliary epithelium . CONCLUSIONS : The rabbit ocular RCP appears to be required for signal transduction at ocular P80511 receptors and is localized to sites previously reported to bind P80511 , which affect intraocular pressure and neurogenic inflammation .\",\n \"Candidate gene studies of ADHD : a meta - analytic review . Quantitative genetic studies ( i . e . , twin and adoption studies ) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder ( ADHD ) . Over the past 15 years , considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD . The first aim of the present study was to conduct a comprehensive meta - analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies . The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results . Significant associations were identified for several candidate genes including Q01959 , P21917 , P21918 , P31645 , P28222 , and P60880 . Further , significant heterogeneity was observed for the associations between ADHD and Q01959 , P21917 , P21918 , P09172 , P08913 , P31645 , Q8IWU9 , P21397 , and P60880 , suggesting that future studies should explore potential moderators of these associations ( e . g . , ADHD subtype diagnoses , gender , exposure to environmental risk factors ) . We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD .\",\n \"Efficacy , safety and tolerability of oral eletriptan in the acute treatment of migraine : results of a phase III , multicentre , placebo - controlled study across three attacks . The efficacy , safety and tolerability of the P28222 / D receptor agonist eletriptan ( 40 mg and 80 mg ) in acute treatment of migraine was evaluated in a multinational , randomized , double - blind , parallel - group , placebo - controlled , three - attack study treating 1153 patients . In the initial attack , significantly more eletriptan patients reported headache relief and complete pain relief at 2 h vs . placebo ( 40 mg 62 % and 32 % , 80 mg 65 % and 34 % , placebo 19 % and 3 % ; P < 0 . 0001 ) . Headache relief occurred faster after eletriptan , with more patients at both doses reporting relief 30 min ( P < 0 . 01 ) and 1 h ( P < 0 . 0001 ) after treatment than after placebo . There was a significantly lower recurrence rate with eletriptan 80 mg compared with placebo ( P < 0 . 01 ) . Adverse events for all treatments were generally mild or moderate and self - limiting . DB00216 40 mg and eletriptan 80 mg both appear to be effective and well - tolerated acute migraine treatments .\",\n \"Characterisation of the contractile activity of eletriptan at the canine vascular P28222 receptor . The functional activity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1 H - indole ) at the contractile serotonin ( 5 - hydroxytryptamine ; 5 - HT ) ' 1B - like ' receptor in dog isolated saphenous vein and basilar artery was investigated . DB00216 , like 5 - HT and sumatriptan potently contracted saphenous vein ( pEC50 : 6 . 3 , 6 . 9 and 6 . 1 , respectively ) and basilar artery ( pEC50 7 . 2 , 7 . 5 and 6 . 8 , respectively ) . The maximum responses evoked by eletriptan was , unlike sumatriptan , significantly lower than that to 5 - HT ( intrinsic activity saphenous vein : eletriptan 0 . 57 , 5 - HT 1 . 0 , sumatriptan 0 . 85 ; basilar artery : eletriptan 0 . 77 , 5 - HT 0 . 98 , sumatriptan 0 . 89 ) . Contractions evoked by eletriptan were antagonised by the P28222 / 1D receptor antagonist GR125743 ( N - [ 4 - methoxy - 3 - ( 4 - methyl piperazin - 1 - yl ) phenyl ] - 3 - methyl - 4 -( 4 - pyridyl ) benzamide ) with pA2 values of 9 . 1 in saphenous vein and 9 . 4 in basilar artery . Affinity estimates ( pKA ) for 5 - HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6 . 6 and 6 . 3 , respectively , compared to the apparent equilibrium dissociation constant ( pKp ) for eletriptan of 6 . 8 . The rank order of relative intrinsic efficacies ( epsilon ) was 5 - HT > sumatriptan > eletriptan . Thus , eletriptan required greater receptor occupancy ( 4 . 4 - fold ) to evoke an equivalent contraction to 5 - HT and sumatriptan in dog isolated saphenous vein . These data demonstrate that eletriptan is a potent partial agonist at the canine vascular P28222 receptor .\",\n \"Serotonergic stimulation of corticotropin - releasing hormone and pro - opiomelanocortin gene expression . The neurotransmitter serotonin ( 5 - HT ) stimulates adrenocorticotropic hormone ( DB01285 ) secretion from the anterior pituitary gland via activation of central 5 - HT1 and 5 - HT2 receptors . The effect of 5 - HT is predominantly indirect and may be mediated via release of hypothalamic corticotropin - releasing hormone ( P06850 ) . We therefore investigated the possible involvement of P06850 in the serotonergic stimulation of DB01285 secretion in male rats . Increased neuronal 5 - HT content induced by systemic administration of the precursor 5 - hydroxytryptophan ( 5 - HTP ) in combination with the 5 - HT reuptake inhibitor fluoxetine raised P06850 mRNA expression in the paraventricular nucleus ( PVN ) by 64 % , increased pro - opiomelanocortin ( P01189 ) mRNA in the anterior pituitary lobe by 17 % and stimulated DB01285 secretion five - fold . Central administration of 5 - HT agonists specific to P08908 , P28222 , 5 - Q13049 or P28335 receptors increased P06850 mRNA in the PVN by 15 - 50 % , P01189 mRNA in the anterior pituitary by 15 - 27 % and DB01285 secretion three - to five - fold , whereas a specific 5 - Q9H205 agonist had no effect . Systemic administration of a specific anti - P06850 antiserum inhibited the DB01285 response to 5 - HTP and fluoxetine and prevented the 5 - HTP and fluoxetine - induced P01189 mRNA response in the anterior pituitary lobe . Central or systemic infusion of 5 - HT increased DB01285 secretion seven - and eight - fold , respectively . Systemic pretreatment with the anti - P06850 antiserum reduced the DB01285 responses to 5 - HT by 80 % and 64 % , respectively . It is concluded that 5 - HT via activation of P08908 , 5 - Q13049 , P28335 and possibly also P28222 receptors increases the synthesis of P06850 in the PVN and P01189 in the anterior pituitary lobe , which results in increased DB01285 secretion . Furthermore , the results indicate that P06850 is an important mediator of the DB01285 response to 5 - HT .\",\n \"Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .\",\n \"___MASK55___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .\",\n \"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK81___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .\",\n \"___MASK66___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .\",\n \"Fluorescence energy transfer analysis of calmodulin - peptide complexes . The interactions between calmodulin and the tryptophan residues of synthetic peptides corresponding to the calmodulin binding domains of skeletal muscle myosin light - chain kinase and the plasma membrane calcium pump were examined . The single tryptophan residue contained in each peptide became relatively immobilized and inaccessible to iodide ion upon binding to calmodulin , indicating that the indole side chain was inserted into a hydrophobic cleft in the surface of calmodulin . Fluorescence energy transfer from peptidyl tryptophan residues to an AEDANS moiety attached to cysteine - 26 of spinach calmodulin was measured . Included in these analyses was a tryptophan - containing peptide analog of the calmodulin binding domain of neuromodulin . These data indicated that the indole ring of each peptide inserted 32 - 35 A away from cysteine - 26 and may therefore interact with the carboxyl - terminal lobe of P62158 in its \\\" bent \\\" conformation [ Persechini & Kretsinger ( 1988a ) J . Cardiovasc . Pharmacol . 12 ( Suppl 5 ) , S1 - P28222 ; Ikura et al . ( 1992 ) Science 256 , 632 - 638 ; Vorherr et al . ( 1992 ) Eur . J . Biochem . 204 , 931 - 937 ] . The interchange of tryptophan - 3 and phenylalanine - 21 of the calcium pump peptide increased the efficiency of energy transfer to the AEDANS - moiety approximately 12 - fold , reducing the calculated distance to 20 A . These data suggest that phenylalanine - 21 of the calcium pump peptide interacts with the hydrophobic cleft in the amino - terminal lobe of P62158 .\",\n \"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK12___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .\",\n \"DB09280 - ___MASK68___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .\",\n \"A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma . Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis . Consistent heterogeneity in chromosome number was found , and most cell lines showed a near - triploid chromosome complement . Several cell lines showed deletions of the P04637 ( alias p53 ) , CDKN2A ( alias p16 ) , and P40337 genes . Multiplex fluorescence in situ hybridization ( M - Q5TCZ1 ) analysis revealed chromosome 3 translocated to several other partners chromosomes , as well as breakage events commonly affecting chromosomes 1 , 5 , 8 , 10 , and 17 . The most common abnormality detected with comparative genomic hybridization ( CGH ) was deletions of chromosome 3p , with loss of the Q9NS23 , P49789 , and p44S10 loci frequently involved . CGH gain of 5q showed overrepresentation of the P18146 and P07333 genes . Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the P00533 , O15164 , and P35250 genes . Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of P11802 and SAS loci . M - Q5TCZ1 revealed several other recurrent translocations , and CGH findings included loss of 9p , 14q , and 18q and gain of 8q , 12 , and 20 . Further genomic microarray changes included loss of Q13126 , IGH @ , P28222 , and Q13485 ( previously Q13485 ) and gains of MYC and P11387 . An excellent correlation was observed between the genomic array and Q5TCZ1 data , demonstrating that this technique is effective and accurate . The aberrations detected here may reflect important pathways in renal cancer pathogenesis .\",\n \"Effects of eletriptan on the peptidergic innervation of the cerebral dura mater and trigeminal ganglion , and on the expression of c - fos and c - jun in the trigeminal complex of the rat in an experimental migraine model . Nociceptive axons and terminals in the supratentorial cerebral dura mater display an intense calcitonin gene - related peptide ( P80511 ) immunoreactivity . In an experimental migraine model , it has been shown that electrical stimulation of the rat trigeminal ganglion induced an increase in the lengths of P80511 - immunoreactive axons , increased size and number of pleomorphic axonal varicosities in the dura mater , and an increased number of c - jun and c - fos protein - expressing nerve cells in the trigeminal complex . We demonstrate the effect of the highly specific and moderately lipophilic serotonin agonist eletriptan ( Pfizer ) which prevents the effects of electrical stimulation in the dura mater . DB00216 also affected the caudal trigeminal complex ; it markedly reduced the numbers of the oncoprotein - expressing cells , mainly after stimulation and to some extent also in nonstimulated animals . DB00216 also affected expression of P80511 in perikarya of trigeminal ganglion cells , insofar as the number of small nerve cells exhibiting a compact P80511 immunoreaction was decreased to one quarter of the original value . In all these respects , eletriptan acted in a similar way to sumatriptan , with the notable exception that eletriptan also blocked the stimulation - induced effects in the nucleus caudalis trigemini and the upper cervical spinal cord ( trigeminal complex ) , whereas sumatriptan did not . It is concluded that eletriptan , acting on perikarya and both the peripheral and the central axon terminals of primary sensory neurons , exerts its antimigraine effect by an agonist action on P28222 / 1D receptors throughout the entire trigeminal system , probably by passing the blood - brain - barrier because of its lipophilic character .\",\n \"[ ___MASK53___ : A new drug of B - cell malignancies ] . ___MASK53___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK53___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK53___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .\",\n \"P01258 gene - related peptide - like immunoreactivity and its relation with neurotensin - and corticotropin - releasing hormone - like immunoreactive neurons in the bed nuclei of the stria terminalis in the rat . The distribution of calcitonin gene - related peptide ( P80511 ) - like immunoreactive ( LI ) nerve cells and terminals ( BST ) was studied in the rat . Only the fusiform nucleus was found to consistently contain P80511 - LI neurons . The CRGP - LI terminals had a wide distribution in the BST , being most numerous in the oval and the fusiform nuclei . In the oval nucleus the P80511 - LI terminals formed characteristic \\\" baskets . \\\" Since the oval nucleus was known to be studded with neurotensin ( NT ) - and corticotropin - releasing hormone ( P06850 ) - LI neurons , the relationship of the P80511 - LI nerves to NT - and P06850 - LI neurons was investigated by means of a double immunostaining technique . A part of the P80511 - LI baskets were found to contain NT - or P80511 - LI neurons . The possible involvement of the P80511 / NT or P06850 relationship in reciprocal connection between the BST and the parabrachial nucleus and in cardiovascular regulation is discussed .\",\n \"___MASK59___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK59___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .\",\n \"Characterisation of the 5 - HT receptor binding profile of eletriptan and kinetics of [ 3H ] eletriptan binding at human P28222 and P28221 receptors . The affinity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1H - indole ) for a range of 5 - HT receptors was compared to values obtained for other P28222 / 1D receptor agonists known to be effective in the treatment of migraine . DB00216 , like sumatriptan , zolmitriptan , naratriptan and rizatriptan had highest affinity for the human P28222 , P28221 and putative 5 - ht1f receptor . Kinetic studies comparing the binding of [ 3H ] eletriptan and [ 3H ] sumatriptan to the human recombinant P28222 and P28221 receptors expressed in HeLa cells revealed that both radioligands bound with high specificity ( > 90 % ) and reached equilibrium within 10 - 15 min . However , [ 3H ] eletriptan had over 6 - fold higher affinity than [ 3H ] sumatriptan at the P28221 receptor ( K ( D ) ) : 0 . 92 and 6 . 58 nM , respectively ) and over 3 - fold higher affinity than [ 3H ] sumatriptan at the P28222 receptor ( K ( D ) : 3 . 14 and 11 . 07 nM , respectively ) . Association and dissociation rates for both radioligands could only be accurately determined at the P28221 receptor and then only at 4 degrees C . At this temperature , [ 3H ] eletriptan had a significantly ( P < 0 . 05 ) faster association rate ( K ( on ) 0 . 249 min (- 1 ) nM (- 1 ) ) than [ 3H ] sumatriptan ( K ( on ) 0 . 024 min (- 1 ) nM (- 1 ) ) and a significantly ( P < 0 . 05 ) slower off - rate ( K ( off ) 0 . 027 min (- 1 ) compared to 0 . 037 min (- 1 ) for [ 3H ] sumatriptan ) . These data indicate that eletriptan is a potent ligand at the human P28222 , P28221 , and 5 - ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache .\",\n \"Emergence of motor circuit activity . In the developing nervous system , ordered neuronal activity patterns can occur even in the absence of sensory input and to investigate how these arise , we have used the model system of the embryonic chicken spinal motor circuit , focusing on motor neurons of the lateral motor column ( O15467 ) . At the earliest stages of their molecular differentiation , we can detect differences between medial and lateral O15467 neurons in terms of expression of neurotransmitter receptor subunits , including P30532 , P36544 , Q12879 , P39086 , P08908 and P28222 , as well as the Q9H2X9 transporter . Using patch - clamp recordings we also demonstrate that medial and lateral O15467 motor neurons have subtly different activity patterns that reflect the differential expression of neurotransmitter receptor subunits . Using a combination of patch - clamp recordings in single neurons and calcium - imaging of motor neuron populations , we demonstrate that inhibition of nicotinic , muscarinic or GABA - ergic activity , has profound effects of motor circuit activity during the initial stages of neuromuscular junction formation . Finally , by analysing the activity of large populations of motor neurons at different developmental stages , we show that the asynchronous , disordered neuronal activity that occurs at early stages of circuit formation develops into organised , synchronous activity evident at the stage of O15467 neuron muscle innervation . In light of the considerable diversity of neurotransmitter receptor expression , activity patterns in the O15467 are surprisingly similar between neuronal types , however the emergence of patterned activity , in conjunction with the differential expression of transmitter systems likely leads to the development of near - mature patterns of locomotor activity by perinatal ages .\",\n \"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK15___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .\",\n \"A DNA hypermethylation profile reveals new potential biomarkers for prostate cancer diagnosis and prognosis . BACKGROUND : DNA hypermethylation has emerged as a novel molecular biomarker for the evaluation of prostate cancer diagnosis and prognosis . Defining the specific gene hypermethylation profile for prostate cancer could involve groups of genes that specifically discriminate patients with indolent and aggressive tumors . METHODS : Genome - wide methylation analysis was performed on 83 tumor and 10 normal prostate samples using the GoldenGate Methylation Cancer Panel I ( Illumina , Inc . ) . All clinical stages of disease were considered . RESULTS : We found 41 genes hypermethylated in more than 20 % of the tumors analyzed ( P < 0 . 01 ) . Of these , we newly identified P28161 and P01210 as being genes that are hypermethylated in prostate cancer and that were simultaneously methylated in 40 . 9 % of the tumors analyzed . We also identified panels of genes that are more frequently methylated in tumor samples with clinico - pathological indicators of poor prognosis : a high Gleason score , elevated Ki - 67 , and advanced disease . Of these , we found simultaneous hypermethylation of P13569 and P28222 to be common in patients with a high Gleason score and high Ki - 67 levels ; this might indicate the population at higher risk of therapeutic failure . The DNA hypermethylation profile was associated with cancer - specific mortality ( log - rank test , P = 0 . 007 ) and biochemical recurrence - free survival ( log - rank test , P = 0 . 0008 ) . CONCLUSIONS : Our findings strongly indicate that epigenetic silencing of P28161 and P01210 is a common event in prostate cancer that could be used as a molecular marker for prostate cancer diagnosis . In addition , simultaneous P28222 and P13569 hypermethylation could help discriminate aggressive from indolent prostate tumors .\",\n \"Porcine carotid vascular effects of eletriptan ( UK - 116 , 044 ) : a new P28222 / 1D receptor agonist with anti - migraine activity . It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine . Indeed , a number of acutely acting anti - migraine drugs , including the ergot alkaloids and sumatriptan , constrict porcine carotid arteriovenous anastomoses . In this study , using pentobarbital anaesthetised pigs , we investigated the effects of eletriptan , a close structural analogue of sumatriptan , on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient ( capillary ) fractions . DB00216 ( 10 , 30 , 100 , 300 and 1000 microg kg (- 1 ) , i . v . ) decreased the total carotid blood flow , exclusively by decreasing cephalic arteriovenous anastomotic blood flow ; nutrient blood flow , particularly to the ear , skin and fat , was significantly increased . The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50 % ( ED50 ) were , respectively , 117 +/- 21 microg kg (- 1 ) ( 251 +/- 45 nmol kg (- 1 ) ) and 184 +/- 42 microg kg (- 1 ) ( 396 +/- 91 nmol kg (- 1 ) ) ; the highest dose caused reductions of 84 +/- 3 % and 77 +/- 4 % , respectively . The eletriptan - induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective P28222 / 1D receptor antagonist GR127935 ( 0 . 5 mg kg (- 1 ) ) . On the basis of these results , we conclude that ( 1 ) the eletriptan - induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by P28222 / 1D receptors , and ( 2 ) eletriptan should be effective in aborting migraine headache . Clinical studies have already demonstrated its therapeutic action in migraine patients .\",\n \"Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis . OBJECTIVE : The accumulation of advanced glycation end products ( AGEs ) , P80511 , and high mobility group box chromosomal protein 1 has been associated with joint inflammation in rheumatoid arthritis ( RA ) . This study was undertaken to determine the induction of the receptor for these proteins , termed receptor for AGEs ( RAGE ) , in synovial tissue ( ST ) macrophages from RA patients . METHODS : RAGE and P34810 expression in ST were determined by 2 - color immunofluorescence labeling . Cell surface and messenger RNA ( mRNA ) expression of RAGE were examined by flow cytometry and reverse transcriptase - polymerase chain reaction ( PCR ) or real - time PCR , respectively . RESULTS : P34810 + lining macrophages , like the vasculature , expressed high levels of RAGE in inflamed ST from RA patients . RAGE mRNA expression was significantly higher in RA ST than in ST from patients with osteoarthritis . RAGE mRNA levels were significantly higher in ST macrophages and normal endothelial cells than in ST P01730 + T cells and synovial fibroblasts stimulated with tumor necrosis factor alpha and interleukin - 1beta ( IL - 1beta ) . Cell surface RAGE was highly induced on normal monocytes after a 24 - hour incubation with a 20 % concentration of RA ST cell culture supernatants . RAGE mRNA expression in adherent monocytes was augmented by various cytokines , most potently by IL - 1beta . CONCLUSION : These results indicate that RAGE overexpression in lining macrophages may be induced , at least in part , by cytokines such as IL - 1 , leading to the amplification of inflammatory responses mediated by RAGE ligands that are abundant in RA joints .\",\n \"Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .\",\n \"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK43___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK43___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK43___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK43___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK43___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .\"\n]"},"candidates":{"kind":"list like","value":["___MASK12___","___MASK15___","___MASK43___","___MASK53___","___MASK55___","___MASK59___","___MASK66___","___MASK68___","___MASK81___"],"string":"[\n \"___MASK12___\",\n \"___MASK15___\",\n \"___MASK43___\",\n \"___MASK53___\",\n \"___MASK55___\",\n \"___MASK59___\",\n \"___MASK66___\",\n \"___MASK68___\",\n \"___MASK81___\"\n]"},"answer":{"kind":"string","value":"___MASK68___"},"id":{"kind":"string","value":"MH_train_483"}}},{"rowIdx":484,"cells":{"query":{"kind":"string","value":"interacts_with DB00624?"},"supports":{"kind":"list like","value":["P10275 targets NFkappaB and TSP1 to suppress prostate tumor growth in vivo . The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions . While androgen ablation drives the regression of normal and cancerous prostate , testosterone may cause both proliferation and apoptosis . Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor ( AR ) , however no mechanistic explanation was offered . In this paper we demonstrate in vivo anti - tumor effect of the AR on prostate cancer growth and identify its molecular mediators . We analyzed the effect of AR on the tumorigenicity of prostate cancer cells . Unexpectedly , the AR - expressing cells formed tumors in male mice at a much lower rate than the AR - negative controls . Moreover , the AR - expressing tumors showed decreased vascularity and massive apoptosis . AR expression lowered the angiogenic potential of cancer cells , by increasing secretion of an anti - angiogenic protein , thrombospondin - 1 . AR activation caused a decrease in RelA , a subunit of the pro - survival transcription factor NFkappaB , reduced its nuclear localization and transcriptional activity . This , in turn , diminished the expression of its anti - apoptotic targets , Bcl - 2 and P05231 . Increased apoptosis within AR - expressing tumors was likely due to the NFkappaB suppression , since it was restricted to the cells lacking nuclear ( active ) NFkappaB . Thus we for the first time identified combined decrease of NFkappaB and increased TSP1 as molecular events underlying the AR anti - tumor activity in vivo . Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal , a standard treatment for early - stage prostate cancer . ( c ) 2007 Wiley - Liss , Inc .","A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK42___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK42___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .","P10275 in nuclei of rat testis . Testis nuclei of hypophysectomized rats selectively accumulate labeled testosterone and 5alpha - dihydrotestosterone following the injection of tritiated testosterone in vivo . DB00624 and 5alpha - dihydrotestosterone are bound to macromolecules in nuclei and can be extracted with 0 . 5 M DB00761 . Accumulation of protein bound radioactive androgens in nuclei of isolated seminiferous tubules is similar to that of whole testis . The relative amounts of testosterone and dihydrotestosterone in purified nuclei were similar to the relative amounts bound to cytoplasmic receptors , suggesting that cytoplasmic androgen - receptor complexes may be transported into the nuclei . Binding of labeled androgen is saturable and inhibited by prior injection of unlabeled testosterone or cyproterone acetate . Nuclear binding sites are destroyed by the proteolytic enzyme pronase , but not by DNase . Like the cytoplasmic androgen - receptor complexes in rat testis , nuclear androgen - protein complexes are heat labile and dissociate slowly at 0 degrees C . androgens fail to accumulate in testis nuclei of the Stanley - Gumbreck androgen insensitive rat , a species lacking cytoplasmic androgen receptors in testis and other androgen target tissues .","The androgen axis in recurrent prostate cancer . PURPOSE : Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen - independent . High levels of expression of androgen receptor and androgen receptor - regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence . EXPERIMENTAL DESIGN : Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied . P10275 expression was measured using monoclonal antibody and automated digital video image analysis . Tissue androgens were measured using radioimmunoassay . RESULTS : Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer ( mean optical density , 0 . 284 +/- SD 0 . 115 and percentage positive nuclei , 83 . 7 +/- 11 . 6 ) was similar to benign prostate ( mean optical density , 0 . 315 +/- 0 . 044 and percentage positive nuclei , 77 . 3 +/- 13 . 0 ) . Tissue levels of testosterone were similar in recurrent prostate cancer ( 2 . 78 +/- 2 . 34 pmol / g tissue ) and benign prostate ( 3 . 26 +/- 2 . 66 pmol / g tissue ) . Tissue levels of dihydrotestosterone , dehydroepiandrosterone , and androstenedione were lower ( Wilcoxon , P = 0 . 0000068 , 0 . 00093 , and 0 . 0089 , respectively ) in recurrent prostate cancer than in benign prostate , and mean dihydrotestosterone levels , although reduced , remained 1 . 45 nM . P10275 activation in recurrent prostate cancer was suggested by the androgen - regulated gene product , prostate - specific antigen , at 8 . 80 +/- 10 . 80 nmol / g tissue . CONCLUSIONS : DB00624 and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor . Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue .","DB00624 stimulates proliferation and inhibits interleukin - 6 production of normal and hereditary gingival fibromatosis fibroblasts . Hereditary gingival fibromatosis ( P14210 ) is a rare oral condition characterized by a slow and progressive enlargement of the gingiva , involving both the maxilla and mandible . In vitro , P14210 fibroblasts demonstrate a proliferative index significantly higher than fibroblasts from normal gingiva ( NG ) . The objective of this study was to determine the effect of dihydrotestosterone on the proliferation of gingival fibroblasts derived from patients with P14210 ( n = 4 ) and from four healthy individuals . Additionally , we analyzed the effect of dihydrotestosterone on interleukin - 6 ( P05231 ) production and determined the expression levels of androgen receptors in NG and P14210 fibroblasts . Gingival fibroblasts from NG and P14210 were incubated with increasing concentrations of dihydrotestosterone with or without androgen blockers , and cultured for 24 h , and the proliferation index was determined by automated cell counter . P05231 production , in this system , was quantified using a \" capture \" enzyme - linked immunosorbent assay ( ELISA ) . Semi - quantitative reverse transcriptase - polymerase chain reaction ( RT - PCR ) was performed to measure the mRNA expression of androgen receptors . The results indicated that dihydrotestosterone simultaneously downregulates the production of P05231 and upregulates the cell proliferation . DB01216 and cyprosterone acetate , two anti - androgens , partially reversed these effects . P10275 mRNA expression was identified in both NG and P14210 fibroblasts ; however , the levels in NG were higher than those observed in P14210 . These results show that testosterone coordinates the proliferation and production of P05231 of normal and P14210 fibroblasts .","___MASK10___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK10___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK10___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK10___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .","Increased dihydrotestosterone receptor levels in high - stage renal adenocarcinoma . Primary renal adenocarcinoma tissue , metastatic deposits , and normal kidney parenchyma from 16 patients were assayed for sex hormone receptors by dextran - coated charcoal adsorption and sucrose gradient centrifugation techniques . DB02901 receptors ( P10275 ) were found in all renal carcinomatous tissue ( 20 / 20 ) and in 93 % ( 13 / 14 ) autologous normal kidneys analyzed . DB00624 receptors were found in 84 % ( 16 / 19 ) of tumors and 93 % ( 14 / 15 ) or normal kidneys analyzed . Estrogen receptors in small amounts ( ER ) were detected in only 5 % ( 1 / 19 ) of tumors and in 7 % ( 1 / 15 ) of normal kidneys . Progesterone receptors ( PR ) in low quantities were detected in 30 % ( 6 / 20 ) of renal tumors and in 40 % ( 6 / 15 ) of normal kidneys . P10275 levels in high - stage tumors ( DB00279 , DB00451 ) were significantly elevated over levels in autologous normal kidney , whereas in low - stage tumors localized to the kidney ( T1 and P24752 tumors ) P10275 levels were not significantly different from autologous normal kidney . The mean levels of P10275 in high - stage kidney tumors were significantly elevated over levels in low - stage tumors ( P less than 0 . 001 ) . P10275 estimation in renal neoplasms may help in biologic staging of renal adenocarcinoma and could define a group of patients in whom anti - androgen therapy may be worth a trial .","Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1 / 2 pluripotent cells through an androgen receptor - mediated pathway . DB00624 supplementation increases skeletal muscle mass and decreases fat mass ; however , the underlying mechanisms are unknown . We hypothesized that testosterone regulates body composition by promoting the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage . Mouse C3H 10T1 / 2 pluripotent cells were treated with testosterone ( 0 - 300 nM ) or dihydrotestosterone ( DB02901 , 0 - 30 nM ) for 0 - 14 d , and myogenic conversion was evaluated by immunocytochemical staining for early ( MyoD ) and late ( myosin heavy chain II ; MHC ) myogenic markers and by measurements of MyoD and MHC mRNA and protein . Adipogenic differentiation was assessed by adipocyte counting and by measurements of peroxisomal proliferator - activated receptor gamma 2 ( Q07869 gamma 2 ) mRNA and Q07869 gamma 2 protein and CCAAT / enhancer binding protein alpha . The number of MyoD + myogenic cells and MHC + myotubes and MyoD and MHC mRNA and protein levels increased dose dependently in response to testosterone and DB02901 treatment . Both testosterone and DB02901 decreased the number of adipocytes and down - regulated the expression of Q07869 gamma 2 mRNA and Q07869 gamma 2 protein and CCAAT / enhancer binding protein alpha . P10275 mRNA and protein levels were low at baseline but increased after testosterone or DB02901 treatment . The effects of testosterone and DB02901 on myogenesis and adipogenesis were blocked by bicalutamide . Therefore , testosterone and DB02901 regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor - mediated pathway . The observation that differentiation of pluripotent cells is androgen dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men .","Serum testosterone plays an important role in the metastatic ability of castration resistant prostate cancer . PURPOSE : Prostate cells are dependent on androgens for growth and proliferation . Androgen deprivation therapy is the recommended treatment for advanced / metastatic prostate cancer . Under this therapy , prostate cancer will inevitably progress to castration resistant prostate cancer ( CRPC ) . Despite putative castration resistance , testosterone might still play a crucial role in the progression of CRPC . The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings . METHODS : In vitro , the effect of testosterone and the non - aromatizable androgen methyltrienolone on migration , invasion and proliferation of a castration - resistant prostate cancer rat cell line ( Dunning R3327 - MATLyLu ) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67 . P10275 status was determined using Western blot . In vivo , Copenhagen rats were divided in four groups ( males , females , castrated males and females with testosterone suppletion ) and inoculated with MATLyLu cells . Tumor size was assessed daily . RESULTS : DB00624 increased cell migration and invasion in a concentration - dependent manner in vitro . DB00624 did not affect in vitro cell proliferation . No difference was shown between the effect of testosterone and methyltrienolone . In vivo , in groups with higher levels of circulating testosterone , more rats had ( micro ) metastases compared with groups with low levels of testosterone . No effect was observed on primary tumor size / growth . CONCLUSIONS : Despite assumed castration resistance , progression of prostate cancer is still influenced by androgens . Therefore , continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted .","P10275 is responsible for rat organic cation transporter 2 gene regulation but not for rOCT1 and rOCT3 . PURPOSE : Organic cation transporters 1 - 3 ( OCT1 - 3 ; Slc22a1 - 3 ) mediate the membrane transport of organic cations in the kidney . We previously reported that rat ( r ) OCT2 expression in the kidney was regulated by testosterone . In this study , we examined the transcriptional mechanisms underlying the testosterone - dependent regulation of rOCT2 expression . METHODS : Approximately 3000 - bp fragments of the rOCT1 - 3 promoter region were isolated , and promoter activities were measured in the renal epithelial cell line LLC - P30613 with the coexpression of rat androgen receptor . RESULTS : Among reporter constructs tested , only rOCT2 promoter activity was stimulated by testosterone . This stimulation was suppressed by nilutamide , an antiandrogen drug . Reporter assays using deletion constructs and mutational constructs of putative androgen response elements ( ARE ) in the rOCT2 promoter region suggested that two AREs , located at approximately - 3000 and - 1300 , respectively , play an important role in the induction by testosterone . CONCLUSIONS : DB00624 induces the expression of rOCT2 , but not of rOCT1 and rOCT3 , via the AR - mediated transcriptional pathway . This is the first study to address the transcriptional mechanisms of testosterone - dependent gene regulation of the Slc22 family .","Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK10___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK10___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK10___ .","Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK20___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .","Functional analysis of discoidin domain receptor 2 in synovial fibroblasts in rheumatoid arthritis . In order to know whether any protein tyrosine kinase ( PTK ) is involved in the over - proliferation and erosiveness of synovial fibroblasts ( SF ) of rheumatoid arthritis ( RA ) patients , RT - PCR and RNA dot blotting were done to analyse PTKs profile in RA SF . Platelet - derived growth factor receptor A ( P16234 ) , insulin - like growth factor 1 receptor ( IGF - 1R ) , P23458 ( P23458 ) , P29597 , discoidin domain receptor 2 ( Q16832 ) , and Lyn were expressed in SF , and the expression of P16234 , IGF - 1R , and Q16832 in SF of RA were higher than that of osteoarthritis ( OA , as control ) . Immunoblotting and gelatinase zymography showed that Q16832 in RA SF , which still secreted active matrix metalloproteinase 1 ( P03956 ) in vitro , were in active form . Stimulation of collagen II could make NIH - 3T3 cells ( as control ) produce P03956 , which could be inhibited by soluble extracellular part of Q16832 . These results indicated that the over - expression of P03956 in RA SF might be related to the activation of Q16832 , and collagen II , act as Q16832 ligand , might be one of the stimulators of the over - expression of P03956 of RA SF .","Broadening of transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model to represent late stage androgen depletion independent cancer . BACKGROUND : The transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model closely mimics PC - progression as it occurs in humans . However , the timing of disease incidence and progression ( especially late stage ) makes it logistically difficult to conduct experiments synchronously and economically . The development and characterization of androgen depletion independent ( ADI ) TRAMP sublines are reported . METHODS : Sublines were derived from androgen - sensitive TRAMP - C1 and TRAMP - P06681 cell lines by androgen deprivation in vitro and in vivo . Epithelial origin ( cytokeratin ) and expression of late stage biomarkers ( P12830 and KAI - 1 ) were evaluated using immunohistochemistry . P10275 ( AR ) status was assessed through quantitative real time PCR , Western blotting , and immunohistochemistry . Coexpression of AR and P12830 was also evaluated . Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays . Proliferation / survival of sublines in response to androgen was assessed by WST - 1 assay . In vivo growth of subcutaneous tumors was assessed in castrated and sham - castrated C57BL / 6 mice . RESULTS : The sublines were epithelial and displayed ADI in vitro and in vivo . Compared to the parental lines , these showed ( 1 ) significantly faster growth rates in vitro and in vivo independent of androgen depletion , ( 2 ) greater tumorigenic , and invasive potential in vitro . All showed substantial downregulation in expression levels of tumor suppressor , P12830 , and metastatis suppressor , KAI - 1 . Interestingly , the percentage of cells expressing AR with downregulated P12830 was higher in ADI cells , suggesting a possible interaction between the two pathways . CONCLUSIONS : The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness .","P10275 - immunoreactive cells in ram hypothalamus : distribution and co - localization patterns with gonadotropin - releasing hormone , somatostatin and tyrosine hydroxylase . DB00624 exerts important feedback effects on the hypothalamus of the ram to influence reproductive functioning . To provide a neuroanatomical basis for understanding this androgen action , the present study has examined androgen receptor ( AR ) immunoreactivity within the hypothalamus and adjacent brain areas of the intact non - breeding season ram . The largest populations of AR - immunoreactive cells were detected in the medial preoptic area , infundibular and premammillary nuclei in addition to the ventromedial nucleus ( VMN ) where cells were found distributed throughout its medial and lateral divisions . Smaller numbers of AR - expressing cells were identified in the bed nucleus of the stria terminalis and anterior hypothalamic area ( DB00551 ) including the paraventricular , but not the supraoptic , nucleus . Double - labelling immunocytochemistry revealed the presence of AR immunoreactivity in only 2 of 460 gonadotropin - releasing hormone ( DB00644 ) neurons . A very small population of TH - immunoreactive cells located in the lateral aspect of the DB00551 was found to contain ARs . Dopaminergic cells elsewhere in the hypothalamus , including the infundibular nucleus , did not display AR immunoreactivity . Nearly 50 % of AR - expressing cells in the lateral VMN were immunoreactive for somatostatin while less than 5 % of periventricular somatostatin neurons displayed AR immunoreactivity . These results show where ARs are expressed in the ram hypothalamus and indicate the neuroanatomical sites at which androgen may act to influence reproductive function . The absence of ARs in the neuroendocrine DB00644 and tuberoinfundibular dopaminergic cells suggests that androgens do not influence the genome of these cells in any direct manner . In contrast , the somatostatin neurons of the VMN appear to be an important target for circulating androgens in the non - breeding season ram .","P10275 in human placental villi . In studies with a synthetic androgen , R 1881 , an androgen - binding component was found in the cytosol of human placental villi . Kinetic analysis indicated that the Kd value of this component was 1 . 4 nM at 0 - 4 degrees C and that binding of R 1881 amounted to 277 +/- 73 fmol / mg protein . glycerol density gradient ultracentrifugation showed a peak of binding activity in the 8S region in a medium of low ionic strength , but in the 4 . 5S region in a medium containing 9 . 5 M DB00761 . The R 1881 - binding component was inactivated by mild heat - or trypsin - treatment , but not by treatment with DNase or RNase . Most of the R 1881 - binding activity was sedimented at 20 to 40 % saturation of ammonium sulfate . These findings indicate that the R 1881 - binding component in human placental cytosol is quite similar in its characteristics to androgen receptors , which are present in various androgen - responsive organs . DB00624 was a more potent competitor of R 1881 - binding than DB02901 or cyproterone acetate . Scatchard plots indicated that the binding site of testosterone was identical with that of R 1881 . These findings suggest that the androgen receptor in placental cytosol is specific for testosterone . The Kd value for testosterone was calculated to be 3 . 2 nM .","Androgens and metabolic syndrome : lessons from androgen receptor knock out ( ARKO ) mice . DB00624 ( T ) is an important factor for determining body composition in males . Abdominal obesity is inversely correlated with serum T levels in men , leading to greater mortality . Pathologically hypogonadal men also have a significantly higher fat mass , which is reversed by T administration . However , the mechanism for such anti - obesity effect of androgen has not been well clarified . P10275 ( AR ) null male mice revealed late - onset obesity . Male ARKO mice were euphagic compared to the wild - type male controls , but also less dynamic and less oxygen consuming . Transcript profiling indicated that male ARKO mice had lower transcripts for the thermogenetic uncoupling protein 1 ( P25874 ) . We also found enhanced secretion of adiponectin , which is insulin - sensitizing , from adipose tissue in comparison to wild type , which might partly explain why the overall insulin sensitivity of male ARKO mice remained almost intact despite their apparent obesity . In addition , decreased lipolysis rather than increased lipid synthesis was observed , which might also account for the increased adiposity in male ARKO mice . The results revealed that AR plays important roles in male metabolism by affecting the energy balance , and is negative to both adiposity and insulin sensitivity .","Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .","DB00624 potentiates the hypoxic ventilatory response of adult male rats subjected to neonatal stress . Neonatal stress disrupts development of homeostatic systems . During adulthood , male rats subjected to neonatal maternal separation ( Q5H8A3 ) are hypertensive and show a larger hypoxic ventilatory response ( HVR ) , with greater respiratory instability during sleep . Neonatal stress also affects sex hormone secretion ; hypoxia increases circulating testosterone of Q5H8A3 ( but not control ) male rats . Given that these effects of Q5H8A3 are not observed in females , we tested the hypothesis that testosterone elevation is necessary for the stress - related increase of the HVR in adult male rats . Pups subjected to Q5H8A3 were placed in an incubator for 3 h per day from postnatal day 3 to 12 . Control pups remained undisturbed . Rats were reared until adulthood , and the HVR was measured by plethysmography ( fractional inspired O2 = 0 . 12 , for 20 min ) . We used gonadectomy to evaluate the effects of reducing testosterone on the HVR . Gonadectomy had no effect on the HVR of control animals but reduced that of Q5H8A3 animals below control levels . Immunohistochemistry was used to quantify androgen receptors in brainstem areas involved in the HVR . P10275 expression was generally greater in Q5H8A3 rats than in control rats ; the most significant increase was noted in the caudal region of the nucleus tractus solitarii . We conclude that the abnormal regulation of testosterone is important in stress - related augmentation of the HVR . The greater number of androgen receptors within the brainstem may explain why Q5H8A3 rats are more sensitive to testosterone withdrawal . Based on the similarities of the cardiorespiratory phenotype of Q5H8A3 rats and patients suffering from sleep - disordered breathing , these results provide new insight into its pathophysiology , especially sex - based differences in its prevalence .","Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK61___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .","Pubertal maturation is associated with an increase in the number of androgen receptor - immunoreactive cells in the brains of male ferrets . P10275 - immunoreactive ( AR - IR ) cells were identified in brains of male ferrets before and after the onset of pubertal maturation . There was a greater number of AR - IR cells after the onset of pubertal maturation in some , but not all , brain regions examined . Regions in which the number of AR - IR cells increased included the preoptic area and the amygdala , areas known to be involved in the control of male reproductive behaviors . The mechanisms responsible for the increase in AR - IR cells are unknown , but might be related to the higher circulating levels of testosterone that were present in the older animals . DB00624 may increase androgen receptor ( AR ) immunoreactivity both by concentrating already existing ARs within the nucleus and by stimulating de novo synthesis of receptor protein .","Androgen Receptor Enhances p27 Degradation in Prostate Cancer Cells through Rapid and Selective Q53ET0 Activation . P10275 ( AR ) plays a central role in prostate cancer ( PCa ) growth , with androgen deprivation or AR down - regulation causing cell - cycle arrest and accumulation of the p27 cyclin - dependent kinase inhibitor . The molecular basis for this AR regulation of cell - cycle progression remains unclear . Here we demonstrate that androgen can rapidly reduce p27 protein in PCa cells by increasing its proteasome - mediated degradation . This rapid androgen - stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157 . Significantly , androgen increased Q53ET0 - mediated AKT S473 phosphorylation without affecting the PDK1 - mediated AKT T308 phosphorylation or Q6UUV9 activity . The Q53ET0 activation was further supported by enhanced P42345 / Q6R327 association and increased phosphorylation of additional Q53ET0 substrates , O00141 and PKCα . The androgen - stimulated nuclear translocation of AR was associated with markedly - increased nuclear Q9BPZ7 , a critical component of Q53ET0 . Finally , the androgen - mediated Q53ET0 / AKT activation targets a subset of AKT substrates including p27 and Q12778 , but not Q96B36 . This study reveals a pathway linking AR to a selective activation of Q53ET0 , the subsequent activation of AKT , and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival . These findings establish that Q53ET0 can function as a central regulator of growth in response to signals that are distinct from those regulating Q6UUV9 , and support efforts to target Q53ET0 for cancer therapy .","Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .","DB00624 inhibits matrix metalloproteinase - 1 production in human endometrial stromal cells in vitro . P10275 ( AR ) is reported to be expressed in human uterine endometrium , but not much information is available on the role of androgens in human endometrium . The purpose of this study is to investigate the role of androgens in the regulation of matrix metalloproteinase ( MMP ) - 1 , which is one of the important MMPs for menstruation and embryo implantation in human endometrium . Human endometrial stromal cells ( HESCs ) were obtained from human endometrium by enzymatic dissociation method . Purified HESCs were incubated with 17beta - estradiol ( E2 ) , testosterone , or E2 + testosterone . Progestins ( natural progesterone or medroxyprogesterone acetate ) or vehicle ( dimethyl sulfoxide ) were also added to the media instead of testosterone . Furthermore , hydroxyflutamide ( FLU ), a specific AR antagonist , was also supplemented to cultured media . The amounts of P03956 in cultured media and in HESC lysates were examined by ELISA measurements and western blotting analysis respectively . The expression of ARmRNA in HESCs RNA was analyzed by RT - PCR . DB00624 significantly inhibited P03956 in both cultured media and cell lysates in a dose - dependent manner . Progestins also inhibited P03956 . Furthermore , FLU completely recovered the decrease of P03956 induced by testosterone . ARmRNA was detected in all HESCs RNA . The present study demonstrated that the secretion and production of P03956 in HESCs in vitro were inhibited by testosterone through androgen receptors in a manner similar to that seen for progesterone . These findings indicate that androgen may play an important role in morphological and functional changes of human endometrium .","P10275 dependent and independent activities of testosterone on hepatic microsomal drug metabolism . Administration of testosterone for 6 days to intact female and castrate male BALB / cJ mice stimulated hepatic microsomal ethylmorphine N - demethylase activity and cytochrome P - 450 content by 50 - 75 % . DB00624 also stimulated hepatic microsomal NADPH - oxidase activity , but to a lesser degree . To probe the mechanism of this effect of androgens , two antiandrogens ( cyproterone acetate and flutamide ) were employed . Since cyproterone acetate was a potent stimulator of hepatic microsomal ethylmorphine N - demethylase activity and cytochrome P - 450 content , no antiandrogenic activity of this steroid could be detected . By contrast , flutamide alone had little effect on either ethylmorphine N - demethylase activity or cytochrome P - 450 content . However , this drug effectively blocked the stimulatory effects of testosterone on ethylmorphine N - demethylase activity and cytochrome P - 450 content but not on NADPH - oxidase activity . This effect was not species specific , since flutamide also prevented androgen stimulation of ethylmorphine metabolism in adult castrate and prepubertal male Fisher rats . The testosterone - induced increase of hepatic weight and microsomal protein content was not affected by the administration of flutamide . The observations are consistent with the hypothesis that androgens have two distinct effects on the liver . First , testosterone may act as a general , nonspecific stimulant of liver weight and microsomal protein content which is independent of the androgen receptor . Secondly , testosterone action in the liver may be expressed via an androgen - specific or androgen receptor - dependent mechanism which controls , in part , the cytochrome P - 450 - dependent demethylase system .","P10275 signaling induced by supraphysiological doses of dihydrotestosterone in human peripheral blood lymphocytes . Anabolic androgenic steroids , a class of steroid hormones related to testosterone , are natural ligands of androgen receptor ( AR ) , a member of the nuclear receptor superfamily of ligand - activated transcription factors . AR binds specific DNA elements , known as androgen - response elements . DB00624 , the main male sexual hormone , binds AR directly and indirectly , through conversion into dihydrotestosterone ( DB02901 ) , its more active metabolite . Anabolic androgenic steroids are frequently detected in the urine of doped athletes ; their consumption is also growing among sport amateurs and adolescents . The effects of androgens can differ depending on the target cells and / or tissues . To gain insight into transcription activation mechanisms of AR , we investigated AR protein signaling in human peripheral blood lymphocytes treated with supraphysiological doses of DB02901 . We performed a comparative proteomic analysis and we identified about 30 differentially expressed proteins . At least five species contained a consensus androgen - response elements sequence in the promoter region of related coding genes . The analysis also revealed that high doses of DB02901 activate the drug detoxification process , could stimulate an increase in cell motility and exert a prosurvival effect rather than an apoptotic one .","Altered levels of angiopoietin 1 and tie 2 are associated with androgen - regulated vascular regression and growth in the ventral prostate in adult mice and rats . The involution of the rat ventral prostate gland after castration could be caused by primary changes in the vasculature . To explore the mechanisms , we studied the effects of castration and testosterone treatment on the vasculature in the ventral prostate in adult rats and mice . P10275 expression , vascular morphology , and the expression of angiopoietin ( ang ) 1 and 2 and their receptor tie 2 were examined 1 , 3 , and 7 d after castration and after testosterone treatment of castrated animals using stereological methods , immunohistochemistry , laser capture microdissection , and Western blotting . One day after castration , the percentage of blood vessels covered with smooth muscle actin , endothelial cell proliferation , and vascular volume had decreased , whereas endothelial cell apoptosis had increased . Simultaneously , ang 1 and tie 2 protein levels decreased . Nuclear expression of androgen receptor was observed not only in glandular and stroma smooth muscle cells but also in the mural cells of prostate arteries and veins and was markedly down - regulated already 1 d after castration . DB00624 administration of castrated mice and rats reversed all the observed effects . At the mRNA level , tie 2 was exclusively , but ang 1 predominantly , expressed in the stroma , compared with the epithelial compartment . Local delivery of soluble tie 2 during testosterone - stimulated growth , inhibited vascular maturation and increased vascular volume and leukocyte infiltration compared with controls . We conclude that androgens may regulate the prostate vasculature by direct effects on mural vascular cells and by influencing the secretion of the angiopoietins , in above all , the stroma cells .","P10275 in Sertoli cells is not required for testosterone - induced suppression of spermatogenesis , but contributes to Sertoli cell organization in Utp14b jsd mice . DB00624 acting through the androgen receptor ( AR ) maintains the arrest of spermatogonial differentiation in juvenile spermatogonial depletion ( jsd mutation in the Utp14b gene ) mutant adult male mice . It is not known which of the somatic cell types expressing AR mediates this inhibition . To determine whether Sertoli cells are responsible , we selectively eliminated AR in Sertoli cells in jsd mice containing a floxed - Ar gene and an anti - Müllerian hormone - Cre transgene . In these Sertoli AR - knockout ( SCARKO ) - jsd mice , spermatogonial differentiation did not recover . However , the normal organization of Sertoli cell nuclei was drastically disrupted in SCARKO - jsd mice compared with SCARKO or jsd mice . In addition , the extent of ectoplasmic specializations was reduced ; tight junctions were not found ; vinculin , an anchoring protein found in ectoplasmic specializations , became uniformly distributed in the cytoplasm ; and the adult Sertoli cells showed excess heterochromatin subjacent to their nuclear envelope . Despite the abnormalities in Sertoli cells in SCARKO - jsd mice , global suppression of testosterone action and levels was still effective in restoring the differentiated germ cells , and this was accompanied by an improved arrangement of Sertoli cell nuclei . We conclude that Sertoli cells are not targets for the testosterone - mediated inhibition of spermatogonial differentiation in jsd mice , and that both AR in Sertoli cells and the presence of differentiated germ cells contribute to maintaining the organization of Sertoli cells within the seminiferous tubules .","P10275 ( CAG ) n polymorphism and androgen levels in women with systemic lupus erythematosus and healthy controls . Systemic lupus erythematosus ( SLE ) is an autoimmune disorder that affects mainly females . Therefore , interrelations between the reproductive and immune system have been assumed . Considering the complex influence of hormones and receptors , we aimed to investigate the influence of androgens and androgen receptor ( AR ) polymorphism in women with SLE . One hundred and sixteen patients and 44 healthy women were investigated . DB00624 , sex hormone - binding globulin ( P04278 ) , dehydroepiandrosterone - sulphate ( DHEAS ) concentrations and AR ( CAG ) n polymorphism were determined . SLE patients had significantly lower levels of total and free testosterone and DHEAS in comparison with the controls . No differences in the CAG repeat length between the groups were established . Women with two alleles carrying more than 22 CAG repeats had significantly higher levels of P04278 ( 101 . 51 ± 61 . 81 vs . 69 . 22 ± 45 . 93 nmol / l , p = 0 . 015 ) and DHEAS ( 3 . 11 ± 2 . 65 vs . 2 . 11 ± 3 . 06 μmol / l , p = 0 . 007 ) and a tendency to higher testosterone concentrations ( 2 . 35 ± 2 . 10 vs . 1 . 71 ± 1 . 70 nmol / l , p = 0 . 056 ) in comparison with other women . The CAG repeat length in the relatively longer ( CAG ) n allele was inversely related to the Systemic Lupus International Collaborating Clinics / P10323 index ( r = - 0 . 258 , p = 0 . 009 ) . In conclusion , the androgen receptor ( CAG ) n polymorphism is not related to the development of SLE , but it could modulate the severity of the lupus chronic damages as well as the androgen levels in women .","P10275 in human skin cytosol . Human skin , an accessible tissue , is an androgen target organ . We have measured the androgen - binding capacity of human skin cytosol using either 5 alpha [ 3H ] dihydrotestosterone ( [ 3H ] DB02901 ) or [ 3H ] methyltrienolone ( [ 3H ] R - 1881 ) as ligand . Samples were incubated for 20 h at 0 C , and dextran - coated charcoal was used to separate bound from free steroids . The androgen receptor has a high affinity for both ligands ( 0 . 23 +/- 0 . 04 nM for [ 3H ] DB02901 ; 0 . 32 +/- 0 . 16 nM for [ 3H ] R - 1881 ) . DB00624 , cyproterone acetate , and , to a lesser extent , estradiol also bind this protein . Progesterone displaces R - 1881 from its binding sites , whereas its 5 alpha - reduced metabolite somewhat inhibits DB02901 binding . The highest binding capacity is measured in cytosol of skin from external genitalia ( 129 . 14 +/- 58 . 0 fmol / g skin ; n = 34 ) ; it is lower in pubic skin ( 21 . 8 +/- 13 fmol / g skin ; n = 6 ) . There is no variation as a function of age or sex in genital skin ; the higher concentrations observed in the cytosol of pubic skin of women compared to that of men are probably related to lower levels of endogenous steroids . Whereas most patients with the complete form of the testicular feminization syndrome do not have detectable concentrations of androgen receptor , one patient with apparent complete clinical androgen insensitivity had a normal androgen - binding capacity . The parity of values in genital skin from men and women , the absence of variation with age , and the presence of a cytosolic androgen receptor in some androgen - insensitive patients suggest that the androgen receptor in human skin cytosol is not regulated by androgens .","Androgen receptors . DB00624 and its active metabolite dihydrotestosterone exert their influence on target cells through a specific intracellular protein receptor . Structural abnormalities of this receptor lead to a diminished androgen action within the cell and result in the syndrome of androgen insensitivity . Androgen insensitivity is classified on the basis of whether the insensitivity is complete or partial and whether the androgen receptor is normally present ( AR (+) ) , absent ( AR (-) ) or diminished ( AR (+/-) ) . All patients with androgen insensitivity have normal or high plasma levels of testosterone and elevated serum LH . Patients with complete androgen insensitivity are phenotypically female . The clinical presentation of partial androgen insensitivity is variable , ranging from a minimal amount of virilization to a completely masculine appearance . All patients described with a syndrome of androgen insensitivity are infertile . The influence of androgen receptor function in the pathogenesis of benign prostatic hypertrophy is being investigated . P10275 content is also being studied as a possible marker of responsiveness to hormonal therapy in prostatic carcinoma .","P10275 is essential for sexual differentiation of responses to olfactory cues in mice . During sexual differentiation males and females are exposed to different levels of testosterone , which promotes sex differences in the adult brain and in behavior . DB00624 can act after aromatization or reduction via a number of steroid hormone receptors . Here we provide new evidence that the androgen receptor ( AR ) is essential for sexual differentiation in mice . We used mice carrying the testicular feminization ( Tfm ) mutation of the AR . Adult Tfm males , wild - type male and female littermates were gonadectomized and given subcutaneous estradiol implants . In all sexually dimorphic traits , Tfm males had responses equivalent to females and different from males . In simultaneous choice tests , males spent significantly more time investigating female - soiled bedding , whereas females and Tfm males preferred to investigate male - soiled bedding . Tfm males and females did not have a partner preference in tests with awake stimulus animals , whereas males showed a preference for females over males . Exposure to male - soiled , but not clean , bedding produced a significant increase in c - Fos - immunoreactive cells in the medial preoptic area and bed nucleus of the stria terminalis in Tfm males and females , no increase was noted in males . Masculine sexual behavior ( mounting and thrusting ) was not sexually dimorphic , and all groups displayed these behaviors . Our results support data collected in humans suggesting a role for the androgen receptor in sexual differentiation of social preferences and neural responses to pheromones .","The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK1___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK1___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .","In utero and lactational exposure to 2 , 3 , 7 , 8 - tetrachlorodibenzo - p - dioxin alters postnatal development of seminal vesicle epithelium . 2 , 3 , 7 , 8 - Tetrachlorodibenzo - p - dioxin ( TCDD ) has been shown to alter male reproductive development of laboratory animals through in utero and lactational exposure . As a result of exposure , the accessory glands of the male reproductive tract , including the seminal vesicle , are decreased in size as determined by total weight of the tissue . Analysis of seminal vesicle weights over time suggests that the changes may be transient . Administration of 1 . 0 microg / kg TCDD during gestation caused a significant decrease in seminal vesicle weights of offspring 8 - 11 months of age . We examined the effects of TCDD on seminal vesicles from rats exposed in utero and lactationally . Pregnant Long Evans rats were gavaged on gestation day 15 with 1 . 0 microg / kg TCDD in corn oil . Male pups were euthanized and necropsied on postnatal days ( P01160 ) 15 , 25 , 32 , 49 , 63 , and 120 . Seminal vesicles were weighed and then fixed in 10 % neutral buffered formalin and processed for microscopic examination . Seminal vesicle weights were not significantly decreased until P01160 32 . P10275 mRNA expression in P01160 25 seminal vesicles was not different from control . In the present study , TCDD exposure decreased seminal vesicle epithelial branching and differentiation . Control epithelial cells had tall columnar morphology with relatively abundant cytoplasm , whereas TCDD - treated cells had rounded nuclei and less cytoplasm . In addition , immunolocalization of proliferating nuclear antigen was confined to undifferentiated basal epithelial cells of controls but was found in both basal and luminal cells of the treated seminal vesicle . Results indicate that the TCDD - induced impaired growth of the rat seminal vesicles is associated with a dramatic decrease in the development of the epithelium .","Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .","p62 links β - adrenergic input to mitochondrial function and thermogenesis . The scaffold protein p62 ( sequestosome 1 ; Q13501 ) is an emerging key molecular link among the metabolic , immune , and proliferative processes of the cell . Here , we report that adipocyte - specific , but not CNS - , liver - , muscle - , or myeloid - specific p62 - deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis . Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue ( Q14032 ) . Accordingly , adipocyte - specific p62 deficiency led to impaired mitochondrial function , causing Q14032 to become unresponsive to β - adrenergic stimuli . Ablation of p62 leads to decreased activation of p38 targets , affecting signaling molecules that control mitochondrial function , such as P15336 , CREB , PGC1α , Q92813 , NRF1 , CYTC , P35354 , ATP5β , and P25874 . p62 ablation in HIB1B and Q14032 primary cells demonstrated that p62 controls thermogenesis in a cell - autonomous manner , independently of brown adipocyte development or differentiation . Together , our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis .","P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK16___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .","P10275 promotes the migration and invasion of upper urinary tract urothelial carcinoma cells through the upregulation of P14780 and P35354 . Dysregulated androgen receptor ( AR ) signaling is implicated in several types of tumor , including carcinomas of the prostate , breast , liver and bladder . However , the contribution of AR to the progression of upper urinary tract urothelial carcinomas ( UUTUC ) has not been fully investigated . In the present study , we demonstrated that the AR is involved in the metastasis and invasiveness of UUTUC cells . We investigated the role of the AR in UUTUC by using UUTUC - derived BFTC 909 cells . The overexpression of AR promotes the migration and invasion of BFTC 909 cells . Expression of migration / invasion - related genes was increased in BFTC 909 cells overexpressing AR determined by qPCR and western blot analyses . The results showed that AR - enhanced migration and invasion of UUTUC cells are linked to the upregulation of the matrix - degrading enzyme P14780 and cyclooxygenase ( P36551 ) - 2 . Subsequently , the blocking of P14780 and P35354 signaling by inhibitors suppressed AR - enhanced cell migration and invasion . The results of the present study provide evidence for the first time of the role of AR in the motility and invasion of UUT cancer cells and support the hypothesis that the AR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia of UUT . Thus , the AR may also serve as a novel biomarker and potential therapeutic target for UUT cancer .","D - DB00128 implication in the modulation of frog brain sex steroid levels . There is evidence that D - aspartate ( D - DB00128 ) modulates sex hormone levels in frog testis by regulating the activity of P450 aromatase ( P450 aro ) , the key enzyme which converts DB00624 ( T ) in 17ß - Estradiol ( E2 ) . Here we report , for the first time , that there is a direct correlation among brain levels of D - DB00128 , P450 aro , E2 and Estradiol Receptor ( ERα ) in the male frogs during the reproductive as well as the post - reproductive phases of the breeding cycle , with highest levels being observed in the post - reproductive period . D - DB00128 i . p . administration to frogs ready for reproduction , induced an increase of brain P450 aro protein expression with concomitant enhancement of both E2 levels and ERα expression ; at the same time , brain T levels and P10275 expression decreased . In contrast , in the post - reproductive frogs , D - DB00128 treatment did not modify any of these parameters . Taken together , these results imply that the regulation of P450 aro expression by D - DB00128 could be an important step in the control of E2 levels in the frog brain .","Androgen action . Androgens are important for male sex development and physiology . Their actions are mediated by the androgen receptor ( AR ) , a ligand - dependent nuclear transcription factor . The activity of the AR is controlled at multiple stages due to ligand binding and induced structural changes assisted by the foldosome , compartmentalization , recruitment of coregulators , posttranslational modifications and chromatin remodeling , leading to subsequent transcription of androgen - responsive target genes . Beside these short - term androgen actions , there is phenomenological and experimental evidence of long - term androgen programming in mammals and in the human during sensitive programming time windows , both pre - and postnatally . At the molecular level , research into androgen insensitivity syndrome has unmasked androgen programming at the transcriptome level , in genital fibroblasts and peripheral blood mononuclear cells , and at the epigenome level . Androgens are crucial for male sex development and physiology during embryogenesis , at puberty and in adult life . DB00624 and its more potent metabolite , dihydrotestosterone , which is converted from testosterone within the target cell by 5α - reductase II , are the main androgens involved in male sex differentiation . Androgen action is mediated by a single AR . The AR belongs to the nuclear receptor 3 group C , composed of the glucocorticoid receptor ( P04150 ) , mineralocorticoid receptor ( P08235 ) , progesterone receptor ( P06401 ) and AR ( P10275 ) , and acts as a ligand - dependent transcription factor .","___MASK23___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK23___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK23___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK23___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .","Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .","Protection of lung epithelial cells from protease - mediated injury by trappin - 2 A62L , an engineered inhibitor of neutrophil serine proteases . Neutrophil serine proteases ( NSPs ) , including elastase , proteinase 3 and cathepsin G , play critical roles in the pathogenesis of chronic inflammatory lung diseases . The release of excess NSPs leads to the destruction of lung tissue and an overexuberant , sustained inflammatory response . Antiproteases could be valuable tools for controlling these NSP - mediated inflammatory events . We have examined the capacity of trappin - 2 A62L , a potent engineered inhibitor of all three NSPs , to protect human lung A549 epithelial cells from the deleterious effects of NSPs . Trappin - 2 A62L , significantly inhibited the detachment of A549 cells and the degradation of the tight - junction proteins , P12830 , β - catenin and ZO - 1 , induced by each individual NSP and by activated neutrophils . Trappin - 2 A62L also decreased the release of the pro - inflammatory cytokines P05231 and P10145 from A549 cells that had been stimulated with elastase or LPS . Trappin - 2 A62D / M63L , a trappin - 2 variant that has no antiprotease activity , has similar properties , suggesting that the anti - inflammatory action of trappin - 2 is independent of its antiprotease activity . Interestingly , we present evidence that trappin - 2 A62L , as well as wild - type trappin - 2 , enter A549 cells and move rapidly to the cytoplasm and nucleus , where they are likely to exert their anti - inflammatory effects . We have also demonstrated that trappin - 2 A62L inhibits the early apoptosis of A549 cells mediated by NSPs . Thus , our data indicate that trappin - 2 A62L is a powerful anti - protease and anti - inflammatory agent that could be used to develop a treatment for patients with inflammatory lung diseases .","Recent androgen receptor antagonists in prostate cancer . P10275 has been shown to promote prostate cell growth and carcinogenesis of prostate cancer by up - regulating its target genes . DB00624 and dihydrotestosterone are two major hormones which bind to and activate androgen receptor . Targeting both the androgen receptor and the enzymes catalyzing the biosynthesis of testosterone and dihydrotestosterone has been shown to be clinically beneficial in the treatment of prostate cancer . Prostate cancer can become castration - resistant after long term treatment with chemo drugs , so efforts in finding compounds with improved efficiency to castration - resistant prostate cancer are urgently needed . In this review we summarized the studies on recent progress in the development of small molecular AR antagonists for the treatment of prostate cancer .","P10275 is widely expressed in bovine placentomes and up - regulated during differentiation of bovine trophoblast giant cells . OBJECTIVES : In cattle no biological role has been definitely identified for placental estrogens and progesterone . However , in the bovine trophoblast androgens may also be produced and have local effects . Thus , the aims of this study were to identify androgen receptor ( AR ) expressing cells and to monitor testosterone tissue concentrations in bovine placentomes throughout gestation . METHODS : Placental AR expression was characterized at the mRNA and protein level applying conventional and real - time RT - qPCR , western blot and immunohistochemistry . DB00624 was measured by radioimmunoassay . RESULTS : AR - mRNA was qualitatively detected from day 50 of gestation until term . Mean relative gene expression levels were constant between day 100 and late gestation . A slight non - significant increase was observed in the prepartal period . With immunohistochemistry distinct nuclear signals were predominantly observed in invasive trophoblast giant cells ( P21980 ) from day 80 until term . In mature P21980 of the trophoblast , immature P21980 and uninucleated trophoblast cells , stromal cells of the chorionic villi , caruncular epithelial and stromal cells immunoreactive score values were low at early and midgestation but increased significantly ( p < 0 . 01 ) during late gestation and remained high until parturition . With western blot in placentomal tissue a specific band of approximately 110 kDa was detected as it was the case in epididymis used as a positive control . DB00624 concentrations increased from 0 . 70 ± 0 . 29 pmol / g wet tissue between days 60 - 220 to 4 . 22 ± 1 . 29 pmol / g during late gestation ( p < 0 . 001 ) . DISCUSSION : The results are consistent with androgens as active products of bovine placental steroidogenesis . The substantial up - regulation of AR expression during P21980 differentiation suggests that androgens may be related to this process .","Gene expression in sexually dimorphic muscles in sheep . DB00624 is known to act differentially on skeletal muscle from different regions of the body . Two genes likely to mediate the testosterone effect are insulin - like growth factor I ( P05019 ) , an important growth regulator acting in an autocrine and paracrine way , and androgen receptor ( AR ) , because receptor density could account for differential muscle growth . Another muscle - specific gene that may play a role in differential muscle growth is myostatin , a member of the transforming growth factor - beta superfamily , shown to be a negative regulator of skeletal muscle mass . The objective of this study was to quantify and compare the steady state expression of these three genes in two different skeletal muscles in sheep . Eleven Dorset rams were slaughtered after reaching puberty and total RNA was extracted from samples of semitendinosus and splenius muscles . P05019 mRNA was measured using a competitive reverse - transcription - polymerase chain reaction . P10275 and myostatin mRNA were measured by a ribonuclease protection assay ( RPA ) with standard curves . The means ( attomoles / microg RNA ) for splenius and semitendinosus muscles were 1 . 39 and 1 . 02 ( SE = 0 . 14 ) , 4 . 05 and 2 . 96 ( SE = 0 . 24 ) , and 4 . 30 and 3 . 85 ( SE = 0 . 37 ) for P05019 , AR , and myostatin , respectively . The difference between the two muscles was significant for P05019 and AR mRNA levels with higher levels in the splenius but not significant for myostatin . Our results show that locally produced P05019 and the regulation of AR expression may be important for sexually dimorphic muscle growth patterns .","Axotomy transiently down - regulates androgen receptors in motoneurons of the spinal nucleus of the bulbocavernosus . DB00624 is an important trophic factor for motoneurons in the spinal nucleus of the bulbocavernosus ( SNB ) , and SNB motoneurons are more responsive to testosterone than are other motoneurons . Axonal injury during early postnatal life prevents the normal development of steroid - sensitivity by adult SNB motoneurons . Axonal injury also causes changes in the expression by motoneurons of a wide range of proteins , including the up - regulation of trophic factor receptors . We have used a polyclonal antibody ( PG - 21 ; G . S . Prins ) to study the expression of androgen receptors in SNB motoneurons after axonal injury . PG - 21 labeled motoneuronal nuclei in the lower lumbar spinal cord of rats in a pattern that matched autoradiographic reports of androgen accumulation in this region of the nervous system . A population of numerous , small cells located dorsal to the central canal also showed evidence of androgen receptor expression . Cutting the axons of SNB motoneurons in adulthood or in development caused a decrease in androgen receptor immunoreactivity in SNB motoneurons . This is the first report that a trophic factor receptor in motoneurons is down - regulated after axonal injury , and is interesting in light of reports that testosterone treatment can facilitate motoneuronal regeneration after nerve cut . P10275 levels subsequently returned to normal , regardless of the age at axotomy , providing no evidence for a lasting effect of developmental axotomy on androgen receptor levels in SNB motoneurons . Thus , axotomy - induced down - regulation of androgen receptors does not underlie the inability of SNB motoneurons to respond to androgen treatment several months after pudendal nerve cut in development .","Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF - IGFBP axis . The IGF axis is critical for the regulation of apoptosis in many human cancer cell lines . Recently , potent anti - tumorigenic effects of pomegranate juice and extracts have been reported . Consequently , pomegranate has potential not only as a treatment but also as a preventative measure against certain types of cancer , including prostate . In this study , we investigated the relationship between pomegranate - induced apoptosis in human prostate cancer cells and the IGF / IGFBP system . Treatment of LAPC4 prostate cancer cells with 10microg / ml POMx , a highly potent pomegranate extract prepared from skin and arils minus seeds and standardized to ellagitannin content ( 37 % punicalagins by HPLC ) , resulted in inhibition of cell proliferation and induction of apoptosis . Interestingly , co - treatment with POMx and P17936 revealed synergistic stimulation of apoptosis and additive inhibition of cell growth . Western blot analysis revealed that treatment with POMx or POMx / P17936 combination resulted in increased JNK phosphorylation , and decreased Akt and P42345 activation , consistent with a growth inhibitory , pro - apoptotic function . We also investigated the relationship between DB01277 and pomegranate - induced apoptosis in 22RV1 prostate cancer cells . Co - treatment with 100ng / ml DB01277 completely blocked apoptosis induction by POMx . In contrast , P05019 failed to inhibit POMx - induced apoptosis in R (-) cells , suggesting the importance of IGF - IR . POMx - treatment decreased Igf1 mRNA expression in a dose - dependent manner indicating that its actions also involve tumor - specific suppression of DB01277 . These studies revealed novel interactions between the IGF system and pomegranate - induced apoptosis .","Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK75___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .","The androgen receptor : a mediator of diverse responses . Androgens mediate a number of diverse responses through the androgen receptor , a 110 kD ligand - activated nuclear receptor . P10275 expression , which is found in a variety of tissues , changes throughout development , aging , and malignant transformation . The androgen receptor can be activated by two ligands , testosterone and dihydrotestosterone , which bind to the androgen receptor with different affinities . This difference in binding affinity results in different levels of activation of the androgen receptor by the two ligands . The androgen receptor acts as a transcriptional modifier of a variety of genes by binding to an androgen response element . The ability to confer androgen specific actions by the androgen response element may depend on other cell - specific transcription factors and cis - acting DNA elements in close proximity to it . DB00624 and dihydrotestosterone appear to act upon an identical nuclear receptor . However , in certain instances , they mediate different physiologic responses . For example , dihydrotestosterone , but not testosterone , is capable of mediating full sexual development of the male external genitalia . In some cases , the androgen receptor may induce opposite physiologic responses in similar tissue types depending on their location . For example , in male pattern baldness , activated androgen receptors may suppress the growth of distinct hair follicle populations through initiating stromal - epithelial actions , whereas other hair follicles continue to proliferate . In other cases , altered androgen receptor activity due to its mutation or altered expression may lead to pathology such as recurrence of prostate cancer due to development of androgen independence allowing tumor cell proliferation under androgen deprivation .","Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824 . P10275 plays a critical role in the development of primary as well as advanced hormone - refractory prostate cancer . Therefore , ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgen - dependent prostate cancer but also for metastatic hormone - refractory prostate cancer , for which there is no effective treatment available . We report here that LAQ824 , a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials , effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations . LAQ824 seemed capable of depleting both the mutant and wild - type androgen receptors in either androgen - dependent and androgen - independent prostate cancer cells . Although LAQ824 may exert its effect through multiple mechanisms , several lines of evidence suggest that inactivation of the heat shock protein - 90 ( Hsp90 ) molecular chaperone is involved in LAQ824 - induced androgen receptor depletion . Besides androgen receptor , LAQ824 reduced the level of Hsp90 client proteins HER - 2 ( ErbB2 ) , Akt / P31749 , and P04049 in LNCaP cells . Another Hsp90 inhibitor , 17 - allyamino - 17 - demethoxygeldanamycin ( 17 - P29372 ) , also induced androgen receptor diminution . LAQ824 induced Hsp90 acetylation in LNCaP cells , which resulted in inhibition of its DB00171 - binding activity , dissociation of Hsp90 - androgen receptor complex , and proteasome - mediated degradation of androgen receptor . Consequently , LAQ824 blocked androgen - induced prostate - specific antigen production in LNCaP cells . LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells . These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer .","Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .","[ Monoamine imbalance of the central nervous system in a case of Shy - Drager syndrome with recurrent attacks of a neuroleptic malignant syndrome ] . A 79 - year - old male suffering from Shy - Drager syndrome was treated with a daily dosage of 300 mg of L - threo - 3 , 4 - dihydroxyphenylserine ( DB06262 ) . He developed a neuroleptic malignant syndrome ( Q5H8A3 ) like state 1 month after teh initiation of DB06262 therapy . And recurrent attacks of Q5H8A3 occurred subsequently despite discontinuation of DB06262 administration . We measured homovanillic acid ( HVA ) , 3 methoxy 4 hydroxyphenylethylenglycol ( MHPG ) , and 5 - hydroxyindoleacetic acid ( 5 - HIAA ) in this corrected brospinal fluid ( P04141 ) , both during his 2 attacks of Q5H8A3 and after recovery . The HVA and 5 HIAA levels after recovery were low compared with those in age - matched normal controls . However , his levels in the active phase were not different from those after recovery . In contrast , MHPG levels were elevated and his HVA / MHPG ratios decreased in the active phase compared with those in the recovery phase . The results indicate that his symptoms of Q5H8A3 are attributed to the imbalance between dopamine and noradrenalin rather than the dopamine receptor blockade in the central nervous system . We suggest further evaluations of P04141 monoamine metabolites in similar cases to determine the pathogenesis of Q5H8A3 .","P10275 - dependent transactivation of growth arrest - specific gene 6 mediates inhibitory effects of testosterone on vascular calcification . Recent epidemiological studies have found that androgen deficiency is associated with a higher incidence of cardiovascular disease in men . However , little is known about the mechanism underlying the cardioprotective effects of androgens . Here we show the inhibitory effects of testosterone on vascular calcification and a critical role of androgen receptor ( AR ) - dependent transactivation of growth arrest - specific gene 6 ( Gas6 ) , a key regulator of inorganic phosphate ( P ( i ) ) - induced calcification of vascular smooth muscle cells ( VSMC ) . DB00624 and nonaromatizable androgen dihydrotestosterone inhibited P ( i )- induced calcification of human aortic VSMC in a concentration - dependent manner . Androgen inhibited P ( i )- induced VSMC apoptosis , an essential process for VSMC calcification . The effects on VSMC calcification were mediated by restoration of P ( i )- induced down - regulation of Gas6 expression and a subsequent reduction of Akt phosphorylation . These effects of androgen were blocked by an AR antagonist , flutamide , but not by an estrogen receptor antagonist , DB00947 . We then explored the mechanistic role of the AR in Gas6 expression and found an abundant expression of AR predominantly in the nucleus of VSMC and two consensus ARE sequences in the Gas6 promoter region . DB02901 stimulated Gas6 promoter activity , and this effect was abrogated by flutamide and by AR siRNA . Site - specific mutation revealed that the proximal ARE was essential for androgen - dependent transactivation of Gas6 . Furthermore , chromatin immunoprecipitation assays demonstrated ligand - dependent binding of the AR to the proximal ARE of Gas6 . These results indicate that AR signaling directly regulates Gas6 transcription , which leads to inhibition of vascular calcification , and provides a mechanistic insight into the cardioprotective action of androgens .","P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( DB02901 ) in castrated male and female mice subjected to DB02901 replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by DB02901 in mice CPs .","DB00624 and androgen receptor in human nephrolithiasis . PURPOSE : We investigated the relationship of kidney calculi with plasma free and total testosterone , and androgen receptor up - regulation in the kidneys of men with nephrolithiasis . MATERIALS AND METHODS : Male patients with kidney stone and healthy men were included in the study . Blood was collected in a tube containing 2 % heparin in the morning . Total and free serum testosterone was measured by enzyme linked immunosorbent assay . All patients underwent percutaneous nephrostolithotomy . At the end of the procedure ultrasound guided puncture biopsy was done to acquire kidney tissue . Normal kidney tissue obtained at autopsy served as the control . P10275 was detected in kidney tissue by immunohistochemistry . Stone composition was analyzed in each patient . RESULTS : The study included 37 male patients 22 to 39 years old and 31 healthy men 24 to 37 years old . All calculi were composed of calcium oxalate monohydrate or calcium oxalate dihydrate and a few also contained protein or uric acid . Mean ± SD serum total and free testosterone was 13 . 29 ± 4 . 79 ng / ml and 63 . 23 ± 28 . 58 pg / ml in patients , and 7 . 30 ± 0 . 82 ng / ml and 35 . 59 ± 24 . 91 pg / ml in healthy men , respectively ( each p < 0 . 001 ) . Immunohistochemistry revealed androgen receptor up - regulation in the kidneys of patients with nephrolithiasis . CONCLUSIONS : Our data suggest the important role of enhanced androgen signaling in human nephrolithiasis .","Sex steroid regulation of chin - marking behavior in male New Zealand rabbits . Chin - marking behavior ( chinning ) was evaluated daily in nine intact adult male rabbits . All subjects ( Ss ) displayed chinning ( mean of means +/- SE = 61 +/- 7 marks / 10 min ) but the frequency of this behavior varied largely across them ( range of mean chinning frequency = 19 - 84 marks / 10 min ) . Chinning frequency showed abrupt variations at intervals of 2 - 3 days , but periodogram analysis did not reveal the existence of an endogenous rhythm in this behavior . Castration significantly decreased ( mean of means +/- SE = 29 +/- 9 marks / 10 min ; p < 0 . 01 ) . but did not suppress chinning . DB00624 propionate ( TP ; 1 mg / day for 16 days ) restored chinning in castrated Ss to slightly below precastration levels ( mean +/- S . E . V 53 +/- 13 marks / 10 min ) . The daily administration of 1 microgram estradiol benzoate ( EB ) plus 1 mg dihydrotestosterone propionate ( DHTP ) stimulated chinning within 2 days ( mean increase = 147 % ; p < 0 . 005 ) . DHTP ( 1 mg / day ) given alone stimulated chinning only after 11 days of treatment ( mean increase = 475 % ; p < 0 . 01 ) . At higher doses , both DHTP ( 10 mg / day ) and EB ( 10 or 50 micrograms / day ) stimulated chinning by 450 % , 80 % , and 100 % , respectively , over baseline values . Results indicate that chinning largely depends on testicular steroids . P10275 occupation by T or DB02901 , which is enhanced by E , optimally activates chinning .","A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK98___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .","Regulation of androgen receptor mRNA in rat Sertoli and peritubular cells . Regulation of 9 . 5 - kb androgen receptor mRNA concentrations in Sertoli and peritubular cells from 20 - day - old rats was studied by Northern blot analysis . Treatment of cells in vitro for 1 - 7 days with 300 ng / ml DB00094 increased androgen receptor mRNA up to 4 - fold in Sertoli cells but not in peritubular cells . DB00624 ( 100 ng / ml ) had no effect or slightly decreased androgen receptor mRNA in Sertoli and peritubular cells . P10275 mRNA concentrations in Sertoli and peritubular cells from rats killed 15 days after hypophysectomy were elevated 4 - 5 - fold over those in cells from intact rats . The androgen receptor mRNA concentration was decreased in both Sertoli and peritubular cells isolated from hypophysectomized animals treated with 500 micrograms / day testosterone propionate in vivo and subsequently with 100 ng / ml testosterone in vitro . DB00094 treatment ( 100 micrograms / day in vivo , followed by 300 ng / ml in vitro ) did not increase androgen receptor mRNA over that in cells from hypophysectomized controls but rather decreased its concentration to varying degrees in Sertoli and peritubular cells . The rise in androgen receptor mRNA in both Sertoli and peritubular cells isolated from hypophysectomized animals is attributable , at least in part , to the absence of the inhibitory influence of testosterone . Other data in the literature suggest positive regulation of Sertoli cell androgen receptor protein by DB00094 and androgens . Consequently , complex mechanisms involving transcriptional , translational , and post - translational regulation probably control androgen receptor concentrations in the cells of the rat seminiferous tubule .","Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males ."],"string":"[\n \"P10275 targets NFkappaB and TSP1 to suppress prostate tumor growth in vivo . The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions . While androgen ablation drives the regression of normal and cancerous prostate , testosterone may cause both proliferation and apoptosis . Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor ( AR ) , however no mechanistic explanation was offered . In this paper we demonstrate in vivo anti - tumor effect of the AR on prostate cancer growth and identify its molecular mediators . We analyzed the effect of AR on the tumorigenicity of prostate cancer cells . Unexpectedly , the AR - expressing cells formed tumors in male mice at a much lower rate than the AR - negative controls . Moreover , the AR - expressing tumors showed decreased vascularity and massive apoptosis . AR expression lowered the angiogenic potential of cancer cells , by increasing secretion of an anti - angiogenic protein , thrombospondin - 1 . AR activation caused a decrease in RelA , a subunit of the pro - survival transcription factor NFkappaB , reduced its nuclear localization and transcriptional activity . This , in turn , diminished the expression of its anti - apoptotic targets , Bcl - 2 and P05231 . Increased apoptosis within AR - expressing tumors was likely due to the NFkappaB suppression , since it was restricted to the cells lacking nuclear ( active ) NFkappaB . Thus we for the first time identified combined decrease of NFkappaB and increased TSP1 as molecular events underlying the AR anti - tumor activity in vivo . Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal , a standard treatment for early - stage prostate cancer . ( c ) 2007 Wiley - Liss , Inc .\",\n \"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK42___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK42___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .\",\n \"P10275 in nuclei of rat testis . Testis nuclei of hypophysectomized rats selectively accumulate labeled testosterone and 5alpha - dihydrotestosterone following the injection of tritiated testosterone in vivo . DB00624 and 5alpha - dihydrotestosterone are bound to macromolecules in nuclei and can be extracted with 0 . 5 M DB00761 . Accumulation of protein bound radioactive androgens in nuclei of isolated seminiferous tubules is similar to that of whole testis . The relative amounts of testosterone and dihydrotestosterone in purified nuclei were similar to the relative amounts bound to cytoplasmic receptors , suggesting that cytoplasmic androgen - receptor complexes may be transported into the nuclei . Binding of labeled androgen is saturable and inhibited by prior injection of unlabeled testosterone or cyproterone acetate . Nuclear binding sites are destroyed by the proteolytic enzyme pronase , but not by DNase . Like the cytoplasmic androgen - receptor complexes in rat testis , nuclear androgen - protein complexes are heat labile and dissociate slowly at 0 degrees C . androgens fail to accumulate in testis nuclei of the Stanley - Gumbreck androgen insensitive rat , a species lacking cytoplasmic androgen receptors in testis and other androgen target tissues .\",\n \"The androgen axis in recurrent prostate cancer . PURPOSE : Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen - independent . High levels of expression of androgen receptor and androgen receptor - regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence . EXPERIMENTAL DESIGN : Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied . P10275 expression was measured using monoclonal antibody and automated digital video image analysis . Tissue androgens were measured using radioimmunoassay . RESULTS : Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer ( mean optical density , 0 . 284 +/- SD 0 . 115 and percentage positive nuclei , 83 . 7 +/- 11 . 6 ) was similar to benign prostate ( mean optical density , 0 . 315 +/- 0 . 044 and percentage positive nuclei , 77 . 3 +/- 13 . 0 ) . Tissue levels of testosterone were similar in recurrent prostate cancer ( 2 . 78 +/- 2 . 34 pmol / g tissue ) and benign prostate ( 3 . 26 +/- 2 . 66 pmol / g tissue ) . Tissue levels of dihydrotestosterone , dehydroepiandrosterone , and androstenedione were lower ( Wilcoxon , P = 0 . 0000068 , 0 . 00093 , and 0 . 0089 , respectively ) in recurrent prostate cancer than in benign prostate , and mean dihydrotestosterone levels , although reduced , remained 1 . 45 nM . P10275 activation in recurrent prostate cancer was suggested by the androgen - regulated gene product , prostate - specific antigen , at 8 . 80 +/- 10 . 80 nmol / g tissue . CONCLUSIONS : DB00624 and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor . Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue .\",\n \"DB00624 stimulates proliferation and inhibits interleukin - 6 production of normal and hereditary gingival fibromatosis fibroblasts . Hereditary gingival fibromatosis ( P14210 ) is a rare oral condition characterized by a slow and progressive enlargement of the gingiva , involving both the maxilla and mandible . In vitro , P14210 fibroblasts demonstrate a proliferative index significantly higher than fibroblasts from normal gingiva ( NG ) . The objective of this study was to determine the effect of dihydrotestosterone on the proliferation of gingival fibroblasts derived from patients with P14210 ( n = 4 ) and from four healthy individuals . Additionally , we analyzed the effect of dihydrotestosterone on interleukin - 6 ( P05231 ) production and determined the expression levels of androgen receptors in NG and P14210 fibroblasts . Gingival fibroblasts from NG and P14210 were incubated with increasing concentrations of dihydrotestosterone with or without androgen blockers , and cultured for 24 h , and the proliferation index was determined by automated cell counter . P05231 production , in this system , was quantified using a \\\" capture \\\" enzyme - linked immunosorbent assay ( ELISA ) . Semi - quantitative reverse transcriptase - polymerase chain reaction ( RT - PCR ) was performed to measure the mRNA expression of androgen receptors . The results indicated that dihydrotestosterone simultaneously downregulates the production of P05231 and upregulates the cell proliferation . DB01216 and cyprosterone acetate , two anti - androgens , partially reversed these effects . P10275 mRNA expression was identified in both NG and P14210 fibroblasts ; however , the levels in NG were higher than those observed in P14210 . These results show that testosterone coordinates the proliferation and production of P05231 of normal and P14210 fibroblasts .\",\n \"___MASK10___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK10___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK10___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK10___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .\",\n \"Increased dihydrotestosterone receptor levels in high - stage renal adenocarcinoma . Primary renal adenocarcinoma tissue , metastatic deposits , and normal kidney parenchyma from 16 patients were assayed for sex hormone receptors by dextran - coated charcoal adsorption and sucrose gradient centrifugation techniques . DB02901 receptors ( P10275 ) were found in all renal carcinomatous tissue ( 20 / 20 ) and in 93 % ( 13 / 14 ) autologous normal kidneys analyzed . DB00624 receptors were found in 84 % ( 16 / 19 ) of tumors and 93 % ( 14 / 15 ) or normal kidneys analyzed . Estrogen receptors in small amounts ( ER ) were detected in only 5 % ( 1 / 19 ) of tumors and in 7 % ( 1 / 15 ) of normal kidneys . Progesterone receptors ( PR ) in low quantities were detected in 30 % ( 6 / 20 ) of renal tumors and in 40 % ( 6 / 15 ) of normal kidneys . P10275 levels in high - stage tumors ( DB00279 , DB00451 ) were significantly elevated over levels in autologous normal kidney , whereas in low - stage tumors localized to the kidney ( T1 and P24752 tumors ) P10275 levels were not significantly different from autologous normal kidney . The mean levels of P10275 in high - stage kidney tumors were significantly elevated over levels in low - stage tumors ( P less than 0 . 001 ) . P10275 estimation in renal neoplasms may help in biologic staging of renal adenocarcinoma and could define a group of patients in whom anti - androgen therapy may be worth a trial .\",\n \"Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1 / 2 pluripotent cells through an androgen receptor - mediated pathway . DB00624 supplementation increases skeletal muscle mass and decreases fat mass ; however , the underlying mechanisms are unknown . We hypothesized that testosterone regulates body composition by promoting the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage . Mouse C3H 10T1 / 2 pluripotent cells were treated with testosterone ( 0 - 300 nM ) or dihydrotestosterone ( DB02901 , 0 - 30 nM ) for 0 - 14 d , and myogenic conversion was evaluated by immunocytochemical staining for early ( MyoD ) and late ( myosin heavy chain II ; MHC ) myogenic markers and by measurements of MyoD and MHC mRNA and protein . Adipogenic differentiation was assessed by adipocyte counting and by measurements of peroxisomal proliferator - activated receptor gamma 2 ( Q07869 gamma 2 ) mRNA and Q07869 gamma 2 protein and CCAAT / enhancer binding protein alpha . The number of MyoD + myogenic cells and MHC + myotubes and MyoD and MHC mRNA and protein levels increased dose dependently in response to testosterone and DB02901 treatment . Both testosterone and DB02901 decreased the number of adipocytes and down - regulated the expression of Q07869 gamma 2 mRNA and Q07869 gamma 2 protein and CCAAT / enhancer binding protein alpha . P10275 mRNA and protein levels were low at baseline but increased after testosterone or DB02901 treatment . The effects of testosterone and DB02901 on myogenesis and adipogenesis were blocked by bicalutamide . Therefore , testosterone and DB02901 regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor - mediated pathway . The observation that differentiation of pluripotent cells is androgen dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men .\",\n \"Serum testosterone plays an important role in the metastatic ability of castration resistant prostate cancer . PURPOSE : Prostate cells are dependent on androgens for growth and proliferation . Androgen deprivation therapy is the recommended treatment for advanced / metastatic prostate cancer . Under this therapy , prostate cancer will inevitably progress to castration resistant prostate cancer ( CRPC ) . Despite putative castration resistance , testosterone might still play a crucial role in the progression of CRPC . The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings . METHODS : In vitro , the effect of testosterone and the non - aromatizable androgen methyltrienolone on migration , invasion and proliferation of a castration - resistant prostate cancer rat cell line ( Dunning R3327 - MATLyLu ) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67 . P10275 status was determined using Western blot . In vivo , Copenhagen rats were divided in four groups ( males , females , castrated males and females with testosterone suppletion ) and inoculated with MATLyLu cells . Tumor size was assessed daily . RESULTS : DB00624 increased cell migration and invasion in a concentration - dependent manner in vitro . DB00624 did not affect in vitro cell proliferation . No difference was shown between the effect of testosterone and methyltrienolone . In vivo , in groups with higher levels of circulating testosterone , more rats had ( micro ) metastases compared with groups with low levels of testosterone . No effect was observed on primary tumor size / growth . CONCLUSIONS : Despite assumed castration resistance , progression of prostate cancer is still influenced by androgens . Therefore , continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted .\",\n \"P10275 is responsible for rat organic cation transporter 2 gene regulation but not for rOCT1 and rOCT3 . PURPOSE : Organic cation transporters 1 - 3 ( OCT1 - 3 ; Slc22a1 - 3 ) mediate the membrane transport of organic cations in the kidney . We previously reported that rat ( r ) OCT2 expression in the kidney was regulated by testosterone . In this study , we examined the transcriptional mechanisms underlying the testosterone - dependent regulation of rOCT2 expression . METHODS : Approximately 3000 - bp fragments of the rOCT1 - 3 promoter region were isolated , and promoter activities were measured in the renal epithelial cell line LLC - P30613 with the coexpression of rat androgen receptor . RESULTS : Among reporter constructs tested , only rOCT2 promoter activity was stimulated by testosterone . This stimulation was suppressed by nilutamide , an antiandrogen drug . Reporter assays using deletion constructs and mutational constructs of putative androgen response elements ( ARE ) in the rOCT2 promoter region suggested that two AREs , located at approximately - 3000 and - 1300 , respectively , play an important role in the induction by testosterone . CONCLUSIONS : DB00624 induces the expression of rOCT2 , but not of rOCT1 and rOCT3 , via the AR - mediated transcriptional pathway . This is the first study to address the transcriptional mechanisms of testosterone - dependent gene regulation of the Slc22 family .\",\n \"Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK10___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK10___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK10___ .\",\n \"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK20___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .\",\n \"Functional analysis of discoidin domain receptor 2 in synovial fibroblasts in rheumatoid arthritis . In order to know whether any protein tyrosine kinase ( PTK ) is involved in the over - proliferation and erosiveness of synovial fibroblasts ( SF ) of rheumatoid arthritis ( RA ) patients , RT - PCR and RNA dot blotting were done to analyse PTKs profile in RA SF . Platelet - derived growth factor receptor A ( P16234 ) , insulin - like growth factor 1 receptor ( IGF - 1R ) , P23458 ( P23458 ) , P29597 , discoidin domain receptor 2 ( Q16832 ) , and Lyn were expressed in SF , and the expression of P16234 , IGF - 1R , and Q16832 in SF of RA were higher than that of osteoarthritis ( OA , as control ) . Immunoblotting and gelatinase zymography showed that Q16832 in RA SF , which still secreted active matrix metalloproteinase 1 ( P03956 ) in vitro , were in active form . Stimulation of collagen II could make NIH - 3T3 cells ( as control ) produce P03956 , which could be inhibited by soluble extracellular part of Q16832 . These results indicated that the over - expression of P03956 in RA SF might be related to the activation of Q16832 , and collagen II , act as Q16832 ligand , might be one of the stimulators of the over - expression of P03956 of RA SF .\",\n \"Broadening of transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model to represent late stage androgen depletion independent cancer . BACKGROUND : The transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model closely mimics PC - progression as it occurs in humans . However , the timing of disease incidence and progression ( especially late stage ) makes it logistically difficult to conduct experiments synchronously and economically . The development and characterization of androgen depletion independent ( ADI ) TRAMP sublines are reported . METHODS : Sublines were derived from androgen - sensitive TRAMP - C1 and TRAMP - P06681 cell lines by androgen deprivation in vitro and in vivo . Epithelial origin ( cytokeratin ) and expression of late stage biomarkers ( P12830 and KAI - 1 ) were evaluated using immunohistochemistry . P10275 ( AR ) status was assessed through quantitative real time PCR , Western blotting , and immunohistochemistry . Coexpression of AR and P12830 was also evaluated . Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays . Proliferation / survival of sublines in response to androgen was assessed by WST - 1 assay . In vivo growth of subcutaneous tumors was assessed in castrated and sham - castrated C57BL / 6 mice . RESULTS : The sublines were epithelial and displayed ADI in vitro and in vivo . Compared to the parental lines , these showed ( 1 ) significantly faster growth rates in vitro and in vivo independent of androgen depletion , ( 2 ) greater tumorigenic , and invasive potential in vitro . All showed substantial downregulation in expression levels of tumor suppressor , P12830 , and metastatis suppressor , KAI - 1 . Interestingly , the percentage of cells expressing AR with downregulated P12830 was higher in ADI cells , suggesting a possible interaction between the two pathways . CONCLUSIONS : The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness .\",\n \"P10275 - immunoreactive cells in ram hypothalamus : distribution and co - localization patterns with gonadotropin - releasing hormone , somatostatin and tyrosine hydroxylase . DB00624 exerts important feedback effects on the hypothalamus of the ram to influence reproductive functioning . To provide a neuroanatomical basis for understanding this androgen action , the present study has examined androgen receptor ( AR ) immunoreactivity within the hypothalamus and adjacent brain areas of the intact non - breeding season ram . The largest populations of AR - immunoreactive cells were detected in the medial preoptic area , infundibular and premammillary nuclei in addition to the ventromedial nucleus ( VMN ) where cells were found distributed throughout its medial and lateral divisions . Smaller numbers of AR - expressing cells were identified in the bed nucleus of the stria terminalis and anterior hypothalamic area ( DB00551 ) including the paraventricular , but not the supraoptic , nucleus . Double - labelling immunocytochemistry revealed the presence of AR immunoreactivity in only 2 of 460 gonadotropin - releasing hormone ( DB00644 ) neurons . A very small population of TH - immunoreactive cells located in the lateral aspect of the DB00551 was found to contain ARs . Dopaminergic cells elsewhere in the hypothalamus , including the infundibular nucleus , did not display AR immunoreactivity . Nearly 50 % of AR - expressing cells in the lateral VMN were immunoreactive for somatostatin while less than 5 % of periventricular somatostatin neurons displayed AR immunoreactivity . These results show where ARs are expressed in the ram hypothalamus and indicate the neuroanatomical sites at which androgen may act to influence reproductive function . The absence of ARs in the neuroendocrine DB00644 and tuberoinfundibular dopaminergic cells suggests that androgens do not influence the genome of these cells in any direct manner . In contrast , the somatostatin neurons of the VMN appear to be an important target for circulating androgens in the non - breeding season ram .\",\n \"P10275 in human placental villi . In studies with a synthetic androgen , R 1881 , an androgen - binding component was found in the cytosol of human placental villi . Kinetic analysis indicated that the Kd value of this component was 1 . 4 nM at 0 - 4 degrees C and that binding of R 1881 amounted to 277 +/- 73 fmol / mg protein . glycerol density gradient ultracentrifugation showed a peak of binding activity in the 8S region in a medium of low ionic strength , but in the 4 . 5S region in a medium containing 9 . 5 M DB00761 . The R 1881 - binding component was inactivated by mild heat - or trypsin - treatment , but not by treatment with DNase or RNase . Most of the R 1881 - binding activity was sedimented at 20 to 40 % saturation of ammonium sulfate . These findings indicate that the R 1881 - binding component in human placental cytosol is quite similar in its characteristics to androgen receptors , which are present in various androgen - responsive organs . DB00624 was a more potent competitor of R 1881 - binding than DB02901 or cyproterone acetate . Scatchard plots indicated that the binding site of testosterone was identical with that of R 1881 . These findings suggest that the androgen receptor in placental cytosol is specific for testosterone . The Kd value for testosterone was calculated to be 3 . 2 nM .\",\n \"Androgens and metabolic syndrome : lessons from androgen receptor knock out ( ARKO ) mice . DB00624 ( T ) is an important factor for determining body composition in males . Abdominal obesity is inversely correlated with serum T levels in men , leading to greater mortality . Pathologically hypogonadal men also have a significantly higher fat mass , which is reversed by T administration . However , the mechanism for such anti - obesity effect of androgen has not been well clarified . P10275 ( AR ) null male mice revealed late - onset obesity . Male ARKO mice were euphagic compared to the wild - type male controls , but also less dynamic and less oxygen consuming . Transcript profiling indicated that male ARKO mice had lower transcripts for the thermogenetic uncoupling protein 1 ( P25874 ) . We also found enhanced secretion of adiponectin , which is insulin - sensitizing , from adipose tissue in comparison to wild type , which might partly explain why the overall insulin sensitivity of male ARKO mice remained almost intact despite their apparent obesity . In addition , decreased lipolysis rather than increased lipid synthesis was observed , which might also account for the increased adiposity in male ARKO mice . The results revealed that AR plays important roles in male metabolism by affecting the energy balance , and is negative to both adiposity and insulin sensitivity .\",\n \"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .\",\n \"DB00624 potentiates the hypoxic ventilatory response of adult male rats subjected to neonatal stress . Neonatal stress disrupts development of homeostatic systems . During adulthood , male rats subjected to neonatal maternal separation ( Q5H8A3 ) are hypertensive and show a larger hypoxic ventilatory response ( HVR ) , with greater respiratory instability during sleep . Neonatal stress also affects sex hormone secretion ; hypoxia increases circulating testosterone of Q5H8A3 ( but not control ) male rats . Given that these effects of Q5H8A3 are not observed in females , we tested the hypothesis that testosterone elevation is necessary for the stress - related increase of the HVR in adult male rats . Pups subjected to Q5H8A3 were placed in an incubator for 3 h per day from postnatal day 3 to 12 . Control pups remained undisturbed . Rats were reared until adulthood , and the HVR was measured by plethysmography ( fractional inspired O2 = 0 . 12 , for 20 min ) . We used gonadectomy to evaluate the effects of reducing testosterone on the HVR . Gonadectomy had no effect on the HVR of control animals but reduced that of Q5H8A3 animals below control levels . Immunohistochemistry was used to quantify androgen receptors in brainstem areas involved in the HVR . P10275 expression was generally greater in Q5H8A3 rats than in control rats ; the most significant increase was noted in the caudal region of the nucleus tractus solitarii . We conclude that the abnormal regulation of testosterone is important in stress - related augmentation of the HVR . The greater number of androgen receptors within the brainstem may explain why Q5H8A3 rats are more sensitive to testosterone withdrawal . Based on the similarities of the cardiorespiratory phenotype of Q5H8A3 rats and patients suffering from sleep - disordered breathing , these results provide new insight into its pathophysiology , especially sex - based differences in its prevalence .\",\n \"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK61___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .\",\n \"Pubertal maturation is associated with an increase in the number of androgen receptor - immunoreactive cells in the brains of male ferrets . P10275 - immunoreactive ( AR - IR ) cells were identified in brains of male ferrets before and after the onset of pubertal maturation . There was a greater number of AR - IR cells after the onset of pubertal maturation in some , but not all , brain regions examined . Regions in which the number of AR - IR cells increased included the preoptic area and the amygdala , areas known to be involved in the control of male reproductive behaviors . The mechanisms responsible for the increase in AR - IR cells are unknown , but might be related to the higher circulating levels of testosterone that were present in the older animals . DB00624 may increase androgen receptor ( AR ) immunoreactivity both by concentrating already existing ARs within the nucleus and by stimulating de novo synthesis of receptor protein .\",\n \"Androgen Receptor Enhances p27 Degradation in Prostate Cancer Cells through Rapid and Selective Q53ET0 Activation . P10275 ( AR ) plays a central role in prostate cancer ( PCa ) growth , with androgen deprivation or AR down - regulation causing cell - cycle arrest and accumulation of the p27 cyclin - dependent kinase inhibitor . The molecular basis for this AR regulation of cell - cycle progression remains unclear . Here we demonstrate that androgen can rapidly reduce p27 protein in PCa cells by increasing its proteasome - mediated degradation . This rapid androgen - stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157 . Significantly , androgen increased Q53ET0 - mediated AKT S473 phosphorylation without affecting the PDK1 - mediated AKT T308 phosphorylation or Q6UUV9 activity . The Q53ET0 activation was further supported by enhanced P42345 / Q6R327 association and increased phosphorylation of additional Q53ET0 substrates , O00141 and PKCα . The androgen - stimulated nuclear translocation of AR was associated with markedly - increased nuclear Q9BPZ7 , a critical component of Q53ET0 . Finally , the androgen - mediated Q53ET0 / AKT activation targets a subset of AKT substrates including p27 and Q12778 , but not Q96B36 . This study reveals a pathway linking AR to a selective activation of Q53ET0 , the subsequent activation of AKT , and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival . These findings establish that Q53ET0 can function as a central regulator of growth in response to signals that are distinct from those regulating Q6UUV9 , and support efforts to target Q53ET0 for cancer therapy .\",\n \"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .\",\n \"DB00624 inhibits matrix metalloproteinase - 1 production in human endometrial stromal cells in vitro . P10275 ( AR ) is reported to be expressed in human uterine endometrium , but not much information is available on the role of androgens in human endometrium . The purpose of this study is to investigate the role of androgens in the regulation of matrix metalloproteinase ( MMP ) - 1 , which is one of the important MMPs for menstruation and embryo implantation in human endometrium . Human endometrial stromal cells ( HESCs ) were obtained from human endometrium by enzymatic dissociation method . Purified HESCs were incubated with 17beta - estradiol ( E2 ) , testosterone , or E2 + testosterone . Progestins ( natural progesterone or medroxyprogesterone acetate ) or vehicle ( dimethyl sulfoxide ) were also added to the media instead of testosterone . Furthermore , hydroxyflutamide ( FLU ), a specific AR antagonist , was also supplemented to cultured media . The amounts of P03956 in cultured media and in HESC lysates were examined by ELISA measurements and western blotting analysis respectively . The expression of ARmRNA in HESCs RNA was analyzed by RT - PCR . DB00624 significantly inhibited P03956 in both cultured media and cell lysates in a dose - dependent manner . Progestins also inhibited P03956 . Furthermore , FLU completely recovered the decrease of P03956 induced by testosterone . ARmRNA was detected in all HESCs RNA . The present study demonstrated that the secretion and production of P03956 in HESCs in vitro were inhibited by testosterone through androgen receptors in a manner similar to that seen for progesterone . These findings indicate that androgen may play an important role in morphological and functional changes of human endometrium .\",\n \"P10275 dependent and independent activities of testosterone on hepatic microsomal drug metabolism . Administration of testosterone for 6 days to intact female and castrate male BALB / cJ mice stimulated hepatic microsomal ethylmorphine N - demethylase activity and cytochrome P - 450 content by 50 - 75 % . DB00624 also stimulated hepatic microsomal NADPH - oxidase activity , but to a lesser degree . To probe the mechanism of this effect of androgens , two antiandrogens ( cyproterone acetate and flutamide ) were employed . Since cyproterone acetate was a potent stimulator of hepatic microsomal ethylmorphine N - demethylase activity and cytochrome P - 450 content , no antiandrogenic activity of this steroid could be detected . By contrast , flutamide alone had little effect on either ethylmorphine N - demethylase activity or cytochrome P - 450 content . However , this drug effectively blocked the stimulatory effects of testosterone on ethylmorphine N - demethylase activity and cytochrome P - 450 content but not on NADPH - oxidase activity . This effect was not species specific , since flutamide also prevented androgen stimulation of ethylmorphine metabolism in adult castrate and prepubertal male Fisher rats . The testosterone - induced increase of hepatic weight and microsomal protein content was not affected by the administration of flutamide . The observations are consistent with the hypothesis that androgens have two distinct effects on the liver . First , testosterone may act as a general , nonspecific stimulant of liver weight and microsomal protein content which is independent of the androgen receptor . Secondly , testosterone action in the liver may be expressed via an androgen - specific or androgen receptor - dependent mechanism which controls , in part , the cytochrome P - 450 - dependent demethylase system .\",\n \"P10275 signaling induced by supraphysiological doses of dihydrotestosterone in human peripheral blood lymphocytes . Anabolic androgenic steroids , a class of steroid hormones related to testosterone , are natural ligands of androgen receptor ( AR ) , a member of the nuclear receptor superfamily of ligand - activated transcription factors . AR binds specific DNA elements , known as androgen - response elements . DB00624 , the main male sexual hormone , binds AR directly and indirectly , through conversion into dihydrotestosterone ( DB02901 ) , its more active metabolite . Anabolic androgenic steroids are frequently detected in the urine of doped athletes ; their consumption is also growing among sport amateurs and adolescents . The effects of androgens can differ depending on the target cells and / or tissues . To gain insight into transcription activation mechanisms of AR , we investigated AR protein signaling in human peripheral blood lymphocytes treated with supraphysiological doses of DB02901 . We performed a comparative proteomic analysis and we identified about 30 differentially expressed proteins . At least five species contained a consensus androgen - response elements sequence in the promoter region of related coding genes . The analysis also revealed that high doses of DB02901 activate the drug detoxification process , could stimulate an increase in cell motility and exert a prosurvival effect rather than an apoptotic one .\",\n \"Altered levels of angiopoietin 1 and tie 2 are associated with androgen - regulated vascular regression and growth in the ventral prostate in adult mice and rats . The involution of the rat ventral prostate gland after castration could be caused by primary changes in the vasculature . To explore the mechanisms , we studied the effects of castration and testosterone treatment on the vasculature in the ventral prostate in adult rats and mice . P10275 expression , vascular morphology , and the expression of angiopoietin ( ang ) 1 and 2 and their receptor tie 2 were examined 1 , 3 , and 7 d after castration and after testosterone treatment of castrated animals using stereological methods , immunohistochemistry , laser capture microdissection , and Western blotting . One day after castration , the percentage of blood vessels covered with smooth muscle actin , endothelial cell proliferation , and vascular volume had decreased , whereas endothelial cell apoptosis had increased . Simultaneously , ang 1 and tie 2 protein levels decreased . Nuclear expression of androgen receptor was observed not only in glandular and stroma smooth muscle cells but also in the mural cells of prostate arteries and veins and was markedly down - regulated already 1 d after castration . DB00624 administration of castrated mice and rats reversed all the observed effects . At the mRNA level , tie 2 was exclusively , but ang 1 predominantly , expressed in the stroma , compared with the epithelial compartment . Local delivery of soluble tie 2 during testosterone - stimulated growth , inhibited vascular maturation and increased vascular volume and leukocyte infiltration compared with controls . We conclude that androgens may regulate the prostate vasculature by direct effects on mural vascular cells and by influencing the secretion of the angiopoietins , in above all , the stroma cells .\",\n \"P10275 in Sertoli cells is not required for testosterone - induced suppression of spermatogenesis , but contributes to Sertoli cell organization in Utp14b jsd mice . DB00624 acting through the androgen receptor ( AR ) maintains the arrest of spermatogonial differentiation in juvenile spermatogonial depletion ( jsd mutation in the Utp14b gene ) mutant adult male mice . It is not known which of the somatic cell types expressing AR mediates this inhibition . To determine whether Sertoli cells are responsible , we selectively eliminated AR in Sertoli cells in jsd mice containing a floxed - Ar gene and an anti - Müllerian hormone - Cre transgene . In these Sertoli AR - knockout ( SCARKO ) - jsd mice , spermatogonial differentiation did not recover . However , the normal organization of Sertoli cell nuclei was drastically disrupted in SCARKO - jsd mice compared with SCARKO or jsd mice . In addition , the extent of ectoplasmic specializations was reduced ; tight junctions were not found ; vinculin , an anchoring protein found in ectoplasmic specializations , became uniformly distributed in the cytoplasm ; and the adult Sertoli cells showed excess heterochromatin subjacent to their nuclear envelope . Despite the abnormalities in Sertoli cells in SCARKO - jsd mice , global suppression of testosterone action and levels was still effective in restoring the differentiated germ cells , and this was accompanied by an improved arrangement of Sertoli cell nuclei . We conclude that Sertoli cells are not targets for the testosterone - mediated inhibition of spermatogonial differentiation in jsd mice , and that both AR in Sertoli cells and the presence of differentiated germ cells contribute to maintaining the organization of Sertoli cells within the seminiferous tubules .\",\n \"P10275 ( CAG ) n polymorphism and androgen levels in women with systemic lupus erythematosus and healthy controls . Systemic lupus erythematosus ( SLE ) is an autoimmune disorder that affects mainly females . Therefore , interrelations between the reproductive and immune system have been assumed . Considering the complex influence of hormones and receptors , we aimed to investigate the influence of androgens and androgen receptor ( AR ) polymorphism in women with SLE . One hundred and sixteen patients and 44 healthy women were investigated . DB00624 , sex hormone - binding globulin ( P04278 ) , dehydroepiandrosterone - sulphate ( DHEAS ) concentrations and AR ( CAG ) n polymorphism were determined . SLE patients had significantly lower levels of total and free testosterone and DHEAS in comparison with the controls . No differences in the CAG repeat length between the groups were established . Women with two alleles carrying more than 22 CAG repeats had significantly higher levels of P04278 ( 101 . 51 ± 61 . 81 vs . 69 . 22 ± 45 . 93 nmol / l , p = 0 . 015 ) and DHEAS ( 3 . 11 ± 2 . 65 vs . 2 . 11 ± 3 . 06 μmol / l , p = 0 . 007 ) and a tendency to higher testosterone concentrations ( 2 . 35 ± 2 . 10 vs . 1 . 71 ± 1 . 70 nmol / l , p = 0 . 056 ) in comparison with other women . The CAG repeat length in the relatively longer ( CAG ) n allele was inversely related to the Systemic Lupus International Collaborating Clinics / P10323 index ( r = - 0 . 258 , p = 0 . 009 ) . In conclusion , the androgen receptor ( CAG ) n polymorphism is not related to the development of SLE , but it could modulate the severity of the lupus chronic damages as well as the androgen levels in women .\",\n \"P10275 in human skin cytosol . Human skin , an accessible tissue , is an androgen target organ . We have measured the androgen - binding capacity of human skin cytosol using either 5 alpha [ 3H ] dihydrotestosterone ( [ 3H ] DB02901 ) or [ 3H ] methyltrienolone ( [ 3H ] R - 1881 ) as ligand . Samples were incubated for 20 h at 0 C , and dextran - coated charcoal was used to separate bound from free steroids . The androgen receptor has a high affinity for both ligands ( 0 . 23 +/- 0 . 04 nM for [ 3H ] DB02901 ; 0 . 32 +/- 0 . 16 nM for [ 3H ] R - 1881 ) . DB00624 , cyproterone acetate , and , to a lesser extent , estradiol also bind this protein . Progesterone displaces R - 1881 from its binding sites , whereas its 5 alpha - reduced metabolite somewhat inhibits DB02901 binding . The highest binding capacity is measured in cytosol of skin from external genitalia ( 129 . 14 +/- 58 . 0 fmol / g skin ; n = 34 ) ; it is lower in pubic skin ( 21 . 8 +/- 13 fmol / g skin ; n = 6 ) . There is no variation as a function of age or sex in genital skin ; the higher concentrations observed in the cytosol of pubic skin of women compared to that of men are probably related to lower levels of endogenous steroids . Whereas most patients with the complete form of the testicular feminization syndrome do not have detectable concentrations of androgen receptor , one patient with apparent complete clinical androgen insensitivity had a normal androgen - binding capacity . The parity of values in genital skin from men and women , the absence of variation with age , and the presence of a cytosolic androgen receptor in some androgen - insensitive patients suggest that the androgen receptor in human skin cytosol is not regulated by androgens .\",\n \"Androgen receptors . DB00624 and its active metabolite dihydrotestosterone exert their influence on target cells through a specific intracellular protein receptor . Structural abnormalities of this receptor lead to a diminished androgen action within the cell and result in the syndrome of androgen insensitivity . Androgen insensitivity is classified on the basis of whether the insensitivity is complete or partial and whether the androgen receptor is normally present ( AR (+) ) , absent ( AR (-) ) or diminished ( AR (+/-) ) . All patients with androgen insensitivity have normal or high plasma levels of testosterone and elevated serum LH . Patients with complete androgen insensitivity are phenotypically female . The clinical presentation of partial androgen insensitivity is variable , ranging from a minimal amount of virilization to a completely masculine appearance . All patients described with a syndrome of androgen insensitivity are infertile . The influence of androgen receptor function in the pathogenesis of benign prostatic hypertrophy is being investigated . P10275 content is also being studied as a possible marker of responsiveness to hormonal therapy in prostatic carcinoma .\",\n \"P10275 is essential for sexual differentiation of responses to olfactory cues in mice . During sexual differentiation males and females are exposed to different levels of testosterone , which promotes sex differences in the adult brain and in behavior . DB00624 can act after aromatization or reduction via a number of steroid hormone receptors . Here we provide new evidence that the androgen receptor ( AR ) is essential for sexual differentiation in mice . We used mice carrying the testicular feminization ( Tfm ) mutation of the AR . Adult Tfm males , wild - type male and female littermates were gonadectomized and given subcutaneous estradiol implants . In all sexually dimorphic traits , Tfm males had responses equivalent to females and different from males . In simultaneous choice tests , males spent significantly more time investigating female - soiled bedding , whereas females and Tfm males preferred to investigate male - soiled bedding . Tfm males and females did not have a partner preference in tests with awake stimulus animals , whereas males showed a preference for females over males . Exposure to male - soiled , but not clean , bedding produced a significant increase in c - Fos - immunoreactive cells in the medial preoptic area and bed nucleus of the stria terminalis in Tfm males and females , no increase was noted in males . Masculine sexual behavior ( mounting and thrusting ) was not sexually dimorphic , and all groups displayed these behaviors . Our results support data collected in humans suggesting a role for the androgen receptor in sexual differentiation of social preferences and neural responses to pheromones .\",\n \"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK1___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK1___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .\",\n \"In utero and lactational exposure to 2 , 3 , 7 , 8 - tetrachlorodibenzo - p - dioxin alters postnatal development of seminal vesicle epithelium . 2 , 3 , 7 , 8 - Tetrachlorodibenzo - p - dioxin ( TCDD ) has been shown to alter male reproductive development of laboratory animals through in utero and lactational exposure . As a result of exposure , the accessory glands of the male reproductive tract , including the seminal vesicle , are decreased in size as determined by total weight of the tissue . Analysis of seminal vesicle weights over time suggests that the changes may be transient . Administration of 1 . 0 microg / kg TCDD during gestation caused a significant decrease in seminal vesicle weights of offspring 8 - 11 months of age . We examined the effects of TCDD on seminal vesicles from rats exposed in utero and lactationally . Pregnant Long Evans rats were gavaged on gestation day 15 with 1 . 0 microg / kg TCDD in corn oil . Male pups were euthanized and necropsied on postnatal days ( P01160 ) 15 , 25 , 32 , 49 , 63 , and 120 . Seminal vesicles were weighed and then fixed in 10 % neutral buffered formalin and processed for microscopic examination . Seminal vesicle weights were not significantly decreased until P01160 32 . P10275 mRNA expression in P01160 25 seminal vesicles was not different from control . In the present study , TCDD exposure decreased seminal vesicle epithelial branching and differentiation . Control epithelial cells had tall columnar morphology with relatively abundant cytoplasm , whereas TCDD - treated cells had rounded nuclei and less cytoplasm . In addition , immunolocalization of proliferating nuclear antigen was confined to undifferentiated basal epithelial cells of controls but was found in both basal and luminal cells of the treated seminal vesicle . Results indicate that the TCDD - induced impaired growth of the rat seminal vesicles is associated with a dramatic decrease in the development of the epithelium .\",\n \"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .\",\n \"p62 links β - adrenergic input to mitochondrial function and thermogenesis . The scaffold protein p62 ( sequestosome 1 ; Q13501 ) is an emerging key molecular link among the metabolic , immune , and proliferative processes of the cell . Here , we report that adipocyte - specific , but not CNS - , liver - , muscle - , or myeloid - specific p62 - deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis . Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue ( Q14032 ) . Accordingly , adipocyte - specific p62 deficiency led to impaired mitochondrial function , causing Q14032 to become unresponsive to β - adrenergic stimuli . Ablation of p62 leads to decreased activation of p38 targets , affecting signaling molecules that control mitochondrial function , such as P15336 , CREB , PGC1α , Q92813 , NRF1 , CYTC , P35354 , ATP5β , and P25874 . p62 ablation in HIB1B and Q14032 primary cells demonstrated that p62 controls thermogenesis in a cell - autonomous manner , independently of brown adipocyte development or differentiation . Together , our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis .\",\n \"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK16___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .\",\n \"P10275 promotes the migration and invasion of upper urinary tract urothelial carcinoma cells through the upregulation of P14780 and P35354 . Dysregulated androgen receptor ( AR ) signaling is implicated in several types of tumor , including carcinomas of the prostate , breast , liver and bladder . However , the contribution of AR to the progression of upper urinary tract urothelial carcinomas ( UUTUC ) has not been fully investigated . In the present study , we demonstrated that the AR is involved in the metastasis and invasiveness of UUTUC cells . We investigated the role of the AR in UUTUC by using UUTUC - derived BFTC 909 cells . The overexpression of AR promotes the migration and invasion of BFTC 909 cells . Expression of migration / invasion - related genes was increased in BFTC 909 cells overexpressing AR determined by qPCR and western blot analyses . The results showed that AR - enhanced migration and invasion of UUTUC cells are linked to the upregulation of the matrix - degrading enzyme P14780 and cyclooxygenase ( P36551 ) - 2 . Subsequently , the blocking of P14780 and P35354 signaling by inhibitors suppressed AR - enhanced cell migration and invasion . The results of the present study provide evidence for the first time of the role of AR in the motility and invasion of UUT cancer cells and support the hypothesis that the AR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia of UUT . Thus , the AR may also serve as a novel biomarker and potential therapeutic target for UUT cancer .\",\n \"D - DB00128 implication in the modulation of frog brain sex steroid levels . There is evidence that D - aspartate ( D - DB00128 ) modulates sex hormone levels in frog testis by regulating the activity of P450 aromatase ( P450 aro ) , the key enzyme which converts DB00624 ( T ) in 17ß - Estradiol ( E2 ) . Here we report , for the first time , that there is a direct correlation among brain levels of D - DB00128 , P450 aro , E2 and Estradiol Receptor ( ERα ) in the male frogs during the reproductive as well as the post - reproductive phases of the breeding cycle , with highest levels being observed in the post - reproductive period . D - DB00128 i . p . administration to frogs ready for reproduction , induced an increase of brain P450 aro protein expression with concomitant enhancement of both E2 levels and ERα expression ; at the same time , brain T levels and P10275 expression decreased . In contrast , in the post - reproductive frogs , D - DB00128 treatment did not modify any of these parameters . Taken together , these results imply that the regulation of P450 aro expression by D - DB00128 could be an important step in the control of E2 levels in the frog brain .\",\n \"Androgen action . Androgens are important for male sex development and physiology . Their actions are mediated by the androgen receptor ( AR ) , a ligand - dependent nuclear transcription factor . The activity of the AR is controlled at multiple stages due to ligand binding and induced structural changes assisted by the foldosome , compartmentalization , recruitment of coregulators , posttranslational modifications and chromatin remodeling , leading to subsequent transcription of androgen - responsive target genes . Beside these short - term androgen actions , there is phenomenological and experimental evidence of long - term androgen programming in mammals and in the human during sensitive programming time windows , both pre - and postnatally . At the molecular level , research into androgen insensitivity syndrome has unmasked androgen programming at the transcriptome level , in genital fibroblasts and peripheral blood mononuclear cells , and at the epigenome level . Androgens are crucial for male sex development and physiology during embryogenesis , at puberty and in adult life . DB00624 and its more potent metabolite , dihydrotestosterone , which is converted from testosterone within the target cell by 5α - reductase II , are the main androgens involved in male sex differentiation . Androgen action is mediated by a single AR . The AR belongs to the nuclear receptor 3 group C , composed of the glucocorticoid receptor ( P04150 ) , mineralocorticoid receptor ( P08235 ) , progesterone receptor ( P06401 ) and AR ( P10275 ) , and acts as a ligand - dependent transcription factor .\",\n \"___MASK23___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK23___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK23___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK23___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .\",\n \"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .\",\n \"Protection of lung epithelial cells from protease - mediated injury by trappin - 2 A62L , an engineered inhibitor of neutrophil serine proteases . Neutrophil serine proteases ( NSPs ) , including elastase , proteinase 3 and cathepsin G , play critical roles in the pathogenesis of chronic inflammatory lung diseases . The release of excess NSPs leads to the destruction of lung tissue and an overexuberant , sustained inflammatory response . Antiproteases could be valuable tools for controlling these NSP - mediated inflammatory events . We have examined the capacity of trappin - 2 A62L , a potent engineered inhibitor of all three NSPs , to protect human lung A549 epithelial cells from the deleterious effects of NSPs . Trappin - 2 A62L , significantly inhibited the detachment of A549 cells and the degradation of the tight - junction proteins , P12830 , β - catenin and ZO - 1 , induced by each individual NSP and by activated neutrophils . Trappin - 2 A62L also decreased the release of the pro - inflammatory cytokines P05231 and P10145 from A549 cells that had been stimulated with elastase or LPS . Trappin - 2 A62D / M63L , a trappin - 2 variant that has no antiprotease activity , has similar properties , suggesting that the anti - inflammatory action of trappin - 2 is independent of its antiprotease activity . Interestingly , we present evidence that trappin - 2 A62L , as well as wild - type trappin - 2 , enter A549 cells and move rapidly to the cytoplasm and nucleus , where they are likely to exert their anti - inflammatory effects . We have also demonstrated that trappin - 2 A62L inhibits the early apoptosis of A549 cells mediated by NSPs . Thus , our data indicate that trappin - 2 A62L is a powerful anti - protease and anti - inflammatory agent that could be used to develop a treatment for patients with inflammatory lung diseases .\",\n \"Recent androgen receptor antagonists in prostate cancer . P10275 has been shown to promote prostate cell growth and carcinogenesis of prostate cancer by up - regulating its target genes . DB00624 and dihydrotestosterone are two major hormones which bind to and activate androgen receptor . Targeting both the androgen receptor and the enzymes catalyzing the biosynthesis of testosterone and dihydrotestosterone has been shown to be clinically beneficial in the treatment of prostate cancer . Prostate cancer can become castration - resistant after long term treatment with chemo drugs , so efforts in finding compounds with improved efficiency to castration - resistant prostate cancer are urgently needed . In this review we summarized the studies on recent progress in the development of small molecular AR antagonists for the treatment of prostate cancer .\",\n \"P10275 is widely expressed in bovine placentomes and up - regulated during differentiation of bovine trophoblast giant cells . OBJECTIVES : In cattle no biological role has been definitely identified for placental estrogens and progesterone . However , in the bovine trophoblast androgens may also be produced and have local effects . Thus , the aims of this study were to identify androgen receptor ( AR ) expressing cells and to monitor testosterone tissue concentrations in bovine placentomes throughout gestation . METHODS : Placental AR expression was characterized at the mRNA and protein level applying conventional and real - time RT - qPCR , western blot and immunohistochemistry . DB00624 was measured by radioimmunoassay . RESULTS : AR - mRNA was qualitatively detected from day 50 of gestation until term . Mean relative gene expression levels were constant between day 100 and late gestation . A slight non - significant increase was observed in the prepartal period . With immunohistochemistry distinct nuclear signals were predominantly observed in invasive trophoblast giant cells ( P21980 ) from day 80 until term . In mature P21980 of the trophoblast , immature P21980 and uninucleated trophoblast cells , stromal cells of the chorionic villi , caruncular epithelial and stromal cells immunoreactive score values were low at early and midgestation but increased significantly ( p < 0 . 01 ) during late gestation and remained high until parturition . With western blot in placentomal tissue a specific band of approximately 110 kDa was detected as it was the case in epididymis used as a positive control . DB00624 concentrations increased from 0 . 70 ± 0 . 29 pmol / g wet tissue between days 60 - 220 to 4 . 22 ± 1 . 29 pmol / g during late gestation ( p < 0 . 001 ) . DISCUSSION : The results are consistent with androgens as active products of bovine placental steroidogenesis . The substantial up - regulation of AR expression during P21980 differentiation suggests that androgens may be related to this process .\",\n \"Gene expression in sexually dimorphic muscles in sheep . DB00624 is known to act differentially on skeletal muscle from different regions of the body . Two genes likely to mediate the testosterone effect are insulin - like growth factor I ( P05019 ) , an important growth regulator acting in an autocrine and paracrine way , and androgen receptor ( AR ) , because receptor density could account for differential muscle growth . Another muscle - specific gene that may play a role in differential muscle growth is myostatin , a member of the transforming growth factor - beta superfamily , shown to be a negative regulator of skeletal muscle mass . The objective of this study was to quantify and compare the steady state expression of these three genes in two different skeletal muscles in sheep . Eleven Dorset rams were slaughtered after reaching puberty and total RNA was extracted from samples of semitendinosus and splenius muscles . P05019 mRNA was measured using a competitive reverse - transcription - polymerase chain reaction . P10275 and myostatin mRNA were measured by a ribonuclease protection assay ( RPA ) with standard curves . The means ( attomoles / microg RNA ) for splenius and semitendinosus muscles were 1 . 39 and 1 . 02 ( SE = 0 . 14 ) , 4 . 05 and 2 . 96 ( SE = 0 . 24 ) , and 4 . 30 and 3 . 85 ( SE = 0 . 37 ) for P05019 , AR , and myostatin , respectively . The difference between the two muscles was significant for P05019 and AR mRNA levels with higher levels in the splenius but not significant for myostatin . Our results show that locally produced P05019 and the regulation of AR expression may be important for sexually dimorphic muscle growth patterns .\",\n \"Axotomy transiently down - regulates androgen receptors in motoneurons of the spinal nucleus of the bulbocavernosus . DB00624 is an important trophic factor for motoneurons in the spinal nucleus of the bulbocavernosus ( SNB ) , and SNB motoneurons are more responsive to testosterone than are other motoneurons . Axonal injury during early postnatal life prevents the normal development of steroid - sensitivity by adult SNB motoneurons . Axonal injury also causes changes in the expression by motoneurons of a wide range of proteins , including the up - regulation of trophic factor receptors . We have used a polyclonal antibody ( PG - 21 ; G . S . Prins ) to study the expression of androgen receptors in SNB motoneurons after axonal injury . PG - 21 labeled motoneuronal nuclei in the lower lumbar spinal cord of rats in a pattern that matched autoradiographic reports of androgen accumulation in this region of the nervous system . A population of numerous , small cells located dorsal to the central canal also showed evidence of androgen receptor expression . Cutting the axons of SNB motoneurons in adulthood or in development caused a decrease in androgen receptor immunoreactivity in SNB motoneurons . This is the first report that a trophic factor receptor in motoneurons is down - regulated after axonal injury , and is interesting in light of reports that testosterone treatment can facilitate motoneuronal regeneration after nerve cut . P10275 levels subsequently returned to normal , regardless of the age at axotomy , providing no evidence for a lasting effect of developmental axotomy on androgen receptor levels in SNB motoneurons . Thus , axotomy - induced down - regulation of androgen receptors does not underlie the inability of SNB motoneurons to respond to androgen treatment several months after pudendal nerve cut in development .\",\n \"Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF - IGFBP axis . The IGF axis is critical for the regulation of apoptosis in many human cancer cell lines . Recently , potent anti - tumorigenic effects of pomegranate juice and extracts have been reported . Consequently , pomegranate has potential not only as a treatment but also as a preventative measure against certain types of cancer , including prostate . In this study , we investigated the relationship between pomegranate - induced apoptosis in human prostate cancer cells and the IGF / IGFBP system . Treatment of LAPC4 prostate cancer cells with 10microg / ml POMx , a highly potent pomegranate extract prepared from skin and arils minus seeds and standardized to ellagitannin content ( 37 % punicalagins by HPLC ) , resulted in inhibition of cell proliferation and induction of apoptosis . Interestingly , co - treatment with POMx and P17936 revealed synergistic stimulation of apoptosis and additive inhibition of cell growth . Western blot analysis revealed that treatment with POMx or POMx / P17936 combination resulted in increased JNK phosphorylation , and decreased Akt and P42345 activation , consistent with a growth inhibitory , pro - apoptotic function . We also investigated the relationship between DB01277 and pomegranate - induced apoptosis in 22RV1 prostate cancer cells . Co - treatment with 100ng / ml DB01277 completely blocked apoptosis induction by POMx . In contrast , P05019 failed to inhibit POMx - induced apoptosis in R (-) cells , suggesting the importance of IGF - IR . POMx - treatment decreased Igf1 mRNA expression in a dose - dependent manner indicating that its actions also involve tumor - specific suppression of DB01277 . These studies revealed novel interactions between the IGF system and pomegranate - induced apoptosis .\",\n \"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK75___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .\",\n \"The androgen receptor : a mediator of diverse responses . Androgens mediate a number of diverse responses through the androgen receptor , a 110 kD ligand - activated nuclear receptor . P10275 expression , which is found in a variety of tissues , changes throughout development , aging , and malignant transformation . The androgen receptor can be activated by two ligands , testosterone and dihydrotestosterone , which bind to the androgen receptor with different affinities . This difference in binding affinity results in different levels of activation of the androgen receptor by the two ligands . The androgen receptor acts as a transcriptional modifier of a variety of genes by binding to an androgen response element . The ability to confer androgen specific actions by the androgen response element may depend on other cell - specific transcription factors and cis - acting DNA elements in close proximity to it . DB00624 and dihydrotestosterone appear to act upon an identical nuclear receptor . However , in certain instances , they mediate different physiologic responses . For example , dihydrotestosterone , but not testosterone , is capable of mediating full sexual development of the male external genitalia . In some cases , the androgen receptor may induce opposite physiologic responses in similar tissue types depending on their location . For example , in male pattern baldness , activated androgen receptors may suppress the growth of distinct hair follicle populations through initiating stromal - epithelial actions , whereas other hair follicles continue to proliferate . In other cases , altered androgen receptor activity due to its mutation or altered expression may lead to pathology such as recurrence of prostate cancer due to development of androgen independence allowing tumor cell proliferation under androgen deprivation .\",\n \"Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824 . P10275 plays a critical role in the development of primary as well as advanced hormone - refractory prostate cancer . Therefore , ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgen - dependent prostate cancer but also for metastatic hormone - refractory prostate cancer , for which there is no effective treatment available . We report here that LAQ824 , a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials , effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations . LAQ824 seemed capable of depleting both the mutant and wild - type androgen receptors in either androgen - dependent and androgen - independent prostate cancer cells . Although LAQ824 may exert its effect through multiple mechanisms , several lines of evidence suggest that inactivation of the heat shock protein - 90 ( Hsp90 ) molecular chaperone is involved in LAQ824 - induced androgen receptor depletion . Besides androgen receptor , LAQ824 reduced the level of Hsp90 client proteins HER - 2 ( ErbB2 ) , Akt / P31749 , and P04049 in LNCaP cells . Another Hsp90 inhibitor , 17 - allyamino - 17 - demethoxygeldanamycin ( 17 - P29372 ) , also induced androgen receptor diminution . LAQ824 induced Hsp90 acetylation in LNCaP cells , which resulted in inhibition of its DB00171 - binding activity , dissociation of Hsp90 - androgen receptor complex , and proteasome - mediated degradation of androgen receptor . Consequently , LAQ824 blocked androgen - induced prostate - specific antigen production in LNCaP cells . LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells . These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer .\",\n \"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .\",\n \"[ Monoamine imbalance of the central nervous system in a case of Shy - Drager syndrome with recurrent attacks of a neuroleptic malignant syndrome ] . A 79 - year - old male suffering from Shy - Drager syndrome was treated with a daily dosage of 300 mg of L - threo - 3 , 4 - dihydroxyphenylserine ( DB06262 ) . He developed a neuroleptic malignant syndrome ( Q5H8A3 ) like state 1 month after teh initiation of DB06262 therapy . And recurrent attacks of Q5H8A3 occurred subsequently despite discontinuation of DB06262 administration . We measured homovanillic acid ( HVA ) , 3 methoxy 4 hydroxyphenylethylenglycol ( MHPG ) , and 5 - hydroxyindoleacetic acid ( 5 - HIAA ) in this corrected brospinal fluid ( P04141 ) , both during his 2 attacks of Q5H8A3 and after recovery . The HVA and 5 HIAA levels after recovery were low compared with those in age - matched normal controls . However , his levels in the active phase were not different from those after recovery . In contrast , MHPG levels were elevated and his HVA / MHPG ratios decreased in the active phase compared with those in the recovery phase . The results indicate that his symptoms of Q5H8A3 are attributed to the imbalance between dopamine and noradrenalin rather than the dopamine receptor blockade in the central nervous system . We suggest further evaluations of P04141 monoamine metabolites in similar cases to determine the pathogenesis of Q5H8A3 .\",\n \"P10275 - dependent transactivation of growth arrest - specific gene 6 mediates inhibitory effects of testosterone on vascular calcification . Recent epidemiological studies have found that androgen deficiency is associated with a higher incidence of cardiovascular disease in men . However , little is known about the mechanism underlying the cardioprotective effects of androgens . Here we show the inhibitory effects of testosterone on vascular calcification and a critical role of androgen receptor ( AR ) - dependent transactivation of growth arrest - specific gene 6 ( Gas6 ) , a key regulator of inorganic phosphate ( P ( i ) ) - induced calcification of vascular smooth muscle cells ( VSMC ) . DB00624 and nonaromatizable androgen dihydrotestosterone inhibited P ( i )- induced calcification of human aortic VSMC in a concentration - dependent manner . Androgen inhibited P ( i )- induced VSMC apoptosis , an essential process for VSMC calcification . The effects on VSMC calcification were mediated by restoration of P ( i )- induced down - regulation of Gas6 expression and a subsequent reduction of Akt phosphorylation . These effects of androgen were blocked by an AR antagonist , flutamide , but not by an estrogen receptor antagonist , DB00947 . We then explored the mechanistic role of the AR in Gas6 expression and found an abundant expression of AR predominantly in the nucleus of VSMC and two consensus ARE sequences in the Gas6 promoter region . DB02901 stimulated Gas6 promoter activity , and this effect was abrogated by flutamide and by AR siRNA . Site - specific mutation revealed that the proximal ARE was essential for androgen - dependent transactivation of Gas6 . Furthermore , chromatin immunoprecipitation assays demonstrated ligand - dependent binding of the AR to the proximal ARE of Gas6 . These results indicate that AR signaling directly regulates Gas6 transcription , which leads to inhibition of vascular calcification , and provides a mechanistic insight into the cardioprotective action of androgens .\",\n \"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( DB02901 ) in castrated male and female mice subjected to DB02901 replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by DB02901 in mice CPs .\",\n \"DB00624 and androgen receptor in human nephrolithiasis . PURPOSE : We investigated the relationship of kidney calculi with plasma free and total testosterone , and androgen receptor up - regulation in the kidneys of men with nephrolithiasis . MATERIALS AND METHODS : Male patients with kidney stone and healthy men were included in the study . Blood was collected in a tube containing 2 % heparin in the morning . Total and free serum testosterone was measured by enzyme linked immunosorbent assay . All patients underwent percutaneous nephrostolithotomy . At the end of the procedure ultrasound guided puncture biopsy was done to acquire kidney tissue . Normal kidney tissue obtained at autopsy served as the control . P10275 was detected in kidney tissue by immunohistochemistry . Stone composition was analyzed in each patient . RESULTS : The study included 37 male patients 22 to 39 years old and 31 healthy men 24 to 37 years old . All calculi were composed of calcium oxalate monohydrate or calcium oxalate dihydrate and a few also contained protein or uric acid . Mean ± SD serum total and free testosterone was 13 . 29 ± 4 . 79 ng / ml and 63 . 23 ± 28 . 58 pg / ml in patients , and 7 . 30 ± 0 . 82 ng / ml and 35 . 59 ± 24 . 91 pg / ml in healthy men , respectively ( each p < 0 . 001 ) . Immunohistochemistry revealed androgen receptor up - regulation in the kidneys of patients with nephrolithiasis . CONCLUSIONS : Our data suggest the important role of enhanced androgen signaling in human nephrolithiasis .\",\n \"Sex steroid regulation of chin - marking behavior in male New Zealand rabbits . Chin - marking behavior ( chinning ) was evaluated daily in nine intact adult male rabbits . All subjects ( Ss ) displayed chinning ( mean of means +/- SE = 61 +/- 7 marks / 10 min ) but the frequency of this behavior varied largely across them ( range of mean chinning frequency = 19 - 84 marks / 10 min ) . Chinning frequency showed abrupt variations at intervals of 2 - 3 days , but periodogram analysis did not reveal the existence of an endogenous rhythm in this behavior . Castration significantly decreased ( mean of means +/- SE = 29 +/- 9 marks / 10 min ; p < 0 . 01 ) . but did not suppress chinning . DB00624 propionate ( TP ; 1 mg / day for 16 days ) restored chinning in castrated Ss to slightly below precastration levels ( mean +/- S . E . V 53 +/- 13 marks / 10 min ) . The daily administration of 1 microgram estradiol benzoate ( EB ) plus 1 mg dihydrotestosterone propionate ( DHTP ) stimulated chinning within 2 days ( mean increase = 147 % ; p < 0 . 005 ) . DHTP ( 1 mg / day ) given alone stimulated chinning only after 11 days of treatment ( mean increase = 475 % ; p < 0 . 01 ) . At higher doses , both DHTP ( 10 mg / day ) and EB ( 10 or 50 micrograms / day ) stimulated chinning by 450 % , 80 % , and 100 % , respectively , over baseline values . Results indicate that chinning largely depends on testicular steroids . P10275 occupation by T or DB02901 , which is enhanced by E , optimally activates chinning .\",\n \"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK98___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .\",\n \"Regulation of androgen receptor mRNA in rat Sertoli and peritubular cells . Regulation of 9 . 5 - kb androgen receptor mRNA concentrations in Sertoli and peritubular cells from 20 - day - old rats was studied by Northern blot analysis . Treatment of cells in vitro for 1 - 7 days with 300 ng / ml DB00094 increased androgen receptor mRNA up to 4 - fold in Sertoli cells but not in peritubular cells . DB00624 ( 100 ng / ml ) had no effect or slightly decreased androgen receptor mRNA in Sertoli and peritubular cells . P10275 mRNA concentrations in Sertoli and peritubular cells from rats killed 15 days after hypophysectomy were elevated 4 - 5 - fold over those in cells from intact rats . The androgen receptor mRNA concentration was decreased in both Sertoli and peritubular cells isolated from hypophysectomized animals treated with 500 micrograms / day testosterone propionate in vivo and subsequently with 100 ng / ml testosterone in vitro . DB00094 treatment ( 100 micrograms / day in vivo , followed by 300 ng / ml in vitro ) did not increase androgen receptor mRNA over that in cells from hypophysectomized controls but rather decreased its concentration to varying degrees in Sertoli and peritubular cells . The rise in androgen receptor mRNA in both Sertoli and peritubular cells isolated from hypophysectomized animals is attributable , at least in part , to the absence of the inhibitory influence of testosterone . Other data in the literature suggest positive regulation of Sertoli cell androgen receptor protein by DB00094 and androgens . Consequently , complex mechanisms involving transcriptional , translational , and post - translational regulation probably control androgen receptor concentrations in the cells of the rat seminiferous tubule .\",\n \"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .\"\n]"},"candidates":{"kind":"list like","value":["___MASK10___","___MASK16___","___MASK1___","___MASK20___","___MASK23___","___MASK42___","___MASK61___","___MASK75___","___MASK98___"],"string":"[\n \"___MASK10___\",\n \"___MASK16___\",\n \"___MASK1___\",\n \"___MASK20___\",\n \"___MASK23___\",\n \"___MASK42___\",\n \"___MASK61___\",\n \"___MASK75___\",\n \"___MASK98___\"\n]"},"answer":{"kind":"string","value":"___MASK98___"},"id":{"kind":"string","value":"MH_train_484"}}},{"rowIdx":485,"cells":{"query":{"kind":"string","value":"interacts_with DB00814?"},"supports":{"kind":"list like","value":["Antiinflammatory and neurological activity of pyrithione and related sulfur - containing pyridine N - oxides from Persian shallot ( Allium stipitatum ) . ETHNOPHARMACOLOGICAL RELEVANCE : Persian shallot ( Allium stipitatum ) is a bulbous plant native to Turkey , Iran and Central Asia . It is frequently used in folk medicine for the treatment of a variety of disorders , including inflammation and stress . Antiinflammatory and neurological activities of pyrithione and four related sulfur - containing pyridine N - oxides which are prominent constituents of Allium stipitatum were tested . METHODS : The antiinflammatory activity was tested by the ability of the compounds to inhibit cyclooxygenase ( P23219 and P35354 ) , whereas the neurological activities were evaluated by assessing the compounds ability to inhibit monoamine oxidase - A ( P21397 ) and acetylcholinesterase ( P22303 ) . The compounds ׳ affinity for the serotonin transport protein ( P31645 ) and the GABAA - benzodiazepine receptor were also investigated . RESULTS : 2 -[( Methylthio ) methyldithio ] pyridine N - oxide showed very high antiinflammatory effects which are comparable with those of common pharmaceuticals ( IC₅₀ of 7 . 8 and 15 . 4 µM for P23219 and P35354 , respectively ) . On the other hand , neurological activities of the compounds were rather modest . Some compounds moderately inhibited P22303 ( IC₅₀ of 104 - 1041 µM ) and P21397 ( IC₅₀ of 98 - 241 µM ) and exhibited an affinity for the P31645 and GABAA - benzodiazepine receptor . CONCLUSIONS : Our findings may help to rationalize the wide use of Persian shallot for the treatment of inflammatory disorders .","Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .","P35354 induction and prostaglandin E2 accumulation in squamous cell carcinoma as a consequence of epidermal growth factor receptor activation by imatinib mesylate . Imatinib mesylate is a novel anti - tumor agent useful in the clinical management of chronic myelogenous leukemia and gastrointestinal stromal tumors with minimal toxicity relative to other forms of cancer therapy . Its clinical activity and minimal toxicity are related to specific inhibition of cellular targets including P11274 - P00519 , platelet - derived growth factor receptor and c - kit kinases , resulting in the collapse of downstream signaling cascades important for transformation . In some patients , unexpected toxicities arise that are not associated with inhibition of any known cellular imatinib target . In this report , we investigated the effects of imatinib on squamous carcinoma cell signaling . Imatinib induced expression of P35354 in a dose - dependent manner with concomitant accumulation of prostaglandin E2 . P35354 induction by imatinib was initiated through epidermal growth factor ( P01133 ) receptor kinase activation and downstream signaling through mitogenic - activated protein kinase . P35354 induction by imatinib was blocked by Q02750 or P01133 receptor inhibition . Imatinib did not activate stressor cytokine - signaling pathways ( p38 kinase , nuclear factor - kB nuclear translocation ) or affect P23219 expression . Imatinib failed to activate P01133 receptor signals in other tumor types , suggesting that P35354 induction in imatinib - treated cells is mediated through release of autocrine factors expressed or activated in squamous tumors . P35354 induction by imatinib in squamous tumors derived from the head and neck region is unique with respect to other target - specific agents and may represent one of the unintended toxic effects of imatinib described in some patients .","Effect of cyclooxygenase inhibitors on the P06850 - induced pituitary - adrenocortical activity during crowding stress . The aim of the present study was to determine the effect of social stress and significance of prostaglandins ( PG ) generated by constitutive and inducible cyclooxygenase ( P23219 and P35354 ) in the stimulation of hypothalamic - pituitary - adrenal ( Q9Y251 ) axis by corticotropin releasing hormone ( P06850 ) under basal and social crowding stress conditions . The stressed rats were crowded in groups of 24 to a cage for 3 or 7 days , whereas the control animals were haused in groups of 7 to a cage of the same size . The activity of Q9Y251 axis was determined by measuring plasma DB01285 and serum corticosterone levels 1 h after i . p . P06850 administration . Inhibitors of P23219 , piroxicam ( 0 . 2 , 2 . 0 , and 5 . 0 mg / kg ) , and P35354 , compound NS - 398 ( 0 . 2 and 2 . 0 mg / kg ) , were administered i . p . 15 min prior to P06850 ( 0 . 1 microg / kg i . p . ) to control or crowded rats . The obtained results indicate that social stress for 3 and 7 days markedly intensifies the stimulatory action of P06850 on DB01285 secretion . Neither piroxicam nor NS - 398 induce any significant effect on the P06850 - elicited DB01285 and corticosterone secretion in non - stressed or crowded rats . Therefore , PG generated by P23219 or P35354 do not participate to a significant extent in the stimulation of Q9Y251 axis by P06850 under either basal conditions or during crowding stress . These results also indicate that the stimulatory action of P06850 on DB01285 secretion is not only completely resistant to desensitization but is sensitized during social crowding stress . The results contrast with a significant involvement of PG in the vasopressin - induced stimulation of Q9Y251 response during crowding stress .","Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .","[ ___MASK57___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK57___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .","Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .","DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . DB00563 ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .","Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .","[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK41___ GITS , Diaprel MR ) . One daily dose of ___MASK41___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .","[ Meloxicam ( DB00814 ) : a review of its pharmacological and clinical profile ] . Meloxicam ( DB00814 ) is a new nonsteroidal anti - inflammatory drug ( NSAID ) derived from enolic acid , exhibiting selectivity for cyclooxygenase ( P36551 ) - 2 over P23219 . Meloxicam has shown potent anti - inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models . It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat , but also of bone and cartilage destruction . The therapeutic range of meloxicam in the rat , with regard to inhibition of adjuvant arthritis , was several times greater than that of other NSAIDs . Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers . In clinical studies , meloxicam has shown reliable efficacy against rheumatoid arthritis , osteoarthritis , lumbago ( low back pain ) , scapulohumeral periarthritis , and neck - shoulder - arm syndrome with low gastrointestinal toxicity .","Nuclear factor kappa B inhibition improves conductance artery function in type 2 diabetic mice . BACKGROUND : We previously reported that enhanced nuclear factor kappa B ( NFκB ) activity is responsible for resistance arteries dysfunction in type 2 diabetic mice . METHODS : In this study , we aimed to determine whether augmented NFκB activity also impairs conductance artery ( thoracic aorta ) function in type 2 diabetic mice . We treated type 2 diabetic ( db (-) / db (-) ) and control ( db (-) / db (+) ) mice with two NFκB inhibitors ( dehydroxymethylepoxyquinomicin , 6 mg / kg , twice a week and IKK - NBD peptide , 500 µg / kg / day ) for 4 weeks . RESULTS : As expected , the NFκB inhibition did not affect blood glucose level and body weight . Thoracic aorta vascular endothelium - dependent relaxation ( EDR ) , determined by the wire myograph , was impaired in diabetic mice compared with control and was significantly improved after NFκB inhibition . Interestingly , thoracic EDR was also rescued in db (-) / db (- p50NFκB -/-) and db (-) / db (- P09874 -/-) double knockout mice compared with db (-) / db (-) mice . Similarly , the acute in vitro down regulation of NFκB - p65 using p65 shRNA lentiviral particles in arteries from db (-) / db (-) mice also improved thoracic aorta EDR . Western blot analysis showed that the p65NFκB phosphorylation , cleaved P09874 and P35354 expression were increased in thoracic aorta from diabetic mice , which were restored after NFκB inhibition and in db (-) / db (- p - 50NFκB -/-) and db (-) / db (- P09874 -/-) mice . CONCLUSIONS : The present results indicate that in male type 2 diabetic mice , the augmented NFκB activity also impairs conductance artery function through P09874 and P35354 - dependent mechanisms .","___MASK79___ binding to human and rat dopamine and 5 - HT receptors . ___MASK79___ ( ___MASK79___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK79___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK79___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK79___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .","Poly ( ADP - ribose ) polymerase - 1 is a nuclear epigenetic regulator of mitochondrial DNA repair and transcription . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a NAD - consuming enzyme with an emerging key role in epigenetic regulation of gene transcription . Although P09874 expression is characteristically restricted to the nucleus , a few studies report the mitochondrial localization of the enzyme and its ability to regulate organelle functioning . Here , we show that , despite exclusive nuclear localization of P09874 , mitochondrial homeostasis is compromised in cell lines exposed to P09874 pharmacological inhibitors or small interfering RNA . P09874 suppression reduces integrity of mitochondrial DNA ( mtDNA ) , as well as expression of mitochondria - encoded respiratory complex subunits P23219 , P35354 , and ND - 2 . Accordingly , P09874 localizes at promoters of nuclear genes encoding both the mtDNA repair proteins P13051 , P12882 , and P27695 and the mtDNA transcription factors Q8WVM0 and Q9H5Q4 . It is noteworthy that poly ( ADP - ribosyl ) ation is required for nuclear gene expression of these mitochondrial proteins . Consistent with these findings , P09874 suppression impairs mitochondrial DB00171 production . Our results indicate that P09874 plays a central role in mitochondrial homeostasis by epigenetically regulating nuclear genes involved in mtDNA repair and transcription . These data might have important implications in pharmacology of P09874 inhibitors as well as clinical oncology and aging .","Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK90___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .","DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK41___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .","[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK82___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK82___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .","___MASK97___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .","DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .","miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro . Decidualization is a morphological and biochemical transformation of endometrial stromal fibroblast into differentiated decidual cells , which is critical for embryo implantation and pregnancy establishment . The complex regulatory networks have been elucidated at both the transcriptome and the proteome levels , however very little is known about the post - transcriptional regulation of this process . miRNAs regulate multiple physiological pathways and their de - regulation is associated with human disorders including gynaecological conditions such as endometriosis and preeclampsia . In this study we profile the miRNAs expression throughout human endometrial stromal ( hESCs ) decidualization and analyze the requirement of the miRNA biogenesis enzyme Dicer during this process . A total of 26 miRNAs were upregulated and 17 miRNAs downregulated in decidualized hESCs compared to non - decidualized hESCs . Three miRNAs families , miR - 181 , miR - 183 and miR - 200 , are down - regulated during the decidualization process . Using miRNAs target prediction algorithms we have identified the potential targets and pathways regulated by these miRNAs . The knockdown of Dicer has a minor effect on hESCs during in vitro decidualization . We have analyzed a battery of decidualization markers such as cell morphology , P01236 , P08833 , P55773 and P35625 secretion as well as P31260 , P35354 , SP1 , C / EBPß and Q12778 expression in decidualized hESCs with decreased Dicer function . We found decreased levels of P31260 and altered intracellular organization of actin filaments in Dicer knockdown decidualized hESCs compared to control . Our results provide the miRNA signature of hESC during the decidualization process in vitro . We also provide the first functional characterization of Dicer during human endometrial decidualization although surprisingly we found that Dicer plays a minor role regulating this process suggesting that alternative biogenesis miRNAs pathways must be involved in human endometrial decidualization .","The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK53___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK53___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK53___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK53___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .","Therapeutic targeting of CPT - 11 induced diarrhea : a case for prophylaxis . CPT - 11 ( irinotecan ) , a P11387 inhibitor is one of the main treatments for colorectal cancer . The main dose limiting toxicities are neutropenia and late onset diarrhea . Though neutropenia is manageable , CPT - 11 induced diarrhea is frequently severe , resulting in hospitalizations , dose reductions or omissions leading to ineffective treatment administration . Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT - 11 induced late onset diarrhea . It is predicted that prophylaxis of CPT - 11 induced diarrhea will reduce sub - therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates . This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity . Covered topics include schedule / dose modification , intestinal alkalization , structural / chemical modification , genetic testing , anti - diarrheal therapies , transporter ( P08183 , Q92887 , Q96JK2 ) inhibitors , enzyme ( β - glucuronidase , P22309 , P08684 , carboxylesterase , P35354 ) inducers and inhibitors , probiotics , antibiotics , adsorbing agents , cytokine and growth factor activators and inhibitors and other miscellaneous agents .","Gene - environment interactions in parkinsonism and Parkinson ' s disease : the Geoparkinson study . OBJECTIVES : To investigate associations of Parkinson ' s disease ( PD ) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene - environment interaction effects that modify risk . METHODS : A case - control study of 959 prevalent cases of parkinsonism ( 767 with PD ) and 1989 controls across five European centres . Occupational hygienists estimated the average annual intensity of exposure to solvents , pesticides and metals , ( iron , copper , manganese ) , blind to disease status . P10635 , P27169 , P09488 , P30711 , P21266 , P09211 , P15559 , Q16678 , P21397 , P27338 , SOD 2 , P07099 , Q01959 , P14416 and NAT2 were genotyped . Results were analysed using multiple logistic regression adjusting for key confounders . RESULTS : There was a modest but significant association between P21397 polymorphism in males and disease risk ( G vs T , OR 1 . 30 , 95 % CI 1 . 02 to 1 . 66 , adjusted ) . The majority of gene - environment analyses did not show significant interaction effects . There were possible interaction effects between P09488 null genotype and solvent exposure ( which were stronger when limited to PD cases only ) . CONCLUSIONS : Many small studies have reported associations between genetic polymorphisms and PD . Fewer have examined gene - environment interactions . This large study was sufficiently powered to examine these aspects . P09488 null subjects heavily exposed to solvents appear to be at increased risk of PD . There was insufficient evidence that the other gene - environment combinations investigated modified disease risk , suggesting they contribute little to the burden of PD .","Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK57___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )","Acetylbritannilactone suppresses lipopolysaccharide - induced vascular smooth muscle cell inflammatory response . To investigate the mechanism of action by which a new anti - inflammatory active compound , 1 - O - acetylbritannilactone ( P00519 ) isolated from Inula britannica - F . , inhibits inflammatory responses in vascular smooth muscle cells ( VSMCs ) . Enzyme immunoassay was used to measure the levels of prostandin E ( 2 ) ( PGE ( 2 ) ) production . Immunocytochemistry staining and Western blot analysis were performed to detect the nuclear translocation of nuclear factor - kappaB ( NF - kappaB ) p65 and the expression of IkappaB - alpha , pIkappaB - alpha and cyclooxygenase - 2 ( P35354 ) . Electrophoretic mobility shift assays ( EMSA ) were used to detect DNA - binding activity of NF - kappaB in VSMCs . P00519 ( 5 , 10 , 20 micrommol / l ) had several concentration - dependent effects , including inhibition of lipopolysaccharide ( LPS ) - induced PGE ( 2 ) production and P35354 expression , and blockade of NF - kappaB activation and translocation . These effects were owing to reductions in IkappaB - alpha phosphorylation and degradation induced by LPS . In addition , P00519 directly inhibited the binding of active NF - kappaB to specific DNA cis - element . These results indicate that P00519 is a potent inhibitor of LPS - stimulated VSMC inflammatory responses through blockade of NF - kappaB activity and inhibition of inflammatory gene P35354 expression .","Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK96___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .","Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .","Role of P34969 receptors in the inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats . The role of calcitonin gene - related peptide ( P80511 ) in the modulation of vascular tone has been widely documented . Indeed , electrical stimulation of the perivascular sensory outflow in pithed rats induces vasodepressor responses by activation of P80511 receptors . This study investigated the role of P34969 receptors in the inhibition of the rat vasodepressor sensory outflow . Male Wistar pithed rats were pretreated with i . v . continuous infusions of hexamethonium and methoxamine , followed by physiological saline or AS - 19 ( a P34969 receptor agonist ) . Then , electrical stimulation of the spinal cord resulted in frequency - dependent decreases in DBP . The infusions of AS - 19 , as compared to those of saline , inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i . v . bolus injections of exogenous α - P80511 . This inhibition by AS - 19 was abolished by the antagonists pimozide ( P34969 ) or sulfisoxazole ( P25101 ) , but not by indomethacin ( P23219 / 2 ) or losartan ( AT1 ) , at doses that did not affect per se the electrically - induced vasodepressor responses . Interestingly , glibenclamide ( an DB00171 - dependent K (+) channel blocker ) attenuated these vasodepressor responses . The present results suggest that AS - 19 - induced inhibition of the rat vasodepressor sensory CGRPergic outflow is mainly mediated by P34969 receptors via endothelin release , with the possible involvement of DB00171 - dependent K (+) channels .","Meloxicam . Meloxicam ( DB00814 trade mark , Boehringer Ingelheim ) is a relatively new oral non - steroidal anti - inflammatory drug ( NSAID ) approved for the treatment of osteoarthritis in the US . It has also been evaluated for the treatment of rheumatoid arthritis , ankylosing spondylitis and acute ' rheumatic ' pain . Meloxicam has been shown to be P35354 preferential , particularly at its lowest therapeutic dose , and is anti - inflammatory by inhibiting prostanoid synthesis in inflammatory cells . Since it is P35354 preferential , it would be expected to have less gastrointestinal toxicity than non - selective NSAIDs . In clinical trials of meloxicam in osteoarthritis , it was found to be as effective as piroxicam , diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations , obstructions and bleeds by meta - analysis . Adverse events , including peripheral oedema and hypertension , occurred at a similar rate as with traditional NSAIDs .","5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .","Regulation of P01160 secretion from isolated atria by prostaglandins and cyclooxygenase - 2 . Cyclooxygenase ( P36551 ) is a key enzyme regulating the production of various prostaglandins ( PGs ) from arachidonic acid . Angiotensin II has been reported to be an important inflammatory mediator , which increases P35354 . The aim of this study was to determine the role of various PGs and P35354 in the regulation of atrial natriuretic peptide ( P01160 ) secretion . PGF2alpha and PGD2 caused dose - dependent increases in P01160 release and intra - atrial pressure . The potency for the stimulation of P01160 secretion by PGF2alpha was higher than that by PGD2 . In contrast , DB00917 , DB01240 , PGJ2 , and thromboxane A2 did not show any significant effects . The increases in intra - atrial pressure and P01160 secretion induced by PGF2alpha and PGD2 were significantly attenuated by the pretreatment with an inhibitor of PGF2alpha receptor . By the pretreatment with an inhibitor for phospholipase C ( P98160 ) , inositol 3 - phosphate ( IP3 ) receptor , protein kinase C ( PKC ) , or myosin light chain kinase ( MLCK ) , PGF2alpha - mediated increase in P01160 secretion and positive inotropy were attenuated . Inhibitor for P23219 or P35354 did not cause any significant effects on atrial parameters . In hypertrophied rat atria , PGF2alpha - induced positive inotropy and P01160 secretion were markedly attenuated whereas P35354 inhibitor stimulated P01160 secretion . The expression of P35354 increased and the expression of PGF2alpha receptor mRNA decreased in hypertrophied rat atria . These results suggest that PGF2alpha increased the P01160 secretion and positive inotropy through P98160 - IP3 - PKC - MLCK pathway , and the modulation of P01160 secretion by P35354 inhibitor and PGF2alpha may partly relate to the development of renal hypertension .","[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK44___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect ."],"string":"[\n \"Antiinflammatory and neurological activity of pyrithione and related sulfur - containing pyridine N - oxides from Persian shallot ( Allium stipitatum ) . ETHNOPHARMACOLOGICAL RELEVANCE : Persian shallot ( Allium stipitatum ) is a bulbous plant native to Turkey , Iran and Central Asia . It is frequently used in folk medicine for the treatment of a variety of disorders , including inflammation and stress . Antiinflammatory and neurological activities of pyrithione and four related sulfur - containing pyridine N - oxides which are prominent constituents of Allium stipitatum were tested . METHODS : The antiinflammatory activity was tested by the ability of the compounds to inhibit cyclooxygenase ( P23219 and P35354 ) , whereas the neurological activities were evaluated by assessing the compounds ability to inhibit monoamine oxidase - A ( P21397 ) and acetylcholinesterase ( P22303 ) . The compounds ׳ affinity for the serotonin transport protein ( P31645 ) and the GABAA - benzodiazepine receptor were also investigated . RESULTS : 2 -[( Methylthio ) methyldithio ] pyridine N - oxide showed very high antiinflammatory effects which are comparable with those of common pharmaceuticals ( IC₅₀ of 7 . 8 and 15 . 4 µM for P23219 and P35354 , respectively ) . On the other hand , neurological activities of the compounds were rather modest . Some compounds moderately inhibited P22303 ( IC₅₀ of 104 - 1041 µM ) and P21397 ( IC₅₀ of 98 - 241 µM ) and exhibited an affinity for the P31645 and GABAA - benzodiazepine receptor . CONCLUSIONS : Our findings may help to rationalize the wide use of Persian shallot for the treatment of inflammatory disorders .\",\n \"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .\",\n \"P35354 induction and prostaglandin E2 accumulation in squamous cell carcinoma as a consequence of epidermal growth factor receptor activation by imatinib mesylate . Imatinib mesylate is a novel anti - tumor agent useful in the clinical management of chronic myelogenous leukemia and gastrointestinal stromal tumors with minimal toxicity relative to other forms of cancer therapy . Its clinical activity and minimal toxicity are related to specific inhibition of cellular targets including P11274 - P00519 , platelet - derived growth factor receptor and c - kit kinases , resulting in the collapse of downstream signaling cascades important for transformation . In some patients , unexpected toxicities arise that are not associated with inhibition of any known cellular imatinib target . In this report , we investigated the effects of imatinib on squamous carcinoma cell signaling . Imatinib induced expression of P35354 in a dose - dependent manner with concomitant accumulation of prostaglandin E2 . P35354 induction by imatinib was initiated through epidermal growth factor ( P01133 ) receptor kinase activation and downstream signaling through mitogenic - activated protein kinase . P35354 induction by imatinib was blocked by Q02750 or P01133 receptor inhibition . Imatinib did not activate stressor cytokine - signaling pathways ( p38 kinase , nuclear factor - kB nuclear translocation ) or affect P23219 expression . Imatinib failed to activate P01133 receptor signals in other tumor types , suggesting that P35354 induction in imatinib - treated cells is mediated through release of autocrine factors expressed or activated in squamous tumors . P35354 induction by imatinib in squamous tumors derived from the head and neck region is unique with respect to other target - specific agents and may represent one of the unintended toxic effects of imatinib described in some patients .\",\n \"Effect of cyclooxygenase inhibitors on the P06850 - induced pituitary - adrenocortical activity during crowding stress . The aim of the present study was to determine the effect of social stress and significance of prostaglandins ( PG ) generated by constitutive and inducible cyclooxygenase ( P23219 and P35354 ) in the stimulation of hypothalamic - pituitary - adrenal ( Q9Y251 ) axis by corticotropin releasing hormone ( P06850 ) under basal and social crowding stress conditions . The stressed rats were crowded in groups of 24 to a cage for 3 or 7 days , whereas the control animals were haused in groups of 7 to a cage of the same size . The activity of Q9Y251 axis was determined by measuring plasma DB01285 and serum corticosterone levels 1 h after i . p . P06850 administration . Inhibitors of P23219 , piroxicam ( 0 . 2 , 2 . 0 , and 5 . 0 mg / kg ) , and P35354 , compound NS - 398 ( 0 . 2 and 2 . 0 mg / kg ) , were administered i . p . 15 min prior to P06850 ( 0 . 1 microg / kg i . p . ) to control or crowded rats . The obtained results indicate that social stress for 3 and 7 days markedly intensifies the stimulatory action of P06850 on DB01285 secretion . Neither piroxicam nor NS - 398 induce any significant effect on the P06850 - elicited DB01285 and corticosterone secretion in non - stressed or crowded rats . Therefore , PG generated by P23219 or P35354 do not participate to a significant extent in the stimulation of Q9Y251 axis by P06850 under either basal conditions or during crowding stress . These results also indicate that the stimulatory action of P06850 on DB01285 secretion is not only completely resistant to desensitization but is sensitized during social crowding stress . The results contrast with a significant involvement of PG in the vasopressin - induced stimulation of Q9Y251 response during crowding stress .\",\n \"Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .\",\n \"[ ___MASK57___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK57___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .\",\n \"Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .\",\n \"DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . DB00563 ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .\",\n \"Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .\",\n \"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK41___ GITS , Diaprel MR ) . One daily dose of ___MASK41___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .\",\n \"[ Meloxicam ( DB00814 ) : a review of its pharmacological and clinical profile ] . Meloxicam ( DB00814 ) is a new nonsteroidal anti - inflammatory drug ( NSAID ) derived from enolic acid , exhibiting selectivity for cyclooxygenase ( P36551 ) - 2 over P23219 . Meloxicam has shown potent anti - inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models . It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat , but also of bone and cartilage destruction . The therapeutic range of meloxicam in the rat , with regard to inhibition of adjuvant arthritis , was several times greater than that of other NSAIDs . Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers . In clinical studies , meloxicam has shown reliable efficacy against rheumatoid arthritis , osteoarthritis , lumbago ( low back pain ) , scapulohumeral periarthritis , and neck - shoulder - arm syndrome with low gastrointestinal toxicity .\",\n \"Nuclear factor kappa B inhibition improves conductance artery function in type 2 diabetic mice . BACKGROUND : We previously reported that enhanced nuclear factor kappa B ( NFκB ) activity is responsible for resistance arteries dysfunction in type 2 diabetic mice . METHODS : In this study , we aimed to determine whether augmented NFκB activity also impairs conductance artery ( thoracic aorta ) function in type 2 diabetic mice . We treated type 2 diabetic ( db (-) / db (-) ) and control ( db (-) / db (+) ) mice with two NFκB inhibitors ( dehydroxymethylepoxyquinomicin , 6 mg / kg , twice a week and IKK - NBD peptide , 500 µg / kg / day ) for 4 weeks . RESULTS : As expected , the NFκB inhibition did not affect blood glucose level and body weight . Thoracic aorta vascular endothelium - dependent relaxation ( EDR ) , determined by the wire myograph , was impaired in diabetic mice compared with control and was significantly improved after NFκB inhibition . Interestingly , thoracic EDR was also rescued in db (-) / db (- p50NFκB -/-) and db (-) / db (- P09874 -/-) double knockout mice compared with db (-) / db (-) mice . Similarly , the acute in vitro down regulation of NFκB - p65 using p65 shRNA lentiviral particles in arteries from db (-) / db (-) mice also improved thoracic aorta EDR . Western blot analysis showed that the p65NFκB phosphorylation , cleaved P09874 and P35354 expression were increased in thoracic aorta from diabetic mice , which were restored after NFκB inhibition and in db (-) / db (- p - 50NFκB -/-) and db (-) / db (- P09874 -/-) mice . CONCLUSIONS : The present results indicate that in male type 2 diabetic mice , the augmented NFκB activity also impairs conductance artery function through P09874 and P35354 - dependent mechanisms .\",\n \"___MASK79___ binding to human and rat dopamine and 5 - HT receptors . ___MASK79___ ( ___MASK79___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK79___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK79___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK79___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .\",\n \"Poly ( ADP - ribose ) polymerase - 1 is a nuclear epigenetic regulator of mitochondrial DNA repair and transcription . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a NAD - consuming enzyme with an emerging key role in epigenetic regulation of gene transcription . Although P09874 expression is characteristically restricted to the nucleus , a few studies report the mitochondrial localization of the enzyme and its ability to regulate organelle functioning . Here , we show that , despite exclusive nuclear localization of P09874 , mitochondrial homeostasis is compromised in cell lines exposed to P09874 pharmacological inhibitors or small interfering RNA . P09874 suppression reduces integrity of mitochondrial DNA ( mtDNA ) , as well as expression of mitochondria - encoded respiratory complex subunits P23219 , P35354 , and ND - 2 . Accordingly , P09874 localizes at promoters of nuclear genes encoding both the mtDNA repair proteins P13051 , P12882 , and P27695 and the mtDNA transcription factors Q8WVM0 and Q9H5Q4 . It is noteworthy that poly ( ADP - ribosyl ) ation is required for nuclear gene expression of these mitochondrial proteins . Consistent with these findings , P09874 suppression impairs mitochondrial DB00171 production . Our results indicate that P09874 plays a central role in mitochondrial homeostasis by epigenetically regulating nuclear genes involved in mtDNA repair and transcription . These data might have important implications in pharmacology of P09874 inhibitors as well as clinical oncology and aging .\",\n \"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK90___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .\",\n \"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK41___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .\",\n \"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK82___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK82___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .\",\n \"___MASK97___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .\",\n \"DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .\",\n \"miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro . Decidualization is a morphological and biochemical transformation of endometrial stromal fibroblast into differentiated decidual cells , which is critical for embryo implantation and pregnancy establishment . The complex regulatory networks have been elucidated at both the transcriptome and the proteome levels , however very little is known about the post - transcriptional regulation of this process . miRNAs regulate multiple physiological pathways and their de - regulation is associated with human disorders including gynaecological conditions such as endometriosis and preeclampsia . In this study we profile the miRNAs expression throughout human endometrial stromal ( hESCs ) decidualization and analyze the requirement of the miRNA biogenesis enzyme Dicer during this process . A total of 26 miRNAs were upregulated and 17 miRNAs downregulated in decidualized hESCs compared to non - decidualized hESCs . Three miRNAs families , miR - 181 , miR - 183 and miR - 200 , are down - regulated during the decidualization process . Using miRNAs target prediction algorithms we have identified the potential targets and pathways regulated by these miRNAs . The knockdown of Dicer has a minor effect on hESCs during in vitro decidualization . We have analyzed a battery of decidualization markers such as cell morphology , P01236 , P08833 , P55773 and P35625 secretion as well as P31260 , P35354 , SP1 , C / EBPß and Q12778 expression in decidualized hESCs with decreased Dicer function . We found decreased levels of P31260 and altered intracellular organization of actin filaments in Dicer knockdown decidualized hESCs compared to control . Our results provide the miRNA signature of hESC during the decidualization process in vitro . We also provide the first functional characterization of Dicer during human endometrial decidualization although surprisingly we found that Dicer plays a minor role regulating this process suggesting that alternative biogenesis miRNAs pathways must be involved in human endometrial decidualization .\",\n \"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK53___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK53___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK53___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK53___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .\",\n \"Therapeutic targeting of CPT - 11 induced diarrhea : a case for prophylaxis . CPT - 11 ( irinotecan ) , a P11387 inhibitor is one of the main treatments for colorectal cancer . The main dose limiting toxicities are neutropenia and late onset diarrhea . Though neutropenia is manageable , CPT - 11 induced diarrhea is frequently severe , resulting in hospitalizations , dose reductions or omissions leading to ineffective treatment administration . Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT - 11 induced late onset diarrhea . It is predicted that prophylaxis of CPT - 11 induced diarrhea will reduce sub - therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates . This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity . Covered topics include schedule / dose modification , intestinal alkalization , structural / chemical modification , genetic testing , anti - diarrheal therapies , transporter ( P08183 , Q92887 , Q96JK2 ) inhibitors , enzyme ( β - glucuronidase , P22309 , P08684 , carboxylesterase , P35354 ) inducers and inhibitors , probiotics , antibiotics , adsorbing agents , cytokine and growth factor activators and inhibitors and other miscellaneous agents .\",\n \"Gene - environment interactions in parkinsonism and Parkinson ' s disease : the Geoparkinson study . OBJECTIVES : To investigate associations of Parkinson ' s disease ( PD ) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene - environment interaction effects that modify risk . METHODS : A case - control study of 959 prevalent cases of parkinsonism ( 767 with PD ) and 1989 controls across five European centres . Occupational hygienists estimated the average annual intensity of exposure to solvents , pesticides and metals , ( iron , copper , manganese ) , blind to disease status . P10635 , P27169 , P09488 , P30711 , P21266 , P09211 , P15559 , Q16678 , P21397 , P27338 , SOD 2 , P07099 , Q01959 , P14416 and NAT2 were genotyped . Results were analysed using multiple logistic regression adjusting for key confounders . RESULTS : There was a modest but significant association between P21397 polymorphism in males and disease risk ( G vs T , OR 1 . 30 , 95 % CI 1 . 02 to 1 . 66 , adjusted ) . The majority of gene - environment analyses did not show significant interaction effects . There were possible interaction effects between P09488 null genotype and solvent exposure ( which were stronger when limited to PD cases only ) . CONCLUSIONS : Many small studies have reported associations between genetic polymorphisms and PD . Fewer have examined gene - environment interactions . This large study was sufficiently powered to examine these aspects . P09488 null subjects heavily exposed to solvents appear to be at increased risk of PD . There was insufficient evidence that the other gene - environment combinations investigated modified disease risk , suggesting they contribute little to the burden of PD .\",\n \"Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK57___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Acetylbritannilactone suppresses lipopolysaccharide - induced vascular smooth muscle cell inflammatory response . To investigate the mechanism of action by which a new anti - inflammatory active compound , 1 - O - acetylbritannilactone ( P00519 ) isolated from Inula britannica - F . , inhibits inflammatory responses in vascular smooth muscle cells ( VSMCs ) . Enzyme immunoassay was used to measure the levels of prostandin E ( 2 ) ( PGE ( 2 ) ) production . Immunocytochemistry staining and Western blot analysis were performed to detect the nuclear translocation of nuclear factor - kappaB ( NF - kappaB ) p65 and the expression of IkappaB - alpha , pIkappaB - alpha and cyclooxygenase - 2 ( P35354 ) . Electrophoretic mobility shift assays ( EMSA ) were used to detect DNA - binding activity of NF - kappaB in VSMCs . P00519 ( 5 , 10 , 20 micrommol / l ) had several concentration - dependent effects , including inhibition of lipopolysaccharide ( LPS ) - induced PGE ( 2 ) production and P35354 expression , and blockade of NF - kappaB activation and translocation . These effects were owing to reductions in IkappaB - alpha phosphorylation and degradation induced by LPS . In addition , P00519 directly inhibited the binding of active NF - kappaB to specific DNA cis - element . These results indicate that P00519 is a potent inhibitor of LPS - stimulated VSMC inflammatory responses through blockade of NF - kappaB activity and inhibition of inflammatory gene P35354 expression .\",\n \"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK96___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .\",\n \"Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .\",\n \"Role of P34969 receptors in the inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats . The role of calcitonin gene - related peptide ( P80511 ) in the modulation of vascular tone has been widely documented . Indeed , electrical stimulation of the perivascular sensory outflow in pithed rats induces vasodepressor responses by activation of P80511 receptors . This study investigated the role of P34969 receptors in the inhibition of the rat vasodepressor sensory outflow . Male Wistar pithed rats were pretreated with i . v . continuous infusions of hexamethonium and methoxamine , followed by physiological saline or AS - 19 ( a P34969 receptor agonist ) . Then , electrical stimulation of the spinal cord resulted in frequency - dependent decreases in DBP . The infusions of AS - 19 , as compared to those of saline , inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i . v . bolus injections of exogenous α - P80511 . This inhibition by AS - 19 was abolished by the antagonists pimozide ( P34969 ) or sulfisoxazole ( P25101 ) , but not by indomethacin ( P23219 / 2 ) or losartan ( AT1 ) , at doses that did not affect per se the electrically - induced vasodepressor responses . Interestingly , glibenclamide ( an DB00171 - dependent K (+) channel blocker ) attenuated these vasodepressor responses . The present results suggest that AS - 19 - induced inhibition of the rat vasodepressor sensory CGRPergic outflow is mainly mediated by P34969 receptors via endothelin release , with the possible involvement of DB00171 - dependent K (+) channels .\",\n \"Meloxicam . Meloxicam ( DB00814 trade mark , Boehringer Ingelheim ) is a relatively new oral non - steroidal anti - inflammatory drug ( NSAID ) approved for the treatment of osteoarthritis in the US . It has also been evaluated for the treatment of rheumatoid arthritis , ankylosing spondylitis and acute ' rheumatic ' pain . Meloxicam has been shown to be P35354 preferential , particularly at its lowest therapeutic dose , and is anti - inflammatory by inhibiting prostanoid synthesis in inflammatory cells . Since it is P35354 preferential , it would be expected to have less gastrointestinal toxicity than non - selective NSAIDs . In clinical trials of meloxicam in osteoarthritis , it was found to be as effective as piroxicam , diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations , obstructions and bleeds by meta - analysis . Adverse events , including peripheral oedema and hypertension , occurred at a similar rate as with traditional NSAIDs .\",\n \"5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .\",\n \"Regulation of P01160 secretion from isolated atria by prostaglandins and cyclooxygenase - 2 . Cyclooxygenase ( P36551 ) is a key enzyme regulating the production of various prostaglandins ( PGs ) from arachidonic acid . Angiotensin II has been reported to be an important inflammatory mediator , which increases P35354 . The aim of this study was to determine the role of various PGs and P35354 in the regulation of atrial natriuretic peptide ( P01160 ) secretion . PGF2alpha and PGD2 caused dose - dependent increases in P01160 release and intra - atrial pressure . The potency for the stimulation of P01160 secretion by PGF2alpha was higher than that by PGD2 . In contrast , DB00917 , DB01240 , PGJ2 , and thromboxane A2 did not show any significant effects . The increases in intra - atrial pressure and P01160 secretion induced by PGF2alpha and PGD2 were significantly attenuated by the pretreatment with an inhibitor of PGF2alpha receptor . By the pretreatment with an inhibitor for phospholipase C ( P98160 ) , inositol 3 - phosphate ( IP3 ) receptor , protein kinase C ( PKC ) , or myosin light chain kinase ( MLCK ) , PGF2alpha - mediated increase in P01160 secretion and positive inotropy were attenuated . Inhibitor for P23219 or P35354 did not cause any significant effects on atrial parameters . In hypertrophied rat atria , PGF2alpha - induced positive inotropy and P01160 secretion were markedly attenuated whereas P35354 inhibitor stimulated P01160 secretion . The expression of P35354 increased and the expression of PGF2alpha receptor mRNA decreased in hypertrophied rat atria . These results suggest that PGF2alpha increased the P01160 secretion and positive inotropy through P98160 - IP3 - PKC - MLCK pathway , and the modulation of P01160 secretion by P35354 inhibitor and PGF2alpha may partly relate to the development of renal hypertension .\",\n \"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK44___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .\"\n]"},"candidates":{"kind":"list like","value":["___MASK41___","___MASK44___","___MASK53___","___MASK57___","___MASK79___","___MASK82___","___MASK90___","___MASK96___","___MASK97___"],"string":"[\n \"___MASK41___\",\n \"___MASK44___\",\n \"___MASK53___\",\n \"___MASK57___\",\n \"___MASK79___\",\n \"___MASK82___\",\n \"___MASK90___\",\n \"___MASK96___\",\n \"___MASK97___\"\n]"},"answer":{"kind":"string","value":"___MASK44___"},"id":{"kind":"string","value":"MH_train_485"}}},{"rowIdx":486,"cells":{"query":{"kind":"string","value":"interacts_with DB00065?"},"supports":{"kind":"list like","value":["DB00065 acts directly on human osteoclast precursors and enhances osteoclast formation induced by receptor activator of nuclear factor kappaB ligand in vitro . DB00065 is known to protect against the development of joint destruction . In the present study , we sought to determine whether DB00065 acts directly on human osteoclast precursors and influences monocyte - osteoclast differentiation induced by receptor activator of nuclear factor kappaB ligand ( O14788 ) in vitro . Peripheral blood mononuclear cells ( PBMCs ) isolated from rheumatoid arthritis ( RA ) patients and normal controls were cultured in the presence of O14788 and macrophage colony stimulating factor . DB00065 , antihuman tumor necrosis factor alpha ( TNFalpha ) , antihuman P01375 soluble receptor p55 ( TNFR p55 ) , and antihuman P01375 soluble receptor p75 ( TNFR p75 ) antibodies were added . Osteoclast formation was determined by assessing the number of tartrate - resistant acid phosphatase ( TRAP ) staining cells and the extent of lacunar resorption . Addition of DB00065 resulted in a marked increase in the number of TRAP - positive multinucleated cells ( TRAP (+) MNCs ) and in the extent of lacunar resorption compared with the control cultures . Antihuman TNFalpha antibody showed the same effect ; however , the addition of neither TNFR p55 nor TNFR p75 antibody affected the extent of TRAP (+) MNCs and lacunar resorption . Our results suggest that infliximab acts directly on early osteoclast precursors , and stimulates osteoclast formation and lacunar resorption induced by O14788 in vitro .","DB00065 in relapsing polychondritis . Relapsing polychondritis ( RP ) is a rare systemic disease of unknown etiology , characterized by recurrent inflammation of cartilaginous structures and other connective tissues , including the ears , nose , joints , respiratory tract , and others . Due to the presence of typical signs and symptoms , biopsy is seldom necessary . Treatment includes corticosteroids , occasionally associated with immunosuppressive agents , but refractory cases are described . Recent reports suggest that anti - P01375 agents , such as infliximab , may be of value in patients who do not respond to conventional therapy , but experience with this treatment is scarce . In this paper , the authors report the case of a patient with RP refractory to combined treatment with corticosteroids and immunosuppressive agents , who showed a good response to infliximab .","Selecting appropriate anti - P01375 agents in inflammatory bowel disease . DB00065 was the first anti - P01375 agent to be approved by the US FDA for the treatment of Crohn ' s disease ( CD ) in 1998 . In the past 10 years , two other agents , adalimumab and certolizumab pegol , have also been approved for the treatment of CD . In the absence of head - to - head comparisons , the efficacy of these agents appear to be similar for the treatment of luminal CD . There are also prospective , randomized , controlled data to support the use of infliximab for the treatment of fistulizing CD and ulcerative colitis , and supportive post hoc data for the use of adalimumab and certolizumab pegol for the treatment of fistulizing CD . Practical matters , such as patient preference regarding the mode of administration , approval by third - party payers and residual patient cost , may actually play a larger role in choosing a particular anti - P01375 agent , as efficacy and safety issues are similar for all three . Unfortunately , many patients do not respond , lose response or develop intolerance to anti - P01375 treatment . Thus , new therapies are needed . DB00108 , the first biologic that is not an anti - P01375 agent , was FDA - approved in January 2008 for the treatment of CD patients who have failed conventional treatment , including anti - P01375 therapy . As we continue to learn more about the pathogenesis of inflammatory bowel disease , novel targets for drug therapy are being developed .","Spinal epidural abscess associated with infliximab treatment for psoriatic arthritis . Case report . P01375 - alpha inhibitors are used to treat numerous chronic inflammatory and rheumatological diseases , such as Crohn disease , rheumatoid arthritis , and psoriatic arthritis . Because the mechanism of these inhibitors is to decrease the body ' s inflammatory response , the primary complication of treatment is infection . The authors present the first case of a spinal epidural abscess in a patient receiving long - term infliximab therapy for severe psoriatic arthritis . DB00065 and its side - effect profile are discussed , along with other associated complications .","[ Efficacy and security of tumor necrosis factor antagonists in the treatment of rheumatoid arthritis ] . In the last decade , tumor necrosis factor ( P01375 ) antagonists had supposed an important therapeutic advance in the treatment of patients with rheumatoid arthritis ( RA ) in both early and established RA . Three agents currently available -- infliximab , etanercept , and adalimumab -- have been designed to modify the biologic effects of P01375 . DB00065 and adalimumab are monoclonal antibodies , whereas etanercept is a soluble protein , with different pharmacokinetic and pharmacodynamic properties , conditioning some possible adverse effects . Although comparative studies are not available , the 3 drugs have demonstrated efficacy and security , with a better quality of life of patients with RA . DB00065 , etanercept and adalimumab have been proved alone and in combination with methotrexate , with a better therapeutic , clinical , radiological and functional response in the group under combined therapy . Both clinical trials and post - market experience have demonstrated the security of these drugs , minimizing the risks with an adequate selection of patients .","Advances in the treatment of Kawasaki disease . PURPOSE OF REVIEW : Intravenous immunoglobulin ( IVIG ) and aspirin is the standard initial therapy in the treatment of Kawasaki disease . Some patients have persistent or recrudescent fever despite this therapy . Although there is no conclusive body of evidence defining the best second and third - line therapies for Kawasaki patients , there have been several recent studies published describing the results of these therapies . RECENT FINDINGS : This review summarizes the current recommendations for the initial therapy and describes the second and third - line therapies studied in Japan and the United States . A recent study in a Japanese population of Kawasaki disease patients at high risk for IVIG resistance found that the group receiving steroids , in addition to IVIG and aspirin , had fewer coronary artery abnormalities than the group receiving IVIG and aspirin alone . Small studies of etanercept and infliximab have showed these P01375 blockers to be well tolerated and effective in the resolution of fever . SUMMARY : Although most practitioners in the USA use IVIG as a second - line therapy for those Kawasaki disease patients who have persistent or recrudescent fever , promising new therapies are under study . DB00065 and steroids are currently the two agents that have been most studied . However , larger studies and studies in genetically diverse populations are needed .","Treatment of inflammatory bowel disease : a review of medical therapy . Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) are chronic inflammatory diseases of the gastrointestinal tract . While a cure remains elusive , both can be treated with medications that induce and maintain remission . With the recent advent of therapies that inhibit tumor necrosis factor ( P01375 ) alpha the overlap in medical therapies for UC and CD has become greater . Although DB00244 agents have been a mainstay in the treatment of both CD and UC , the data for their efficacy in patients with CD , particularly as maintenance therapy , are equivocal . Antibiotics may have a limited role in the treatment of colonic CD . Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy ; non - systemic steroids such as oral and rectal budesonide for ileal and right - sided CD and distal UC respectively are also effective in mild - moderate disease . 6 - mercaptopurine ( DB01033 ) and its prodrug azathioprine are steroid - sparing immunomodulators effective in the maintenance of remission of both CD and UC , while methotrexate may be used in both induction and maintenance of CD . DB00065 and adalimumab are anti - P01375 agents approved in the US and Europe for the treatment of Crohn ' s disease , and infliximab is also approved for the treatment of UC .","Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK55___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .","Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK34___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .","Anti - P01375 immunotherapy is associated with increased gingival inflammation without clinical attachment loss in subjects with rheumatoid arthritis . BACKGROUND : Because periodontitis presents many similarities with rheumatoid arthritis ( RA ) with regard to tumor necrosis factor - alpha ( P01375 ) - induced bone resorption , the benefits of P01375 blockade in RA prompted us to determine its efficacy in treating coexisting periodontitis . METHODS : Periodontal status was evaluated in 40 subjects with RA who were divided into two groups : Group I contained 20 subjects who had received infliximab every 6 weeks for > or = 22 months at the time of periodontal evaluation . The 20 subjects in group II were evaluated before their first infusion with infliximab . Nine subjects in group II had periodontitis . These subjects were reevaluated after they received nine infusions of infliximab . RESULTS : DB00065 tended to aggravate gingival inflammation as indicated by differences in the modified gingival and papillary bleeding indices between subjects in groups I and II with coexisting periodontitis before and after treatment . DB00563 had no effect on periodontal status . Although the plaque index revealed that bacterial infection persisted , the probing depth was equal in groups I and II and equivalent before and after treatment in subjects with periodontitis , whereas attachment loss was decreased after infliximab treatment . CONCLUSIONS : Inflammation and destruction constitute two interrelated yet separate components of periodontitis in patients with RA . Therefore , P01375 blockade could be beneficial in the treatment of periodontitis .","[ The immune status changes in patients with inflammatory bowel disease under the influence of mesenchymal stromal cells and infliximab therapy ] . Out of 28 patients with inflammatory bowel disease in 11 ( 39 . 3 % ) revealed the presence of autoantibodies to gastric parietal cells . Appointment of O60682 and infliximab did not lead to a reduction in antibody levels , in fact , in 6 ( 21 . 4 % ) patients had a further increase in the content of mentioned autoantibodies . Identification of autoantibodies to gastric parietal cells is considered as adherence to Q9UKU7 autoimmune gastritis ( formation of a systemic process ) that requires use of corticosteroids . Transplantation of mesenchymal stromal cells in Q9UKU7 reduces enhanced circulation of autoantibodies against antigens of neutrophils cytoplasmic structures , thereby reducing the severity of autoimmune reactions . Transplantation of MSCs reduces autoaggression in patients with ulcerative colitis , reducing the autoreactive clone of B lymphocytes ( P15391 + P06127 + ) . Analysis effectiveness of the therapy . Transplantation of MSCs in Q9UKU7 has a systemic immunoregulatory effect : on the one hand , stimulates oppressed cytokine synthesis , on the other -- reduses the intensity of the autoimmune reactions and activity of pathological processes . DB00065 selectively blocks P01375 , without affecting other proinflammatory cytokines .","DB00065 : lack of efficacy on perforating complications in Crohn ' s disease . BACKGROUND : DB00065 ( Remicade ) , a chimeric monoclonal antibody against tumor necrosis factor alpha ( P01375 ) , has emerged as promising therapeutic option in perianal fistulizing Crohn ' s disease ( CD ) . However , little knowledge exists about its use for the treatment of internal fistulas in CD . We present our experience with infliximab in this situation . METHODS : Four patients with CD who had internal fistulas ( Case 1 : entero - enteral and entero - abdominal ; Case 2 : entero - enteral ; Case 3 : entero - enteral and parastomal ; Case 4 : entero - vesical ) were treated with 3 infusions of infliximab ( 5 mg / kg body weight ) with intervals of 2 and 4 weeks . In addition , 3 patients had strictures and 2 patients had perianal fistulas . RESULTS : After the three infusions of infliximab ( 5 mg / kg body weight ) , internal fistulas remained unchanged in all patients . The perianal fistulas present in 2 cases were healed . Administration of infliximab was safe and well tolerated in all cases . CONCLUSION : Treatment with 3 infusions of infliximab ( 5 mg / kg body weight ) led to healing of only the perianal fistulas , whereas the internal fistulas were not influenced . We conclude that in these 4 cases , infliximab was well tolerated but not effective for the management of internal fistulas and was no alternative for surgery .","Redo Ileal pouch - anal anastomosis combined with anti - P01375 - α maintenance therapy for Crohn ' s disease with pelvic fistula : report of two cases . Pouch failure has been reported to occur after ileal pouch - anal anastomosis for Crohn ' s disease . We report two cases of patients with Crohn ' s disease , who underwent redo ileal pouch - anal anastomosis ( redo - IPAA ) combined with anti - P01375 - α maintenance therapy , with good functional results . The first patient , a man with presumed ulcerative colitis , suffered pelvic fistula recurrence and anastomotic dehiscence . He underwent redo - IPAA , at which time longitudinal ulcers were found . DB00065 was started 4 days postoperatively and continued . The second patient , a woman treated for ulcerative colitis , underwent laparoscopic IPAA 8 years later . After the development of a pelvic fistula , twisted mesentery of the ileal pouch was found intraoperatively and Crohn ' s disease was diagnosed . DB00051 therapy resulted in fistula closure . Redo - IPAA was performed to normalize the twisted mesentery of the ileal pouch . No complications have been observed in either patient , both of whom have experienced good functional results after closure of the covering stomas .","DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK93___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .","Genetic polymorphisms of tumour necrosis factor receptor superfamily 1A and 1B affect responses to infliximab in Japanese patients with Crohn ' s disease . BACKGROUND : Tumour necrosis factor alpha is the key inflammatory cytokine involved in the pathogenesis of Crohn ' s disease . DB00065 , a chimaeric monoclonal antibody of tumour necrosis factor - alpha is successfully used for the treatment of Crohn ' s disease , although the response to infliximab therapy differs among patients . The genetic background of the individual may partially explain the differences of the responsiveness . AIM : To investigate whether the polymorphisms in these genes are associated with the response to infliximab treatment as tumour necrosis factor - alpha exerts its biological activity through P01375 receptor superfamily 1A and 1B . METHODS : Eighty Crohn ' s disease patients were enrolled in the study and classified into responder and nonresponder according to the efficacy of infliximab treatment . Single nucleotide polymorphisms of P01375 receptor superfamily 1A ( rs767455 and rs4149570 ) and P01375 receptor superfamily 1B ( rs1061622 , rs1061624 and rs3397 ) were determined . RESULTS : The minor allele carrier of rs767455 showed a significant association with a lack of efficacy compared to the major genotype ( OR = 0 . 26 ; 95 % CI : 0 . 08 - 0 . 91 ) . A P01375 receptor superfamily 1B haplotype inferred by rs1061624 and rs3397 also showed significant differences in the distribution between responder and nonresponder ( P = 0 . 01 ) . CONCLUSION : These results suggest that tumour necrosis factor receptor genotypes may be involved in the different responses to infliximab in Japanese patients with Crohn ' s disease .","Screening of 134 single nucleotide polymorphisms ( SNPs ) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes . More than 120 published reports have described associations between single nucleotide polymorphisms ( SNPs ) and type 2 diabetes . However , multiple studies of the same variant have often been discordant . From a literature search , we identified previously reported type 2 diabetes - associated SNPs . We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium ( r ( 2 ) > 0 . 8 ) with another typed SNP . Of the 114 SNPs examined , we followed up the 20 most significant SNPs ( P < 0 . 10 ) on an additional 384 case subjects and 366 control subjects from a population - based study in Finland . In the combined data , we replicated association ( P < 0 . 05 ) for 12 SNPs : P37231 Pro12Ala and His447 , Q14654 Glu23Lys and rs5210 , P01375 - 857 , P11168 Ile110Thr , P20823 / TCF1 rs2701175 and GE117881_360 , P35558 - 232 , Q13562 Thr45Ala , P05231 - 598 , and P22413 Lys121Gln . The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association ( P = 0 . 012 ) . We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample ( P = 0 . 03 ) , although we also replicated 4 of 58 SNPs from genes that had only one previous report of association .","P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK28___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .","Experiences with a long - term treatment of a massive gluteal acne inversa with infliximab in Crohn ' s disease . BACKGROUND : In 40 % of all cases of Crohn ' s disease fistulas emerge during the course of disease . Nevertheless , acne inversa has to be taken into account as an infrequent differential diagnosis . DB00065 as an antibody against the pro - inflammatory mediator P01375 is active in cases of acute Crohn ' s disease , concomitant fistulas and cutaneous manifestations . CASE REPORT : We report on the case of a 54 - year - old patient suffering for five years from a severe suppurative fistuling cutaneous disease concomitant to Crohn ' s disease . At the start of treatment the histological findings of a specimen presented chronically fibrosing lymphoplasmacellular dermatitis with both a very high number of plasma cells and a burrow - like fistula system . Due to superinfection the treatment was at first based on the administration of intravenous and oral doses of antibiotic agents , followed by a treatment course of 14 months with methotrexate and seven applications of infliximab . During the Crohn ' s disease , which was accompanied by persisting concomitant discomforts , an extensive surgical sanitation of the fistulous tracts was performed . Acne inversa was diagnosed in the subsequent histological analysis of the operative specimen . CONCLUSIONS : Acne inversa is a very rare cutaneous disease . Several case reports describe the successful treatment of acne inversa concomitant to Crohn ' s disease using anti - P01375 - antibodies . The long - term course of the case presented here shows that the non - response to infliximab might be caused by both the long duration and the distinct grade of seriousness of the acne inversa .","DB00065 in ulcerative colitis . DB00065 , a monoclonal anti - P01375 antibody , is commonly used for treatment of moderate to severe Crohn ' s disease ( CD ) . Its role in the treatment for ulcerative colitis ( UC ) remains controversial . We review the role of P01375 in the pathogenesis of UC and describe the randomized , double - blind , placebo - controlled trials and systematic reviews that assess the efficacy of infliximab in the treatment of moderate to severe UC .","The link between unpredictable chronic mild stress model for depression and vascular inflammation ? Inflammation has been suggested to be associated with stress - induced depression and cardiovascular dysfunction . P01375 alpha ( P01375 - α ) is a major cytokine in the activation of neuroendocrine , immune , and behavioral responses . In this study , we investigated the effects of infliximab ( a P01375 - α inhibitor ) on endothelium - dependent vascular reactivity , systemic blood pressure , and endothelial nitric oxide synthase ( P29474 ) immunoreactivity in the unpredictable chronic mild stress ( UCMS ) model of depression in rats . There was no significant change between all groups in the systemic blood pressure . In UCMS , endothelium - dependent relaxation of the smooth muscle in response to carbachol was significantly decreased with 50 % maximal response ( E max ) and pD2 values compared with the controls . DB00065 was able to reverse this UCMS effect . Relaxation in response to the nitric oxide ( NO ) donor sodium nitroprusside and papaverine and DB00761 - induced contractile responses was similar between groups . In UCMS , decreased expression of P29474 was detected . Moreover , there was no significant change in UCMS + infliximab group with respect to control rats . Our results suggest that tumor necrosis factor - alpha ( P01375 - α ) could be a major mediator of vascular dysfunction associated with UCMS , leading to decreased expression of P29474 .","Linkage assignment of eleven genes to the porcine genome . We report comparative linkage mapping of eleven genes in the swine genome by RFLP analysis . These genes include : Acid phosphatase type 5 ( P13686 ) , Cholecystokinin Type B Receptor ( P32239 ) , Antibiotic Peptide ( P49913 ) , P01308 - like Growth Factor 1 Receptor ( P08069 ) , Integrin Alpha M ( P11215 ) , Integrin Beta 2 ( ITGbeta2 ) , Opioid Receptor Mu - 1 ( P35372 ) , Pro - hormone Converter ( PC1 / 3 ) , DB00162 Binding Q12988 ( P10745 ) , Ribosomal DNA ( RNR1 ) , and Zona Pellucida Glycoprotein 1 ( P60852 ) . The P32239 and ITGbeta2 loci define the ends of the linkage groups on Chromosomes ( Chro ) ( SSC ) 9p and 13qter , respectively .","DB00065 for the therapy of chronic sarcoidosis , Baughman RP , Drent M , Kavuru M et al . : DB00065 therapy in patients with chronic sarcoidosis and pulmonary involvement . Am . J . Respir . Crit . Care Med . ( 2006 ) 174 ( 7 ): 795 - 802 . Sarcoidosis is an inflammatory multiorgan disease in which the lungs are the most commonly affected . It can also involve the skin , lupus pernio being a common form of chronic cutaneous sarcoidosis . The histopathologically specific lesion is represented by non - caseating granulomas occurring in the involved organs , with P01375 playing a role in granuloma generation . Several therapies are available , with corticosteroids representing the conventional therapy given as topic or systemic formulations . Anti - P01375 therapies ( such as etanercept or infliximab ) have been assessed so far , the latter most commonly in refractory sarcoidosis . The discussed study evaluates the safety and efficacy of infliximab in chronic sarcoidosis with pulmonary manifestations .","Niacin reduces plasma P11597 levels by diminishing liver macrophage content in P11597 transgenic mice . The anti - dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of P11597 . Since liver macrophages contribute to hepatic P11597 expression , we investigated the role of macrophages in the P11597 - lowering effect of niacin in mice . In vitro studies showed that niacin does not directly attenuate P11597 expression in macrophages . Treatment of normolipidemic human P11597 transgenic mice , fed a Western - type diet with niacin for 4 weeks , significantly reduced the hepatic cholesterol concentration ( - 20 % ) , hepatic P11597 gene expression ( - 20 % ) , and plasma P11597 mass ( - 30 % ) . Concomitantly , niacin decreased the hepatic expression of P34810 ( - 44 % ) and P45844 ( - 32 % ) , both of which are specific markers for the hepatic macrophage content . The decrease in hepatic P11597 expression was significantly correlated with the reduction of hepatic macrophage markers . Furthermore , niacin attenuated atherogenic diet - induced inflammation in liver , as evident from decreased expression of P01375 ( - 43 % ) . Niacin similarly decreased the macrophage markers and absolute macrophage content in hyperlipidemic P02649 * 3 - Leiden . P11597 transgenic mice on a Western - type diet . In conclusion , niacin decreases hepatic P11597 expression and plasma P11597 mass by attenuating liver inflammation and macrophage content in response to its primary lipid - lowering effect , rather than by attenuating the macrophage P11597 expression level .","Is there a benefit from the concomitant use of immunosupression with anti - P01375 in Crohn ' s disease ; heads or tails ? Over the last some years the increasing knowledge on the pathogenesis of Crohn ' s disease led to the development of a number of biological agents targeting specific molecules involved in gut inflammation , first of all P01375 and its receptors . DB00065 , adalimumab and certolizumab have been successful in inducing and maintaining remission in Crohn ' s disease at both short and long term . This was recently confirmed by a Cochrane meta - analysis and also open label extension follow - up and cohort studies . Emerging new data however indicate that combination therapy with infliximab - azathioprine appears to have added benefit in inducing steroid - free remission and mucosal healing than either infliximab or azathioprine alone in azathioprine - naïve patients with early disease . Similarly the combination of steroids induction and infliximab was efficacious in luminal Crohn ' s disease . In contrast , there seems to be no synergism between methotrexate and infliximab . It is also less clear whether it is beneficial to use short or long - term infliximab - azathioprine combination in patients who previously failed therapy with azathioprine . In contrast , combination may potentially be associated with increased risk for infection and cancer . In case control - studies , especially the combination of steroids and anti - P01375 and older age increased the risk for infectious complications , while scattered case reports point to the potentially increased risk of a rare form of non - Hodgkin ' s lymphoma ( Hepatosplenic T cell lymphoma ) with the use of azathioprine - anti - P01375 combination . The aim of this review is to summarize the benefits and risks for the use combination therapy with P01375 inhibitors in the treatment of Crohn ' s disease .","High - dose infliximab prophylaxis in endotoxin - induced uveitis . PURPOSE : The aim of this study to analyze the preventive effect of high - dose infliximab in endotoxin - induced uveitis ( EIU ) in rabbits . METHODS : An experimental study was conducted on 64 rabbits . Salmonella typhimurium lipopolysaccharide endotoxin was intravitreally injected . DB00065 was intravenously ( i . v . ) injected 24 h before the intravitreal injection ( 20 mg / kg ) . The animals were randomly assigned to five groups : group A , saline intravitreal injection ; group B , DB00065 i . v . group C , infliximab + saline ; group D , intravitreal endotoxin and group E , infliximab i . v . + intravitreal endotoxin . With two masked observers , a microscopic examination of aqueous humor ( cells , tumor necrosis factor [ P01375 ] alpha ) and aqueous protein level were performed 24 h after an endotoxin injection and 48 h after an infliximab infusion . RESULTS : DB00065 treatment , at a dose of 20 mg / kg , significantly improved all the parameters . Inflammatory cell infiltration was significantly reduced in the iris , ciliary body , and anterior chamber ( U Mann - Whitney test , P = 0 . 01 ) . Associated with a lower level of P01375 and protein exudate in aqueous humor ( U Mann - Whitney test , P = 0 . 01 ) . CONCLUSIONS : DB00065 , at a dose of 20 mg / kg , is effective in the prophylaxis of the EIU .","Treatment with infliximab : Implications in oral surgery ? A case report . DB00065 is a tumour necrosis factor - alpha ( P01375 ) inhibitor ( neutralising antibody ) , which is increasingly being used as an immunosuppressant to manage inflammatory conditions including rheumatoid arthritis , ankylosing spondylitis and Crohn ' s disease . Its side effects include diabetes mellitus , an increased incidence of lymphoma and greater susceptibility to infections such as pulmonary tuberculosis . In patients on infliximab , the oral cavity may act as a bacterial reservoir leading to unwanted local or systemic complications . To date no report describes the potential implication / s of infliximab in patients having oral surgery . This case report may be the first in the English language to report the development of mandibular osteomyelitis after surgical extraction in a patient on infliximab .","Earlobe sarcoidosis . BACKGROUND : DB00065 , a P01375 blocking agent , is an upcoming therapeutic option for cases of refractory sarcoidosis . In pulmonary sarcoidosis , changes imaged by DB09150 - PET during infliximab treatment in sarcoidosis patients correlate with signs of clinical improvement . DESIGN : Case - report . RESULTS AND CONCLUSIONS : A patient with severe earlobe sarcoidosis , treated with infliximab , is presented . This case shows that even relatively small extrapulmonary localisations of sarcoidosis can be visualised by DB09150 - PET , and that a decrease of DB09150 - uptake correlates well with clinical improvement on infliximab treatment .","[ Proteomic analysis of changes in the serum protein profile by anti - P01375 therapy ] . We analyzed the alternation in serum protein by infliximab therapy using proteomics - based technique . More than 50 gel spots were seen to increase or decrease in correlation with clinical improvements of rheumatoid arthritis ( RA ) . Spots of interest were identified by two dimensional electrophoresis and mass spectrometry . DB00065 therapy reduced the inflammatory proteins such as P02741 , serum amyloid protein A , serum amyloid protein P , and alpha1 - acid glycoprotein , while the therapy increased Apo A - I , retinol - binding protein , vitamin D - binding protein , and gelsolin . This suggested that infliximab therapy shifted the inflammatory status of serum protein profile of RA patients to normal and modified the extracellular actin - scavenging system as well as vitamin and lipid profile .","[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK70___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .","Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK67___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK67___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .","Anti - inflammatory effects of pravastatin on Helicobacter pylori - induced gastritis in mice . ___MASK96___ , an P04035 inhibitor , exerts anti - inflammatory effects via several mechanisms including induction of endothelial nitric oxide synthase ( P29474 ) . We investigated the effect of pravastatin on Helicobacter pylori - induced gastritis in mice . Mice with or without H . pylori infection received intraperitoneal pravastatin daily for 1 week . Expression of P29474 mRNA and tumor necrosis factor - alpha mRNA and myeloperoxidase activity in gastric tissue was determined . P05164 activity was reduced in a dose - dependent manner by pravastatin , with activity inhibited by 53 . 5 and 73 . 7 % at doses of 0 . 3 and 1 mg / kg , respectively . At a dose of 1 mg / kg , pravastatin reduced the level of tumor necrosis factor - alpha mRNA by 52 . 7 % , while it did not affect P29474 expression . ___MASK96___ had no effects on these inflammatory parameters in uninfected mice . ___MASK96___ did not affect the viability of H . pylori . In conclusion , pravastatin exerts an anti - inflammatory effect on H . pylori - induced gastritis in mice without affecting P29474 expression .","Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .","Effect of infliximab on the healing of intestinal anastomosis . An experimental study in rats . BACKGROUND AND AIM : DB00065 is effective in the induction and maintenance of remission in Crohn ' s disease . Whether , the perioperative administration of anti - P01375 compromises intestinal healing leading to anastomotic failure and increased risk of postoperative complications , remains controversial . The aim of the study was to evaluate the effect of DB00065 on intestinal anastomosis healing . METHODS : Fifty six wistar rats were divided into 4 groups : ( a ) 20 rats were subjected to excision of part of the terminal ileum followed by anastomosis which was evaluated on the 3rd or 7th postoperative day ; ( b ) 20 rats received DB00065 and thereafter , the same surgical protocol as group ( a ) was followed ; ( c ) 8 rats received DB00065 and served as relative control group ; and ( d ) 8 served as absolute control group . Bursting pressure was used for testing intestinal healing . Additionally , the anastomoses were examined macroscopically , histologically and immunohistochemically for TGFb1 , P03956 , P08253 and Collagen V . The results were confirmed by Western blot analysis . RESULTS : There were no significant differences in bursting pressures and septic intra - abdominal events among non - DB00065 ( a ) and DB00065 - treated ( b ) groups . DB00065 - treated ( b ) group showed mild to moderate inflammation , whereas the non - DB00065 ( a ) group exhibited severe inflammation . Expression of TGFb1 , P08253 and collagen V was significantly higher in the DB00065 - treated ( b ) group . CONCLUSION : DB00065 seems to influence intestinal healing in terms of less inflammatory activity and higher tissue remodeling activity .","Chronic P01375 - α neutralization does not improve insulin resistance or endothelial function in \" healthy \" men with metabolic syndrome . The possible contribution of tumor necrosis factor - α ( P01375 - α ) to the development of obesity - associated insulin resistance in humans is still controversial . Our study investigated the effect of P01375 - α neutralization on insulin resistance in healthy , obese and insulin resistant men . We performed a prospective , randomized , double - blind placebo - controlled trial in nine young , healthy obese male subjects with metabolic syndrome and insulin resistance . Volunteers received three infusions ( wks 0 , 2 and 6 ) of infliximab or placebo . P01308 resistance was measured at baseline and after 70 d by homeostatic model assessment ( HOMA ) index as well as by minimal model analysis of an intravenous glucose tolerance test . Endothelial function was accessed before and after intervention by flow mediated dilation . DB00065 improved the inflammatory status as indicated by reduced high sensitivity P02741 ( hsCRP ) and fibrinogen levels ( 2 . 77 ± 0 . 6 to 1 . 8 ± 0 . 5 μg / L , and 3 . 42 ± 0 . 18 to 3 . 18 ± 0 . 28 g / L ; ( day 0 and day 70 , P = 0 . 020 and 0 . 037 respectively ) , but did not improve insulin resistance ( HOMA index and intravenous glucose - tolerance test [ ivGGT ] ) or endothelial function . Despite improvements in inflammatory status , chronic P01375 - α neutralization does not improve insulin resistance or endothelial function in seemingly healthy , but obese , insulin - resistant volunteers . This study severely questions the proposal that P01375 - α is a causative link between adiposity and insulin resistance .","Mechanisms for cytotoxic effects of anti - tumor necrosis factor agents on transmembrane tumor necrosis factor alpha - expressing cells : comparison among infliximab , etanercept , and adalimumab . OBJECTIVE : Three anti - tumor necrosis factor alpha ( anti - TNFalpha ) agents have been proved to be effective for rheumatoid arthritis ( RA ) and other inflammatory disorders . DB00065 and adalimumab have been generated as anti - TNFalpha monoclonal antibodies , while etanercept is engineered from human type II P01375 receptors . In spite of all 3 agents ' equal efficacy for RA , both infliximab and adalimumab are effective for other diseases such as Crohn ' s disease and Wegener ' s granulomatosis , while etanercept is not . We undertook this study to understand the different clinical effects of these anti - TNFalpha agents by analyzing their biologic activities on transmembrane TNFalpha . METHODS : Jurkat T cells stably expressing an uncleavable form of transmembrane TNFalpha were used for the following studies : 1 ) flow cytometric analysis of binding activities of anti - P01375 agents to cell surface transmembrane TNFalpha , 2 ) complement - dependent cytotoxicity ( CDC ) , 3 ) antibody - dependent cell - mediated cytotoxicity ( ADCC ) by using peripheral blood mononuclear cells , and 4 ) outside - to - inside ( reverse ) signal transduction through transmembrane TNFalpha estimated by apoptosis and cell cycle analysis using flow cytometry . RESULTS : All of the anti - TNFalpha agents bound to transmembrane TNFalpha . DB00065 and adalimumab exerted almost equal CDC activities , while etanercept showed considerably lower activity . ADCC activities were almost equal among these 3 agents . DB00051 and infliximab induced apoptosis and cell cycle arrest in transmembrane TNFalpha - expressing Jurkat T cells , reflecting an outside - to - inside signal transduction through transmembrane TNFalpha . CONCLUSION : Three different anti - P01375 agents showed different biologic effects on transmembrane TNFalpha . This finding suggests that CDC and outside - to - inside signals by anti - TNFalpha antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn ' s disease and Wegener ' s granulomatosis .","Treatment of immune - mediated extraintestinal manifestations of inflammatory bowel disease with infliximab . The introduction of infliximab into clinical practice is one of the most significant advances in the care of patients who have Q9UKU7 . DB00065 has become an important part of the medical armamentarium to treat extraintestinal manifestations that often are refractory to other medications and are a significant cause of morbidity in these patients . Two other P01375 inhibitors recently have demonstrated efficacy in CD : certolizumab pegol and adalimumab . The Food and Drug Administration has approved adalimumab for use in RA . One predicts that these agents also may have activity in the extraintestinal manifestation for Q9UKU7 . To determine whether future biologics are effective in the EIM of Q9UKU7 , one may need to look no further than the vast clinical trial experience in primary chronic inflammatory diseases of the joints and skin : RA and psoriasis . For example , the Food and DRug Administration recently has approved an anti - B - cell therapy , rituximab , and a T - cell costimulation modulator , abatacept , for use in RA . It certainly will be of interest to determine whether these biologic agents demonstrate efficacy in the intestinal and EIM of Q9UKU7 .","P01375 alpha antibody ( infliximab ) therapy profoundly down - regulates the inflammation in Crohn ' s ileocolitis . BACKGROUND & AIMS : Anti - tumor necrosis factor alpha monoclonal antibody treatment ( infliximab ) reduces clinical signs and symptoms in patients with Crohn ' s disease . The effects of infliximab on mucosal histopathologic abnormalities in Crohn ' s ileocolitis were studied . METHODS : Thirteen patients with steroid - refractory Crohn ' s disease were treated with a single infusion of infliximab ( 5 - 20 mg / kg ) , and 5 were treated with placebo . Ileal and colonic biopsy specimens of all patients were collected before and 4 weeks after therapy . Severity of inflammation was assessed by a histological score . Immunohistochemical stainings with antibodies against HLA - DR , P34810 , tumor necrosis factor alpha , intercellular adhesion molecule 1 , lymphocyte function - associated antigen , P01730 , CD8 , and interleukin 4 were performed . RESULTS : Total histological activity score was reduced significantly in both ileitis and colitis after infliximab . This is caused by a virtual disappearance of the neutrophils and a reduction of mononuclear cells . Mucosal architecture returned to normal in 4 patients at 4 weeks . The number of lamina propria mononuclear cells decreased because of a global reduction of P01730 (+) and CD8 (+) T lymphocytes and P34810 (+) monocytes . Aberrant colonic epithelial HLA - DR expression completely disappeared . The percentage of intercellular adhesion molecule 1 and lymphocyte function - associated antigen 1 - expressing and interleukin 4 - and tumor necrosis factor - positive lamina propria mononuclear cells sharply decreased . CONCLUSIONS : DB00065 dramatically decreases histological disease activity in Crohn ' s ileocolitis . Signs of active inflammation nearly disappear accompanied by a profound down - regulation of mucosal inflammatory mediators .","Differential effect of DB03932 , pravastatin , and fluvastatin on production of Q14116 and expression of P05362 and P25942 in human monocytes . A novel , proinflammatory cytokine , interleukin ( IL ) - 18 production was detected in the medium of human monocytes treated with 3 - hydroxy - 3 - methylglutaryl coenzyme - A ( HMG - DB01992 ) reductase inhibitors , pravastatin , and fluvastatin ( 0 . 1 and 1 muM ) but not with the statin - derived lymphocyte function - associated antigen - 1 ( LFA - 1 ) inhibitor DB03932 , which did not inhibit P04035 . ___MASK96___ and fluvastatin also induced the production of Q14116 , tumor necrosis factor alpha ( P01375 ) and interferon - gamma ( P01579 ) in human peripheral blood mononuclear cells ( PBMC ) in contrast to DB03932 . Q14116 production by PBMC is located upstream of the cytokine cascade activated by these statins . The Q14116 - induced cytokine production was demonstrated to be dependent on adhesion molecule expression on monocytes . In the absence and presence of lower concentrations ( 0 . 1 and 1 ng / ml ) of Q14116 , pravastatin and fluvastatin inhibited the expression of intercellular adhesion molecule ( ICAM ) - 1 and induced the expression of P25942 , whereas DB03932 had no effect . In the presence of higher concentrations ( 5 , 10 , and 100 ng / ml ) of Q14116 , pravastatin , fluvastatin , and DB03932 similarly inhibited the expression of P05362 and P25942 as well as the production of IL - 12 , P01375 , and P01579 in PBMC . The effects of pravastatin and fluvastatin but not DB03932 were abolished by the addition of mevalonate , indicating the involvement of P04035 in the action of pravastatin and fluvastatin . Thus , the effects of DB03932 were distinct from those of pravastatin and fluvastatin in the presence of lower concentrations of Q14116 . It was concluded that DB03932 has the inhibitory effect on an Q14116 - initiated immune response without any activation on monocytes .","DB00065 monotherapy for refractory psoriasis : preliminary results . Tumour necrosis factor ( P01375 ) - alpha plays an important role in the pathogenesis of psoriasis . DB00065 is an anti - P01375 chimeric monoclonal antibody , which is licensed for the treatment of rheumatoid arthritis and Crohn ' s disease . Some reports have shown the efficacy of infliximab , either in monotherapy or in combination with methotrexate , for the treatment of psoriatic arthropathy and psoriasis . The efficacy and tolerability of infliximab monotherapy was evaluated in 29 patients with moderate to severe psoriasis , unresponsive to conventional treatments . Fourteen patients suffered from concomitant arthropathy . Patients received intravenous infliximab , 5mg / kg , at weeks 0 , 2 , and 6 . After this 3 - dose - induction regimen , patients were followed - up at monthly intervals and retreated with a single - dose infusion in case of relapse of signs and symptoms . Clinical assessment was performed using the psoriasis area and severity index ( PASI ) to monitor psoriasis activity ; pruritus and joint pain were assessed on a scale of 0 to 3 . A marked improvement of skin lesions and subjective symptoms was noted in the majority of patients ; an excellent reduction of PASI score ( > or = 75 % ) was observed in 13 . 8 % of cases at week 2 , 71 . 4 % at week 6 and 78 . 6 % at week 10 . During the follow - up period , some patients maintained satisfactory clinical results without requiring any additional infusions . In general , skin lesions showed a trend towards a more prolonged and sustained improvement as compared with subjective symptoms . Treatment was well tolerated and no serious adverse events occurred .","Clinical use and mechanisms of infliximab treatment on inflammatory bowel disease : a recent update . The pathogenesis and treatment of inflammatory bowel disease ( Q9UKU7 ) have been recently advanced , while it is still challenged with high morbidity and poor prognosis . DB00065 , a monoclonal antibody of tumor necrosis factor ( P01375 ) , has emerged as an efficient treatment with many clinical benefits such as quick disease activity reduction and Q9UKU7 patient life quality improvement . However , the biological effects of infliximab on Q9UKU7 need to be elucidated . This paper reviewed the clinical use and recently advanced biological action of infliximab on Q9UKU7 . By forming the stable complex with the soluble or the membrane form of P01375 in fluid environment or on cell surface of immune cell , fibroblast , endothelium , and epithelium , infliximab quenches P01375 activity and performs the important biological actions which lead to amelioration and remission of immune responses . The mechanisms of infliximab treatment for Q9UKU7 were intensively discussed . The recent advances on two topics including predictors and side effects of infliximab treatment were also reviewed .","Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK22___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .","DB00065 treatment reduces the serum levels of interleukin - 23 in patients with rheumatoid arthritis . In this study , we investigated the effect of the antitumor necrosis factor alpha ( anti - P01375 ) antibody , infliximab , combined with methotrexate ( MTX ) and MTX alone on the serum levels of interleukin ( IL ) - 23 and Q16552 in rheumatoid arthritis ( RA ) patients . DB00065 combined with MTX was administered to 26 patients with RA ( infliximab group ) , and MTX alone was given to 20 patients with RA ( MTX group ) . We evaluated clinical and laboratory parameters , including the Disease Activity Scores of 28 joints ( DAS28 ) and serum levels of IL - 23 and Q16552 at baseline and at 14 and 30 weeks after the initial treatment with these drugs . Single regression analysis was performed between the levels of serum IL - 23 and other clinical and laboratory parameters at baseline before the initial treatment with infliximab or MTX . A significant reduction of DAS28 scores was observed in both the infliximab and the MTX group at 14 and 30 weeks after the initial treatment . A significant decrease in serum levels of IL - 23 was observed in the infliximab group but not in the MTX group at 14 and 30 weeks after the initial treatment . Serum Q16552 levels did not show a significant change during the follow - up period . At baseline , before the initial treatment with infliximab or MTX , serum IL - 23 levels showed a significant correlation with DAS28 and the number of swollen joints . This study indicated that the reduction of serum IL - 23 levels in RA patients was a novel action of infliximab .","[ The effect of blocking P01375 in patients with cancer - related cachexia and anorexia ] . Cancer - related cachexia and anorexia are present in more than 80 % of patients with malignancies . The pathophysiology is not fully known and during the past several years major attention was attributed to the function of secreted cytokines , such as P01375 , as a fundamental part of the process . In the attempt to prevent the weight loss , which in many cases causes the patients ' death , many studies have been conducted where the effect of the cytokine P01375 was blocked . This article presents two different studies from the past several years where the effect was inhibited by two different methods : one by the monoclonal antibody DB00065 and the other by blocking the P01375 receptor with DB00005 . Both were double - blinded and the patients were randomly divided into arms , with the control group treated with placebo . In both groups , primary and secondary outcomes were defined , however , in the end , no statistical significance was achieved . In conclusion , cancer - related cachexia and anorexia are not the result of one cytokine by itself and blocking it causes only a minimal change without any statistical significance in cancer patients . It is reasonable to assume that the body adaptation to the tumor , which results in cachexia , is due to several mediators working together rather than a single major mediator .","8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .","Experimental autoimmune encephalomyelitis in the Wistar rat : dependence of MBP - specific T cell responsiveness on P33681 costimulation . Experimental autoimmune encephalomyelitis ( EAE ) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology . EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains . In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin ( PT ) . T cell responses were induced to myelin basic protein . Autoreactive T cells could be totally blocked by the in vitro treatment with ___MASK97___ , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 could reverse the inhibition seen in vitro with ___MASK97___ . The effects of inhibition of P33681 costimulation were also examined by an analysis of cytokine responses and P60568 receptor on T cells . ___MASK97___ treatment in vitro reduced the expression of P60568 receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 , P01579 and P01375 . ___MASK97___ treatment had no effect on P22301 synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 blocking therapies as a potential treatment for models of multiple sclerosis . The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity .","P05362 - independent lymphocyte transmigration across high endothelium : differential up - regulation by interferon gamma , tumor necrosis factor - alpha and interleukin 1 beta . The adhesion of lymphocytes to cytokine - treated high endothelium was studied using cultured high endothelial cells ( O14777 ) . Pretreatment of the O14777 layer with a variety of cytokines caused up - regulation of lymphocyte adhesion with the effects ordered interferon gamma ( P01579 ) greater than tumor necrosis factor - alpha ( P01375 ) greater than or equal to interleukin 1 beta ( IL 1 beta ) . Increased lymphocyte adhesion was found to be independent of P05362 as expression by O14777 was not increased by cytokines and antibodies against P05362 did not block adhesion . The peptide CS1 and anti - beta 1 integrin subunit antibodies , however , caused partial inhibition of lymphocyte adhesion thus indicating a role for fibronectin on O14777 and alpha 4 beta 1 on lymphocytes . Study of the kinetics of lymphocyte adhesion showed that the effects of P01579 and P01375 were persistent and remained detectable 2 . 5 h after removal of the cytokines whereas the effects of IL 1 beta were transient and were not sustained beyond 1 h . All of the cytokines used caused transient increases in the number of surface - bound lymphocytes with P01579 greater than P01375 greater than or equal to IL 1 beta , however , the most dramatic effect was on the transmigration of lymphocytes across the O14777 . Both P01579 and P01375 caused sustained increased transmigration with P01579 having the greater effect . IL 1 beta had little effect on transmigration . This model demonstrates that the binding and transmigration of lymphocytes across O14777 can be differentially regulated by the actions of individual cytokines . These results support the concept that locally produced cytokines regulate O14777 function within the lymph node .","The role of pharmacogenomics in the prediction of efficacy of anti - P01375 therapy in patients with Crohn ' s disease . P01375 plays a central role in the pathophysiology of Crohn ' s disease . DB00065 , a chimeric monoclonal antibody against P01375 , has been shown to be effective and well - tolerated in several large placebo - controlled trials and has become a common treatment for Crohn ' s disease . The blockade of P01375 through the infusion of infliximab is characterized by high clinical efficacy and rapid onset of action . A single infusion of infliximab results in a remission rate of 30 - 40 % . Lack of response appears to be a stable trait even after repeated infusions , suggesting that it might be genetically determined . Mutations in the P01375 gene have been extensively studied as predictors of response with various results . Polymorphisms in the P01375 receptors P19438 and P01375 - R2 have been found not to be associated with treatment response . Similarly , the three mutations in the Q9HC29 gene , which are independently associated with susceptibility to Crohn ' s disease , have also been found not to be associated with treatment response .","Severe gram positive bacterial infection in an ulcerative colitis patient treated with DB00065 . Tumour necrosis factor - alpha ( P01375 - α ) inhibitors represent an important treatment advance for a number of inflammatory conditions , including inflammatory bowel disease . Since their introduction in 1999 , it has become clear that some biological therapies may be associated with an increased risk for bacterial infections . Herein we present the first case of septic arthritis and spine empyema , caused by S . aureus , in a 63 year - old patient with ulcerative colitis , who was under treatment with DB00065 and with 40mg per day of prednisolone .","DB00065 dependency in children with Crohn ' s disease . BACKGROUND : Recently , infliximab dependency has been described . AIM : To assess frequency of ID in 82 consecutive Crohn ' s disease children treated with infliximab 2000 - 2006 and to describe clinical and genetic predictors of long - term infliximab response . METHODS : A phenotype model of infliximab dependency was used to assess treatment response : ' immediate outcome ' ( 30 days after infliximab start ) -- complete / partial / no response . ' Long - term outcome ' : ( i ) prolonged response : maintenance of complete / partial response ; ( ii ) infliximab dependency : relapse < or = 90 days after intended infliximab cessation requiring repeated infusions to regain complete / partial response or need of infliximab > 12 months to sustain response . Polymorphisms P01375 - 308 A > G , P01375 - 857 C > T , Casp9 93 C > T , P48023 - 844 C > T , P01374 252 C > T and Q9HC29 ( R702W , G908R , 1007fs ) were analysed . RESULTS : Ninety - four per cent of children obtained complete / partial response . In long - term outcome , 22 % maintained prolonged response , 12 % had no response , while 66 % became infliximab dependent . Perianal disease and no previous surgery were associated with infliximab dependency ( OR 5 . 34 , 95 % CI : 1 . 24 - 22 . 55 ; OR 6 . 7 , 95 % CI : 1 . 67 - 26 . 61 ) . No association was found with studied polymorphisms . The cumulative probability of surgery 50 months after starting infliximab was 10 % in infliximab dependency , 30 % in prolonged responders and 70 % in nonresponders ( P = 0 . 0002 ) . CONCLUSIONS : Sixty - six per cent of children became infliximab dependent . Perianal disease and no surgery prior to infliximab were associated with infliximab dependency phenotype .","Anti - P01375 therapy for polymyalgia rheumatica : report of 99 cases and review of the literature . The objective of this study was to analyze the clinical , laboratorial , and therapeutical response of polymyalgia rheumatica ( PMR ) to anti - tumor necrosis factor ( anti - P01375 ) treatment . We systematically searched English articles on the subjects of PMR who were treated with P01375 blockers in Pubmed from 1994 to 2010 . In addition , we reported on two patients with PMR who were treated by the Rheumatology Division of the Hospital das Clínicas da Faculdade de Medicina da Universidade in São Paulo , Brazil . Ninety - nine cases of patients with PMR treated with anti - P01375 were reviewed . The age of these patients ranged from 63 to 84 years , and 70 . 7 % of them were female . Disease duration varied from 10 . 5 weeks to 95 months , and time of follow - up varied from 2 weeks to 21 months . DB00065 was the anti - P01375 of choice in three studies , while etanercept was in five . Time to response varied from 2 to 8 weeks . After anti - P01375 treatment , prednisone reduction was observed in all studies . Clinical improvement was found in 7 / 7 studies , and laboratory improvement of at least 50 % of inflammatory markers was observed in 6 / 7 studies . This study demonstrated a good clinical and laboratory response to anti - P01375 therapy in patients with PMR , with or without glucocorticoid .","DB00065 therapy in pediatric Takayasu ' s arteritis : report of two cases . Takayasu arteritis ( TA ) is a chronic vasculitis of unknown etiology . Experience with anti - tumor necrosis factor alpha ( anti - P01375 ) agents in difficult - to - treat patients with TA is limited and refers to adult patients . Here , we present two cases of pediatric TA treated with infliximab , in which clinical remission was observed . Anti - P01375 treatment represents a useful therapy in pediatric Takayasu arteritis too , especially to avoid the risk of long - term corticosteroids toxicity .","[ DB00065 in the treatment of rheumatoid arthritis ] . DB00065 is a chimeric monoclonal antibody capable of neutralizing human P01375 alpha . A number of clinical trials for the treatment of rheumatoid arthritis ( RA ) with infliximab indicated that P01375 alpha blockade was effective and well tolerated with the excellent results occurring at 3 and 10 mg / kg in combination with methotrexate . Treatment of RA patients with the combination of infliximab and methotrexate also prevented radiographic evidence of progression of joint damage . If the clinical efficacy is sustained and the safety is confirmed over the long term , infliximab may become an essential agent of choice for the treatment of RA .","[ DB00065 therapy for three adolescent patients with refractory Takayasu ' s arteritis ] . Takayasu ' s arteritis ( TA ) is a chronic idiopathic inflammatory disease affecting primarily aorta and its proximal branches . Pediatric patients with TA tend to have more severe clinical course and be refractory to conventional treatments compared with adults . Corticosteroids are major treatment of TA , however , high dose is required to get remission . Particularly , adolescent patients are usually suffering from side - effects of excessive dose of corticosteroids . Immunosuppressants are added expecting the corticosteroid sparing agents . However , some patients , such as HLA - B52 positive , tend to be registant to these conventional treatments . Recently , several reports showed the efficacy of DB00065 , anti - tumor necrosis factor ( P01375 ) alpha monoclonal antibody , for adult patients with refractory TA . We described three cases of adolescents with TA treated with DB00065 . It was initially effective in all three patients . However , serious infusion reaction occurred in one of them during 11 ( th ) times of DB00065 infusion and she discontinued the therapy . Other two patients showed good response in initial phase , but clinical manifestations and laboratory findings became worse after several months . In these patients with secondary failure to DB00065 , increased dosage and shortening the interval of infusions provided effectiveness again . DB00065 would be a good choice for adolescent patients with TA refractory to conventional treatments . However , we should carefully monitor safety and efficacy of this agent considering its peculiarity .","Mycoepoxydiene , a fungal polyketide inhibits MCF - 7 cells through simultaneously targeting p53 and NF - κB pathways . Mycoepoxydiene ( Q9UQD0 ) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp . HLY - 1 , which is associated with mangroves ; however , the mechanism of action of Q9UQD0 remains unknown . Here , we report the molecular mechanisms of apoptosis activation and growth inhibition induced by Q9UQD0 in MCF - 7 cells . The present results show that Q9UQD0 induces DNA damage through the production of reactive oxygen species ( ROS ) , which resulted in the phosphorylation of P16104 and the activation of the Q13315 kinase ( Q13315 ) and p53 signaling pathways . In addition , Q9UQD0 increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27 , which eventually resulted in the inhibition of P01375 - α - induced NF - κB transactivation . Therefore , we conclude that Q9UQD0 inhibits MCF - 7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF - κB to disrupt cell proliferation . Because small molecules having both of these effects are rare , further exploration of Q9UQD0 as an antitumor lead compound is needed .","Mechanisms of action of infliximab in inflammatory bowel disease : an anti - inflammatory multitasker . The pro - inflammatory cytokine tumor necrosis factor - alpha ( P01375 ) plays a central role in mucosal inflammation and is a key mediator in the inflammatory cascade in both Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) . DB00065 , a monoclonal antibody against P01375 has been proved highly effective in the clinical management of both forms of Q9UKU7 . Aim of this paper is to review the mechanisms of action of infliximab in Q9UKU7 .","Interstitial pneumonitis associated with infliximab therapy without methotrexate treatment . P01375 ( P01375 ) - α inhibitors are increasingly being used to treat rheumatoid arthritis . DB00065 ( P27352 ) is a P01375 - α inhibitor that is usually used in combination with methotrexate ( MTX ) . Interstitial lung disease ( ILD ) during combination therapy has been attributed to MTX rather than P27352 . However , P27352 - associated ILD without combination with MTX has recently been reported . We describe herein a case of severe ILD secondary to P27352 without MTX therapy .","DB00065 in two patients with juvenile ankylosing spondylitis . DB00065 , a monoclonal chimeric anti - tumor necrosis factor alpha ( anti - P01375 ) antibody , was tried in two patients suffering from severe refractory juvenile ankylosing spondylarthritis with disease duration of more than 10 years . To assess the response , validated clinical activity parameters were monitored prospectively . In both patients , treatment with infliximab at a dosage of 5 mg / kg body weight already led to considerable improvement with loss of joint pain the day after it was given . Bath Ankylosing Spondylitis Functional Index scores decreased from 5 . 8 to 0 and 7 . 2 to 1 . 0 and the Bath Ankylosing Spondylitis Disease Activity Index from 2 . 6 to 1 . 4 and 9 . 0 to 1 . 0 . In one patient , the response to a single infusion continued for more than 8 months . Because of a recurrence of symptoms in intervals of 2 months , the fourth infusion has now been given to the second patient , resulting in immediate clinical response . No side effects have been noted . DB00065 seems to be a promising agent for treatment of active and refractory juvenile ankylosing spondylitis . Controlled studies and long - term observations are warranted .","[ Inhibitors of tumour necrosis factor - alpha for the treatment of arthritis and uveitis in childhood ] . BACKGROUND : Chronic uveitis in childhood is a common complication of juvenile idiopathic arthritis ( JIA ) that frequently leads to loss of vision . Besides from corticosteroids and immunosuppressive drugs , Tumour necrosis factor - alpha ( P01375 ) inhibitors are used frequently . MATERIALS AND METHODS : The literature published before September 2006 was evaluated for the usefulness of P01375 inhibitors ( etanercept , infliximab , adalimumab ) for the treatment of JIA - associated uveitis . RESULTS : P01375 inhibitors are effective drugs for the treatment of chronic uveitis in childhood . The response rate of uveitis in childhood to etanercept was approximately 50 % . However , disease recurrence , first manifestations of uveitis and new complications occurred during the treatment . DB00065 and adalimumab appear to be more effective for the treatment of uveitis in childhood than etanercept . CONCLUSIONS : The therapy with P01375 inhibitors is expensive and increases the long - term risk for secondary diseases , such as tuberculosis and probably malignant lymphoma . Their use should be restricted to uveitis patients not responding to corticosteroids and at least one of established immunosuppressive drugs ."],"string":"[\n \"DB00065 acts directly on human osteoclast precursors and enhances osteoclast formation induced by receptor activator of nuclear factor kappaB ligand in vitro . DB00065 is known to protect against the development of joint destruction . In the present study , we sought to determine whether DB00065 acts directly on human osteoclast precursors and influences monocyte - osteoclast differentiation induced by receptor activator of nuclear factor kappaB ligand ( O14788 ) in vitro . Peripheral blood mononuclear cells ( PBMCs ) isolated from rheumatoid arthritis ( RA ) patients and normal controls were cultured in the presence of O14788 and macrophage colony stimulating factor . DB00065 , antihuman tumor necrosis factor alpha ( TNFalpha ) , antihuman P01375 soluble receptor p55 ( TNFR p55 ) , and antihuman P01375 soluble receptor p75 ( TNFR p75 ) antibodies were added . Osteoclast formation was determined by assessing the number of tartrate - resistant acid phosphatase ( TRAP ) staining cells and the extent of lacunar resorption . Addition of DB00065 resulted in a marked increase in the number of TRAP - positive multinucleated cells ( TRAP (+) MNCs ) and in the extent of lacunar resorption compared with the control cultures . Antihuman TNFalpha antibody showed the same effect ; however , the addition of neither TNFR p55 nor TNFR p75 antibody affected the extent of TRAP (+) MNCs and lacunar resorption . Our results suggest that infliximab acts directly on early osteoclast precursors , and stimulates osteoclast formation and lacunar resorption induced by O14788 in vitro .\",\n \"DB00065 in relapsing polychondritis . Relapsing polychondritis ( RP ) is a rare systemic disease of unknown etiology , characterized by recurrent inflammation of cartilaginous structures and other connective tissues , including the ears , nose , joints , respiratory tract , and others . Due to the presence of typical signs and symptoms , biopsy is seldom necessary . Treatment includes corticosteroids , occasionally associated with immunosuppressive agents , but refractory cases are described . Recent reports suggest that anti - P01375 agents , such as infliximab , may be of value in patients who do not respond to conventional therapy , but experience with this treatment is scarce . In this paper , the authors report the case of a patient with RP refractory to combined treatment with corticosteroids and immunosuppressive agents , who showed a good response to infliximab .\",\n \"Selecting appropriate anti - P01375 agents in inflammatory bowel disease . DB00065 was the first anti - P01375 agent to be approved by the US FDA for the treatment of Crohn ' s disease ( CD ) in 1998 . In the past 10 years , two other agents , adalimumab and certolizumab pegol , have also been approved for the treatment of CD . In the absence of head - to - head comparisons , the efficacy of these agents appear to be similar for the treatment of luminal CD . There are also prospective , randomized , controlled data to support the use of infliximab for the treatment of fistulizing CD and ulcerative colitis , and supportive post hoc data for the use of adalimumab and certolizumab pegol for the treatment of fistulizing CD . Practical matters , such as patient preference regarding the mode of administration , approval by third - party payers and residual patient cost , may actually play a larger role in choosing a particular anti - P01375 agent , as efficacy and safety issues are similar for all three . Unfortunately , many patients do not respond , lose response or develop intolerance to anti - P01375 treatment . Thus , new therapies are needed . DB00108 , the first biologic that is not an anti - P01375 agent , was FDA - approved in January 2008 for the treatment of CD patients who have failed conventional treatment , including anti - P01375 therapy . As we continue to learn more about the pathogenesis of inflammatory bowel disease , novel targets for drug therapy are being developed .\",\n \"Spinal epidural abscess associated with infliximab treatment for psoriatic arthritis . Case report . P01375 - alpha inhibitors are used to treat numerous chronic inflammatory and rheumatological diseases , such as Crohn disease , rheumatoid arthritis , and psoriatic arthritis . Because the mechanism of these inhibitors is to decrease the body ' s inflammatory response , the primary complication of treatment is infection . The authors present the first case of a spinal epidural abscess in a patient receiving long - term infliximab therapy for severe psoriatic arthritis . DB00065 and its side - effect profile are discussed , along with other associated complications .\",\n \"[ Efficacy and security of tumor necrosis factor antagonists in the treatment of rheumatoid arthritis ] . In the last decade , tumor necrosis factor ( P01375 ) antagonists had supposed an important therapeutic advance in the treatment of patients with rheumatoid arthritis ( RA ) in both early and established RA . Three agents currently available -- infliximab , etanercept , and adalimumab -- have been designed to modify the biologic effects of P01375 . DB00065 and adalimumab are monoclonal antibodies , whereas etanercept is a soluble protein , with different pharmacokinetic and pharmacodynamic properties , conditioning some possible adverse effects . Although comparative studies are not available , the 3 drugs have demonstrated efficacy and security , with a better quality of life of patients with RA . DB00065 , etanercept and adalimumab have been proved alone and in combination with methotrexate , with a better therapeutic , clinical , radiological and functional response in the group under combined therapy . Both clinical trials and post - market experience have demonstrated the security of these drugs , minimizing the risks with an adequate selection of patients .\",\n \"Advances in the treatment of Kawasaki disease . PURPOSE OF REVIEW : Intravenous immunoglobulin ( IVIG ) and aspirin is the standard initial therapy in the treatment of Kawasaki disease . Some patients have persistent or recrudescent fever despite this therapy . Although there is no conclusive body of evidence defining the best second and third - line therapies for Kawasaki patients , there have been several recent studies published describing the results of these therapies . RECENT FINDINGS : This review summarizes the current recommendations for the initial therapy and describes the second and third - line therapies studied in Japan and the United States . A recent study in a Japanese population of Kawasaki disease patients at high risk for IVIG resistance found that the group receiving steroids , in addition to IVIG and aspirin , had fewer coronary artery abnormalities than the group receiving IVIG and aspirin alone . Small studies of etanercept and infliximab have showed these P01375 blockers to be well tolerated and effective in the resolution of fever . SUMMARY : Although most practitioners in the USA use IVIG as a second - line therapy for those Kawasaki disease patients who have persistent or recrudescent fever , promising new therapies are under study . DB00065 and steroids are currently the two agents that have been most studied . However , larger studies and studies in genetically diverse populations are needed .\",\n \"Treatment of inflammatory bowel disease : a review of medical therapy . Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) are chronic inflammatory diseases of the gastrointestinal tract . While a cure remains elusive , both can be treated with medications that induce and maintain remission . With the recent advent of therapies that inhibit tumor necrosis factor ( P01375 ) alpha the overlap in medical therapies for UC and CD has become greater . Although DB00244 agents have been a mainstay in the treatment of both CD and UC , the data for their efficacy in patients with CD , particularly as maintenance therapy , are equivocal . Antibiotics may have a limited role in the treatment of colonic CD . Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy ; non - systemic steroids such as oral and rectal budesonide for ileal and right - sided CD and distal UC respectively are also effective in mild - moderate disease . 6 - mercaptopurine ( DB01033 ) and its prodrug azathioprine are steroid - sparing immunomodulators effective in the maintenance of remission of both CD and UC , while methotrexate may be used in both induction and maintenance of CD . DB00065 and adalimumab are anti - P01375 agents approved in the US and Europe for the treatment of Crohn ' s disease , and infliximab is also approved for the treatment of UC .\",\n \"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK55___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .\",\n \"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK34___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .\",\n \"Anti - P01375 immunotherapy is associated with increased gingival inflammation without clinical attachment loss in subjects with rheumatoid arthritis . BACKGROUND : Because periodontitis presents many similarities with rheumatoid arthritis ( RA ) with regard to tumor necrosis factor - alpha ( P01375 ) - induced bone resorption , the benefits of P01375 blockade in RA prompted us to determine its efficacy in treating coexisting periodontitis . METHODS : Periodontal status was evaluated in 40 subjects with RA who were divided into two groups : Group I contained 20 subjects who had received infliximab every 6 weeks for > or = 22 months at the time of periodontal evaluation . The 20 subjects in group II were evaluated before their first infusion with infliximab . Nine subjects in group II had periodontitis . These subjects were reevaluated after they received nine infusions of infliximab . RESULTS : DB00065 tended to aggravate gingival inflammation as indicated by differences in the modified gingival and papillary bleeding indices between subjects in groups I and II with coexisting periodontitis before and after treatment . DB00563 had no effect on periodontal status . Although the plaque index revealed that bacterial infection persisted , the probing depth was equal in groups I and II and equivalent before and after treatment in subjects with periodontitis , whereas attachment loss was decreased after infliximab treatment . CONCLUSIONS : Inflammation and destruction constitute two interrelated yet separate components of periodontitis in patients with RA . Therefore , P01375 blockade could be beneficial in the treatment of periodontitis .\",\n \"[ The immune status changes in patients with inflammatory bowel disease under the influence of mesenchymal stromal cells and infliximab therapy ] . Out of 28 patients with inflammatory bowel disease in 11 ( 39 . 3 % ) revealed the presence of autoantibodies to gastric parietal cells . Appointment of O60682 and infliximab did not lead to a reduction in antibody levels , in fact , in 6 ( 21 . 4 % ) patients had a further increase in the content of mentioned autoantibodies . Identification of autoantibodies to gastric parietal cells is considered as adherence to Q9UKU7 autoimmune gastritis ( formation of a systemic process ) that requires use of corticosteroids . Transplantation of mesenchymal stromal cells in Q9UKU7 reduces enhanced circulation of autoantibodies against antigens of neutrophils cytoplasmic structures , thereby reducing the severity of autoimmune reactions . Transplantation of MSCs reduces autoaggression in patients with ulcerative colitis , reducing the autoreactive clone of B lymphocytes ( P15391 + P06127 + ) . Analysis effectiveness of the therapy . Transplantation of MSCs in Q9UKU7 has a systemic immunoregulatory effect : on the one hand , stimulates oppressed cytokine synthesis , on the other -- reduses the intensity of the autoimmune reactions and activity of pathological processes . DB00065 selectively blocks P01375 , without affecting other proinflammatory cytokines .\",\n \"DB00065 : lack of efficacy on perforating complications in Crohn ' s disease . BACKGROUND : DB00065 ( Remicade ) , a chimeric monoclonal antibody against tumor necrosis factor alpha ( P01375 ) , has emerged as promising therapeutic option in perianal fistulizing Crohn ' s disease ( CD ) . However , little knowledge exists about its use for the treatment of internal fistulas in CD . We present our experience with infliximab in this situation . METHODS : Four patients with CD who had internal fistulas ( Case 1 : entero - enteral and entero - abdominal ; Case 2 : entero - enteral ; Case 3 : entero - enteral and parastomal ; Case 4 : entero - vesical ) were treated with 3 infusions of infliximab ( 5 mg / kg body weight ) with intervals of 2 and 4 weeks . In addition , 3 patients had strictures and 2 patients had perianal fistulas . RESULTS : After the three infusions of infliximab ( 5 mg / kg body weight ) , internal fistulas remained unchanged in all patients . The perianal fistulas present in 2 cases were healed . Administration of infliximab was safe and well tolerated in all cases . CONCLUSION : Treatment with 3 infusions of infliximab ( 5 mg / kg body weight ) led to healing of only the perianal fistulas , whereas the internal fistulas were not influenced . We conclude that in these 4 cases , infliximab was well tolerated but not effective for the management of internal fistulas and was no alternative for surgery .\",\n \"Redo Ileal pouch - anal anastomosis combined with anti - P01375 - α maintenance therapy for Crohn ' s disease with pelvic fistula : report of two cases . Pouch failure has been reported to occur after ileal pouch - anal anastomosis for Crohn ' s disease . We report two cases of patients with Crohn ' s disease , who underwent redo ileal pouch - anal anastomosis ( redo - IPAA ) combined with anti - P01375 - α maintenance therapy , with good functional results . The first patient , a man with presumed ulcerative colitis , suffered pelvic fistula recurrence and anastomotic dehiscence . He underwent redo - IPAA , at which time longitudinal ulcers were found . DB00065 was started 4 days postoperatively and continued . The second patient , a woman treated for ulcerative colitis , underwent laparoscopic IPAA 8 years later . After the development of a pelvic fistula , twisted mesentery of the ileal pouch was found intraoperatively and Crohn ' s disease was diagnosed . DB00051 therapy resulted in fistula closure . Redo - IPAA was performed to normalize the twisted mesentery of the ileal pouch . No complications have been observed in either patient , both of whom have experienced good functional results after closure of the covering stomas .\",\n \"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK93___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .\",\n \"Genetic polymorphisms of tumour necrosis factor receptor superfamily 1A and 1B affect responses to infliximab in Japanese patients with Crohn ' s disease . BACKGROUND : Tumour necrosis factor alpha is the key inflammatory cytokine involved in the pathogenesis of Crohn ' s disease . DB00065 , a chimaeric monoclonal antibody of tumour necrosis factor - alpha is successfully used for the treatment of Crohn ' s disease , although the response to infliximab therapy differs among patients . The genetic background of the individual may partially explain the differences of the responsiveness . AIM : To investigate whether the polymorphisms in these genes are associated with the response to infliximab treatment as tumour necrosis factor - alpha exerts its biological activity through P01375 receptor superfamily 1A and 1B . METHODS : Eighty Crohn ' s disease patients were enrolled in the study and classified into responder and nonresponder according to the efficacy of infliximab treatment . Single nucleotide polymorphisms of P01375 receptor superfamily 1A ( rs767455 and rs4149570 ) and P01375 receptor superfamily 1B ( rs1061622 , rs1061624 and rs3397 ) were determined . RESULTS : The minor allele carrier of rs767455 showed a significant association with a lack of efficacy compared to the major genotype ( OR = 0 . 26 ; 95 % CI : 0 . 08 - 0 . 91 ) . A P01375 receptor superfamily 1B haplotype inferred by rs1061624 and rs3397 also showed significant differences in the distribution between responder and nonresponder ( P = 0 . 01 ) . CONCLUSION : These results suggest that tumour necrosis factor receptor genotypes may be involved in the different responses to infliximab in Japanese patients with Crohn ' s disease .\",\n \"Screening of 134 single nucleotide polymorphisms ( SNPs ) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes . More than 120 published reports have described associations between single nucleotide polymorphisms ( SNPs ) and type 2 diabetes . However , multiple studies of the same variant have often been discordant . From a literature search , we identified previously reported type 2 diabetes - associated SNPs . We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium ( r ( 2 ) > 0 . 8 ) with another typed SNP . Of the 114 SNPs examined , we followed up the 20 most significant SNPs ( P < 0 . 10 ) on an additional 384 case subjects and 366 control subjects from a population - based study in Finland . In the combined data , we replicated association ( P < 0 . 05 ) for 12 SNPs : P37231 Pro12Ala and His447 , Q14654 Glu23Lys and rs5210 , P01375 - 857 , P11168 Ile110Thr , P20823 / TCF1 rs2701175 and GE117881_360 , P35558 - 232 , Q13562 Thr45Ala , P05231 - 598 , and P22413 Lys121Gln . The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association ( P = 0 . 012 ) . We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample ( P = 0 . 03 ) , although we also replicated 4 of 58 SNPs from genes that had only one previous report of association .\",\n \"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK28___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .\",\n \"Experiences with a long - term treatment of a massive gluteal acne inversa with infliximab in Crohn ' s disease . BACKGROUND : In 40 % of all cases of Crohn ' s disease fistulas emerge during the course of disease . Nevertheless , acne inversa has to be taken into account as an infrequent differential diagnosis . DB00065 as an antibody against the pro - inflammatory mediator P01375 is active in cases of acute Crohn ' s disease , concomitant fistulas and cutaneous manifestations . CASE REPORT : We report on the case of a 54 - year - old patient suffering for five years from a severe suppurative fistuling cutaneous disease concomitant to Crohn ' s disease . At the start of treatment the histological findings of a specimen presented chronically fibrosing lymphoplasmacellular dermatitis with both a very high number of plasma cells and a burrow - like fistula system . Due to superinfection the treatment was at first based on the administration of intravenous and oral doses of antibiotic agents , followed by a treatment course of 14 months with methotrexate and seven applications of infliximab . During the Crohn ' s disease , which was accompanied by persisting concomitant discomforts , an extensive surgical sanitation of the fistulous tracts was performed . Acne inversa was diagnosed in the subsequent histological analysis of the operative specimen . CONCLUSIONS : Acne inversa is a very rare cutaneous disease . Several case reports describe the successful treatment of acne inversa concomitant to Crohn ' s disease using anti - P01375 - antibodies . The long - term course of the case presented here shows that the non - response to infliximab might be caused by both the long duration and the distinct grade of seriousness of the acne inversa .\",\n \"DB00065 in ulcerative colitis . DB00065 , a monoclonal anti - P01375 antibody , is commonly used for treatment of moderate to severe Crohn ' s disease ( CD ) . Its role in the treatment for ulcerative colitis ( UC ) remains controversial . We review the role of P01375 in the pathogenesis of UC and describe the randomized , double - blind , placebo - controlled trials and systematic reviews that assess the efficacy of infliximab in the treatment of moderate to severe UC .\",\n \"The link between unpredictable chronic mild stress model for depression and vascular inflammation ? Inflammation has been suggested to be associated with stress - induced depression and cardiovascular dysfunction . P01375 alpha ( P01375 - α ) is a major cytokine in the activation of neuroendocrine , immune , and behavioral responses . In this study , we investigated the effects of infliximab ( a P01375 - α inhibitor ) on endothelium - dependent vascular reactivity , systemic blood pressure , and endothelial nitric oxide synthase ( P29474 ) immunoreactivity in the unpredictable chronic mild stress ( UCMS ) model of depression in rats . There was no significant change between all groups in the systemic blood pressure . In UCMS , endothelium - dependent relaxation of the smooth muscle in response to carbachol was significantly decreased with 50 % maximal response ( E max ) and pD2 values compared with the controls . DB00065 was able to reverse this UCMS effect . Relaxation in response to the nitric oxide ( NO ) donor sodium nitroprusside and papaverine and DB00761 - induced contractile responses was similar between groups . In UCMS , decreased expression of P29474 was detected . Moreover , there was no significant change in UCMS + infliximab group with respect to control rats . Our results suggest that tumor necrosis factor - alpha ( P01375 - α ) could be a major mediator of vascular dysfunction associated with UCMS , leading to decreased expression of P29474 .\",\n \"Linkage assignment of eleven genes to the porcine genome . We report comparative linkage mapping of eleven genes in the swine genome by RFLP analysis . These genes include : Acid phosphatase type 5 ( P13686 ) , Cholecystokinin Type B Receptor ( P32239 ) , Antibiotic Peptide ( P49913 ) , P01308 - like Growth Factor 1 Receptor ( P08069 ) , Integrin Alpha M ( P11215 ) , Integrin Beta 2 ( ITGbeta2 ) , Opioid Receptor Mu - 1 ( P35372 ) , Pro - hormone Converter ( PC1 / 3 ) , DB00162 Binding Q12988 ( P10745 ) , Ribosomal DNA ( RNR1 ) , and Zona Pellucida Glycoprotein 1 ( P60852 ) . The P32239 and ITGbeta2 loci define the ends of the linkage groups on Chromosomes ( Chro ) ( SSC ) 9p and 13qter , respectively .\",\n \"DB00065 for the therapy of chronic sarcoidosis , Baughman RP , Drent M , Kavuru M et al . : DB00065 therapy in patients with chronic sarcoidosis and pulmonary involvement . Am . J . Respir . Crit . Care Med . ( 2006 ) 174 ( 7 ): 795 - 802 . Sarcoidosis is an inflammatory multiorgan disease in which the lungs are the most commonly affected . It can also involve the skin , lupus pernio being a common form of chronic cutaneous sarcoidosis . The histopathologically specific lesion is represented by non - caseating granulomas occurring in the involved organs , with P01375 playing a role in granuloma generation . Several therapies are available , with corticosteroids representing the conventional therapy given as topic or systemic formulations . Anti - P01375 therapies ( such as etanercept or infliximab ) have been assessed so far , the latter most commonly in refractory sarcoidosis . The discussed study evaluates the safety and efficacy of infliximab in chronic sarcoidosis with pulmonary manifestations .\",\n \"Niacin reduces plasma P11597 levels by diminishing liver macrophage content in P11597 transgenic mice . The anti - dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of P11597 . Since liver macrophages contribute to hepatic P11597 expression , we investigated the role of macrophages in the P11597 - lowering effect of niacin in mice . In vitro studies showed that niacin does not directly attenuate P11597 expression in macrophages . Treatment of normolipidemic human P11597 transgenic mice , fed a Western - type diet with niacin for 4 weeks , significantly reduced the hepatic cholesterol concentration ( - 20 % ) , hepatic P11597 gene expression ( - 20 % ) , and plasma P11597 mass ( - 30 % ) . Concomitantly , niacin decreased the hepatic expression of P34810 ( - 44 % ) and P45844 ( - 32 % ) , both of which are specific markers for the hepatic macrophage content . The decrease in hepatic P11597 expression was significantly correlated with the reduction of hepatic macrophage markers . Furthermore , niacin attenuated atherogenic diet - induced inflammation in liver , as evident from decreased expression of P01375 ( - 43 % ) . Niacin similarly decreased the macrophage markers and absolute macrophage content in hyperlipidemic P02649 * 3 - Leiden . P11597 transgenic mice on a Western - type diet . In conclusion , niacin decreases hepatic P11597 expression and plasma P11597 mass by attenuating liver inflammation and macrophage content in response to its primary lipid - lowering effect , rather than by attenuating the macrophage P11597 expression level .\",\n \"Is there a benefit from the concomitant use of immunosupression with anti - P01375 in Crohn ' s disease ; heads or tails ? Over the last some years the increasing knowledge on the pathogenesis of Crohn ' s disease led to the development of a number of biological agents targeting specific molecules involved in gut inflammation , first of all P01375 and its receptors . DB00065 , adalimumab and certolizumab have been successful in inducing and maintaining remission in Crohn ' s disease at both short and long term . This was recently confirmed by a Cochrane meta - analysis and also open label extension follow - up and cohort studies . Emerging new data however indicate that combination therapy with infliximab - azathioprine appears to have added benefit in inducing steroid - free remission and mucosal healing than either infliximab or azathioprine alone in azathioprine - naïve patients with early disease . Similarly the combination of steroids induction and infliximab was efficacious in luminal Crohn ' s disease . In contrast , there seems to be no synergism between methotrexate and infliximab . It is also less clear whether it is beneficial to use short or long - term infliximab - azathioprine combination in patients who previously failed therapy with azathioprine . In contrast , combination may potentially be associated with increased risk for infection and cancer . In case control - studies , especially the combination of steroids and anti - P01375 and older age increased the risk for infectious complications , while scattered case reports point to the potentially increased risk of a rare form of non - Hodgkin ' s lymphoma ( Hepatosplenic T cell lymphoma ) with the use of azathioprine - anti - P01375 combination . The aim of this review is to summarize the benefits and risks for the use combination therapy with P01375 inhibitors in the treatment of Crohn ' s disease .\",\n \"High - dose infliximab prophylaxis in endotoxin - induced uveitis . PURPOSE : The aim of this study to analyze the preventive effect of high - dose infliximab in endotoxin - induced uveitis ( EIU ) in rabbits . METHODS : An experimental study was conducted on 64 rabbits . Salmonella typhimurium lipopolysaccharide endotoxin was intravitreally injected . DB00065 was intravenously ( i . v . ) injected 24 h before the intravitreal injection ( 20 mg / kg ) . The animals were randomly assigned to five groups : group A , saline intravitreal injection ; group B , DB00065 i . v . group C , infliximab + saline ; group D , intravitreal endotoxin and group E , infliximab i . v . + intravitreal endotoxin . With two masked observers , a microscopic examination of aqueous humor ( cells , tumor necrosis factor [ P01375 ] alpha ) and aqueous protein level were performed 24 h after an endotoxin injection and 48 h after an infliximab infusion . RESULTS : DB00065 treatment , at a dose of 20 mg / kg , significantly improved all the parameters . Inflammatory cell infiltration was significantly reduced in the iris , ciliary body , and anterior chamber ( U Mann - Whitney test , P = 0 . 01 ) . Associated with a lower level of P01375 and protein exudate in aqueous humor ( U Mann - Whitney test , P = 0 . 01 ) . CONCLUSIONS : DB00065 , at a dose of 20 mg / kg , is effective in the prophylaxis of the EIU .\",\n \"Treatment with infliximab : Implications in oral surgery ? A case report . DB00065 is a tumour necrosis factor - alpha ( P01375 ) inhibitor ( neutralising antibody ) , which is increasingly being used as an immunosuppressant to manage inflammatory conditions including rheumatoid arthritis , ankylosing spondylitis and Crohn ' s disease . Its side effects include diabetes mellitus , an increased incidence of lymphoma and greater susceptibility to infections such as pulmonary tuberculosis . In patients on infliximab , the oral cavity may act as a bacterial reservoir leading to unwanted local or systemic complications . To date no report describes the potential implication / s of infliximab in patients having oral surgery . This case report may be the first in the English language to report the development of mandibular osteomyelitis after surgical extraction in a patient on infliximab .\",\n \"Earlobe sarcoidosis . BACKGROUND : DB00065 , a P01375 blocking agent , is an upcoming therapeutic option for cases of refractory sarcoidosis . In pulmonary sarcoidosis , changes imaged by DB09150 - PET during infliximab treatment in sarcoidosis patients correlate with signs of clinical improvement . DESIGN : Case - report . RESULTS AND CONCLUSIONS : A patient with severe earlobe sarcoidosis , treated with infliximab , is presented . This case shows that even relatively small extrapulmonary localisations of sarcoidosis can be visualised by DB09150 - PET , and that a decrease of DB09150 - uptake correlates well with clinical improvement on infliximab treatment .\",\n \"[ Proteomic analysis of changes in the serum protein profile by anti - P01375 therapy ] . We analyzed the alternation in serum protein by infliximab therapy using proteomics - based technique . More than 50 gel spots were seen to increase or decrease in correlation with clinical improvements of rheumatoid arthritis ( RA ) . Spots of interest were identified by two dimensional electrophoresis and mass spectrometry . DB00065 therapy reduced the inflammatory proteins such as P02741 , serum amyloid protein A , serum amyloid protein P , and alpha1 - acid glycoprotein , while the therapy increased Apo A - I , retinol - binding protein , vitamin D - binding protein , and gelsolin . This suggested that infliximab therapy shifted the inflammatory status of serum protein profile of RA patients to normal and modified the extracellular actin - scavenging system as well as vitamin and lipid profile .\",\n \"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK70___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .\",\n \"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK67___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK67___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .\",\n \"Anti - inflammatory effects of pravastatin on Helicobacter pylori - induced gastritis in mice . ___MASK96___ , an P04035 inhibitor , exerts anti - inflammatory effects via several mechanisms including induction of endothelial nitric oxide synthase ( P29474 ) . We investigated the effect of pravastatin on Helicobacter pylori - induced gastritis in mice . Mice with or without H . pylori infection received intraperitoneal pravastatin daily for 1 week . Expression of P29474 mRNA and tumor necrosis factor - alpha mRNA and myeloperoxidase activity in gastric tissue was determined . P05164 activity was reduced in a dose - dependent manner by pravastatin , with activity inhibited by 53 . 5 and 73 . 7 % at doses of 0 . 3 and 1 mg / kg , respectively . At a dose of 1 mg / kg , pravastatin reduced the level of tumor necrosis factor - alpha mRNA by 52 . 7 % , while it did not affect P29474 expression . ___MASK96___ had no effects on these inflammatory parameters in uninfected mice . ___MASK96___ did not affect the viability of H . pylori . In conclusion , pravastatin exerts an anti - inflammatory effect on H . pylori - induced gastritis in mice without affecting P29474 expression .\",\n \"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .\",\n \"Effect of infliximab on the healing of intestinal anastomosis . An experimental study in rats . BACKGROUND AND AIM : DB00065 is effective in the induction and maintenance of remission in Crohn ' s disease . Whether , the perioperative administration of anti - P01375 compromises intestinal healing leading to anastomotic failure and increased risk of postoperative complications , remains controversial . The aim of the study was to evaluate the effect of DB00065 on intestinal anastomosis healing . METHODS : Fifty six wistar rats were divided into 4 groups : ( a ) 20 rats were subjected to excision of part of the terminal ileum followed by anastomosis which was evaluated on the 3rd or 7th postoperative day ; ( b ) 20 rats received DB00065 and thereafter , the same surgical protocol as group ( a ) was followed ; ( c ) 8 rats received DB00065 and served as relative control group ; and ( d ) 8 served as absolute control group . Bursting pressure was used for testing intestinal healing . Additionally , the anastomoses were examined macroscopically , histologically and immunohistochemically for TGFb1 , P03956 , P08253 and Collagen V . The results were confirmed by Western blot analysis . RESULTS : There were no significant differences in bursting pressures and septic intra - abdominal events among non - DB00065 ( a ) and DB00065 - treated ( b ) groups . DB00065 - treated ( b ) group showed mild to moderate inflammation , whereas the non - DB00065 ( a ) group exhibited severe inflammation . Expression of TGFb1 , P08253 and collagen V was significantly higher in the DB00065 - treated ( b ) group . CONCLUSION : DB00065 seems to influence intestinal healing in terms of less inflammatory activity and higher tissue remodeling activity .\",\n \"Chronic P01375 - α neutralization does not improve insulin resistance or endothelial function in \\\" healthy \\\" men with metabolic syndrome . The possible contribution of tumor necrosis factor - α ( P01375 - α ) to the development of obesity - associated insulin resistance in humans is still controversial . Our study investigated the effect of P01375 - α neutralization on insulin resistance in healthy , obese and insulin resistant men . We performed a prospective , randomized , double - blind placebo - controlled trial in nine young , healthy obese male subjects with metabolic syndrome and insulin resistance . Volunteers received three infusions ( wks 0 , 2 and 6 ) of infliximab or placebo . P01308 resistance was measured at baseline and after 70 d by homeostatic model assessment ( HOMA ) index as well as by minimal model analysis of an intravenous glucose tolerance test . Endothelial function was accessed before and after intervention by flow mediated dilation . DB00065 improved the inflammatory status as indicated by reduced high sensitivity P02741 ( hsCRP ) and fibrinogen levels ( 2 . 77 ± 0 . 6 to 1 . 8 ± 0 . 5 μg / L , and 3 . 42 ± 0 . 18 to 3 . 18 ± 0 . 28 g / L ; ( day 0 and day 70 , P = 0 . 020 and 0 . 037 respectively ) , but did not improve insulin resistance ( HOMA index and intravenous glucose - tolerance test [ ivGGT ] ) or endothelial function . Despite improvements in inflammatory status , chronic P01375 - α neutralization does not improve insulin resistance or endothelial function in seemingly healthy , but obese , insulin - resistant volunteers . This study severely questions the proposal that P01375 - α is a causative link between adiposity and insulin resistance .\",\n \"Mechanisms for cytotoxic effects of anti - tumor necrosis factor agents on transmembrane tumor necrosis factor alpha - expressing cells : comparison among infliximab , etanercept , and adalimumab . OBJECTIVE : Three anti - tumor necrosis factor alpha ( anti - TNFalpha ) agents have been proved to be effective for rheumatoid arthritis ( RA ) and other inflammatory disorders . DB00065 and adalimumab have been generated as anti - TNFalpha monoclonal antibodies , while etanercept is engineered from human type II P01375 receptors . In spite of all 3 agents ' equal efficacy for RA , both infliximab and adalimumab are effective for other diseases such as Crohn ' s disease and Wegener ' s granulomatosis , while etanercept is not . We undertook this study to understand the different clinical effects of these anti - TNFalpha agents by analyzing their biologic activities on transmembrane TNFalpha . METHODS : Jurkat T cells stably expressing an uncleavable form of transmembrane TNFalpha were used for the following studies : 1 ) flow cytometric analysis of binding activities of anti - P01375 agents to cell surface transmembrane TNFalpha , 2 ) complement - dependent cytotoxicity ( CDC ) , 3 ) antibody - dependent cell - mediated cytotoxicity ( ADCC ) by using peripheral blood mononuclear cells , and 4 ) outside - to - inside ( reverse ) signal transduction through transmembrane TNFalpha estimated by apoptosis and cell cycle analysis using flow cytometry . RESULTS : All of the anti - TNFalpha agents bound to transmembrane TNFalpha . DB00065 and adalimumab exerted almost equal CDC activities , while etanercept showed considerably lower activity . ADCC activities were almost equal among these 3 agents . DB00051 and infliximab induced apoptosis and cell cycle arrest in transmembrane TNFalpha - expressing Jurkat T cells , reflecting an outside - to - inside signal transduction through transmembrane TNFalpha . CONCLUSION : Three different anti - P01375 agents showed different biologic effects on transmembrane TNFalpha . This finding suggests that CDC and outside - to - inside signals by anti - TNFalpha antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn ' s disease and Wegener ' s granulomatosis .\",\n \"Treatment of immune - mediated extraintestinal manifestations of inflammatory bowel disease with infliximab . The introduction of infliximab into clinical practice is one of the most significant advances in the care of patients who have Q9UKU7 . DB00065 has become an important part of the medical armamentarium to treat extraintestinal manifestations that often are refractory to other medications and are a significant cause of morbidity in these patients . Two other P01375 inhibitors recently have demonstrated efficacy in CD : certolizumab pegol and adalimumab . The Food and Drug Administration has approved adalimumab for use in RA . One predicts that these agents also may have activity in the extraintestinal manifestation for Q9UKU7 . To determine whether future biologics are effective in the EIM of Q9UKU7 , one may need to look no further than the vast clinical trial experience in primary chronic inflammatory diseases of the joints and skin : RA and psoriasis . For example , the Food and DRug Administration recently has approved an anti - B - cell therapy , rituximab , and a T - cell costimulation modulator , abatacept , for use in RA . It certainly will be of interest to determine whether these biologic agents demonstrate efficacy in the intestinal and EIM of Q9UKU7 .\",\n \"P01375 alpha antibody ( infliximab ) therapy profoundly down - regulates the inflammation in Crohn ' s ileocolitis . BACKGROUND & AIMS : Anti - tumor necrosis factor alpha monoclonal antibody treatment ( infliximab ) reduces clinical signs and symptoms in patients with Crohn ' s disease . The effects of infliximab on mucosal histopathologic abnormalities in Crohn ' s ileocolitis were studied . METHODS : Thirteen patients with steroid - refractory Crohn ' s disease were treated with a single infusion of infliximab ( 5 - 20 mg / kg ) , and 5 were treated with placebo . Ileal and colonic biopsy specimens of all patients were collected before and 4 weeks after therapy . Severity of inflammation was assessed by a histological score . Immunohistochemical stainings with antibodies against HLA - DR , P34810 , tumor necrosis factor alpha , intercellular adhesion molecule 1 , lymphocyte function - associated antigen , P01730 , CD8 , and interleukin 4 were performed . RESULTS : Total histological activity score was reduced significantly in both ileitis and colitis after infliximab . This is caused by a virtual disappearance of the neutrophils and a reduction of mononuclear cells . Mucosal architecture returned to normal in 4 patients at 4 weeks . The number of lamina propria mononuclear cells decreased because of a global reduction of P01730 (+) and CD8 (+) T lymphocytes and P34810 (+) monocytes . Aberrant colonic epithelial HLA - DR expression completely disappeared . The percentage of intercellular adhesion molecule 1 and lymphocyte function - associated antigen 1 - expressing and interleukin 4 - and tumor necrosis factor - positive lamina propria mononuclear cells sharply decreased . CONCLUSIONS : DB00065 dramatically decreases histological disease activity in Crohn ' s ileocolitis . Signs of active inflammation nearly disappear accompanied by a profound down - regulation of mucosal inflammatory mediators .\",\n \"Differential effect of DB03932 , pravastatin , and fluvastatin on production of Q14116 and expression of P05362 and P25942 in human monocytes . A novel , proinflammatory cytokine , interleukin ( IL ) - 18 production was detected in the medium of human monocytes treated with 3 - hydroxy - 3 - methylglutaryl coenzyme - A ( HMG - DB01992 ) reductase inhibitors , pravastatin , and fluvastatin ( 0 . 1 and 1 muM ) but not with the statin - derived lymphocyte function - associated antigen - 1 ( LFA - 1 ) inhibitor DB03932 , which did not inhibit P04035 . ___MASK96___ and fluvastatin also induced the production of Q14116 , tumor necrosis factor alpha ( P01375 ) and interferon - gamma ( P01579 ) in human peripheral blood mononuclear cells ( PBMC ) in contrast to DB03932 . Q14116 production by PBMC is located upstream of the cytokine cascade activated by these statins . The Q14116 - induced cytokine production was demonstrated to be dependent on adhesion molecule expression on monocytes . In the absence and presence of lower concentrations ( 0 . 1 and 1 ng / ml ) of Q14116 , pravastatin and fluvastatin inhibited the expression of intercellular adhesion molecule ( ICAM ) - 1 and induced the expression of P25942 , whereas DB03932 had no effect . In the presence of higher concentrations ( 5 , 10 , and 100 ng / ml ) of Q14116 , pravastatin , fluvastatin , and DB03932 similarly inhibited the expression of P05362 and P25942 as well as the production of IL - 12 , P01375 , and P01579 in PBMC . The effects of pravastatin and fluvastatin but not DB03932 were abolished by the addition of mevalonate , indicating the involvement of P04035 in the action of pravastatin and fluvastatin . Thus , the effects of DB03932 were distinct from those of pravastatin and fluvastatin in the presence of lower concentrations of Q14116 . It was concluded that DB03932 has the inhibitory effect on an Q14116 - initiated immune response without any activation on monocytes .\",\n \"DB00065 monotherapy for refractory psoriasis : preliminary results . Tumour necrosis factor ( P01375 ) - alpha plays an important role in the pathogenesis of psoriasis . DB00065 is an anti - P01375 chimeric monoclonal antibody , which is licensed for the treatment of rheumatoid arthritis and Crohn ' s disease . Some reports have shown the efficacy of infliximab , either in monotherapy or in combination with methotrexate , for the treatment of psoriatic arthropathy and psoriasis . The efficacy and tolerability of infliximab monotherapy was evaluated in 29 patients with moderate to severe psoriasis , unresponsive to conventional treatments . Fourteen patients suffered from concomitant arthropathy . Patients received intravenous infliximab , 5mg / kg , at weeks 0 , 2 , and 6 . After this 3 - dose - induction regimen , patients were followed - up at monthly intervals and retreated with a single - dose infusion in case of relapse of signs and symptoms . Clinical assessment was performed using the psoriasis area and severity index ( PASI ) to monitor psoriasis activity ; pruritus and joint pain were assessed on a scale of 0 to 3 . A marked improvement of skin lesions and subjective symptoms was noted in the majority of patients ; an excellent reduction of PASI score ( > or = 75 % ) was observed in 13 . 8 % of cases at week 2 , 71 . 4 % at week 6 and 78 . 6 % at week 10 . During the follow - up period , some patients maintained satisfactory clinical results without requiring any additional infusions . In general , skin lesions showed a trend towards a more prolonged and sustained improvement as compared with subjective symptoms . Treatment was well tolerated and no serious adverse events occurred .\",\n \"Clinical use and mechanisms of infliximab treatment on inflammatory bowel disease : a recent update . The pathogenesis and treatment of inflammatory bowel disease ( Q9UKU7 ) have been recently advanced , while it is still challenged with high morbidity and poor prognosis . DB00065 , a monoclonal antibody of tumor necrosis factor ( P01375 ) , has emerged as an efficient treatment with many clinical benefits such as quick disease activity reduction and Q9UKU7 patient life quality improvement . However , the biological effects of infliximab on Q9UKU7 need to be elucidated . This paper reviewed the clinical use and recently advanced biological action of infliximab on Q9UKU7 . By forming the stable complex with the soluble or the membrane form of P01375 in fluid environment or on cell surface of immune cell , fibroblast , endothelium , and epithelium , infliximab quenches P01375 activity and performs the important biological actions which lead to amelioration and remission of immune responses . The mechanisms of infliximab treatment for Q9UKU7 were intensively discussed . The recent advances on two topics including predictors and side effects of infliximab treatment were also reviewed .\",\n \"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK22___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .\",\n \"DB00065 treatment reduces the serum levels of interleukin - 23 in patients with rheumatoid arthritis . In this study , we investigated the effect of the antitumor necrosis factor alpha ( anti - P01375 ) antibody , infliximab , combined with methotrexate ( MTX ) and MTX alone on the serum levels of interleukin ( IL ) - 23 and Q16552 in rheumatoid arthritis ( RA ) patients . DB00065 combined with MTX was administered to 26 patients with RA ( infliximab group ) , and MTX alone was given to 20 patients with RA ( MTX group ) . We evaluated clinical and laboratory parameters , including the Disease Activity Scores of 28 joints ( DAS28 ) and serum levels of IL - 23 and Q16552 at baseline and at 14 and 30 weeks after the initial treatment with these drugs . Single regression analysis was performed between the levels of serum IL - 23 and other clinical and laboratory parameters at baseline before the initial treatment with infliximab or MTX . A significant reduction of DAS28 scores was observed in both the infliximab and the MTX group at 14 and 30 weeks after the initial treatment . A significant decrease in serum levels of IL - 23 was observed in the infliximab group but not in the MTX group at 14 and 30 weeks after the initial treatment . Serum Q16552 levels did not show a significant change during the follow - up period . At baseline , before the initial treatment with infliximab or MTX , serum IL - 23 levels showed a significant correlation with DAS28 and the number of swollen joints . This study indicated that the reduction of serum IL - 23 levels in RA patients was a novel action of infliximab .\",\n \"[ The effect of blocking P01375 in patients with cancer - related cachexia and anorexia ] . Cancer - related cachexia and anorexia are present in more than 80 % of patients with malignancies . The pathophysiology is not fully known and during the past several years major attention was attributed to the function of secreted cytokines , such as P01375 , as a fundamental part of the process . In the attempt to prevent the weight loss , which in many cases causes the patients ' death , many studies have been conducted where the effect of the cytokine P01375 was blocked . This article presents two different studies from the past several years where the effect was inhibited by two different methods : one by the monoclonal antibody DB00065 and the other by blocking the P01375 receptor with DB00005 . Both were double - blinded and the patients were randomly divided into arms , with the control group treated with placebo . In both groups , primary and secondary outcomes were defined , however , in the end , no statistical significance was achieved . In conclusion , cancer - related cachexia and anorexia are not the result of one cytokine by itself and blocking it causes only a minimal change without any statistical significance in cancer patients . It is reasonable to assume that the body adaptation to the tumor , which results in cachexia , is due to several mediators working together rather than a single major mediator .\",\n \"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .\",\n \"Experimental autoimmune encephalomyelitis in the Wistar rat : dependence of MBP - specific T cell responsiveness on P33681 costimulation . Experimental autoimmune encephalomyelitis ( EAE ) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology . EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains . In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin ( PT ) . T cell responses were induced to myelin basic protein . Autoreactive T cells could be totally blocked by the in vitro treatment with ___MASK97___ , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 could reverse the inhibition seen in vitro with ___MASK97___ . The effects of inhibition of P33681 costimulation were also examined by an analysis of cytokine responses and P60568 receptor on T cells . ___MASK97___ treatment in vitro reduced the expression of P60568 receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 , P01579 and P01375 . ___MASK97___ treatment had no effect on P22301 synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 blocking therapies as a potential treatment for models of multiple sclerosis . The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity .\",\n \"P05362 - independent lymphocyte transmigration across high endothelium : differential up - regulation by interferon gamma , tumor necrosis factor - alpha and interleukin 1 beta . The adhesion of lymphocytes to cytokine - treated high endothelium was studied using cultured high endothelial cells ( O14777 ) . Pretreatment of the O14777 layer with a variety of cytokines caused up - regulation of lymphocyte adhesion with the effects ordered interferon gamma ( P01579 ) greater than tumor necrosis factor - alpha ( P01375 ) greater than or equal to interleukin 1 beta ( IL 1 beta ) . Increased lymphocyte adhesion was found to be independent of P05362 as expression by O14777 was not increased by cytokines and antibodies against P05362 did not block adhesion . The peptide CS1 and anti - beta 1 integrin subunit antibodies , however , caused partial inhibition of lymphocyte adhesion thus indicating a role for fibronectin on O14777 and alpha 4 beta 1 on lymphocytes . Study of the kinetics of lymphocyte adhesion showed that the effects of P01579 and P01375 were persistent and remained detectable 2 . 5 h after removal of the cytokines whereas the effects of IL 1 beta were transient and were not sustained beyond 1 h . All of the cytokines used caused transient increases in the number of surface - bound lymphocytes with P01579 greater than P01375 greater than or equal to IL 1 beta , however , the most dramatic effect was on the transmigration of lymphocytes across the O14777 . Both P01579 and P01375 caused sustained increased transmigration with P01579 having the greater effect . IL 1 beta had little effect on transmigration . This model demonstrates that the binding and transmigration of lymphocytes across O14777 can be differentially regulated by the actions of individual cytokines . These results support the concept that locally produced cytokines regulate O14777 function within the lymph node .\",\n \"The role of pharmacogenomics in the prediction of efficacy of anti - P01375 therapy in patients with Crohn ' s disease . P01375 plays a central role in the pathophysiology of Crohn ' s disease . DB00065 , a chimeric monoclonal antibody against P01375 , has been shown to be effective and well - tolerated in several large placebo - controlled trials and has become a common treatment for Crohn ' s disease . The blockade of P01375 through the infusion of infliximab is characterized by high clinical efficacy and rapid onset of action . A single infusion of infliximab results in a remission rate of 30 - 40 % . Lack of response appears to be a stable trait even after repeated infusions , suggesting that it might be genetically determined . Mutations in the P01375 gene have been extensively studied as predictors of response with various results . Polymorphisms in the P01375 receptors P19438 and P01375 - R2 have been found not to be associated with treatment response . Similarly , the three mutations in the Q9HC29 gene , which are independently associated with susceptibility to Crohn ' s disease , have also been found not to be associated with treatment response .\",\n \"Severe gram positive bacterial infection in an ulcerative colitis patient treated with DB00065 . Tumour necrosis factor - alpha ( P01375 - α ) inhibitors represent an important treatment advance for a number of inflammatory conditions , including inflammatory bowel disease . Since their introduction in 1999 , it has become clear that some biological therapies may be associated with an increased risk for bacterial infections . Herein we present the first case of septic arthritis and spine empyema , caused by S . aureus , in a 63 year - old patient with ulcerative colitis , who was under treatment with DB00065 and with 40mg per day of prednisolone .\",\n \"DB00065 dependency in children with Crohn ' s disease . BACKGROUND : Recently , infliximab dependency has been described . AIM : To assess frequency of ID in 82 consecutive Crohn ' s disease children treated with infliximab 2000 - 2006 and to describe clinical and genetic predictors of long - term infliximab response . METHODS : A phenotype model of infliximab dependency was used to assess treatment response : ' immediate outcome ' ( 30 days after infliximab start ) -- complete / partial / no response . ' Long - term outcome ' : ( i ) prolonged response : maintenance of complete / partial response ; ( ii ) infliximab dependency : relapse < or = 90 days after intended infliximab cessation requiring repeated infusions to regain complete / partial response or need of infliximab > 12 months to sustain response . Polymorphisms P01375 - 308 A > G , P01375 - 857 C > T , Casp9 93 C > T , P48023 - 844 C > T , P01374 252 C > T and Q9HC29 ( R702W , G908R , 1007fs ) were analysed . RESULTS : Ninety - four per cent of children obtained complete / partial response . In long - term outcome , 22 % maintained prolonged response , 12 % had no response , while 66 % became infliximab dependent . Perianal disease and no previous surgery were associated with infliximab dependency ( OR 5 . 34 , 95 % CI : 1 . 24 - 22 . 55 ; OR 6 . 7 , 95 % CI : 1 . 67 - 26 . 61 ) . No association was found with studied polymorphisms . The cumulative probability of surgery 50 months after starting infliximab was 10 % in infliximab dependency , 30 % in prolonged responders and 70 % in nonresponders ( P = 0 . 0002 ) . CONCLUSIONS : Sixty - six per cent of children became infliximab dependent . Perianal disease and no surgery prior to infliximab were associated with infliximab dependency phenotype .\",\n \"Anti - P01375 therapy for polymyalgia rheumatica : report of 99 cases and review of the literature . The objective of this study was to analyze the clinical , laboratorial , and therapeutical response of polymyalgia rheumatica ( PMR ) to anti - tumor necrosis factor ( anti - P01375 ) treatment . We systematically searched English articles on the subjects of PMR who were treated with P01375 blockers in Pubmed from 1994 to 2010 . In addition , we reported on two patients with PMR who were treated by the Rheumatology Division of the Hospital das Clínicas da Faculdade de Medicina da Universidade in São Paulo , Brazil . Ninety - nine cases of patients with PMR treated with anti - P01375 were reviewed . The age of these patients ranged from 63 to 84 years , and 70 . 7 % of them were female . Disease duration varied from 10 . 5 weeks to 95 months , and time of follow - up varied from 2 weeks to 21 months . DB00065 was the anti - P01375 of choice in three studies , while etanercept was in five . Time to response varied from 2 to 8 weeks . After anti - P01375 treatment , prednisone reduction was observed in all studies . Clinical improvement was found in 7 / 7 studies , and laboratory improvement of at least 50 % of inflammatory markers was observed in 6 / 7 studies . This study demonstrated a good clinical and laboratory response to anti - P01375 therapy in patients with PMR , with or without glucocorticoid .\",\n \"DB00065 therapy in pediatric Takayasu ' s arteritis : report of two cases . Takayasu arteritis ( TA ) is a chronic vasculitis of unknown etiology . Experience with anti - tumor necrosis factor alpha ( anti - P01375 ) agents in difficult - to - treat patients with TA is limited and refers to adult patients . Here , we present two cases of pediatric TA treated with infliximab , in which clinical remission was observed . Anti - P01375 treatment represents a useful therapy in pediatric Takayasu arteritis too , especially to avoid the risk of long - term corticosteroids toxicity .\",\n \"[ DB00065 in the treatment of rheumatoid arthritis ] . DB00065 is a chimeric monoclonal antibody capable of neutralizing human P01375 alpha . A number of clinical trials for the treatment of rheumatoid arthritis ( RA ) with infliximab indicated that P01375 alpha blockade was effective and well tolerated with the excellent results occurring at 3 and 10 mg / kg in combination with methotrexate . Treatment of RA patients with the combination of infliximab and methotrexate also prevented radiographic evidence of progression of joint damage . If the clinical efficacy is sustained and the safety is confirmed over the long term , infliximab may become an essential agent of choice for the treatment of RA .\",\n \"[ DB00065 therapy for three adolescent patients with refractory Takayasu ' s arteritis ] . Takayasu ' s arteritis ( TA ) is a chronic idiopathic inflammatory disease affecting primarily aorta and its proximal branches . Pediatric patients with TA tend to have more severe clinical course and be refractory to conventional treatments compared with adults . Corticosteroids are major treatment of TA , however , high dose is required to get remission . Particularly , adolescent patients are usually suffering from side - effects of excessive dose of corticosteroids . Immunosuppressants are added expecting the corticosteroid sparing agents . However , some patients , such as HLA - B52 positive , tend to be registant to these conventional treatments . Recently , several reports showed the efficacy of DB00065 , anti - tumor necrosis factor ( P01375 ) alpha monoclonal antibody , for adult patients with refractory TA . We described three cases of adolescents with TA treated with DB00065 . It was initially effective in all three patients . However , serious infusion reaction occurred in one of them during 11 ( th ) times of DB00065 infusion and she discontinued the therapy . Other two patients showed good response in initial phase , but clinical manifestations and laboratory findings became worse after several months . In these patients with secondary failure to DB00065 , increased dosage and shortening the interval of infusions provided effectiveness again . DB00065 would be a good choice for adolescent patients with TA refractory to conventional treatments . However , we should carefully monitor safety and efficacy of this agent considering its peculiarity .\",\n \"Mycoepoxydiene , a fungal polyketide inhibits MCF - 7 cells through simultaneously targeting p53 and NF - κB pathways . Mycoepoxydiene ( Q9UQD0 ) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp . HLY - 1 , which is associated with mangroves ; however , the mechanism of action of Q9UQD0 remains unknown . Here , we report the molecular mechanisms of apoptosis activation and growth inhibition induced by Q9UQD0 in MCF - 7 cells . The present results show that Q9UQD0 induces DNA damage through the production of reactive oxygen species ( ROS ) , which resulted in the phosphorylation of P16104 and the activation of the Q13315 kinase ( Q13315 ) and p53 signaling pathways . In addition , Q9UQD0 increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27 , which eventually resulted in the inhibition of P01375 - α - induced NF - κB transactivation . Therefore , we conclude that Q9UQD0 inhibits MCF - 7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF - κB to disrupt cell proliferation . Because small molecules having both of these effects are rare , further exploration of Q9UQD0 as an antitumor lead compound is needed .\",\n \"Mechanisms of action of infliximab in inflammatory bowel disease : an anti - inflammatory multitasker . The pro - inflammatory cytokine tumor necrosis factor - alpha ( P01375 ) plays a central role in mucosal inflammation and is a key mediator in the inflammatory cascade in both Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) . DB00065 , a monoclonal antibody against P01375 has been proved highly effective in the clinical management of both forms of Q9UKU7 . Aim of this paper is to review the mechanisms of action of infliximab in Q9UKU7 .\",\n \"Interstitial pneumonitis associated with infliximab therapy without methotrexate treatment . P01375 ( P01375 ) - α inhibitors are increasingly being used to treat rheumatoid arthritis . DB00065 ( P27352 ) is a P01375 - α inhibitor that is usually used in combination with methotrexate ( MTX ) . Interstitial lung disease ( ILD ) during combination therapy has been attributed to MTX rather than P27352 . However , P27352 - associated ILD without combination with MTX has recently been reported . We describe herein a case of severe ILD secondary to P27352 without MTX therapy .\",\n \"DB00065 in two patients with juvenile ankylosing spondylitis . DB00065 , a monoclonal chimeric anti - tumor necrosis factor alpha ( anti - P01375 ) antibody , was tried in two patients suffering from severe refractory juvenile ankylosing spondylarthritis with disease duration of more than 10 years . To assess the response , validated clinical activity parameters were monitored prospectively . In both patients , treatment with infliximab at a dosage of 5 mg / kg body weight already led to considerable improvement with loss of joint pain the day after it was given . Bath Ankylosing Spondylitis Functional Index scores decreased from 5 . 8 to 0 and 7 . 2 to 1 . 0 and the Bath Ankylosing Spondylitis Disease Activity Index from 2 . 6 to 1 . 4 and 9 . 0 to 1 . 0 . In one patient , the response to a single infusion continued for more than 8 months . Because of a recurrence of symptoms in intervals of 2 months , the fourth infusion has now been given to the second patient , resulting in immediate clinical response . No side effects have been noted . DB00065 seems to be a promising agent for treatment of active and refractory juvenile ankylosing spondylitis . Controlled studies and long - term observations are warranted .\",\n \"[ Inhibitors of tumour necrosis factor - alpha for the treatment of arthritis and uveitis in childhood ] . BACKGROUND : Chronic uveitis in childhood is a common complication of juvenile idiopathic arthritis ( JIA ) that frequently leads to loss of vision . Besides from corticosteroids and immunosuppressive drugs , Tumour necrosis factor - alpha ( P01375 ) inhibitors are used frequently . MATERIALS AND METHODS : The literature published before September 2006 was evaluated for the usefulness of P01375 inhibitors ( etanercept , infliximab , adalimumab ) for the treatment of JIA - associated uveitis . RESULTS : P01375 inhibitors are effective drugs for the treatment of chronic uveitis in childhood . The response rate of uveitis in childhood to etanercept was approximately 50 % . However , disease recurrence , first manifestations of uveitis and new complications occurred during the treatment . DB00065 and adalimumab appear to be more effective for the treatment of uveitis in childhood than etanercept . CONCLUSIONS : The therapy with P01375 inhibitors is expensive and increases the long - term risk for secondary diseases , such as tuberculosis and probably malignant lymphoma . Their use should be restricted to uveitis patients not responding to corticosteroids and at least one of established immunosuppressive drugs .\"\n]"},"candidates":{"kind":"list like","value":["___MASK22___","___MASK28___","___MASK34___","___MASK55___","___MASK67___","___MASK70___","___MASK93___","___MASK96___","___MASK97___"],"string":"[\n \"___MASK22___\",\n \"___MASK28___\",\n \"___MASK34___\",\n \"___MASK55___\",\n \"___MASK67___\",\n \"___MASK70___\",\n \"___MASK93___\",\n \"___MASK96___\",\n \"___MASK97___\"\n]"},"answer":{"kind":"string","value":"___MASK97___"},"id":{"kind":"string","value":"MH_train_486"}}},{"rowIdx":487,"cells":{"query":{"kind":"string","value":"interacts_with DB09029?"},"supports":{"kind":"list like","value":["Cyclophosphamide and other new agents for the treatment of severe aplastic anemia . Severe aplastic anemia ( P0DJI8 ) has a poor prognosis in the absence of treatment . Current accepted therapeutic strategies include allogeneic stem - cell transplantation and immunosuppression , both resulting in long - term survival in the majority of patients . Although human leukocyte antigen ( HLA ) - matched sibling stem - cell transplantation is highly effective , the 25 % probability of finding a suitable sibling donor within a family renders this approach available to only a minority of patients . Transplantation using HLA - matched , unrelated donors carries a high risk of treatment failure along with considerable toxicity . While combined immunosuppression with both antithymocyte globulin ( ATG ) and cyclosporine A ( Q13216 ) produces hematologic improvement in most patients , relapse is common . Late evolution of aplastic anemia to other serious hematologic disorders , including paroxysmal nocturnal hemoglobinuria ( PNH ) , myelodysplasia , and acute leukemia , is also a significant problem following treatment with ATG / Q13216 . Recently , results of immunosuppression in P0DJI8 with another potent immunosuppressive agent , cyclophosphamide , were reported in a small number of patients . The overall response rate was similar to that seen with ATG / Q13216 , but relapse and late clonal disease were not observed during a long period of follow - up . A larger randomized trial comparing sustained hematologic response rates to either conventional immunosuppression with ATG / Q13216 or high - dose cyclophosphamide and Q13216 is now underway ; secondary end points include response duration , event - free survival , and overall survival . Additionally , a number of protocols designed to test the efficacy of alternative immunosuppressive or immunomodulatory agents are being developed .","Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .","8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .","The influence of non - HLA gene polymorphisms and interactions on disease risk in a Western Australian multiple sclerosis cohort . Non - Human Leukocyte Antigen ( HLA ) genes have concomitant , although modest , effects on multiple sclerosis ( MS ) susceptibility ; however findings have varied in different populations . Here we present the results of an association study of 16 single nucleotide polymorphisms ( SNPs ) in 10 non - HLA genes ( P16871 , P01589 , CLEC - 16A , P29597 , P19256 , Q13568 , P40763 , P16410 , P02649 , P05362 ) in a Western Australian cohort of 350 MS patients and 498 population control subjects . Our results indicate that in this population , SNPs in P16871 , P29597 , Q13568 and P02649 have modifying effects on MS susceptibility . We also found evidence of interactive protective effects between polymorphisms in the P16871 / P19256 , CLEC - 16A / P16410 , and P29597 / Q13568 genes , which in some instances are restricted within HLA - or gender - defined groups .","Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK58___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .","Bacterial translocation in cirrhotic rats stimulates P29474 - derived NO production and impairs mesenteric vascular contractility . DB00435 ( NO ) has been implicated in the arterial vasodilation and associated vascular hyporesponsiveness to vasoconstrictors observed in liver cirrhosis . Bacteria , potent activators of NO and P01375 synthesis , are found in the mesenteric lymph nodes ( MLNs ) of ascitic cirrhotic rats . Here , we investigated the impact of bacterial translocation ( BT ) to MLNs on P01375 production , vascular NO release , and contractility in the mesenteric vasculature of ascitic cirrhotic rats . Vascular response to the alpha - adrenoagonist methoxamine , which is diminished in the superior mesenteric arterial beds of cirrhotic rats , is further blunted in the presence of BT . BT promoted vascular NO release in cirrhotic rats , an effect that depended on pressure - induced shear stress and was blocked by the NO inhibitor N ( omega )- nitro - L - arginine . Removing the endothelium had the same effect . Endothelial NO synthase ( P29474 ) , but not the inducible isoform ( P35228 ) , was present in mesenteric vasculature of cirrhotic rats with and without BT , and its expression was enhanced compared with controls . P01375 was induced in MLNs by BT and accumulated in parallel in the serum . This P01375 production was associated with elevated levels of tetrahydrobiopterin ( BH ( 4 ) ) , a P01375 - stimulated cofactor and enhancer of P29474 - derived NO biosynthesis and NOS activity in mesenteric vasculature . These findings establish a link between BT to MLNs and increased P01375 production and elevated BH ( 4 ) levels enhancing P29474 - derived NO overproduction , further impairing contractility in the cirrhotic mesenteric vasculature .","A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK89___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .","___MASK99___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .","Synergism between bosutinib ( ___MASK48___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .","Desmopressin ( ___MASK89___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK89___ ) also has strong vasodilatory effects . ___MASK89___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK89___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK89___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK89___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK89___ - induced vasodilation .","Novel real - time polymerase chain reaction assay for simultaneous detection of recurrent fusion genes in acute myeloid leukemia . The recent World Health Organization classification recognizes different subtypes of acute myeloid leukemia ( AML ) according to the presence of several recurrent genetic abnormalities . Detection of these abnormalities and other molecular changes is of increasing interest because it contributes to a refined diagnosis and prognostic assessment in AML and enables monitoring of minimal residual disease . These genetic abnormalities can be detected using single RT - PCR , although the screening is still labor intensive and costly . We have developed a novel real - time RT - PCR assay to simultaneously detect 15 AML - associated rearrangements that is a simple and easily applicable method for use in clinical diagnostic laboratories . This method showed 100 % specificity and sensitivity ( 95 % confidence interval , 91 % to 100 % and 92 % to 100 % , respectively ) . The procedure was validated in a series of 105 patients with AML . The method confirmed all translocations detected using standard cytogenetics and fluorescence in situ hybridization and some additional undetected rearrangements . Two patients demonstrated two molecular rearrangements simultaneously , with P11274 - P00519 implicated in both , in addition to Q01196 - MECOM in one patient and P29590 - P10276 in another . In conclusion , this novel real - time RT - PCR assay for simultaneous detection of multiple AML - associated fusion genes is a versatile and sensitive method for reliable screening of recurrent rearrangements in AML .","Serotonin receptor activation leads to neurite outgrowth and neuronal survival . Serotonin 5 - HT1 receptors are implicated in anxiety and depression . These receptors belong to the family A of G - protein - coupled receptors and couple to inhibitory G - proteins . Recent studies show that chronic activation of P08908 receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants . However , the molecular mechanisms and pathways involved are not understood . We used Neuro 2A cells transfected with P08908 receptors and SK - N - SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth . We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G - proteins and proteasomal degradation in this process . Interestingly , the small G - protein Rap and the transcription factor P35610 - 3 are also involved since reducing the levels of Rap1 ( using small interfering RNA ) or P35610 - 3 ( using dominant negative P40763 ) significantly blocks P08908 - receptor - mediated neurite outgrowth . The observed increase in the phosphorylation of Src and P35610 - 3 , at sites leading to their activation , further supports a crucial role for these proteins in neurite outgrowth . We also find that prolonged activation of endogenous P08908 receptors leads to increased cell survival even under starving conditions ; this is completely blocked by co - treatment with the antagonist . Taken together , these findings indicate that activation of the P08908 receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long - term changes required for neurogenesis .","Lung carcinogenesis from chronic obstructive pulmonary disease : characteristics of lung cancer from P48444 and contribution of signal transducers and lung stem cells in the inflammatory microenvironment . Chronic obstructive pulmonary disease ( P48444 ) and lung cancer are closely related . The annual incidence of lung cancer arising from P48444 has been reported to be 0 . 8 - 1 . 7 % . Treatment of lung cancer from P48444 is very difficult due to low cardiopulmonary function , rapid tumor growth , and resistance to molecularly targeted therapies . Chronic inflammation caused by toxic gases can induce P48444 and lung cancer . Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair . Cellular damage can induce induction of necrotic cell death and loss of tissue integrity . Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues . However , inflammatory mediators may promote the growth of bronchioalveolar stem cells , and activation of NF - κB and signal transducer and activator of transcription 3 ( P40763 ) play crucial roles in the development of lung cancer from P48444 . Many of the protumorgenic effects of NF - κB and P40763 activation in immune cells are mediated through paracrine signaling . NF - κB and P40763 also contribute to epithelial - mesenchymal transition . To improve lung cancer treatment outcomes , lung cancer from P48444 must be overcome . In this article , we review the characteristics of lung cancer from P48444 and the mechanisms of carcinogenesis in the inflammatory microenvironment . We also propose the necessity of identifying the mechanisms underlying progression of P48444 to lung cancer , and comment on the clinical implications with respect to lung cancer prevention , screening , and therapy .","Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK47___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .","Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK24___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .","The cleaved cytoplasmic tail of polycystin - 1 regulates Src - dependent P40763 activation . P98161 ( PC1 ) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease ( ADPKD ) . The transcription factor P40763 ( signal transducer and activator of transcription 3 ) was shown to be activated in cyst - lining cells in ADPKD and Q15139 mouse models and may drive renal cyst growth , but the mechanisms leading to persistent P40763 activation are unknown . A proteolytic fragment of PC1 corresponding to the cytoplasmic tail , PC1 - p30 , is overexpressed in ADPKD . Here , we show that PC1 - p30 interacts with the nonreceptor tyrosine kinase Src , resulting in Src - dependent activation of P40763 by tyrosine phosphorylation . The PC1 - p30 - mediated activation of Src / P40763 was independent of JAK family kinases and insensitive to the P40763 inhibitor suppressor of cytokine signaling 3 . Signaling by the P01133 receptor ( P00533 ) or DB02527 amplified the activation of Src / P40763 by PC1 - p30 . Expression of PC1 - p30 changed the cellular response to DB02527 signaling . In the absence of PC1 - p30 , DB02527 dampened P00533 - or P05231 - dependent activation of P40763 ; in the presence of PC1 - p30 , DB02527 amplified Src - dependent activation of P40763 . In the polycystic kidney ( PCK ) rat model , activation of P40763 in renal cystic cells depended on vasopressin receptor 2 ( P30518 ) signaling , which increased DB02527 levels . Genetic inhibition of vasopressin expression or treatment with a pharmacologic P30518 inhibitor strongly suppressed P40763 activation and reduced renal cyst growth . These results suggest that PC1 , via its cleaved cytoplasmic tail , integrates signaling inputs from P00533 and DB02527 , resulting in Src - dependent activation of P40763 and a proliferative response .","Identification of the fused bicyclic 4 - amino - 2 - phenylpyrimidine derivatives as novel and potent DB05876 inhibitors . 2 - Phenyl - 4 - piperidinyl - 6 , 7 - dihydrothieno [ 3 , 4 - d ] pyrimidine derivative ( 2 ) was found to be a new DB05876 inhibitor with moderate Q07343 activity ( IC50 = 150 nM ) . A number of derivatives with a variety of 4 - amino substituents and fused bicyclic pyrimidines were synthesized . Among these , 5 , 5 - dioxo - 7 , 8 - dihydro - 6H - thiopyrano [ 3 , 2 - d ] pyrimidine derivative ( 18 ) showed potent Q07343 inhibitory activity ( IC50 = 25 nM ) . Finally , N - propylacetamide derivative ( 31b ) was determined as a potent inhibitor for both Q07343 ( IC50 = 7 . 5 nM ) and P01375 - α production in mouse splenocytes ( IC50 = 9 . 8 nM ) and showed good in vivo anti - inflammatory activity in the LPS - induced lung inflammation model in mice ( ID50 = 18 mg / kg ) . The binding mode of the new inhibitor ( 31e ) in the catalytic site of Q07343 is presented based on an X - ray crystal structure of the ligand - enzyme complex .","Inhibition of Q16552 as a pharmacological approach for Q9UKU7 . Several experimental approaches have been utilized , in order to critically examine the roles of Q16552 family members in intestinal inflammation . These approaches have included : ( 1 ) the use of Q16552 and Q96PD4 - deficient mice , ( 2 ) specific antibodies directed against Q16552 , ( 3 ) an Q16552 vaccine , ( 4 ) methods to block the Q16552 receptor and ( 5 ) small - molecule inhibitors of Q16552 . Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease ( Q9UKU7 ) , using specific strains of Q16552 - deficient mice . This paper will review the preclinical results using various pharmacological approaches [ specific Q16552 antibodies , an Q16552 receptor fusion protein , IL - 12 / IL - 23 p40 subunit and Q16552 vaccine approaches , as well as a small molecule inhibitor ( Vidofludimus ) ] to inhibit Q16552 in animal models of Q9UKU7 . Recent clinical results in patients with Q9UKU7 will also be discussed for DB09029 ( an Q16552 antibody ) , Brodalumab ( an Q16552 receptor antibody ) and two small - molecule drugs ( Vidofludimus and DB08895 ) , which inhibit Q16552 as part of their overall pharmacological profiles . This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti - Q16552 drugs , as related to drug pharmacodynamics , Q16552 receptor subtypes and other pertinent factors . Finally , future pharmacological approaches of interest will be discussed , such as : ( 1 ) Retinoic acid receptor - related orphan nuclear receptor gamma t ( Rorγt ) antagonists , ( 2 ) P10276 ( RARα ) antagonists , ( 3 ) Pim - 1 kinase inhibitors and ( 4 ) Dual small - molecule inhibitors of NF - κB and P40763 , like synthetic triterpenoids .","A negative feedback loop mediated by P40763 limits human Th17 responses . The transcription factor P40763 is critically required for the differentiation of Th17 cells , a T cell subset involved in various chronic inflammatory diseases . In this article , we report that P40763 also drives a negative - feedback loop that limits the formation of Q16552 - producing T cells within a memory population . By activating human memory P01730 (+) CD45RO (+) T cells at a high density ( HiD ) or a low density ( LoD ) in the presence of the pro - Th17 cytokines IL - 1β , IL - 23 , and TGF - β , we observed that the numbers of Th17 cells were significantly higher under LoD conditions . Assessment of P40763 phosphorylation revealed a more rapid and stronger P40763 activation in HiD cells than in LoD cells . Transient inhibition of active P40763 in HiD cultures significantly enhanced Th17 cell numbers . Expression of the P40763 - regulated ectonucleotidase P49961 , which catalyzes DB00171 hydrolysis , was higher in HiD , than in LoD , cell cultures . Interestingly , inhibition of P49961 ectonucleotidase activity enhanced Th17 responses under HiD conditions . Conversely , blocking the DB00171 receptor Q99572 reduced Th17 responses in LoD cultures . These data suggest that P40763 negatively regulates Th17 cells by limiting the availability of DB00171 . This negative - feedback loop may provide a safety mechanism to limit tissue damage by Th17 cells during chronic inflammation . Furthermore , our results have relevance for the design of novel immunotherapeutics that target the P40763 - signaling pathway , because inhibition of this pathway may enhance , rather than suppress , memory Th17 responses .","DAPk1 inhibits NF - κB activation through P01375 - α and P27352 - γ - induced apoptosis . Recent studies have shown DAPk as a molecular modulator induced by the second messenger , responsible for controlling cell destiny decisions , but the detailed mechanism mediating the role of DAPk1 during cell death is still not fully understood . In this present report , we attempted to characterize the effects of P01375 - α and P27352 - γ on DAPk1 in human ovarian carcinoma cell lines , OVCAR - 3 . Both P01375 - α and P27352 - γ significantly induce DAPk1 levels in a time - dependent manner . At the same time , they both arrested cell cycle progression in the G ( 0 )- G ( 1 ) and G2 / M phase , down - regulated cyclin D1 , P11802 and NF - κB expression , while also up - regulating p27 and p16 expression . Subsequently , the efficacy of the combined treatment with DAPk1 was investigated . In the presence of DAPk1 , P01375 - α or P27352 - γ - induced apoptosis was additively increased , while P01375 - α or P27352 - γ - induced NF - κB activity was inhibited . Conversely , P01375 - α or P27352 - γ - dependent NF - κB activity was further enhanced by the inhibition of DAPk1 with its specific siRNA . The activity of NF - κB was dependent on the level of DAPk1 , indicating the requirement of DAPk1 for the activation of NF - κB . Low levels of DAPk1 expression were frequently observed in different human patient ' s tissue and cancer cell lines compared to normal samples . In addition , over - expression of DAPk1 from either P01375 - α or P27352 - γ - treatment cells suppressed the anti - apoptosis protein P98170 as well as P35354 and P05362 , more than control . Taken together , our data findings suggest that DAPk1 can mediate the pro - apoptotic activity of P01375 - α and P27352 - γ via the NF - κB signaling pathways .","Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .","Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .","The potential role of PD0332991 ( ___MASK13___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK13___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .","Not all monoclonals are created equal - lessons from failed drug trials in Crohn ' s disease . The recent success of the anti - integrin antibody DB09033 can barely conceal the fact that the biologics armamentarium in Crohn ' s disease has barely evolved beyond P01375 blockers so far . This contrasts with other immune - related diseases considered mechanistically and genetically closely related , such as psoriasis and rheumatoid arthritis , where approved biologics target a variety of independent biological mechanisms . Several pharmacological assets that entered clinical development have proven ineffective , or less effective than originally anticipated . While blockade of Q16552 and its receptor via DB09029 and Brodalumab , respectively , worsened Crohn ' s disease , the beneficial effect of IL - 12 / 23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn ' s disease patients who have previously failed on P01375 blockers . Clinical development of the IFNγ blocker DB05111 was stopped despite demonstrating some clinical benefit , while the T cell co - stimulation blocker DB01281 did not exhibit any hint towards efficacy in Crohn ' s disease . Here I review results from these individual development programmes , and also reflect on the lack of efficacy of the P01375 blocker DB00005 . I will discuss aspects of individual trials that might have confounded their interpretation and highlight the evolution in primary and secondary endpoints that have contributed to increasing robustness of results obtained in recent years . Finally , I suggest that mechanistic studies in murine genetic models combined with exploratory immunological studies incorporated in early drug development may represent the key for identifying the next generation of successful pharmacological targets in Crohn ' s disease .","Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK77___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .","Novel path to P05231 trans - signaling through thrombin - induced soluble P05231 receptor release by platelets . Interleukin ( IL ) - 6 is a multifunctional cytokine with a critical role in inflammatory , immunoregulatory and haemopoietic responses . Its receptor consists of an ubiquitously expressed membrane transducing element ( P40189 ) and of the specific element P08887 ( P08887 ) , present only on hepatocytes and some leukocyte subsets . P08887 also exists as soluble protein ( sIL - 6R ) that , in the presence of P05231 , forms a complex able to bind P40189 and , thanks to the mechanism called trans - signaling , transduces P05231 effect through tyrosine phosphorylation and activation of the signal transducer and transcription activator ( P35610 ) - 3 . The aim of this study was to analyze the bidirectional relationships between platelet aggregation and P05231 - dependent effects . While platelets do not produce P05231 , we found that resting platelets express P40189 , but not P08887 , on their membranes . Upon activation by thrombin or calcium ionophore A23187 , but not by ADP , the P08887 is released in soluble form , while cangrelor , the specific inhibitor of Q9H244 receptor , can partially inhibit sIL - 6R release . This sIL - 6R is biologically active and , in the presence of P05231 , can trigger P05231 trans - signaling , inducing an autocrine activation loop ( as measured by an increase in P08887 and P40189 content ) and P40763 phosphorylation . On the other hand , P05231 trans - signaling has no effect on platelet degranulation or aggregation by itself , nor on thrombin - induced platelet aggregation . Our data add an important piece to the puzzle of thrombosis and inflammation : in the presence of P05231 , which can be produced by stressed endothelial cells , the platelet - derived P05231 trans - signaling could be crucial for the evolution of inflammation within a damaged vessel .","Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .","DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .","Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of P40763 signaling pathway . Signal Transducer and Activator of Transcription 3 ( P40763 ) , a common oncogenic mediator , is constitutively activated in many types of human cancers ; therefore it is a major focus in the development of novel anti - cancer agents . Hedyotis diffusa Willd has been used as a major component in several Chinese medicine formulas for the clinical treatment of colorectal cancer ( CRC ) . However , the precise mechanism of its anti - tumor activity remains largely unclear . Using a CRC mouse xenograft model , in the present study we evaluated the effect of the ethanol extract of Hedyotis diffusa Willd ( EEHDW ) on tumor growth in vivo and investigated the underlying molecular mechanisms . We found that EEHDW reduced tumor volume and tumor weight , but had no effect on body weight gain in CRC mice , demonstrating that EEHDW can inhibit CRC growth in vivo without apparent adverse effect . In addition , EEHDW treatment suppressed P40763 phosphorylation in tumor tissues , which in turn resulted in the promotion of cancer cell apoptosis and inhibition of proliferation . Moreover , EEHDW treatment altered the expression pattern of several important target genes of the P40763 signaling pathway , i . e . , decreased expression of P12004 D1 , P11802 and Bcl - 2 as well as up - regulated P38936 and Bax . These results suggest that suppression of the P40763 pathway might be one of the mechanisms by which EEHDW treats colorectal cancer .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","[ New therapeutic strategy for autoimmune and chronic inflammatory disease based on clinical results using P05231 blocking therapy with a humanized anti - P05231 receptor antibody ] . Remarkable clinical effects were observed by P05231 blockage with a humanized anti P05231 receptor antibody in patients with Castleman ' s disease , rheumatoid arthritis , and juvenile inflammatory arthritis . This evidence suggests that the hyper - function of P05231 is an essential key cytokine in the pathogenesis of the above diseases , in which many cytokines , chemokines , and inflammatory molecules are activated . We found , for example , P01375 blocking therapy showed a reduction of acute phase proteins , such as CRP and P0DJI8 , however , the P05231 blockade induced not only reduction but also normalization of CRP and P0DJI8 serum levels . To elucidate this in vivo phenomenon , we analyzed the expression of cytokine inducing CRP and P0DJI8 mRNA with the intracellular signal transduction mechanism in vitro . The results , indicated that the P05231 signal was essential though the activation of P40763 for the induction and augmentation of CRP or P0DJI8 by the associated stimulation with P01375 or IL - 1 . Recently , it is now known that P05231 is a regulatory molecule in the induction of Th17 cells with TGF - beta . Therefore , P05231 blockage may potentially improve autoimmune diseases , beginning with the pathogenic initiation phase . We believe that unknown pathogenic inflammatory phenomena can be clarified using this analytical strategy and cytokine blocking therapy . Furthermore , in the future we hope to induce complete remission of autoimmune diseases by using cytokine blockage freely .","Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK20___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor ."],"string":"[\n \"Cyclophosphamide and other new agents for the treatment of severe aplastic anemia . Severe aplastic anemia ( P0DJI8 ) has a poor prognosis in the absence of treatment . Current accepted therapeutic strategies include allogeneic stem - cell transplantation and immunosuppression , both resulting in long - term survival in the majority of patients . Although human leukocyte antigen ( HLA ) - matched sibling stem - cell transplantation is highly effective , the 25 % probability of finding a suitable sibling donor within a family renders this approach available to only a minority of patients . Transplantation using HLA - matched , unrelated donors carries a high risk of treatment failure along with considerable toxicity . While combined immunosuppression with both antithymocyte globulin ( ATG ) and cyclosporine A ( Q13216 ) produces hematologic improvement in most patients , relapse is common . Late evolution of aplastic anemia to other serious hematologic disorders , including paroxysmal nocturnal hemoglobinuria ( PNH ) , myelodysplasia , and acute leukemia , is also a significant problem following treatment with ATG / Q13216 . Recently , results of immunosuppression in P0DJI8 with another potent immunosuppressive agent , cyclophosphamide , were reported in a small number of patients . The overall response rate was similar to that seen with ATG / Q13216 , but relapse and late clonal disease were not observed during a long period of follow - up . A larger randomized trial comparing sustained hematologic response rates to either conventional immunosuppression with ATG / Q13216 or high - dose cyclophosphamide and Q13216 is now underway ; secondary end points include response duration , event - free survival , and overall survival . Additionally , a number of protocols designed to test the efficacy of alternative immunosuppressive or immunomodulatory agents are being developed .\",\n \"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .\",\n \"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .\",\n \"The influence of non - HLA gene polymorphisms and interactions on disease risk in a Western Australian multiple sclerosis cohort . Non - Human Leukocyte Antigen ( HLA ) genes have concomitant , although modest , effects on multiple sclerosis ( MS ) susceptibility ; however findings have varied in different populations . Here we present the results of an association study of 16 single nucleotide polymorphisms ( SNPs ) in 10 non - HLA genes ( P16871 , P01589 , CLEC - 16A , P29597 , P19256 , Q13568 , P40763 , P16410 , P02649 , P05362 ) in a Western Australian cohort of 350 MS patients and 498 population control subjects . Our results indicate that in this population , SNPs in P16871 , P29597 , Q13568 and P02649 have modifying effects on MS susceptibility . We also found evidence of interactive protective effects between polymorphisms in the P16871 / P19256 , CLEC - 16A / P16410 , and P29597 / Q13568 genes , which in some instances are restricted within HLA - or gender - defined groups .\",\n \"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK58___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .\",\n \"Bacterial translocation in cirrhotic rats stimulates P29474 - derived NO production and impairs mesenteric vascular contractility . DB00435 ( NO ) has been implicated in the arterial vasodilation and associated vascular hyporesponsiveness to vasoconstrictors observed in liver cirrhosis . Bacteria , potent activators of NO and P01375 synthesis , are found in the mesenteric lymph nodes ( MLNs ) of ascitic cirrhotic rats . Here , we investigated the impact of bacterial translocation ( BT ) to MLNs on P01375 production , vascular NO release , and contractility in the mesenteric vasculature of ascitic cirrhotic rats . Vascular response to the alpha - adrenoagonist methoxamine , which is diminished in the superior mesenteric arterial beds of cirrhotic rats , is further blunted in the presence of BT . BT promoted vascular NO release in cirrhotic rats , an effect that depended on pressure - induced shear stress and was blocked by the NO inhibitor N ( omega )- nitro - L - arginine . Removing the endothelium had the same effect . Endothelial NO synthase ( P29474 ) , but not the inducible isoform ( P35228 ) , was present in mesenteric vasculature of cirrhotic rats with and without BT , and its expression was enhanced compared with controls . P01375 was induced in MLNs by BT and accumulated in parallel in the serum . This P01375 production was associated with elevated levels of tetrahydrobiopterin ( BH ( 4 ) ) , a P01375 - stimulated cofactor and enhancer of P29474 - derived NO biosynthesis and NOS activity in mesenteric vasculature . These findings establish a link between BT to MLNs and increased P01375 production and elevated BH ( 4 ) levels enhancing P29474 - derived NO overproduction , further impairing contractility in the cirrhotic mesenteric vasculature .\",\n \"A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK89___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .\",\n \"___MASK99___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .\",\n \"Synergism between bosutinib ( ___MASK48___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .\",\n \"Desmopressin ( ___MASK89___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK89___ ) also has strong vasodilatory effects . ___MASK89___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK89___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK89___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK89___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK89___ - induced vasodilation .\",\n \"Novel real - time polymerase chain reaction assay for simultaneous detection of recurrent fusion genes in acute myeloid leukemia . The recent World Health Organization classification recognizes different subtypes of acute myeloid leukemia ( AML ) according to the presence of several recurrent genetic abnormalities . Detection of these abnormalities and other molecular changes is of increasing interest because it contributes to a refined diagnosis and prognostic assessment in AML and enables monitoring of minimal residual disease . These genetic abnormalities can be detected using single RT - PCR , although the screening is still labor intensive and costly . We have developed a novel real - time RT - PCR assay to simultaneously detect 15 AML - associated rearrangements that is a simple and easily applicable method for use in clinical diagnostic laboratories . This method showed 100 % specificity and sensitivity ( 95 % confidence interval , 91 % to 100 % and 92 % to 100 % , respectively ) . The procedure was validated in a series of 105 patients with AML . The method confirmed all translocations detected using standard cytogenetics and fluorescence in situ hybridization and some additional undetected rearrangements . Two patients demonstrated two molecular rearrangements simultaneously , with P11274 - P00519 implicated in both , in addition to Q01196 - MECOM in one patient and P29590 - P10276 in another . In conclusion , this novel real - time RT - PCR assay for simultaneous detection of multiple AML - associated fusion genes is a versatile and sensitive method for reliable screening of recurrent rearrangements in AML .\",\n \"Serotonin receptor activation leads to neurite outgrowth and neuronal survival . Serotonin 5 - HT1 receptors are implicated in anxiety and depression . These receptors belong to the family A of G - protein - coupled receptors and couple to inhibitory G - proteins . Recent studies show that chronic activation of P08908 receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants . However , the molecular mechanisms and pathways involved are not understood . We used Neuro 2A cells transfected with P08908 receptors and SK - N - SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth . We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G - proteins and proteasomal degradation in this process . Interestingly , the small G - protein Rap and the transcription factor P35610 - 3 are also involved since reducing the levels of Rap1 ( using small interfering RNA ) or P35610 - 3 ( using dominant negative P40763 ) significantly blocks P08908 - receptor - mediated neurite outgrowth . The observed increase in the phosphorylation of Src and P35610 - 3 , at sites leading to their activation , further supports a crucial role for these proteins in neurite outgrowth . We also find that prolonged activation of endogenous P08908 receptors leads to increased cell survival even under starving conditions ; this is completely blocked by co - treatment with the antagonist . Taken together , these findings indicate that activation of the P08908 receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long - term changes required for neurogenesis .\",\n \"Lung carcinogenesis from chronic obstructive pulmonary disease : characteristics of lung cancer from P48444 and contribution of signal transducers and lung stem cells in the inflammatory microenvironment . Chronic obstructive pulmonary disease ( P48444 ) and lung cancer are closely related . The annual incidence of lung cancer arising from P48444 has been reported to be 0 . 8 - 1 . 7 % . Treatment of lung cancer from P48444 is very difficult due to low cardiopulmonary function , rapid tumor growth , and resistance to molecularly targeted therapies . Chronic inflammation caused by toxic gases can induce P48444 and lung cancer . Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair . Cellular damage can induce induction of necrotic cell death and loss of tissue integrity . Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues . However , inflammatory mediators may promote the growth of bronchioalveolar stem cells , and activation of NF - κB and signal transducer and activator of transcription 3 ( P40763 ) play crucial roles in the development of lung cancer from P48444 . Many of the protumorgenic effects of NF - κB and P40763 activation in immune cells are mediated through paracrine signaling . NF - κB and P40763 also contribute to epithelial - mesenchymal transition . To improve lung cancer treatment outcomes , lung cancer from P48444 must be overcome . In this article , we review the characteristics of lung cancer from P48444 and the mechanisms of carcinogenesis in the inflammatory microenvironment . We also propose the necessity of identifying the mechanisms underlying progression of P48444 to lung cancer , and comment on the clinical implications with respect to lung cancer prevention , screening , and therapy .\",\n \"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK47___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .\",\n \"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK24___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .\",\n \"The cleaved cytoplasmic tail of polycystin - 1 regulates Src - dependent P40763 activation . P98161 ( PC1 ) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease ( ADPKD ) . The transcription factor P40763 ( signal transducer and activator of transcription 3 ) was shown to be activated in cyst - lining cells in ADPKD and Q15139 mouse models and may drive renal cyst growth , but the mechanisms leading to persistent P40763 activation are unknown . A proteolytic fragment of PC1 corresponding to the cytoplasmic tail , PC1 - p30 , is overexpressed in ADPKD . Here , we show that PC1 - p30 interacts with the nonreceptor tyrosine kinase Src , resulting in Src - dependent activation of P40763 by tyrosine phosphorylation . The PC1 - p30 - mediated activation of Src / P40763 was independent of JAK family kinases and insensitive to the P40763 inhibitor suppressor of cytokine signaling 3 . Signaling by the P01133 receptor ( P00533 ) or DB02527 amplified the activation of Src / P40763 by PC1 - p30 . Expression of PC1 - p30 changed the cellular response to DB02527 signaling . In the absence of PC1 - p30 , DB02527 dampened P00533 - or P05231 - dependent activation of P40763 ; in the presence of PC1 - p30 , DB02527 amplified Src - dependent activation of P40763 . In the polycystic kidney ( PCK ) rat model , activation of P40763 in renal cystic cells depended on vasopressin receptor 2 ( P30518 ) signaling , which increased DB02527 levels . Genetic inhibition of vasopressin expression or treatment with a pharmacologic P30518 inhibitor strongly suppressed P40763 activation and reduced renal cyst growth . These results suggest that PC1 , via its cleaved cytoplasmic tail , integrates signaling inputs from P00533 and DB02527 , resulting in Src - dependent activation of P40763 and a proliferative response .\",\n \"Identification of the fused bicyclic 4 - amino - 2 - phenylpyrimidine derivatives as novel and potent DB05876 inhibitors . 2 - Phenyl - 4 - piperidinyl - 6 , 7 - dihydrothieno [ 3 , 4 - d ] pyrimidine derivative ( 2 ) was found to be a new DB05876 inhibitor with moderate Q07343 activity ( IC50 = 150 nM ) . A number of derivatives with a variety of 4 - amino substituents and fused bicyclic pyrimidines were synthesized . Among these , 5 , 5 - dioxo - 7 , 8 - dihydro - 6H - thiopyrano [ 3 , 2 - d ] pyrimidine derivative ( 18 ) showed potent Q07343 inhibitory activity ( IC50 = 25 nM ) . Finally , N - propylacetamide derivative ( 31b ) was determined as a potent inhibitor for both Q07343 ( IC50 = 7 . 5 nM ) and P01375 - α production in mouse splenocytes ( IC50 = 9 . 8 nM ) and showed good in vivo anti - inflammatory activity in the LPS - induced lung inflammation model in mice ( ID50 = 18 mg / kg ) . The binding mode of the new inhibitor ( 31e ) in the catalytic site of Q07343 is presented based on an X - ray crystal structure of the ligand - enzyme complex .\",\n \"Inhibition of Q16552 as a pharmacological approach for Q9UKU7 . Several experimental approaches have been utilized , in order to critically examine the roles of Q16552 family members in intestinal inflammation . These approaches have included : ( 1 ) the use of Q16552 and Q96PD4 - deficient mice , ( 2 ) specific antibodies directed against Q16552 , ( 3 ) an Q16552 vaccine , ( 4 ) methods to block the Q16552 receptor and ( 5 ) small - molecule inhibitors of Q16552 . Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease ( Q9UKU7 ) , using specific strains of Q16552 - deficient mice . This paper will review the preclinical results using various pharmacological approaches [ specific Q16552 antibodies , an Q16552 receptor fusion protein , IL - 12 / IL - 23 p40 subunit and Q16552 vaccine approaches , as well as a small molecule inhibitor ( Vidofludimus ) ] to inhibit Q16552 in animal models of Q9UKU7 . Recent clinical results in patients with Q9UKU7 will also be discussed for DB09029 ( an Q16552 antibody ) , Brodalumab ( an Q16552 receptor antibody ) and two small - molecule drugs ( Vidofludimus and DB08895 ) , which inhibit Q16552 as part of their overall pharmacological profiles . This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti - Q16552 drugs , as related to drug pharmacodynamics , Q16552 receptor subtypes and other pertinent factors . Finally , future pharmacological approaches of interest will be discussed , such as : ( 1 ) Retinoic acid receptor - related orphan nuclear receptor gamma t ( Rorγt ) antagonists , ( 2 ) P10276 ( RARα ) antagonists , ( 3 ) Pim - 1 kinase inhibitors and ( 4 ) Dual small - molecule inhibitors of NF - κB and P40763 , like synthetic triterpenoids .\",\n \"A negative feedback loop mediated by P40763 limits human Th17 responses . The transcription factor P40763 is critically required for the differentiation of Th17 cells , a T cell subset involved in various chronic inflammatory diseases . In this article , we report that P40763 also drives a negative - feedback loop that limits the formation of Q16552 - producing T cells within a memory population . By activating human memory P01730 (+) CD45RO (+) T cells at a high density ( HiD ) or a low density ( LoD ) in the presence of the pro - Th17 cytokines IL - 1β , IL - 23 , and TGF - β , we observed that the numbers of Th17 cells were significantly higher under LoD conditions . Assessment of P40763 phosphorylation revealed a more rapid and stronger P40763 activation in HiD cells than in LoD cells . Transient inhibition of active P40763 in HiD cultures significantly enhanced Th17 cell numbers . Expression of the P40763 - regulated ectonucleotidase P49961 , which catalyzes DB00171 hydrolysis , was higher in HiD , than in LoD , cell cultures . Interestingly , inhibition of P49961 ectonucleotidase activity enhanced Th17 responses under HiD conditions . Conversely , blocking the DB00171 receptor Q99572 reduced Th17 responses in LoD cultures . These data suggest that P40763 negatively regulates Th17 cells by limiting the availability of DB00171 . This negative - feedback loop may provide a safety mechanism to limit tissue damage by Th17 cells during chronic inflammation . Furthermore , our results have relevance for the design of novel immunotherapeutics that target the P40763 - signaling pathway , because inhibition of this pathway may enhance , rather than suppress , memory Th17 responses .\",\n \"DAPk1 inhibits NF - κB activation through P01375 - α and P27352 - γ - induced apoptosis . Recent studies have shown DAPk as a molecular modulator induced by the second messenger , responsible for controlling cell destiny decisions , but the detailed mechanism mediating the role of DAPk1 during cell death is still not fully understood . In this present report , we attempted to characterize the effects of P01375 - α and P27352 - γ on DAPk1 in human ovarian carcinoma cell lines , OVCAR - 3 . Both P01375 - α and P27352 - γ significantly induce DAPk1 levels in a time - dependent manner . At the same time , they both arrested cell cycle progression in the G ( 0 )- G ( 1 ) and G2 / M phase , down - regulated cyclin D1 , P11802 and NF - κB expression , while also up - regulating p27 and p16 expression . Subsequently , the efficacy of the combined treatment with DAPk1 was investigated . In the presence of DAPk1 , P01375 - α or P27352 - γ - induced apoptosis was additively increased , while P01375 - α or P27352 - γ - induced NF - κB activity was inhibited . Conversely , P01375 - α or P27352 - γ - dependent NF - κB activity was further enhanced by the inhibition of DAPk1 with its specific siRNA . The activity of NF - κB was dependent on the level of DAPk1 , indicating the requirement of DAPk1 for the activation of NF - κB . Low levels of DAPk1 expression were frequently observed in different human patient ' s tissue and cancer cell lines compared to normal samples . In addition , over - expression of DAPk1 from either P01375 - α or P27352 - γ - treatment cells suppressed the anti - apoptosis protein P98170 as well as P35354 and P05362 , more than control . Taken together , our data findings suggest that DAPk1 can mediate the pro - apoptotic activity of P01375 - α and P27352 - γ via the NF - κB signaling pathways .\",\n \"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .\",\n \"Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .\",\n \"The potential role of PD0332991 ( ___MASK13___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK13___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .\",\n \"Not all monoclonals are created equal - lessons from failed drug trials in Crohn ' s disease . The recent success of the anti - integrin antibody DB09033 can barely conceal the fact that the biologics armamentarium in Crohn ' s disease has barely evolved beyond P01375 blockers so far . This contrasts with other immune - related diseases considered mechanistically and genetically closely related , such as psoriasis and rheumatoid arthritis , where approved biologics target a variety of independent biological mechanisms . Several pharmacological assets that entered clinical development have proven ineffective , or less effective than originally anticipated . While blockade of Q16552 and its receptor via DB09029 and Brodalumab , respectively , worsened Crohn ' s disease , the beneficial effect of IL - 12 / 23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn ' s disease patients who have previously failed on P01375 blockers . Clinical development of the IFNγ blocker DB05111 was stopped despite demonstrating some clinical benefit , while the T cell co - stimulation blocker DB01281 did not exhibit any hint towards efficacy in Crohn ' s disease . Here I review results from these individual development programmes , and also reflect on the lack of efficacy of the P01375 blocker DB00005 . I will discuss aspects of individual trials that might have confounded their interpretation and highlight the evolution in primary and secondary endpoints that have contributed to increasing robustness of results obtained in recent years . Finally , I suggest that mechanistic studies in murine genetic models combined with exploratory immunological studies incorporated in early drug development may represent the key for identifying the next generation of successful pharmacological targets in Crohn ' s disease .\",\n \"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK77___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .\",\n \"Novel path to P05231 trans - signaling through thrombin - induced soluble P05231 receptor release by platelets . Interleukin ( IL ) - 6 is a multifunctional cytokine with a critical role in inflammatory , immunoregulatory and haemopoietic responses . Its receptor consists of an ubiquitously expressed membrane transducing element ( P40189 ) and of the specific element P08887 ( P08887 ) , present only on hepatocytes and some leukocyte subsets . P08887 also exists as soluble protein ( sIL - 6R ) that , in the presence of P05231 , forms a complex able to bind P40189 and , thanks to the mechanism called trans - signaling , transduces P05231 effect through tyrosine phosphorylation and activation of the signal transducer and transcription activator ( P35610 ) - 3 . The aim of this study was to analyze the bidirectional relationships between platelet aggregation and P05231 - dependent effects . While platelets do not produce P05231 , we found that resting platelets express P40189 , but not P08887 , on their membranes . Upon activation by thrombin or calcium ionophore A23187 , but not by ADP , the P08887 is released in soluble form , while cangrelor , the specific inhibitor of Q9H244 receptor , can partially inhibit sIL - 6R release . This sIL - 6R is biologically active and , in the presence of P05231 , can trigger P05231 trans - signaling , inducing an autocrine activation loop ( as measured by an increase in P08887 and P40189 content ) and P40763 phosphorylation . On the other hand , P05231 trans - signaling has no effect on platelet degranulation or aggregation by itself , nor on thrombin - induced platelet aggregation . Our data add an important piece to the puzzle of thrombosis and inflammation : in the presence of P05231 , which can be produced by stressed endothelial cells , the platelet - derived P05231 trans - signaling could be crucial for the evolution of inflammation within a damaged vessel .\",\n \"Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .\",\n \"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .\",\n \"Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of P40763 signaling pathway . Signal Transducer and Activator of Transcription 3 ( P40763 ) , a common oncogenic mediator , is constitutively activated in many types of human cancers ; therefore it is a major focus in the development of novel anti - cancer agents . Hedyotis diffusa Willd has been used as a major component in several Chinese medicine formulas for the clinical treatment of colorectal cancer ( CRC ) . However , the precise mechanism of its anti - tumor activity remains largely unclear . Using a CRC mouse xenograft model , in the present study we evaluated the effect of the ethanol extract of Hedyotis diffusa Willd ( EEHDW ) on tumor growth in vivo and investigated the underlying molecular mechanisms . We found that EEHDW reduced tumor volume and tumor weight , but had no effect on body weight gain in CRC mice , demonstrating that EEHDW can inhibit CRC growth in vivo without apparent adverse effect . In addition , EEHDW treatment suppressed P40763 phosphorylation in tumor tissues , which in turn resulted in the promotion of cancer cell apoptosis and inhibition of proliferation . Moreover , EEHDW treatment altered the expression pattern of several important target genes of the P40763 signaling pathway , i . e . , decreased expression of P12004 D1 , P11802 and Bcl - 2 as well as up - regulated P38936 and Bax . These results suggest that suppression of the P40763 pathway might be one of the mechanisms by which EEHDW treats colorectal cancer .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"[ New therapeutic strategy for autoimmune and chronic inflammatory disease based on clinical results using P05231 blocking therapy with a humanized anti - P05231 receptor antibody ] . Remarkable clinical effects were observed by P05231 blockage with a humanized anti P05231 receptor antibody in patients with Castleman ' s disease , rheumatoid arthritis , and juvenile inflammatory arthritis . This evidence suggests that the hyper - function of P05231 is an essential key cytokine in the pathogenesis of the above diseases , in which many cytokines , chemokines , and inflammatory molecules are activated . We found , for example , P01375 blocking therapy showed a reduction of acute phase proteins , such as CRP and P0DJI8 , however , the P05231 blockade induced not only reduction but also normalization of CRP and P0DJI8 serum levels . To elucidate this in vivo phenomenon , we analyzed the expression of cytokine inducing CRP and P0DJI8 mRNA with the intracellular signal transduction mechanism in vitro . The results , indicated that the P05231 signal was essential though the activation of P40763 for the induction and augmentation of CRP or P0DJI8 by the associated stimulation with P01375 or IL - 1 . Recently , it is now known that P05231 is a regulatory molecule in the induction of Th17 cells with TGF - beta . Therefore , P05231 blockage may potentially improve autoimmune diseases , beginning with the pathogenic initiation phase . We believe that unknown pathogenic inflammatory phenomena can be clarified using this analytical strategy and cytokine blocking therapy . Furthermore , in the future we hope to induce complete remission of autoimmune diseases by using cytokine blockage freely .\",\n \"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK20___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .\"\n]"},"candidates":{"kind":"list like","value":["___MASK13___","___MASK20___","___MASK24___","___MASK47___","___MASK48___","___MASK58___","___MASK77___","___MASK89___","___MASK99___"],"string":"[\n \"___MASK13___\",\n \"___MASK20___\",\n \"___MASK24___\",\n \"___MASK47___\",\n \"___MASK48___\",\n \"___MASK58___\",\n \"___MASK77___\",\n \"___MASK89___\",\n \"___MASK99___\"\n]"},"answer":{"kind":"string","value":"___MASK20___"},"id":{"kind":"string","value":"MH_train_487"}}},{"rowIdx":488,"cells":{"query":{"kind":"string","value":"interacts_with DB00159?"},"supports":{"kind":"list like","value":["Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .","Basal cell carcinoma and variants in genes coding for immune response , DNA repair , folate and iron metabolism . Basal cell carcinoma ( BCC ) is one of the most common neoplasms in the world and its incidence has been increasing worldwide in recent years . BCCs are caused by an interplay between genetic and environment factors . We conducted a case - control association study in BCC patients and controls from Sweden and Finland . Fifteen single nucleotide polymorphisms ( SNPs ) , P05231 - 174G / C , - 634G / C , and - 597G / A ; P22301 - 1082G / A and - 592C / A ; IL - 1beta - 511C / T ; NBS1 exon 5 Glu185Gln ; Q01831 exon 15 Lys939Gln ; P18074 exon 23 Lys751Gln ; P18887 exon 10 Arg399Gln ; O43542 exon 7 Thr241Met ; cyclin D1 exon 4 G870A ; P42898 exon 4 Ala222Val and exon 7 Glu429Ala ; Q30201 exon 4 C282Y were performed by Pyrosequencing and RFLP techniques . Most of the genotype distributions were in accordance with the Hardy - Weinberg equilibrium ( HWE ) , except for P22301 - 1082G / A , where cases with BCC showed a significant deviation from HWE ( P = 0 . 04 ) . Linkage disequilibrium was observed between the - 174 and - 597 alleles in the P05231 gene in the present populations . No difference between BCC and controls appeared in any of the SNPs analyzed . Only the combined distributions of TT / AA genotypes in P42898 exon 4 ( C / T ) and exon 7 ( A / C ) showed slight increase in BCC compared to controls ( P < 0 . 07 , OR : 1 . 94 ; 95 % CI : 0 . 96 - 3 . 89 ) .","Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .","DB00159 modulates DB00091 - induced proinflammatory cytokine over - expression in osteoblastic cells in vitro . Several adverse outcomes are reported in subjects undergoing long term DB00091 ( DB00091 ) treatment . Severe osteopenia has been described in clinical and experimental reports , while beneficial effects of n - 3 polyunsaturated fatty acids ( PUFAs ) on bone metabolism are recognized . In the present study we investigated the effects of n - 3 versus n - 6 PUFAs on osteoblastic cells treated with DB00091 , evaluating the expression of interleukin ( IL ) - 1 & # 223 ; , interleukin - 6 ( P05231 ) , inducible nitric oxide synthase ( P35228 ) , and cyclooxygenase - 2 ( P35354 ) in two different experimental protocols and the production of P05231 , IL - 1 & # 223 ; , and tumor necrosis factor alpha ( TNFalpha ) in cells challenged simultaneously with DB00091 and eicosapentaenoic acid ( EPA ) for 48h . IL - 1 & # 223 ; and P05231 up - regulation , induced by DB00091 , was counteracted by the addition of EPA in both protocols ; on the contrary , arachidonic acid ( AA ) magnified DB00091 the effects . P35354 and P35228 levels were not modified by DB00091 treatment . These in vitro results , that substantiate clinical reports of DB00091 - induced osteopenia , demonstrate a beneficial effect of EPA on DB00091 - altered cytokine profile , opening new perspectives in the non - pharmacological management of adverse outcomes in DB00091 - treated patients .","Glucocorticoid - independent repression of tumor necrosis factor ( P01375 ) alpha - stimulated interleukin ( IL ) - 6 expression by the glucocorticoid receptor : a potential mechanism for protection against an excessive inflammatory response . TNFα signaling and cytokine levels play a crucial role in cervical immunity and the host response to infections . We investigated the role of liganded and unliganded glucocorticoid receptor ( GR ) in P05231 and P10145 gene regulation in response to TNFα in the End1 / E6E7 immortalized human endocervical epithelial cell line . In the absence of glucocorticoids , both decreasing GR protein levels by an siRNA strategy and results with the GR antagonist DB00834 suggest a role for the unliganded GR in reduction of TNFα - induced P05231 and P10145 mRNA levels in End1 / E6E7 cells . Moreover , GR - dependent repression of endogenous P05231 mRNA as well as a minimal P05231 promoter - reporter gene is also demonstrated in COS - 1 cells in the absence of GR ligand , suggesting a transcriptional mechanism that is not cell - specific . TNFα induced recruitment of both the unliganded GR and GR - interacting protein type 1 ( Q9Y3R0 ) to the P05231 promoter . This , together with Q9Y3R0 overexpression studies , suggests a function for Q9Y3R0 as a GR co - repressor in this context . TNFα was shown to induce phosphorylation of the unliganded human GR at DB00133 - 226 but not DB00133 - 211 , unlike dexamethasone , which induced hyperphosphorylation at both serine residues . DB00133 - 226 is shown to be required for the ligand - independent GR - mediated repression of P05231 in response to TNFα . Taken together , these results support a model whereby the unliganded GR attenuates TNFα - stimulated P05231 transcription by a mechanism involving selective phosphorylation and recruitment of the unliganded GR and Q9Y3R0 to the P05231 promoter . These findings suggest the presence of a novel autoregulatory mechanism that may prevent overproduction of P05231 in the endocervix , possibly protecting against negative effects of excessive inflammation .","Adipose tissue dysfunction in nascent metabolic syndrome . The metabolic syndrome ( MetS ) confers an increased risk for both type 2 diabetes mellitus ( T2DM ) and cardiovascular disease ( CVD ) . Moreover , studies on adipose tissue biology in nascent MetS uncomplicated by T2DM and / or CVD are scanty . Recently , we demonstrated that adipose tissue dysregulation and aberrant adipokine secretion contribute towards the syndrome ' s low - grade chronic proinflammatory state and insulin resistance . Specifically , we have made the novel observation that subcutaneous adipose tissue ( P21673 ) in subjects with nascent MetS has increased macrophage recruitment with cardinal crown - like structures . We have also shown that subjects with nascent MetS have increased the levels of P21673 - secreted adipokines ( IL - 1 , P05231 , P10145 , leptin , P02753 - 4 , CRP , P0DJI8 , P05121 , P13500 , and chemerin ) and plasma adipokines ( IL - 1 , P05231 , leptin , P02753 - 4 , CRP , P0DJI8 , and chemerin ) , as well as decreased levels of plasma adiponectin and both plasma and P21673 omentin - 1 . The majority of these abnormalities persisted following correction for increased adiposity . Our data , as well as data from other investigators , thus , highlight the importance of subcutaneous adipose tissue dysfunction in subjects with MetS and its contribution to the proinflammatory state and insulin resistance . This adipokine profile may contribute to increased insulin resistance and low - grade inflammation , promoting the increased risk of T2DM and CVD .","A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK33___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .","Peroxisome - proliferator activator receptor - gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator - activated receptor ( Q07869 ) - gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well - established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co - culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co - cultured without prior treatment with CTZ ) . Next , attachment of CTZ - treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0 . 01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0 . 01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0 . 056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion .","Studies on induction of lamotrigine metabolism in transgenic UGT1 mice . A transgenic ' knock - in ' mouse model expressing a human UGT1 locus ( P01266 - UGT1 ) was recently developed and validated . Although these animals express mouse P22309 proteins , P22310 is a pseudo - gene in mice . Therefore , P01266 - UGT1 mice serve as a ' humanized ' P22310 animal model . Lamotrigine ( LTG ) is primarily metabolized to its N - glucuronide ( LTGG ) by hUGT1A4 . This investigation aimed at examining the impact of pregnane X receptor ( O75469 ) , constitutive androstane receptor ( CAR ) and peroxisome proliferator - activated receptor ( Q07869 ) activators on LTG glucuronidation in vivo and in vitro . P01266 - UGT1 mice were administered the inducers phenobarbital ( CAR ) , pregnenolone - 16alpha - carbonitrile ( O75469 ) , WY - 14643 ( Q07869 ) , ciglitazone ( P37231 ) , or L - 165041 ( Q03181 ) , once daily for 3 or 4 days . Thereafter , LTG was administered orally and blood samples were collected over 24 h . LTG was measured in blood and formation of LTGG was measured in pooled microsomes made from the livers of treated animals . A three - fold increase in in vivo LTG clearance was seen after phenobarbital administration . In microsomes prepared from phenobarbital - treated P01266 - UGT1 animals , 13 - fold higher CL ( int ) ( Vmax / K ( m ) ) value was observed as compared with the untreated transgenic mice . A trend toward induction of catalytic activity in vitro and in vivo was also observed following pregnenolone - 16alpha - carbonitrile and WY - 14643 treatment . This study demonstrates the successful application of P01266 - UGT1 mice as a novel tool to study the impact of induction and regulation on metabolism of P22310 substrates .","Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .","15 - Deoxy - delta 12 , 14 - prostaglandin J2 inhibits the expression of granulocyte - macrophage colony - stimulating factor in endothelial cells stimulated with lipopolysaccharide . P04141 ( GM - P04141 ) , one of major hematopoietic growth factors , activates mature leukocytes . GM - P04141 is produced by endothelial cells stimulated with lipopolysaccharide ( LPS ) , and the LPS - induced GM - P04141 production may play an important role in the activation of neutrophils on the endothelial surface . 15 - Deoxy - delta 12 , 14 - prostaglandin J2 ( 15d - PGJ2 ) is a ligand for peroxisome proliferator - activated receptor - gamma ( P37231 ) and modulates inflammatory reactions by regulating the expression of various genes . We studied the effect of 15d - PGJ2 on the LPS - induced GM - P04141 expression in endothelial cells . Human umbilical vein endothelial cells ( HUVEC ) were cultured and the expressions of GM - P04141 mRNA and protein were analyzed by reverse transcription - polymerase chain reaction and enzyme - linked immunosorbent assay , respectively . 15d - PGJ2 inhibited the LPS - induced GM - P04141 expression in a concentration - dependent manner ; but ciglitazone , another agonist for P37231 , had no effect . This suggests that 15d - PGJ2 inhibits GM - P04141 expression through a mechanism unrelated to P37231 . 15d - PGJ2 induced , by itself , the expression of interleukin - 8 , a potent proinflammatory chemokine , in HUVEC . 15d - PGJ2 may regulate inflammatory reactions by controlling the balance of various cytokines .","Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP3A ) , a phase II enzyme ( P22309 / 6 / 9 ) , two drug transporters ( P - gp and Q9Y6L6 ) and a component of the renal function ( Videau et al . 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat . The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC - MS / MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated . The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1 / 2 with omeprazole / omeprazole - sulfone , midazolam / 1 '- hydroxymidazolam or 4 - hydroxymidazolam and / or dextromethorphan / 3 - methoxymorphinan , CYP2C6 / 11 with tolbutamide / 4 - hydroxytolbutamide , CYP2D1 / 2 with omeprazole / 5 - hydroxyomeprazole or dextromethorphan / dextrorphan , and P19224 / 7 with acetaminophen / acetaminophen - glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP2C11 and CYP2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors .","Tumor cell - derived prostaglandin E2 inhibits monocyte function by interfering with P51681 and Mac - 1 . The cyclooxygenases ( P36551 ) - 1 and P35354 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids . Whereas P23219 is expressed ubiquitously , P35354 is an immediate - early gene often associated with malignant transformation , and a role for the P36551 enzymes in tumor initiation and promotion is discussed . Nonsteroidal anti - inflammatory drugs ( NSAIDs ) like aspirin and indomethacin that block P23219 and - 2 have been shown to have beneficial effects for tumor patients . Therefore , these compounds have gained interest also among oncologists . However , the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood . The prostaglandin - dependent and - independent effect may both account for their antineoplastic action . We show here that tumor cells derived from different tumors regularly produce prostaglandin E ( 2 ) ( PGE ( 2 ) ) interfering with the function of monocytes . In particular , PGE ( 2 ) inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell . This inhibition is most probably due to a modulation of the chemokine receptor P51681 and the beta2 - integrin Mac - 1 . Both down - regulation of P51681 and reduced expression of Mac - 1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues . Since both dysfunctions can be restored with NSAIDs , our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression .","Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK10___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .","Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK39___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK39___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .","Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .","___MASK94___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .","Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK88___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .","Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .","A structural and in vitro characterization of asoprisnil : a selective progesterone receptor modulator . Selective progesterone receptor modulators ( SPRMs ) have been suggested as therapeutic agents for treatment of gynecological disorders . One such SPRM , asoprisnil , was recently in clinical trials for treatment of uterine fibroids and endometriosis . We present the crystal structures of progesterone receptor ( PR ) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor ( NCoR ) and Q9Y618 . This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors . These structures show PR in a different conformation than PR complexed with progesterone ( P4 ) . We profiled asoprisnil in PR - dependent assays to understand further the PR - mediated mechanism of action . We confirmed previous findings that asoprisnil demonstrated antagonism , but not agonism , in a PR - B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay . Asoprisnil , but not DB00834 , weakly recruited the coactivators Q15788 and Q9Y6Q9 . However , asoprisnil strongly recruited the corepressor NCoR in a manner similar to DB00834 . Unlike DB00834 , NCoR binding to asoprisnil - bound PR could be displaced with equal affinity by NCoR or Q15596 peptides . We further showed that it weakly activated T47D cell gene expression of Sgk - 1 and O60437 and antagonized P4 - induced expression of both genes . In rat leiomyoma ELT3 cells , asoprisnil demonstrated partial P4 - like inhibition of cyclooxygenase ( P36551 ) enzymatic activity and P35354 gene expression . In the rat uterotrophic assay , asoprisnil demonstrated no P4 - like ability to oppose estrogen . Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to DB00834 or P4 , and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus .","ω - 3 fatty acid eicosapentaenoic acid attenuates P25189 +- induced neurodegeneration in fully differentiated human SH - SY5Y and primary mesencephalic cells . DB00159 ( EPA ) , a neuroactive omega - 3 fatty acid , has been demonstrated to exert neuroprotective effects in experimental models of Parkinson ' s disease ( PD ) , but the cellular mechanisms of protection are unknown . Here , we studied the effects of EPA in fully differentiated human SH - SY5Y cells and primary mesencephalic neurons treated with P25189 (+) . In both in - vitro models of PD , EPA attenuated an P25189 (+) - induced reduction in cell viability . EPA also prevented the presence of electron - dense cytoplasmic inclusions in SH - SY5Y cells . Then , possible mechanisms of the neuroprotection were studied . In primary neurons , EPA attenuated an P25189 (+) - induced increase in Tyrosine - related kinase B ( TrkB ) receptors . In SH - SY5Y cells , EPA down - regulated reactive oxygen species and nitric oxide . This antioxidant effect of EPA may have been mediated by its inhibition of neuronal NADPH oxidase and cyclo - oxygenase - 2 ( P35354 ) , as P25189 (+) increased the expression of these enzymes . Furthermore , EPA prevented an increase in cytosolic phospholipase A2 ( P47712 ) , an enzyme linked with P35354 in the potentially pro - inflammatory arachidonic acid cascade . Lastly , EPA attenuated an increase in the bax : bcl - 2 ratio , and cytochrome c release . However , EPA did not prevent mitochondrial enlargement or a decrease in mitochondrial membrane potential . This study demonstrated cellular mechanisms by which EPA provided neuroprotective effects in experimental PD .","Chromosomal changes in high - and low - invasive mouse lung adenocarcinoma cell strains derived from early passage mouse lung adenocarcinoma cell strains . The incidence of adenocarcinoma of the lung is increasing in the United States , however , the difficulties in obtaining lung cancer families and representative samples of early to late stages of the disease have lead to the study of mouse models for lung cancer . We used Spectral Karyotyping ( Q06418 ) , mapping with fluorescently labeled genomic clones ( Q5TCZ1 ) , comparative genomic hybridization ( CGH ) arrays , gene expression arrays , Western immunoblot and real time polymerase chain reaction ( PCR ) to analyze nine pairs of high - invasive and low - invasive tumor cell strains derived from early passage mouse lung adenocarcinoma cells to detect molecular changes associated with tumor invasion . The duplication of chromosomes 1 and 15 and deletion of chromosome 8 were significantly associated with a high - invasive phenotype . The duplication of chromosome 1 at band C4 and E1 / 2 - H1 were the most significant chromosomal changes in the high - invasive cell strains . Mapping with Q5TCZ1 and CGH array further narrowed the minimum region of duplication of chromosome 1 to 71 - 82 centimorgans ( cM ) . Expression array analysis and confirmation by real time PCR demonstrated increased expression of P35354 , Q15631 ( TB - P02753 ) , O43781 , Q9H1E3 and Tubulin - alpha4 genes in the high - invasive cell strains . Elevated expression and copy number of these genes , which are involved in inflammation , cell movement , proliferation , inhibition of apoptosis and telomere elongation , were associated with an invasive phenotype . Similar linkage groups are altered in invasive human lung adenocarcinoma , implying that the mouse is a valid genetic model for the study of the progression of human lung adenocarcinoma .","Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK65___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .","DB00159 inhibits prostaglandin D2 generation by inhibiting cyclo - oxygenase - 2 in cultured human mast cells . BACKGROUND : DB00159 ( EPA ) is catalysed by cyclo - oxygenase ( P36551 ) , as is arachidonic acid , and is a competitive inhibitor of arachidonate metabolism . OBJECTIVES : We examined the effect of EPA on prostaglandin ( PG ) D2 generation in the cultured human mast cells with IgE - anti - IgE challenge incubation . METHODS : Cultured human mast cells were incubated with EPA ( 1 micromol / L ) for 20 h , then challenged with anti - IgE incubation after treatment with IgE . At the same time , P36551 inhibitors were tested to identify P23219 and P35354 activity . PGD2 synthetic activity was also assayed in a cell - free homogenate of cultured mast cells with P36551 inhibitors and EPA . DB11320 in the culture medium and in cells was assayed with the HPLC - fluorescent method . PGD2 and PGD3 were assayed with gas chromatography - mass spectrometry and the stable isotope dilution method . RESULTS : Although EPA incubation did not affect histamine release by cultured human mast cells in response to IgE - anti - IgE challenge incubation , it did decrease PGD2 generation by inhibiting the P35354 pathway . In contrast , in the cell - free homogenate of cultured human mast cells , EPA inhibited both P23219 and P35354 activities . CONCLUSION : Pre - incubation with EPA primarily affects the P35354 pathway in cultured human mast cells and reduces PGD2 generation in response to IgE - anti - IgE challenge incubation . These findings suggest that P23219 and P35354 have different substrate flow systems in mast cells . They also suggest that endogenous EPA diet supplementation would reduce PGD2 production and could serve as an anti - inflammatory substrate in human mast cells .","Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .","Creating a genotype - based dosing algorithm for acenocoumarol steady dose . ___MASK33___ is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries . In counterpart of warfarin , there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation . The aim of this study was to develop an algorithm of prediction for acenocoumarol . The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2 , 683 patients . The best regression model to predict stable dosage in the Primary Cohort included clinical factors ( age and body mass index , BSA ) and genetic variants ( Q9BQB6 , P11712 * and P78329 polymorphisms ) and explained up to 50 % of stable dose . In the validation study the clinical algorithm yielded an adjusted R² = 0 . 15 ( estimation ´ s standard error = 4 . 5 ) and the genetic approach improved the dose forecast up to 30 % ( estimation ´ s standard error = 4 . 6 ) . Again , the best model combined clinical and genetic factors ( R² = 0 . 48 ; estimation ´ s standard error = 4 ) which provided the best results of doses estimates within 20 % of the real dose in patients taking lower ( ≤ 7 mg / week ) or higher ( ≥ 25 mg / week ) acenocoumarol doses . In conclusion , we developed a prediction algorithm using clinical data and three polymorphisms in Q9BQB6 , P11712 * and P78329 genes that provided a steady acenocoumarol dose for about 50 % of patients in the Validation Cohort . Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses , those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication .","Cytochromes P450 are differently expressed in normal and varicose human saphenous veins : linkage with varicosis . The expression of cytochrome P450 ( CYP ) enzymes and cyclo - oxygenases ( P36551 ) was investigated in human saphenous veins by reverse transcription - polymerase chain reaction analysis . Non - varicose veins were obtained from patients undergoing aortocoronary bypass grafting , whereas varicose veins were obtained from patients undergoing stripping removal of varicose saphenous veins . In non - varicose veins , Q16678 , CYP2C , P05181 and Q02928 were detected , whereas P51589 , P20815 , P23219 and P35354 were detected almost exclusively in varicose veins . P78329 was not detectable . Except for Q02928 , the levels of individual CYP mRNA were higher in varicose veins than in control veins . Smooth muscle cell volume , determined by a colour image - analysis system , was increased approximately 1 . 5 - fold in varicose veins . Because CYPs and COXs produce various vasoactive compounds , increased expression of these enzymes could be involved in the impairment of vascular tone and may contribute to varicose pathology . Then , CYP or P36551 modulators may be potentially active in the treatment of chronic venous insufficiency .","Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK8___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .","Crosstalk between circulating peroxisome proliferator - activated receptor gamma , adipokines and metabolic syndrome in obese subjects . BACKGROUND : P37231 ( PPARγ ) has direct and indirect function in adipokines production process . We aimed to assess the possible influence of circulating PPARγ on relative risk of metabolic syndrome and also examine the association between circulating PPARγ and adipokines levels among obese subjects . METHODS : A total of 96 obese subjects ( body mass index ( BMI ) ≥ 30 ) were included in the current cross - sectional study . We assessed the body composition with the use of Body Composition Analyzer BC - 418MA - Tanita . The MetS ( metabolic syndrome ) was defined based on the National DB04540 Education Program Adult Treatment Panel III . All baseline blood samples were obtained following an overnight fasting . Serum concentrations of adipokines including DB00162 binding protein 4 ( P02753 ) , omentin - 1 , vaspin , progranulin , nesfatin - 1 and circulating PPARγ was measured with the use of an enzyme - linked immunosorbent assay method . Statistical analyses were performed using software package used for statistical analysis ( SPSS ) . RESULTS : We found main association between circulating PPARγ and body composition in obese population . The risk of metabolic syndrome in subjects with higher concentration of PPARγ was 1 . 9 fold in compared with lower concentration of PPARγ after adjustment for age , sex and BMI . There was significant association between PPARγ and adipokines , specially nesfatin - 1 and progranulin . Defined adipokines pattern among participants demonstrated the markedly higher concentration of vaspin , P02753 and nesfatin - 1 in participants with MetS compared to non - MetS subjects . CONCLUSIONS : It appears all of studied adipokines might have association with PPARγ level and might simultaneously be involve in some common pathway to make susceptible obese subjects for MetS .","Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK76___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK76___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK76___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK76___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK76___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK76___ increased the protein expression of hepatic P05181 and ___MASK76___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK76___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK76___ and RFP - induced hepatotoxicity .","Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .","Mutation of the calmodulin binding motif IQ of the L - type Ca ( v ) 1 . 2 Ca2 + channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation - contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca ( 2 +)/ calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca ( v ) 1 . 2 channel and induces Ca ( 2 +)- dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca ( v ) 1 . 2 ( I1624E ) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca ( v ) 1 . 2 ( Q401N2 ) allele by tamoxifen - induced cardiac - specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca ( v ) 1 . 2 ( I1624E ) hearts , the activity of phospho - P62158 kinase II and phospho - MAPK was increased . CMs expressed reduced levels of Ca ( v ) 1 . 2 ( I1624E ) channel protein and I ( Ca ) . The Ca ( v ) 1 . 2 ( I1624E ) channel showed \" CDI \" kinetics . Despite a lower sarcoplasmic reticulum Ca ( 2 +) content , cellular contractility and global Ca ( 2 +) transients remained unchanged because the EC coupling gain was up - regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca ( v ) 1 . 2 ( I1624E ) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death .","P37231 ( PPARgamma ) and immunoregulation : enhancement of regulatory T cells through PPARgamma - dependent and - independent mechanisms . Peroxisome proliferator - activated receptor ( Q07869 ) gamma is a nuclear hormone receptor primarily characterized for its effect on insulin metabolism . PPARgamma ligands , used to treat human type 2 diabetes , also down - regulate most immune system cells including APCs and pathogenic T cells . These effects putatively underlie the efficacy of PPARgamma ligands in treating animal models of autoimmunity , leading to projections of therapeutic potential in human autoimmunity . However , the relationship between PPARgamma ligands and P01730 + CD25 + regulatory T cells ( Tregs ) has not been examined . Specifically , no studies have examined the role of Tregs in mediating the in vivo immunoregulatory effects of PPARgamma ligands , and there have been no investigations of the use of PPARgamma ligands to treat autoimmunity in the absence of Tregs . We now characterize the novel relationship between ciglitazone , a thiazolidinedione class of PPARgamma ligand , and both murine natural Tregs ( nTregs ) and inducible Tregs ( iTregs ) . In vitro , ciglitazone significantly enhances generation of iTregs in a PPARgamma - independent manner . Surprisingly , and contrary to the current paradigm , we find that , in a model of graft - vs - host disease , the immunotherapeutic effect of ciglitazone requires the presence of nTregs that express PPARgamma . Overall , our results indicate that , unlike its down - regulatory effect on other cells of the immune system , ciglitazone has an enhancing effect on both iTregs and nTregs , and this finding may have important implications for using PPARgamma ligands in treating human autoimmune disease .","Omega - 3 polyunsaturated fatty acids and inflammatory processes : nutrition or pharmacology ? DB00159 ( EPA ) and docosahexaenoic acid ( DB01708 ) are n - 3 fatty acids found in oily fish and fish oil supplements . These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis , adhesion molecule expression and leucocyte - endothelial adhesive interactions , production of eicosanoids like prostaglandins and leukotrienes from the n - 6 fatty acid arachidonic acid , production of inflammatory cytokines and T cell reactivity . In parallel , EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DB01708 give rise to anti - inflammatory and inflammation resolving resolvins and protectins . Mechanisms underlying the anti - inflammatory actions of n - 3 fatty acids include altered cell membrane phospholipid fatty acid composition , disruption of lipid rafts , inhibition of activation of the pro - inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes , activation of the anti - inflammatory transcription factor P37231 ( i . e . peroxisome proliferator activated receptor γ ) and binding to the G protein coupled receptor Q5NUL3 . These mechanisms are interlinked . In adult humans , an EPA plus DB01708 intake greater than 2 g day ⁻ ¹ seems to be required to elicit anti - inflammatory actions , but few dose finding studies have been performed . Animal models demonstrate benefit from n - 3 fatty acids in rheumatoid arthritis ( RA ) , inflammatory bowel disease ( Q9UKU7 ) and asthma . Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta - analyses of the data . Clinical trails of fish oil in patients with Q9UKU7 and asthma are inconsistent with no overall clear evidence of efficacy .","Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case - control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population - based case - control study . We examined nutrient density - adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0 . 026 ) , cooked by pan - frying ( trend P = 0 . 035 ) , and cooked until well - done ( trend P = 0 . 013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0 . 023 ) . A gene - by - diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0 . 008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology .","Gamma tocopherol upregulates the expression of 15 - S - HETE and induces growth arrest through a Q07869 gamma - dependent mechanism in PC - 3 human prostate cancer cells . Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer . Our previous studies in the colon have demonstrated that gamma - tocopherol treatment could upregulate the expression of peroxisome proliferator - activated preceptors ( Q07869 ) gamma , a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation . In this study , we explored the possibility that gamma - tocopherol could induce growth arrest in PC - 3 prostate cancer cells through the regulation of fatty acid metabolism . Growth arrest ( 40 % ) and Q07869 gamma mRNA and protein upregulation was achieved with gamma - tocopherol within 6 h . gamma - Tocopherol - mediated growth arrest was demonstrated to be Q07869 gamma dependent using the agonist GW9662 and a Q07869 gamma dominant negative vector . gamma - tocopherol was shown not to be a direct Q07869 gamma ligand , but rather 15 - S - HETE ( an endogenous Q07869 gamma ligand ) was upregulated by gamma - tocopherol treatment . 15 - Lipoxygenase - 2 , a tumor suppressor and the enzyme that converts arachidonic acid to 15 - S - HETE , was upregulated at 3 h following gamma - tocopherol treatment . Expression of proteins downstream of the Q07869 gamma pathway were examined . P12004 D1 , cyclin D3 , bcl - 2 , and NFkappa B proteins were found to be downregulated following gamma - tocopherol treatment . These data demonstrate that the growth arrest mediated by gamma - tocopherol follows a P37231 - dependent mechanism .","Neem leaf glycoprotein suppresses regulatory T cell mediated suppression of monocyte / macrophage functions . We have shown that neem leaf glycoprotein ( NLGP ) inhibits the regulatory T cell ( Tregs ) induced suppression of tumoricidal functions of P08571 (+) P34810 (+) monocyte / macrophages ( MO / Mφ ) from human peripheral blood . Cytotoxic efficacy of MO / Mφ toward macrophage sensitive cells , U937 , is decreased in presence of Tregs ( induced ) , however , it was increased further by supplementation of NLGP in culture . Associated Treg mediated inhibition of perforin / granzyme B expression and nitric oxide release from MO / Mφ was normalized by NLGP . Altered status of signature cytokines , like , IL - 12 , P22301 , P05231 , TNFα from MO / Mφ under influence of Tregs is also rectified by NLGP . Tregs significantly enhanced the expression of altered marker , mannose receptor ( CD206 ) on P34810 (+) cells that was downregulated upon NLGP exposure . In addition to tumoricidal functions , antigen presenting ability of MO / Mφ is hampered by Treg induced downregulation of P33681 , P42081 and HLA - DB01048 . NLGP upregulated these molecules in MO / Mφ even in the presence of Tregs . Treg mediated inhibition of MO / Mφ chemotaxis in contact dependent manner was also normalized partially by NLGP , where participation of P51681 was documented . Overall results suggest that Treg influenced pro - tumor MO / Mφ functions are rectified in a significant extent by NLGP to create an anti - tumor immune environment .","Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK27___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK27___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK27___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .","Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space ."],"string":"[\n \"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .\",\n \"Basal cell carcinoma and variants in genes coding for immune response , DNA repair , folate and iron metabolism . Basal cell carcinoma ( BCC ) is one of the most common neoplasms in the world and its incidence has been increasing worldwide in recent years . BCCs are caused by an interplay between genetic and environment factors . We conducted a case - control association study in BCC patients and controls from Sweden and Finland . Fifteen single nucleotide polymorphisms ( SNPs ) , P05231 - 174G / C , - 634G / C , and - 597G / A ; P22301 - 1082G / A and - 592C / A ; IL - 1beta - 511C / T ; NBS1 exon 5 Glu185Gln ; Q01831 exon 15 Lys939Gln ; P18074 exon 23 Lys751Gln ; P18887 exon 10 Arg399Gln ; O43542 exon 7 Thr241Met ; cyclin D1 exon 4 G870A ; P42898 exon 4 Ala222Val and exon 7 Glu429Ala ; Q30201 exon 4 C282Y were performed by Pyrosequencing and RFLP techniques . Most of the genotype distributions were in accordance with the Hardy - Weinberg equilibrium ( HWE ) , except for P22301 - 1082G / A , where cases with BCC showed a significant deviation from HWE ( P = 0 . 04 ) . Linkage disequilibrium was observed between the - 174 and - 597 alleles in the P05231 gene in the present populations . No difference between BCC and controls appeared in any of the SNPs analyzed . Only the combined distributions of TT / AA genotypes in P42898 exon 4 ( C / T ) and exon 7 ( A / C ) showed slight increase in BCC compared to controls ( P < 0 . 07 , OR : 1 . 94 ; 95 % CI : 0 . 96 - 3 . 89 ) .\",\n \"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .\",\n \"DB00159 modulates DB00091 - induced proinflammatory cytokine over - expression in osteoblastic cells in vitro . Several adverse outcomes are reported in subjects undergoing long term DB00091 ( DB00091 ) treatment . Severe osteopenia has been described in clinical and experimental reports , while beneficial effects of n - 3 polyunsaturated fatty acids ( PUFAs ) on bone metabolism are recognized . In the present study we investigated the effects of n - 3 versus n - 6 PUFAs on osteoblastic cells treated with DB00091 , evaluating the expression of interleukin ( IL ) - 1 & # 223 ; , interleukin - 6 ( P05231 ) , inducible nitric oxide synthase ( P35228 ) , and cyclooxygenase - 2 ( P35354 ) in two different experimental protocols and the production of P05231 , IL - 1 & # 223 ; , and tumor necrosis factor alpha ( TNFalpha ) in cells challenged simultaneously with DB00091 and eicosapentaenoic acid ( EPA ) for 48h . IL - 1 & # 223 ; and P05231 up - regulation , induced by DB00091 , was counteracted by the addition of EPA in both protocols ; on the contrary , arachidonic acid ( AA ) magnified DB00091 the effects . P35354 and P35228 levels were not modified by DB00091 treatment . These in vitro results , that substantiate clinical reports of DB00091 - induced osteopenia , demonstrate a beneficial effect of EPA on DB00091 - altered cytokine profile , opening new perspectives in the non - pharmacological management of adverse outcomes in DB00091 - treated patients .\",\n \"Glucocorticoid - independent repression of tumor necrosis factor ( P01375 ) alpha - stimulated interleukin ( IL ) - 6 expression by the glucocorticoid receptor : a potential mechanism for protection against an excessive inflammatory response . TNFα signaling and cytokine levels play a crucial role in cervical immunity and the host response to infections . We investigated the role of liganded and unliganded glucocorticoid receptor ( GR ) in P05231 and P10145 gene regulation in response to TNFα in the End1 / E6E7 immortalized human endocervical epithelial cell line . In the absence of glucocorticoids , both decreasing GR protein levels by an siRNA strategy and results with the GR antagonist DB00834 suggest a role for the unliganded GR in reduction of TNFα - induced P05231 and P10145 mRNA levels in End1 / E6E7 cells . Moreover , GR - dependent repression of endogenous P05231 mRNA as well as a minimal P05231 promoter - reporter gene is also demonstrated in COS - 1 cells in the absence of GR ligand , suggesting a transcriptional mechanism that is not cell - specific . TNFα induced recruitment of both the unliganded GR and GR - interacting protein type 1 ( Q9Y3R0 ) to the P05231 promoter . This , together with Q9Y3R0 overexpression studies , suggests a function for Q9Y3R0 as a GR co - repressor in this context . TNFα was shown to induce phosphorylation of the unliganded human GR at DB00133 - 226 but not DB00133 - 211 , unlike dexamethasone , which induced hyperphosphorylation at both serine residues . DB00133 - 226 is shown to be required for the ligand - independent GR - mediated repression of P05231 in response to TNFα . Taken together , these results support a model whereby the unliganded GR attenuates TNFα - stimulated P05231 transcription by a mechanism involving selective phosphorylation and recruitment of the unliganded GR and Q9Y3R0 to the P05231 promoter . These findings suggest the presence of a novel autoregulatory mechanism that may prevent overproduction of P05231 in the endocervix , possibly protecting against negative effects of excessive inflammation .\",\n \"Adipose tissue dysfunction in nascent metabolic syndrome . The metabolic syndrome ( MetS ) confers an increased risk for both type 2 diabetes mellitus ( T2DM ) and cardiovascular disease ( CVD ) . Moreover , studies on adipose tissue biology in nascent MetS uncomplicated by T2DM and / or CVD are scanty . Recently , we demonstrated that adipose tissue dysregulation and aberrant adipokine secretion contribute towards the syndrome ' s low - grade chronic proinflammatory state and insulin resistance . Specifically , we have made the novel observation that subcutaneous adipose tissue ( P21673 ) in subjects with nascent MetS has increased macrophage recruitment with cardinal crown - like structures . We have also shown that subjects with nascent MetS have increased the levels of P21673 - secreted adipokines ( IL - 1 , P05231 , P10145 , leptin , P02753 - 4 , CRP , P0DJI8 , P05121 , P13500 , and chemerin ) and plasma adipokines ( IL - 1 , P05231 , leptin , P02753 - 4 , CRP , P0DJI8 , and chemerin ) , as well as decreased levels of plasma adiponectin and both plasma and P21673 omentin - 1 . The majority of these abnormalities persisted following correction for increased adiposity . Our data , as well as data from other investigators , thus , highlight the importance of subcutaneous adipose tissue dysfunction in subjects with MetS and its contribution to the proinflammatory state and insulin resistance . This adipokine profile may contribute to increased insulin resistance and low - grade inflammation , promoting the increased risk of T2DM and CVD .\",\n \"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK33___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .\",\n \"Peroxisome - proliferator activator receptor - gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator - activated receptor ( Q07869 ) - gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well - established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co - culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co - cultured without prior treatment with CTZ ) . Next , attachment of CTZ - treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0 . 01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0 . 01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0 . 056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion .\",\n \"Studies on induction of lamotrigine metabolism in transgenic UGT1 mice . A transgenic ' knock - in ' mouse model expressing a human UGT1 locus ( P01266 - UGT1 ) was recently developed and validated . Although these animals express mouse P22309 proteins , P22310 is a pseudo - gene in mice . Therefore , P01266 - UGT1 mice serve as a ' humanized ' P22310 animal model . Lamotrigine ( LTG ) is primarily metabolized to its N - glucuronide ( LTGG ) by hUGT1A4 . This investigation aimed at examining the impact of pregnane X receptor ( O75469 ) , constitutive androstane receptor ( CAR ) and peroxisome proliferator - activated receptor ( Q07869 ) activators on LTG glucuronidation in vivo and in vitro . P01266 - UGT1 mice were administered the inducers phenobarbital ( CAR ) , pregnenolone - 16alpha - carbonitrile ( O75469 ) , WY - 14643 ( Q07869 ) , ciglitazone ( P37231 ) , or L - 165041 ( Q03181 ) , once daily for 3 or 4 days . Thereafter , LTG was administered orally and blood samples were collected over 24 h . LTG was measured in blood and formation of LTGG was measured in pooled microsomes made from the livers of treated animals . A three - fold increase in in vivo LTG clearance was seen after phenobarbital administration . In microsomes prepared from phenobarbital - treated P01266 - UGT1 animals , 13 - fold higher CL ( int ) ( Vmax / K ( m ) ) value was observed as compared with the untreated transgenic mice . A trend toward induction of catalytic activity in vitro and in vivo was also observed following pregnenolone - 16alpha - carbonitrile and WY - 14643 treatment . This study demonstrates the successful application of P01266 - UGT1 mice as a novel tool to study the impact of induction and regulation on metabolism of P22310 substrates .\",\n \"Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .\",\n \"15 - Deoxy - delta 12 , 14 - prostaglandin J2 inhibits the expression of granulocyte - macrophage colony - stimulating factor in endothelial cells stimulated with lipopolysaccharide . P04141 ( GM - P04141 ) , one of major hematopoietic growth factors , activates mature leukocytes . GM - P04141 is produced by endothelial cells stimulated with lipopolysaccharide ( LPS ) , and the LPS - induced GM - P04141 production may play an important role in the activation of neutrophils on the endothelial surface . 15 - Deoxy - delta 12 , 14 - prostaglandin J2 ( 15d - PGJ2 ) is a ligand for peroxisome proliferator - activated receptor - gamma ( P37231 ) and modulates inflammatory reactions by regulating the expression of various genes . We studied the effect of 15d - PGJ2 on the LPS - induced GM - P04141 expression in endothelial cells . Human umbilical vein endothelial cells ( HUVEC ) were cultured and the expressions of GM - P04141 mRNA and protein were analyzed by reverse transcription - polymerase chain reaction and enzyme - linked immunosorbent assay , respectively . 15d - PGJ2 inhibited the LPS - induced GM - P04141 expression in a concentration - dependent manner ; but ciglitazone , another agonist for P37231 , had no effect . This suggests that 15d - PGJ2 inhibits GM - P04141 expression through a mechanism unrelated to P37231 . 15d - PGJ2 induced , by itself , the expression of interleukin - 8 , a potent proinflammatory chemokine , in HUVEC . 15d - PGJ2 may regulate inflammatory reactions by controlling the balance of various cytokines .\",\n \"Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP3A ) , a phase II enzyme ( P22309 / 6 / 9 ) , two drug transporters ( P - gp and Q9Y6L6 ) and a component of the renal function ( Videau et al . 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat . The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC - MS / MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated . The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1 / 2 with omeprazole / omeprazole - sulfone , midazolam / 1 '- hydroxymidazolam or 4 - hydroxymidazolam and / or dextromethorphan / 3 - methoxymorphinan , CYP2C6 / 11 with tolbutamide / 4 - hydroxytolbutamide , CYP2D1 / 2 with omeprazole / 5 - hydroxyomeprazole or dextromethorphan / dextrorphan , and P19224 / 7 with acetaminophen / acetaminophen - glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP2C11 and CYP2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors .\",\n \"Tumor cell - derived prostaglandin E2 inhibits monocyte function by interfering with P51681 and Mac - 1 . The cyclooxygenases ( P36551 ) - 1 and P35354 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids . Whereas P23219 is expressed ubiquitously , P35354 is an immediate - early gene often associated with malignant transformation , and a role for the P36551 enzymes in tumor initiation and promotion is discussed . Nonsteroidal anti - inflammatory drugs ( NSAIDs ) like aspirin and indomethacin that block P23219 and - 2 have been shown to have beneficial effects for tumor patients . Therefore , these compounds have gained interest also among oncologists . However , the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood . The prostaglandin - dependent and - independent effect may both account for their antineoplastic action . We show here that tumor cells derived from different tumors regularly produce prostaglandin E ( 2 ) ( PGE ( 2 ) ) interfering with the function of monocytes . In particular , PGE ( 2 ) inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell . This inhibition is most probably due to a modulation of the chemokine receptor P51681 and the beta2 - integrin Mac - 1 . Both down - regulation of P51681 and reduced expression of Mac - 1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues . Since both dysfunctions can be restored with NSAIDs , our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression .\",\n \"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK10___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .\",\n \"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK39___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK39___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .\",\n \"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .\",\n \"___MASK94___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .\",\n \"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK88___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .\",\n \"Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .\",\n \"A structural and in vitro characterization of asoprisnil : a selective progesterone receptor modulator . Selective progesterone receptor modulators ( SPRMs ) have been suggested as therapeutic agents for treatment of gynecological disorders . One such SPRM , asoprisnil , was recently in clinical trials for treatment of uterine fibroids and endometriosis . We present the crystal structures of progesterone receptor ( PR ) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor ( NCoR ) and Q9Y618 . This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors . These structures show PR in a different conformation than PR complexed with progesterone ( P4 ) . We profiled asoprisnil in PR - dependent assays to understand further the PR - mediated mechanism of action . We confirmed previous findings that asoprisnil demonstrated antagonism , but not agonism , in a PR - B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay . Asoprisnil , but not DB00834 , weakly recruited the coactivators Q15788 and Q9Y6Q9 . However , asoprisnil strongly recruited the corepressor NCoR in a manner similar to DB00834 . Unlike DB00834 , NCoR binding to asoprisnil - bound PR could be displaced with equal affinity by NCoR or Q15596 peptides . We further showed that it weakly activated T47D cell gene expression of Sgk - 1 and O60437 and antagonized P4 - induced expression of both genes . In rat leiomyoma ELT3 cells , asoprisnil demonstrated partial P4 - like inhibition of cyclooxygenase ( P36551 ) enzymatic activity and P35354 gene expression . In the rat uterotrophic assay , asoprisnil demonstrated no P4 - like ability to oppose estrogen . Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to DB00834 or P4 , and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus .\",\n \"ω - 3 fatty acid eicosapentaenoic acid attenuates P25189 +- induced neurodegeneration in fully differentiated human SH - SY5Y and primary mesencephalic cells . DB00159 ( EPA ) , a neuroactive omega - 3 fatty acid , has been demonstrated to exert neuroprotective effects in experimental models of Parkinson ' s disease ( PD ) , but the cellular mechanisms of protection are unknown . Here , we studied the effects of EPA in fully differentiated human SH - SY5Y cells and primary mesencephalic neurons treated with P25189 (+) . In both in - vitro models of PD , EPA attenuated an P25189 (+) - induced reduction in cell viability . EPA also prevented the presence of electron - dense cytoplasmic inclusions in SH - SY5Y cells . Then , possible mechanisms of the neuroprotection were studied . In primary neurons , EPA attenuated an P25189 (+) - induced increase in Tyrosine - related kinase B ( TrkB ) receptors . In SH - SY5Y cells , EPA down - regulated reactive oxygen species and nitric oxide . This antioxidant effect of EPA may have been mediated by its inhibition of neuronal NADPH oxidase and cyclo - oxygenase - 2 ( P35354 ) , as P25189 (+) increased the expression of these enzymes . Furthermore , EPA prevented an increase in cytosolic phospholipase A2 ( P47712 ) , an enzyme linked with P35354 in the potentially pro - inflammatory arachidonic acid cascade . Lastly , EPA attenuated an increase in the bax : bcl - 2 ratio , and cytochrome c release . However , EPA did not prevent mitochondrial enlargement or a decrease in mitochondrial membrane potential . This study demonstrated cellular mechanisms by which EPA provided neuroprotective effects in experimental PD .\",\n \"Chromosomal changes in high - and low - invasive mouse lung adenocarcinoma cell strains derived from early passage mouse lung adenocarcinoma cell strains . The incidence of adenocarcinoma of the lung is increasing in the United States , however , the difficulties in obtaining lung cancer families and representative samples of early to late stages of the disease have lead to the study of mouse models for lung cancer . We used Spectral Karyotyping ( Q06418 ) , mapping with fluorescently labeled genomic clones ( Q5TCZ1 ) , comparative genomic hybridization ( CGH ) arrays , gene expression arrays , Western immunoblot and real time polymerase chain reaction ( PCR ) to analyze nine pairs of high - invasive and low - invasive tumor cell strains derived from early passage mouse lung adenocarcinoma cells to detect molecular changes associated with tumor invasion . The duplication of chromosomes 1 and 15 and deletion of chromosome 8 were significantly associated with a high - invasive phenotype . The duplication of chromosome 1 at band C4 and E1 / 2 - H1 were the most significant chromosomal changes in the high - invasive cell strains . Mapping with Q5TCZ1 and CGH array further narrowed the minimum region of duplication of chromosome 1 to 71 - 82 centimorgans ( cM ) . Expression array analysis and confirmation by real time PCR demonstrated increased expression of P35354 , Q15631 ( TB - P02753 ) , O43781 , Q9H1E3 and Tubulin - alpha4 genes in the high - invasive cell strains . Elevated expression and copy number of these genes , which are involved in inflammation , cell movement , proliferation , inhibition of apoptosis and telomere elongation , were associated with an invasive phenotype . Similar linkage groups are altered in invasive human lung adenocarcinoma , implying that the mouse is a valid genetic model for the study of the progression of human lung adenocarcinoma .\",\n \"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK65___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .\",\n \"DB00159 inhibits prostaglandin D2 generation by inhibiting cyclo - oxygenase - 2 in cultured human mast cells . BACKGROUND : DB00159 ( EPA ) is catalysed by cyclo - oxygenase ( P36551 ) , as is arachidonic acid , and is a competitive inhibitor of arachidonate metabolism . OBJECTIVES : We examined the effect of EPA on prostaglandin ( PG ) D2 generation in the cultured human mast cells with IgE - anti - IgE challenge incubation . METHODS : Cultured human mast cells were incubated with EPA ( 1 micromol / L ) for 20 h , then challenged with anti - IgE incubation after treatment with IgE . At the same time , P36551 inhibitors were tested to identify P23219 and P35354 activity . PGD2 synthetic activity was also assayed in a cell - free homogenate of cultured mast cells with P36551 inhibitors and EPA . DB11320 in the culture medium and in cells was assayed with the HPLC - fluorescent method . PGD2 and PGD3 were assayed with gas chromatography - mass spectrometry and the stable isotope dilution method . RESULTS : Although EPA incubation did not affect histamine release by cultured human mast cells in response to IgE - anti - IgE challenge incubation , it did decrease PGD2 generation by inhibiting the P35354 pathway . In contrast , in the cell - free homogenate of cultured human mast cells , EPA inhibited both P23219 and P35354 activities . CONCLUSION : Pre - incubation with EPA primarily affects the P35354 pathway in cultured human mast cells and reduces PGD2 generation in response to IgE - anti - IgE challenge incubation . These findings suggest that P23219 and P35354 have different substrate flow systems in mast cells . They also suggest that endogenous EPA diet supplementation would reduce PGD2 production and could serve as an anti - inflammatory substrate in human mast cells .\",\n \"Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .\",\n \"Creating a genotype - based dosing algorithm for acenocoumarol steady dose . ___MASK33___ is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries . In counterpart of warfarin , there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation . The aim of this study was to develop an algorithm of prediction for acenocoumarol . The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2 , 683 patients . The best regression model to predict stable dosage in the Primary Cohort included clinical factors ( age and body mass index , BSA ) and genetic variants ( Q9BQB6 , P11712 * and P78329 polymorphisms ) and explained up to 50 % of stable dose . In the validation study the clinical algorithm yielded an adjusted R² = 0 . 15 ( estimation ´ s standard error = 4 . 5 ) and the genetic approach improved the dose forecast up to 30 % ( estimation ´ s standard error = 4 . 6 ) . Again , the best model combined clinical and genetic factors ( R² = 0 . 48 ; estimation ´ s standard error = 4 ) which provided the best results of doses estimates within 20 % of the real dose in patients taking lower ( ≤ 7 mg / week ) or higher ( ≥ 25 mg / week ) acenocoumarol doses . In conclusion , we developed a prediction algorithm using clinical data and three polymorphisms in Q9BQB6 , P11712 * and P78329 genes that provided a steady acenocoumarol dose for about 50 % of patients in the Validation Cohort . Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses , those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication .\",\n \"Cytochromes P450 are differently expressed in normal and varicose human saphenous veins : linkage with varicosis . The expression of cytochrome P450 ( CYP ) enzymes and cyclo - oxygenases ( P36551 ) was investigated in human saphenous veins by reverse transcription - polymerase chain reaction analysis . Non - varicose veins were obtained from patients undergoing aortocoronary bypass grafting , whereas varicose veins were obtained from patients undergoing stripping removal of varicose saphenous veins . In non - varicose veins , Q16678 , CYP2C , P05181 and Q02928 were detected , whereas P51589 , P20815 , P23219 and P35354 were detected almost exclusively in varicose veins . P78329 was not detectable . Except for Q02928 , the levels of individual CYP mRNA were higher in varicose veins than in control veins . Smooth muscle cell volume , determined by a colour image - analysis system , was increased approximately 1 . 5 - fold in varicose veins . Because CYPs and COXs produce various vasoactive compounds , increased expression of these enzymes could be involved in the impairment of vascular tone and may contribute to varicose pathology . Then , CYP or P36551 modulators may be potentially active in the treatment of chronic venous insufficiency .\",\n \"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK8___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .\",\n \"Crosstalk between circulating peroxisome proliferator - activated receptor gamma , adipokines and metabolic syndrome in obese subjects . BACKGROUND : P37231 ( PPARγ ) has direct and indirect function in adipokines production process . We aimed to assess the possible influence of circulating PPARγ on relative risk of metabolic syndrome and also examine the association between circulating PPARγ and adipokines levels among obese subjects . METHODS : A total of 96 obese subjects ( body mass index ( BMI ) ≥ 30 ) were included in the current cross - sectional study . We assessed the body composition with the use of Body Composition Analyzer BC - 418MA - Tanita . The MetS ( metabolic syndrome ) was defined based on the National DB04540 Education Program Adult Treatment Panel III . All baseline blood samples were obtained following an overnight fasting . Serum concentrations of adipokines including DB00162 binding protein 4 ( P02753 ) , omentin - 1 , vaspin , progranulin , nesfatin - 1 and circulating PPARγ was measured with the use of an enzyme - linked immunosorbent assay method . Statistical analyses were performed using software package used for statistical analysis ( SPSS ) . RESULTS : We found main association between circulating PPARγ and body composition in obese population . The risk of metabolic syndrome in subjects with higher concentration of PPARγ was 1 . 9 fold in compared with lower concentration of PPARγ after adjustment for age , sex and BMI . There was significant association between PPARγ and adipokines , specially nesfatin - 1 and progranulin . Defined adipokines pattern among participants demonstrated the markedly higher concentration of vaspin , P02753 and nesfatin - 1 in participants with MetS compared to non - MetS subjects . CONCLUSIONS : It appears all of studied adipokines might have association with PPARγ level and might simultaneously be involve in some common pathway to make susceptible obese subjects for MetS .\",\n \"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK76___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK76___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK76___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK76___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK76___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK76___ increased the protein expression of hepatic P05181 and ___MASK76___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK76___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK76___ and RFP - induced hepatotoxicity .\",\n \"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .\",\n \"Mutation of the calmodulin binding motif IQ of the L - type Ca ( v ) 1 . 2 Ca2 + channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation - contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca ( 2 +)/ calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca ( v ) 1 . 2 channel and induces Ca ( 2 +)- dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca ( v ) 1 . 2 ( I1624E ) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca ( v ) 1 . 2 ( Q401N2 ) allele by tamoxifen - induced cardiac - specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca ( v ) 1 . 2 ( I1624E ) hearts , the activity of phospho - P62158 kinase II and phospho - MAPK was increased . CMs expressed reduced levels of Ca ( v ) 1 . 2 ( I1624E ) channel protein and I ( Ca ) . The Ca ( v ) 1 . 2 ( I1624E ) channel showed \\\" CDI \\\" kinetics . Despite a lower sarcoplasmic reticulum Ca ( 2 +) content , cellular contractility and global Ca ( 2 +) transients remained unchanged because the EC coupling gain was up - regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca ( v ) 1 . 2 ( I1624E ) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death .\",\n \"P37231 ( PPARgamma ) and immunoregulation : enhancement of regulatory T cells through PPARgamma - dependent and - independent mechanisms . Peroxisome proliferator - activated receptor ( Q07869 ) gamma is a nuclear hormone receptor primarily characterized for its effect on insulin metabolism . PPARgamma ligands , used to treat human type 2 diabetes , also down - regulate most immune system cells including APCs and pathogenic T cells . These effects putatively underlie the efficacy of PPARgamma ligands in treating animal models of autoimmunity , leading to projections of therapeutic potential in human autoimmunity . However , the relationship between PPARgamma ligands and P01730 + CD25 + regulatory T cells ( Tregs ) has not been examined . Specifically , no studies have examined the role of Tregs in mediating the in vivo immunoregulatory effects of PPARgamma ligands , and there have been no investigations of the use of PPARgamma ligands to treat autoimmunity in the absence of Tregs . We now characterize the novel relationship between ciglitazone , a thiazolidinedione class of PPARgamma ligand , and both murine natural Tregs ( nTregs ) and inducible Tregs ( iTregs ) . In vitro , ciglitazone significantly enhances generation of iTregs in a PPARgamma - independent manner . Surprisingly , and contrary to the current paradigm , we find that , in a model of graft - vs - host disease , the immunotherapeutic effect of ciglitazone requires the presence of nTregs that express PPARgamma . Overall , our results indicate that , unlike its down - regulatory effect on other cells of the immune system , ciglitazone has an enhancing effect on both iTregs and nTregs , and this finding may have important implications for using PPARgamma ligands in treating human autoimmune disease .\",\n \"Omega - 3 polyunsaturated fatty acids and inflammatory processes : nutrition or pharmacology ? DB00159 ( EPA ) and docosahexaenoic acid ( DB01708 ) are n - 3 fatty acids found in oily fish and fish oil supplements . These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis , adhesion molecule expression and leucocyte - endothelial adhesive interactions , production of eicosanoids like prostaglandins and leukotrienes from the n - 6 fatty acid arachidonic acid , production of inflammatory cytokines and T cell reactivity . In parallel , EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DB01708 give rise to anti - inflammatory and inflammation resolving resolvins and protectins . Mechanisms underlying the anti - inflammatory actions of n - 3 fatty acids include altered cell membrane phospholipid fatty acid composition , disruption of lipid rafts , inhibition of activation of the pro - inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes , activation of the anti - inflammatory transcription factor P37231 ( i . e . peroxisome proliferator activated receptor γ ) and binding to the G protein coupled receptor Q5NUL3 . These mechanisms are interlinked . In adult humans , an EPA plus DB01708 intake greater than 2 g day ⁻ ¹ seems to be required to elicit anti - inflammatory actions , but few dose finding studies have been performed . Animal models demonstrate benefit from n - 3 fatty acids in rheumatoid arthritis ( RA ) , inflammatory bowel disease ( Q9UKU7 ) and asthma . Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta - analyses of the data . Clinical trails of fish oil in patients with Q9UKU7 and asthma are inconsistent with no overall clear evidence of efficacy .\",\n \"Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case - control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population - based case - control study . We examined nutrient density - adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0 . 026 ) , cooked by pan - frying ( trend P = 0 . 035 ) , and cooked until well - done ( trend P = 0 . 013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0 . 023 ) . A gene - by - diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0 . 008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology .\",\n \"Gamma tocopherol upregulates the expression of 15 - S - HETE and induces growth arrest through a Q07869 gamma - dependent mechanism in PC - 3 human prostate cancer cells . Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer . Our previous studies in the colon have demonstrated that gamma - tocopherol treatment could upregulate the expression of peroxisome proliferator - activated preceptors ( Q07869 ) gamma , a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation . In this study , we explored the possibility that gamma - tocopherol could induce growth arrest in PC - 3 prostate cancer cells through the regulation of fatty acid metabolism . Growth arrest ( 40 % ) and Q07869 gamma mRNA and protein upregulation was achieved with gamma - tocopherol within 6 h . gamma - Tocopherol - mediated growth arrest was demonstrated to be Q07869 gamma dependent using the agonist GW9662 and a Q07869 gamma dominant negative vector . gamma - tocopherol was shown not to be a direct Q07869 gamma ligand , but rather 15 - S - HETE ( an endogenous Q07869 gamma ligand ) was upregulated by gamma - tocopherol treatment . 15 - Lipoxygenase - 2 , a tumor suppressor and the enzyme that converts arachidonic acid to 15 - S - HETE , was upregulated at 3 h following gamma - tocopherol treatment . Expression of proteins downstream of the Q07869 gamma pathway were examined . P12004 D1 , cyclin D3 , bcl - 2 , and NFkappa B proteins were found to be downregulated following gamma - tocopherol treatment . These data demonstrate that the growth arrest mediated by gamma - tocopherol follows a P37231 - dependent mechanism .\",\n \"Neem leaf glycoprotein suppresses regulatory T cell mediated suppression of monocyte / macrophage functions . We have shown that neem leaf glycoprotein ( NLGP ) inhibits the regulatory T cell ( Tregs ) induced suppression of tumoricidal functions of P08571 (+) P34810 (+) monocyte / macrophages ( MO / Mφ ) from human peripheral blood . Cytotoxic efficacy of MO / Mφ toward macrophage sensitive cells , U937 , is decreased in presence of Tregs ( induced ) , however , it was increased further by supplementation of NLGP in culture . Associated Treg mediated inhibition of perforin / granzyme B expression and nitric oxide release from MO / Mφ was normalized by NLGP . Altered status of signature cytokines , like , IL - 12 , P22301 , P05231 , TNFα from MO / Mφ under influence of Tregs is also rectified by NLGP . Tregs significantly enhanced the expression of altered marker , mannose receptor ( CD206 ) on P34810 (+) cells that was downregulated upon NLGP exposure . In addition to tumoricidal functions , antigen presenting ability of MO / Mφ is hampered by Treg induced downregulation of P33681 , P42081 and HLA - DB01048 . NLGP upregulated these molecules in MO / Mφ even in the presence of Tregs . Treg mediated inhibition of MO / Mφ chemotaxis in contact dependent manner was also normalized partially by NLGP , where participation of P51681 was documented . Overall results suggest that Treg influenced pro - tumor MO / Mφ functions are rectified in a significant extent by NLGP to create an anti - tumor immune environment .\",\n \"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK27___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK27___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK27___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .\",\n \"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .\"\n]"},"candidates":{"kind":"list like","value":["___MASK10___","___MASK27___","___MASK33___","___MASK39___","___MASK65___","___MASK76___","___MASK88___","___MASK8___","___MASK94___"],"string":"[\n \"___MASK10___\",\n \"___MASK27___\",\n \"___MASK33___\",\n \"___MASK39___\",\n \"___MASK65___\",\n \"___MASK76___\",\n \"___MASK88___\",\n \"___MASK8___\",\n \"___MASK94___\"\n]"},"answer":{"kind":"string","value":"___MASK33___"},"id":{"kind":"string","value":"MH_train_488"}}},{"rowIdx":489,"cells":{"query":{"kind":"string","value":"interacts_with DB00153?"},"supports":{"kind":"list like","value":["Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK60___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .","Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .","MicroRNA - 21 targets the vitamin D - dependent antimicrobial pathway in leprosy . Leprosy provides a model to investigate mechanisms of immune regulation in humans , given that the disease forms a spectrum of clinical presentations that correlate with host immune responses . Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous ( L - lep ) versus the self - limited tuberculoid ( T - lep ) disease . Bioinformatic analysis revealed a significant enrichment of L - lep - specific miRNAs that preferentially target key immune genes downregulated in L - lep versus T - lep lesions . The most differentially expressed miRNA in L - lep lesions , hsa - mir - 21 , was upregulated in Mycobacterium leprae - infected monocytes . By directly downregulating O60603 / 1 heterodimer ( O60603 / 1 ) - induced O15528 and P01584 expression as well as indirectly upregulating interleukin - 10 ( P22301 ) , hsa - mir - 21 inhibited expression of the genes encoding two vitamin D - dependent antimicrobial peptides , CAMP and O15263 . Conversely , knockdown of hsa - mir - 21 in M . leprae - infected monocytes enhanced expression of CAMP and O15263 and restored O60603 / 1 - mediated antimicrobial activity against M . leprae . Therefore , the ability of M . leprae to upregulate hsa - mir - 21 targets multiple genes associated with the immunologically localized disease form , providing an effective mechanism to escape from the vitamin D - dependent antimicrobial pathway .","Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK20___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK20___ peptide content within the pituitary , and plasma ___MASK20___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK20___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK20___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK20___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .","Relative Expression of Vitamin D Hydroxylases , O15528 and Q07973 , and of P35354 and Heterogeneity of Human Colorectal Cancer in Relation to Age , Gender , Tumor Location , and Malignancy : Results from Factor and Cluster Analysis . Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1 , 25 -( OH ) 2D3 and prostaglandin cellular signaling networks . The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases , i . e . , O15528 - encoded 25 - hydroxyvitamin D - 1a - hydroxylase and Q07973 - encoded 25 - hydroxyvitamin D - 24 - hydroxylase , and inflammation - induced cyclooxygenase - 2 ( P35354 ) . Data from 105 cancer patients on O15528 , P11473 , Q07973 , and P35354 mRNA expression in relation to tumor grade , anatomical location , gender and age were fit into a multivariate model of exploratory factor analysis . Nearly identical results were obtained by the principal factor and the maximum likelihood method , and these were confirmed by hierarchical cluster analysis : Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis : ( i ) Escape of P35354 activity from restraints by the O15528 / P11473 system can initiate cancer growth anywhere in the colorectum regardless of age and gender ; ( ii ) variations in P35354 expression are mainly responsible for differences in cancer incidence in relation to tumor location ; ( iii ) advancing age has a strong gender - specific influence on cancer incidence ; ( iv ) progression from well differentiated to undifferentiated cancer is solely associated with a rise in Q07973 expression .","Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis - affected brain tissue . Vitamin D deficiency has been implicated as a risk factor for multiple sclerosis ( MS ) , but how vitamin D metabolism affects MS pathophysiology is not understood . We studied the expression of vitamin D receptor ( P11473 ) and related enzymes , including 1 , 25 ( OH )( 2 ) D - 24 - hydroxylase ( Q07973 ; Q07973 ) and 25 ( OH ) D - 1α - hydroxylase ( O15528 ) , in CNS tissues of 39 MS patients and 20 controls and in primary human glial cells in vitro . In control and MS normal - appearing white matter ( NAWM ) , nuclear P11473 immunostaining was observed in oligodendrocyte - like cells , human leukocyte antigen ( HLA ) - positive microglia , and glial fibrillary acidic protein - positive astrocytes . There was a 2 - fold increase in P11473 transcripts in MS NAWM versus control white matter ( p = 0 . 03 ) . In chronic active MS lesions , HLA - positive microglia / macrophages showed nuclear P11473 staining ; astrocytes showed nuclear and cytoplasmic P11473 staining . Staining for Q07973 was restricted to astrocytes . P11473 and O15528 mRNA expressions were increased in active MS lesions versus NAWM ( p < 0 . 01 , p = 0 . 04 , respectively ) . In primary human astrocytes in vitro , the active form of vitamin D , 1 , 25 ( OH )( 2 ) D ( 3 ) , induced upregulation of P11473 and Q07973 . P01375 and interferon - γ upregulated O15528 mRNA in primary human microglia and astrocytes . Increased P11473 expression in MS NAWM and inflammatory cytokine - induced amplified expression of P11473 and O15528 in chronic active MS lesions suggest increased sensitivity to vitamin D in NAWM and a possible endogenous role for vitamin D metabolism in the suppression of active MS lesions .","A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK49___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .","Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .","___MASK9___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK9___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .","Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK31___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .","Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK77___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .","Effects of 25 - hydroxyvitamin D3 and 1 , 25 - dihydroxyvitamin D3 on cytokine production by human decidual cells . The active form of vitamin D , 1 , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 [ OH ]( 2 ) D ( 3 ) ) is a potent immunomodulatory seco - steroid . We have demonstrated that several components of vitamin D metabolism and signaling are strongly expressed in human uterine decidua from first trimester pregnancies , suggesting that locally produced 1 , 25 ( OH )( 2 ) D ( 3 ) may exert immunosuppressive effects during early stages of gestation . To investigate this further , we used primary cultures of human decidual cells from first and third trimester pregnancies to demonstrate expression and activity of the enzyme that catalyzes synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) , 1alpha - hydroxylase ( O15528 ) . Synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) was higher in first trimester decidual cells ( 41 +/- 11 . 8 fmoles / h / mg protein ) than in third trimester cells ( 8 +/- 4 . 4 fmoles / h / mg protein ; P < 0 . 05 ) . Purification of decidual cells followed by quantitative RT - PCR analysis showed that O15528 was expressed by both CD10 (+ VE ) stromal - enriched and CD10 (- VE ) stromal - depleted cells , with higher levels of mRNA in first trimester pregnancies . Expression of O15528 correlated with O00206 and P14902 . Functional responses to 1 , 25 ( OH )( 2 ) D ( 3 ) were studied using CD56 (+ VE ) natural killer ( NK ) cells isolated from first trimester decidua . Decidual NK cells treated with 1 , 25 ( OH )( 2 ) D ( 3 ) or precursor 25 - hydroxyvitamin D ( 3 ) ( 25OHD ( 3 ) ) for 28 h showed decreased synthesis of cytokines , such as granulocyte - macrophage colony stimulating factor 2 ( P04141 ) , tumor necrosis factor , and interleukin 6 , but increased expression of mRNA for the antimicrobial peptide cathelicidin antimicrobial peptide . These data indicate that human decidual cells are able to synthesize active 1 , 25 ( OH )( 2 ) D ( 3 ) , particularly in early gestation , and this may act in an autocrine / paracrine fashion to regulate both acquired and innate immune responses at the fetal - maternal interface .","___MASK29___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK29___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .","The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .","Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .","Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .","P18509 , interleukin - 6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells . There is increasing evidence that hormones play an important role in the control of endothelial cell function and growth by regulating the production of vascular endothelial growth factor ( P15692 ) . P15692 regulates vascular permeability and represents the most powerful growth factor for endothelial cells . In the normal anterior pituitary , P15692 has been detected only in folliculostellate ( FS ) cells . In the present study , the regulation of the release of P15692 from FS - like mouse TtT / GF cells , and from FS cells of rat pituitary monolayer cell cultures was investigated using a specific P15692 ELISA . Basal release of P15692 was demonstrated in cultures of both TtT / GF cells and rat pituitary cells . Interestingly , the P15692 secretion was stimulated by both forms of pituitary adenylate cyclase - activating polypeptide ( PACAP - 38 and PACAP - 27 ) , indicating that this hypothalamic peptide regulates endothelial cell function and growth within the pituitary . P15692 secretion was also stimulated by interleukin - 6 ( P05231 ) whereas basal , P05231 - and PACAP - stimulated secretion was inhibited by the synthetic glucocorticoid dexamethasone . The inhibitory action of dexamethasone was reversed by the glucocorticoid receptor antagonist DB00834 , suggesting that in FS cells functional glucocorticoid receptors mediate the inhibitory action of glucocorticoids on the P15692 secretion . The endocrine and auto -/ paracrine control of P15692 production in pituitary FS cells by PACAP , P05231 and glucocorticoids may play an important role both in angiogenesis and vascular permeability regulation within the pituitary under physiological and pathophysiological conditions .","DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .","Vitamin D and the regulation of placental inflammation . The vitamin D - activating enzyme 1α - hydroxylase ( O15528 ) and vitamin D receptor ( P11473 ) support anti - inflammatory responses to vitamin D in many tissues . Given the high basal expression of O15528 and P11473 in trophoblastic cells from the placenta , we hypothesized that anti - inflammatory effects of vitamin D may be particularly important in this organ . Pregnant wild type ( WT ) mice i . p . injected with LPS showed elevated expression of mouse Cyp27b1 ( 4 - fold ) and P11473 ( 6 - fold ) . Similar results were also obtained after ex vivo treatment of WT placentas with LPS . To assess the functional impact of this , we carried out ex vivo studies using placentas -/- for fetal ( trophoblastic ) Cyp27b1 or P11473 . Vehicle - treated -/- placentas showed increased expression of IFN - γ and decreased expression of P22301 relative to +/+ placentas . LPS - treated -/- placentas showed increased expression of O60603 , IFN - γ , and P05231 . Array analyses identified other inflammatory factors that are dysregulated in Cyp27b1 (-/-) versus Cyp27b1 (+/+) placentas after LPS challenge . Data highlighted enhanced expression of P05112 , P40933 , and Q14116 , as well as several chemokines and their receptors , in Cyp27b1 (-/-) placentas . Similar results for P05231 expression were observed with placentas -/- for trophoblastic P11473 . Finally , ex vivo treatment of WT placentas with the substrate for Cyp27b1 , 25 - hydroxyvitamin D ( 3 ) , suppressed LPS - induced expression of P05231 and the chemokine Ccl11 . These data indicate that fetal ( trophoblastic ) vitamin D plays a pivotal role in controlling placental inflammation . In humans , this may be a key factor in placental responses to infection and associated adverse outcomes of pregnancy .","[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK45___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .","Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK26___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers ."],"string":"[\n \"Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK60___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .\",\n \"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .\",\n \"MicroRNA - 21 targets the vitamin D - dependent antimicrobial pathway in leprosy . Leprosy provides a model to investigate mechanisms of immune regulation in humans , given that the disease forms a spectrum of clinical presentations that correlate with host immune responses . Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous ( L - lep ) versus the self - limited tuberculoid ( T - lep ) disease . Bioinformatic analysis revealed a significant enrichment of L - lep - specific miRNAs that preferentially target key immune genes downregulated in L - lep versus T - lep lesions . The most differentially expressed miRNA in L - lep lesions , hsa - mir - 21 , was upregulated in Mycobacterium leprae - infected monocytes . By directly downregulating O60603 / 1 heterodimer ( O60603 / 1 ) - induced O15528 and P01584 expression as well as indirectly upregulating interleukin - 10 ( P22301 ) , hsa - mir - 21 inhibited expression of the genes encoding two vitamin D - dependent antimicrobial peptides , CAMP and O15263 . Conversely , knockdown of hsa - mir - 21 in M . leprae - infected monocytes enhanced expression of CAMP and O15263 and restored O60603 / 1 - mediated antimicrobial activity against M . leprae . Therefore , the ability of M . leprae to upregulate hsa - mir - 21 targets multiple genes associated with the immunologically localized disease form , providing an effective mechanism to escape from the vitamin D - dependent antimicrobial pathway .\",\n \"Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK20___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK20___ peptide content within the pituitary , and plasma ___MASK20___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK20___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK20___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK20___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .\",\n \"Relative Expression of Vitamin D Hydroxylases , O15528 and Q07973 , and of P35354 and Heterogeneity of Human Colorectal Cancer in Relation to Age , Gender , Tumor Location , and Malignancy : Results from Factor and Cluster Analysis . Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1 , 25 -( OH ) 2D3 and prostaglandin cellular signaling networks . The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases , i . e . , O15528 - encoded 25 - hydroxyvitamin D - 1a - hydroxylase and Q07973 - encoded 25 - hydroxyvitamin D - 24 - hydroxylase , and inflammation - induced cyclooxygenase - 2 ( P35354 ) . Data from 105 cancer patients on O15528 , P11473 , Q07973 , and P35354 mRNA expression in relation to tumor grade , anatomical location , gender and age were fit into a multivariate model of exploratory factor analysis . Nearly identical results were obtained by the principal factor and the maximum likelihood method , and these were confirmed by hierarchical cluster analysis : Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis : ( i ) Escape of P35354 activity from restraints by the O15528 / P11473 system can initiate cancer growth anywhere in the colorectum regardless of age and gender ; ( ii ) variations in P35354 expression are mainly responsible for differences in cancer incidence in relation to tumor location ; ( iii ) advancing age has a strong gender - specific influence on cancer incidence ; ( iv ) progression from well differentiated to undifferentiated cancer is solely associated with a rise in Q07973 expression .\",\n \"Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis - affected brain tissue . Vitamin D deficiency has been implicated as a risk factor for multiple sclerosis ( MS ) , but how vitamin D metabolism affects MS pathophysiology is not understood . We studied the expression of vitamin D receptor ( P11473 ) and related enzymes , including 1 , 25 ( OH )( 2 ) D - 24 - hydroxylase ( Q07973 ; Q07973 ) and 25 ( OH ) D - 1α - hydroxylase ( O15528 ) , in CNS tissues of 39 MS patients and 20 controls and in primary human glial cells in vitro . In control and MS normal - appearing white matter ( NAWM ) , nuclear P11473 immunostaining was observed in oligodendrocyte - like cells , human leukocyte antigen ( HLA ) - positive microglia , and glial fibrillary acidic protein - positive astrocytes . There was a 2 - fold increase in P11473 transcripts in MS NAWM versus control white matter ( p = 0 . 03 ) . In chronic active MS lesions , HLA - positive microglia / macrophages showed nuclear P11473 staining ; astrocytes showed nuclear and cytoplasmic P11473 staining . Staining for Q07973 was restricted to astrocytes . P11473 and O15528 mRNA expressions were increased in active MS lesions versus NAWM ( p < 0 . 01 , p = 0 . 04 , respectively ) . In primary human astrocytes in vitro , the active form of vitamin D , 1 , 25 ( OH )( 2 ) D ( 3 ) , induced upregulation of P11473 and Q07973 . P01375 and interferon - γ upregulated O15528 mRNA in primary human microglia and astrocytes . Increased P11473 expression in MS NAWM and inflammatory cytokine - induced amplified expression of P11473 and O15528 in chronic active MS lesions suggest increased sensitivity to vitamin D in NAWM and a possible endogenous role for vitamin D metabolism in the suppression of active MS lesions .\",\n \"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK49___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .\",\n \"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .\",\n \"___MASK9___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK9___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .\",\n \"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK31___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .\",\n \"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK77___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .\",\n \"Effects of 25 - hydroxyvitamin D3 and 1 , 25 - dihydroxyvitamin D3 on cytokine production by human decidual cells . The active form of vitamin D , 1 , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 [ OH ]( 2 ) D ( 3 ) ) is a potent immunomodulatory seco - steroid . We have demonstrated that several components of vitamin D metabolism and signaling are strongly expressed in human uterine decidua from first trimester pregnancies , suggesting that locally produced 1 , 25 ( OH )( 2 ) D ( 3 ) may exert immunosuppressive effects during early stages of gestation . To investigate this further , we used primary cultures of human decidual cells from first and third trimester pregnancies to demonstrate expression and activity of the enzyme that catalyzes synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) , 1alpha - hydroxylase ( O15528 ) . Synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) was higher in first trimester decidual cells ( 41 +/- 11 . 8 fmoles / h / mg protein ) than in third trimester cells ( 8 +/- 4 . 4 fmoles / h / mg protein ; P < 0 . 05 ) . Purification of decidual cells followed by quantitative RT - PCR analysis showed that O15528 was expressed by both CD10 (+ VE ) stromal - enriched and CD10 (- VE ) stromal - depleted cells , with higher levels of mRNA in first trimester pregnancies . Expression of O15528 correlated with O00206 and P14902 . Functional responses to 1 , 25 ( OH )( 2 ) D ( 3 ) were studied using CD56 (+ VE ) natural killer ( NK ) cells isolated from first trimester decidua . Decidual NK cells treated with 1 , 25 ( OH )( 2 ) D ( 3 ) or precursor 25 - hydroxyvitamin D ( 3 ) ( 25OHD ( 3 ) ) for 28 h showed decreased synthesis of cytokines , such as granulocyte - macrophage colony stimulating factor 2 ( P04141 ) , tumor necrosis factor , and interleukin 6 , but increased expression of mRNA for the antimicrobial peptide cathelicidin antimicrobial peptide . These data indicate that human decidual cells are able to synthesize active 1 , 25 ( OH )( 2 ) D ( 3 ) , particularly in early gestation , and this may act in an autocrine / paracrine fashion to regulate both acquired and innate immune responses at the fetal - maternal interface .\",\n \"___MASK29___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK29___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .\",\n \"The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .\",\n \"Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .\",\n \"Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .\",\n \"P18509 , interleukin - 6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells . There is increasing evidence that hormones play an important role in the control of endothelial cell function and growth by regulating the production of vascular endothelial growth factor ( P15692 ) . P15692 regulates vascular permeability and represents the most powerful growth factor for endothelial cells . In the normal anterior pituitary , P15692 has been detected only in folliculostellate ( FS ) cells . In the present study , the regulation of the release of P15692 from FS - like mouse TtT / GF cells , and from FS cells of rat pituitary monolayer cell cultures was investigated using a specific P15692 ELISA . Basal release of P15692 was demonstrated in cultures of both TtT / GF cells and rat pituitary cells . Interestingly , the P15692 secretion was stimulated by both forms of pituitary adenylate cyclase - activating polypeptide ( PACAP - 38 and PACAP - 27 ) , indicating that this hypothalamic peptide regulates endothelial cell function and growth within the pituitary . P15692 secretion was also stimulated by interleukin - 6 ( P05231 ) whereas basal , P05231 - and PACAP - stimulated secretion was inhibited by the synthetic glucocorticoid dexamethasone . The inhibitory action of dexamethasone was reversed by the glucocorticoid receptor antagonist DB00834 , suggesting that in FS cells functional glucocorticoid receptors mediate the inhibitory action of glucocorticoids on the P15692 secretion . The endocrine and auto -/ paracrine control of P15692 production in pituitary FS cells by PACAP , P05231 and glucocorticoids may play an important role both in angiogenesis and vascular permeability regulation within the pituitary under physiological and pathophysiological conditions .\",\n \"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .\",\n \"Vitamin D and the regulation of placental inflammation . The vitamin D - activating enzyme 1α - hydroxylase ( O15528 ) and vitamin D receptor ( P11473 ) support anti - inflammatory responses to vitamin D in many tissues . Given the high basal expression of O15528 and P11473 in trophoblastic cells from the placenta , we hypothesized that anti - inflammatory effects of vitamin D may be particularly important in this organ . Pregnant wild type ( WT ) mice i . p . injected with LPS showed elevated expression of mouse Cyp27b1 ( 4 - fold ) and P11473 ( 6 - fold ) . Similar results were also obtained after ex vivo treatment of WT placentas with LPS . To assess the functional impact of this , we carried out ex vivo studies using placentas -/- for fetal ( trophoblastic ) Cyp27b1 or P11473 . Vehicle - treated -/- placentas showed increased expression of IFN - γ and decreased expression of P22301 relative to +/+ placentas . LPS - treated -/- placentas showed increased expression of O60603 , IFN - γ , and P05231 . Array analyses identified other inflammatory factors that are dysregulated in Cyp27b1 (-/-) versus Cyp27b1 (+/+) placentas after LPS challenge . Data highlighted enhanced expression of P05112 , P40933 , and Q14116 , as well as several chemokines and their receptors , in Cyp27b1 (-/-) placentas . Similar results for P05231 expression were observed with placentas -/- for trophoblastic P11473 . Finally , ex vivo treatment of WT placentas with the substrate for Cyp27b1 , 25 - hydroxyvitamin D ( 3 ) , suppressed LPS - induced expression of P05231 and the chemokine Ccl11 . These data indicate that fetal ( trophoblastic ) vitamin D plays a pivotal role in controlling placental inflammation . In humans , this may be a key factor in placental responses to infection and associated adverse outcomes of pregnancy .\",\n \"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK45___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .\",\n \"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK26___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .\"\n]"},"candidates":{"kind":"list like","value":["___MASK20___","___MASK26___","___MASK29___","___MASK31___","___MASK45___","___MASK49___","___MASK60___","___MASK77___","___MASK9___"],"string":"[\n \"___MASK20___\",\n \"___MASK26___\",\n \"___MASK29___\",\n \"___MASK31___\",\n \"___MASK45___\",\n \"___MASK49___\",\n \"___MASK60___\",\n \"___MASK77___\",\n \"___MASK9___\"\n]"},"answer":{"kind":"string","value":"___MASK49___"},"id":{"kind":"string","value":"MH_train_489"}}},{"rowIdx":490,"cells":{"query":{"kind":"string","value":"interacts_with DB05294?"},"supports":{"kind":"list like","value":["Endogenous concentrations of ouabain act as a cofactor to stimulate fluid secretion and cyst growth of in vitro ADPKD models via DB02527 and P00533 - Src - MEK pathways . In autosomal - dominant polycystic kidney disease ( ADPKD ) , renal cysts develop by aberrant epithelial cell proliferation and transepithelial fluid secretion . We previously showed that ouabain increases proliferation of cultured human ADPKD cells via stimulation of the P01133 receptor ( P00533 ) - Src - MEK / P29323 signaling pathway . We examined whether ouabain affects fluid secretion and in vitro cyst growth of human ADPKD cell monolayers , ADPKD cell microcysts cultured in a three - dimensional collagen matrix , and metanephric organ cultures from Pkd1 ( m1Bei ) mice . Physiological concentrations of ouabain alone did not affect net transepithelial basal - to - apical fluid transport in ADPKD monolayers or growth of cultured ADPKD microcysts . In contrast , in the presence of forskolin or 8 - bromo - DB02527 , ouabain significantly enhanced ADPKD fluid secretion and microcyst expansion . Ouabain exerted this effect by enhancing DB02527 - dependent Cl (-) secretion via the P13569 . Similarly , ouabain accelerated DB02527 - dependent cyst enlargement in Pkd1 ( m1Bei ) mice metanephroi , with a more prominent response in homozygous than heterozygous mice . Ouabain had no effect on fluid secretion and cystogenesis of normal human kidney cells and caused only slight cystic dilations in wild - type mouse kidneys . The effects of ouabain in ADPKD cells and Pkd1 ( m1Bei ) metanephroi were prevented by inhibitors of P00533 ( AG1478 ) , Src ( Q99463 ) , and MEK ( U0126 ) . Together , our results show that ouabain , used in physiological concentrations , has synergistic effects on DB02527 - mediated fluid secretion and cyst growth , via activation of the P00533 - Src - MEK pathway . These data provide important evidence for the role of ouabain as an endogenous hormone that exacerbates ADPKD cyst progression .","A randomized phase II efficacy and safety study of vandetanib ( DB05294 ) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration - resistant prostate cancer . PURPOSE : To investigate the efficacy and safety of combining vandetanib , an orally available multi - targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor - 2 ( P35968 ) and epidermal growth factor receptor ( P00533 ) , with bicalutamide in patients with metastatic castration - resistant prostate cancer ( mCRPC ) . METHODS : This was an open - label , randomized phase II multi - center study . Eligible patients had rising PSA on androgen deprivation therapy , minimal symptoms and were chemotherapy - naïve . Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily ( Arm A ) or bicalutamide 50 mg oral daily alone ( Arm B ) with cross - over to vandetanib monotherapy at progression . The primary endpoint was PSA response ( ≥ 50 % decline from baseline ) . RESULTS : Thirty - nine patients were recruited , 19 in Arm A and 20 in Arm B . PSA response was comparable in Arm A and Arm B ( 18 vs . 19 % ) . Time to PSA progression was 3 . 16 months ( 95 % confidence interval ( CI ) : 1 . 09 , not reached ( NR ) ) for Arm A and 3 . 09 months ( 95 % CI : 1 . 22 , NR ) for Arm B . Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B ( 42 vs . 5 % ; p = 0 . 019 ) . Treatment with vandetanib was associated with a reduction in soluble P35968 levels after two cycles but an increase in plasma P15692 levels . CONCLUSION : The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone . Further evaluation of this combination is not warranted in mCRPC .","Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .","Combined vascular endothelial growth factor receptor and epidermal growth factor receptor ( P00533 ) blockade inhibits tumor growth in xenograft models of P00533 inhibitor resistance . PURPOSE : The epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKI ) gefitinib and erlotinib benefit some non - small cell lung cancer ( NSCLC ) patients , but most do not respond ( primary resistance ) and those who initially respond eventually progress ( acquired resistance ) . P00533 TKI resistance is not completely understood and has been associated with certain P00533 and K - DB01367 mutations and MET amplification . EXPERIMENTAL DESIGN : We hypothesized that dual inhibition of the vascular endothelial growth factor ( P15692 ) and P00533 pathways may overcome primary and acquired resistance . We investigated the P15692 receptor / P00533 TKI vandetanib , and the combination of bevacizumab and erlotinib in vivo using xenograft models of P00533 TKI sensitivity , primary resistance , and three models of acquired resistance , including models with mutated K - DB01367 and secondary P00533 T790M mutation . RESULTS : DB05294 , gefitinib , and erlotinib had similar profiles of in vitro activity and caused sustained tumor regressions in vivo in the sensitive HCC827 model . In all four resistant models , vandetanib and bevacizumab / erlotinib were significantly more effective than erlotinib or gefitinib alone . Erlotinib resistance was associated with a rise in both host and tumor - derived P15692 but not P00533 secondary mutations in the P01116 mutant - bearing A549 xenografts . Dual inhibition reduced tumor endothelial proliferation compared with P15692 or P00533 blockade alone , suggesting that the enhanced activity of dual inhibition is due at least in part to antiendothelial effects . CONCLUSION : These studies suggest that erlotinib resistance may be associated with a rise in both tumor cell and host stromal P15692 and that combined blockade of the VEGFR and P00533 pathways can abrogate primary or acquired resistance to P00533 TKIs . This approach merits further evaluation in NSCLC patients .","Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .","Q8NFH3 / Q8TCB0 mitogen - activated protein kinases inhibit atrial natriuretic peptide mRNA transcription in P40189 - mediated hypertrophic ventricular myocytes . OBJECTIVE : To understand the role of P01160 mRNA transcription regulation in P40189 - mediated cardiomyocyte hypertrophy , and the involved mitogen - activated protein kinase kinase ( MEK ) - extracellular signal - regulated kinase ( P29323 , also called Q8NFH3 / Q8TCB0 MAPK ) signaling pathway . METHODS : Isolated neonatal ventricular myocytes were treated with different concentrations of Q16619 ( 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) mol / L ) . MTT was used to analyze the viability and RT - PCR was used to detect P01160 mRNA levels in cardiomyocyte . To inhibit Q8NFH3 / Q8TCB0 MAPK activity in hypertrophic cardiomyocytes , the cells were pretreated with a specific Q02750 inhibitor . RESULTS : Q16619 significantly induced P01160 mRNA expression and the viability of cardiomyocytes in a dose - and time - dependent manner . Furthermore , blocking Q8NFH3 / Q8TCB0 MAPK activity by the special Q02750 inhibitor upregulated the P01160 mRNA . CONCLUSIONS : Q8NFH3 / Q8TCB0 MAPK have an important role in suppressing P01160 mRNA transcription and cell activity in P40189 - mediated hypertrophic ventricular myocytes .","Activation of alternative pathways of angiogenesis and involvement of stem cells following anti - angiogenesis treatment in glioma . Malignant gliomas are hypervascular tumors that are highly resistant to all the currently available multimodal treatments . Therefore , anti - angiogenic therapies targeting P15692 or P15692 receptors ( VEGFRs ) were designed and thought to be an effective tool for controlling the growth of malignant gliomas . However , recent results of early clinical trials using humanized monoclonal antibodies against P15692 ( DB00112 ) , as well as small - molecule tyrosine kinase inhibitors that target different P15692 receptors ( VEGFRs ) ( DB04879 , DB05294 , DB01268 , DB00398 , etc ) alone or in combination with other therapeutic agents demonstrated differing outcomes , with the majority of reports indicating that glioma developed resistance to the employed anti - angiogenic treatments . It has been noted that continued anti - angiogenic therapy targeting only the P15692 - VEGFR system might affect pro - angiogenic factors other than P15692 , such as basic fibroblast growth factor ( P09038 ) , stromal derived factor 1 ( P48061 ) and Tie - 2 . These factors may in turn stimulate angiogenesis by mobilizing bone marrow derived precursor cells , such as endothelial progenitor cells ( EPCs ) , which are known to promote angiogenesis and vasculogenesis . In this short review , the current antiangiogenic treatments , possible mechanisms of activation of alternative pathways of angiogenesis , and possible involvement of bone marrow derived progenitor cells in the failure of anti - angiogenic treatments are discussed .","DB05294 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model . Angiogenesis inhibitors have been used to treat some cancers , but the therapeutic potential of these agents for gastric cancer has remained unclear . To investigate their therapeutic potential , we examined the effect of DB05294 , an agent that selectively targets vascular endothelial growth factor receptor - 2 ( P35968 ; P35968 ) tyrosine kinase and epidermal growth factor receptor ( P00533 ) tyrosine kinase , in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line , 58As1 . DB05294 ( 100 mg / kg / day , p . o . , 2 weeks ) significantly inhibited tumor growth ( p < 0 . 05 vs . control ) and reduced tumor dissemination into the peritoneal cavity ( p < 0 . 05 vs . control ) . In addition , to identify putative tumor biomarkers that would reflect the effects of DB05294 treatment in clinical settings , we examined the gene expression profiles of implanted gastric tumors treated with DB05294 in vivo . Twenty - eight candidate genes were identified , including P17936 , P35318 , Q9BY76 , O00469 , Q99576 , Q92597 , P09104 , Q9Y5L2 and O60238 , which are known to be hypoxia - inducible genes . These genes and gene products may be useful biomarkers for monitoring the effects of DB05294 treatment . DB05294 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line , 44As3 . In conclusion , our results suggest that DB05294 may have clinical activity against gastric cancer , particularly undifferentiated gastric cancer with peritoneal dissemination . We also identified putative biomarkers for monitoring the pharmacodynamic effects of DB05294 by gene expression profiling .","DB05294 for the treatment of medullary thyroid cancer . DB05294 ( DB05294 , Caprelsa , AstraZeneca ) , an oral small - molecule tyrosine kinase inhibitor ( TKI ) that targets the rearranged during transfection receptor ( P07949 ) , P15692 receptor ( P35968 - 3 ) , and P01133 receptor ( P00533 ) , is the first systemic therapy approved by the U . S . Food and Drug Administration ( FDA ) for the treatment of symptomatic or progressive advanced medullary thyroid cancer ( P04629 ) . In a randomized phase III trial of patients with unresectable , locally advanced , or metastatic P04629 , vandetanib improved progression - free survival compared with placebo [ HR , 0 . 46 ; 95 % confidence interval ( CI ) , 0 . 31 - 0 . 69 ; P < 0 . 001 ] . However , the benefits in delaying disease progression need to be balanced against the associated and potentially serious toxicities , including diarrhea , hypertension , and QTc prolongation . Here , we review the clinical development of vandetanib leading to its integration into the current treatment paradigm and highlight the ongoing and future challenges in TKI use in P04629 .","Investigation of two dosing schedules of vandetanib ( DB05294 ) , an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling , in combination with irinotecan in a human colon cancer xenograft model . PURPOSE : This in vivo study was designed to determine the optimal doses and schedules of vandetanib , a dual epidermal growth factor receptor ( P00533 ) - vascular endothelial growth factor receptor tyrosine kinase inhibitor , in combination with irinotecan in a murine xenograft model of human colon cancer . EXPERIMENTAL DESIGN : HT - 29 tumor - bearing nude mice were treated with two doses of vandetanib ( 12 . 5 and 25 mg / kg / d ) with or without irinotecan ( 100 mg / kg ) using either sequential or concurrent schedules for 30 days . Tumor size was measured using standard variables , whereas the antiangiogenic response was evaluated using dynamic contrast - enhanced magnetic resonance imaging . Additionally , effects on P00533 - dependent signal transduction pathways and proliferation were assessed using immunohistochemistry . These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and / or to plasma / tumor concentrations of vandetanib . RESULTS : The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously ( concurrent schedule ) , alone or in combination with irinotecan . These dosing schedules resulted in significant effects on tumor vasculature , with decreased volume transfer constants , area under the curve , and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment . In addition , these groups showed the greatest inhibition of P00533 signaling . Interestingly , tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule , possibly due to decreased tumor perfusion in this group . CONCLUSIONS : These data suggest that higher , sustained concentrations of vandetanib ( versus intermittent ) , alone and in combination with irinotecan , result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug .","Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK30___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK30___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .","Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes : evidence for in situ t - cell activation and therapeutic efficacy . After adoptive transfer of pre - activated lymphocytes into the operation cavity of glioma patients , tumor regression and improved survival have been reported in some patients . Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied . In this study , we attempted to avoid time - consuming pre - activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the P01133 receptor ( P00533 ) on tumor cells and to CD3 and P10747 on T cells . Eleven patients with high - grade malignant glioma received 3 injections of 2 bispecific antibody fragments ( P00533 x CD3 and P00533 x P10747 ) together with freshly isolated autologous lymphocytes via an Ommaya reservoir . Intracavitary fluid aspirated during immunotherapy was examined for markers of T - cell activation . Increased levels of soluble P60568 receptor and P01375 were detected in the intracavitary fluid of all patients tested . Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent Q9BWK5 scans and prolonged survival . Side effects were transient and consisted of fever , nausea , headache and aggravation of pre - existing neurologic deficits . These adverse effects were most likely due to the antibody construct containing anti - CD3 specificity . Two patients developed cerebral edema and required steroid treatment .","Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .","DB05294 alters the protein pattern in malignant glioma and normal brain in the BT4C rat glioma model . The treatment of glioblastoma is unsatisfactory . Improved understanding of the biological effects of treatment , together with development of new tools to predict outcome of the initiated treatment are therefore of great need . DB05294 ( DB05294 ) is mainly a vascular endothelial growth factor ( P15692 ) and epidermal growth factor ( P01133 ) receptor tyrosine kinase inhibitor . This study investigated the pattern of protein expression in brain tumor and normal brain tissue , following treatment with vandetanib in a rat glioma model . BT4C - cells were stereotactically implanted into the brain of BD IX rats . The rats were divided into three different experiments . The treatment schedule for experiments one and two consisted of daily , oral doses of vandetanib from day 6 until day 12 or 20 after implantation , respectively . In the third experiment , each animal received a single dose of vandetanib on day 19 after implantation and was then sacrificed 2 , 8 or 24 h thereafter . The protein expression profiles were analyzed by SELDI - TOF - MS and evaluated with multivariate statistical methods . Following treatment with vandetanib , we found significantly altered protein expression pattern in malignant glioma and normal brain . Analyzing protein spectra is an interesting option to assess biological effects induced in brain tissue by signal transduction inhibitors such as vandetanib .","Modeling the neurovascular niche : murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn . Preterm birth results in significant cognitive and motor disabilities , but recent evidence suggests that there is variable recovery over time . One possibility that may explain this variable recovery entails variable neurogenic responses in the subventricular zone ( SVZ ) following the period of chronic hypoxia experienced by these neonates . In this report , we have characterized the responses to chronic hypoxia of two mouse strains that represent a wide range of susceptibility to chronic hypoxia . We determined that C57BL / 6 pups and neural progenitor cells ( NPCs ) derived from them exhibit a blunted response to hypoxic insult compared with CD - 1 pups and NPCs . Specifically , C57BL / 6 pups and NPCs exhibited blunted in vivo and in vitro proliferative and increased apoptotic responses to hypoxic insult . Additionally , C57BL / 6 NPCs exhibited lower baseline levels and hypoxia - induced levels of selected transcription factors , growth factors , and receptors ( including HIF - 1alpha , Q9GZT9 , P23560 , P15692 , P48061 , TrkB , Nrp - 1 , P61073 , and NO ) that determine , in part , the responsiveness to chronic hypoxic insult compared with CD - 1 pups and NPCs , providing insight into this important and timely problem in perinatology .","P00533 gene expression in avian epiphyseal growth - plate cartilage cells : effect of serum , parathyroid hormone and atrial natriuretic peptide . Avian chondrocytes and fibroblasts , derived from epiphyseal growth - plate and skin , respectively , were cultured in vitro . In chondrocytes , epidermal growth factor ( P01133 ) caused a dose - dependent stimulation of proliferation . P01133 receptor mRNA was not detected with the v - erb B probe in chondrocytes cultured in the presence of 5 % fetal calf serum ( FCS ) . In the absence of FCS in the medium , a time - dependent increase in the level of P01133 receptor mRNA was observed . Parallel changes were also observed in the level of P01133 receptor , as demonstrated by immunofluorescence using antibodies directed against avian P01133 receptor . In avian fibroblasts , P01133 receptor mRNA and P01133 receptor levels were not affected by FCS . Furthermore , FCS did not affect the level of thyroid hormone receptor mRNA ( using v - erb A as a probe ) in either chondrocytes or fibroblasts . Parathyroid hormone ( PTH ) , which acts as a mitogen in avian chondrocytes attenuated -- whereas atrial natriuretic peptide ( P01160 ) , a suppressor of chondrocyte proliferation , enhanced -- P01133 receptor mRNA . The present results show that avian growth - plate chondrocytes respond to P01133 and bear P01133 receptors . The levels of P01133 mRNA and P01133 receptor are inversely related to cell proliferation . The results also support previous suggestions that PTH and P01160 play important roles in chondrocyte proliferation , possibly through their effect on the synthesis of the P01133 receptor .","Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK93___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .","P00533 inhibitors in development for the treatment of non - small cell lung cancer . The epidermal growth factor receptor ( P00533 ) inhibitors erlotinib , gefitinib , and cetuximab have undergone extensive clinical testing and have established clinical activity in non - small cell lung cancer and other types of solid tumors . A number of newer inhibitors are currently in clinical development with different spectra of activity or mechanisms of receptor inhibition . These include monoclonal antibodies , such as panitumumab and matuzumab ; dual inhibitors of P00533 and vascular endothelial growth factor receptor , such as DB05294 and AEE788 ; inhibitors of multiple P00533 family members , such as lapatinib ; and irreversible inhibitors , such as canertinib and HKI272 . Preclinical studies suggest that several of these agents may have activity in tumors refractory to erlotinib or gefitinib . Among these agents , DB05294 has undergone the most extensive clinical testing . The antitumor activity of DB05294 in these two randomized phase II clinical trials in patients with non - small cell lung cancer was felt to be sufficiently promising to warrant phase III clinical testing . Several of the other P00533 inhibitors are also undergoing advanced clinical testing , either alone or in combination with other agents . P00533 has now been validated as a clinically relevant target , and several different types of agents inhibiting this receptor are currently in development . Future research will be needed to elucidate the role of these agents in patients with P00533 inhibitor - naive and P00533 inhibitor - refractory disease , to define the molecular characteristics that predict response , and to determine whether these drugs should be used in combination with other targeted agents or chemotherapy .","DB05294 is effective in P00533 - mutant lung cancer cells with P60484 deficiency . The effectiveness of vandetanib , an agent that targets P07949 , VEGFR and P00533 signaling , against P00533 - mutant lung cancer cells with P60484 loss was investigated . Two P00533 mutant non - small cell lung cancer ( NSCLC ) cell lines , PC - 9 ( P60484 wild type ) and NCI - H1650 ( P60484 null ) , were used . We transfected an intact P60484 gene into H1650 cells and knocked down P60484 expression in PC - 9 cells using shRNA . The effectiveness of gefitinib and vandetanib was assessed using a xenograft model . While PC - 9 cells were more resistant to vandetanib than gefitinib , H1650 cells were more sensitive to vandetanib than gefitinib . Both gefitinib and vandetanib suppressed the activation of P00533 and MAPK in H1650 cells , although phosphorylated AKT levels were not affected . In an H1650 cell xenograft model , vandetanib was also more effective than gefitinib . Although P60484 - transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro , the xenograft tumors responded to gefitinib and vandetanib . Knockdown of P60484 in PC - 9 cells caused resistance to gefitinib . In conclusion , vandetanib might be effective in NSCLC with P00533 mutations that lack P60484 expression . The contribution of P60484 absence to vandetanib activity in NSCLC cells harboring P00533 mutations should be further examined .","P15692 - associated tyrosine kinase inhibition increases the tumor response to single and fractionated dose radiotherapy . PURPOSE : In this study , the efficacy of combining DB05294 ( DB05294 ) , a vascular endothelial growth factor ( P15692 ) receptor 2 - associated tyrosine kinase inhibitor currently undergoing Phase II clinical trial evaluation , with single and fractionated dose radiation exposures was examined in a human colorectal carcinoma model ( HT29 ) . METHODS AND MATERIALS : HT29 xenograft - bearing mice were treated with either single - dose ( 10 Gy ) or multifraction ( 2 Gy / day for 2 weeks ) radiotherapy alone or in conjunction with a 2 - week course of DB05294 ( 25 mg / kg ) . In the single - dose investigation , DB05294 treatment followed radiotherapy , whereas in the fractionated dose studies the antiangiogenic therapy was given before , after , or concurrent with the radiation . Tumor response was determined by tumor growth delay . RESULTS : DB05294 increased the response of HT29 xenografts to both single and fractionated dose radiotherapy . In the fractionation studies sequencing of therapies had little impact on treatment outcomes ; the time for the median tumors in each of the treatment groups to grow to five times the starting size was 53 , 53 . 5 , and 49 days , respectively . CONCLUSIONS : These studies indicate that DB05294 , when used in conjunction with radiation therapy , has a clear therapeutic advantage , providing a rationale for considering the combination of this agent with radiotherapy in the clinic .","Identification of a lung adenocarcinoma cell line with Q16204 - P07949 fusion gene and the effect of P07949 inhibitors in vitro and in vivo . Rearrangements of the proto - oncogene P07949 are newly identified potential driver mutations in lung adenocarcinoma ( LAD ) . However , the absence of cell lines harboring P07949 fusion genes has hampered the investigation of the biological relevance of P07949 and the development of P07949 - targeted therapy . Thus , we aimed to identify a P07949 fusion positive LAD cell line . Eleven LAD cell lines were screened for P07949 fusion transcripts by reverse transcription - polymerase chain reaction . The biological relevance of the Q16204 - P07949 gene products was assessed by cell growth , survival and phosphorylation of P27361 / 2 and AKT with or without the suppression of P07949 expression using RNA interference . The efficacy of P07949 inhibitors was evaluated in vitro using a culture system and in an in vivo xenograft model . Expression of the Q16204 - P07949 fusion gene in LC - 2 / ad cells was demonstrated by the mRNA and protein levels , and the genomic break - point was confirmed by genomic DNA sequencing . Mutations in P01116 and P00533 were not observed in the LC - 2 / ad cells . Q16204 - P07949 was constitutively active , and the introduction of a siRNA targeting the P07949 3 ' region decreased cell proliferation by downregulating P07949 and P27361 / 2 phosphorylation . Moreover , treatment with P07949 - inhibitors , including vandetanib , reduced cell viability , which was accompanied by the downregulation of the AKT and P27361 / 2 signaling pathways . DB05294 exhibited anti - tumor effects in the xenograft model . Endogenously expressing Q16204 - P07949 contributed to cell growth . The inhibition of kinase activity could be an effective treatment strategy for LAD . LC - 2 / ad is a useful model for developing fusion P07949 - targeted therapy .","Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .","A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re - vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly - developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 - based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically - used drugs operating on the P00797 - Angiotensin - DB04630 - System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point - of - no - return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling - reversing drugs to pathways other than RAAS , a specific inhibitor of 11β - hydroxy - steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy - associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization - induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling - reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects .","DB05294 , a multitargeted inhibitor for receptor tyrosine kinases , suppresses growth of gliomas expressing an epidermal growth factor receptor mutant , EGFRvIII , in the brain . P00533 ( P00533 ) vIII is a mutated P00533 that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors . In this study , we investigate the effect of DB05294 ( ZACTIMA , vandetanib ) , a dual inhibitor for vascular endothelial growth factor receptor 2 and P00533 on growth and angiogenesis of gliomas expressing EGFRvIII . We used two glioma xenograft models , U87MG cells overexpressing EGFRvIII and short - term cultured primary glioma GBM8 cells with EGFRvIII . DB05294 inhibited tumor growth and angiogenesis and induced cell apoptosis in various brain gliomas . Moreover , significant inhibition of EGFRvIII - expressing U87MG and GBM8 gliomas was observed compared with their controls . Magnetic resonance imaging analysis using the apparent diffusion coefficient and three - dimensional P24752 * weighed measurements validated DB05294 inhibition on tumor growth and angiogenesis in EGFRvIII - expressing GBM8 gliomas . Mechanistically , DB05294 shows better inhibition of cell growth and survival of U87MG / EGFRvIII , GBM6 , and GBM8 cells that express EGFRvIII than U87MG or GBM14 cells that have nondetectable EGFRvIII through attenuation of activated phosphorylation of signal transducer and activator of transcription 3 , Akt , and Bcl - X ( L ) expression . Albeit in lesser extent , DB05294 also displays suppressions of U87MG / P00533 and GBM12 cells that overexpress wild - type P00533 . Additionally , DB05294 inhibits activation of extracellular signal - regulated kinase 1 / 2 in both types of cells , and expression of a constitutively active phosphoinositide 3 - kinases partially rescued DB05294 inhibition in U87MG / EGFRvIII cells . Taken together , these data show that DB05294 significantly inhibited growth and angiogenesis of gliomas expressing EGFRvIII by specifically blocking EGFRvIII - activated signaling mediators , suggesting a potential application of DB05294 in treatments for glioblastomas that overexpress EGFRvIII . Mol Cancer Ther ; 9 ( 4 ) ; 929 - 41 . ( c ) 2010 AACR .","Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 for erlotinib and gefitinib in non - small - cell lung cancer ; P01116 against the use of cetuximab and panitumumab in colorectal cancer ; P04626 ( P04626 / neu ) for trastuzumab in breast cancer ; P11274 - P00519 for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 / RARα for all - trans - retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia .","Prolonged exposure of colon cancer cells to the epidermal growth factor receptor inhibitor gefitinib ( DB00317 ( TM ) ) and to the antiangiogenic agent DB05294 : Cytotoxic and biomolecular effects . AIM : To analyze the biological effects of prolonged in vitro exposure of HT - 29 and LoVo colon cancer cell lines to gefitinib ( DB00317 ) , an inhibitor of epidermal growth factor receptor ( P00533 ) activity , and DB05294 , an inhibitor of both P35968 and P00533 activities . METHODS : Cells were treated with each drug for up to 2 wk using either a continuous or an intermittent ( 4 d of drug exposure followed by 3 d of washout each week ) schedule . RESULTS : In both cell types , prolonged exposure ( up to 14 d ) to gefitinib or DB05294 produced a similar inhibition of cell growth that was persistent and independent of the treatment schedule . The effects on cell growth were associated with a pronounced inhibition of p - P00533 and / or p - P35968 expression . Treatment with gefitinib or DB05294 also inhibited the expression of P00533 downstream signal molecules , p - Erk1 / 2 and p - Akt , although the magnitude of these effects varied between treatments and cell lines . Furthermore , expression of the drug resistance - related protein Q9UNQ0 was shown to significantly increase after 14 d of continuous exposure to the two drugs . CONCLUSION : We conclude that long - term exposure of colon cancer cells to gefitinib and DB05294 does not modify their cytotoxic effects but it might have an effect on sensitivity to classical cytotoxic drugs .","DB05294 , an inhibitor of VEGFR and P00533 tyrosine kinase activity in combination with radiotherapy . Radiation enhances both epithelial growth factor receptor ( P00533 ) and vascular endothelial growth factor ( P15692 ) expression , which are a part of key pathways for tumor progression . Some tumors may not respond well to P00533 inhibitors alone or may develop resistance to P00533 inhibitors . Therefore , drug therapy targeted to P15692 receptors and EGFRs , when combined with radiotherapy ( RT ) , may improve tumor control and provide wider applicability . This article focuses on DB05294 , an inhibitor of P00533 and P15692 receptor signaling in combination with RT . We discuss preclinical and clinical studies with RT and inhibitors of P15692 or P00533 signaling first . We then address issues associated with DB05294 pharmacokinetic dosing , and scheduling when combined with RT . We also discuss DB05294 in the context of anti - P00533 therapy resistance . Dual inhibition of P00533 and P15692 receptor signaling pathways shows promise in enhancing RT efficacy .","Vascular endothelial growth factor receptor tyrosine kinase inhibitors vandetanib ( DB05294 ) and DB04849 in lung cancer . Vascular endothelial growth factor ( P15692 ) is a rational target for advanced non - small cell lung cancer ( NSCLC ) , a hypothesis validated by the recent Eastern Cooperative Oncology Group E4599 trial showing that the addition of the P15692 monoclonal antibody bevacizumab to chemotherapy prolongs overall survival . Several new tyrosine kinase inhibitors targeting the P15692 pathway are currently in advanced clinical development for NSCLC and offer several possible advantages compared with monoclonal antibodies , including oral administration , more flexible dosing , a broader spectrum of target inhibition , and different toxicity profiles . Among these agents , vandetanib ( DB05294 ) , an inhibitor of the P15692 receptor ( VEGFR ) - 2 and epidermal growth factor receptor tyrosine kinase , has been the most extensively studied . In a randomized phase II study of patients with platinum - refractory NSCLC , including squamous histology , vandetanib prolonged progression - free survival compared with gefitinib . In another phase II trial , an improvement in progression - free survival was observed for vandetanib in combination with docetaxel compared with docetaxel alone . DB04849 is an inhibitor of P17948 , P35968 , and P35916 and other tyrosine kinases that has shown clinical activity in NSCLC in combination with carboplatin and paclitaxel . Several phase III trials are under way testing these agents either as monotherapy or in combination with chemotherapy in patients with lung cancer . Early results with these agents , and others being tested , raise the possibility that there will eventually be multiple P15692 - targeted therapies available in the clinic that can potentially benefit a broader range of patients with advanced - stage NSCLC .","Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with ___MASK89___ , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20 - week - old Zucker obese and 16 - week - old ZDF rats were treated with ___MASK89___ ( 25 mg / kg / day ) or Enalapril ( 20 mg / kg / day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75 - 175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with ___MASK89___ or Enalapril .","The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK76___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .","Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines . ___MASK100___ and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the P15692 tyrosine kinase receptors 1 , 2 and 3 ( pazopanib ) , and the P00533 and P04626 receptors in a dual manner ( lapatinib ) . ___MASK100___ has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as P09619 and c - kit . Here , we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non - small - cell lung cancer cells . Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases ( such as c - DB00134 ) that were not or only partially affected by either of the two agents alone . We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells , some of which were specific for the combination of both agents . Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up - or downregulation reflected the combined action of pazopanib and lapatinib . Indeed , pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non - small - cell lung cancer cells as well as on unrelated carcinomas . Altogether , these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects . Such combinations may lead to a ' collapse ' of pro - survival signal transduction pathways that leads to apoptotic cell death .","Current status of vandetanib ( DB05294 ) in the treatment of non - small cell lung cancer . DB05294 ( DB05294 ) is an oral small molecule inhibitor of multiple intracellular receptor kinases , including the vascular endothelial growth factor receptor ( VEGFR ) - 2 and epidermal growth factor receptor ( P00533 ) . Both VEGFR and P00533 pathways have emerged as instrumental in the growth and metastasis of multiple malignancies , including non - small cell lung cancer ( NSCLC ) . Indeed , inhibitors of each pathway have been approved by the US Food and Drug Administration for use in advanced NSCLC . As there is considerable cross talk between these pathways , dual inhibition with such agents has become an attractive strategy , with encouraging Phase II clinical trial data to date . The convenience of one oral agent targeting both pathways is clear , and clinical trials have established the maximum tolerated daily dose of vandetanib , with data from randomized Phase III trials emerging . This report will review completed and ongoing NSCLC clinical trials evaluating vandetanib , and speculate on the future of this agent in NSCLC .","Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials : current status and future directions . Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination . The vascular endothelial growth factor ( P15692 ) family of peptide growth factors and receptors are key regulators of this process . Agents directed either against P15692 or P15692 receptors ( VEGFRs ) have been developed . The tyrosine kinase inhibitors of VEGFRs are low - molecular - weight , DB00171 - mimetic proteins that bind to the DB00171 - binding catalytic site of the tyrosine kinase domain of VEG - FRs , resulting in blockade of intracellular signaling . Several of these agents are currently in different phases of clinical development . Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies , respectively . Positive results also have been reported with the combination of DB05294 and chemotherapy in previously treated non - small cell lung cancer patients . For other agents , such as vatalanib , contrasting outcomes in metastatic colorectal cancer patients have been reported : the final results of these trials are expected in 2006 . However , several key questions remain to be addressed , regarding the choice of an adequate dose or schedule , the presence of \" off - target \" effects , the safety of long - term administration , and the research of new clinical end points or methodological approaches for the optimal clinical development of these agents .","DB05294 restores head and neck squamous cell carcinoma cells ' sensitivity to cisplatin and radiation in vivo and in vitro . PURPOSE : We investigated whether vandetanib , an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor - 2 ( P35968 ) , epidermal growth factor receptor ( P00533 ) , and rearranged during transfection ( P07949 ) , could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma ( HNSCC ) . EXPERIMENTAL DESIGN : P48449 - 19 and P0CJ72 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib , cisplatin , and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model . Treatment effects were assessed using clonogenic survival assay , tumor volume , bioluminescence imaging , tumor growth delay , survival , microvessel density , tumor and endothelial cell apoptosis , and P00533 and Akt phosphorylation data . RESULTS : DB05294 plus cisplatin radiosensitized HNSCC cells in vitro and in vivo . The combination treatment with vandetanib , cisplatin , and radiation was superior to the rest of treatments ( including the double combinations ) in antitumoral effects , prolonging survival , decreasing cervical lymph node metastases in vivo . It also increased both tumor and tumor - associated endothelial cell apoptosis and decreased microvessel density in vivo . An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo . All vandetanib - containing treatments inhibited P00533 and Akt phosphorylation in vitro and in vivo . CONCLUSION : The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC . Further study of this regimen in clinical trials may be warranted .","Contrast - enhanced Ultrasound Imaging of Antiangiogenic Tumor Therapy . BACKGROUND / AIM : Anti - angiogenic treatment is a promising strategy for cancer therapy and is currently evaluated in clinical trials . The aim of the present study was to further investigate the effects of an anti - angiogenic therapy , inhibiting vascular endothelial growth factor ( P15692 ) and endothelial growth factor ( P01133 ) using a tyrosine kinase inhibitor for blocking tumor angiogenesis and tumor progression in vivo . MATERIALS AND METHODS : Experiments were performed using C57 / Bl6 mice ( 25 ± 5 g of body weight ( b . w . ) ) implanted with subcutaneous Lewis lung carcinoma ( LLC - 1 ) . From day 7 till 21 after tumor cell implantation , animals ( n = 7 per group ) were treated by monotherapy using DB05294 ( 50 mg / kg b . w . per os ( p . o . ) ) daily . A control group received only the solvent polysorbate 80 . Using contrast enhanced ultrasound ( CE - US ) parameters of intra - tumoral microcirculation animals were examined 24 h after the last application of DB05294 . Moreover , subcutaneous tumor growth was measured over the whole therapy period . Finally , histological analyses were performed to analyze the functional vessel density in the tumor tissue . RESULTS : DB05294 reduced tumor growth of LLC - 1 in C57 / Bl6 mice significantly . A significant difference of maximal signal intensity ( ΔSImax ) and area below the intensity time curve ( AUC ) after antiangiogenic therapy was recorded in the tumor center by CE - US . Vessel density after hematoxyline and eosin , as well as CD31 , staining showed no significant difference in both groups . CONCLUSION : Anti - angiogenic effects can be quantitatively demonstrated using CE - US imaging , which represents the spreading of efficient vessels in the tumor tissue , especially in the tumor center .","DB05294 and indwelling pleural catheter for non - small - cell lung cancer with recurrent malignant pleural effusion . INTRODUCTION / BACKGROUND : Non - small - cell lung cancer patients with malignant pleural effusion have a poor overall median survival ( 4 . 3 months ) . P15692 is a key regulator of pleural effusion production . It is unknown if pharmacological inhibition of P15692 signaling modifies the disease course of non - small - cell lung cancer patients with recurrent malignant pleural effusion . We report the final results of a single - arm phase II clinical trial of the P15692 receptor inhibitor , vandetanib , combined with intrapleural catheter placement in patients with non - small - cell lung cancer and recurrent malignant pleural effusion , to determine whether vandetanib reduces time to pleurodesis . PATIENTS AND METHODS : Non - small - cell lung cancer patients with proven metastatic disease to the pleural space using pleural fluid cytology or pleural biopsy who required intrapleural catheter placement were eligible for enrollment . On the same day of the intrapleural catheter insertion , the patients were started on a daily oral dose of 300 mg vandetanib , for a maximum of 10 weeks . The primary end point was time to pleurodesis , with response rate as the secondary end point . Exploratory analyses included measurement of pleural fluid cytokines and angiogenic factors before and during therapy . RESULTS : Twenty eligible patients were included in the trial . Eleven patients completed 10 weeks of treatment . Median time to pleurodesis was 35 days ( 95 % confidence interval , 15 - not applicable ) . Median time to pleurodesis in the historical cohort was 63 days ( 95 % confidence interval , 45 - 86 ) when adjusted for Eastern Cooperative Oncology Group performance status ≤ 2 . CONCLUSION : DB05294 therapy was well tolerated ; however , it did not significantly reduce time to pleurodesis .","Inhibition of P35968 prevents DMBA - induced mammary tumor formation . Preinvasive mammary pathologies in humans and rat chemical carcinogenesis model systems have an increased microvascular density relative to normal tissue . This suggests the possibility of preventing invasive breast cancer by inhibiting angiogenesis . Vascular endothelial cell growth factor ( P15692 ) is a potent angiogenic growth factor , commonly involved in tumor - induced angiogenesis . Here , we show that both P15692 and P35968 expression increase with histological progression to invasive disease in the rat 7 , 12 - dimethylbenz [ a ] anthracene ( DMBA ) model . Other P15692 receptors , P17948 , neuropilin 1 and neuropilin 2 , are constitutively expressed throughout progression . To examine whether P15692 signaling is functionally relevant to tumor - induced endothelial tubule formation in vitro and for tumor formation in vivo , we utilized the P35968 inhibitor , DB05294 . In vitro endothelial cell tubulogenesis induced by isolated mammary organoids or carcinoma in situ from DMBA - treated rats is inhibited by DB05294 , in a dose - dependent fashion . The administration of DB05294 to DMBA - treated rats inhibits the formation of atypical ductal hyperplasia and carcinoma in situ by greater than 95 % ( P < 0 . 05 ) , when administered 1 week or 6 weeks post - DMBA initiation . Invasive disease was absent in all DB05294 cohorts . These data support the hypothesis that progression of DMBA - induced preinvasive mammary pathologies to palpable disease requires angiogenesis via a P15692 - dependent mechanism .","DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .","Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto - maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription - polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) - gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) - alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL - 1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL - 1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts .","Tyrosine phosphorylation of Q92835 promotes its proteasomal degradation . OBJECTIVE : The activity of the SH2 - containing - phosphatidylinositol - 5 '- phosphatase ( Q92835 , also known as Q92835 ) , a critical hematopoietic - restricted negative regulator of the P19957 kinase ( PI3K ) pathway , is regulated in large part via its protein levels . We sought to determine the mechanism ( s ) involved in its downregulation by P11274 - P00519 and by interleukin ( IL ) - 4 . MATERIALS AND METHODS : We used Ba / P13726 ( Q92817 - tetOFF ) cells to study the downregulation of Q92835 by P11274 - P00519 and bone marrow - derived macrophages to study Q92835 ' s downregulation by P05112 . RESULTS : We show herein that P11274 - P00519 downregulates Q92835 , but not O15357 or P60484 , and this can be blocked with the Src kinase inhibitor Q99463 , which inhibits the tyrosine phosphorylation of Q92835 , or with the proteasomal inhibitor MG - 132 . We also show , using anti - Q92835 immunoprecipitates , that c - Cbl and Cbl - b are associated with Q92835 and that P11274 - P00519 induces Q92835 ' s polyubiquitination . This ubiquitination can be blocked with Q99463 , consistent with the tyrosine phosphorylation of Q92835 acting as a signal for its ubiquitination . In bone marrow - derived macrophages , P05112 also leads to the proteasomal degradation of Q92835 but , unlike in Ba / P13726 ( Q92817 - tetOFF ) cells , O15357 is also proteasomally degraded and the degradation of both inositol phosphatases can be prevented with Q99463 or MG - 132 . CONCLUSION : Our results suggest that Q92835 protein levels can be reduced via P11274 - P00519 and / or Src family member - induced tyrosine phosphorylation of Q92835 because this triggers its polyubiquitination and degradation within the proteasome .","Evaluation of antileukaemic effects of rapamycin in patients with imatinib - resistant chronic myeloid leukaemia . BACKGROUND : Recent data suggest that the mammalian target of rapamycin ( P42345 ) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia ( CML ) . PATIENTS AND METHODS : We treated six patients with imatinib - resistant CML in haematological relapse ( leukocytes > 20 , 000 microL (- 1 ) ) with rapamycin at 2 mg per os daily for 14 consecutive days , with dose - adjustment allowed to reach a target rapamycin serum concentration of 10 - 20 pg mL (- 1 ) . RESULTS : A major leukocyte response with decrease to less than 10 , 000 microL (- 1 ) was obtained in two patients , and a minor transient response was seen in two other patients . In responding patients , we also observed a decrease in vascular endothelial growth factor ( P15692 ) mRNA levels in circulating leukaemic cells . Side effects during rapamycin treatment were mild in most patients . In one patient , pneumonia developed . DB00877 was also found to counteract growth of CML cells in vitro as determined by ( 3 ) H - thymidine incorporation . Moreover , rapamycin inhibited the growth of Ba / P13726 cells exhibiting various imatinib - resistant mutants of P11274 / P00519 , including the T315I variant that exhibits resistance against most currently available P11274 / P00519 kinase inhibitors . CONCLUSIONS : DB00877 shows antileukaemic effects in imatinib - resistant CML in vitro and in vivo . Larger trials with rapamycin or rapamycin - derivatives in combination with other targeted drugs are warranted to further determine clinical efficacy in CML .","Differential effects of vascular endothelial growth factor receptor - 2 inhibitor DB05294 on circulating endothelial progenitors and mature circulating endothelial cells : implications for use as a surrogate marker of antiangiogenic activity . PURPOSE : Circulating endothelial cells ( CEC ) comprise at least two distinct populations : bone marrow - derived circulating endothelial progenitors ( CEP ) and mature CECs derived from existing vasculature . We hypothesized that antiangiogenic agents may have differential effects on CEPs and mature CECs and that these changes may serve as a marker of biological activity . EXPERIMENTAL DESIGN : The effect of angiogenesis inhibitors on CECs was evaluated by flow cytometry after vascular endothelial growth factor ( P15692 ) - induced mobilization and in mice bearing Lewis lung carcinoma ( LLC ) . Tumor angiogenesis was evaluated in parallel by immunohistochemistry . RESULTS : In nontumor - bearing mice , P15692 administration increased both mature CECs and CEPs . This increase was inhibited by the P15692 receptor 2 inhibitor DB05294 as well as the P15692 inhibitor - soluble Flt - 1 . DB05294 had no significant effect on CECs in the absence of exogenous P15692 stimulation . In contrast , LLC - bearing mice had an increase in mature CECs but not CEPs after 3 days of treatment with DB05294 . The increase in mature CECs was dose - dependent , accompanied by a decrease in tumor microvessel density , and preceded reduction in tumor volume . Treatment of LLC - bearing mice with the vascular targeting agent ZD6126 also increased mature CECs . CONCLUSIONS : P15692 inhibitors can have differential effects on mature CECs and CEPs , and agents inhibiting tumor angiogenesis may cause a concomitant increase in mature CECs . This increase occurs in tumor - bearing but not in nontumor - bearing mice , suggesting that tumor endothelium is a potential source of mature CECs . Therefore , assessing both mature CECs and CEPs may provide insights into the mechanism of antiangiogenic agents and serve as an early surrogate marker of biological activity .","DB05294 improves anti - tumor effects of L19mTNFalpha in xenograft models of esophageal cancer . PURPOSE : Targeting the tumor vasculature by vascular disrupting agents ( VDAs ) has shown therapeutic activity in mouse models . In most cases , however , VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass . In this study , we investigated anti - tumor effects of L19mTNFα , a fusion protein composed of Q9Y2K2 ( scFv ) , specific for the angiogenesis - associated ED - B containing fibronectin isoform , and murine TNFα , in xenograft models of esophageal cancer . EXPERIMENTAL DESIGN : We evaluated ED - B expression in esophageal cancer samples . Subsequently , we generated subcutaneous xenografts from primary tumors , treated them with the L19mTNFα scFv , and determined effects on tumor vasculature , viability and proliferation , and P15692 expression and infiltration by hematopoietic cells . To overcome tumor resistance , L19mTNFα scFv was combined with vandetanib , a tyrosine kinase inhibitor of P15692 receptor , epidermal growth factor receptor , and P07949 signaling . RESULTS : ED - B was broadly expressed by esophageal cancer cell lines , as well as xenografts and primary surgical samples of esophageal cancer . Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis , indicating a VDA - like activity of this immunoconjugate . This event was followed , however , by rapid tumor growth recovery associated with increased expression of P15692 and recruitment of CD11b + Gr1 + myeloid cells into tumors . Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors , leading to a reduction of cell proliferation and increased necrosis , without apparent signs of toxicity . CONCLUSION : These findings indicate that a combination of vascular damaging agents with anti - angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer .","Genetic mechanism of aspirin - induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin - related hypersensitivity often associated with aspirin - intolerant asthma . Genetic studies on aspirin - intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin - induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin - induced urticaria / angioedema . A polymorphism study that examined nine single - nucleotide polymorphisms of five leukotriene - related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 - activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( - 1708A > G ) and Q9Y271 ( - 634C > T ) were significantly different between aspirin - intolerant asthma and aspirin - induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine - related genes , did not find any significant associations with aspirin - induced urticaria / angioedema for the genes P50135 ( encoding histamine N - methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high - affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin - induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin - induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .","Administration of P15692 receptor tyrosine kinase inhibitor increases P15692 production causing angiogenesis in human small - cell lung cancer xenografts . Angiogenesis is mediated mainly by vascular endothelial growth factor ( P15692 ) , and P15692 causes rapid growth in cancers , including human small - cell lung cancer ( SCLC ) . The anti - angiogenic strategy of treating cancer using P15692 receptor ( VEGFR ) inhibition is currently of great interest . We tested the effects of the P35968 tyrosine kinase inhibitor ( TKI ) vandetanib on the proliferation of two kinds of SCLC cell lines : SBC - 1 cells , with detectable P35968 expression and MS - 1 - L cells , without detectable P35968 expression . To evaluate the anti - tumor and anti - angiogenic effects of vandetanib in vivo , we grafted SBC - 1 and MS - 1 - L cells into mice . After a 3 - week treatment , we measured the tumor size and histologically evaluated necrosis and apoptosis using H & E and TUNEL staining , respectively . The microvessels in the xenografts were also quantified by immunostaining of CD31 . DB05294 did not affect the proliferation of SBC - 1 cells , but stimulated the growth of MS - 1 - L cells . In the SCLC xenograft model , vandetanib inhibited growth and tumor angiogenesis in a dose - dependent manner in SBC - 1 xenografts . DB05294 inhibited the growth of MS - 1 - L xenografts at a low dose ( < 12 . 5 mg / kg / day ) , but it did not affect tumor size or change microvessel counts at a higher dose . Interestingly , secretion of P15692 increased significantly in the MS - 1 - L cell line in the presence of a high dose of vandetanib in vitro . The effects of vandetanib on tumor angiogenesis were different in SBC - 1 and MS - 1 - L cell lines . Production of angiogenic factors such as P15692 by the tumor potentially stimulates tumor angiogenesis and results in the acquisition of resistance to VEGFR TKI .","Antitumor effects of DB05294 on head and neck squamous cell carcinoma . Angiogenesis is required for tumor growth and metastasis and , therefore , represents a target for cancer treatment . While many factors have been implicated in promoting angiogenesis , vascular endothelial growth factor ( P15692 ) plays a key role in tumor angiogenesis . DB05294 is a potent P15692 receptor - 2 ( P35968 ) tyrosine kinase inhibitor which also has activity against the epidermal growth factor receptor ( P00533 ) tyrosine kinase . The purpose of this study was to investigate the sensitivity of head and neck squamous cell carcinoma ( HNSCC ) cell lines to DB05294 , and to evaluate its antitumor efficacy on HNSCC xenografts . This is the first demonstration of antitumor effects of DB05294 on HNSCC . In vitro DB05294 displayed antiproliferative effects on HNSCC cells and inhibition of P35968 and P00533 pathways . In vivo DB05294 displayed antitumor activity , induced apoptosis and antiangiogenic activity on nude mice bearing an established xenograft of YCU - H891 cells . These results suggest that DB05294 has the potential to inhibit two key pathways in tumor growth via inhibition of P15692 - dependent tumor angiogenesis and via inhibition of P00533 - dependent tumor cell proliferation .","Use of dynamic contrast - enhanced Q9BWK5 to evaluate acute treatment with DB05294 , a P15692 signalling inhibitor , in PC - 3 prostate tumours . Dynamic contrast - enhanced magnetic resonance imaging ( DCE - Q9BWK5 ) , using gadopentetate dimeglumine , was used to monitor acute effects on tumour vascular permeability following inhibition of vascular endothelial growth factor - A ( P15692 ) signal transduction . Mice bearing PC - 3 human prostate adenocarcinoma xenografts were treated with DB05294 , a P15692 receptor - 2 ( P35968 ) tyrosine kinase inhibitor . The pharmacokinetic parameter K ( trans ) was obtained , which reflects vascular permeability and perfusion . Mice were imaged immediately before , and following , acute treatment with DB05294 ( 12 . 5 - 100 mg x kg (- 1 ) orally ) . Whole tumours were analysed to obtain mean K ( trans ) values , and a histogram approach was used to examine intratumour heterogeneity . Reproducibility of K ( trans ) measurements gave inter - and intra - animal coefficients of variation of 40 and 18 % , respectively . Dose - related reductions in K ( trans ) were evident following acute DB05294 treatment . A K ( trans ) reduction of approximately 30 % ( P < 0 . 001 ) was evident with 50 and 100 mg x kg (- 1 ) DB05294 , a reduction of 12 . 5 % ( P < 0 . 05 ) at 25 mg x kg (- 1 ) , and a reduction that did not reach statistical significance at 12 . 5 mg kg (- 1 ) . A correlation between this dose response and the growth inhibitory effect of DB05294 following chronic treatment was also observed . The histogram analysis of the data indicated that DB05294 - induced a K ( trans ) reduction in both the most enhancing rim and the core of PC - 3 tumours . Dynamic contrast - enhanced magnetic resonance imaging may have a role in assessing the acute effects of P15692 signalling inhibition , in clinical dose - ranging studies .","Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK47___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .","Targeting angiogenesis : a review of angiogenesis inhibitors in the treatment of lung cancer . It has now been almost 30 years since Dr J . Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer ; however , it is only recently that anti - angiogenesis agents have entered the clinical setting . The search for novel therapies is particularly important in lung cancer , where the majority of patients succumb to their disease despite aggressive treatments . Several classes of agents now exist that target the different steps involved in angiogenesis . These include drugs inhibiting matrix breakdown , the matrix metalloproteinase inhibitors ( MMPIs ) , such as marimastat , prinomastat , BMS275291 , BAY12 - 9566 , and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor ( P15692 ) and its receptor ( VEGFR ) including rhuMAb P15692 , SU5416 , SU6668 , DB05294 , CP - 547 , 632 and ZD4190 . Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin , angiostatin and interferons . There has also been renewed interest in thalidomide . Drugs such as squalamine , celecoxib , ZD6126 , TNP - 470 and those targeting the integrins are also being evaluated in lung cancer . Despite early enthusiasm for many of these agents , Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue . It is hoped that as our understanding of the complex process of angiogenesis increases , so will our ability to design more effective targeted therapies .","DB09280 - ___MASK28___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .","___MASK3___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .","The tyrosine kinase inhibitor DB05294 blocks proliferation of P07949 mutant medullary thyroid carcinoma cells . Oncogenic conversion of the P07949 tyrosine kinase is a frequent feature of medullary thyroid carcinoma ( P04629 ) . DB05294 ( vandetanib ) is an DB00171 - competitive inhibitor of P07949 , epidermal growth factor receptor ( P00533 ) , and vascular endothelial growth factor receptors kinases . In this study , we have studied DB05294 mechanism of action in TT and MZ - CRC - 1 human P04629 cell lines , carrying cysteine 634 to tryptophan ( C634W ) and methionine 918 to threonine ( M918T ) P07949 mutation respectively . DB05294 blunted P04629 cell proliferation and P07949 , Shc and Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) phosphorylation . Single receptor knockdown by RNA interference showed that P04629 cells depended on P07949 for proliferation . Adoptive expression of the DB05294 - resistant V804M P07949 mutant rescued proliferation of TT cells under DB05294 treatment , showing that P07949 is a key DB05294 target in these P04629 cells . Upon P07949 inhibition , adoptive stimulation of P00533 partially rescued TT cell proliferation , MAPK signaling , and expression of cell - cycle - related genes . This suggests that simultaneous inhibition of P07949 and P00533 by DB05294 may overcome the risk of P04629 cells to escape from P07949 blockade through compensatory over - activation of P00533 .","Identification of a variant in P35968 associated with serum P35968 and pharmacodynamics of ___MASK100___ . PURPOSE : P15692 receptor ( VEGFR ) kinases are important drug targets in oncology that affect function of systemic endothelial cells . To discover genetic markers that affect VEGFR inhibitor pharmacodynamics , we performed a genome - wide association study of serum soluble vascular P35968 concentrations [ sVEGFR2 ] , a pharmacodynamic biomarker for P35968 inhibitors . EXPERIMENTAL DESIGN : We conducted a genome - wide association study ( GWAS ) of [ sVEGFR2 ] in 736 healthy Old Order Amish volunteers . Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [ sVEGFR2 ] measurements , and in 121 patients with renal carcinoma with [ sVEGFR2 ] measured before and during pazopanib therapy . RESULTS : rs34231037 ( C482R ) in P35968 , the gene encoding sVEGFR2 was found to be highly associated with [ sVEGFR2 ] , explaining 23 % of the variance ( P = 2 . 7 × 10 (- 37 ) ) . Association of rs34231037 with [ sVEGFR2 ] was replicated in 128 patients with cancer with comparable effect size ( P = 0 . 025 ) . Furthermore , rs34231037 was a significant predictor of changes in [ sVEGFR2 ] in response to pazopanib ( P = 0 . 01 ) . CONCLUSION : Our findings suggest that genome - wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers . Genotyping for germline variants in P35968 may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of P35968 kinase inhibitors .","Targeted molecular therapy of head and neck squamous cell carcinoma with the tyrosine kinase inhibitor vandetanib in a mouse model . BACKGROUND : We investigated the effects of vandetanib , an inhibitor of vascular endothelial growth factor receptor 2 ( P35968 ) and epidermal growth factor receptor ( P00533 ) , alone and in combination with paclitaxel in an orthotopic mouse model of human head and neck squamous cell carcinoma ( HNSCC ) . METHODS : The in vitro effects of vandetanib ( ZACTIMA ) were assessed in 2 HNSCC cell lines on cell growth , apoptosis , receptor and downstream signaling molecule expression , and phosphorylation levels . We assessed in vivo effects of vandetanib and / or paclitaxel by measuring tumor cell apoptosis , endothelial cell apoptosis , microvessel density , tumor size , and animal survival . RESULTS : In vitro , vandetanib inhibited the phosphorylation of P00533 and its downstream targets in HNSCC cells and inhibited proliferation and induced apoptosis of HNSCC cells and extended survival and inhibited tumor growth in nude mice orthotopically injected with human HNSCC . CONCLUSION : DB05294 has the potential to be a novel molecular targeted therapy for HNSCC .","Potent antitumor efficacy of interleukin - 18 delivered by conditionally replicative adenovirus vector in renal cell carcinoma - bearing nude mice via inhibition of angiogenesis . It has been demonstrated that interleukin 18 ( Q14116 ) exerts antitumor activity . In this study , we investigated whether oncolytic adenovirus - mediated gene transfer of Q14116 could induce strong antitumor activity . A tumor - selective replicating adenovirus expressing Q14116 ( ZD55 - Q14116 ) was constructed by insertion of an Q14116 expression cassette into the ZD55 vector , which is based on deletion of the adenoviral E1B 55 - kDa gene . ZD55 - Q14116 could express substantially more Q14116 than Ad - Q14116 because of replication of the vector . It has been shown that ZD55 - Q14116 exerted a strong cytopathic effect and significant apoptosis in renal cell carcinoma . ZD55 - Q14116 significantly decreased P15692 and P28906 expression in the tumor cells . Treatment of established tumors with ZD55 - Q14116 showed much stronger antitumor activity than that induced by ZD55 - EGFP or Ad - Q14116 . These data indicated that oncolytic adenovirus expressing Q14116 could exert potential antitumor activity via inhibition of angiogenesis and offer a novel approach to cancer therapy .","Targeted therapy against VEGFR and P00533 with DB05294 enhances the therapeutic efficacy of irradiation in an orthotopic model of human non - small - cell lung cancer . PURPOSE : Conventional therapies for patients with lung cancer have reached a therapeutic plateau . We therefore evaluated the feasibility of combined vascular endothelial growth factor ( P15692 ) receptor 2 ( P35968 ) and epidermal growth factor ( P01133 ) receptor ( P00533 ) targeting with radiation therapy in an orthotopic model that closely recapitulates the clinical presentation of human lung cancer . METHODS AND MATERIALS : Effects of irradiation and / or DB05294 , a small - molecule inhibitor of P35968 and P00533 tyrosine kinases , were studied in vitro for human lung adenocarcinoma cells by using proliferation and clonogenic assays . The feasibility of combining DB05294 with radiation therapy was then evaluated in an orthotopic model of human lung adenocarcinoma . Lung tumor burden and spread within the thorax were assessed , and tumor and adjacent tissues were analyzed by means of immunohistochemical staining for multiple parameters , including CD31 , P15692 , P35968 , P01133 , P00533 , matrix metalloproteinase - 2 and - 9 , and basic fibroblast growth factor . RESULTS : DB05294 enhanced the radioresponse of NCI - H441 human lung adenocarcinoma cells by a factor of 1 . 37 and markedly inhibited sublethal damage repair . In vivo , the combined blockade of P35968 and P00533 by DB05294 blocked pleural effusion formation and angiogenesis and enhanced the antivascular and antitumor effects of radiation therapy in the orthotopic human lung cancer model and was superior to chemoradiotherapy . CONCLUSIONS : When radiation therapy is combined with P35968 and P00533 blockade , significant enhancement of antiangiogenic , antivascular , and antitumor effects are seen in an orthotopic model of lung cancer . These data provide support for clinical trials of biologically targeted and conventional therapies for human lung cancer .","Tyrosine kinase blockers : new hope for successful cancer therapy . Tyrosine kinases ( TKs ) are attractive targets for cancer therapy , as quite often their abnormal signaling has been linked with tumor development and growth . Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair , apoptosis , and cell proliferation . During the last few years , thorough analysis of the mechanism underlying tyrosine kinase ' s activity led to novel cancer therapy using TKs blockers . These drugs are remarkably effective in the treatment of various human tumors including head and neck , gastric , prostate and breast cancer and leukemias . The most successful example of kinase blockers is Imatinib ( Imatinib mesylate , Gleevec , STI571 ) , the inhibitor of Bcr / Abl oncoprotein , which has become a first - line therapy for chronic myelogenous leukemia . The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed . Others kinase inhibitors used recently in cancer therapy include Dasatinib ( BMS - 354825 ) specific for P00519 non - receptor cytoplasmic kinase , Gefitinib ( DB00317 ) , Erlotinib ( DB00530 , Tarceva ) and DB01268 ( SU 11248 , Sutent ) specific for P15692 receptor kinase , AMN107 ( DB04868 ) and INNO - 406 ( NS - 187 ) specific for c - P10721 kinase . The following TK blockers for treatment of various human tumors are in clinical development : DB01259 ( DB01259 ditosylate , DB01259 , GW - 572016 ) , Canertinib ( DB05424 ) , DB05294 ( DB05294 ) , DB04879 ( PTK787 / ZK 222584 ) , DB00398 ( Bay 43 - 9006 , Nexavar ) , and Leflunomide ( SU101 , DB01097 ) . Herein , we discuss the chemistry , biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment .","___MASK3___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK3___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .","DB05294 -- clinical experience to date . DB05294 selectively targets two key pathways in tumour growth by inhibiting vascular endothelial growth factor ( P15692 ) - dependent tumour angiogenesis and epidermal growth factor ( P01133 ) - dependent tumour cell proliferation and survival . Phase I clinical evaluation has shown DB05294 to be generally well tolerated , with a pharmacokinetic profile appropriate for once - daily oral dosing . Phase II evaluation of DB05294 at doses of 100 - 300 mg is ongoing in a range of patient types in single and combination regimens . These include three randomised studies of patients with non - small - cell lung cancer . In one of these trials , the efficacy of DB05294 monotherapy is being compared with that of the P01133 receptor tyrosine kinase inhibitor gefitinib ( DB00317 ) in previously treated patients . In the other two trials , the efficacy of DB05294 in combination with certain standard chemotherapy regimens is being compared with that of standard chemotherapy alone : one with carboplatin and paclitaxel in previously untreated patients , and the second with docetaxel in patients who progressed after platinum - containing therapy . The advent of novel molecular - targeted agents such as DB05294 has necessitated a re - evaluation of conventional cancer study design in order to optimise appraisal of this new generation of anticancer agents . The specific considerations of the DB05294 clinical programme are discussed .","Antitumor activity of DB05294 , a vascular endothelial growth factor - 2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor , in combination with SC - 236 , a cyclooxygenase - 2 inhibitor . PURPOSE : The epidermal growth factor receptor ( P00533 ) autocrine pathway plays an important role in cancer cell growth . Vascular endothelial growth factor ( P15692 ) is a key regulator of tumor - induced endothelial cell proliferation and vascular permeability . Enhanced cyclooxygenase - 2 ( P35354 ) expression has been linked to cancer cell proliferation , P00533 activation , P15692 secretion , and tumor - induced angiogenesis . DB05294 is an orally available , small molecule , dual P15692 receptor - 2 ( P35968 ) and P00533 tyrosine kinase inhibitor . We investigated the activity of DB05294 in combination with SC - 236 , a selective P35354 inhibitor , to determine the antitumor activity of the simultaneous blockade of P00533 , P35354 , and P15692 functions . EXPERIMENTAL DESIGN : The antitumor activity in vitro and in vivo of DB05294 and / or SC - 236 was tested in human cancer cell lines with a functional P00533 autocrine pathway . RESULTS : The combination of DB05294 and SC - 236 determined supra - additive growth inhibition in all cancer cell lines tested . In nude mice bearing established human colon ( GEO ) or lung adenocarcinoma ( A549 ) cancer xenografts and treated with DB05294 and / or SC - 236 for 3 weeks , a reversible tumor growth inhibition was seen with each agent , whereas a more prolonged growth inhibition that lasted for 3 to 5 weeks following the end of treatment resulted from the combination of the two agents . A long - term , 10 - week treatment with DB05294 plus SC - 236 resulted in sustained tumor growth inhibition in all mice with tumor eradication in 3 of 10 GEO tumor - bearing mice and in 4 of 10 A549 tumor - bearing mice . CONCLUSIONS : This study provides a rationale for evaluating the simultaneous blockade of P00533 , P35354 , and P15692 signaling as cancer therapy in a clinical setting .","P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .","Inhibition of the liver expression of arylalkylamine N - acetyltransferase increases the expression of angiogenic factors in cholangiocytes . BACKGROUND AND AIMS : Reduction of biliary serotonin N - acetyltransferase ( Q16613 ) expression and melatonin administration / secretion in cholangiocytes increases biliary proliferation and the expression of SR , P13569 and Cl (-)/ HCO3 ( - ) P04920 . The balance between biliary proliferation / damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor - A / C ( P15692 / C ) . VEGFs are secreted by several epithelia , where they modulate cell growth by autocrine and paracrine mechanisms . No data exists regarding the effect of Q16613 modulation on the expressions of VEGFs by cholangiocytes . METHODS : In this study , we evaluated the effect of local modulation of biliary Q16613 expression on the cholangiocytes synthesis of P15692 / C . RESULTS : The decrease in Q16613 expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of P15692 / C . Overexpression of Q16613 in cholangiocyte lines decreased the expression of P15692 / C . CONCLUSIONS : Modulation of melatonin synthesis may affect the expression of P15692 / C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of P15692 / C expression regulating biliary functions .","Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK6___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 ."],"string":"[\n \"Endogenous concentrations of ouabain act as a cofactor to stimulate fluid secretion and cyst growth of in vitro ADPKD models via DB02527 and P00533 - Src - MEK pathways . In autosomal - dominant polycystic kidney disease ( ADPKD ) , renal cysts develop by aberrant epithelial cell proliferation and transepithelial fluid secretion . We previously showed that ouabain increases proliferation of cultured human ADPKD cells via stimulation of the P01133 receptor ( P00533 ) - Src - MEK / P29323 signaling pathway . We examined whether ouabain affects fluid secretion and in vitro cyst growth of human ADPKD cell monolayers , ADPKD cell microcysts cultured in a three - dimensional collagen matrix , and metanephric organ cultures from Pkd1 ( m1Bei ) mice . Physiological concentrations of ouabain alone did not affect net transepithelial basal - to - apical fluid transport in ADPKD monolayers or growth of cultured ADPKD microcysts . In contrast , in the presence of forskolin or 8 - bromo - DB02527 , ouabain significantly enhanced ADPKD fluid secretion and microcyst expansion . Ouabain exerted this effect by enhancing DB02527 - dependent Cl (-) secretion via the P13569 . Similarly , ouabain accelerated DB02527 - dependent cyst enlargement in Pkd1 ( m1Bei ) mice metanephroi , with a more prominent response in homozygous than heterozygous mice . Ouabain had no effect on fluid secretion and cystogenesis of normal human kidney cells and caused only slight cystic dilations in wild - type mouse kidneys . The effects of ouabain in ADPKD cells and Pkd1 ( m1Bei ) metanephroi were prevented by inhibitors of P00533 ( AG1478 ) , Src ( Q99463 ) , and MEK ( U0126 ) . Together , our results show that ouabain , used in physiological concentrations , has synergistic effects on DB02527 - mediated fluid secretion and cyst growth , via activation of the P00533 - Src - MEK pathway . These data provide important evidence for the role of ouabain as an endogenous hormone that exacerbates ADPKD cyst progression .\",\n \"A randomized phase II efficacy and safety study of vandetanib ( DB05294 ) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration - resistant prostate cancer . PURPOSE : To investigate the efficacy and safety of combining vandetanib , an orally available multi - targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor - 2 ( P35968 ) and epidermal growth factor receptor ( P00533 ) , with bicalutamide in patients with metastatic castration - resistant prostate cancer ( mCRPC ) . METHODS : This was an open - label , randomized phase II multi - center study . Eligible patients had rising PSA on androgen deprivation therapy , minimal symptoms and were chemotherapy - naïve . Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily ( Arm A ) or bicalutamide 50 mg oral daily alone ( Arm B ) with cross - over to vandetanib monotherapy at progression . The primary endpoint was PSA response ( ≥ 50 % decline from baseline ) . RESULTS : Thirty - nine patients were recruited , 19 in Arm A and 20 in Arm B . PSA response was comparable in Arm A and Arm B ( 18 vs . 19 % ) . Time to PSA progression was 3 . 16 months ( 95 % confidence interval ( CI ) : 1 . 09 , not reached ( NR ) ) for Arm A and 3 . 09 months ( 95 % CI : 1 . 22 , NR ) for Arm B . Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B ( 42 vs . 5 % ; p = 0 . 019 ) . Treatment with vandetanib was associated with a reduction in soluble P35968 levels after two cycles but an increase in plasma P15692 levels . CONCLUSION : The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone . Further evaluation of this combination is not warranted in mCRPC .\",\n \"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .\",\n \"Combined vascular endothelial growth factor receptor and epidermal growth factor receptor ( P00533 ) blockade inhibits tumor growth in xenograft models of P00533 inhibitor resistance . PURPOSE : The epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKI ) gefitinib and erlotinib benefit some non - small cell lung cancer ( NSCLC ) patients , but most do not respond ( primary resistance ) and those who initially respond eventually progress ( acquired resistance ) . P00533 TKI resistance is not completely understood and has been associated with certain P00533 and K - DB01367 mutations and MET amplification . EXPERIMENTAL DESIGN : We hypothesized that dual inhibition of the vascular endothelial growth factor ( P15692 ) and P00533 pathways may overcome primary and acquired resistance . We investigated the P15692 receptor / P00533 TKI vandetanib , and the combination of bevacizumab and erlotinib in vivo using xenograft models of P00533 TKI sensitivity , primary resistance , and three models of acquired resistance , including models with mutated K - DB01367 and secondary P00533 T790M mutation . RESULTS : DB05294 , gefitinib , and erlotinib had similar profiles of in vitro activity and caused sustained tumor regressions in vivo in the sensitive HCC827 model . In all four resistant models , vandetanib and bevacizumab / erlotinib were significantly more effective than erlotinib or gefitinib alone . Erlotinib resistance was associated with a rise in both host and tumor - derived P15692 but not P00533 secondary mutations in the P01116 mutant - bearing A549 xenografts . Dual inhibition reduced tumor endothelial proliferation compared with P15692 or P00533 blockade alone , suggesting that the enhanced activity of dual inhibition is due at least in part to antiendothelial effects . CONCLUSION : These studies suggest that erlotinib resistance may be associated with a rise in both tumor cell and host stromal P15692 and that combined blockade of the VEGFR and P00533 pathways can abrogate primary or acquired resistance to P00533 TKIs . This approach merits further evaluation in NSCLC patients .\",\n \"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .\",\n \"Q8NFH3 / Q8TCB0 mitogen - activated protein kinases inhibit atrial natriuretic peptide mRNA transcription in P40189 - mediated hypertrophic ventricular myocytes . OBJECTIVE : To understand the role of P01160 mRNA transcription regulation in P40189 - mediated cardiomyocyte hypertrophy , and the involved mitogen - activated protein kinase kinase ( MEK ) - extracellular signal - regulated kinase ( P29323 , also called Q8NFH3 / Q8TCB0 MAPK ) signaling pathway . METHODS : Isolated neonatal ventricular myocytes were treated with different concentrations of Q16619 ( 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) mol / L ) . MTT was used to analyze the viability and RT - PCR was used to detect P01160 mRNA levels in cardiomyocyte . To inhibit Q8NFH3 / Q8TCB0 MAPK activity in hypertrophic cardiomyocytes , the cells were pretreated with a specific Q02750 inhibitor . RESULTS : Q16619 significantly induced P01160 mRNA expression and the viability of cardiomyocytes in a dose - and time - dependent manner . Furthermore , blocking Q8NFH3 / Q8TCB0 MAPK activity by the special Q02750 inhibitor upregulated the P01160 mRNA . CONCLUSIONS : Q8NFH3 / Q8TCB0 MAPK have an important role in suppressing P01160 mRNA transcription and cell activity in P40189 - mediated hypertrophic ventricular myocytes .\",\n \"Activation of alternative pathways of angiogenesis and involvement of stem cells following anti - angiogenesis treatment in glioma . Malignant gliomas are hypervascular tumors that are highly resistant to all the currently available multimodal treatments . Therefore , anti - angiogenic therapies targeting P15692 or P15692 receptors ( VEGFRs ) were designed and thought to be an effective tool for controlling the growth of malignant gliomas . However , recent results of early clinical trials using humanized monoclonal antibodies against P15692 ( DB00112 ) , as well as small - molecule tyrosine kinase inhibitors that target different P15692 receptors ( VEGFRs ) ( DB04879 , DB05294 , DB01268 , DB00398 , etc ) alone or in combination with other therapeutic agents demonstrated differing outcomes , with the majority of reports indicating that glioma developed resistance to the employed anti - angiogenic treatments . It has been noted that continued anti - angiogenic therapy targeting only the P15692 - VEGFR system might affect pro - angiogenic factors other than P15692 , such as basic fibroblast growth factor ( P09038 ) , stromal derived factor 1 ( P48061 ) and Tie - 2 . These factors may in turn stimulate angiogenesis by mobilizing bone marrow derived precursor cells , such as endothelial progenitor cells ( EPCs ) , which are known to promote angiogenesis and vasculogenesis . In this short review , the current antiangiogenic treatments , possible mechanisms of activation of alternative pathways of angiogenesis , and possible involvement of bone marrow derived progenitor cells in the failure of anti - angiogenic treatments are discussed .\",\n \"DB05294 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model . Angiogenesis inhibitors have been used to treat some cancers , but the therapeutic potential of these agents for gastric cancer has remained unclear . To investigate their therapeutic potential , we examined the effect of DB05294 , an agent that selectively targets vascular endothelial growth factor receptor - 2 ( P35968 ; P35968 ) tyrosine kinase and epidermal growth factor receptor ( P00533 ) tyrosine kinase , in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line , 58As1 . DB05294 ( 100 mg / kg / day , p . o . , 2 weeks ) significantly inhibited tumor growth ( p < 0 . 05 vs . control ) and reduced tumor dissemination into the peritoneal cavity ( p < 0 . 05 vs . control ) . In addition , to identify putative tumor biomarkers that would reflect the effects of DB05294 treatment in clinical settings , we examined the gene expression profiles of implanted gastric tumors treated with DB05294 in vivo . Twenty - eight candidate genes were identified , including P17936 , P35318 , Q9BY76 , O00469 , Q99576 , Q92597 , P09104 , Q9Y5L2 and O60238 , which are known to be hypoxia - inducible genes . These genes and gene products may be useful biomarkers for monitoring the effects of DB05294 treatment . DB05294 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line , 44As3 . In conclusion , our results suggest that DB05294 may have clinical activity against gastric cancer , particularly undifferentiated gastric cancer with peritoneal dissemination . We also identified putative biomarkers for monitoring the pharmacodynamic effects of DB05294 by gene expression profiling .\",\n \"DB05294 for the treatment of medullary thyroid cancer . DB05294 ( DB05294 , Caprelsa , AstraZeneca ) , an oral small - molecule tyrosine kinase inhibitor ( TKI ) that targets the rearranged during transfection receptor ( P07949 ) , P15692 receptor ( P35968 - 3 ) , and P01133 receptor ( P00533 ) , is the first systemic therapy approved by the U . S . Food and Drug Administration ( FDA ) for the treatment of symptomatic or progressive advanced medullary thyroid cancer ( P04629 ) . In a randomized phase III trial of patients with unresectable , locally advanced , or metastatic P04629 , vandetanib improved progression - free survival compared with placebo [ HR , 0 . 46 ; 95 % confidence interval ( CI ) , 0 . 31 - 0 . 69 ; P < 0 . 001 ] . However , the benefits in delaying disease progression need to be balanced against the associated and potentially serious toxicities , including diarrhea , hypertension , and QTc prolongation . Here , we review the clinical development of vandetanib leading to its integration into the current treatment paradigm and highlight the ongoing and future challenges in TKI use in P04629 .\",\n \"Investigation of two dosing schedules of vandetanib ( DB05294 ) , an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling , in combination with irinotecan in a human colon cancer xenograft model . PURPOSE : This in vivo study was designed to determine the optimal doses and schedules of vandetanib , a dual epidermal growth factor receptor ( P00533 ) - vascular endothelial growth factor receptor tyrosine kinase inhibitor , in combination with irinotecan in a murine xenograft model of human colon cancer . EXPERIMENTAL DESIGN : HT - 29 tumor - bearing nude mice were treated with two doses of vandetanib ( 12 . 5 and 25 mg / kg / d ) with or without irinotecan ( 100 mg / kg ) using either sequential or concurrent schedules for 30 days . Tumor size was measured using standard variables , whereas the antiangiogenic response was evaluated using dynamic contrast - enhanced magnetic resonance imaging . Additionally , effects on P00533 - dependent signal transduction pathways and proliferation were assessed using immunohistochemistry . These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and / or to plasma / tumor concentrations of vandetanib . RESULTS : The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously ( concurrent schedule ) , alone or in combination with irinotecan . These dosing schedules resulted in significant effects on tumor vasculature , with decreased volume transfer constants , area under the curve , and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment . In addition , these groups showed the greatest inhibition of P00533 signaling . Interestingly , tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule , possibly due to decreased tumor perfusion in this group . CONCLUSIONS : These data suggest that higher , sustained concentrations of vandetanib ( versus intermittent ) , alone and in combination with irinotecan , result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug .\",\n \"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK30___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK30___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .\",\n \"Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes : evidence for in situ t - cell activation and therapeutic efficacy . After adoptive transfer of pre - activated lymphocytes into the operation cavity of glioma patients , tumor regression and improved survival have been reported in some patients . Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied . In this study , we attempted to avoid time - consuming pre - activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the P01133 receptor ( P00533 ) on tumor cells and to CD3 and P10747 on T cells . Eleven patients with high - grade malignant glioma received 3 injections of 2 bispecific antibody fragments ( P00533 x CD3 and P00533 x P10747 ) together with freshly isolated autologous lymphocytes via an Ommaya reservoir . Intracavitary fluid aspirated during immunotherapy was examined for markers of T - cell activation . Increased levels of soluble P60568 receptor and P01375 were detected in the intracavitary fluid of all patients tested . Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent Q9BWK5 scans and prolonged survival . Side effects were transient and consisted of fever , nausea , headache and aggravation of pre - existing neurologic deficits . These adverse effects were most likely due to the antibody construct containing anti - CD3 specificity . Two patients developed cerebral edema and required steroid treatment .\",\n \"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .\",\n \"DB05294 alters the protein pattern in malignant glioma and normal brain in the BT4C rat glioma model . The treatment of glioblastoma is unsatisfactory . Improved understanding of the biological effects of treatment , together with development of new tools to predict outcome of the initiated treatment are therefore of great need . DB05294 ( DB05294 ) is mainly a vascular endothelial growth factor ( P15692 ) and epidermal growth factor ( P01133 ) receptor tyrosine kinase inhibitor . This study investigated the pattern of protein expression in brain tumor and normal brain tissue , following treatment with vandetanib in a rat glioma model . BT4C - cells were stereotactically implanted into the brain of BD IX rats . The rats were divided into three different experiments . The treatment schedule for experiments one and two consisted of daily , oral doses of vandetanib from day 6 until day 12 or 20 after implantation , respectively . In the third experiment , each animal received a single dose of vandetanib on day 19 after implantation and was then sacrificed 2 , 8 or 24 h thereafter . The protein expression profiles were analyzed by SELDI - TOF - MS and evaluated with multivariate statistical methods . Following treatment with vandetanib , we found significantly altered protein expression pattern in malignant glioma and normal brain . Analyzing protein spectra is an interesting option to assess biological effects induced in brain tissue by signal transduction inhibitors such as vandetanib .\",\n \"Modeling the neurovascular niche : murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn . Preterm birth results in significant cognitive and motor disabilities , but recent evidence suggests that there is variable recovery over time . One possibility that may explain this variable recovery entails variable neurogenic responses in the subventricular zone ( SVZ ) following the period of chronic hypoxia experienced by these neonates . In this report , we have characterized the responses to chronic hypoxia of two mouse strains that represent a wide range of susceptibility to chronic hypoxia . We determined that C57BL / 6 pups and neural progenitor cells ( NPCs ) derived from them exhibit a blunted response to hypoxic insult compared with CD - 1 pups and NPCs . Specifically , C57BL / 6 pups and NPCs exhibited blunted in vivo and in vitro proliferative and increased apoptotic responses to hypoxic insult . Additionally , C57BL / 6 NPCs exhibited lower baseline levels and hypoxia - induced levels of selected transcription factors , growth factors , and receptors ( including HIF - 1alpha , Q9GZT9 , P23560 , P15692 , P48061 , TrkB , Nrp - 1 , P61073 , and NO ) that determine , in part , the responsiveness to chronic hypoxic insult compared with CD - 1 pups and NPCs , providing insight into this important and timely problem in perinatology .\",\n \"P00533 gene expression in avian epiphyseal growth - plate cartilage cells : effect of serum , parathyroid hormone and atrial natriuretic peptide . Avian chondrocytes and fibroblasts , derived from epiphyseal growth - plate and skin , respectively , were cultured in vitro . In chondrocytes , epidermal growth factor ( P01133 ) caused a dose - dependent stimulation of proliferation . P01133 receptor mRNA was not detected with the v - erb B probe in chondrocytes cultured in the presence of 5 % fetal calf serum ( FCS ) . In the absence of FCS in the medium , a time - dependent increase in the level of P01133 receptor mRNA was observed . Parallel changes were also observed in the level of P01133 receptor , as demonstrated by immunofluorescence using antibodies directed against avian P01133 receptor . In avian fibroblasts , P01133 receptor mRNA and P01133 receptor levels were not affected by FCS . Furthermore , FCS did not affect the level of thyroid hormone receptor mRNA ( using v - erb A as a probe ) in either chondrocytes or fibroblasts . Parathyroid hormone ( PTH ) , which acts as a mitogen in avian chondrocytes attenuated -- whereas atrial natriuretic peptide ( P01160 ) , a suppressor of chondrocyte proliferation , enhanced -- P01133 receptor mRNA . The present results show that avian growth - plate chondrocytes respond to P01133 and bear P01133 receptors . The levels of P01133 mRNA and P01133 receptor are inversely related to cell proliferation . The results also support previous suggestions that PTH and P01160 play important roles in chondrocyte proliferation , possibly through their effect on the synthesis of the P01133 receptor .\",\n \"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK93___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .\",\n \"P00533 inhibitors in development for the treatment of non - small cell lung cancer . The epidermal growth factor receptor ( P00533 ) inhibitors erlotinib , gefitinib , and cetuximab have undergone extensive clinical testing and have established clinical activity in non - small cell lung cancer and other types of solid tumors . A number of newer inhibitors are currently in clinical development with different spectra of activity or mechanisms of receptor inhibition . These include monoclonal antibodies , such as panitumumab and matuzumab ; dual inhibitors of P00533 and vascular endothelial growth factor receptor , such as DB05294 and AEE788 ; inhibitors of multiple P00533 family members , such as lapatinib ; and irreversible inhibitors , such as canertinib and HKI272 . Preclinical studies suggest that several of these agents may have activity in tumors refractory to erlotinib or gefitinib . Among these agents , DB05294 has undergone the most extensive clinical testing . The antitumor activity of DB05294 in these two randomized phase II clinical trials in patients with non - small cell lung cancer was felt to be sufficiently promising to warrant phase III clinical testing . Several of the other P00533 inhibitors are also undergoing advanced clinical testing , either alone or in combination with other agents . P00533 has now been validated as a clinically relevant target , and several different types of agents inhibiting this receptor are currently in development . Future research will be needed to elucidate the role of these agents in patients with P00533 inhibitor - naive and P00533 inhibitor - refractory disease , to define the molecular characteristics that predict response , and to determine whether these drugs should be used in combination with other targeted agents or chemotherapy .\",\n \"DB05294 is effective in P00533 - mutant lung cancer cells with P60484 deficiency . The effectiveness of vandetanib , an agent that targets P07949 , VEGFR and P00533 signaling , against P00533 - mutant lung cancer cells with P60484 loss was investigated . Two P00533 mutant non - small cell lung cancer ( NSCLC ) cell lines , PC - 9 ( P60484 wild type ) and NCI - H1650 ( P60484 null ) , were used . We transfected an intact P60484 gene into H1650 cells and knocked down P60484 expression in PC - 9 cells using shRNA . The effectiveness of gefitinib and vandetanib was assessed using a xenograft model . While PC - 9 cells were more resistant to vandetanib than gefitinib , H1650 cells were more sensitive to vandetanib than gefitinib . Both gefitinib and vandetanib suppressed the activation of P00533 and MAPK in H1650 cells , although phosphorylated AKT levels were not affected . In an H1650 cell xenograft model , vandetanib was also more effective than gefitinib . Although P60484 - transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro , the xenograft tumors responded to gefitinib and vandetanib . Knockdown of P60484 in PC - 9 cells caused resistance to gefitinib . In conclusion , vandetanib might be effective in NSCLC with P00533 mutations that lack P60484 expression . The contribution of P60484 absence to vandetanib activity in NSCLC cells harboring P00533 mutations should be further examined .\",\n \"P15692 - associated tyrosine kinase inhibition increases the tumor response to single and fractionated dose radiotherapy . PURPOSE : In this study , the efficacy of combining DB05294 ( DB05294 ) , a vascular endothelial growth factor ( P15692 ) receptor 2 - associated tyrosine kinase inhibitor currently undergoing Phase II clinical trial evaluation , with single and fractionated dose radiation exposures was examined in a human colorectal carcinoma model ( HT29 ) . METHODS AND MATERIALS : HT29 xenograft - bearing mice were treated with either single - dose ( 10 Gy ) or multifraction ( 2 Gy / day for 2 weeks ) radiotherapy alone or in conjunction with a 2 - week course of DB05294 ( 25 mg / kg ) . In the single - dose investigation , DB05294 treatment followed radiotherapy , whereas in the fractionated dose studies the antiangiogenic therapy was given before , after , or concurrent with the radiation . Tumor response was determined by tumor growth delay . RESULTS : DB05294 increased the response of HT29 xenografts to both single and fractionated dose radiotherapy . In the fractionation studies sequencing of therapies had little impact on treatment outcomes ; the time for the median tumors in each of the treatment groups to grow to five times the starting size was 53 , 53 . 5 , and 49 days , respectively . CONCLUSIONS : These studies indicate that DB05294 , when used in conjunction with radiation therapy , has a clear therapeutic advantage , providing a rationale for considering the combination of this agent with radiotherapy in the clinic .\",\n \"Identification of a lung adenocarcinoma cell line with Q16204 - P07949 fusion gene and the effect of P07949 inhibitors in vitro and in vivo . Rearrangements of the proto - oncogene P07949 are newly identified potential driver mutations in lung adenocarcinoma ( LAD ) . However , the absence of cell lines harboring P07949 fusion genes has hampered the investigation of the biological relevance of P07949 and the development of P07949 - targeted therapy . Thus , we aimed to identify a P07949 fusion positive LAD cell line . Eleven LAD cell lines were screened for P07949 fusion transcripts by reverse transcription - polymerase chain reaction . The biological relevance of the Q16204 - P07949 gene products was assessed by cell growth , survival and phosphorylation of P27361 / 2 and AKT with or without the suppression of P07949 expression using RNA interference . The efficacy of P07949 inhibitors was evaluated in vitro using a culture system and in an in vivo xenograft model . Expression of the Q16204 - P07949 fusion gene in LC - 2 / ad cells was demonstrated by the mRNA and protein levels , and the genomic break - point was confirmed by genomic DNA sequencing . Mutations in P01116 and P00533 were not observed in the LC - 2 / ad cells . Q16204 - P07949 was constitutively active , and the introduction of a siRNA targeting the P07949 3 ' region decreased cell proliferation by downregulating P07949 and P27361 / 2 phosphorylation . Moreover , treatment with P07949 - inhibitors , including vandetanib , reduced cell viability , which was accompanied by the downregulation of the AKT and P27361 / 2 signaling pathways . DB05294 exhibited anti - tumor effects in the xenograft model . Endogenously expressing Q16204 - P07949 contributed to cell growth . The inhibition of kinase activity could be an effective treatment strategy for LAD . LC - 2 / ad is a useful model for developing fusion P07949 - targeted therapy .\",\n \"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .\",\n \"A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re - vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly - developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 - based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically - used drugs operating on the P00797 - Angiotensin - DB04630 - System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point - of - no - return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling - reversing drugs to pathways other than RAAS , a specific inhibitor of 11β - hydroxy - steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy - associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization - induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling - reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects .\",\n \"DB05294 , a multitargeted inhibitor for receptor tyrosine kinases , suppresses growth of gliomas expressing an epidermal growth factor receptor mutant , EGFRvIII , in the brain . P00533 ( P00533 ) vIII is a mutated P00533 that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors . In this study , we investigate the effect of DB05294 ( ZACTIMA , vandetanib ) , a dual inhibitor for vascular endothelial growth factor receptor 2 and P00533 on growth and angiogenesis of gliomas expressing EGFRvIII . We used two glioma xenograft models , U87MG cells overexpressing EGFRvIII and short - term cultured primary glioma GBM8 cells with EGFRvIII . DB05294 inhibited tumor growth and angiogenesis and induced cell apoptosis in various brain gliomas . Moreover , significant inhibition of EGFRvIII - expressing U87MG and GBM8 gliomas was observed compared with their controls . Magnetic resonance imaging analysis using the apparent diffusion coefficient and three - dimensional P24752 * weighed measurements validated DB05294 inhibition on tumor growth and angiogenesis in EGFRvIII - expressing GBM8 gliomas . Mechanistically , DB05294 shows better inhibition of cell growth and survival of U87MG / EGFRvIII , GBM6 , and GBM8 cells that express EGFRvIII than U87MG or GBM14 cells that have nondetectable EGFRvIII through attenuation of activated phosphorylation of signal transducer and activator of transcription 3 , Akt , and Bcl - X ( L ) expression . Albeit in lesser extent , DB05294 also displays suppressions of U87MG / P00533 and GBM12 cells that overexpress wild - type P00533 . Additionally , DB05294 inhibits activation of extracellular signal - regulated kinase 1 / 2 in both types of cells , and expression of a constitutively active phosphoinositide 3 - kinases partially rescued DB05294 inhibition in U87MG / EGFRvIII cells . Taken together , these data show that DB05294 significantly inhibited growth and angiogenesis of gliomas expressing EGFRvIII by specifically blocking EGFRvIII - activated signaling mediators , suggesting a potential application of DB05294 in treatments for glioblastomas that overexpress EGFRvIII . Mol Cancer Ther ; 9 ( 4 ) ; 929 - 41 . ( c ) 2010 AACR .\",\n \"Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 for erlotinib and gefitinib in non - small - cell lung cancer ; P01116 against the use of cetuximab and panitumumab in colorectal cancer ; P04626 ( P04626 / neu ) for trastuzumab in breast cancer ; P11274 - P00519 for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 / RARα for all - trans - retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia .\",\n \"Prolonged exposure of colon cancer cells to the epidermal growth factor receptor inhibitor gefitinib ( DB00317 ( TM ) ) and to the antiangiogenic agent DB05294 : Cytotoxic and biomolecular effects . AIM : To analyze the biological effects of prolonged in vitro exposure of HT - 29 and LoVo colon cancer cell lines to gefitinib ( DB00317 ) , an inhibitor of epidermal growth factor receptor ( P00533 ) activity , and DB05294 , an inhibitor of both P35968 and P00533 activities . METHODS : Cells were treated with each drug for up to 2 wk using either a continuous or an intermittent ( 4 d of drug exposure followed by 3 d of washout each week ) schedule . RESULTS : In both cell types , prolonged exposure ( up to 14 d ) to gefitinib or DB05294 produced a similar inhibition of cell growth that was persistent and independent of the treatment schedule . The effects on cell growth were associated with a pronounced inhibition of p - P00533 and / or p - P35968 expression . Treatment with gefitinib or DB05294 also inhibited the expression of P00533 downstream signal molecules , p - Erk1 / 2 and p - Akt , although the magnitude of these effects varied between treatments and cell lines . Furthermore , expression of the drug resistance - related protein Q9UNQ0 was shown to significantly increase after 14 d of continuous exposure to the two drugs . CONCLUSION : We conclude that long - term exposure of colon cancer cells to gefitinib and DB05294 does not modify their cytotoxic effects but it might have an effect on sensitivity to classical cytotoxic drugs .\",\n \"DB05294 , an inhibitor of VEGFR and P00533 tyrosine kinase activity in combination with radiotherapy . Radiation enhances both epithelial growth factor receptor ( P00533 ) and vascular endothelial growth factor ( P15692 ) expression , which are a part of key pathways for tumor progression . Some tumors may not respond well to P00533 inhibitors alone or may develop resistance to P00533 inhibitors . Therefore , drug therapy targeted to P15692 receptors and EGFRs , when combined with radiotherapy ( RT ) , may improve tumor control and provide wider applicability . This article focuses on DB05294 , an inhibitor of P00533 and P15692 receptor signaling in combination with RT . We discuss preclinical and clinical studies with RT and inhibitors of P15692 or P00533 signaling first . We then address issues associated with DB05294 pharmacokinetic dosing , and scheduling when combined with RT . We also discuss DB05294 in the context of anti - P00533 therapy resistance . Dual inhibition of P00533 and P15692 receptor signaling pathways shows promise in enhancing RT efficacy .\",\n \"Vascular endothelial growth factor receptor tyrosine kinase inhibitors vandetanib ( DB05294 ) and DB04849 in lung cancer . Vascular endothelial growth factor ( P15692 ) is a rational target for advanced non - small cell lung cancer ( NSCLC ) , a hypothesis validated by the recent Eastern Cooperative Oncology Group E4599 trial showing that the addition of the P15692 monoclonal antibody bevacizumab to chemotherapy prolongs overall survival . Several new tyrosine kinase inhibitors targeting the P15692 pathway are currently in advanced clinical development for NSCLC and offer several possible advantages compared with monoclonal antibodies , including oral administration , more flexible dosing , a broader spectrum of target inhibition , and different toxicity profiles . Among these agents , vandetanib ( DB05294 ) , an inhibitor of the P15692 receptor ( VEGFR ) - 2 and epidermal growth factor receptor tyrosine kinase , has been the most extensively studied . In a randomized phase II study of patients with platinum - refractory NSCLC , including squamous histology , vandetanib prolonged progression - free survival compared with gefitinib . In another phase II trial , an improvement in progression - free survival was observed for vandetanib in combination with docetaxel compared with docetaxel alone . DB04849 is an inhibitor of P17948 , P35968 , and P35916 and other tyrosine kinases that has shown clinical activity in NSCLC in combination with carboplatin and paclitaxel . Several phase III trials are under way testing these agents either as monotherapy or in combination with chemotherapy in patients with lung cancer . Early results with these agents , and others being tested , raise the possibility that there will eventually be multiple P15692 - targeted therapies available in the clinic that can potentially benefit a broader range of patients with advanced - stage NSCLC .\",\n \"Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with ___MASK89___ , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20 - week - old Zucker obese and 16 - week - old ZDF rats were treated with ___MASK89___ ( 25 mg / kg / day ) or Enalapril ( 20 mg / kg / day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75 - 175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with ___MASK89___ or Enalapril .\",\n \"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK76___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .\",\n \"Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines . ___MASK100___ and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the P15692 tyrosine kinase receptors 1 , 2 and 3 ( pazopanib ) , and the P00533 and P04626 receptors in a dual manner ( lapatinib ) . ___MASK100___ has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as P09619 and c - kit . Here , we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non - small - cell lung cancer cells . Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases ( such as c - DB00134 ) that were not or only partially affected by either of the two agents alone . We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells , some of which were specific for the combination of both agents . Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up - or downregulation reflected the combined action of pazopanib and lapatinib . Indeed , pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non - small - cell lung cancer cells as well as on unrelated carcinomas . Altogether , these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects . Such combinations may lead to a ' collapse ' of pro - survival signal transduction pathways that leads to apoptotic cell death .\",\n \"Current status of vandetanib ( DB05294 ) in the treatment of non - small cell lung cancer . DB05294 ( DB05294 ) is an oral small molecule inhibitor of multiple intracellular receptor kinases , including the vascular endothelial growth factor receptor ( VEGFR ) - 2 and epidermal growth factor receptor ( P00533 ) . Both VEGFR and P00533 pathways have emerged as instrumental in the growth and metastasis of multiple malignancies , including non - small cell lung cancer ( NSCLC ) . Indeed , inhibitors of each pathway have been approved by the US Food and Drug Administration for use in advanced NSCLC . As there is considerable cross talk between these pathways , dual inhibition with such agents has become an attractive strategy , with encouraging Phase II clinical trial data to date . The convenience of one oral agent targeting both pathways is clear , and clinical trials have established the maximum tolerated daily dose of vandetanib , with data from randomized Phase III trials emerging . This report will review completed and ongoing NSCLC clinical trials evaluating vandetanib , and speculate on the future of this agent in NSCLC .\",\n \"Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials : current status and future directions . Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination . The vascular endothelial growth factor ( P15692 ) family of peptide growth factors and receptors are key regulators of this process . Agents directed either against P15692 or P15692 receptors ( VEGFRs ) have been developed . The tyrosine kinase inhibitors of VEGFRs are low - molecular - weight , DB00171 - mimetic proteins that bind to the DB00171 - binding catalytic site of the tyrosine kinase domain of VEG - FRs , resulting in blockade of intracellular signaling . Several of these agents are currently in different phases of clinical development . Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies , respectively . Positive results also have been reported with the combination of DB05294 and chemotherapy in previously treated non - small cell lung cancer patients . For other agents , such as vatalanib , contrasting outcomes in metastatic colorectal cancer patients have been reported : the final results of these trials are expected in 2006 . However , several key questions remain to be addressed , regarding the choice of an adequate dose or schedule , the presence of \\\" off - target \\\" effects , the safety of long - term administration , and the research of new clinical end points or methodological approaches for the optimal clinical development of these agents .\",\n \"DB05294 restores head and neck squamous cell carcinoma cells ' sensitivity to cisplatin and radiation in vivo and in vitro . PURPOSE : We investigated whether vandetanib , an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor - 2 ( P35968 ) , epidermal growth factor receptor ( P00533 ) , and rearranged during transfection ( P07949 ) , could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma ( HNSCC ) . EXPERIMENTAL DESIGN : P48449 - 19 and P0CJ72 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib , cisplatin , and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model . Treatment effects were assessed using clonogenic survival assay , tumor volume , bioluminescence imaging , tumor growth delay , survival , microvessel density , tumor and endothelial cell apoptosis , and P00533 and Akt phosphorylation data . RESULTS : DB05294 plus cisplatin radiosensitized HNSCC cells in vitro and in vivo . The combination treatment with vandetanib , cisplatin , and radiation was superior to the rest of treatments ( including the double combinations ) in antitumoral effects , prolonging survival , decreasing cervical lymph node metastases in vivo . It also increased both tumor and tumor - associated endothelial cell apoptosis and decreased microvessel density in vivo . An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo . All vandetanib - containing treatments inhibited P00533 and Akt phosphorylation in vitro and in vivo . CONCLUSION : The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC . Further study of this regimen in clinical trials may be warranted .\",\n \"Contrast - enhanced Ultrasound Imaging of Antiangiogenic Tumor Therapy . BACKGROUND / AIM : Anti - angiogenic treatment is a promising strategy for cancer therapy and is currently evaluated in clinical trials . The aim of the present study was to further investigate the effects of an anti - angiogenic therapy , inhibiting vascular endothelial growth factor ( P15692 ) and endothelial growth factor ( P01133 ) using a tyrosine kinase inhibitor for blocking tumor angiogenesis and tumor progression in vivo . MATERIALS AND METHODS : Experiments were performed using C57 / Bl6 mice ( 25 ± 5 g of body weight ( b . w . ) ) implanted with subcutaneous Lewis lung carcinoma ( LLC - 1 ) . From day 7 till 21 after tumor cell implantation , animals ( n = 7 per group ) were treated by monotherapy using DB05294 ( 50 mg / kg b . w . per os ( p . o . ) ) daily . A control group received only the solvent polysorbate 80 . Using contrast enhanced ultrasound ( CE - US ) parameters of intra - tumoral microcirculation animals were examined 24 h after the last application of DB05294 . Moreover , subcutaneous tumor growth was measured over the whole therapy period . Finally , histological analyses were performed to analyze the functional vessel density in the tumor tissue . RESULTS : DB05294 reduced tumor growth of LLC - 1 in C57 / Bl6 mice significantly . A significant difference of maximal signal intensity ( ΔSImax ) and area below the intensity time curve ( AUC ) after antiangiogenic therapy was recorded in the tumor center by CE - US . Vessel density after hematoxyline and eosin , as well as CD31 , staining showed no significant difference in both groups . CONCLUSION : Anti - angiogenic effects can be quantitatively demonstrated using CE - US imaging , which represents the spreading of efficient vessels in the tumor tissue , especially in the tumor center .\",\n \"DB05294 and indwelling pleural catheter for non - small - cell lung cancer with recurrent malignant pleural effusion . INTRODUCTION / BACKGROUND : Non - small - cell lung cancer patients with malignant pleural effusion have a poor overall median survival ( 4 . 3 months ) . P15692 is a key regulator of pleural effusion production . It is unknown if pharmacological inhibition of P15692 signaling modifies the disease course of non - small - cell lung cancer patients with recurrent malignant pleural effusion . We report the final results of a single - arm phase II clinical trial of the P15692 receptor inhibitor , vandetanib , combined with intrapleural catheter placement in patients with non - small - cell lung cancer and recurrent malignant pleural effusion , to determine whether vandetanib reduces time to pleurodesis . PATIENTS AND METHODS : Non - small - cell lung cancer patients with proven metastatic disease to the pleural space using pleural fluid cytology or pleural biopsy who required intrapleural catheter placement were eligible for enrollment . On the same day of the intrapleural catheter insertion , the patients were started on a daily oral dose of 300 mg vandetanib , for a maximum of 10 weeks . The primary end point was time to pleurodesis , with response rate as the secondary end point . Exploratory analyses included measurement of pleural fluid cytokines and angiogenic factors before and during therapy . RESULTS : Twenty eligible patients were included in the trial . Eleven patients completed 10 weeks of treatment . Median time to pleurodesis was 35 days ( 95 % confidence interval , 15 - not applicable ) . Median time to pleurodesis in the historical cohort was 63 days ( 95 % confidence interval , 45 - 86 ) when adjusted for Eastern Cooperative Oncology Group performance status ≤ 2 . CONCLUSION : DB05294 therapy was well tolerated ; however , it did not significantly reduce time to pleurodesis .\",\n \"Inhibition of P35968 prevents DMBA - induced mammary tumor formation . Preinvasive mammary pathologies in humans and rat chemical carcinogenesis model systems have an increased microvascular density relative to normal tissue . This suggests the possibility of preventing invasive breast cancer by inhibiting angiogenesis . Vascular endothelial cell growth factor ( P15692 ) is a potent angiogenic growth factor , commonly involved in tumor - induced angiogenesis . Here , we show that both P15692 and P35968 expression increase with histological progression to invasive disease in the rat 7 , 12 - dimethylbenz [ a ] anthracene ( DMBA ) model . Other P15692 receptors , P17948 , neuropilin 1 and neuropilin 2 , are constitutively expressed throughout progression . To examine whether P15692 signaling is functionally relevant to tumor - induced endothelial tubule formation in vitro and for tumor formation in vivo , we utilized the P35968 inhibitor , DB05294 . In vitro endothelial cell tubulogenesis induced by isolated mammary organoids or carcinoma in situ from DMBA - treated rats is inhibited by DB05294 , in a dose - dependent fashion . The administration of DB05294 to DMBA - treated rats inhibits the formation of atypical ductal hyperplasia and carcinoma in situ by greater than 95 % ( P < 0 . 05 ) , when administered 1 week or 6 weeks post - DMBA initiation . Invasive disease was absent in all DB05294 cohorts . These data support the hypothesis that progression of DMBA - induced preinvasive mammary pathologies to palpable disease requires angiogenesis via a P15692 - dependent mechanism .\",\n \"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .\",\n \"Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto - maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription - polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) - gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) - alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL - 1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL - 1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts .\",\n \"Tyrosine phosphorylation of Q92835 promotes its proteasomal degradation . OBJECTIVE : The activity of the SH2 - containing - phosphatidylinositol - 5 '- phosphatase ( Q92835 , also known as Q92835 ) , a critical hematopoietic - restricted negative regulator of the P19957 kinase ( PI3K ) pathway , is regulated in large part via its protein levels . We sought to determine the mechanism ( s ) involved in its downregulation by P11274 - P00519 and by interleukin ( IL ) - 4 . MATERIALS AND METHODS : We used Ba / P13726 ( Q92817 - tetOFF ) cells to study the downregulation of Q92835 by P11274 - P00519 and bone marrow - derived macrophages to study Q92835 ' s downregulation by P05112 . RESULTS : We show herein that P11274 - P00519 downregulates Q92835 , but not O15357 or P60484 , and this can be blocked with the Src kinase inhibitor Q99463 , which inhibits the tyrosine phosphorylation of Q92835 , or with the proteasomal inhibitor MG - 132 . We also show , using anti - Q92835 immunoprecipitates , that c - Cbl and Cbl - b are associated with Q92835 and that P11274 - P00519 induces Q92835 ' s polyubiquitination . This ubiquitination can be blocked with Q99463 , consistent with the tyrosine phosphorylation of Q92835 acting as a signal for its ubiquitination . In bone marrow - derived macrophages , P05112 also leads to the proteasomal degradation of Q92835 but , unlike in Ba / P13726 ( Q92817 - tetOFF ) cells , O15357 is also proteasomally degraded and the degradation of both inositol phosphatases can be prevented with Q99463 or MG - 132 . CONCLUSION : Our results suggest that Q92835 protein levels can be reduced via P11274 - P00519 and / or Src family member - induced tyrosine phosphorylation of Q92835 because this triggers its polyubiquitination and degradation within the proteasome .\",\n \"Evaluation of antileukaemic effects of rapamycin in patients with imatinib - resistant chronic myeloid leukaemia . BACKGROUND : Recent data suggest that the mammalian target of rapamycin ( P42345 ) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia ( CML ) . PATIENTS AND METHODS : We treated six patients with imatinib - resistant CML in haematological relapse ( leukocytes > 20 , 000 microL (- 1 ) ) with rapamycin at 2 mg per os daily for 14 consecutive days , with dose - adjustment allowed to reach a target rapamycin serum concentration of 10 - 20 pg mL (- 1 ) . RESULTS : A major leukocyte response with decrease to less than 10 , 000 microL (- 1 ) was obtained in two patients , and a minor transient response was seen in two other patients . In responding patients , we also observed a decrease in vascular endothelial growth factor ( P15692 ) mRNA levels in circulating leukaemic cells . Side effects during rapamycin treatment were mild in most patients . In one patient , pneumonia developed . DB00877 was also found to counteract growth of CML cells in vitro as determined by ( 3 ) H - thymidine incorporation . Moreover , rapamycin inhibited the growth of Ba / P13726 cells exhibiting various imatinib - resistant mutants of P11274 / P00519 , including the T315I variant that exhibits resistance against most currently available P11274 / P00519 kinase inhibitors . CONCLUSIONS : DB00877 shows antileukaemic effects in imatinib - resistant CML in vitro and in vivo . Larger trials with rapamycin or rapamycin - derivatives in combination with other targeted drugs are warranted to further determine clinical efficacy in CML .\",\n \"Differential effects of vascular endothelial growth factor receptor - 2 inhibitor DB05294 on circulating endothelial progenitors and mature circulating endothelial cells : implications for use as a surrogate marker of antiangiogenic activity . PURPOSE : Circulating endothelial cells ( CEC ) comprise at least two distinct populations : bone marrow - derived circulating endothelial progenitors ( CEP ) and mature CECs derived from existing vasculature . We hypothesized that antiangiogenic agents may have differential effects on CEPs and mature CECs and that these changes may serve as a marker of biological activity . EXPERIMENTAL DESIGN : The effect of angiogenesis inhibitors on CECs was evaluated by flow cytometry after vascular endothelial growth factor ( P15692 ) - induced mobilization and in mice bearing Lewis lung carcinoma ( LLC ) . Tumor angiogenesis was evaluated in parallel by immunohistochemistry . RESULTS : In nontumor - bearing mice , P15692 administration increased both mature CECs and CEPs . This increase was inhibited by the P15692 receptor 2 inhibitor DB05294 as well as the P15692 inhibitor - soluble Flt - 1 . DB05294 had no significant effect on CECs in the absence of exogenous P15692 stimulation . In contrast , LLC - bearing mice had an increase in mature CECs but not CEPs after 3 days of treatment with DB05294 . The increase in mature CECs was dose - dependent , accompanied by a decrease in tumor microvessel density , and preceded reduction in tumor volume . Treatment of LLC - bearing mice with the vascular targeting agent ZD6126 also increased mature CECs . CONCLUSIONS : P15692 inhibitors can have differential effects on mature CECs and CEPs , and agents inhibiting tumor angiogenesis may cause a concomitant increase in mature CECs . This increase occurs in tumor - bearing but not in nontumor - bearing mice , suggesting that tumor endothelium is a potential source of mature CECs . Therefore , assessing both mature CECs and CEPs may provide insights into the mechanism of antiangiogenic agents and serve as an early surrogate marker of biological activity .\",\n \"DB05294 improves anti - tumor effects of L19mTNFalpha in xenograft models of esophageal cancer . PURPOSE : Targeting the tumor vasculature by vascular disrupting agents ( VDAs ) has shown therapeutic activity in mouse models . In most cases , however , VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass . In this study , we investigated anti - tumor effects of L19mTNFα , a fusion protein composed of Q9Y2K2 ( scFv ) , specific for the angiogenesis - associated ED - B containing fibronectin isoform , and murine TNFα , in xenograft models of esophageal cancer . EXPERIMENTAL DESIGN : We evaluated ED - B expression in esophageal cancer samples . Subsequently , we generated subcutaneous xenografts from primary tumors , treated them with the L19mTNFα scFv , and determined effects on tumor vasculature , viability and proliferation , and P15692 expression and infiltration by hematopoietic cells . To overcome tumor resistance , L19mTNFα scFv was combined with vandetanib , a tyrosine kinase inhibitor of P15692 receptor , epidermal growth factor receptor , and P07949 signaling . RESULTS : ED - B was broadly expressed by esophageal cancer cell lines , as well as xenografts and primary surgical samples of esophageal cancer . Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis , indicating a VDA - like activity of this immunoconjugate . This event was followed , however , by rapid tumor growth recovery associated with increased expression of P15692 and recruitment of CD11b + Gr1 + myeloid cells into tumors . Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors , leading to a reduction of cell proliferation and increased necrosis , without apparent signs of toxicity . CONCLUSION : These findings indicate that a combination of vascular damaging agents with anti - angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer .\",\n \"Genetic mechanism of aspirin - induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin - related hypersensitivity often associated with aspirin - intolerant asthma . Genetic studies on aspirin - intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin - induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin - induced urticaria / angioedema . A polymorphism study that examined nine single - nucleotide polymorphisms of five leukotriene - related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 - activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( - 1708A > G ) and Q9Y271 ( - 634C > T ) were significantly different between aspirin - intolerant asthma and aspirin - induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine - related genes , did not find any significant associations with aspirin - induced urticaria / angioedema for the genes P50135 ( encoding histamine N - methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high - affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin - induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin - induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .\",\n \"Administration of P15692 receptor tyrosine kinase inhibitor increases P15692 production causing angiogenesis in human small - cell lung cancer xenografts . Angiogenesis is mediated mainly by vascular endothelial growth factor ( P15692 ) , and P15692 causes rapid growth in cancers , including human small - cell lung cancer ( SCLC ) . The anti - angiogenic strategy of treating cancer using P15692 receptor ( VEGFR ) inhibition is currently of great interest . We tested the effects of the P35968 tyrosine kinase inhibitor ( TKI ) vandetanib on the proliferation of two kinds of SCLC cell lines : SBC - 1 cells , with detectable P35968 expression and MS - 1 - L cells , without detectable P35968 expression . To evaluate the anti - tumor and anti - angiogenic effects of vandetanib in vivo , we grafted SBC - 1 and MS - 1 - L cells into mice . After a 3 - week treatment , we measured the tumor size and histologically evaluated necrosis and apoptosis using H & E and TUNEL staining , respectively . The microvessels in the xenografts were also quantified by immunostaining of CD31 . DB05294 did not affect the proliferation of SBC - 1 cells , but stimulated the growth of MS - 1 - L cells . In the SCLC xenograft model , vandetanib inhibited growth and tumor angiogenesis in a dose - dependent manner in SBC - 1 xenografts . DB05294 inhibited the growth of MS - 1 - L xenografts at a low dose ( < 12 . 5 mg / kg / day ) , but it did not affect tumor size or change microvessel counts at a higher dose . Interestingly , secretion of P15692 increased significantly in the MS - 1 - L cell line in the presence of a high dose of vandetanib in vitro . The effects of vandetanib on tumor angiogenesis were different in SBC - 1 and MS - 1 - L cell lines . Production of angiogenic factors such as P15692 by the tumor potentially stimulates tumor angiogenesis and results in the acquisition of resistance to VEGFR TKI .\",\n \"Antitumor effects of DB05294 on head and neck squamous cell carcinoma . Angiogenesis is required for tumor growth and metastasis and , therefore , represents a target for cancer treatment . While many factors have been implicated in promoting angiogenesis , vascular endothelial growth factor ( P15692 ) plays a key role in tumor angiogenesis . DB05294 is a potent P15692 receptor - 2 ( P35968 ) tyrosine kinase inhibitor which also has activity against the epidermal growth factor receptor ( P00533 ) tyrosine kinase . The purpose of this study was to investigate the sensitivity of head and neck squamous cell carcinoma ( HNSCC ) cell lines to DB05294 , and to evaluate its antitumor efficacy on HNSCC xenografts . This is the first demonstration of antitumor effects of DB05294 on HNSCC . In vitro DB05294 displayed antiproliferative effects on HNSCC cells and inhibition of P35968 and P00533 pathways . In vivo DB05294 displayed antitumor activity , induced apoptosis and antiangiogenic activity on nude mice bearing an established xenograft of YCU - H891 cells . These results suggest that DB05294 has the potential to inhibit two key pathways in tumor growth via inhibition of P15692 - dependent tumor angiogenesis and via inhibition of P00533 - dependent tumor cell proliferation .\",\n \"Use of dynamic contrast - enhanced Q9BWK5 to evaluate acute treatment with DB05294 , a P15692 signalling inhibitor , in PC - 3 prostate tumours . Dynamic contrast - enhanced magnetic resonance imaging ( DCE - Q9BWK5 ) , using gadopentetate dimeglumine , was used to monitor acute effects on tumour vascular permeability following inhibition of vascular endothelial growth factor - A ( P15692 ) signal transduction . Mice bearing PC - 3 human prostate adenocarcinoma xenografts were treated with DB05294 , a P15692 receptor - 2 ( P35968 ) tyrosine kinase inhibitor . The pharmacokinetic parameter K ( trans ) was obtained , which reflects vascular permeability and perfusion . Mice were imaged immediately before , and following , acute treatment with DB05294 ( 12 . 5 - 100 mg x kg (- 1 ) orally ) . Whole tumours were analysed to obtain mean K ( trans ) values , and a histogram approach was used to examine intratumour heterogeneity . Reproducibility of K ( trans ) measurements gave inter - and intra - animal coefficients of variation of 40 and 18 % , respectively . Dose - related reductions in K ( trans ) were evident following acute DB05294 treatment . A K ( trans ) reduction of approximately 30 % ( P < 0 . 001 ) was evident with 50 and 100 mg x kg (- 1 ) DB05294 , a reduction of 12 . 5 % ( P < 0 . 05 ) at 25 mg x kg (- 1 ) , and a reduction that did not reach statistical significance at 12 . 5 mg kg (- 1 ) . A correlation between this dose response and the growth inhibitory effect of DB05294 following chronic treatment was also observed . The histogram analysis of the data indicated that DB05294 - induced a K ( trans ) reduction in both the most enhancing rim and the core of PC - 3 tumours . Dynamic contrast - enhanced magnetic resonance imaging may have a role in assessing the acute effects of P15692 signalling inhibition , in clinical dose - ranging studies .\",\n \"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK47___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .\",\n \"Targeting angiogenesis : a review of angiogenesis inhibitors in the treatment of lung cancer . It has now been almost 30 years since Dr J . Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer ; however , it is only recently that anti - angiogenesis agents have entered the clinical setting . The search for novel therapies is particularly important in lung cancer , where the majority of patients succumb to their disease despite aggressive treatments . Several classes of agents now exist that target the different steps involved in angiogenesis . These include drugs inhibiting matrix breakdown , the matrix metalloproteinase inhibitors ( MMPIs ) , such as marimastat , prinomastat , BMS275291 , BAY12 - 9566 , and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor ( P15692 ) and its receptor ( VEGFR ) including rhuMAb P15692 , SU5416 , SU6668 , DB05294 , CP - 547 , 632 and ZD4190 . Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin , angiostatin and interferons . There has also been renewed interest in thalidomide . Drugs such as squalamine , celecoxib , ZD6126 , TNP - 470 and those targeting the integrins are also being evaluated in lung cancer . Despite early enthusiasm for many of these agents , Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue . It is hoped that as our understanding of the complex process of angiogenesis increases , so will our ability to design more effective targeted therapies .\",\n \"DB09280 - ___MASK28___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .\",\n \"___MASK3___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .\",\n \"The tyrosine kinase inhibitor DB05294 blocks proliferation of P07949 mutant medullary thyroid carcinoma cells . Oncogenic conversion of the P07949 tyrosine kinase is a frequent feature of medullary thyroid carcinoma ( P04629 ) . DB05294 ( vandetanib ) is an DB00171 - competitive inhibitor of P07949 , epidermal growth factor receptor ( P00533 ) , and vascular endothelial growth factor receptors kinases . In this study , we have studied DB05294 mechanism of action in TT and MZ - CRC - 1 human P04629 cell lines , carrying cysteine 634 to tryptophan ( C634W ) and methionine 918 to threonine ( M918T ) P07949 mutation respectively . DB05294 blunted P04629 cell proliferation and P07949 , Shc and Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) phosphorylation . Single receptor knockdown by RNA interference showed that P04629 cells depended on P07949 for proliferation . Adoptive expression of the DB05294 - resistant V804M P07949 mutant rescued proliferation of TT cells under DB05294 treatment , showing that P07949 is a key DB05294 target in these P04629 cells . Upon P07949 inhibition , adoptive stimulation of P00533 partially rescued TT cell proliferation , MAPK signaling , and expression of cell - cycle - related genes . This suggests that simultaneous inhibition of P07949 and P00533 by DB05294 may overcome the risk of P04629 cells to escape from P07949 blockade through compensatory over - activation of P00533 .\",\n \"Identification of a variant in P35968 associated with serum P35968 and pharmacodynamics of ___MASK100___ . PURPOSE : P15692 receptor ( VEGFR ) kinases are important drug targets in oncology that affect function of systemic endothelial cells . To discover genetic markers that affect VEGFR inhibitor pharmacodynamics , we performed a genome - wide association study of serum soluble vascular P35968 concentrations [ sVEGFR2 ] , a pharmacodynamic biomarker for P35968 inhibitors . EXPERIMENTAL DESIGN : We conducted a genome - wide association study ( GWAS ) of [ sVEGFR2 ] in 736 healthy Old Order Amish volunteers . Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [ sVEGFR2 ] measurements , and in 121 patients with renal carcinoma with [ sVEGFR2 ] measured before and during pazopanib therapy . RESULTS : rs34231037 ( C482R ) in P35968 , the gene encoding sVEGFR2 was found to be highly associated with [ sVEGFR2 ] , explaining 23 % of the variance ( P = 2 . 7 × 10 (- 37 ) ) . Association of rs34231037 with [ sVEGFR2 ] was replicated in 128 patients with cancer with comparable effect size ( P = 0 . 025 ) . Furthermore , rs34231037 was a significant predictor of changes in [ sVEGFR2 ] in response to pazopanib ( P = 0 . 01 ) . CONCLUSION : Our findings suggest that genome - wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers . Genotyping for germline variants in P35968 may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of P35968 kinase inhibitors .\",\n \"Targeted molecular therapy of head and neck squamous cell carcinoma with the tyrosine kinase inhibitor vandetanib in a mouse model . BACKGROUND : We investigated the effects of vandetanib , an inhibitor of vascular endothelial growth factor receptor 2 ( P35968 ) and epidermal growth factor receptor ( P00533 ) , alone and in combination with paclitaxel in an orthotopic mouse model of human head and neck squamous cell carcinoma ( HNSCC ) . METHODS : The in vitro effects of vandetanib ( ZACTIMA ) were assessed in 2 HNSCC cell lines on cell growth , apoptosis , receptor and downstream signaling molecule expression , and phosphorylation levels . We assessed in vivo effects of vandetanib and / or paclitaxel by measuring tumor cell apoptosis , endothelial cell apoptosis , microvessel density , tumor size , and animal survival . RESULTS : In vitro , vandetanib inhibited the phosphorylation of P00533 and its downstream targets in HNSCC cells and inhibited proliferation and induced apoptosis of HNSCC cells and extended survival and inhibited tumor growth in nude mice orthotopically injected with human HNSCC . CONCLUSION : DB05294 has the potential to be a novel molecular targeted therapy for HNSCC .\",\n \"Potent antitumor efficacy of interleukin - 18 delivered by conditionally replicative adenovirus vector in renal cell carcinoma - bearing nude mice via inhibition of angiogenesis . It has been demonstrated that interleukin 18 ( Q14116 ) exerts antitumor activity . In this study , we investigated whether oncolytic adenovirus - mediated gene transfer of Q14116 could induce strong antitumor activity . A tumor - selective replicating adenovirus expressing Q14116 ( ZD55 - Q14116 ) was constructed by insertion of an Q14116 expression cassette into the ZD55 vector , which is based on deletion of the adenoviral E1B 55 - kDa gene . ZD55 - Q14116 could express substantially more Q14116 than Ad - Q14116 because of replication of the vector . It has been shown that ZD55 - Q14116 exerted a strong cytopathic effect and significant apoptosis in renal cell carcinoma . ZD55 - Q14116 significantly decreased P15692 and P28906 expression in the tumor cells . Treatment of established tumors with ZD55 - Q14116 showed much stronger antitumor activity than that induced by ZD55 - EGFP or Ad - Q14116 . These data indicated that oncolytic adenovirus expressing Q14116 could exert potential antitumor activity via inhibition of angiogenesis and offer a novel approach to cancer therapy .\",\n \"Targeted therapy against VEGFR and P00533 with DB05294 enhances the therapeutic efficacy of irradiation in an orthotopic model of human non - small - cell lung cancer . PURPOSE : Conventional therapies for patients with lung cancer have reached a therapeutic plateau . We therefore evaluated the feasibility of combined vascular endothelial growth factor ( P15692 ) receptor 2 ( P35968 ) and epidermal growth factor ( P01133 ) receptor ( P00533 ) targeting with radiation therapy in an orthotopic model that closely recapitulates the clinical presentation of human lung cancer . METHODS AND MATERIALS : Effects of irradiation and / or DB05294 , a small - molecule inhibitor of P35968 and P00533 tyrosine kinases , were studied in vitro for human lung adenocarcinoma cells by using proliferation and clonogenic assays . The feasibility of combining DB05294 with radiation therapy was then evaluated in an orthotopic model of human lung adenocarcinoma . Lung tumor burden and spread within the thorax were assessed , and tumor and adjacent tissues were analyzed by means of immunohistochemical staining for multiple parameters , including CD31 , P15692 , P35968 , P01133 , P00533 , matrix metalloproteinase - 2 and - 9 , and basic fibroblast growth factor . RESULTS : DB05294 enhanced the radioresponse of NCI - H441 human lung adenocarcinoma cells by a factor of 1 . 37 and markedly inhibited sublethal damage repair . In vivo , the combined blockade of P35968 and P00533 by DB05294 blocked pleural effusion formation and angiogenesis and enhanced the antivascular and antitumor effects of radiation therapy in the orthotopic human lung cancer model and was superior to chemoradiotherapy . CONCLUSIONS : When radiation therapy is combined with P35968 and P00533 blockade , significant enhancement of antiangiogenic , antivascular , and antitumor effects are seen in an orthotopic model of lung cancer . These data provide support for clinical trials of biologically targeted and conventional therapies for human lung cancer .\",\n \"Tyrosine kinase blockers : new hope for successful cancer therapy . Tyrosine kinases ( TKs ) are attractive targets for cancer therapy , as quite often their abnormal signaling has been linked with tumor development and growth . Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair , apoptosis , and cell proliferation . During the last few years , thorough analysis of the mechanism underlying tyrosine kinase ' s activity led to novel cancer therapy using TKs blockers . These drugs are remarkably effective in the treatment of various human tumors including head and neck , gastric , prostate and breast cancer and leukemias . The most successful example of kinase blockers is Imatinib ( Imatinib mesylate , Gleevec , STI571 ) , the inhibitor of Bcr / Abl oncoprotein , which has become a first - line therapy for chronic myelogenous leukemia . The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed . Others kinase inhibitors used recently in cancer therapy include Dasatinib ( BMS - 354825 ) specific for P00519 non - receptor cytoplasmic kinase , Gefitinib ( DB00317 ) , Erlotinib ( DB00530 , Tarceva ) and DB01268 ( SU 11248 , Sutent ) specific for P15692 receptor kinase , AMN107 ( DB04868 ) and INNO - 406 ( NS - 187 ) specific for c - P10721 kinase . The following TK blockers for treatment of various human tumors are in clinical development : DB01259 ( DB01259 ditosylate , DB01259 , GW - 572016 ) , Canertinib ( DB05424 ) , DB05294 ( DB05294 ) , DB04879 ( PTK787 / ZK 222584 ) , DB00398 ( Bay 43 - 9006 , Nexavar ) , and Leflunomide ( SU101 , DB01097 ) . Herein , we discuss the chemistry , biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment .\",\n \"___MASK3___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK3___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .\",\n \"DB05294 -- clinical experience to date . DB05294 selectively targets two key pathways in tumour growth by inhibiting vascular endothelial growth factor ( P15692 ) - dependent tumour angiogenesis and epidermal growth factor ( P01133 ) - dependent tumour cell proliferation and survival . Phase I clinical evaluation has shown DB05294 to be generally well tolerated , with a pharmacokinetic profile appropriate for once - daily oral dosing . Phase II evaluation of DB05294 at doses of 100 - 300 mg is ongoing in a range of patient types in single and combination regimens . These include three randomised studies of patients with non - small - cell lung cancer . In one of these trials , the efficacy of DB05294 monotherapy is being compared with that of the P01133 receptor tyrosine kinase inhibitor gefitinib ( DB00317 ) in previously treated patients . In the other two trials , the efficacy of DB05294 in combination with certain standard chemotherapy regimens is being compared with that of standard chemotherapy alone : one with carboplatin and paclitaxel in previously untreated patients , and the second with docetaxel in patients who progressed after platinum - containing therapy . The advent of novel molecular - targeted agents such as DB05294 has necessitated a re - evaluation of conventional cancer study design in order to optimise appraisal of this new generation of anticancer agents . The specific considerations of the DB05294 clinical programme are discussed .\",\n \"Antitumor activity of DB05294 , a vascular endothelial growth factor - 2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor , in combination with SC - 236 , a cyclooxygenase - 2 inhibitor . PURPOSE : The epidermal growth factor receptor ( P00533 ) autocrine pathway plays an important role in cancer cell growth . Vascular endothelial growth factor ( P15692 ) is a key regulator of tumor - induced endothelial cell proliferation and vascular permeability . Enhanced cyclooxygenase - 2 ( P35354 ) expression has been linked to cancer cell proliferation , P00533 activation , P15692 secretion , and tumor - induced angiogenesis . DB05294 is an orally available , small molecule , dual P15692 receptor - 2 ( P35968 ) and P00533 tyrosine kinase inhibitor . We investigated the activity of DB05294 in combination with SC - 236 , a selective P35354 inhibitor , to determine the antitumor activity of the simultaneous blockade of P00533 , P35354 , and P15692 functions . EXPERIMENTAL DESIGN : The antitumor activity in vitro and in vivo of DB05294 and / or SC - 236 was tested in human cancer cell lines with a functional P00533 autocrine pathway . RESULTS : The combination of DB05294 and SC - 236 determined supra - additive growth inhibition in all cancer cell lines tested . In nude mice bearing established human colon ( GEO ) or lung adenocarcinoma ( A549 ) cancer xenografts and treated with DB05294 and / or SC - 236 for 3 weeks , a reversible tumor growth inhibition was seen with each agent , whereas a more prolonged growth inhibition that lasted for 3 to 5 weeks following the end of treatment resulted from the combination of the two agents . A long - term , 10 - week treatment with DB05294 plus SC - 236 resulted in sustained tumor growth inhibition in all mice with tumor eradication in 3 of 10 GEO tumor - bearing mice and in 4 of 10 A549 tumor - bearing mice . CONCLUSIONS : This study provides a rationale for evaluating the simultaneous blockade of P00533 , P35354 , and P15692 signaling as cancer therapy in a clinical setting .\",\n \"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .\",\n \"Inhibition of the liver expression of arylalkylamine N - acetyltransferase increases the expression of angiogenic factors in cholangiocytes . BACKGROUND AND AIMS : Reduction of biliary serotonin N - acetyltransferase ( Q16613 ) expression and melatonin administration / secretion in cholangiocytes increases biliary proliferation and the expression of SR , P13569 and Cl (-)/ HCO3 ( - ) P04920 . The balance between biliary proliferation / damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor - A / C ( P15692 / C ) . VEGFs are secreted by several epithelia , where they modulate cell growth by autocrine and paracrine mechanisms . No data exists regarding the effect of Q16613 modulation on the expressions of VEGFs by cholangiocytes . METHODS : In this study , we evaluated the effect of local modulation of biliary Q16613 expression on the cholangiocytes synthesis of P15692 / C . RESULTS : The decrease in Q16613 expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of P15692 / C . Overexpression of Q16613 in cholangiocyte lines decreased the expression of P15692 / C . CONCLUSIONS : Modulation of melatonin synthesis may affect the expression of P15692 / C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of P15692 / C expression regulating biliary functions .\",\n \"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK6___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .\"\n]"},"candidates":{"kind":"list like","value":["___MASK100___","___MASK28___","___MASK30___","___MASK3___","___MASK47___","___MASK6___","___MASK76___","___MASK89___","___MASK93___"],"string":"[\n \"___MASK100___\",\n \"___MASK28___\",\n \"___MASK30___\",\n \"___MASK3___\",\n \"___MASK47___\",\n \"___MASK6___\",\n \"___MASK76___\",\n \"___MASK89___\",\n \"___MASK93___\"\n]"},"answer":{"kind":"string","value":"___MASK100___"},"id":{"kind":"string","value":"MH_train_490"}}},{"rowIdx":491,"cells":{"query":{"kind":"string","value":"interacts_with DB06681?"},"supports":{"kind":"list like","value":["Suppressing T cell motility induced by anti - P16410 monotherapy improves antitumor effects . A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance , such as cytotoxic T lymphocyte - associated protein 4 ( P16410 ) . However , the determinants of response to anti - P16410 mAb treatment remain incompletely understood . In murine models , anti - P16410 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions , including local ionizing radiation ( IR ) therapy . We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor - infiltrating CD8 + T lymphocytes ( TILs ) following treatment with the anti - P16410 mAb 9H10 . Alone , 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo . In contrast , the combination of 9H10 and IR restored MHC class I - dependent arrest . After implantation , the carcinoma cells had reduced expression of retinoic acid early inducible - 1 ( RAE - 1 ) , a ligand for natural killer cell group 2D ( P26718 ) receptor . We found that RAE - 1 expression was induced by IR in vivo and that anti - P26718 mAb blocked the Q15399 arrest induced by IR / 9H10 combination therapy . These results demonstrate that anti - P16410 mAb therapy induces motility of Q15399 and that P26718 ligation offsets this effect to enhance TILs arrest and antitumor activity .","DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .","Haemostasis unbalance in Pugh - scored liver cirrhosis : characteristic changes of plasma levels of protein C versus protein S . Liver cirrhosis leads to a protido - synthetic impairment that alters the levels of blood clotting factors and haemostasis . The aim of this study was to assess the alterations of haemostatic parameters in the evolution of liver cirrhosis scored according to Child ' s classification , with Pugh ' s modifications . Thirty - seven patients suffering from alcoholic and non - alcoholic liver cirrhosis , representing stages A5 , A6 , P33681 , B8 and Q99622 , were tested for the main blood clotting parameters , i . e . prothrombin time , factor VII , partial activated thromboplastin time , fibrinogen , plasminogen , alpha 2 - antiplasmin and physiological inhibitors [ antithrombin III ( P01008 ) , protein C ( PC ) , protein S ( PS ) ] . No variations were observed between substages A5 and A6 in any of the parameters , except for coagulation inhibitor levels . Most parameters showed a progressive decrease in stages B and C of the disease . The most significant alterations were found in the physiological coagulation inhibitors , with a sharper decrease in PC and AT III level and a lesser decrease in the level of PS through stages A5 and B8 : this evidence could assume an important biological and diagnostic significance .","The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .","Viral - induced P10747 loss evokes costimulation independent alloimmunity . BACKGROUND : DB06681 , a P33681 - specific fusion protein , blocks P10747 - P33681 costimulation and prevents kidney allograft rejection . However , it is ineffective in a sizable minority of patients . Although T - cell receptor and P10747 engagement are known to initiate T - cell activation , many human antigen - experienced T - cells lose P10747 , and can be activated independent of P10747 signals . We posit that these cells are central drivers of costimulation blockade resistant rejection ( CoBRR ) and propose that CoBRR might relate to an accumulation of P10747 (-) T - cells resulting from viral antigen exposure . MATERIALS AND METHODS : We infected C57BL / 6 mice with polyomavirus ( a BK virus analog ) , murine cytomegalovirus ( a human cytomegalovirus analog ) , and gammaherpesvirus ( HV68 ; an Epstein - Barr virus analog ) and assessed for P10747 expression relative to mock infection controls . We then used mixed lymphocyte reaction ( P08235 ) assays to assess the alloreactive response of these mice against major histocompatibility complex - mismatched cells . RESULTS : We demonstrated that infection with polyomavirus , murine CMV , and HV68 can induce P10747 downregulation in mice . We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic , costimulation blockade resistant , alloreactive response against major histocompatibility complex - mismatched cells without prior alloantigen exposure . Further analysis revealed that gammherpesvirus - induced oligoclonal T - cell expansion is required for the increased alloreactivity . CONCLUSIONS : Virus exposure results in reduced T - cell expression of P10747 , the target of costimulation blockade therapy . These viruses also contribute to increased alloreactivity . Thus , P10747 downregulation after viral infection may play a seminal role in driving CoBRR .","Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .","Human umbilical cord Wharton ' s jelly stem cells : immune property genes assay and effect of transplantation on the immune cells of heart failure patients . Stem cells derived from umbilical cord Wharton ' s jelly ( WJSCs ) are not immunogenic and have immunosuppressive effects . To evaluate the related mechanisms and the effect of transplantation on body immune cells , we examined immune property genes expression in WJSCs and levels of T - lymphocytes subgroups and immunoglobulins ( Ig ) in heart failure ( HF ) patients with and without WJSCs transplantation . WJSCs express immune tolerance genes P13747 , P17693 and P30511 and immunomodulation genes P15692 , TGFβ1 , P14210 , P09601 , IL1β , P05231 , P15018 , LGALS - 1 / 3 / 8 , P23219 / 2 and PTGE , while they do not express immune response - related genes HLA - DR , HLA - DQ , HLA - DP , P33681 , P42081 , P25942 and P29965 . No obvious changes of T - lymphocytes subgroups and plasma IgG / IgM were observed in HF patients with WJSCs transplantation . Our results suggest that the immune properties of WJSCs are due to the expression of immune avoidance and immunomodulation genes in the absence of immune response - related genes . WJSCs are secure in immunological aspects when used as seed cells for cardiac repair .","Differential inhibition of autoreactive memory - and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 ( sCTLA4 ) , DB01281 and DB06681 . Cytotoxic T lymphocyte antigen 4 ( P16410 ) is a potent inhibitory co - stimulatory molecule believed to be involved in type 1 diabetes and other autoimmune diseases . An association has been reported of both mRNA expression and serum levels of the soluble splice variant of P16410 ( sCTLA4 ) with type 1 diabetes . Furthermore , recombinant fusion proteins DB01281 and DB06681 have been proposed as therapies for type 1 diabetes . We studied the role of ( s ) P16410 in islet autoimmunity . Binding capacity of the proteins to antigen - presenting cells was determined by flow cytometry in competition and binding assays . Functionality of sCTLA4 as well as the therapeutic inhibitory fusion proteins DB01281 and DB06681 was measured in a dose - response lymphocyte stimulation test , using a panel of diabetes - associated T cell clones reactive to islet autoantigens . As controls , mixed lymphocyte reactions ( P08235 ) were performed to assess functionality of these proteins in a primary alloreactive setting . All three P16410 molecules were able to bind to antigen - presenting cells and inhibit the expression of P33681 / P42081 . sCTLA4 was able to suppress proliferation of different committed autoreactive T cell clones in a dose - dependent manner , whereas DB01281 and DB06681 were not . Conversely , DB01281 and DB06681 , rather than sCTLA4 , were able to suppress naive alloreactive proliferation in a P08235 . Our results indicate a differential role for sCTLA4 , DB01281 and DB06681 proteins in memory versus primary immune responses with implications for efficacy in intervention therapy .","DB06681 and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion . DB06681 is an inhibitor of P10747 / P33681 costimulation that is clinically indicated as a calcineurin inhibitor ( CNI ) alternative in combination with mycophenolate mofetil and steroids after renal transplantation . We sought to develop a clinically translatable , nonlymphocyte depleting , belatacept - based regimen that could obviate the need for both CNIs and steroids . Thus , based on murine data showing synergy between costimulation blockade and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched renal allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on costimulation blockade - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . DB06681 and sirolimus therapy successfully prevented rejection in all animals . Tolerance was not induced , as animals rejected after withdrawal of therapy . The regimen did not deplete T cells . Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen , despite causing an intended depletion of memory T cells , and caused a marked reduction in regulatory T cells . Furthermore , alefacept - treated animals had a significantly increased incidence of CMV reactivation , suggesting that this combination overly compromised protective immunity . These data support belatacept and sirolimus as a clinically translatable , nondepleting , CNI - free , steroid - sparing immunomodulatory regimen that promotes sustained rejection - free allograft survival after renal transplantation .","Linkage of protein kinase C - beta activation and intracellular interleukin - 2 accumulation in human naive P01730 T cells . A critical role for protein kinase C ( PKC ) in signal transduction events has been well established . Moreover , studies of regulation in PKC levels suggest participation in mediating long - term cellular functions . Protein kinase C - beta ( P05771 ) has been reported to be involved in interleukin - 2 ( P60568 ) synthesis in T lymphocytes . In this study , the role of P05771 in intracellular accumulation of P60568 was investigated using specific inhibitors . Preincubation with two different PKC inhibitors , one specific for classical isotypes ( alpha and beta I ) Go6976 , and one which inhibits both classical and non - classical isotypes , GF109203X , caused a complete block in cytoplasmic P60568 accumulation when naive P01730 T cells were stimulated in the presence of P06729 + P10747 + phorbol myristate acetate ( PMA ) . In contrast , preincubation with up to 1000 ng / ml of cyclosporin A ( DB00091 ) resulted in a reduction in the intracellular P60568 detected , as observed by a decrease in the proportion of positive cells as well as a fall in the mean fluorescence intensity ( MFI ) . DB00091 did not influence P05771 translocation . Flow cytometric assessments of P05771 and its isoforms beta I and beta II correlated with Western blotting analysis and these results were further supported by the use of P05771 - positive ( HUT 78 ) and - negative ( BW5147 ) T - cell lines . Using the specific inhibitors , Go6976 and GF109203X , the findings in this study suggest that activation and translocation of P05771 is critical for accumulation of intracellular P60568 . The influence of DB00091 in reducing but not blocking P60568 synthesis is discussed . PMA - induced down - regulation of the P01730 antigen was observed in the presence of Go6976 and but not GF109203X , suggesting regulation by non - classical PKC isoforms .","P52333 activity is necessary for phosphorylation of cytosolic phospholipase A2 and prostaglandin E2 synthesis by macrophages infected with Francisella tularensis live vaccine strain . Francisella tularensis , the causative agent of tularemia , modulates the host immune response to gain a survival advantage within the host . One mechanism of immune evasion is the ability of F . tularensis to induce the synthesis of the small lipid mediator prostaglandin E2 ( DB00917 ) , which alters the host T cell response making the host more susceptible to Francisella growth . DB00917 is synthesized by a tightly regulated biosynthetic pathway following stimulation . The synthesis of DB00917 begins with the liberation of arachidonic acid ( AA ) from membrane phospholipids by cytosolic phospholipase A2 ( P47712 ) . AA is subsequently converted to the unstable intermediate PGH2 by cyclooxygenase - 2 ( P35354 ) , and PGH2 undergoes an isomerization reaction to generate DB00917 . Our objective was to identify F . tularensis - activated host signaling pathways that regulate the activity of the enzymes in the DB00917 - biosynthetic pathway . In this study , we show that P47712 , p38 mitogen - activated protein kinase ( MAPK ) , and P52333 ( P52333 ) signaling are necessary for F . tularensis - induced DB00917 production . Inhibition of P52333 activity reduced the phosphorylation of P47712 and P35354 protein levels . In addition , P52333 regulates P47712 phosphorylation independent of transcription . Moreover , p38 MAPK activity is required for F . tularensis - induced P35354 protein synthesis , but not for the phosphorylation of P47712 . This research highlights a unique signaling axis in which P52333 and p38 MAPK regulate the activity of multiple enzymes of the DB00917 - biosynthetic pathway in macrophages infected with F . tularensis .","DB06681 : a new era of immunosuppression ? Q8N1N2 T - cell activation in alloimmunity requires the engagement of several costimulatory molecules . P16410 - Ig and its commercially available fusion proteins , belatacept and abatacept , are used to block P33681 / 86 and promote T - cell tolerance . DB06681 , a higher binding affinity molecule , is currently approved for clinical use in renal transplantation . The results of two Phase III clinical trials showed a similar patient / graft survival , with better renal function at a 3 - year follow - up compared with conventional immunosuppression . There was a higher risk of early rejection and post - transplant lymphoproliferative disorder , especially with EBV - negative patients receiving kidneys from EBV - positive donors . DB06681 - treated groups had a better cardiovascular and metabolic profile . The authors review both preclinical and human studies of P16410 - Igs .","Safety and immunogenicity of a V3 loop synthetic peptide conjugated to purified protein derivative in HIV - seronegative volunteers . OBJECTIVES : To develop a peptide - based model for a preventive vaccine for HIV - 1 infection . DESIGN : Phase I trial in HIV - 1 - seronegative volunteers . PARTICIPANTS : Adult healthy subjects HIV - 1 - antibody - seronegative in an enzyme - linked immunosorbent assay , screened for tuberculin [ purified protein derivative ( PPD ) ] reactivity with 2 tuberculin units PPD - administered intradermally . INTERVENTIONS : Submicrogram doses of a PPD conjugate with a peptide of the primary neutralizing domain ( P01160 ) of HIV - 1MN ( PPD - MN - P01160 ) were administered intradermally to tuberculin skin - test - positive and - negative volunteers . RESULTS : Antibodies to the MN - P01160 were measured after two immunizations in 10 out of 11 PPD skin - test - positive volunteers . After the fourth immunization high - affinity antibodies were detected , which persisted for over 1 year . High titers of MN - P01160 - specific immunoglobulin ( Ig ) G and IgA were detected in the serum and saliva of all volunteers tested . Serum antibodies were cross - reactive with P01160 peptide from some other HIV - 1 strains but neutralized only the HIV - 1MN prototype . Human leukocyte antigen ( HLA ) - P33681 - restricted MN - P01160 - specific cytotoxic T lymphocytes ( CTL ) were also detected . CONCLUSIONS : The PPD - MN - P01160 vaccine at submicrogram doses is safe and immunogenic in PPD skin - test - positive healthy adult volunteers . Long lasting humoral immune responses in the serum and saliva were possibly accompanied by HLA - P33681 - restricted CTL responses . This is a vaccine prototype that can be rapidly and inexpensively modified to include other peptide epitopes . It is especially suitable for use in a worldwide multibillion Bacillus Calmette - Guérin ( BCG ) - primed or tuberculosis - exposed population at risk for HIV - 1 infection .","[ Use of new non - nephrotoxic immunosuppressive drugs in kidney transplantation , especially after ischemia - reperfusion injury ] . Medium - and long - term renal graft survival depends on 4 main factors : the quality of the harvested graft , ischemia - reperfusion injury during harvesting and re - implantation , rejection , and the nephrotoxicity of certain drugs ( especially immunosuppressants ) used in this setting . The most nephrotoxic immunosuppressive drugs are the anticalcineurins ( cyclosporine A and tacrolimus ) , a class discovered in the late 1970s and currently representing a basic component of all immunosuppressive protocols for solid organ graft recipients . The renal tubular and vascular toxicity of anticalcineurins is due to their immunosuppressive mechanism : they block the calcineurin pathway and thereby prevent transmission of the first signal from the T cell receptor to the nucleus , which normally triggers cytokine synthesis , New non - nephrotoxic immunosuppressants are therefore needed , especially for grafts of poor quality or subject to severe ischemia - reperfusion injury . Attention is turning to \" old \" molecules such as anti - thymocyte globulins , but exciting new immunosuppressants are now appearing . DB00092 is a fusion protein that binds to the immunological synapse - associated molecule P06729 , which normally interacts with LFA - 3 . DB06681 , another fusion protein , blocks the T cell second signal CD 28 - P33681 . 1 / P33681 . 2 . Finally , new chemical agents are being developed , such as sautrasporine , a tyrosine kinase inhibitor , and tofacitinib , a Jak inhibitor .","Costimulatory blockade with belatacept in clinical and experimental transplantation - a review . BACKGROUND : Current maintenance immunosuppression agents have been critical to the improved graft and patient survival rates in solid organ transplantation observed over the past decade . However , long - term follow - up has revealed that these agents are associated with troublesome side effects and chronic toxicity , contributing to graft loss and death . OBJECTIVES : Costimulation blockade has long been recognized as an important target for immunomodulation in solid organ transplantation . DB06681 , a high - affinity chimeric fusion protein that binds to P33681 / P42081 on antigen - presenting cells , has shown great promise in renal transplantation and is now in Phase III trials . METHODS : This review explores the development and efficacy of belatacept , compared with currently approved immunosuppressive agents used in transplantation . RESULTS : DB06681 seems to be an effective alternative to current maintenance immunosuppressive therapies , with no apparent end organ toxicity and a minimal side - effect profile . This agent works best when used in combination with therapies that target different pathways of T - cell activation , but the optimal regimen has not yet been identified . Data generated in ongoing clinical trials will be essential in validating previous studies and for further development of belatacept - based combinatorial strategies .","Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK100___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK100___ is also being investigated as part of triplet drug regimens . ___MASK100___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .","___MASK88___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK88___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK88___ is a promising pharmacological tool in the treatment of renal edema .","Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK20___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK20___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK20___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK20___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .","Neonatal estrogen exposure disrupts uterine development in the postnatal sheep . Postnatal development of the ovine uterus between birth and postnatal day ( P01160 ) 56 involves budding differentiation of the endometrial glandular epithelium from the luminal epithelium ( LE ) followed by extensive coiling and branching morphogenesis of the tubular glands . To determine the short - and long - term effects of estrogen on neonatal ovine uterine development after P01160 14 , neonatal sheep were randomly assigned at birth ( P01160 0 ) to be treated daily with estradiol - 17beta benzoate ( EB ; 0 , 0 . 01 , 0 . 1 , 1 , or 10 microg / kg body weight . d ) during one of two developmental periods ( P01160 14 - 27 or 42 - 55 ) . All ewes were hemiovariohysterectomized at the end of EB treatment on either P01160 28 or 56 , and the remaining uterine horn and ovary removed on P01160 112 . Immediate responses to EB treatment included dose - and age - dependent increases in uterine wet weight , thickness of the endometrium , myometrium , and LE , but decreases in endometrial glands on P01160 28 and 56 . Transient exposure to EB decreased gland number and thickness of the endometrium and LE on P01160 112 but did not affect extrauterine reproductive tract structures . The mechanism of estrogen inhibition of uterine development did not involve effects on cell proliferation . Real - time PCR analyses found that EB exposure disrupted normal patterns of growth factor ( P05019 , P01344 , fibroblast growth factor - 7 , fibroblast growth factor - 10 , and hepatocyte growth factor ) and receptor mRNA expression in the uterus . Transient exposure of the neonatal ewe to estrogens during critical periods specifically alters growth factor networks that perturb normal development of the uterus , leading to permanent alterations in uterine structure and function .","DB01645 enhancement of respiratory allergen trimellitic anhydride - induced IgE production by adult B6C3F1 mice following in utero and postnatal exposure . The objective of the present study was to determine if exposure to the phytoestrogen genistein ( GEN ) during immune development had any effects on the production of IgE by adult mice following dermal treatment with trimellitic anhydride ( TMA ) , a respiratory allergen . B6C3F1 mice were exposed to GEN either by feeding at 500 ppm or by gavage ( 20 mg / kg ) for varied periods from gestation day ( GD ) 14 to postnatal day ( P01160 ) 84 . In utero exposure to GEN by feeding increased the production of IgE at P01160 84 in male mice but not in female mice . In male mice , continuous exposure to GEN postnatally diminished the in utero exposure - induced enhancement in serum total IgE production . However , continuous exposure to GEN from GD 14 to P01160 84 was required to increase serum total IgE production in female mice . In utero exposure to GEN by gavage increased the production of IgE at P01160 84 in female mice but not in male mice when the mice were maintained on the NIH - 07 rodent diet in which a medium level of phytoestrogens was present . The enhancement in IgE production after GEN exposure in females but not in males was associated with decreases in the percentages of P01730 (+) CD25 (+) T suppressor cells , and increases in the natural killer ( NK ) cell activity , the basal splenocyte proliferation , the expression of P42081 by B cells , and the production of P60568 and P05112 . Overall , the results demonstrated that GEN differentially modulated the developing immune system in male and female mice , and that more IgE was produced upon exposure to TMA in the adult .","Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK84___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .","Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK7___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .","Expression of cyclooxygenase - 2 in urinary bladder in rats with cyclophosphamide - induced cystitis . These studies examined the expression of cyclooxygenase - 2 ( P35354 ) expression in the urothelium and suburothelial space and detrusor from rats treated with cyclophosphamide ( CYP ) to induce acute ( 4 h ) , intermediate ( 48 h ) , or chronic ( 10 - day ) cystitis . Western blot analysis and immunohistochemistry were used to demonstrate P35354 expression . In whole mount preparations of urinary bladder , nerve fibers in the suburothelial plexus , and inflammatory cell infiltrates were characterized for P35354 expression after CYP - induced cystitis . P35354 expression significantly ( P < or = 0 . 01 ) increased in the urothelium + suburothelium and detrusor smooth muscle with acute , intermediate , and chronic ( 10 - day ) CYP - induced cystitis , but expression in urothelium + suburothelium was significantly greater . CYP - induced upregulation of P35354 showed by immunostaining in the urothelium + suburothelium was similar to that observed with Western blot analysis and also demonstrated P35354 inflammatory cell infiltrates ( P42081 + ) and nerve fibers ( A6NDG6 + ) in the suburothelial plexus . Although P35354 expression was significantly ( P < or = 0 . 01 ) increased in detrusor smooth muscle , immunohistochemistry failed to demonstrate an obvious change in P35354 - immunoreactivity ( IR ) in detrusor muscle , but P35354 inflammatory infiltrates were present throughout the detrusor . P35354 - IR nerve fibers exhibited increased density in the suburothelial plexus with acute or chronic CYP - induced cystitis . P35354 - IR macrophages ( P42081 + ) were present throughout the urinary bladder with acute and chronic CYP - induced cystitis . These studies demonstrate cellular targets in the urinary bladder where P35354 inhibitors may act .","Human Lung Mast Cell Products Regulate Airway Smooth Muscle P02778 Levels . In asthma , the airway smooth muscle ( P17405 ) produces P02778 which may attract P49682 (+) mast / T cells to it . Our aim was to investigate the effects of mast cell products on P17405 cell P02778 production . P17405 cells from people with and without asthma were stimulated with IL - 1 β , P01375 - α , and / or IFN γ and treated with histamine ( 1 - 100 μ M ) ± chlorpheniramine ( P35367 antagonist ; 1 μ M ) or ranitidine ( P25021 antagonist ; 50 μ M ) or tryptase ( 1 nM ) ± leupeptin ( serine protease inhibitor ; 50 μ M ) , heat - inactivated tryptase , or vehicle for 4 h or 24 h . Human lung mast cells ( MC ) were isolated and activated with IgE / anti - IgE and supernatants were collected after 2 h or 24 h . The supernatants were added to P17405 cells for 48 h and P17405 cell P02778 production detected using ELISA ( protein ) and real - time PCR ( mRNA ) . DB11320 reduced IL - 1 β / P01375 - α - induced P02778 protein , but not mRNA , levels independent of H1 and H2 receptor activation , whereas tryptase and MC 2 h supernatants reduced all cytokine - induced P02778 . Tryptase also reduced P02778 levels in a cell - free system . Leupeptin inhibited the effects of tryptase and MC 2 h supernatants . MC 24 h supernatants contained P01375 - α and amplified IFN γ - induced P17405 cell P02778 production . This is the first evidence that MC can regulate P17405 cell P02778 production and its degradation . Thus MC may regulate airway myositis in asthma .","Co - signals in organ transplantation . PURPOSE OF REVIEW : The nonimmune effects of currently used immunosuppressive drugs result in a high incidence of late graft loss due to nephrotoxicity and death . As an immune - specific alternative to conventional immunosuppressants , new biotechnology tools can be used to block the costimulation signal of T - cell activation . RECENT FINDINGS : Many experimental studies , particularly preclinical studies in nonhuman primates , have focused on blocking ' classical ' P33681 / P10747 and P25942 / P29965 pathways , which are critical in primary T - cell activation , but also on new P33681 / P10747 and P01375 / P01375 - R pathways families of costimulatory molecules that can deliver positive or negative costimulation signals to regulate the alloimmune response . SUMMARY : DB06681 is a new fusion protein derived from P16410 - Ig that can be used to prevent acute rejection in renal transplantation instead of calcineurin inhibitors . DB06681 can also prevent acute rejection efficiently in humans and , more interestingly , can improve renal function and cardiovascular risk factors in this population .","DB11320 H3 receptors aggravate cerebral ischaemic injury by histamine - independent mechanisms . The role of the histamine H3 receptor ( Q9Y5N1 ) in cerebral ischaemia / reperfusion ( I / R ) injury remains unknown . Here we show that Q9Y5N1 expression is upregulated after I / R in two mouse models . Q9Y5N1 antagonists and Q9Y5N1 knockout attenuate I / R injury , which is reversed by an Q9Y5N1 - selective agonist . Interestingly , P35367 and P25021 antagonists , a histidine decarboxylase ( HDC ) inhibitor and HDC knockout all fail to compromise the protection by Q9Y5N1 blockade . Q9Y5N1 blockade inhibits P42345 phosphorylation and reinforces autophagy . The neuroprotection by Q9Y5N1 antagonism is reversed by 3 - methyladenine and siRNA for Atg7 , and is diminished in Atg5 ⁻/⁻ mouse embryonic fibroblasts . Furthermore , the peptide Tat - Q9Y5N1 ( CT414 - 436 ) , which blocks Q9Y696 binding with H3Rs , or siRNA for Q9Y696 , further increases I / R - induced autophagy and protects against I / R injury . Therefore , Q9Y5N1 promotes I / R injury while its antagonism protects against ischaemic injury via histamine - independent mechanisms that involve suppressing Q9Y5N1 / Q9Y696 binding - activated autophagy , suggesting that Q9Y5N1 inhibition is a therapeutic target for cerebral ischaemia .","P25942 activation induces p53 - dependent vascular endothelial growth factor secretion in human multiple myeloma cells . It was previously demonstrated that p53 status in human multiple myeloma ( MM ) cells regulates distinct cell cycle responses to P25942 activation . In this study , the production of vascular endothelial growth factor ( P15692 ) and migration in MM cells triggered by P25942 activation was examined , and the influence of p53 status in regulating this process was determined . Two human MM cell lines that express wild - type p53 at permissive ( 28 degrees C ) and mutant p53 at restrictive ( 37 degrees C ) temperatures were used as a model system . P25942 activation induces a 4 - fold ( RPMI 8226 ) and a 6 - fold ( SV ) increase in P15692 transcripts , respectively , under restrictive , but not permissive , temperatures . P15692 expression is significantly induced after P25942 activation in patient MM cells expressing mutant p53 . Increased P15692 transcripts result in increased protein and secretion levels , as evidenced by immunoblotting and enzyme - linked immunosorbent assay . In a double - chamber transmigration assay , P25942 activation of MM cells induced a 3 - fold ( RPMI 8226 ) and a 5 - fold ( SV ) increase in migration under restrictive , but not permissive , conditions . A 2 - to 8 - fold induction in migration of patient MM cells expressing mutant p53 was similarly observed . Transduction of MM cells with a luciferase reporter under the control of a human P15692 promoter further indicated that P25942 - induced P15692 expression was mediated through a transcriptional control mechanism . Finally , adenovirus - mediated wild - type p53 overexpression down - regulated P25942 - induced P15692 expression and transmigration in MM cells expressing mutant p53 . These studies demonstrate that P25942 induces P15692 secretion and MM cell migration , suggesting a role for P25942 in regulating MM homing and angiogenesis .","Mesenchymal stem cells control alloreactive CD8 (+) P10747 (-) T cells . P10747 / P33681 co - stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients . However , cells lacking P10747 are not susceptible to belatacept treatment . As CD8 (+) P10747 (-) T - cells have cytotoxic and pathogenic properties , we investigated whether DB05914 ( O60682 ) are effective in controlling these cells . In mixed lymphocyte reactions ( P08235 ) , O60682 and belatacept inhibited peripheral blood mononuclear cell ( PBMC ) proliferation in a dose - dependent manner . O60682 at O60682 / effector cell ratios of 1 : 160 and 1 : 2 · 5 reduced proliferation by 38 · 8 and 92 · 2 % , respectively . DB06681 concentrations of 0 · 1 μg / ml and 10 μg / ml suppressed proliferation by 20 · 7 and 80 · 6 % , respectively . Both treatments in combination did not inhibit each other ' s function . Allostimulated CD8 (+) P10747 (-) T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B , interferon ( IFN ) - γ and tumour necrosis factor ( P01375 ) - α . While belatacept did not affect the proliferation of CD8 (+) P10747 (-) T cells , O60682 reduced the percentage of P10747 (-) T cells in the proliferating CD8 (+) T cell fraction by 45 · 9 % ( P = 0 · 009 ) . CD8 (+) P10747 (-) T cells as effector cells in P08235 in the presence of P01730 (+) T cell help gained P10747 expression , an effect independent of O60682 . In contrast , allostimulated P10747 (+) T cells did not lose P10747 expression in P08235 - O60682 co - culture , suggesting that O60682 control pre - existing P10747 (-) T cells and not newly induced P10747 (-) T cells . In conclusion , alloreactive CD8 (+) P10747 (-) T cells that remain unaffected by belatacept treatment are inhibited by O60682 . This study indicates the potential of an O60682 - belatacept combination therapy to control alloreactivity .","Challenges and opportunities in targeting the costimulation pathway in solid organ transplantation . Signaling through the costimulatory pathway is critical in the regulation of T cell activation . DB01281 , a selective costimulatory antagonist FDA approved for the treatment of moderate to severe rheumatoid arthritis , binds to P33681 and P42081 on antigen presenting cells , blocking the interaction with P10747 on T cells . DB06681 , a second generation P16410 - Ig with 2 amino acid substitutions , has shown considerable promise in clinical transplantation as part of a maintenance immunosuppression regimen . This review will summarize the role of costimulation in T cell activation , detail the development of costimulation antagonists and highlight the pertinent clinical trials completed and ongoing utilizing belatacept as part of an immunosuppressive regimen in organ transplantation .","Generation and Molecular Mapping of a Sequence Characterized Amplified Region Marker Linked with the Bct Gene for Resistance to Beet curly top virus in Common Bean . ABSTRACT A random amplified polymorphic DNA ( RAPD ) marker directly linked ( 0 . 0 cM ) with a resistance gene was identified in a snap bean recombinant inbred population ( Moncayo x Primo ) consisting of 94 F ( 5 : 7 ) recombinant inbred lines that had uniform segregation for disease reaction to Beet curly top virus ( BCTV ) across three field locations . Resistance was conditioned by a single dominant allele tentatively designated Bct . Seven hundred and fifty decamer primers were screened to obtain the linked RAPD marker that was then converted to a sequence characterized amplified region ( P62701 ) marker SAS8 . 1550 . The P62701 mapped within a cluster of resistance genes on linkage group P33681 of the core map . A survey of 103 BCTV - resistant and - susceptible snap and dry bean genotypes was conducted using SAS8 . 1550 . Results showed that the P62701 would be highly useful for marker - assisted selection of Bct in snap and dry bean originating from the Andean gene pool . Marker - assisted selection for Bct will expedite the development of BCTV - resistant cultivars and minimize the need for cumbersome pathogen tests .","Five - year safety and efficacy of belatacept in renal transplantation . DB06681 is a first - in - class co - stimulation blocker in development for primary maintenance immunosuppression . A Phase II study comparing belatacept with cyclosporine ( DB00091 ) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured Q92565 at 1 year for belatacept , but the incidence of posttransplantation lymphoproliferative disorder was higher . Here , we present the results for the extension of this trial , which aimed to assess long - term safety and efficacy of belatacept . Seventy - eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving DB00091 completed the long - term extension period . Q92565 remained stable in patients who were receiving belatacept for 5 years , and the incidences of death / graft loss or acute rejection were low . The frequencies of serious infections were 16 % for belatacept and 27 % for DB00091 , and neoplasms occurred in 12 % of each group . No patients who were treated with belatacept and one patient who was treated with DB00091 developed posttransplantation lymphoproliferative disorder during the follow - up period . Serious gastrointestinal disorders occurred more frequently with belatacept ( 12 % belatacept versus 8 % DB00091 ) , and serious cardiac disorders occurred more frequently with DB00091 ( 2 % belatacept versus 12 % DB00091 ) . Pharmacokinetic analyses showed consistent exposure to belatacept over time . P42081 receptor saturation was higher in patients who were receiving belatacept every 4 weeks ( 74 % ) compared with every 8 weeks ( 56 % ) . In conclusion , this study demonstrated high patient persistence with intravenous belatacept , stable renal function , predictable pharmacokinetics , and good safety with belatacept over 5 years .","Rational development of DB06681 ( belatacept ) , a high - affinity variant of P16410 - Ig with potent immunosuppressive properties . Current success in organ transplantation is dependent upon the use of calcineurin - inhibitor - based immunosuppressive regimens . Unfortunately , current immunotherapy targets molecules with ubiquitous expression resulting in devastating non - immune side effects . T - cell costimulation has been identified as a new potential immunosuppressive target . The best characterized pathway includes P10747 , its homologue P16410 and their ligands P33681 and P42081 . While an immunoglobulin fusion protein construct of P16410 suppressed rejection in rodents , it lacked efficacy in primate transplant models . In an attempt to increase the biologic potency of the parent molecule a novel , modified version of P16410 - Ig , DB06681 ( belatacept ) , was constructed . Two amino acid substitutions ( L104E and A29Y ) gave rise to slower dissociation rates for both P42081 and P33681 . The increased avidity resulted in a 10 - fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre - clinical primate model . The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants .","T - cell phenotype in protocol renal biopsy from transplant recipients treated with belatacept - mediated co - stimulatory blockade . BACKGROUND : DB06681 is thought to disrupt the interaction between P33681 / 86 and P10747 , thus preventing T - cell activation by blocking the co - stimulatory second signal . However , the consequences on the T - cell profile in human renal transplant cases have not been determined . METHODS : In this study , we analysed intra - graft levels of the mRNAs for Treg ( Q9BZS1 ) , cytotoxic CD8 T cells ( P10144 ) , Th1 ( INFγ , Tbet ) , Th2 ( P23771 ) and Th17 ( RORγt and Q16552 ) in protocol biopsies obtained 12 months after renal transplantation in recipients treated with DB06681 or calcineurin inhibitor ( CNI ) . RESULTS : Only the intra - graft abundance of Q9BZS1 mRNA was significantly lower ( P < 0 . 001 ) in the DB06681 group than the CNI group . Conclusions . These results are in agreement with in vitro data suggesting that P10747 is a major co - stimulatory signal of both Tregs development and peripheral homeostasis but contrast with clinical trials showing a better 1 - year graft function and a lower incidence of chronic allograft nephropathy in patients receiving DB06681 than patients treated with CNI . They suggest that immune benefits induced by DB06681 are not mediated by Treg expansion and that Q9BZS1 is not by itself a prognostic marker of long - term graft function in a non - inflammatory context . These results have to be , however , considered as preliminary since the size of our study population is limited .","Biomedical nanoparticles modulate specific P01730 + T cell stimulation by inhibition of antigen processing in dendritic cells . Understanding how nanoparticles may affect immune responses is an essential prerequisite to developing novel clinical applications . To investigate nanoparticle - dependent outcomes on immune responses , dendritic cells ( DCs ) were treated with model biomedical poly ( vinylalcohol )- coated super - paramagnetic iron oxide nanoparticles ( P32926 - SPIONs ) . P32926 - SPIONs uptake by human monocyte - derived DCs ( MDDCs ) was analyzed by flow cytometry ( FACS ) and advanced imaging techniques . Viability , activation , function , and stimulatory capacity of MDDCs were assessed by FACS and an in vitro P01730 + T cell assay . P32926 - SPION uptake was dose - dependent , decreased by lipopolysaccharide ( LPS ) - induced MDDC maturation at higher particle concentrations , and was inhibited by cytochalasin D pre - treatment . P32926 - SPIONs did not alter surface marker expression ( P33681 , Q01151 , P42081 , myeloid / plasmacytoid DC markers ) or antigen - uptake , but decreased the capacity of MDDCs to process antigen , stimulate P01730 + T cells , and induce cytokines . The decreased antigen processing and P01730 + T cell stimulation capability of MDDCs following P32926 - SPION treatment suggests that MDDCs may revert to a more functionally immature state following particle exposure .","Costimulation blockade in autoimmunity and transplantation . Signaling through the costimulation receptors is a critical pathway in the regulation of T - cell activation . The selective costimulation inhibitor abatacept ( cytotoxic T lymphocyte - associated antigen 4 - Ig ) binds to P33681 and P42081 on antigen - presenting cells , blocking interaction with P10747 on T cells , and is approved for the treatment of moderate to severe rheumatoid arthritis . DB06681 ( DB06681 ) , currently enrolling phase III trials in renal transplantation , was rationally designed from abatacept to bind with more avidity to P42081 , providing the more potent immunosuppressive properties required for immunosuppression in transplantation . This review describes the relevant preclinical studies and summarizes recent clinical findings on these 2 molecules in autoimmune diseases and organ transplantation . Although both inhibit the P10747 costimulatory pathway , they are tailored for specific disease states -- abatacept for autoimmune diseases and belatacept for transplantation .","Technology evaluation : DB06681 , Bristol - Myers Squibb . Bristol - Myers Squibb is developing belatacept , a soluble fusion protein of the P33681 - binding domain of P16410 with amino acid changes A29Y and L104E and an Ig tail , which inhibits lymphocyte co - stimulation through P10747 , for the potential treatment of solid organ transplant rejection . DB06681 is currently undergoing phase III clinical trials .","Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK63___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .","DB06681 and sirolimus prolong nonhuman primate islet allograft survival : adverse consequences of concomitant alefacept therapy . Calcineurin inhibitors ( CNI ) and steroids are known to promote insulin resistance , and their avoidance after islet transplantation is preferred from a metabolic standpoint . DB06681 , a P33681 - specific mediator of costimulation blockade ( CoB ) , is clinically indicated as a CNI alternative in renal transplantation , and we have endeavored to develop a clinically translatable , belatacept - based regimen that could obviate the need for both CNIs and steroids . Based on the known synergy between CoB and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched islet allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on CoB - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . Nine rhesus macaques were rendered diabetic with streptozotocin and underwent islet allotransplantation . All received belatacept and sirolimus ; six also received alefacept . DB06681 and sirolimus significantly prolonged rejection - free graft survival ( median 225 days compared to 8 days in controls receiving basiliximab and sirolimus ; p = 0 . 022 ) . The addition of alefacept provided no additional survival benefit , but was associated with Cytomegalovirus reactivation in four of six animals . No recipients produced donor - specific alloantibodies . The combination of belatacept and sirolimus successfully prevents islet allograft survival in rhesus monkeys , but induction with alefacept provides no survival benefit and increases the risk of viral reactivation .","Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .","Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing P04626 . In an attempt to treat cancer patients with P04626 overexpressing tumors , we developed a chimeric antigen receptor ( CAR ) based on the widely used humanized monoclonal antibody ( mAb ) ___MASK100___ ( Herceptin ) . An optimized CAR vector containing P10747 , 4 - 1BB , and CD3zeta signaling moieties was assembled in a gamma - retroviral vector and used to transduce autologous peripheral blood lymphocytes ( PBLs ) from a patient with colon cancer metastatic to the lungs and liver , refractory to multiple standard treatments . The gene transfer efficiency into autologous T cells was 79 % CAR (+) in CD3 (+) cells and these cells demonstrated high - specific reactivity in in vitro coculture assays . Following completion of nonmyeloablative conditioning , the patient received 10 ( 10 ) cells intravenously . Within 15 minutes after cell infusion the patient experienced respiratory distress , and displayed a dramatic pulmonary infiltrate on chest X - ray . She was intubated and despite intensive medical intervention the patient died 5 days after treatment . Serum samples after cell infusion showed marked increases in interferon - gamma ( P01579 ) , granulocyte macrophage - colony stimulating factor ( GM - P04141 ) , tumor necrosis factor - alpha ( P01375 ) , interleukin - 6 ( P05231 ) , and P22301 , consistent with a cytokine storm . We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of P04626 on lung epithelial cells .","Selective measurement of white matter and gray matter diffusion trace values in normal human brain . The trace of the diffusion tensor ( or simply the trace ) is diagnostically valuable for detecting acute ischemic lesions . A number of studies indicate that the trace of human gray matter ( GM ) and white matter ( WM ) are quite similar . This is somewhat surprising considering the different cellular environments of GM and WM . It is possible that partial volume averaging ( P32926 ) effects between GM and WM , inherent in many of the ultrafast imaging sequences used for diffusion measurements , are responsible for this observation . In order to minimize P32926 effects , the trace values of GM and WM have been selectively measured by implementing double inversion recovery ( P30518 ) echo planar imaging ( P10646 ) pulse sequences . Results on six normal volunteers indicate that the trace values of WM and GM are not statistically different .","[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .","A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK69___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .","Synergistic activity of ixabepilone plus other anticancer agents : preclinical and clinical evidence . DB04845 demonstrates marked synergistic activity in combination with capecitabine , which served as the rationale for the evaluation of this combination in the clinic . DB04845 plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer ( MBC ) progressing after treatment with an anthracycline and a taxane ; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy . An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab , bevacizumab , brivanib , and cetuximab ; with immune - modulating agents such as anti - P16410 antibody ; and with other chemotherapy drugs such as irinotecan and epirubicin . Notably , experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab - paclitaxel combined with bevacizumab . These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in P04626 - positive breast cancer ; with bevacizumab in breast cancer , endometrial cancer , renal cancer , and non - small cell lung cancer ( NSCLC ) ; with cetuximab in breast cancer , NSCLC , and pancreatic cancer ; and with brivanib , dasatinib , sorafinib , sunitinib , or vorinostat in MBC . Preliminary results from several of these trials suggest that ixabepilone - based combinations have promising anticancer activity .","Electrostatic modeling of peptides derived from the V3 - loop of HIV - 1 gp120 : implications of the interaction with chemokine receptor P51681 . Infection of P01730 + T cells by macrophage - tropic HIV - 1 strains involves interaction of viral gp120 with the host cell chemokine receptor P51681 . The principle neutralizing determinant ( P01160 ) of the V3 - loop of the HIV - 1 gp120 was investigated for its interaction with P51681 by computational modeling methods at atomic resolution and electrostatic calculations to complement experimental findings . The study focused on the recognition step and examined possible peptide - peptide interactions between various P01160 - derived peptides from the V3 - loop and the N - terminal ( Nt ) domain of P51681 . These recognition interactions are possible because of the complementary character of the spatial distribution of the predominantly positive electrostatic potentials of the P01160 - derived peptides and the predominantly negative electrostatic potential of the CCR5Nt domain . The CCR5Nt appears more amenable to interaction with the V3 peptides , than the other P51681 extracellular domains ( ECL ) , because of its length and the domination of its negative electrostatic potential . On the contrary , ECL2 possesses a predominantly positive electrostatic potential . There are positive patches in Nt and negative patches in ECL2 , which , following the non - specific recognition of the V3 - loop by P51681 and with the expected local structural rearrangements to facilitate specific binding , may be contributing to the stabilization of the complex . A sequential two - step specific binding , involving different extracellular domains , is conceivable . Although the electrostatic potentials may play a role in a V3 - P51681 interaction , a more specific model can not be derived in the absence of a three - dimensional structure of a gp120 / P01730 / P51681 complex .","What ' s in the pipeline ? New immunosuppressive drugs in transplantation . In the pipeline , there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials . The major target of new agents are cell - surface molecules important in immune cell interactions ( especially the costimulatory pathway ) , signaling pathways that activate T cells , T - cell proliferation and trafficking and recruitment of immune cells responsible for rejection . The most promising biologic agents include a humanized anti - CD11a ( anti - LFA1 ) , humanized anti - P33681 . 1 / P33681 . 2 , a second - generation DB01281 ( DB06681 ) and a humanized antibody to anti - P08575 RB . Inhibitors of T - cell activation and signaling are still in preclinical development . The most interesting inhibitors of T - cell proliferation include inhibitors of the Janus protein tyrosine kinase , P52333 , and FK778 , a leflunomide analog . Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes . Early trials of FTY720 , a synthetic small molecule with functional homology to sphingosine - 1 phosphate leading to lymphocyte sequestration , appear very promising ; however , enthusiasm for this drug is mitigated by its potential cardiac side - effects . Antagonists to several chemokine receptors , including P32246 , P49682 and P51681 , have been shown to be effective in experimental transplantation and are likely to be considered for clinical development .","Introduction to the use of belatacept : a fusion protein for the prevention of posttransplant kidney rejection . The development of new immunosuppressive drugs for kidney transplantation resulted both in better short - term outcomes and in decreased metabolic , cardiovascular , and nephrotoxicity risk . DB06681 belongs to a new class of immunosuppressive drugs that selectively inhibits T - cell activation by preventing P10747 activation and by binding its ligands P33681 - 1 and P33681 - 2 . The result is an inactivation of costimulatory pathways . A comparative analysis of the BENEFIT and BENEFIT - EXT datasets showed belatacept regimens resulted in better cardiovascular and metabolic risk profiles than did cyclosporin A ( DB00091 ) regimens : belatacept likewise outperformed DB00091 in terms of lower blood pressure and serum lipids and less new onset diabetes after transplantation . About 20 % of belatacept - treated patients developed adverse effects which included anemia , pyrexia , neutropenia , diarrhea , urinary tract infection , headache , and peripheral edema . At present , belatacept does not seem to predispose patients to a higher rate of infection than DB00091 maintenance immunosuppression . The risk of posttransplant lymphoproliferative diseases was higher in Epstein - Barr virus ( EBV ) - seronegative patients than in EBV - seropositive patients , but the risk may be reduced by use of a less intensive regimen and avoidance of EBV - negative patients and of patients whose pretransplant EBV serology is unknown . DB06681 provides a new option for immunosuppressive therapy in kidney transplantation , but needs further evaluation in terms of the late effects that may derive from prolonged blockage of the costimulatory system and the induction of tolerance status .","Chronic induction . What ' s new in the pipeline . Induction therapy with biological agents was introduced the in the 1970s and the rationale , concepts and approach have remained almost unchanged for 30 years . However , the novel biological agents being developed for induction therapy are being designed for chronic rather than short - term therapy with several objectives : reduce dependence on toxic and nephrotoxic agents , improve outcome and ultimately facilitate the emergence of tolerance . The biological agents include efalizumab , a humanized anti - CD11a ( anti - LFA1 ) , anti - CD154 , anti - P25942 , a number of agents targeting P40933 and its receptor , and costimulation blockade with humanized antibodies to P33681 / P42081 and the fusion receptor protein DB06681 , a second generation DB01281 . The past decade has witnessed an unprecedented number of small molecules / oral drugs that have been developed and approved for renal transplantation ; the next decade , however , may witness the emergence of a new class of biological induction agents that may displace some of the currently used drugs .","___MASK69___ inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : ___MASK69___ is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti - cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 / 2 ) and P45983 and 2 ( JNK 1 / 2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound - healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC ( 50 ) = 8 . 6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 / 2 expression , upregulation of p - P45983 / 2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .","[ Use of P30518 - PCR for elaboration of molecular markers of intraspecies bacterial groups as exemplified by Bacillus thuringiensis ] . A recently developed PCR - fingerprinting method , the so - called P30518 ( diverged inverted repeats ) - PCR , was used for quick search for molecular markers of Bacillus thuringiensis subspecies carrying the cry1 genes . The analysis of the fingerprints obtained by this method made it possible to reveal PCR fragments characteristic of the subspecies that produce proteins toxic for insects of the order Lepidoptera . Cloning and sequencing of these fragments allowed systems of P62701 ( sequence characterized amplified region ) primers to be designed , which are specific to the above group of B . thuringiensis strains . Comparison of the specific fragments with sequences available in the GenBank database revealed their homology with the rpoC gene family and the adjacent spacer region , suggesting chromosomal localization of these markers . This increases the reliability of the designed system of P62701 primers , because plasmids may be lost or transferred by transformation between closely related strains . It was demonstrated that the P30518 - PCR method allows markers to be developed that are linked to diagnostic genotypic and phenotypic characteristics of bacteria .","Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK63___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .","Advances in immunosuppression for kidney transplantation : new strategies for preserving kidney function and reducing cardiovascular risk . The development of new immunosuppressants for renal transplantation is aimed not only at improving & nbsp ; short - term outcomes , but also at achieving better safety , cardiovascular , and metabolic profiles and at decreasing & nbsp ; nephrotoxicity . DB06681 is a fusion protein that inhibits T cell activation by binding to P33681 and P42081 antigens . Clinical trials , particularly the BENEFIT and BENEFIT - EXT studies , have shown that belatacept preserves function and structure in renal grafts . The effects of belatacept provide long - term , sustained results , and the safety and efficacy of this drug have been demonstrated in cases of renal transplantation from expanded criteria donors . Compared to calcineurin inhibitors , belatacept is associated with a lower incidence of chronic allograft nephropathy and a more favourable cardiovascular and metabolic profile .","P40933 augments antitumoral activity of an ErbB2 / P04626 cancer vaccine targeted to professional antigen - presenting cells . Targeted delivery of tumor - associated antigens to professional antigen - presenting cells ( P25054 ) is being explored as a strategy to enhance the antitumoral activity of cancer vaccines . Here , we generated a cell - based system for continuous in vivo production of a P16410 - ErbB2 fusion protein as a therapeutic vaccine . The chimeric P16410 - ErbB2 molecule contains the extracellular domain of P16410 for specific targeting to costimulatory P33681 molecules on the surface of P25054 , genetically fused to residues 1 - 222 of human ErbB2 ( P04626 ) as an antigenic determinant . In wild - type BALB / c mice , inoculation of syngeneic epithelial cells continuously secreting the P16410 - ErbB2 fusion vaccine in the vicinity of subcutaneously growing ErbB2 - expressing renal cell carcinomas resulted in the rejection of established tumors , accompanied by the induction of ErbB2 - specific antibodies and cytotoxic T cells . In contrast , treatment with P16410 - ErbB2 vaccine - secreting producer cells alone was insufficient to induce tumor rejection in ErbB2 - transgenic WAP - Her - 2 F1 mice , which are characterized by pronounced immunological tolerance to the human self - antigen . When P16410 - ErbB2 producer cells were modified to additionally secrete interleukin ( IL ) - 15 , antigen - specific antitumoral activity of the vaccine in WAP - Her - 2 F1 mice was restored , documented by an increase in survival , and marked inhibition of the growth of established ErbB2 - expressing , but not antigen - negative tumors . Our results demonstrate that continuous in vivo expression of an P25054 - targeted ErbB2 fusion protein results in antigen - specific immune responses and antitumoral activity in tumor - bearing hosts , which is augmented by the pleiotropic cytokine P40933 . This provides a rationale for further development of this approach for specific cancer immunotherapy .","Pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept in adult kidney transplant recipients . BACKGROUND AND OBJECTIVES : DB06681 is a first - in - class , selective co - stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients . The objective of this study was to report the pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept . METHODS : The pharmacokinetics , pharmacodynamics ( P42081 receptor occupancy ) , and immunogenicity of belatacept were studied in de novo adult kidney transplant recipients in phase II and III clinical studies . RESULTS : Following multiple doses of 5 or 10 mg / kg , the geometric mean ( percentage coefficient of variation ) maximum serum concentration and area under the serum concentration - time curve over one dosing interval of belatacept were 136 ( 20 % ) and 238 ( 27 % ) μg / mL , and 13 , 587 ( 27 % ) and 21 , 241 ( 35 % ) μg · h / mL , respectively . The median belatacept elimination half - life was 8 - 9 days . DB06681 exhibited concentration - dependent binding to P42081 receptors . The pre - dose P42081 receptor occupancy by belatacept decreased from 94 to 65 % between day 5 and 1 year post - transplant , with corresponding pre - dose trough serum concentrations of belatacept decreasing from ~ 35 to 4 μg / mL during this period . The cumulative incidence of developing anti - belatacept antibodies was 5 . 3 % up to 3 years post - transplant and had no impact on belatacept exposure . CONCLUSIONS : DB06681 in adult kidney transplant demonstrated linear pharmacokinetics with low variability , concentration - dependent pharmacodynamics , and a low incidence of anti - drug antibodies .","Dietary phytochemicals alter epigenetic events and signaling pathways for inhibition of metastasis cascade : phytoblockers of metastasis cascade . Cancer metastasis is a multistep process in which a cancer cell spreads from the site of the primary lesion , passes through the circulatory system , and establishes a secondary tumor at a new nonadjacent organ or part . Inhibition of cancer progression by dietary phytochemicals ( DPs ) offers significant promise for reducing the incidence and mortality of cancer . Consumption of DPs in the diet has been linked to a decrease in the rate of metastatic cancer in a number of preclinical animal models and human epidemiological studies . DPs have been reported to modulate the numerous biological events including epigenetic events ( noncoding micro - RNAs , histone modification , and DNA methylation ) and multiple signaling transduction pathways ( Wnt / β - catenin , Notch , Sonic hedgehog , P35354 , P00533 , MAPK - P29323 , JAK - P35610 , Akt / PI3K / P42345 , NF - κB , AP - 1 , etc . ) , which can play a key role in regulation of metastasis cascade . Extensive studies have also been performed to determine the molecular mechanisms underlying antimetastatic activity of DPs , with results indicating that these DPs have significant inhibitory activity at nearly every step of the metastatic cascade . DPs have anticancer effects by inducing apoptosis and by inhibiting cell growth , migration , invasion , and angiogenesis . Growing evidence has also shown that these natural agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways . In this review , we discuss the variety of molecular mechanisms by which DPs regulate metastatic cascade and highlight the potentials of these DPs as promising therapeutic inhibitors of cancer .","P45983 , but not P45984 , is required in two mechanistically distinct models of inflammatory arthritis . The roles of the c - Jun N - terminal kinases ( JNKs ) in inflammatory arthritis have been investigated ; however , the roles of each isotype ( ie , P45983 and P45984 ) in rheumatoid arthritis and conclusions about whether inhibition of one or both is necessary for amelioration of disease are unclear . By using P45983 - or P45984 - deficient mice in the collagen - induced arthritis and the KRN T - cell receptor transgenic mouse on C57BL / 6 nonobese diabetic ( K / BxN ) serum transfer arthritis models , we demonstrate that P45983 deficiency results in protection from arthritis , as judged by clinical score and histological evaluation in both models of inflammatory arthritis . In contrast , abrogation of P45984 exacerbates disease . In collagen - induced arthritis , the distinct roles of the JNK isotypes can , at least in part , be explained by altered regulation of P42081 expression in P45983 - or P45984 - deficient macrophages in response to microbial products , thereby affecting T - cell - mediated immunity . The protection from K / BxN serum - induced arthritis in Jnk1 (-/-) mice can also be explained by inept macrophage function because adoptive transfer of wild - type macrophages to Jnk1 (-/-) mice restored disease susceptibility . Thus , our results provide a possible explanation for the modest therapeutic effects of broad JNK inhibitors and suggest that future therapies should selectively target the P45983 isoform .","Gateways to clinical trials . Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses . The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity , the drug discovery and development portal , http :// integrity . prous . com . This issue focuses on the following selection of drugs : 2F5 , 2G12 , abetimus sodium , ABI - 007 , adalimumab , adefovir dipivoxil , DB05387 , alefacept , altropane , aminolevulinic acid hydrochloride , aminolevulinic acid methyl ester , aminopterin , anakinra , aprinocarsen sodium , atazanavir , atlizumab , atomoxetine hydrochloride ; P33681 - 1 vaccine , bevacizumab , DB04851 dicitrate , BMS - 188667 , brasofensine sulfate , bryostatin 1 ; cantuzumab mertansine , Q99698 - 828 , cinacalcet hydrochloride , cipamfylline , creatine , CVT - 3146 ; darbepoetin alfa , DITPA , drotrecogin alfa ( activated ) , duloxetine hydrochloride ; edatrexate , efalizumab , ENMD - 0997 , epoetin , erlosamide , esomeprazole magnesium , etiprednol dicloacetate , etoricoxib , everolimus , ezetimibe ; fampridine , fenretinide , FTY - 720 ; P05019 / P17936 , IL - 1 cytokine trap , ilodecakin , interferon beta , ISIS - 104838 , ISIS - 2503 , ISIS - 5132 , ivabradine hydrochloride ; lafutidine , lanthanum carbonate , l - DB00125 hydrochloride , DB06681 , lerdelimumab , levetiracetam , levobupivacaine hydrochloride , levosimendan , lopinavir ; melagatran , mibefradil hydrochloride , miglustat , morphine - 6 - glucuronide ; nesiritide ; omalizumab , omapatrilat ; p24 - VLP , parecoxib sodium , peginterferon alfa - 2a , peginterferon alfa - 2b , pegsunercept , pitavastatin calcium , plevitrexed , prasterone , pregabalin , PRO - 2000 , prucalopride ; rapacuronium bromide , rebimastat , RGA - 0853 , rubitecan , ruboxistaurin mesilate hydrate , RWJ - 67657 ; S - 16020 - 2 , sarizotan , SLV - 306 , stiripentol ; DB05809 , tenecteplase , teriparatide , tezacitabine , tipifarnib , trabectedin , troglitazone ; valdecoxib , vardenafil ; Z - 338 , ziconotide .","Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK91___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK91___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK91___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK91___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK91___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK91___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK91___ .","Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK77___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .","Production and characterization of DB06681 , a variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin , in Pichia pastoris . Blocking the P10747 / P33681 costimulatory pathway is a promising strategy in the treatment of graft rejection , graft - versus - host disease and autoimmune diseases . DB06681 , a high - affinity variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin ( DB01281 ) , is a more potent inhibitor of the interaction between P10747 and P33681 than is DB01281 . In a previous study , DB06681 was produced in a mammalian cell system , which is time - consuming and expensive . To obtain DB06681 more efficiently and cost effectively , we attempted to produce DB06681 using a Pichia pastoris expression system . The gene encoding DB06681 , with an additional 6 - DB00117 tag at the N - terminus , was cloned into the yeast vector pPIC9K and expressed in the P . pastoris strain GS115 . Under the optimized induction conditions for protein expression ( inoculum density , OD ( 600 ) = 80 ; methanol concentration added daily , 1 . 0 - 3 . 0 % ; induction time point , 72 - 96 h ; culture medium pH = 6 . 0 ) , the yield of purified DB06681 was approximately 30 mg l (- 1 ) by one - step Ni - agarose affinity chromatography . Q96IV0 F treatment showed the purified DB06681 to be post - translational modified by N - linked glycosylation . In biological function assays , DB06681 expressed in P . pastoris demonstrated specific binding to P33681 - 1 / P33681 - 2 - positive Raji cells and also suppressed lymphocyte proliferation in a dose - dependent manner . These results suggest that DB06681 produced in P . pastoris is biologically active and will be useful for experimental therapy on immunotherapy for transplant rejection and autoimmune diseases .","Polymorphisms of genes related to endothelial cells are associated with primary biliary cirrhosis patients of Cretan origin . BACKGROUND : Primary biliary cirrhosis ( P10515 ) is an organ specific autoimmune disease of still unidentified genetic etiology . We have shown that endothelins ( ETs ) , produced by the liver endothelial cells are increased in P10515 and may play a major pathogenetic role . AIMS : To study gene polymorphisms related to the endothelial cells ( P29474 , P10153 - 1 genes ) and , to investigate whether the previously reported association of P16410 gene polymorphisms is replicated in a genetically homogeneous Greek population . PATIENTS AND METHODS : Genomic DNA was extracted from 100 P10515 patients ( 83 females , 93 % AMA + , 74 / 100 Ludwig stage I - II ) and 158 healthy controls . P29474 , P16410 and ET1 polymorphisms were determined by PCR - RFLPs analysis . RESULTS : Both P29474 intron4 VNTR and P29474 exon7 G894T SNP were significantly associated with increased risk in P10515 . P10153 - 11 rs2071942 \" A \" and rs5370 \" T \" alleles appeared a tendency for association with disease progression . No association was found between P10515 and the P16410 SNPs analyzed . CONCLUSIONS : We demonstrated that P29474 , a gene related to the liver endothelium function is associated with P10515 . Contrarily , the important in adaptive immunity gene P16410 was not associated with the disease in the homogeneous population analyzed . These results are compatible partially with our previous hypothesis that defects of the liver endothelial system , leading to endothelin overproduction , may be a fundamental early pathogenetic mechanism in P10515 ."],"string":"[\n \"Suppressing T cell motility induced by anti - P16410 monotherapy improves antitumor effects . A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance , such as cytotoxic T lymphocyte - associated protein 4 ( P16410 ) . However , the determinants of response to anti - P16410 mAb treatment remain incompletely understood . In murine models , anti - P16410 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions , including local ionizing radiation ( IR ) therapy . We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor - infiltrating CD8 + T lymphocytes ( TILs ) following treatment with the anti - P16410 mAb 9H10 . Alone , 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo . In contrast , the combination of 9H10 and IR restored MHC class I - dependent arrest . After implantation , the carcinoma cells had reduced expression of retinoic acid early inducible - 1 ( RAE - 1 ) , a ligand for natural killer cell group 2D ( P26718 ) receptor . We found that RAE - 1 expression was induced by IR in vivo and that anti - P26718 mAb blocked the Q15399 arrest induced by IR / 9H10 combination therapy . These results demonstrate that anti - P16410 mAb therapy induces motility of Q15399 and that P26718 ligation offsets this effect to enhance TILs arrest and antitumor activity .\",\n \"DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .\",\n \"Haemostasis unbalance in Pugh - scored liver cirrhosis : characteristic changes of plasma levels of protein C versus protein S . Liver cirrhosis leads to a protido - synthetic impairment that alters the levels of blood clotting factors and haemostasis . The aim of this study was to assess the alterations of haemostatic parameters in the evolution of liver cirrhosis scored according to Child ' s classification , with Pugh ' s modifications . Thirty - seven patients suffering from alcoholic and non - alcoholic liver cirrhosis , representing stages A5 , A6 , P33681 , B8 and Q99622 , were tested for the main blood clotting parameters , i . e . prothrombin time , factor VII , partial activated thromboplastin time , fibrinogen , plasminogen , alpha 2 - antiplasmin and physiological inhibitors [ antithrombin III ( P01008 ) , protein C ( PC ) , protein S ( PS ) ] . No variations were observed between substages A5 and A6 in any of the parameters , except for coagulation inhibitor levels . Most parameters showed a progressive decrease in stages B and C of the disease . The most significant alterations were found in the physiological coagulation inhibitors , with a sharper decrease in PC and AT III level and a lesser decrease in the level of PS through stages A5 and B8 : this evidence could assume an important biological and diagnostic significance .\",\n \"The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .\",\n \"Viral - induced P10747 loss evokes costimulation independent alloimmunity . BACKGROUND : DB06681 , a P33681 - specific fusion protein , blocks P10747 - P33681 costimulation and prevents kidney allograft rejection . However , it is ineffective in a sizable minority of patients . Although T - cell receptor and P10747 engagement are known to initiate T - cell activation , many human antigen - experienced T - cells lose P10747 , and can be activated independent of P10747 signals . We posit that these cells are central drivers of costimulation blockade resistant rejection ( CoBRR ) and propose that CoBRR might relate to an accumulation of P10747 (-) T - cells resulting from viral antigen exposure . MATERIALS AND METHODS : We infected C57BL / 6 mice with polyomavirus ( a BK virus analog ) , murine cytomegalovirus ( a human cytomegalovirus analog ) , and gammaherpesvirus ( HV68 ; an Epstein - Barr virus analog ) and assessed for P10747 expression relative to mock infection controls . We then used mixed lymphocyte reaction ( P08235 ) assays to assess the alloreactive response of these mice against major histocompatibility complex - mismatched cells . RESULTS : We demonstrated that infection with polyomavirus , murine CMV , and HV68 can induce P10747 downregulation in mice . We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic , costimulation blockade resistant , alloreactive response against major histocompatibility complex - mismatched cells without prior alloantigen exposure . Further analysis revealed that gammherpesvirus - induced oligoclonal T - cell expansion is required for the increased alloreactivity . CONCLUSIONS : Virus exposure results in reduced T - cell expression of P10747 , the target of costimulation blockade therapy . These viruses also contribute to increased alloreactivity . Thus , P10747 downregulation after viral infection may play a seminal role in driving CoBRR .\",\n \"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .\",\n \"Human umbilical cord Wharton ' s jelly stem cells : immune property genes assay and effect of transplantation on the immune cells of heart failure patients . Stem cells derived from umbilical cord Wharton ' s jelly ( WJSCs ) are not immunogenic and have immunosuppressive effects . To evaluate the related mechanisms and the effect of transplantation on body immune cells , we examined immune property genes expression in WJSCs and levels of T - lymphocytes subgroups and immunoglobulins ( Ig ) in heart failure ( HF ) patients with and without WJSCs transplantation . WJSCs express immune tolerance genes P13747 , P17693 and P30511 and immunomodulation genes P15692 , TGFβ1 , P14210 , P09601 , IL1β , P05231 , P15018 , LGALS - 1 / 3 / 8 , P23219 / 2 and PTGE , while they do not express immune response - related genes HLA - DR , HLA - DQ , HLA - DP , P33681 , P42081 , P25942 and P29965 . No obvious changes of T - lymphocytes subgroups and plasma IgG / IgM were observed in HF patients with WJSCs transplantation . Our results suggest that the immune properties of WJSCs are due to the expression of immune avoidance and immunomodulation genes in the absence of immune response - related genes . WJSCs are secure in immunological aspects when used as seed cells for cardiac repair .\",\n \"Differential inhibition of autoreactive memory - and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 ( sCTLA4 ) , DB01281 and DB06681 . Cytotoxic T lymphocyte antigen 4 ( P16410 ) is a potent inhibitory co - stimulatory molecule believed to be involved in type 1 diabetes and other autoimmune diseases . An association has been reported of both mRNA expression and serum levels of the soluble splice variant of P16410 ( sCTLA4 ) with type 1 diabetes . Furthermore , recombinant fusion proteins DB01281 and DB06681 have been proposed as therapies for type 1 diabetes . We studied the role of ( s ) P16410 in islet autoimmunity . Binding capacity of the proteins to antigen - presenting cells was determined by flow cytometry in competition and binding assays . Functionality of sCTLA4 as well as the therapeutic inhibitory fusion proteins DB01281 and DB06681 was measured in a dose - response lymphocyte stimulation test , using a panel of diabetes - associated T cell clones reactive to islet autoantigens . As controls , mixed lymphocyte reactions ( P08235 ) were performed to assess functionality of these proteins in a primary alloreactive setting . All three P16410 molecules were able to bind to antigen - presenting cells and inhibit the expression of P33681 / P42081 . sCTLA4 was able to suppress proliferation of different committed autoreactive T cell clones in a dose - dependent manner , whereas DB01281 and DB06681 were not . Conversely , DB01281 and DB06681 , rather than sCTLA4 , were able to suppress naive alloreactive proliferation in a P08235 . Our results indicate a differential role for sCTLA4 , DB01281 and DB06681 proteins in memory versus primary immune responses with implications for efficacy in intervention therapy .\",\n \"DB06681 and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion . DB06681 is an inhibitor of P10747 / P33681 costimulation that is clinically indicated as a calcineurin inhibitor ( CNI ) alternative in combination with mycophenolate mofetil and steroids after renal transplantation . We sought to develop a clinically translatable , nonlymphocyte depleting , belatacept - based regimen that could obviate the need for both CNIs and steroids . Thus , based on murine data showing synergy between costimulation blockade and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched renal allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on costimulation blockade - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . DB06681 and sirolimus therapy successfully prevented rejection in all animals . Tolerance was not induced , as animals rejected after withdrawal of therapy . The regimen did not deplete T cells . Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen , despite causing an intended depletion of memory T cells , and caused a marked reduction in regulatory T cells . Furthermore , alefacept - treated animals had a significantly increased incidence of CMV reactivation , suggesting that this combination overly compromised protective immunity . These data support belatacept and sirolimus as a clinically translatable , nondepleting , CNI - free , steroid - sparing immunomodulatory regimen that promotes sustained rejection - free allograft survival after renal transplantation .\",\n \"Linkage of protein kinase C - beta activation and intracellular interleukin - 2 accumulation in human naive P01730 T cells . A critical role for protein kinase C ( PKC ) in signal transduction events has been well established . Moreover , studies of regulation in PKC levels suggest participation in mediating long - term cellular functions . Protein kinase C - beta ( P05771 ) has been reported to be involved in interleukin - 2 ( P60568 ) synthesis in T lymphocytes . In this study , the role of P05771 in intracellular accumulation of P60568 was investigated using specific inhibitors . Preincubation with two different PKC inhibitors , one specific for classical isotypes ( alpha and beta I ) Go6976 , and one which inhibits both classical and non - classical isotypes , GF109203X , caused a complete block in cytoplasmic P60568 accumulation when naive P01730 T cells were stimulated in the presence of P06729 + P10747 + phorbol myristate acetate ( PMA ) . In contrast , preincubation with up to 1000 ng / ml of cyclosporin A ( DB00091 ) resulted in a reduction in the intracellular P60568 detected , as observed by a decrease in the proportion of positive cells as well as a fall in the mean fluorescence intensity ( MFI ) . DB00091 did not influence P05771 translocation . Flow cytometric assessments of P05771 and its isoforms beta I and beta II correlated with Western blotting analysis and these results were further supported by the use of P05771 - positive ( HUT 78 ) and - negative ( BW5147 ) T - cell lines . Using the specific inhibitors , Go6976 and GF109203X , the findings in this study suggest that activation and translocation of P05771 is critical for accumulation of intracellular P60568 . The influence of DB00091 in reducing but not blocking P60568 synthesis is discussed . PMA - induced down - regulation of the P01730 antigen was observed in the presence of Go6976 and but not GF109203X , suggesting regulation by non - classical PKC isoforms .\",\n \"P52333 activity is necessary for phosphorylation of cytosolic phospholipase A2 and prostaglandin E2 synthesis by macrophages infected with Francisella tularensis live vaccine strain . Francisella tularensis , the causative agent of tularemia , modulates the host immune response to gain a survival advantage within the host . One mechanism of immune evasion is the ability of F . tularensis to induce the synthesis of the small lipid mediator prostaglandin E2 ( DB00917 ) , which alters the host T cell response making the host more susceptible to Francisella growth . DB00917 is synthesized by a tightly regulated biosynthetic pathway following stimulation . The synthesis of DB00917 begins with the liberation of arachidonic acid ( AA ) from membrane phospholipids by cytosolic phospholipase A2 ( P47712 ) . AA is subsequently converted to the unstable intermediate PGH2 by cyclooxygenase - 2 ( P35354 ) , and PGH2 undergoes an isomerization reaction to generate DB00917 . Our objective was to identify F . tularensis - activated host signaling pathways that regulate the activity of the enzymes in the DB00917 - biosynthetic pathway . In this study , we show that P47712 , p38 mitogen - activated protein kinase ( MAPK ) , and P52333 ( P52333 ) signaling are necessary for F . tularensis - induced DB00917 production . Inhibition of P52333 activity reduced the phosphorylation of P47712 and P35354 protein levels . In addition , P52333 regulates P47712 phosphorylation independent of transcription . Moreover , p38 MAPK activity is required for F . tularensis - induced P35354 protein synthesis , but not for the phosphorylation of P47712 . This research highlights a unique signaling axis in which P52333 and p38 MAPK regulate the activity of multiple enzymes of the DB00917 - biosynthetic pathway in macrophages infected with F . tularensis .\",\n \"DB06681 : a new era of immunosuppression ? Q8N1N2 T - cell activation in alloimmunity requires the engagement of several costimulatory molecules . P16410 - Ig and its commercially available fusion proteins , belatacept and abatacept , are used to block P33681 / 86 and promote T - cell tolerance . DB06681 , a higher binding affinity molecule , is currently approved for clinical use in renal transplantation . The results of two Phase III clinical trials showed a similar patient / graft survival , with better renal function at a 3 - year follow - up compared with conventional immunosuppression . There was a higher risk of early rejection and post - transplant lymphoproliferative disorder , especially with EBV - negative patients receiving kidneys from EBV - positive donors . DB06681 - treated groups had a better cardiovascular and metabolic profile . The authors review both preclinical and human studies of P16410 - Igs .\",\n \"Safety and immunogenicity of a V3 loop synthetic peptide conjugated to purified protein derivative in HIV - seronegative volunteers . OBJECTIVES : To develop a peptide - based model for a preventive vaccine for HIV - 1 infection . DESIGN : Phase I trial in HIV - 1 - seronegative volunteers . PARTICIPANTS : Adult healthy subjects HIV - 1 - antibody - seronegative in an enzyme - linked immunosorbent assay , screened for tuberculin [ purified protein derivative ( PPD ) ] reactivity with 2 tuberculin units PPD - administered intradermally . INTERVENTIONS : Submicrogram doses of a PPD conjugate with a peptide of the primary neutralizing domain ( P01160 ) of HIV - 1MN ( PPD - MN - P01160 ) were administered intradermally to tuberculin skin - test - positive and - negative volunteers . RESULTS : Antibodies to the MN - P01160 were measured after two immunizations in 10 out of 11 PPD skin - test - positive volunteers . After the fourth immunization high - affinity antibodies were detected , which persisted for over 1 year . High titers of MN - P01160 - specific immunoglobulin ( Ig ) G and IgA were detected in the serum and saliva of all volunteers tested . Serum antibodies were cross - reactive with P01160 peptide from some other HIV - 1 strains but neutralized only the HIV - 1MN prototype . Human leukocyte antigen ( HLA ) - P33681 - restricted MN - P01160 - specific cytotoxic T lymphocytes ( CTL ) were also detected . CONCLUSIONS : The PPD - MN - P01160 vaccine at submicrogram doses is safe and immunogenic in PPD skin - test - positive healthy adult volunteers . Long lasting humoral immune responses in the serum and saliva were possibly accompanied by HLA - P33681 - restricted CTL responses . This is a vaccine prototype that can be rapidly and inexpensively modified to include other peptide epitopes . It is especially suitable for use in a worldwide multibillion Bacillus Calmette - Guérin ( BCG ) - primed or tuberculosis - exposed population at risk for HIV - 1 infection .\",\n \"[ Use of new non - nephrotoxic immunosuppressive drugs in kidney transplantation , especially after ischemia - reperfusion injury ] . Medium - and long - term renal graft survival depends on 4 main factors : the quality of the harvested graft , ischemia - reperfusion injury during harvesting and re - implantation , rejection , and the nephrotoxicity of certain drugs ( especially immunosuppressants ) used in this setting . The most nephrotoxic immunosuppressive drugs are the anticalcineurins ( cyclosporine A and tacrolimus ) , a class discovered in the late 1970s and currently representing a basic component of all immunosuppressive protocols for solid organ graft recipients . The renal tubular and vascular toxicity of anticalcineurins is due to their immunosuppressive mechanism : they block the calcineurin pathway and thereby prevent transmission of the first signal from the T cell receptor to the nucleus , which normally triggers cytokine synthesis , New non - nephrotoxic immunosuppressants are therefore needed , especially for grafts of poor quality or subject to severe ischemia - reperfusion injury . Attention is turning to \\\" old \\\" molecules such as anti - thymocyte globulins , but exciting new immunosuppressants are now appearing . DB00092 is a fusion protein that binds to the immunological synapse - associated molecule P06729 , which normally interacts with LFA - 3 . DB06681 , another fusion protein , blocks the T cell second signal CD 28 - P33681 . 1 / P33681 . 2 . Finally , new chemical agents are being developed , such as sautrasporine , a tyrosine kinase inhibitor , and tofacitinib , a Jak inhibitor .\",\n \"Costimulatory blockade with belatacept in clinical and experimental transplantation - a review . BACKGROUND : Current maintenance immunosuppression agents have been critical to the improved graft and patient survival rates in solid organ transplantation observed over the past decade . However , long - term follow - up has revealed that these agents are associated with troublesome side effects and chronic toxicity , contributing to graft loss and death . OBJECTIVES : Costimulation blockade has long been recognized as an important target for immunomodulation in solid organ transplantation . DB06681 , a high - affinity chimeric fusion protein that binds to P33681 / P42081 on antigen - presenting cells , has shown great promise in renal transplantation and is now in Phase III trials . METHODS : This review explores the development and efficacy of belatacept , compared with currently approved immunosuppressive agents used in transplantation . RESULTS : DB06681 seems to be an effective alternative to current maintenance immunosuppressive therapies , with no apparent end organ toxicity and a minimal side - effect profile . This agent works best when used in combination with therapies that target different pathways of T - cell activation , but the optimal regimen has not yet been identified . Data generated in ongoing clinical trials will be essential in validating previous studies and for further development of belatacept - based combinatorial strategies .\",\n \"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK100___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK100___ is also being investigated as part of triplet drug regimens . ___MASK100___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .\",\n \"___MASK88___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK88___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK88___ is a promising pharmacological tool in the treatment of renal edema .\",\n \"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK20___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK20___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK20___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK20___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .\",\n \"Neonatal estrogen exposure disrupts uterine development in the postnatal sheep . Postnatal development of the ovine uterus between birth and postnatal day ( P01160 ) 56 involves budding differentiation of the endometrial glandular epithelium from the luminal epithelium ( LE ) followed by extensive coiling and branching morphogenesis of the tubular glands . To determine the short - and long - term effects of estrogen on neonatal ovine uterine development after P01160 14 , neonatal sheep were randomly assigned at birth ( P01160 0 ) to be treated daily with estradiol - 17beta benzoate ( EB ; 0 , 0 . 01 , 0 . 1 , 1 , or 10 microg / kg body weight . d ) during one of two developmental periods ( P01160 14 - 27 or 42 - 55 ) . All ewes were hemiovariohysterectomized at the end of EB treatment on either P01160 28 or 56 , and the remaining uterine horn and ovary removed on P01160 112 . Immediate responses to EB treatment included dose - and age - dependent increases in uterine wet weight , thickness of the endometrium , myometrium , and LE , but decreases in endometrial glands on P01160 28 and 56 . Transient exposure to EB decreased gland number and thickness of the endometrium and LE on P01160 112 but did not affect extrauterine reproductive tract structures . The mechanism of estrogen inhibition of uterine development did not involve effects on cell proliferation . Real - time PCR analyses found that EB exposure disrupted normal patterns of growth factor ( P05019 , P01344 , fibroblast growth factor - 7 , fibroblast growth factor - 10 , and hepatocyte growth factor ) and receptor mRNA expression in the uterus . Transient exposure of the neonatal ewe to estrogens during critical periods specifically alters growth factor networks that perturb normal development of the uterus , leading to permanent alterations in uterine structure and function .\",\n \"DB01645 enhancement of respiratory allergen trimellitic anhydride - induced IgE production by adult B6C3F1 mice following in utero and postnatal exposure . The objective of the present study was to determine if exposure to the phytoestrogen genistein ( GEN ) during immune development had any effects on the production of IgE by adult mice following dermal treatment with trimellitic anhydride ( TMA ) , a respiratory allergen . B6C3F1 mice were exposed to GEN either by feeding at 500 ppm or by gavage ( 20 mg / kg ) for varied periods from gestation day ( GD ) 14 to postnatal day ( P01160 ) 84 . In utero exposure to GEN by feeding increased the production of IgE at P01160 84 in male mice but not in female mice . In male mice , continuous exposure to GEN postnatally diminished the in utero exposure - induced enhancement in serum total IgE production . However , continuous exposure to GEN from GD 14 to P01160 84 was required to increase serum total IgE production in female mice . In utero exposure to GEN by gavage increased the production of IgE at P01160 84 in female mice but not in male mice when the mice were maintained on the NIH - 07 rodent diet in which a medium level of phytoestrogens was present . The enhancement in IgE production after GEN exposure in females but not in males was associated with decreases in the percentages of P01730 (+) CD25 (+) T suppressor cells , and increases in the natural killer ( NK ) cell activity , the basal splenocyte proliferation , the expression of P42081 by B cells , and the production of P60568 and P05112 . Overall , the results demonstrated that GEN differentially modulated the developing immune system in male and female mice , and that more IgE was produced upon exposure to TMA in the adult .\",\n \"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK84___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .\",\n \"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK7___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .\",\n \"Expression of cyclooxygenase - 2 in urinary bladder in rats with cyclophosphamide - induced cystitis . These studies examined the expression of cyclooxygenase - 2 ( P35354 ) expression in the urothelium and suburothelial space and detrusor from rats treated with cyclophosphamide ( CYP ) to induce acute ( 4 h ) , intermediate ( 48 h ) , or chronic ( 10 - day ) cystitis . Western blot analysis and immunohistochemistry were used to demonstrate P35354 expression . In whole mount preparations of urinary bladder , nerve fibers in the suburothelial plexus , and inflammatory cell infiltrates were characterized for P35354 expression after CYP - induced cystitis . P35354 expression significantly ( P < or = 0 . 01 ) increased in the urothelium + suburothelium and detrusor smooth muscle with acute , intermediate , and chronic ( 10 - day ) CYP - induced cystitis , but expression in urothelium + suburothelium was significantly greater . CYP - induced upregulation of P35354 showed by immunostaining in the urothelium + suburothelium was similar to that observed with Western blot analysis and also demonstrated P35354 inflammatory cell infiltrates ( P42081 + ) and nerve fibers ( A6NDG6 + ) in the suburothelial plexus . Although P35354 expression was significantly ( P < or = 0 . 01 ) increased in detrusor smooth muscle , immunohistochemistry failed to demonstrate an obvious change in P35354 - immunoreactivity ( IR ) in detrusor muscle , but P35354 inflammatory infiltrates were present throughout the detrusor . P35354 - IR nerve fibers exhibited increased density in the suburothelial plexus with acute or chronic CYP - induced cystitis . P35354 - IR macrophages ( P42081 + ) were present throughout the urinary bladder with acute and chronic CYP - induced cystitis . These studies demonstrate cellular targets in the urinary bladder where P35354 inhibitors may act .\",\n \"Human Lung Mast Cell Products Regulate Airway Smooth Muscle P02778 Levels . In asthma , the airway smooth muscle ( P17405 ) produces P02778 which may attract P49682 (+) mast / T cells to it . Our aim was to investigate the effects of mast cell products on P17405 cell P02778 production . P17405 cells from people with and without asthma were stimulated with IL - 1 β , P01375 - α , and / or IFN γ and treated with histamine ( 1 - 100 μ M ) ± chlorpheniramine ( P35367 antagonist ; 1 μ M ) or ranitidine ( P25021 antagonist ; 50 μ M ) or tryptase ( 1 nM ) ± leupeptin ( serine protease inhibitor ; 50 μ M ) , heat - inactivated tryptase , or vehicle for 4 h or 24 h . Human lung mast cells ( MC ) were isolated and activated with IgE / anti - IgE and supernatants were collected after 2 h or 24 h . The supernatants were added to P17405 cells for 48 h and P17405 cell P02778 production detected using ELISA ( protein ) and real - time PCR ( mRNA ) . DB11320 reduced IL - 1 β / P01375 - α - induced P02778 protein , but not mRNA , levels independent of H1 and H2 receptor activation , whereas tryptase and MC 2 h supernatants reduced all cytokine - induced P02778 . Tryptase also reduced P02778 levels in a cell - free system . Leupeptin inhibited the effects of tryptase and MC 2 h supernatants . MC 24 h supernatants contained P01375 - α and amplified IFN γ - induced P17405 cell P02778 production . This is the first evidence that MC can regulate P17405 cell P02778 production and its degradation . Thus MC may regulate airway myositis in asthma .\",\n \"Co - signals in organ transplantation . PURPOSE OF REVIEW : The nonimmune effects of currently used immunosuppressive drugs result in a high incidence of late graft loss due to nephrotoxicity and death . As an immune - specific alternative to conventional immunosuppressants , new biotechnology tools can be used to block the costimulation signal of T - cell activation . RECENT FINDINGS : Many experimental studies , particularly preclinical studies in nonhuman primates , have focused on blocking ' classical ' P33681 / P10747 and P25942 / P29965 pathways , which are critical in primary T - cell activation , but also on new P33681 / P10747 and P01375 / P01375 - R pathways families of costimulatory molecules that can deliver positive or negative costimulation signals to regulate the alloimmune response . SUMMARY : DB06681 is a new fusion protein derived from P16410 - Ig that can be used to prevent acute rejection in renal transplantation instead of calcineurin inhibitors . DB06681 can also prevent acute rejection efficiently in humans and , more interestingly , can improve renal function and cardiovascular risk factors in this population .\",\n \"DB11320 H3 receptors aggravate cerebral ischaemic injury by histamine - independent mechanisms . The role of the histamine H3 receptor ( Q9Y5N1 ) in cerebral ischaemia / reperfusion ( I / R ) injury remains unknown . Here we show that Q9Y5N1 expression is upregulated after I / R in two mouse models . Q9Y5N1 antagonists and Q9Y5N1 knockout attenuate I / R injury , which is reversed by an Q9Y5N1 - selective agonist . Interestingly , P35367 and P25021 antagonists , a histidine decarboxylase ( HDC ) inhibitor and HDC knockout all fail to compromise the protection by Q9Y5N1 blockade . Q9Y5N1 blockade inhibits P42345 phosphorylation and reinforces autophagy . The neuroprotection by Q9Y5N1 antagonism is reversed by 3 - methyladenine and siRNA for Atg7 , and is diminished in Atg5 ⁻/⁻ mouse embryonic fibroblasts . Furthermore , the peptide Tat - Q9Y5N1 ( CT414 - 436 ) , which blocks Q9Y696 binding with H3Rs , or siRNA for Q9Y696 , further increases I / R - induced autophagy and protects against I / R injury . Therefore , Q9Y5N1 promotes I / R injury while its antagonism protects against ischaemic injury via histamine - independent mechanisms that involve suppressing Q9Y5N1 / Q9Y696 binding - activated autophagy , suggesting that Q9Y5N1 inhibition is a therapeutic target for cerebral ischaemia .\",\n \"P25942 activation induces p53 - dependent vascular endothelial growth factor secretion in human multiple myeloma cells . It was previously demonstrated that p53 status in human multiple myeloma ( MM ) cells regulates distinct cell cycle responses to P25942 activation . In this study , the production of vascular endothelial growth factor ( P15692 ) and migration in MM cells triggered by P25942 activation was examined , and the influence of p53 status in regulating this process was determined . Two human MM cell lines that express wild - type p53 at permissive ( 28 degrees C ) and mutant p53 at restrictive ( 37 degrees C ) temperatures were used as a model system . P25942 activation induces a 4 - fold ( RPMI 8226 ) and a 6 - fold ( SV ) increase in P15692 transcripts , respectively , under restrictive , but not permissive , temperatures . P15692 expression is significantly induced after P25942 activation in patient MM cells expressing mutant p53 . Increased P15692 transcripts result in increased protein and secretion levels , as evidenced by immunoblotting and enzyme - linked immunosorbent assay . In a double - chamber transmigration assay , P25942 activation of MM cells induced a 3 - fold ( RPMI 8226 ) and a 5 - fold ( SV ) increase in migration under restrictive , but not permissive , conditions . A 2 - to 8 - fold induction in migration of patient MM cells expressing mutant p53 was similarly observed . Transduction of MM cells with a luciferase reporter under the control of a human P15692 promoter further indicated that P25942 - induced P15692 expression was mediated through a transcriptional control mechanism . Finally , adenovirus - mediated wild - type p53 overexpression down - regulated P25942 - induced P15692 expression and transmigration in MM cells expressing mutant p53 . These studies demonstrate that P25942 induces P15692 secretion and MM cell migration , suggesting a role for P25942 in regulating MM homing and angiogenesis .\",\n \"Mesenchymal stem cells control alloreactive CD8 (+) P10747 (-) T cells . P10747 / P33681 co - stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients . However , cells lacking P10747 are not susceptible to belatacept treatment . As CD8 (+) P10747 (-) T - cells have cytotoxic and pathogenic properties , we investigated whether DB05914 ( O60682 ) are effective in controlling these cells . In mixed lymphocyte reactions ( P08235 ) , O60682 and belatacept inhibited peripheral blood mononuclear cell ( PBMC ) proliferation in a dose - dependent manner . O60682 at O60682 / effector cell ratios of 1 : 160 and 1 : 2 · 5 reduced proliferation by 38 · 8 and 92 · 2 % , respectively . DB06681 concentrations of 0 · 1 μg / ml and 10 μg / ml suppressed proliferation by 20 · 7 and 80 · 6 % , respectively . Both treatments in combination did not inhibit each other ' s function . Allostimulated CD8 (+) P10747 (-) T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B , interferon ( IFN ) - γ and tumour necrosis factor ( P01375 ) - α . While belatacept did not affect the proliferation of CD8 (+) P10747 (-) T cells , O60682 reduced the percentage of P10747 (-) T cells in the proliferating CD8 (+) T cell fraction by 45 · 9 % ( P = 0 · 009 ) . CD8 (+) P10747 (-) T cells as effector cells in P08235 in the presence of P01730 (+) T cell help gained P10747 expression , an effect independent of O60682 . In contrast , allostimulated P10747 (+) T cells did not lose P10747 expression in P08235 - O60682 co - culture , suggesting that O60682 control pre - existing P10747 (-) T cells and not newly induced P10747 (-) T cells . In conclusion , alloreactive CD8 (+) P10747 (-) T cells that remain unaffected by belatacept treatment are inhibited by O60682 . This study indicates the potential of an O60682 - belatacept combination therapy to control alloreactivity .\",\n \"Challenges and opportunities in targeting the costimulation pathway in solid organ transplantation . Signaling through the costimulatory pathway is critical in the regulation of T cell activation . DB01281 , a selective costimulatory antagonist FDA approved for the treatment of moderate to severe rheumatoid arthritis , binds to P33681 and P42081 on antigen presenting cells , blocking the interaction with P10747 on T cells . DB06681 , a second generation P16410 - Ig with 2 amino acid substitutions , has shown considerable promise in clinical transplantation as part of a maintenance immunosuppression regimen . This review will summarize the role of costimulation in T cell activation , detail the development of costimulation antagonists and highlight the pertinent clinical trials completed and ongoing utilizing belatacept as part of an immunosuppressive regimen in organ transplantation .\",\n \"Generation and Molecular Mapping of a Sequence Characterized Amplified Region Marker Linked with the Bct Gene for Resistance to Beet curly top virus in Common Bean . ABSTRACT A random amplified polymorphic DNA ( RAPD ) marker directly linked ( 0 . 0 cM ) with a resistance gene was identified in a snap bean recombinant inbred population ( Moncayo x Primo ) consisting of 94 F ( 5 : 7 ) recombinant inbred lines that had uniform segregation for disease reaction to Beet curly top virus ( BCTV ) across three field locations . Resistance was conditioned by a single dominant allele tentatively designated Bct . Seven hundred and fifty decamer primers were screened to obtain the linked RAPD marker that was then converted to a sequence characterized amplified region ( P62701 ) marker SAS8 . 1550 . The P62701 mapped within a cluster of resistance genes on linkage group P33681 of the core map . A survey of 103 BCTV - resistant and - susceptible snap and dry bean genotypes was conducted using SAS8 . 1550 . Results showed that the P62701 would be highly useful for marker - assisted selection of Bct in snap and dry bean originating from the Andean gene pool . Marker - assisted selection for Bct will expedite the development of BCTV - resistant cultivars and minimize the need for cumbersome pathogen tests .\",\n \"Five - year safety and efficacy of belatacept in renal transplantation . DB06681 is a first - in - class co - stimulation blocker in development for primary maintenance immunosuppression . A Phase II study comparing belatacept with cyclosporine ( DB00091 ) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured Q92565 at 1 year for belatacept , but the incidence of posttransplantation lymphoproliferative disorder was higher . Here , we present the results for the extension of this trial , which aimed to assess long - term safety and efficacy of belatacept . Seventy - eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving DB00091 completed the long - term extension period . Q92565 remained stable in patients who were receiving belatacept for 5 years , and the incidences of death / graft loss or acute rejection were low . The frequencies of serious infections were 16 % for belatacept and 27 % for DB00091 , and neoplasms occurred in 12 % of each group . No patients who were treated with belatacept and one patient who was treated with DB00091 developed posttransplantation lymphoproliferative disorder during the follow - up period . Serious gastrointestinal disorders occurred more frequently with belatacept ( 12 % belatacept versus 8 % DB00091 ) , and serious cardiac disorders occurred more frequently with DB00091 ( 2 % belatacept versus 12 % DB00091 ) . Pharmacokinetic analyses showed consistent exposure to belatacept over time . P42081 receptor saturation was higher in patients who were receiving belatacept every 4 weeks ( 74 % ) compared with every 8 weeks ( 56 % ) . In conclusion , this study demonstrated high patient persistence with intravenous belatacept , stable renal function , predictable pharmacokinetics , and good safety with belatacept over 5 years .\",\n \"Rational development of DB06681 ( belatacept ) , a high - affinity variant of P16410 - Ig with potent immunosuppressive properties . Current success in organ transplantation is dependent upon the use of calcineurin - inhibitor - based immunosuppressive regimens . Unfortunately , current immunotherapy targets molecules with ubiquitous expression resulting in devastating non - immune side effects . T - cell costimulation has been identified as a new potential immunosuppressive target . The best characterized pathway includes P10747 , its homologue P16410 and their ligands P33681 and P42081 . While an immunoglobulin fusion protein construct of P16410 suppressed rejection in rodents , it lacked efficacy in primate transplant models . In an attempt to increase the biologic potency of the parent molecule a novel , modified version of P16410 - Ig , DB06681 ( belatacept ) , was constructed . Two amino acid substitutions ( L104E and A29Y ) gave rise to slower dissociation rates for both P42081 and P33681 . The increased avidity resulted in a 10 - fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre - clinical primate model . The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants .\",\n \"T - cell phenotype in protocol renal biopsy from transplant recipients treated with belatacept - mediated co - stimulatory blockade . BACKGROUND : DB06681 is thought to disrupt the interaction between P33681 / 86 and P10747 , thus preventing T - cell activation by blocking the co - stimulatory second signal . However , the consequences on the T - cell profile in human renal transplant cases have not been determined . METHODS : In this study , we analysed intra - graft levels of the mRNAs for Treg ( Q9BZS1 ) , cytotoxic CD8 T cells ( P10144 ) , Th1 ( INFγ , Tbet ) , Th2 ( P23771 ) and Th17 ( RORγt and Q16552 ) in protocol biopsies obtained 12 months after renal transplantation in recipients treated with DB06681 or calcineurin inhibitor ( CNI ) . RESULTS : Only the intra - graft abundance of Q9BZS1 mRNA was significantly lower ( P < 0 . 001 ) in the DB06681 group than the CNI group . Conclusions . These results are in agreement with in vitro data suggesting that P10747 is a major co - stimulatory signal of both Tregs development and peripheral homeostasis but contrast with clinical trials showing a better 1 - year graft function and a lower incidence of chronic allograft nephropathy in patients receiving DB06681 than patients treated with CNI . They suggest that immune benefits induced by DB06681 are not mediated by Treg expansion and that Q9BZS1 is not by itself a prognostic marker of long - term graft function in a non - inflammatory context . These results have to be , however , considered as preliminary since the size of our study population is limited .\",\n \"Biomedical nanoparticles modulate specific P01730 + T cell stimulation by inhibition of antigen processing in dendritic cells . Understanding how nanoparticles may affect immune responses is an essential prerequisite to developing novel clinical applications . To investigate nanoparticle - dependent outcomes on immune responses , dendritic cells ( DCs ) were treated with model biomedical poly ( vinylalcohol )- coated super - paramagnetic iron oxide nanoparticles ( P32926 - SPIONs ) . P32926 - SPIONs uptake by human monocyte - derived DCs ( MDDCs ) was analyzed by flow cytometry ( FACS ) and advanced imaging techniques . Viability , activation , function , and stimulatory capacity of MDDCs were assessed by FACS and an in vitro P01730 + T cell assay . P32926 - SPION uptake was dose - dependent , decreased by lipopolysaccharide ( LPS ) - induced MDDC maturation at higher particle concentrations , and was inhibited by cytochalasin D pre - treatment . P32926 - SPIONs did not alter surface marker expression ( P33681 , Q01151 , P42081 , myeloid / plasmacytoid DC markers ) or antigen - uptake , but decreased the capacity of MDDCs to process antigen , stimulate P01730 + T cells , and induce cytokines . The decreased antigen processing and P01730 + T cell stimulation capability of MDDCs following P32926 - SPION treatment suggests that MDDCs may revert to a more functionally immature state following particle exposure .\",\n \"Costimulation blockade in autoimmunity and transplantation . Signaling through the costimulation receptors is a critical pathway in the regulation of T - cell activation . The selective costimulation inhibitor abatacept ( cytotoxic T lymphocyte - associated antigen 4 - Ig ) binds to P33681 and P42081 on antigen - presenting cells , blocking interaction with P10747 on T cells , and is approved for the treatment of moderate to severe rheumatoid arthritis . DB06681 ( DB06681 ) , currently enrolling phase III trials in renal transplantation , was rationally designed from abatacept to bind with more avidity to P42081 , providing the more potent immunosuppressive properties required for immunosuppression in transplantation . This review describes the relevant preclinical studies and summarizes recent clinical findings on these 2 molecules in autoimmune diseases and organ transplantation . Although both inhibit the P10747 costimulatory pathway , they are tailored for specific disease states -- abatacept for autoimmune diseases and belatacept for transplantation .\",\n \"Technology evaluation : DB06681 , Bristol - Myers Squibb . Bristol - Myers Squibb is developing belatacept , a soluble fusion protein of the P33681 - binding domain of P16410 with amino acid changes A29Y and L104E and an Ig tail , which inhibits lymphocyte co - stimulation through P10747 , for the potential treatment of solid organ transplant rejection . DB06681 is currently undergoing phase III clinical trials .\",\n \"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK63___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .\",\n \"DB06681 and sirolimus prolong nonhuman primate islet allograft survival : adverse consequences of concomitant alefacept therapy . Calcineurin inhibitors ( CNI ) and steroids are known to promote insulin resistance , and their avoidance after islet transplantation is preferred from a metabolic standpoint . DB06681 , a P33681 - specific mediator of costimulation blockade ( CoB ) , is clinically indicated as a CNI alternative in renal transplantation , and we have endeavored to develop a clinically translatable , belatacept - based regimen that could obviate the need for both CNIs and steroids . Based on the known synergy between CoB and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched islet allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on CoB - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . Nine rhesus macaques were rendered diabetic with streptozotocin and underwent islet allotransplantation . All received belatacept and sirolimus ; six also received alefacept . DB06681 and sirolimus significantly prolonged rejection - free graft survival ( median 225 days compared to 8 days in controls receiving basiliximab and sirolimus ; p = 0 . 022 ) . The addition of alefacept provided no additional survival benefit , but was associated with Cytomegalovirus reactivation in four of six animals . No recipients produced donor - specific alloantibodies . The combination of belatacept and sirolimus successfully prevents islet allograft survival in rhesus monkeys , but induction with alefacept provides no survival benefit and increases the risk of viral reactivation .\",\n \"Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .\",\n \"Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing P04626 . In an attempt to treat cancer patients with P04626 overexpressing tumors , we developed a chimeric antigen receptor ( CAR ) based on the widely used humanized monoclonal antibody ( mAb ) ___MASK100___ ( Herceptin ) . An optimized CAR vector containing P10747 , 4 - 1BB , and CD3zeta signaling moieties was assembled in a gamma - retroviral vector and used to transduce autologous peripheral blood lymphocytes ( PBLs ) from a patient with colon cancer metastatic to the lungs and liver , refractory to multiple standard treatments . The gene transfer efficiency into autologous T cells was 79 % CAR (+) in CD3 (+) cells and these cells demonstrated high - specific reactivity in in vitro coculture assays . Following completion of nonmyeloablative conditioning , the patient received 10 ( 10 ) cells intravenously . Within 15 minutes after cell infusion the patient experienced respiratory distress , and displayed a dramatic pulmonary infiltrate on chest X - ray . She was intubated and despite intensive medical intervention the patient died 5 days after treatment . Serum samples after cell infusion showed marked increases in interferon - gamma ( P01579 ) , granulocyte macrophage - colony stimulating factor ( GM - P04141 ) , tumor necrosis factor - alpha ( P01375 ) , interleukin - 6 ( P05231 ) , and P22301 , consistent with a cytokine storm . We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of P04626 on lung epithelial cells .\",\n \"Selective measurement of white matter and gray matter diffusion trace values in normal human brain . The trace of the diffusion tensor ( or simply the trace ) is diagnostically valuable for detecting acute ischemic lesions . A number of studies indicate that the trace of human gray matter ( GM ) and white matter ( WM ) are quite similar . This is somewhat surprising considering the different cellular environments of GM and WM . It is possible that partial volume averaging ( P32926 ) effects between GM and WM , inherent in many of the ultrafast imaging sequences used for diffusion measurements , are responsible for this observation . In order to minimize P32926 effects , the trace values of GM and WM have been selectively measured by implementing double inversion recovery ( P30518 ) echo planar imaging ( P10646 ) pulse sequences . Results on six normal volunteers indicate that the trace values of WM and GM are not statistically different .\",\n \"[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .\",\n \"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK69___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .\",\n \"Synergistic activity of ixabepilone plus other anticancer agents : preclinical and clinical evidence . DB04845 demonstrates marked synergistic activity in combination with capecitabine , which served as the rationale for the evaluation of this combination in the clinic . DB04845 plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer ( MBC ) progressing after treatment with an anthracycline and a taxane ; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy . An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab , bevacizumab , brivanib , and cetuximab ; with immune - modulating agents such as anti - P16410 antibody ; and with other chemotherapy drugs such as irinotecan and epirubicin . Notably , experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab - paclitaxel combined with bevacizumab . These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in P04626 - positive breast cancer ; with bevacizumab in breast cancer , endometrial cancer , renal cancer , and non - small cell lung cancer ( NSCLC ) ; with cetuximab in breast cancer , NSCLC , and pancreatic cancer ; and with brivanib , dasatinib , sorafinib , sunitinib , or vorinostat in MBC . Preliminary results from several of these trials suggest that ixabepilone - based combinations have promising anticancer activity .\",\n \"Electrostatic modeling of peptides derived from the V3 - loop of HIV - 1 gp120 : implications of the interaction with chemokine receptor P51681 . Infection of P01730 + T cells by macrophage - tropic HIV - 1 strains involves interaction of viral gp120 with the host cell chemokine receptor P51681 . The principle neutralizing determinant ( P01160 ) of the V3 - loop of the HIV - 1 gp120 was investigated for its interaction with P51681 by computational modeling methods at atomic resolution and electrostatic calculations to complement experimental findings . The study focused on the recognition step and examined possible peptide - peptide interactions between various P01160 - derived peptides from the V3 - loop and the N - terminal ( Nt ) domain of P51681 . These recognition interactions are possible because of the complementary character of the spatial distribution of the predominantly positive electrostatic potentials of the P01160 - derived peptides and the predominantly negative electrostatic potential of the CCR5Nt domain . The CCR5Nt appears more amenable to interaction with the V3 peptides , than the other P51681 extracellular domains ( ECL ) , because of its length and the domination of its negative electrostatic potential . On the contrary , ECL2 possesses a predominantly positive electrostatic potential . There are positive patches in Nt and negative patches in ECL2 , which , following the non - specific recognition of the V3 - loop by P51681 and with the expected local structural rearrangements to facilitate specific binding , may be contributing to the stabilization of the complex . A sequential two - step specific binding , involving different extracellular domains , is conceivable . Although the electrostatic potentials may play a role in a V3 - P51681 interaction , a more specific model can not be derived in the absence of a three - dimensional structure of a gp120 / P01730 / P51681 complex .\",\n \"What ' s in the pipeline ? New immunosuppressive drugs in transplantation . In the pipeline , there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials . The major target of new agents are cell - surface molecules important in immune cell interactions ( especially the costimulatory pathway ) , signaling pathways that activate T cells , T - cell proliferation and trafficking and recruitment of immune cells responsible for rejection . The most promising biologic agents include a humanized anti - CD11a ( anti - LFA1 ) , humanized anti - P33681 . 1 / P33681 . 2 , a second - generation DB01281 ( DB06681 ) and a humanized antibody to anti - P08575 RB . Inhibitors of T - cell activation and signaling are still in preclinical development . The most interesting inhibitors of T - cell proliferation include inhibitors of the Janus protein tyrosine kinase , P52333 , and FK778 , a leflunomide analog . Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes . Early trials of FTY720 , a synthetic small molecule with functional homology to sphingosine - 1 phosphate leading to lymphocyte sequestration , appear very promising ; however , enthusiasm for this drug is mitigated by its potential cardiac side - effects . Antagonists to several chemokine receptors , including P32246 , P49682 and P51681 , have been shown to be effective in experimental transplantation and are likely to be considered for clinical development .\",\n \"Introduction to the use of belatacept : a fusion protein for the prevention of posttransplant kidney rejection . The development of new immunosuppressive drugs for kidney transplantation resulted both in better short - term outcomes and in decreased metabolic , cardiovascular , and nephrotoxicity risk . DB06681 belongs to a new class of immunosuppressive drugs that selectively inhibits T - cell activation by preventing P10747 activation and by binding its ligands P33681 - 1 and P33681 - 2 . The result is an inactivation of costimulatory pathways . A comparative analysis of the BENEFIT and BENEFIT - EXT datasets showed belatacept regimens resulted in better cardiovascular and metabolic risk profiles than did cyclosporin A ( DB00091 ) regimens : belatacept likewise outperformed DB00091 in terms of lower blood pressure and serum lipids and less new onset diabetes after transplantation . About 20 % of belatacept - treated patients developed adverse effects which included anemia , pyrexia , neutropenia , diarrhea , urinary tract infection , headache , and peripheral edema . At present , belatacept does not seem to predispose patients to a higher rate of infection than DB00091 maintenance immunosuppression . The risk of posttransplant lymphoproliferative diseases was higher in Epstein - Barr virus ( EBV ) - seronegative patients than in EBV - seropositive patients , but the risk may be reduced by use of a less intensive regimen and avoidance of EBV - negative patients and of patients whose pretransplant EBV serology is unknown . DB06681 provides a new option for immunosuppressive therapy in kidney transplantation , but needs further evaluation in terms of the late effects that may derive from prolonged blockage of the costimulatory system and the induction of tolerance status .\",\n \"Chronic induction . What ' s new in the pipeline . Induction therapy with biological agents was introduced the in the 1970s and the rationale , concepts and approach have remained almost unchanged for 30 years . However , the novel biological agents being developed for induction therapy are being designed for chronic rather than short - term therapy with several objectives : reduce dependence on toxic and nephrotoxic agents , improve outcome and ultimately facilitate the emergence of tolerance . The biological agents include efalizumab , a humanized anti - CD11a ( anti - LFA1 ) , anti - CD154 , anti - P25942 , a number of agents targeting P40933 and its receptor , and costimulation blockade with humanized antibodies to P33681 / P42081 and the fusion receptor protein DB06681 , a second generation DB01281 . The past decade has witnessed an unprecedented number of small molecules / oral drugs that have been developed and approved for renal transplantation ; the next decade , however , may witness the emergence of a new class of biological induction agents that may displace some of the currently used drugs .\",\n \"___MASK69___ inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : ___MASK69___ is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti - cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 / 2 ) and P45983 and 2 ( JNK 1 / 2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound - healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC ( 50 ) = 8 . 6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 / 2 expression , upregulation of p - P45983 / 2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .\",\n \"[ Use of P30518 - PCR for elaboration of molecular markers of intraspecies bacterial groups as exemplified by Bacillus thuringiensis ] . A recently developed PCR - fingerprinting method , the so - called P30518 ( diverged inverted repeats ) - PCR , was used for quick search for molecular markers of Bacillus thuringiensis subspecies carrying the cry1 genes . The analysis of the fingerprints obtained by this method made it possible to reveal PCR fragments characteristic of the subspecies that produce proteins toxic for insects of the order Lepidoptera . Cloning and sequencing of these fragments allowed systems of P62701 ( sequence characterized amplified region ) primers to be designed , which are specific to the above group of B . thuringiensis strains . Comparison of the specific fragments with sequences available in the GenBank database revealed their homology with the rpoC gene family and the adjacent spacer region , suggesting chromosomal localization of these markers . This increases the reliability of the designed system of P62701 primers , because plasmids may be lost or transferred by transformation between closely related strains . It was demonstrated that the P30518 - PCR method allows markers to be developed that are linked to diagnostic genotypic and phenotypic characteristics of bacteria .\",\n \"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK63___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .\",\n \"Advances in immunosuppression for kidney transplantation : new strategies for preserving kidney function and reducing cardiovascular risk . The development of new immunosuppressants for renal transplantation is aimed not only at improving & nbsp ; short - term outcomes , but also at achieving better safety , cardiovascular , and metabolic profiles and at decreasing & nbsp ; nephrotoxicity . DB06681 is a fusion protein that inhibits T cell activation by binding to P33681 and P42081 antigens . Clinical trials , particularly the BENEFIT and BENEFIT - EXT studies , have shown that belatacept preserves function and structure in renal grafts . The effects of belatacept provide long - term , sustained results , and the safety and efficacy of this drug have been demonstrated in cases of renal transplantation from expanded criteria donors . Compared to calcineurin inhibitors , belatacept is associated with a lower incidence of chronic allograft nephropathy and a more favourable cardiovascular and metabolic profile .\",\n \"P40933 augments antitumoral activity of an ErbB2 / P04626 cancer vaccine targeted to professional antigen - presenting cells . Targeted delivery of tumor - associated antigens to professional antigen - presenting cells ( P25054 ) is being explored as a strategy to enhance the antitumoral activity of cancer vaccines . Here , we generated a cell - based system for continuous in vivo production of a P16410 - ErbB2 fusion protein as a therapeutic vaccine . The chimeric P16410 - ErbB2 molecule contains the extracellular domain of P16410 for specific targeting to costimulatory P33681 molecules on the surface of P25054 , genetically fused to residues 1 - 222 of human ErbB2 ( P04626 ) as an antigenic determinant . In wild - type BALB / c mice , inoculation of syngeneic epithelial cells continuously secreting the P16410 - ErbB2 fusion vaccine in the vicinity of subcutaneously growing ErbB2 - expressing renal cell carcinomas resulted in the rejection of established tumors , accompanied by the induction of ErbB2 - specific antibodies and cytotoxic T cells . In contrast , treatment with P16410 - ErbB2 vaccine - secreting producer cells alone was insufficient to induce tumor rejection in ErbB2 - transgenic WAP - Her - 2 F1 mice , which are characterized by pronounced immunological tolerance to the human self - antigen . When P16410 - ErbB2 producer cells were modified to additionally secrete interleukin ( IL ) - 15 , antigen - specific antitumoral activity of the vaccine in WAP - Her - 2 F1 mice was restored , documented by an increase in survival , and marked inhibition of the growth of established ErbB2 - expressing , but not antigen - negative tumors . Our results demonstrate that continuous in vivo expression of an P25054 - targeted ErbB2 fusion protein results in antigen - specific immune responses and antitumoral activity in tumor - bearing hosts , which is augmented by the pleiotropic cytokine P40933 . This provides a rationale for further development of this approach for specific cancer immunotherapy .\",\n \"Pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept in adult kidney transplant recipients . BACKGROUND AND OBJECTIVES : DB06681 is a first - in - class , selective co - stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients . The objective of this study was to report the pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept . METHODS : The pharmacokinetics , pharmacodynamics ( P42081 receptor occupancy ) , and immunogenicity of belatacept were studied in de novo adult kidney transplant recipients in phase II and III clinical studies . RESULTS : Following multiple doses of 5 or 10 mg / kg , the geometric mean ( percentage coefficient of variation ) maximum serum concentration and area under the serum concentration - time curve over one dosing interval of belatacept were 136 ( 20 % ) and 238 ( 27 % ) μg / mL , and 13 , 587 ( 27 % ) and 21 , 241 ( 35 % ) μg · h / mL , respectively . The median belatacept elimination half - life was 8 - 9 days . DB06681 exhibited concentration - dependent binding to P42081 receptors . The pre - dose P42081 receptor occupancy by belatacept decreased from 94 to 65 % between day 5 and 1 year post - transplant , with corresponding pre - dose trough serum concentrations of belatacept decreasing from ~ 35 to 4 μg / mL during this period . The cumulative incidence of developing anti - belatacept antibodies was 5 . 3 % up to 3 years post - transplant and had no impact on belatacept exposure . CONCLUSIONS : DB06681 in adult kidney transplant demonstrated linear pharmacokinetics with low variability , concentration - dependent pharmacodynamics , and a low incidence of anti - drug antibodies .\",\n \"Dietary phytochemicals alter epigenetic events and signaling pathways for inhibition of metastasis cascade : phytoblockers of metastasis cascade . Cancer metastasis is a multistep process in which a cancer cell spreads from the site of the primary lesion , passes through the circulatory system , and establishes a secondary tumor at a new nonadjacent organ or part . Inhibition of cancer progression by dietary phytochemicals ( DPs ) offers significant promise for reducing the incidence and mortality of cancer . Consumption of DPs in the diet has been linked to a decrease in the rate of metastatic cancer in a number of preclinical animal models and human epidemiological studies . DPs have been reported to modulate the numerous biological events including epigenetic events ( noncoding micro - RNAs , histone modification , and DNA methylation ) and multiple signaling transduction pathways ( Wnt / β - catenin , Notch , Sonic hedgehog , P35354 , P00533 , MAPK - P29323 , JAK - P35610 , Akt / PI3K / P42345 , NF - κB , AP - 1 , etc . ) , which can play a key role in regulation of metastasis cascade . Extensive studies have also been performed to determine the molecular mechanisms underlying antimetastatic activity of DPs , with results indicating that these DPs have significant inhibitory activity at nearly every step of the metastatic cascade . DPs have anticancer effects by inducing apoptosis and by inhibiting cell growth , migration , invasion , and angiogenesis . Growing evidence has also shown that these natural agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways . In this review , we discuss the variety of molecular mechanisms by which DPs regulate metastatic cascade and highlight the potentials of these DPs as promising therapeutic inhibitors of cancer .\",\n \"P45983 , but not P45984 , is required in two mechanistically distinct models of inflammatory arthritis . The roles of the c - Jun N - terminal kinases ( JNKs ) in inflammatory arthritis have been investigated ; however , the roles of each isotype ( ie , P45983 and P45984 ) in rheumatoid arthritis and conclusions about whether inhibition of one or both is necessary for amelioration of disease are unclear . By using P45983 - or P45984 - deficient mice in the collagen - induced arthritis and the KRN T - cell receptor transgenic mouse on C57BL / 6 nonobese diabetic ( K / BxN ) serum transfer arthritis models , we demonstrate that P45983 deficiency results in protection from arthritis , as judged by clinical score and histological evaluation in both models of inflammatory arthritis . In contrast , abrogation of P45984 exacerbates disease . In collagen - induced arthritis , the distinct roles of the JNK isotypes can , at least in part , be explained by altered regulation of P42081 expression in P45983 - or P45984 - deficient macrophages in response to microbial products , thereby affecting T - cell - mediated immunity . The protection from K / BxN serum - induced arthritis in Jnk1 (-/-) mice can also be explained by inept macrophage function because adoptive transfer of wild - type macrophages to Jnk1 (-/-) mice restored disease susceptibility . Thus , our results provide a possible explanation for the modest therapeutic effects of broad JNK inhibitors and suggest that future therapies should selectively target the P45983 isoform .\",\n \"Gateways to clinical trials . Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses . The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity , the drug discovery and development portal , http :// integrity . prous . com . This issue focuses on the following selection of drugs : 2F5 , 2G12 , abetimus sodium , ABI - 007 , adalimumab , adefovir dipivoxil , DB05387 , alefacept , altropane , aminolevulinic acid hydrochloride , aminolevulinic acid methyl ester , aminopterin , anakinra , aprinocarsen sodium , atazanavir , atlizumab , atomoxetine hydrochloride ; P33681 - 1 vaccine , bevacizumab , DB04851 dicitrate , BMS - 188667 , brasofensine sulfate , bryostatin 1 ; cantuzumab mertansine , Q99698 - 828 , cinacalcet hydrochloride , cipamfylline , creatine , CVT - 3146 ; darbepoetin alfa , DITPA , drotrecogin alfa ( activated ) , duloxetine hydrochloride ; edatrexate , efalizumab , ENMD - 0997 , epoetin , erlosamide , esomeprazole magnesium , etiprednol dicloacetate , etoricoxib , everolimus , ezetimibe ; fampridine , fenretinide , FTY - 720 ; P05019 / P17936 , IL - 1 cytokine trap , ilodecakin , interferon beta , ISIS - 104838 , ISIS - 2503 , ISIS - 5132 , ivabradine hydrochloride ; lafutidine , lanthanum carbonate , l - DB00125 hydrochloride , DB06681 , lerdelimumab , levetiracetam , levobupivacaine hydrochloride , levosimendan , lopinavir ; melagatran , mibefradil hydrochloride , miglustat , morphine - 6 - glucuronide ; nesiritide ; omalizumab , omapatrilat ; p24 - VLP , parecoxib sodium , peginterferon alfa - 2a , peginterferon alfa - 2b , pegsunercept , pitavastatin calcium , plevitrexed , prasterone , pregabalin , PRO - 2000 , prucalopride ; rapacuronium bromide , rebimastat , RGA - 0853 , rubitecan , ruboxistaurin mesilate hydrate , RWJ - 67657 ; S - 16020 - 2 , sarizotan , SLV - 306 , stiripentol ; DB05809 , tenecteplase , teriparatide , tezacitabine , tipifarnib , trabectedin , troglitazone ; valdecoxib , vardenafil ; Z - 338 , ziconotide .\",\n \"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK91___ and its - in terms of P36551 - inhibition - \\\" inactive \\\" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK91___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK91___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK91___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK91___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK91___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK91___ .\",\n \"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK77___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .\",\n \"Production and characterization of DB06681 , a variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin , in Pichia pastoris . Blocking the P10747 / P33681 costimulatory pathway is a promising strategy in the treatment of graft rejection , graft - versus - host disease and autoimmune diseases . DB06681 , a high - affinity variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin ( DB01281 ) , is a more potent inhibitor of the interaction between P10747 and P33681 than is DB01281 . In a previous study , DB06681 was produced in a mammalian cell system , which is time - consuming and expensive . To obtain DB06681 more efficiently and cost effectively , we attempted to produce DB06681 using a Pichia pastoris expression system . The gene encoding DB06681 , with an additional 6 - DB00117 tag at the N - terminus , was cloned into the yeast vector pPIC9K and expressed in the P . pastoris strain GS115 . Under the optimized induction conditions for protein expression ( inoculum density , OD ( 600 ) = 80 ; methanol concentration added daily , 1 . 0 - 3 . 0 % ; induction time point , 72 - 96 h ; culture medium pH = 6 . 0 ) , the yield of purified DB06681 was approximately 30 mg l (- 1 ) by one - step Ni - agarose affinity chromatography . Q96IV0 F treatment showed the purified DB06681 to be post - translational modified by N - linked glycosylation . In biological function assays , DB06681 expressed in P . pastoris demonstrated specific binding to P33681 - 1 / P33681 - 2 - positive Raji cells and also suppressed lymphocyte proliferation in a dose - dependent manner . These results suggest that DB06681 produced in P . pastoris is biologically active and will be useful for experimental therapy on immunotherapy for transplant rejection and autoimmune diseases .\",\n \"Polymorphisms of genes related to endothelial cells are associated with primary biliary cirrhosis patients of Cretan origin . BACKGROUND : Primary biliary cirrhosis ( P10515 ) is an organ specific autoimmune disease of still unidentified genetic etiology . We have shown that endothelins ( ETs ) , produced by the liver endothelial cells are increased in P10515 and may play a major pathogenetic role . AIMS : To study gene polymorphisms related to the endothelial cells ( P29474 , P10153 - 1 genes ) and , to investigate whether the previously reported association of P16410 gene polymorphisms is replicated in a genetically homogeneous Greek population . PATIENTS AND METHODS : Genomic DNA was extracted from 100 P10515 patients ( 83 females , 93 % AMA + , 74 / 100 Ludwig stage I - II ) and 158 healthy controls . P29474 , P16410 and ET1 polymorphisms were determined by PCR - RFLPs analysis . RESULTS : Both P29474 intron4 VNTR and P29474 exon7 G894T SNP were significantly associated with increased risk in P10515 . P10153 - 11 rs2071942 \\\" A \\\" and rs5370 \\\" T \\\" alleles appeared a tendency for association with disease progression . No association was found between P10515 and the P16410 SNPs analyzed . CONCLUSIONS : We demonstrated that P29474 , a gene related to the liver endothelium function is associated with P10515 . Contrarily , the important in adaptive immunity gene P16410 was not associated with the disease in the homogeneous population analyzed . These results are compatible partially with our previous hypothesis that defects of the liver endothelial system , leading to endothelin overproduction , may be a fundamental early pathogenetic mechanism in P10515 .\"\n]"},"candidates":{"kind":"list like","value":["___MASK100___","___MASK20___","___MASK63___","___MASK69___","___MASK77___","___MASK7___","___MASK84___","___MASK88___","___MASK91___"],"string":"[\n \"___MASK100___\",\n \"___MASK20___\",\n \"___MASK63___\",\n \"___MASK69___\",\n \"___MASK77___\",\n \"___MASK7___\",\n \"___MASK84___\",\n \"___MASK88___\",\n \"___MASK91___\"\n]"},"answer":{"kind":"string","value":"___MASK100___"},"id":{"kind":"string","value":"MH_train_491"}}},{"rowIdx":492,"cells":{"query":{"kind":"string","value":"interacts_with DB06674?"},"supports":{"kind":"list like","value":["Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK54___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK54___ who were treated with a single dose of mifepristone .","Apoptosis and the FLIP and NF - kappa B proteins as pharmacodynamic criteria for biosimilar P01375 antagonists . Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale . The imminent expiration of the patents on reference biological products which block the cytokine P01375 - α ( tumor necrosis factor - α ) raises the possibility of bringing so - called biosimilars to the market ( similar to the biologicals of reference products ) . This occurrence is inevitable , but criteria to adequately evaluate these medications are now needed . Even among controversy , there is a demand from publications correlating the pro - apoptotic mechanism of the original P01375 - α antagonists ( etanercept , infliximab , adalimumab , DB06674 , and certolizumab pegol ) in the treatment of rheumatoid arthritis and other diseases . In this article , the authors discuss the possibility of utilizing the pro - apoptotic effect correlated with the regulation of the anti - apoptotic proteins FLIP and NF - κB as new criteria for analyzing the pharmacodynamics of possible biosimilar P01375 - α antagonists which should be submitted to regulatory agencies for evaluation .","anti - P01375 agents as therapeutic choice in immune - mediated inflammatory diseases : focus on adalimumab . The complex pathogenesis of immune - mediated inflammatory diseases ( IMIDs ) has been extensively investigated and dysregulation of cytokines , such as tumour necrosis factor ( P01375 ) has been shown to play a dominant role in the pathogenesis of various IMIDs , such as rheumatoid arthritis , ankylosing spondylitis , Crohn ' s disease , ulcerative colitis , psoriasis and psoriatic arthritis . The subsequent development of biological agents capable of blocking P01375 has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with P01375 having a predominant role . Five P01375 inhibitors have currently been approved for treatment of one or more IMIDs ; these include infliximab , etanercept , adalimumab , DB06674 and certolizumab pegol . Given the similarities in the pathogenic background of IMIDs , one could expect that anti - P01375 agents be similarly effective and with comparable tolerability profiles ; however , this may not be the case . Structural and pharmacological differences among the anti - P01375 drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs , together with differences in potency , therapeutic dose ranges , dosing regimens , administration routes , and propensity for immunogenicity . Among the five P01375 inhibitors approved for treatment of IMIDs , adalimumab has the widest range of indications . Data from controlled clinical trials of adalimumab , showing its excellent efficacy and tolerability in a wide range of indications , are supported by real - world long - term data from observational studies , which confirm the value of adalimumab as a suitable choice in the management of IMIDs .","New biologic therapeutics for ulcerative colitis and Crohn ' s disease . INTRODUCTION : Some inflammatory bowel disease ( Q9UKU7 ) patients especially those with refractory Crohn ' s disease ( CD ) or relapsing ulcerative colitis ( UC ) do not respond to current therapies . The newly introduced biological drugs have got some interest due to their specificity and selectivity in modulation of inflammatory elements . AREAS COVERED : In 46 included randomized , placebo - controlled clinical trials , the efficacy and safety of different biologic drugs have been evaluated in moderately to severely active CD or UC patients . Current investigated drugs include new anti - P01375 drugs ( adalimumab , certolizumab pegol , etanercept , onercept and DB06674 ) , anti - P11836 ( rituximab ) , T - cell inhibitors ( abatacept ) and anti - α4 integrins ( natalizumab and vedolizumab ) . DB00051 , certolizumab , and DB06674 showed significant efficacy in induction of remission and maintenance in CD and UC patients with a rate of adverse events similar to placebo in the major trials . DB00108 and vedolizumab were effective in the treatment of moderately to severely active CD and UC patients . However , vedolizumab caused less adverse effects than natalizumab . onercept , etanercept , rituximab and abatacept were all well tolerated but were not effective in CD or UC patients . EXPERT OPINION : Anti - P01375 drugs , except for onercept and etanercept , and anti - α4 integrins exhibit beneficial therapeutic effects . Although they were all well tolerated , the incidence of progressive multifocal leukoencephalopathy associated with natalizumab should not be missed .","An update on anti - P01375 agents in ulcerative colitis . Anti - tumor necrosis factor - α agents are key therapeutic options for the treatment of ulcerative colitis . Their efficacy and safety have been shown in large randomized controlled trials . The key evidence gained from these trials of infliximab , adalimumab , and DB06674 is reviewed along with their effect on mucosal healing and long - term outcomes . Also reviewed are methods for optimizing their effectiveness , including therapeutic drug monitoring and treat - to - target strategies . Finally , remaining unresolved questions regarding their role and effectiveness are considered including how these may be addressed in future clinical trials .","Safety of anti - tumour necrosis factor agents in patients with chronic hepatitis C infection : a systematic review . OBJECTIVES : To identify all of the patients affected by chronic hepatitis C infection treated with P01375 - α blockers ( adalimumab , certolizumab pegol , etanercept , DB06674 and infliximab ) in order to evaluate the safety profile . METHODS : A systematic review of the literature from January 1990 to October 2010 . RESULTS : In total , 37 publications with data on 153 patients who were treated with anti - P01375 - α agents in the setting of HCV infection were found . The mean anti - P01375 - α treatment duration was 11 . 9 months . Ninety - one patients had RA , 22 had psoriasis , 6 had Crohn ' s disease and 14 patients had other chronic inflammatory diseases . To date , etanercept is the biological agent that has been most extensively used in the patients with HCV infection , with only one definitely confirmed case of HCV hepatitis worsening and five suspected cases ( elevation of transaminases not associated with an increase in the HCV viral load and vice versa ) in 110 treated patients . Treatment with this agent resulted in stable levels of liver transaminases and a stable viral load in 74 patients , with an improvement in HCV chronic liver disease in combination with IFN - ribavirin therapy in 29 patients . CONCLUSIONS : The safety profile of anti - P01375 - α agents in the setting of HCV infection seems to be acceptable , even if differences in the hepatotoxic profile are apparent between different agents . In the absence of long - term and large , controlled clinical trials a definitive statement on the safety of anti - P01375 - α therapies in the setting of chronic HCV infection can not be made .","P01375 inhibitors in asthma and P48444 : we must not throw the baby out with the bath water . P01375 ( P01375 ) - alpha , a pleiotropic cytokine that exerts a variety of effects , such as growth promotion , growth inhibition , angiogenesis , cytotoxicity , inflammation , and immunomodulation , has been implicated in several inflammatory conditions . It plays a significant role in many inflammatory diseases of lungs . Given that there is significant literature supporting the pathobiologic role of P01375 in asthma , mainly in severe refractory asthma , and P48444 , P01375 inhibitors ( infliximab , DB06674 and etanercept ) are now regarded as the potential new medications in asthma and P48444 management . The studies reported in literature indicate that P01375 inhibitors are effective in a relatively small subgroup of patients with severe asthma , possibly defined by an increased P01375 axis , but they seem to be ineffective in P48444 , although an observational study demonstrated that P01375 inhibitors were associated with a reduction in the rate of P48444 hospitalisation among patients with P48444 receiving these agents to treat their rheumatoid arthritis . These findings require a smart approach because there is still good reason to target P01375 , perhaps in a more carefully selected patient group . P01375 treatment should , therefore , not be thrown out , or abandoned . Indeed , since severe asthma and P48444 are heterogeneous diseases that have characteristics that occur with different phenotypes that remained poorly characterized and little known about the underlying pathobiology contributing to them , it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from P01375 inhibitors .","P01375 - alpha and X - linked adrenoleukodystrophy . The two most common forms of X - linked adrenoleukodystrophy ( X - P33897 ) , the childhood cerebral form ( CCER ) and the adult form , adrenomyeloneuropathy ( Q9BXJ7 ) , arise from the same mutations in the X - P33897 gene at Xq28 . These two forms are distinguished by the degree of cerebral inflammation . Segregation analysis suggests that an autosomal modifying gene may be a major determinant of phenotype in X - P33897 . Thus , a modifying gene could be involved in initiating or promoting the inflammatory response . In this study we detected a difference in tumor necrosis factor - alpha ( P01375 ) bioactivity , but not P01375 protein levels , in serum from some advanced CCER patients . Early - stage CCER patients and Q9BXJ7 patients were in the normal range . Allelic differences in P01375 or levels of soluble P01375 receptor did not account for bioactivity differences or phenotypic heterogeneity in X - P33897 .","Pharmacology of P01375 blockade in rheumatoid arthritis and other chronic inflammatory diseases . P01375 - alpha ( P01375 ) has been unequivocally validated as a therapeutic target in a number of immune - mediated inflammatory disorders ( IMIDs ) . There is now increasing choice of biologic agents within the class all of which successfully neutralize sTNF . But approaches to P01375 inhibition differ and currently include mAbs ( infliximab , adalimumab , and DB06674 ) , either chimeric or human in sequence , a PEGylated Fab ' fragment ( certolizumab ) , and an IgG1 - P20333 fusion protein ( etanercept ) . It is emerging that the pharmacological properties of these three anti - P01375 subtypes differ with respect to Fc function , binding of tmTNF and the possible consequences of this , as well as the ability to form complexes . The mode of administration of each agent , clearance and the local tissue concentrations achieved may also confer unique characteristics of relevance with respect to efficacy and safety .","Aspects of P01375 inhibitor therapy in rheumatoid arthritis . Treatment outcomes in rheumatoid arthritis ( RA ) have improved considerably with the use of biological therapies . Since the discovery of the role of tumor necrosis factor ( P01375 ) alpha in the pathogenesis of the disease , three P01375 inhibitors , infliximab , etanercept and adalimumab , have become widely used for the treatment of RA . More recently , two newer P01375 inhibitors - certolizumab pegol and DB06674 - have become available , increasing the armamentarium of therapy . With improved therapies , treatment strategies have also changed , with the aims now being to achieve and maintain remission . This article addresses some of these aspects of treating RA , reviewing the studies on these two newer P01375 inhibitors , certolizumab pegol and DB06674 , and those addressing the induction of remission or low disease activity with P01375 inhibitors and maintenance with less intensive treatment .","Current , new and future biological agents on the horizon for the treatment of inflammatory bowel diseases . Biological agents for inflammatory bowel diseases ( Q9UKU7 ) targeting tumor necrosis factor ( P01375 ) have changed the way to treat Q9UKU7 refractory to standard medications and allowed us to reach new therapeutic goals such as mucosal healing and deep remission . A better understanding of the components of the pathological processes that are a hallmark of Q9UKU7 has led to the development of a new family of biological agents in Crohn ' s disease and ulcerative colitis . Biosimilars , which are copy versions of currently licensed biological agents , will be soon available . The biosimilar of infliximab is as effective and as safe as its originator in rheumatologic conditions , while a new anti - P01375 agent , namely DB06674 , has been recently approved for refractory ulcerative colitis . Beyond P01375 blockers , anti - adhesion molecules appear to be a potent drug class for Q9UKU7 . DB09033 was recently approved for both Crohn ' s disease and ulcerative colitis . Numerous other compounds are in the pipeline . Ustekinumab looks very promising for Crohn ' s disease . O15105 antisense oligonucleotide might enrich our armamentarium if preliminary data are confirmed in upcoming clinical trials . Herein , we review the efficacy and safety of new and emerging biological agents that are currently investigated in Q9UKU7 clinical trials .","Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK91___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK91___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .","Update on biologic therapies in ankylosing spondylitis : a literature review . AIM : The present paper aims to review the recent advances in diagnosis and management of ankylosing spondylitis ( AS ) . METHOD : Medline and abstracts submitted to the recent European League Against Rheumatism ( EULAR ) congress were searched to obtain quality - controlled information on the management of AS . RESULTS : The use of magnetic resonance imaging ( Q9BWK5 ) allows the diagnosis of AS to be made in the pre - radiographic stage . The Assessment in Spondylarthritis International Society recommendations for the management of AS have been modified so that patients with non - radiographic spondyloarthritis ( SpA ) can now be considered for biological therapy . The ' older ' anti - tumour necrosis factor ( P01375 ) continued to be effective in longer - term studies . Studies with longer duration of follow - up have shown that some patients with pre - radiographic SpA entered into prolonged drug - free remission . It is likely that in the foreseeable future , more AS patients will be treated with biological therapies at an earlier stage of the disease . New biologic therapies , DB06674 and secukinumab , are looking promising in improving the signs and symptoms of AS , at least in the short - term . CONCLUSION : Longer - term studies of AS patients treated with infliximab , etanercept and adalimumab continued to show a good clinical response . There is a need for more long - term studies to examine the longitudinal efficacy of DB06674 and secukinumab in AS .","Safety issues and concerns of new immunomodulators in rheumatology . INTRODUCTION : The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis . Since the first anti - P01375 - α therapies , numerous molecules have been identified as targets of immunomodulatory therapies , such as IL - 1 ( anakinra , canakinumab ) , P05231 ( tocilizumab ) , P11836 (+) B cells ( rituximab ) , P16410 ( abatacept ) and two additional anti - P01375 - α therapies ( certolizumab pegol , DB06674 ) . AREAS COVERED : In the present review , we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy . The risk of infection should be identified before initiating a biologic treatment and markers checked over time , in particular for tuberculosis and hepatitis B and C viruses . Other infections ( bacterial , viral , parasitic ; opportunistic ; surgery - related ) and safety issues may require temporary interruption of the treatment until complete resolution . No significantly increased risk of malignancy , both hematological and solid , has been associated with the use of biologic agents . In all cases , it is difficult to dissect the risks related to biologics from those related to baseline treatments . EXPERT OPINION : Detailed medical history and laboratory screening should be performed before starting biologic therapies . Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects .","___MASK71___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK71___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK71___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .","Round window membrane permeability to DB06674 in guinea pigs : a pilot study . OBJECTIVES / HYPOTHESIS : Autoimmune inner ear disorder is one of a few types of sensorineural hearing loss that is treatable and potentially reversible . Treatment involves oral steroids and methotrexate . Other treatment modalities have been tried with variable success . All such treatments are systemic , with inherent side effects limiting their effectiveness . Recently , tumor necrosis factor ( P01375 ) - α blockers have been suggested as a modality of treatment . The objective of this study was to assess the round window membrane permeability to DB06674 , a P01375 - α blocker . This study is the first to look at the feasibility of local DB06674 delivery into the inner ear , which may allow for targeted immune modulation of autoimmune inner ear disorders without the consequences of systemic treatment . STUDY DESIGN : This is a single - blinded , placebo - controlled , pilot study using guinea pigs to assess round window membrane permeability to DB06674 . METHODS : Golimumab was instilled into the guinea pigs ' middle ear . Inner ear fluid was sampled through the round window membrane after approximately 30 minutes of drug exposure . Golimumab presence in the inner ear was assessed by enzyme - linked immunosorbent assay in both drug - treated and control ears . RESULTS : Higher concentrations of DB06674 were detected in the inner ear fluid samples of DB06674 - exposed ears than in the control ears . The difference was statistically significant ( P < . 001 ) . CONCLUSIONS : Golimumab crosses the round window membrane and is detected in measurable concentrations in the inner ear fluid after 30 minutes of exposure to the membrane . Further studies are needed to learn its pharmacokinetics and the time needed to reach optimal concentration in the inner ear . LEVEL OF EVIDENCE : NA . Laryngoscope , 123 : 2840 - 2844 , 2013 .","Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases . BACKGROUND : Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases ( Q9UKU7 ) . To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis , we investigated their effects on endotoxin - induced tumour necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 1 beta and P05231 release by elutriation - purified human monocytes in vitro . METHODS : Drugs tested were dexamethasone , DB00244 , sulphapyridine and zileuton ( a P09917 inhibitor ) . Monocytes were isolated and stimulated with endotoxin , and P01375 , IL - 1 and P05231 levels were determined using an enzyme - linked immunosorbent assay . RESULTS : Monocyte stimulation with endotoxin resulted in an average P01375 release of 2464 +/- 64 pg / 10 ( 6 ) cells , IL - 1 release of 616 +/- 47 pg / 10 ( 6 ) cells and P05231 release of 2259 +/- 148 pg / 10 ( 6 ) cells . Addition of dexamethasone resulted in a reduction of P01375 , IL - 1 and P05231 release to below background levels . DB00891 significantly reduced P01375 and induced IL - 1 release in a dose - dependent fashion , but had no significant effect on P05231 release . 5 - ___MASK73___ did not modulate P05231 synthesis , but significantly reduced IL - 1 and enhanced P01375 synthesis . Zileuton reduced P01375 and P05231 release , but enhanced IL - 1 release . CONCLUSION : We conclude that these anti - inflammatory drugs are able to modulate cytokine release by human monocytes . Further studies are needed to determine whether these effects are related to their therapeutic efficacy in Q9UKU7 .","The antibody response against human and chimeric anti - P01375 therapeutic antibodies primarily targets the P01375 binding region . BACKGROUND : In a subset of patients , anti tumour necrosis factor ( P01375 ) therapeutic antibodies are immunogenic , resulting in the formation of antidrug antibodies ( ADAs ) . Neutralising ADAs compete with P01375 for its binding site and reduces the effective serum concentration , causing clinical non - response . It is however unknown to which extent ADAs are neutralising . OBJECTIVES : To study which proportion of antibodies to human ( ised ) anti - P01375 ( adalimumab , DB06674 , certolizumab ) as well as chimeric anti - P01375 ( infliximab ) is neutralising . METHODS : Neutralising capacity of ADAs was assessed using a P01375 competition assay in P00813 - positive sera of patients treated with adalimumab ( n = 21 ) , DB06674 ( n = 4 ) , certolizumab ( n = 9 ) or infliximab ( n = 34 ) sent in to our diagnostic department . RESULTS : In 34 sera with ADAs to adalimumab , DB06674 or certolizumab , > 97 % of the antibodies were neutralising . In 34 sera with ADAs to infliximab > 90 % of the antibodies were neutralising . Further characterisation of the broader antibody response to infliximab revealed that non - neutralising antibodies to infliximab do not target murine domains , but may bind infliximab - unique domains not involved in P01375 binding ( located outside the paratope ) . CONCLUSIONS : Our study shows that ADAs to human ( ised ) as well as chimeric anti - P01375 therapeutic antibodies are largely neutralising . This highly restricted P00813 response suggests an immunodominant role for the paratope of anti - P01375 therapeutics .","Clinically relevant advances in rheumatoid arthritis therapy . Owing to the success of biologics in the treatment of rheumatoid arthritis ( RA ) , several novel drugs have been introduced in the therapeutic armamentarium , although not all of them have been approved in all countries worldwide . Among the drugs are tumour necrosis factor ( P01375 ) inhibitors such as certolizumab pegol and DB06674 ( the latter of which was the first P01375 blocker shown to be effective in patients who had been unsuccessfully treated with other P01375 blockers and which can be applied only once a month ) , and the interleukin - 6 receptor antagonist tocilizumab , which not only opens up a completely new field of anti - inflammatory modulation of RA pathophysiology , but also highlights the challenge of novel potential side effects . Moreover , aside from clinical studies showing efficacy in the inhibition of osteoclast activation by the anti - O14788 ( receptor activator of nuclear factor - kappa B ligand ) antibody denosumab , an improved form of steroid application known as slow - release ' tempus tablet ' for treatment of RA and several developments in the small - molecule area have been addressed by clinical trials .","Combination systemic therapies in psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic , progressive , and debilitating disorder . When monotherapy fails , combination therapy is necessary for the long - term management of these patients . There is currently no review on this subject , and the purpose of this study was to investigate and describe the current literature on combination therapy in PsA . A PubMed MeSH search was performed for psoriatic arthritis and combination therapy , which yielded at total of 83 articles . After excluding reviews and commentaries , and pursuing relevant citations , a total of 21 articles on the subject were found : one study of NSAIDs and methotrexate , three studies of cyclosporine and methotrexate , three studies of non - P01375 biologic inhibitors ( alefacept , ustekinumab ) and methotrexate , and 14 studies of anti - P01375 - inhibitors ( etanercept , adalimumab , infliximab , DB06674 ) and methotrexate . The combination of cyclosporine and methotrexate reduces the dosages and also the side effects of each agent , allowing better disease control with less toxicity . DB00563 in combination with biologic agents , either non - P01375 inhibitors or anti - P01375 inhibitors , may have a role in decreasing side effects , but it does not appear to improve clinical symptoms beyond those attained by biologic monotherapy .","Emerging drugs for the treatment of axial and peripheral spondyloarthritis . INTRODUCTION : The topic under discussion is of strong relevance to the field of spondyloarthritis ( SpA ) because , in addition to established biological , there are new promising compounds . The reason for the review is to put all available data together to allow for an overview on recent developments and to especially inform readers about emerging drugs , biologics and small molecules in the field of SpA . AREAS COVERED : This review on new therapies in axial and peripheral SpA comprising psoriatic arthritis ( PsA ) shows , that , in addition to the established anti - P01375 agents infliximab , etanercept , adalimumab , DB06674 , certolizumab and the first biosimilar approved in the EU , there are at least two emerging biologics in the field of SpA : ustekinumab , a compound targeting IL12 / IL - 23 via the p40 subunit of both cytokines works for psoriasis and PsA and probably also for Crohn ' s disease , and the anti - Q16552 antibody secukinumab which has also been shown to work in psoriasis , both compounds seem to also work in ankylosing spondylitis . In addition , the potential of two small molecules , apremilast a phoshodiesterase4 inhibitor and tofacitinib , a januskinase inhibitor is discussed . EXPERT OPINION : Since , in contrast to rheumatoid arthritis , the therapeutic array in SpA is currently limited to P01375 - blockers , and since there is still an unmet need because some patients do not respond to anti - P01375 therapy at all or they loose response , new agents with a different mechanism of action are eagerly awaited .","Selective P01375 - α inhibitor - induced injection site reactions . INTRODUCTION : During the last decade , many new biological immune modulators entered the market as new therapeutic principles . P01375 - α is a pro - inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune - mediated or inflammatory diseases . P01375 - α blockers have demonstrated efficacy in large , randomized controlled clinical trials either as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs . AREAS COVERED : Although generally well tolerated and safe , potential adverse events may be associated with P01375 - α inhibitor treatment . The authors will briefly review the potential adverse drug reactions and the immunological mechanisms of injection site reactions ( ISRs ) in patients treated with etanercept and adalimumab . EXPERT OPINION : Patients treated with P01375 - α inhibitors can develop ISR around the sites of injections . ' Type IV delayed type reaction ' or ' recall ISRs ' . Eosinophilic cellulitis or ' Wells syndrome ' , ' type III ' and ' type I ' reactions are reported . Long - term studies are necessary to determine the durability of response and the real risk of ISRs with DB06674 and certolizumab pegol . Further studies are also necessary to evaluate the immunogenicity of these drugs .","P01375 inhibitors - state of knowledge . P01375 ( P01375 ) is considered a major proinflammatory cytokine , affecting various aspects of the immune reaction . All five P01375 inhibitors currently available on the market ( i . e . , etanercept , infliximab , adalimumab , certolizumab and DB06674 ) are top sellers , although indicated only in autoimmune diseases , including rheumatoid arthritis , Crohn ' s disease and psoriasis . This article briefly discusses the background and place for P01375 inhibitors in modern therapy . The main safety aspects of P01375 inhibitor administration are described in particular , with special consideration of the available meta - analyses . Finally , perspectives on the next - generation P01375 inhibitors and their use in the clinic are given .","Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK93___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .","Subacute lupus erythematosus during treatment with DB06674 for seronegative rheumatoid arthritis . We report on a 52 - year - old woman with a history of severe seronegative rheumatoid arthritis . Several conventional therapies and biological therapy with etanercept and infliximab had been unsuccessful . In 2010 she was given DB06674 subcutaneously at a monthly dose of 50 mg . She had a negative Q14201 titre . After 16 months of uninterrupted therapy and sustained response , she developed skin lesions on the upper trunk , back and upper extremities , which worsened on exposure to the sun . The skin biopsy was compatible with subacute lupus erythematosus . Laboratory findings included an Q14201 titre 1 : 640 , negative anti - Ro / SSA and anti - DNA antibodies . Topical corticosteroid therapy proved inadequate . The patient ' s condition improved only after discontinuation of DB06674 . The causal relationship between subacute cutaneous lupus erythematosus and DB06674 is not dose - related and occurs with some delay ( a typical feature of immunological adverse reactions ) . The association is likely , but not confirmed ( because re - challenge was not performed ) . However , a clear improvement was noted after withdrawal . Based on this case , we hypothesized the aetiological role of DB06674 - associated immunogenicity . P01375 - α antagonist - induced lupus - like syndrome ( TAILS ) is a well - known side effect of this class of substances . The British Society of Rheumatology recommends discontinuation of the causal anti - P01375 - α treatment in patients with TAILS .","Tailored therapy for severe asthma . Patients with severe asthma or P48444 have often a suboptimal symptom control due to inadequate treatment . A better understanding of pathogenetic mechanisms , phenotypes , endotypes and the new technologies available in the fields of molecular biology and immunogenetics have made it possible to synthesize specific monoclonal antibodies virtually able to interact with any target antigen , or to open a way for new therapeutic target options . At the moment , the only biologic drug available in clinical practice is omalizumab . To overcome the limits of omalizumab , the research has focused on new monoclonal antibodies presenting higher avidity for IgE ( e . g . ligelizumab and lumiximab ) and ability to interact also with low affinity IgE receptor ( FcϵRII ) . At present , many new biological drugs with different mechanisms of action and targets are matter of research . It is very important to identify the asthmatic phenotype in order to select the most appropriate drug for the individual patient . The most promising agents are targeted against cytokines of Th2 pattern and related receptors , such as P60568 ( daclizumab ) and P35225 ( lebrikizumab ) or P05113 in patients with hypereosinophilia ( mepolizumab , reslizumab and benralizumab ) . Other interesting drugs have as a target P01375 - α or its soluble receptor ( infliximab , DB06674 and etanercept ) or IL - 1 ( canakinumab ) , a cytokine with an important systemic proinflammatory action . Finally , the discovery of increased levels of C5a in the airways of asthmatic patients has led to the synthesis of a specific monoclonal antibody ( eculizumab ) . Further help should come from the identification of biomarkers that can guide in choosing the best treatment for the individual patient , such as IgE for omalizumab or periostin for lebrikizumab .","Treatment of ulcerative colitis . PURPOSE OF REVIEW : Ulcerative colitis is a chronic inflammatory disease of the colon of unknown cause that is characterized by alternating intervals of active and inactive disease in 80 - 90 % of patients . The primary goal of treatment is to induce and maintain remission using therapy tailored to the individual patient . The purpose of this review was to describe the management of ulcerative colitis with emphasis on the use of anti - tumor necrosis factor ( P01375 ) agents . RECENT FINDINGS : Recent research has shown that new anti - P01375 agents , adalimumab ( P00813 ) and DB06674 , are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis . In a recent study , infliximab was found to have comparable efficacy to cyclosporine in treatment of acute severe refractory to corticosteroids ulcerative colitis . SUMMARY : Anti - P01375 therapy should be initiated in patients with acute severe refractory to corticosteroids ulcerative colitis and in patients with moderate - to - severe ulcerative colitis who are not responsive to conventional treatment with aminosalicylates , corticosteroids and immune modulators . Alternatives to infliximab are P00813 and DB06674 . Future research is needed to further assess the long - term efficacy and safety of P00813 and DB06674 in ulcerative colitis .","Pharmacogenetics and future therapeutic scenarios : what affects the prediction of response to treatment with etanercept ? There are five tumor necrosis factor alpha ( P01375 - α ) inhibitors available for clinical use that have demonstrated efficacy as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs ( DMARDs ) in the treatment of immune - mediated diseases . These include the anti - P01375 - α monoclonal antibodies infliximab , adalimumab , DB06674 , and certolizumab pegol , and the fusion protein , etanercept . The use of pharmacogenetic testing has the potential to increase drug efficiency by identifying genetic factors responsible for a lack of response to , or toxicities from , P01375 - α inhibitors , and could be used to individualize therapy . Several studies have reported associations between genetic polymorphisms and the response to etanercept , but most are small and insufficiently powered to detect effect , and markers tend to be more prognostic than predictive of therapeutic response . Limitations of pharmacogenetic studies include the use of single nucleotide polymorphisms ( SNPs ) , genes in linkage with other loci , interaction of environmental factors , and cohort heterogeneity , all of which can complicate the relationship between genetic polymorphisms and treatment response . Further studies are needed for pharmacogenetics to become a routine part of daily clinical therapeutic practice .","P01375 inhibitors in psoriasis : an update . Three inhibitors of tumor necrosis factor ( P01375 ) currently are approved for the treatment of psoriasis : etanercept , infliximab , and adalimumab . The other two P01375 inhibitors , DB06674 and certolizumab pegol , have shown efficacy against plaque psoriasis in clinical trials of psoriatic arthritis ( PsA ) . This article reviews the most recent evidence on the efficacy and safety of the P01375 inhibitors in psoriasis , with special attention to preventing and managing immunogenicity .","Screening of 134 single nucleotide polymorphisms ( SNPs ) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes . More than 120 published reports have described associations between single nucleotide polymorphisms ( SNPs ) and type 2 diabetes . However , multiple studies of the same variant have often been discordant . From a literature search , we identified previously reported type 2 diabetes - associated SNPs . We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium ( r ( 2 ) > 0 . 8 ) with another typed SNP . Of the 114 SNPs examined , we followed up the 20 most significant SNPs ( P < 0 . 10 ) on an additional 384 case subjects and 366 control subjects from a population - based study in Finland . In the combined data , we replicated association ( P < 0 . 05 ) for 12 SNPs : P37231 Pro12Ala and His447 , Q14654 Glu23Lys and rs5210 , P01375 - 857 , P11168 Ile110Thr , P20823 / TCF1 rs2701175 and GE117881_360 , P35558 - 232 , Q13562 Thr45Ala , P05231 - 598 , and P22413 Lys121Gln . The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association ( P = 0 . 012 ) . We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample ( P = 0 . 03 ) , although we also replicated 4 of 58 SNPs from genes that had only one previous report of association .","Long term efficacy and safety of etanercept in the treatment of psoriasis and psoriatic arthritis . Psoriasis is a chronic , immune - mediated inflammatory disease affecting both the skin and joints . Approximately 20 % of patients suffer a moderate to severe form of skin disease and up to 30 % have joint involvement . Standard therapies for psoriasis include topical medications , phototherapy , and both oral systemic and biological therapies whereas therapies for psoriatic arthritis include nonsteroidal anti - inflammatory drugs followed by disease modifying antirheumatic drugs and / or tumor necrosis factor ( P01375 ) - α inhibitors and interleukin - 12 / 23p40 inhibitors . Treatment of both diseases is typically driven by disease severity . In the past decade , major advances in the understanding of the immunopathogenesis of psoriasis and psoriatic arthritis have led to the development of numerous biological therapies , which have revolutionized the treatment for moderate to severe plaque psoriasis and psoriatic arthritis . Anti - P01375 - α agents are currently considered as first line biological therapies for the treatment of moderate to severe psoriasis and psoriatic arthritis . Currently approved anti - P01375 - α agents include etanercept , adalimumab , and infliximab for psoriasis and psoriatic arthritis as well as DB06674 and certolizumab for psoriatic arthritis . In this article , we aim to evaluate the long term safety and efficacy of etanercept in psoriasis and psoriatic arthritis .","Optimizing outcomes in rheumatoid arthritis patients with inadequate responses to disease - modifying anti - rheumatic drugs . Conventional DMARDs such as MTX are the mainstay of treatment for patients with RA . However , failure to achieve adequate disease control in many patients , even with combination therapy , has spurred the development of agents that target various immune mediators involved in the disease process . In the past decade , biologic agents have proved viable as alternative or add - on therapy to DMARDs in patients whose disease is inadequately controlled . Well - controlled clinical trials have evaluated the effects of these agents not only on disease activity , but also on inhibition of structural change and improvement in physical function . This article reviews phase 3 clinical trial results on biologic agents that inhibit T - and B - cell activation ( abatacept and rituximab , respectively ) , inflammatory cytokines such as P01375 - α ( adalimumab , etanercept , infliximab , DB06674 and certolizumab ) and P05231 ( tocilizumab ) . Although data comparing the efficacy of the various biologic agents are limited , the availability of biologic therapies with differing mechanisms of action expands therapeutic options for patients whose disease is inadequately controlled with DMARDs and allows for greater individualization of treatment .","Psoriasiform exfoliative erythroderma induced by DB06674 . Golimumab is a fully human anti - tumour necrosis factor ( P01375 ) - α monoclonal antibody approved for use in the treatment of active rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis . Psoriasis induced by treatment with anti - P01375 drugs is well documented , but to our knowledge , the development of clinical features of psoriasiform exfoliative erythroderma during treatment with DB06674 has not been previously described .","Golimumab and immunogenicity ? 2010 and beyond . Immunogenicity is a frequent adverse event observed with biological agents ' therapy . Challenges of management in patients with rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis treated with DB06674 , an anti - P01375 blocker , include limited generation of antibodies like anti - nuclear , anti - DB06674 , and anti - double stranded DNA antibodies . We conducted here a meta - analysis study in order to evaluate and compare the newly generated antibody levels after DB06674 therapy . The examination of original clinical trials revealed that their levels were neither higher nor significant . Moreover , no evident associations between the induced - antibodies and lupus - like syndromes and / or infusion site reaction were reported . The reduced patients cohort and the absence of systematic newly generated antibodies follow - up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy , and / or predicting for their worse prognosis . Hence , further studies are required to ascertain the real impact of the induced antibodies after DB06674 ' s therapy .","Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .","Anti - P01375 agents in familial Mediterranean fever : report of three cases and review of the literature . Familial Mediterranean fever ( FMF ) is an autoinflammatory disease characterized by recurrent fever , peritonitis / pleuritis , or arthritis attacks . Patients may have FMF - associated mutations of pyrin . The role of biologics such as anti - tumor necrosis factor ( P01375 ) agents ( infliximab , etanercept , adalimumab , DB06674 ) and anakinra , canakinumab , or rilonacept in the treatment of FMF needs to be clarified . Herein we present reports of three patients ( all were positive for HLA Q8TCY5 ) with typical spondylitis associated with FMF who were successfully managed with anti - P01375 agents , along with a literature review . The patients were a 37 - year - old man with concomitant Crohn ' s disease and amyloidosis who was treated with infliximab ( P27352 , 5 mg / kg for 3 years ) and switched to adalimumab ( P00813 ) , and two female patients ( a 24 - year - old and a 31 - year - old ) with FMF who developed severe spondylitis and who were also treated with P00813 . Anti - P01375 agents can control FMF attacks quite effectively and they reveal a promising role in the treatment of FMF - associated amyloidosis and spondylitis .","Concomitant loss of p120 - catenin and β - catenin membrane expression and oral carcinoma progression with P12830 reduction . The binding of p120 - catenin and β - catenin to the cytoplasmic domain of P12830 establishes epithelial cell - cell adhesion . Reduction and loss of catenin expression degrades P12830 - mediated carcinoma cell - cell adhesion and causes carcinomas to progress into aggressive states . Since both catenins are differentially regulated and play distinct roles when they dissociate from P12830 , evaluation of their expression , subcellular localization and the correlation with P12830 expression are important subjects . However , the same analyses are not readily performed on squamous cell carcinomas in which P12830 expression determines the disease progression . In the present study , we examined expression and subcellular localization of p120 - catenin and β - catenin in oral carcinomas ( n = 67 ) and its implications in the carcinoma progression and P12830 expression using immunohitochemistry . At the invasive front , catenin - membrane - positive carcinoma cells were decreased in the dedifferentiated ( p120 - catenin , P < 0 . 05 ; β - catenin , P < 0 . 05 ) and invasive carcinomas ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 05 ) and with the P12830 staining ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 01 ) . Carcinoma cells with β - catenin cytoplasmic and / or nuclear staining were increased at the invasive front compared to the center of tumors ( P < 0 . 01 ) . Although the p120 - catenin isoform shift from three to one associates with carcinoma progression , it was not observed after TGF - β , P01133 or P01375 - α treatments . The total amount of p120 - catenin expression was decreased upon co - treatment of TGF - β with P01133 or P01375 - α . The above data indicate that catenin membrane staining is a primary determinant for P12830 - mediated cell - cell adhesion and progression of oral carcinomas . Furthermore , it suggests that loss of p120 - catenin expression and cytoplasmic localization of β - catenin fine - tune the carcinoma progression .","Golimumab . Inflammatory rheumatism : just another P01375 alpha antagonist , no advantage . In the absence of head - to - head comparisons with other P01375 alpha antagonists , which are perfectly feasible , there is no firm evidence that DB06674 has a better risk - benefit balance than other immunosuppressants .","Tumour necrosis factor α antagonists in the treatment of rheumatoid arthritis : an immunological perspective . Rheumatoid arthritis ( RA ) is one of the most prevalent autoimmune conditions , affecting approximately 1 % of the adult population . It is associated with decreased quality of life and considerable morbidity and mortality . Various inflammatory cells , including macrophages , neutrophils , mast cells , natural killer cells , B and T cells and stromal cells play key pathophysiological roles in joint inflammation and RA progression . Several cytokines , including interleukin ( IL ) - 1α and / or IL - 1β , and tumour necrosis factor ( P01375 ) - α , are involved at each stage of RA pathogenesis ; namely , by augmenting autoimmunity , sustaining long - term inflammatory synovitis and promoting joint damage . Different cell types are involved in RA pathogenesis through upregulation of several cytokine and soluble pro - inflammatory mediators . As early as the late 1980s , P01375 had been identified as a potential target in RA . Five anti - P01375 drugs , infliximab , adalimumab , certolizumab pegol , etanercept and DB06674 , are now approved for the treatment of RA in various countries . All are bivalent monoclonal antibodies , with the exception of the monovalent certolizumab and etanercept , which is an engineered dimeric receptor . Although all react with and neutralise soluble P01375 in vitro , structural differences in the molecules may contribute to differences in their therapeutic effects and the occurrence of side effects . Pegylated certolizumab permits once - monthly dosing . Other mechanisms of action proposed to be important for the efficacy of anti - P01375 agents are as follows : induction of apoptosis of both monocytes and T cells ; neutralization of membrane P01375 ; antibody - dependent cell - mediated and complement - dependent cytotoxicity ; and reverse signaling via membrane P01375 .","Golimumab for severe asthma . BACKGROUND : In severe asthma anti - P01375 therapies might be effective in improving disease control based on preclinical results and on clinical short - term data . However , the long - term efficacy and safety is not known . OBJECTIVE : To discuss the data on DB06674 , an anti - P01375 monoclonal antibody currently used in various forms of arthritis , evaluated as an add - on anti - inflammatory therapy in severe asthma . METHODS / RESULTS : Critical appraisal of the efficacy and safety clinical data . Golimumab was not found to be generally efficacious and demonstrated an unfavourable risk - benefit ratio , but in some asthma subsets its better therapeutic effects might support its use provided the long - term safety is acceptable . CONCLUSIONS : Although at first sight the safety and efficacy data of long - term use of DB06674 in severe asthma might be unsupportive , in some disease subsets it might be really effective .","[ Fully human anti P01375 monoclonal antibodies ( adalimumab , DB06674 ) ] . A number of studies have emphasized the critical role of P01375 in the pathogenesis of rheumatoid arthritis ( RA ) . New therapeutics called \" bilologicals \" have been recently admitted for treatment of RA , including infliximab and etanercept , also in Japan . Of note , fully human anti - P01375 a monoclonal antibodies , adalimumab and DB06674 , have been developed to overcome several major problems resulting from the chimeric natures of infliximab . The efficacy and safety of adalimumab have been demonstrated in several clinical trials , as highlighted in this review . Thus , adalimumab has already been approved for treatment of RA in the United States and European Union . The clinical trials of another fully human anti - P01375 monoclonal antibody DB06674 are now under way .","Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK3___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK3___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .","Golimumab in patients affected by moderate to severe psoriatic arthritis : an open - label study in thirty - two patients previously treated with other biologics . BACKGROUND : Clinical trials have demonstrated the efficacy of DB06674 ( GLB ) in improving the signs and symptoms of psoriatic arthritis ( PsA ) . OBJECTIVE : The aim of this study was to evaluate the efficacy of GLB in monotherapy in patients affected by PsA with cutaneous involvement unresponsive to other anti - tumor necrosis factor - α ( P01375 - α ) agents . METHODS : This study included 32 patients treated with GLB as monotherapy , at a dosage of 50 mg , subcutaneously , every 4 weeks . Patients were divided into 3 groups ( A , B , and C ) according to their number of previous anti - P01375 - α treatments ( 1 , 2 , or 3 ) . Clinical and laboratory evaluations were performed at weeks 0 , 12 , and 24 . RESULTS : All patients showed significant improvement of their clinical , inflammatory , and quality of life indexes . CONCLUSION : Data suggest that GLB can be successful and safe in patients affected by PsA with skin involvement previously treated with other anti - P01375 - α agents .","Golimumab : clinical update on its use for ulcerative colitis . Monoclonal antibodies directed against tumor necrosis factor alpha ( anti - P01375 - α agents ) have dramatically changed the therapeutical approach to inflammatory bowel diseases , such as Crohn ' s disease and ulcerative colitis . A new anti - P01375 drug , DB06674 , has recently been approved for patients with moderate to severe ulcerative colitis . Its efficacy has been demonstrated by preclinical and clinical studies and the drug showed an efficacy and safety profile in line with the other anti - P01375 agents , such as infliximab and adalimumab . This review gives an overview on DB06674 in the treatment of moderate to severe ulcerative colitis .","Golimumab : a new anti - P01375 agent for rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis . Rheumatoid arthritis ( RA ) is a chronic inflammatory systemic disease characterized by symmetric arthritis leading to progressive erosion of cartilage and bone . Psoriatic arthritis and ankylosing spondylitis are also inflammatory arthritides that belong to the spondyloarthritides . Disease - modifying anti - rheumatic drugs and biologic therapies including anti - P01375 agents are used in their treatment . The P01375 antagonists have shown rapid and sustained therapeutic responses . However , a substantial number of patients fail to respond to anti - P01375 agents or experience side effects . Golimumab is a human monoclonal antibody to P01375 - α requiring less frequent administration compared with current anti - P01375 products . Various trials have shown promising results in terms of efficacy and safety in methotrexate - naive and - resistant patients with RA as well as in patients previously treated with other anti - P01375 agents . The efficacy of DB06674 has also been demonstrated in patients with psoriatic arthritis and ankylosing spondylitis .","The effect of neutralizing antibodies on the sustainable efficacy of biologic therapies : what ' s in it for African and Middle Eastern rheumatologists . Over the last decade , biologic therapeutic proteins have advanced the treatment of diseases such as rheumatoid arthritis ( RA ) . Therapeutic antibodies such as infliximab , adalimumab , rituximab , tocilizumab , DB06674 , certolizumab pegol , the receptor construct etanercept , and abatacept , an anticluster of differentiation ( CD ) 80 / anti - P42081 fusion protein , are used as treatment for RA and ankylosing spondylitis ( AS ) . DB00065 , adalimumab , DB06674 , certolizumab pegol , and etanercept are inhibitors of tumor necrosis factor ( P01375 ) , a key regulator of inflammation . Left untreated , progression of rheumatic diseases due to inflammation can lead to irreversible joint damage and serious disability . One limitation for the use of therapeutic antibodies is immunogenicity , the induction of antibodies by the adaptive immune system in response to foreign substances . The development of antidrug antibodies ( ADAs ) has a varying impact on the clinical efficacy of biologic agents for the treatment of RA and AS , depending on whether the ADAs are neutralizing or non - neutralizing . Studies have indicated that neutralizing ADAs are associated with a reduced efficacy , decreased drug survival , increased instances of dose escalation , and adverse events . Comparison studies of anti - P01375 biologics have demonstrated that each drug has a different sustained efficacy profile depending on immunogenicity . The purpose of this review is to provide rheumatologists with information regarding the effect of neutralizing antibodies on the sustainable efficacy of anti - P01375 biologic therapies . This information will be of value to practicing rheumatologists in Africa and the Middle East who should take into account the potential for changes in the efficacy and safety of biologic therapies and closely monitor patients under their care .","Advances in the management of psoriatic arthritis . Psoriatic arthritis ( PsA ) , which affects musculoskeletal structures , skin and nails , is a heterogeneous chronic inflammatory disease with a wide clinical spectrum and variable course . Patients with PsA are more likely than healthy individuals to have metabolic syndrome or cardiovascular disease . To include these comorbidities , ' psoriatic disease ' has been suggested as an umbrella term . The management of PsA has changed tremendously over the past decade owing to early diagnosis and improvement in treatment strategies , including , early referral from dermatologists and primary - care physicians to rheumatologists , early initiation of therapy , treating to the target of remission or low disease activity , and advances in pharmacological therapy . Outcome assessment is also improving , because of validated instruments for clinical disease manifestations . The commercialization of P01375 blockers , including adalimumab , etanercept , DB06674 and infliximab , is representative of a revolution in the treatment of PsA . A new anti - P01375 agent , certolizumab pegol , and a fully human monoclonal antibody against IL - 12 and IL - 23 , ustekinumab , are approved for the treatment of active PsA . The efficacy of ustekinumab suggests that inhibiting the type 17 T helper pathway might be an alternative to blocking P01375 . PsA management must now use improved measures to predict patient outcomes and define remission , and develop better - targeted therapies .","Current and emerging biologics for ulcerative colitis . Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy . Hence , different biological agents that target specific immunological pathways are be - ing investigated for treating ulcerative colitis . Anti - tumor necrosis factor ( P01375 ) agents were the first biologics to be used for treating inflammatory bowel disease . For example , infliximab and adalimumab , which are anti - P01375 agents , are be - ing used for treating ulcerative colitis . Recently , DB06674 , another anti - P01375 agent , and vedolizumab , an anti - adhesion therapy , have been approved for ulcerative colitis by the U . S . Food and Drug Administration . In addition , new medications such as tofacitinib , a Janus kinase inhibitor , and etrolizumab , another anti - adhesion therapy , are emerging as therapeutic agents . Therefore , there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage .","Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .","Role of DB06674 , a P01375 inhibitor , in the treatment of the psoriatic arthritis . Psoriatic arthritis ( PsA ) is an inflammatory arthritis that affects many psoriasis patients and can often have a debilitating disease progression . Golimumab is a new tumor necrosis factor ( P01375 ) antagonist recently approved by the FDA for controlling signs and symptoms of psoriatic arthritis . In a Phase III clinical trial in patients with PsA , patients receiving DB06674 showed significant improvement in the signs and symptoms of disease . It was usually well tolerated , but adverse events generally occurred more in patients receiving DB06674 compared to placebo . Golimumab has also recently shown efficacy in slowing structural damage in PsA . This new biologic therapy provides physicians with another option in the treatment of this inflammatory arthritis while offering patients certain advantages over other P01375 antagonists .","Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK43___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK43___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .","Current evidence in the field of the management with P01375 - α inhibitors in psoriatic arthritis and concomitant hepatitis C virus infection . INTRODUCTION : Psoriatic arthritis ( PsA ) is a chronic inflammatory condition involving the spine , enthesis and peripheral joints , which is associated with psoriasis . PsA therapy varies from use of NSAIDs to disease - modifying anti - rheumatic agents ( DMARDs ) . However , their use can represent a limitation in patients with concomitant hepatitis C virus ( HCV ) infection . In the last few decades , anti - P01375 - α therapy has opened new horizons in the treatment of PsA . Hence , the purpose of this review is to explore the efficacy and safety of anti - P01375 - α agents in PsA and concomitant HCV infection . AREAS COVERED : We reviewed the available medical literature to find all cases of PsA and concomitant HCV infection treated with P01375 - α inhibitors . We found a total of 38 cases of patients with PsA and concomitant HCV infection in therapy with anti - P01375 - α agents . EXPERT OPINION : The available literature , summarized in this review , still remains very limited . Data suggest that therapy with the anti - P01375 - α agents , mainly etanercept and adalimumab , at least with short - term use , would appear efficacious and reasonably safe in the management of PsA patients with concomitant HCV infection . With regard to infliximab , efficacy and safety have been scarcely explored , whereas in the case of DB06674 and certolizumab no report was found , may be due to their recent introduction on the market .","P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK20___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .","Catecholamine - producing cells in the synovial tissue during arthritis : modulation of sympathetic neurotransmitters as new therapeutic target . BACKGROUND : The proinflammatory and anti - inflammatory role of the sympathetic nervous system in early and late inflammation is an unresolved paradox . A drastic loss of sympathetic nerve fibres in the synovial tissue of patients with rheumatoid arthritis ( RA ) has previously been demonstrated . The presence of tyrosine hydroxylase ( TH ) - positive cells in RA and osteoarthritis ( OA ) has been determined , but the role of these cells in inflammation is still unclear . OBJECTIVE : To characterise TH - positive cells in inflamed RA and OA synovial tissue and to study their role in inflammation . METHODS : Synovial samples were obtained from 32 patients with OA and 19 patients with RA and from 10 control patients . Synovial tissue samples were used for immunofluorescence staining . Synovial cells were isolated by tissue digestion and immediately used for cell culture . For in vivo experiments , collagen type - II arthritis in DBA / 1J mice was induced . RESULTS : TH + cells were present only in inflamed tissue and not in controls . Catecholamine - storing vesicles and vesicular monoamine transporter 2 ( Q05940 ) were identified in the synovial tissue . Experimental increase of cytoplasmic catecholamines by Q05940 blockade strongly reduced tumour necrosis factor ( P01375 ) independently of canonical extracellular β - adrenergic signalling . In addition , Q05940 blockade increased cyclic AMP ( DB02527 ) and DB02527 responsive element binding protein , responsible for P01375 inhibition . In vivo , appearance of Q05940 positive cells was confirmed . Q05940 blockade ameliorated inflammation also in vivo . CONCLUSIONS : This study demonstrates that local catecholamine - producing cells start to replace sympathetic nerve fibres around the onset of disease , and modulation of locally produced catecholamines has strong anti - inflammatory effects in vivo and in vitro .","Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization .","Efficacy of antitumor necrosis factor ( α ) agents on patients with ankylosing spondylitis . OBJECTIVES : This study was designed to investigate the efficacy of antitumor necrosis factor ( P01375 )( a ) agents ( etanercept , infliximab , DB06674 or adalimumab ) in ankylosing spondylitis ( AS ) . METHODS : A literature search was done using PubMed , Embaseand Cochrane databases . The reference section of all primary studies was inspected for additional references , and only those reporting the results of a randomized - controlled trial comparing etanercept , infliximab or adalimumab with placebo for patients with AS were included in this analysis . RESULTS : Eleven trials with 1851 patients were included . Compared with placebo , anti - P01375 ( α ) agents was associated with significantly higher rates of Assessment in Ankylosing Spondylitis ( ASAS ) 20 responders ( risk ratio [ RR ] : 2 . 45 , 95 % confidence interval [ CI ] : 2 . 13 - 2 . 82 ; P < 0 . 00001 ) , ASAS 50 responders ( RR : 3 . 77 , 95 % CI : 2 . 87 - 4 . 95 ; P < 0 . 00001 ) , ASAS 70 responders ( RR : 3 . 25 , 95 % CI : 1 . 97 - 5 . 35 ; P < 0 . 00001 ) and patients with partial remission ( RR : 5 . 39 , 95 % CI : 3 . 25 - 8 . 93 ; P < 0 . 00001 ) . In addition , there were more patients with at least 50 % improvement in the Bath Ankylosing Spondylitis Disease Activity Index score in the experimental groups ( RR : 3 . 07 , 95 % CI : 2 . 44 - 3 . 86 ; P < 0 . 00001 ) . Most adverse events in both treatment groups were mild or moderate in severity . CONCLUSIONS : Anti - P01375 ( a ) agents is an effective and well - tolerated treatment for reducing clinical symptoms of AS .","Two cases of Takayasu ' s arteritis occurring under anti - P01375 therapy . Takayasu ' s arteritis is a granulomatous , large vessel vasculitis that affects the aorta , its major branches and the pulmonary arteries . Compelling evidence exists to support the notion that Takayasu ' s arteritis is a T - cell mediated process and that tumor necrosis factor alpha ( TNFa ) is an important factor in the pathogenesis of this disease . Moreover , encouraging results from recent studies support the use of anti - TNFa therapy for relapsing or resistant cases of Takayasu ' s arteritis . Here , however , we describe the case of two patients : one with seropositive rheumatoid arthritis , the other with HLA - Q8TCY5 negative spondylarthropathy , who developed Takayasu ' s arteritis during treatment with TNFa inhibitors ( adalimumab and DB06674 respectively ) . This is the first report of Takayasu ' s arteritis in rheumatic patients under TNFa blocking agents which suggests the presence of different pathogenetic mechanism in a subgroup of patients with Takayasu ' s arteritis , as well as a potential role of TNFa blockers as triggers of this disease in some cases .","___MASK77___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK77___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .","Immunogenicity of anti - P01375 biologic therapies for rheumatoid arthritis . Currently , five anti - P01375 biologic agents are approved for the treatment of rheumatoid arthritis ( RA ) : adalimumab , infliximab , etanercept , DB06674 and certolizumab pegol . Formation of anti - drug antibodies ( P00813 ) has been associated with all five agents . In the case of adalimumab and infliximab , immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response , but for the other three agents , data on immunogenicity are scarce , suggesting that further research would be valuable . Low P00813 levels might not influence the efficacy of anti - P01375 therapy , whereas high P00813 levels impair treatment efficacy by considerably reducing unbound drug levels . Immunogenicity is not only an issue in patients treated with anti - P01375 biologic agents ; the immunogenicity of other therapeutic proteins , such as factor VIII and interferons , is well known and has been investigated for many years . The results of such studies suggest that investigations to determine the optimal treatment regimen ( drug dosing , treatment schedule and co - medication ) required to minimize the likelihood of P00813 formation might be an effective and practical way to deal with the immunogenicity of anti - P01375 biologic agents for RA .","DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .","Novel P01375 antagonists for the treatment of rheumatoid arthritis . IMPORTANCE OF THE FIELD : P01375 antagonists have become an integral part of the standard of care for patients with rheumatoid arthritis ( RA ) . Two additional P01375 antagonists have recently been approved in the US for this indication , and clinicians will need to understand the data on the efficacy and safety of these agents in order to properly place them into the clinical treatment algorithm . AREAS COVERED IN THIS REVIEW : This review covers the published clinical trial data on the use of certolizumab and DB06674 for RA . The literature search included manuscripts published through September 2009 and abstracts from major meetings ( P10323 and EULAR ) in 2007 - 2009 . WHAT THE READER WILL GAIN : This paper will review the efficacy and safety of DB06674 and certolizumab in the treatment of RA at various stages of disease . Use of these agents will be described in the context of other available alternatives , including other P01375 antagonists and other biologic therapies . TAKE HOME MESSAGE : Certolizumab and DB06674 have comparable efficacy and safety profiles compared with previously approved P01375 antagonists . These two agents have several unique theoretical benefits when compared to existing agents , but the available published data do not suggest a clear clinical advantage at this time ."],"string":"[\n \"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK54___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK54___ who were treated with a single dose of mifepristone .\",\n \"Apoptosis and the FLIP and NF - kappa B proteins as pharmacodynamic criteria for biosimilar P01375 antagonists . Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale . The imminent expiration of the patents on reference biological products which block the cytokine P01375 - α ( tumor necrosis factor - α ) raises the possibility of bringing so - called biosimilars to the market ( similar to the biologicals of reference products ) . This occurrence is inevitable , but criteria to adequately evaluate these medications are now needed . Even among controversy , there is a demand from publications correlating the pro - apoptotic mechanism of the original P01375 - α antagonists ( etanercept , infliximab , adalimumab , DB06674 , and certolizumab pegol ) in the treatment of rheumatoid arthritis and other diseases . In this article , the authors discuss the possibility of utilizing the pro - apoptotic effect correlated with the regulation of the anti - apoptotic proteins FLIP and NF - κB as new criteria for analyzing the pharmacodynamics of possible biosimilar P01375 - α antagonists which should be submitted to regulatory agencies for evaluation .\",\n \"anti - P01375 agents as therapeutic choice in immune - mediated inflammatory diseases : focus on adalimumab . The complex pathogenesis of immune - mediated inflammatory diseases ( IMIDs ) has been extensively investigated and dysregulation of cytokines , such as tumour necrosis factor ( P01375 ) has been shown to play a dominant role in the pathogenesis of various IMIDs , such as rheumatoid arthritis , ankylosing spondylitis , Crohn ' s disease , ulcerative colitis , psoriasis and psoriatic arthritis . The subsequent development of biological agents capable of blocking P01375 has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with P01375 having a predominant role . Five P01375 inhibitors have currently been approved for treatment of one or more IMIDs ; these include infliximab , etanercept , adalimumab , DB06674 and certolizumab pegol . Given the similarities in the pathogenic background of IMIDs , one could expect that anti - P01375 agents be similarly effective and with comparable tolerability profiles ; however , this may not be the case . Structural and pharmacological differences among the anti - P01375 drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs , together with differences in potency , therapeutic dose ranges , dosing regimens , administration routes , and propensity for immunogenicity . Among the five P01375 inhibitors approved for treatment of IMIDs , adalimumab has the widest range of indications . Data from controlled clinical trials of adalimumab , showing its excellent efficacy and tolerability in a wide range of indications , are supported by real - world long - term data from observational studies , which confirm the value of adalimumab as a suitable choice in the management of IMIDs .\",\n \"New biologic therapeutics for ulcerative colitis and Crohn ' s disease . INTRODUCTION : Some inflammatory bowel disease ( Q9UKU7 ) patients especially those with refractory Crohn ' s disease ( CD ) or relapsing ulcerative colitis ( UC ) do not respond to current therapies . The newly introduced biological drugs have got some interest due to their specificity and selectivity in modulation of inflammatory elements . AREAS COVERED : In 46 included randomized , placebo - controlled clinical trials , the efficacy and safety of different biologic drugs have been evaluated in moderately to severely active CD or UC patients . Current investigated drugs include new anti - P01375 drugs ( adalimumab , certolizumab pegol , etanercept , onercept and DB06674 ) , anti - P11836 ( rituximab ) , T - cell inhibitors ( abatacept ) and anti - α4 integrins ( natalizumab and vedolizumab ) . DB00051 , certolizumab , and DB06674 showed significant efficacy in induction of remission and maintenance in CD and UC patients with a rate of adverse events similar to placebo in the major trials . DB00108 and vedolizumab were effective in the treatment of moderately to severely active CD and UC patients . However , vedolizumab caused less adverse effects than natalizumab . onercept , etanercept , rituximab and abatacept were all well tolerated but were not effective in CD or UC patients . EXPERT OPINION : Anti - P01375 drugs , except for onercept and etanercept , and anti - α4 integrins exhibit beneficial therapeutic effects . Although they were all well tolerated , the incidence of progressive multifocal leukoencephalopathy associated with natalizumab should not be missed .\",\n \"An update on anti - P01375 agents in ulcerative colitis . Anti - tumor necrosis factor - α agents are key therapeutic options for the treatment of ulcerative colitis . Their efficacy and safety have been shown in large randomized controlled trials . The key evidence gained from these trials of infliximab , adalimumab , and DB06674 is reviewed along with their effect on mucosal healing and long - term outcomes . Also reviewed are methods for optimizing their effectiveness , including therapeutic drug monitoring and treat - to - target strategies . Finally , remaining unresolved questions regarding their role and effectiveness are considered including how these may be addressed in future clinical trials .\",\n \"Safety of anti - tumour necrosis factor agents in patients with chronic hepatitis C infection : a systematic review . OBJECTIVES : To identify all of the patients affected by chronic hepatitis C infection treated with P01375 - α blockers ( adalimumab , certolizumab pegol , etanercept , DB06674 and infliximab ) in order to evaluate the safety profile . METHODS : A systematic review of the literature from January 1990 to October 2010 . RESULTS : In total , 37 publications with data on 153 patients who were treated with anti - P01375 - α agents in the setting of HCV infection were found . The mean anti - P01375 - α treatment duration was 11 . 9 months . Ninety - one patients had RA , 22 had psoriasis , 6 had Crohn ' s disease and 14 patients had other chronic inflammatory diseases . To date , etanercept is the biological agent that has been most extensively used in the patients with HCV infection , with only one definitely confirmed case of HCV hepatitis worsening and five suspected cases ( elevation of transaminases not associated with an increase in the HCV viral load and vice versa ) in 110 treated patients . Treatment with this agent resulted in stable levels of liver transaminases and a stable viral load in 74 patients , with an improvement in HCV chronic liver disease in combination with IFN - ribavirin therapy in 29 patients . CONCLUSIONS : The safety profile of anti - P01375 - α agents in the setting of HCV infection seems to be acceptable , even if differences in the hepatotoxic profile are apparent between different agents . In the absence of long - term and large , controlled clinical trials a definitive statement on the safety of anti - P01375 - α therapies in the setting of chronic HCV infection can not be made .\",\n \"P01375 inhibitors in asthma and P48444 : we must not throw the baby out with the bath water . P01375 ( P01375 ) - alpha , a pleiotropic cytokine that exerts a variety of effects , such as growth promotion , growth inhibition , angiogenesis , cytotoxicity , inflammation , and immunomodulation , has been implicated in several inflammatory conditions . It plays a significant role in many inflammatory diseases of lungs . Given that there is significant literature supporting the pathobiologic role of P01375 in asthma , mainly in severe refractory asthma , and P48444 , P01375 inhibitors ( infliximab , DB06674 and etanercept ) are now regarded as the potential new medications in asthma and P48444 management . The studies reported in literature indicate that P01375 inhibitors are effective in a relatively small subgroup of patients with severe asthma , possibly defined by an increased P01375 axis , but they seem to be ineffective in P48444 , although an observational study demonstrated that P01375 inhibitors were associated with a reduction in the rate of P48444 hospitalisation among patients with P48444 receiving these agents to treat their rheumatoid arthritis . These findings require a smart approach because there is still good reason to target P01375 , perhaps in a more carefully selected patient group . P01375 treatment should , therefore , not be thrown out , or abandoned . Indeed , since severe asthma and P48444 are heterogeneous diseases that have characteristics that occur with different phenotypes that remained poorly characterized and little known about the underlying pathobiology contributing to them , it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from P01375 inhibitors .\",\n \"P01375 - alpha and X - linked adrenoleukodystrophy . The two most common forms of X - linked adrenoleukodystrophy ( X - P33897 ) , the childhood cerebral form ( CCER ) and the adult form , adrenomyeloneuropathy ( Q9BXJ7 ) , arise from the same mutations in the X - P33897 gene at Xq28 . These two forms are distinguished by the degree of cerebral inflammation . Segregation analysis suggests that an autosomal modifying gene may be a major determinant of phenotype in X - P33897 . Thus , a modifying gene could be involved in initiating or promoting the inflammatory response . In this study we detected a difference in tumor necrosis factor - alpha ( P01375 ) bioactivity , but not P01375 protein levels , in serum from some advanced CCER patients . Early - stage CCER patients and Q9BXJ7 patients were in the normal range . Allelic differences in P01375 or levels of soluble P01375 receptor did not account for bioactivity differences or phenotypic heterogeneity in X - P33897 .\",\n \"Pharmacology of P01375 blockade in rheumatoid arthritis and other chronic inflammatory diseases . P01375 - alpha ( P01375 ) has been unequivocally validated as a therapeutic target in a number of immune - mediated inflammatory disorders ( IMIDs ) . There is now increasing choice of biologic agents within the class all of which successfully neutralize sTNF . But approaches to P01375 inhibition differ and currently include mAbs ( infliximab , adalimumab , and DB06674 ) , either chimeric or human in sequence , a PEGylated Fab ' fragment ( certolizumab ) , and an IgG1 - P20333 fusion protein ( etanercept ) . It is emerging that the pharmacological properties of these three anti - P01375 subtypes differ with respect to Fc function , binding of tmTNF and the possible consequences of this , as well as the ability to form complexes . The mode of administration of each agent , clearance and the local tissue concentrations achieved may also confer unique characteristics of relevance with respect to efficacy and safety .\",\n \"Aspects of P01375 inhibitor therapy in rheumatoid arthritis . Treatment outcomes in rheumatoid arthritis ( RA ) have improved considerably with the use of biological therapies . Since the discovery of the role of tumor necrosis factor ( P01375 ) alpha in the pathogenesis of the disease , three P01375 inhibitors , infliximab , etanercept and adalimumab , have become widely used for the treatment of RA . More recently , two newer P01375 inhibitors - certolizumab pegol and DB06674 - have become available , increasing the armamentarium of therapy . With improved therapies , treatment strategies have also changed , with the aims now being to achieve and maintain remission . This article addresses some of these aspects of treating RA , reviewing the studies on these two newer P01375 inhibitors , certolizumab pegol and DB06674 , and those addressing the induction of remission or low disease activity with P01375 inhibitors and maintenance with less intensive treatment .\",\n \"Current , new and future biological agents on the horizon for the treatment of inflammatory bowel diseases . Biological agents for inflammatory bowel diseases ( Q9UKU7 ) targeting tumor necrosis factor ( P01375 ) have changed the way to treat Q9UKU7 refractory to standard medications and allowed us to reach new therapeutic goals such as mucosal healing and deep remission . A better understanding of the components of the pathological processes that are a hallmark of Q9UKU7 has led to the development of a new family of biological agents in Crohn ' s disease and ulcerative colitis . Biosimilars , which are copy versions of currently licensed biological agents , will be soon available . The biosimilar of infliximab is as effective and as safe as its originator in rheumatologic conditions , while a new anti - P01375 agent , namely DB06674 , has been recently approved for refractory ulcerative colitis . Beyond P01375 blockers , anti - adhesion molecules appear to be a potent drug class for Q9UKU7 . DB09033 was recently approved for both Crohn ' s disease and ulcerative colitis . Numerous other compounds are in the pipeline . Ustekinumab looks very promising for Crohn ' s disease . O15105 antisense oligonucleotide might enrich our armamentarium if preliminary data are confirmed in upcoming clinical trials . Herein , we review the efficacy and safety of new and emerging biological agents that are currently investigated in Q9UKU7 clinical trials .\",\n \"Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK91___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK91___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .\",\n \"Update on biologic therapies in ankylosing spondylitis : a literature review . AIM : The present paper aims to review the recent advances in diagnosis and management of ankylosing spondylitis ( AS ) . METHOD : Medline and abstracts submitted to the recent European League Against Rheumatism ( EULAR ) congress were searched to obtain quality - controlled information on the management of AS . RESULTS : The use of magnetic resonance imaging ( Q9BWK5 ) allows the diagnosis of AS to be made in the pre - radiographic stage . The Assessment in Spondylarthritis International Society recommendations for the management of AS have been modified so that patients with non - radiographic spondyloarthritis ( SpA ) can now be considered for biological therapy . The ' older ' anti - tumour necrosis factor ( P01375 ) continued to be effective in longer - term studies . Studies with longer duration of follow - up have shown that some patients with pre - radiographic SpA entered into prolonged drug - free remission . It is likely that in the foreseeable future , more AS patients will be treated with biological therapies at an earlier stage of the disease . New biologic therapies , DB06674 and secukinumab , are looking promising in improving the signs and symptoms of AS , at least in the short - term . CONCLUSION : Longer - term studies of AS patients treated with infliximab , etanercept and adalimumab continued to show a good clinical response . There is a need for more long - term studies to examine the longitudinal efficacy of DB06674 and secukinumab in AS .\",\n \"Safety issues and concerns of new immunomodulators in rheumatology . INTRODUCTION : The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis . Since the first anti - P01375 - α therapies , numerous molecules have been identified as targets of immunomodulatory therapies , such as IL - 1 ( anakinra , canakinumab ) , P05231 ( tocilizumab ) , P11836 (+) B cells ( rituximab ) , P16410 ( abatacept ) and two additional anti - P01375 - α therapies ( certolizumab pegol , DB06674 ) . AREAS COVERED : In the present review , we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy . The risk of infection should be identified before initiating a biologic treatment and markers checked over time , in particular for tuberculosis and hepatitis B and C viruses . Other infections ( bacterial , viral , parasitic ; opportunistic ; surgery - related ) and safety issues may require temporary interruption of the treatment until complete resolution . No significantly increased risk of malignancy , both hematological and solid , has been associated with the use of biologic agents . In all cases , it is difficult to dissect the risks related to biologics from those related to baseline treatments . EXPERT OPINION : Detailed medical history and laboratory screening should be performed before starting biologic therapies . Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects .\",\n \"___MASK71___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK71___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK71___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .\",\n \"Round window membrane permeability to DB06674 in guinea pigs : a pilot study . OBJECTIVES / HYPOTHESIS : Autoimmune inner ear disorder is one of a few types of sensorineural hearing loss that is treatable and potentially reversible . Treatment involves oral steroids and methotrexate . Other treatment modalities have been tried with variable success . All such treatments are systemic , with inherent side effects limiting their effectiveness . Recently , tumor necrosis factor ( P01375 ) - α blockers have been suggested as a modality of treatment . The objective of this study was to assess the round window membrane permeability to DB06674 , a P01375 - α blocker . This study is the first to look at the feasibility of local DB06674 delivery into the inner ear , which may allow for targeted immune modulation of autoimmune inner ear disorders without the consequences of systemic treatment . STUDY DESIGN : This is a single - blinded , placebo - controlled , pilot study using guinea pigs to assess round window membrane permeability to DB06674 . METHODS : Golimumab was instilled into the guinea pigs ' middle ear . Inner ear fluid was sampled through the round window membrane after approximately 30 minutes of drug exposure . Golimumab presence in the inner ear was assessed by enzyme - linked immunosorbent assay in both drug - treated and control ears . RESULTS : Higher concentrations of DB06674 were detected in the inner ear fluid samples of DB06674 - exposed ears than in the control ears . The difference was statistically significant ( P < . 001 ) . CONCLUSIONS : Golimumab crosses the round window membrane and is detected in measurable concentrations in the inner ear fluid after 30 minutes of exposure to the membrane . Further studies are needed to learn its pharmacokinetics and the time needed to reach optimal concentration in the inner ear . LEVEL OF EVIDENCE : NA . Laryngoscope , 123 : 2840 - 2844 , 2013 .\",\n \"Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases . BACKGROUND : Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases ( Q9UKU7 ) . To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis , we investigated their effects on endotoxin - induced tumour necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 1 beta and P05231 release by elutriation - purified human monocytes in vitro . METHODS : Drugs tested were dexamethasone , DB00244 , sulphapyridine and zileuton ( a P09917 inhibitor ) . Monocytes were isolated and stimulated with endotoxin , and P01375 , IL - 1 and P05231 levels were determined using an enzyme - linked immunosorbent assay . RESULTS : Monocyte stimulation with endotoxin resulted in an average P01375 release of 2464 +/- 64 pg / 10 ( 6 ) cells , IL - 1 release of 616 +/- 47 pg / 10 ( 6 ) cells and P05231 release of 2259 +/- 148 pg / 10 ( 6 ) cells . Addition of dexamethasone resulted in a reduction of P01375 , IL - 1 and P05231 release to below background levels . DB00891 significantly reduced P01375 and induced IL - 1 release in a dose - dependent fashion , but had no significant effect on P05231 release . 5 - ___MASK73___ did not modulate P05231 synthesis , but significantly reduced IL - 1 and enhanced P01375 synthesis . Zileuton reduced P01375 and P05231 release , but enhanced IL - 1 release . CONCLUSION : We conclude that these anti - inflammatory drugs are able to modulate cytokine release by human monocytes . Further studies are needed to determine whether these effects are related to their therapeutic efficacy in Q9UKU7 .\",\n \"The antibody response against human and chimeric anti - P01375 therapeutic antibodies primarily targets the P01375 binding region . BACKGROUND : In a subset of patients , anti tumour necrosis factor ( P01375 ) therapeutic antibodies are immunogenic , resulting in the formation of antidrug antibodies ( ADAs ) . Neutralising ADAs compete with P01375 for its binding site and reduces the effective serum concentration , causing clinical non - response . It is however unknown to which extent ADAs are neutralising . OBJECTIVES : To study which proportion of antibodies to human ( ised ) anti - P01375 ( adalimumab , DB06674 , certolizumab ) as well as chimeric anti - P01375 ( infliximab ) is neutralising . METHODS : Neutralising capacity of ADAs was assessed using a P01375 competition assay in P00813 - positive sera of patients treated with adalimumab ( n = 21 ) , DB06674 ( n = 4 ) , certolizumab ( n = 9 ) or infliximab ( n = 34 ) sent in to our diagnostic department . RESULTS : In 34 sera with ADAs to adalimumab , DB06674 or certolizumab , > 97 % of the antibodies were neutralising . In 34 sera with ADAs to infliximab > 90 % of the antibodies were neutralising . Further characterisation of the broader antibody response to infliximab revealed that non - neutralising antibodies to infliximab do not target murine domains , but may bind infliximab - unique domains not involved in P01375 binding ( located outside the paratope ) . CONCLUSIONS : Our study shows that ADAs to human ( ised ) as well as chimeric anti - P01375 therapeutic antibodies are largely neutralising . This highly restricted P00813 response suggests an immunodominant role for the paratope of anti - P01375 therapeutics .\",\n \"Clinically relevant advances in rheumatoid arthritis therapy . Owing to the success of biologics in the treatment of rheumatoid arthritis ( RA ) , several novel drugs have been introduced in the therapeutic armamentarium , although not all of them have been approved in all countries worldwide . Among the drugs are tumour necrosis factor ( P01375 ) inhibitors such as certolizumab pegol and DB06674 ( the latter of which was the first P01375 blocker shown to be effective in patients who had been unsuccessfully treated with other P01375 blockers and which can be applied only once a month ) , and the interleukin - 6 receptor antagonist tocilizumab , which not only opens up a completely new field of anti - inflammatory modulation of RA pathophysiology , but also highlights the challenge of novel potential side effects . Moreover , aside from clinical studies showing efficacy in the inhibition of osteoclast activation by the anti - O14788 ( receptor activator of nuclear factor - kappa B ligand ) antibody denosumab , an improved form of steroid application known as slow - release ' tempus tablet ' for treatment of RA and several developments in the small - molecule area have been addressed by clinical trials .\",\n \"Combination systemic therapies in psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic , progressive , and debilitating disorder . When monotherapy fails , combination therapy is necessary for the long - term management of these patients . There is currently no review on this subject , and the purpose of this study was to investigate and describe the current literature on combination therapy in PsA . A PubMed MeSH search was performed for psoriatic arthritis and combination therapy , which yielded at total of 83 articles . After excluding reviews and commentaries , and pursuing relevant citations , a total of 21 articles on the subject were found : one study of NSAIDs and methotrexate , three studies of cyclosporine and methotrexate , three studies of non - P01375 biologic inhibitors ( alefacept , ustekinumab ) and methotrexate , and 14 studies of anti - P01375 - inhibitors ( etanercept , adalimumab , infliximab , DB06674 ) and methotrexate . The combination of cyclosporine and methotrexate reduces the dosages and also the side effects of each agent , allowing better disease control with less toxicity . DB00563 in combination with biologic agents , either non - P01375 inhibitors or anti - P01375 inhibitors , may have a role in decreasing side effects , but it does not appear to improve clinical symptoms beyond those attained by biologic monotherapy .\",\n \"Emerging drugs for the treatment of axial and peripheral spondyloarthritis . INTRODUCTION : The topic under discussion is of strong relevance to the field of spondyloarthritis ( SpA ) because , in addition to established biological , there are new promising compounds . The reason for the review is to put all available data together to allow for an overview on recent developments and to especially inform readers about emerging drugs , biologics and small molecules in the field of SpA . AREAS COVERED : This review on new therapies in axial and peripheral SpA comprising psoriatic arthritis ( PsA ) shows , that , in addition to the established anti - P01375 agents infliximab , etanercept , adalimumab , DB06674 , certolizumab and the first biosimilar approved in the EU , there are at least two emerging biologics in the field of SpA : ustekinumab , a compound targeting IL12 / IL - 23 via the p40 subunit of both cytokines works for psoriasis and PsA and probably also for Crohn ' s disease , and the anti - Q16552 antibody secukinumab which has also been shown to work in psoriasis , both compounds seem to also work in ankylosing spondylitis . In addition , the potential of two small molecules , apremilast a phoshodiesterase4 inhibitor and tofacitinib , a januskinase inhibitor is discussed . EXPERT OPINION : Since , in contrast to rheumatoid arthritis , the therapeutic array in SpA is currently limited to P01375 - blockers , and since there is still an unmet need because some patients do not respond to anti - P01375 therapy at all or they loose response , new agents with a different mechanism of action are eagerly awaited .\",\n \"Selective P01375 - α inhibitor - induced injection site reactions . INTRODUCTION : During the last decade , many new biological immune modulators entered the market as new therapeutic principles . P01375 - α is a pro - inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune - mediated or inflammatory diseases . P01375 - α blockers have demonstrated efficacy in large , randomized controlled clinical trials either as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs . AREAS COVERED : Although generally well tolerated and safe , potential adverse events may be associated with P01375 - α inhibitor treatment . The authors will briefly review the potential adverse drug reactions and the immunological mechanisms of injection site reactions ( ISRs ) in patients treated with etanercept and adalimumab . EXPERT OPINION : Patients treated with P01375 - α inhibitors can develop ISR around the sites of injections . ' Type IV delayed type reaction ' or ' recall ISRs ' . Eosinophilic cellulitis or ' Wells syndrome ' , ' type III ' and ' type I ' reactions are reported . Long - term studies are necessary to determine the durability of response and the real risk of ISRs with DB06674 and certolizumab pegol . Further studies are also necessary to evaluate the immunogenicity of these drugs .\",\n \"P01375 inhibitors - state of knowledge . P01375 ( P01375 ) is considered a major proinflammatory cytokine , affecting various aspects of the immune reaction . All five P01375 inhibitors currently available on the market ( i . e . , etanercept , infliximab , adalimumab , certolizumab and DB06674 ) are top sellers , although indicated only in autoimmune diseases , including rheumatoid arthritis , Crohn ' s disease and psoriasis . This article briefly discusses the background and place for P01375 inhibitors in modern therapy . The main safety aspects of P01375 inhibitor administration are described in particular , with special consideration of the available meta - analyses . Finally , perspectives on the next - generation P01375 inhibitors and their use in the clinic are given .\",\n \"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK93___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .\",\n \"Subacute lupus erythematosus during treatment with DB06674 for seronegative rheumatoid arthritis . We report on a 52 - year - old woman with a history of severe seronegative rheumatoid arthritis . Several conventional therapies and biological therapy with etanercept and infliximab had been unsuccessful . In 2010 she was given DB06674 subcutaneously at a monthly dose of 50 mg . She had a negative Q14201 titre . After 16 months of uninterrupted therapy and sustained response , she developed skin lesions on the upper trunk , back and upper extremities , which worsened on exposure to the sun . The skin biopsy was compatible with subacute lupus erythematosus . Laboratory findings included an Q14201 titre 1 : 640 , negative anti - Ro / SSA and anti - DNA antibodies . Topical corticosteroid therapy proved inadequate . The patient ' s condition improved only after discontinuation of DB06674 . The causal relationship between subacute cutaneous lupus erythematosus and DB06674 is not dose - related and occurs with some delay ( a typical feature of immunological adverse reactions ) . The association is likely , but not confirmed ( because re - challenge was not performed ) . However , a clear improvement was noted after withdrawal . Based on this case , we hypothesized the aetiological role of DB06674 - associated immunogenicity . P01375 - α antagonist - induced lupus - like syndrome ( TAILS ) is a well - known side effect of this class of substances . The British Society of Rheumatology recommends discontinuation of the causal anti - P01375 - α treatment in patients with TAILS .\",\n \"Tailored therapy for severe asthma . Patients with severe asthma or P48444 have often a suboptimal symptom control due to inadequate treatment . A better understanding of pathogenetic mechanisms , phenotypes , endotypes and the new technologies available in the fields of molecular biology and immunogenetics have made it possible to synthesize specific monoclonal antibodies virtually able to interact with any target antigen , or to open a way for new therapeutic target options . At the moment , the only biologic drug available in clinical practice is omalizumab . To overcome the limits of omalizumab , the research has focused on new monoclonal antibodies presenting higher avidity for IgE ( e . g . ligelizumab and lumiximab ) and ability to interact also with low affinity IgE receptor ( FcϵRII ) . At present , many new biological drugs with different mechanisms of action and targets are matter of research . It is very important to identify the asthmatic phenotype in order to select the most appropriate drug for the individual patient . The most promising agents are targeted against cytokines of Th2 pattern and related receptors , such as P60568 ( daclizumab ) and P35225 ( lebrikizumab ) or P05113 in patients with hypereosinophilia ( mepolizumab , reslizumab and benralizumab ) . Other interesting drugs have as a target P01375 - α or its soluble receptor ( infliximab , DB06674 and etanercept ) or IL - 1 ( canakinumab ) , a cytokine with an important systemic proinflammatory action . Finally , the discovery of increased levels of C5a in the airways of asthmatic patients has led to the synthesis of a specific monoclonal antibody ( eculizumab ) . Further help should come from the identification of biomarkers that can guide in choosing the best treatment for the individual patient , such as IgE for omalizumab or periostin for lebrikizumab .\",\n \"Treatment of ulcerative colitis . PURPOSE OF REVIEW : Ulcerative colitis is a chronic inflammatory disease of the colon of unknown cause that is characterized by alternating intervals of active and inactive disease in 80 - 90 % of patients . The primary goal of treatment is to induce and maintain remission using therapy tailored to the individual patient . The purpose of this review was to describe the management of ulcerative colitis with emphasis on the use of anti - tumor necrosis factor ( P01375 ) agents . RECENT FINDINGS : Recent research has shown that new anti - P01375 agents , adalimumab ( P00813 ) and DB06674 , are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis . In a recent study , infliximab was found to have comparable efficacy to cyclosporine in treatment of acute severe refractory to corticosteroids ulcerative colitis . SUMMARY : Anti - P01375 therapy should be initiated in patients with acute severe refractory to corticosteroids ulcerative colitis and in patients with moderate - to - severe ulcerative colitis who are not responsive to conventional treatment with aminosalicylates , corticosteroids and immune modulators . Alternatives to infliximab are P00813 and DB06674 . Future research is needed to further assess the long - term efficacy and safety of P00813 and DB06674 in ulcerative colitis .\",\n \"Pharmacogenetics and future therapeutic scenarios : what affects the prediction of response to treatment with etanercept ? There are five tumor necrosis factor alpha ( P01375 - α ) inhibitors available for clinical use that have demonstrated efficacy as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs ( DMARDs ) in the treatment of immune - mediated diseases . These include the anti - P01375 - α monoclonal antibodies infliximab , adalimumab , DB06674 , and certolizumab pegol , and the fusion protein , etanercept . The use of pharmacogenetic testing has the potential to increase drug efficiency by identifying genetic factors responsible for a lack of response to , or toxicities from , P01375 - α inhibitors , and could be used to individualize therapy . Several studies have reported associations between genetic polymorphisms and the response to etanercept , but most are small and insufficiently powered to detect effect , and markers tend to be more prognostic than predictive of therapeutic response . Limitations of pharmacogenetic studies include the use of single nucleotide polymorphisms ( SNPs ) , genes in linkage with other loci , interaction of environmental factors , and cohort heterogeneity , all of which can complicate the relationship between genetic polymorphisms and treatment response . Further studies are needed for pharmacogenetics to become a routine part of daily clinical therapeutic practice .\",\n \"P01375 inhibitors in psoriasis : an update . Three inhibitors of tumor necrosis factor ( P01375 ) currently are approved for the treatment of psoriasis : etanercept , infliximab , and adalimumab . The other two P01375 inhibitors , DB06674 and certolizumab pegol , have shown efficacy against plaque psoriasis in clinical trials of psoriatic arthritis ( PsA ) . This article reviews the most recent evidence on the efficacy and safety of the P01375 inhibitors in psoriasis , with special attention to preventing and managing immunogenicity .\",\n \"Screening of 134 single nucleotide polymorphisms ( SNPs ) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes . More than 120 published reports have described associations between single nucleotide polymorphisms ( SNPs ) and type 2 diabetes . However , multiple studies of the same variant have often been discordant . From a literature search , we identified previously reported type 2 diabetes - associated SNPs . We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium ( r ( 2 ) > 0 . 8 ) with another typed SNP . Of the 114 SNPs examined , we followed up the 20 most significant SNPs ( P < 0 . 10 ) on an additional 384 case subjects and 366 control subjects from a population - based study in Finland . In the combined data , we replicated association ( P < 0 . 05 ) for 12 SNPs : P37231 Pro12Ala and His447 , Q14654 Glu23Lys and rs5210 , P01375 - 857 , P11168 Ile110Thr , P20823 / TCF1 rs2701175 and GE117881_360 , P35558 - 232 , Q13562 Thr45Ala , P05231 - 598 , and P22413 Lys121Gln . The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association ( P = 0 . 012 ) . We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample ( P = 0 . 03 ) , although we also replicated 4 of 58 SNPs from genes that had only one previous report of association .\",\n \"Long term efficacy and safety of etanercept in the treatment of psoriasis and psoriatic arthritis . Psoriasis is a chronic , immune - mediated inflammatory disease affecting both the skin and joints . Approximately 20 % of patients suffer a moderate to severe form of skin disease and up to 30 % have joint involvement . Standard therapies for psoriasis include topical medications , phototherapy , and both oral systemic and biological therapies whereas therapies for psoriatic arthritis include nonsteroidal anti - inflammatory drugs followed by disease modifying antirheumatic drugs and / or tumor necrosis factor ( P01375 ) - α inhibitors and interleukin - 12 / 23p40 inhibitors . Treatment of both diseases is typically driven by disease severity . In the past decade , major advances in the understanding of the immunopathogenesis of psoriasis and psoriatic arthritis have led to the development of numerous biological therapies , which have revolutionized the treatment for moderate to severe plaque psoriasis and psoriatic arthritis . Anti - P01375 - α agents are currently considered as first line biological therapies for the treatment of moderate to severe psoriasis and psoriatic arthritis . Currently approved anti - P01375 - α agents include etanercept , adalimumab , and infliximab for psoriasis and psoriatic arthritis as well as DB06674 and certolizumab for psoriatic arthritis . In this article , we aim to evaluate the long term safety and efficacy of etanercept in psoriasis and psoriatic arthritis .\",\n \"Optimizing outcomes in rheumatoid arthritis patients with inadequate responses to disease - modifying anti - rheumatic drugs . Conventional DMARDs such as MTX are the mainstay of treatment for patients with RA . However , failure to achieve adequate disease control in many patients , even with combination therapy , has spurred the development of agents that target various immune mediators involved in the disease process . In the past decade , biologic agents have proved viable as alternative or add - on therapy to DMARDs in patients whose disease is inadequately controlled . Well - controlled clinical trials have evaluated the effects of these agents not only on disease activity , but also on inhibition of structural change and improvement in physical function . This article reviews phase 3 clinical trial results on biologic agents that inhibit T - and B - cell activation ( abatacept and rituximab , respectively ) , inflammatory cytokines such as P01375 - α ( adalimumab , etanercept , infliximab , DB06674 and certolizumab ) and P05231 ( tocilizumab ) . Although data comparing the efficacy of the various biologic agents are limited , the availability of biologic therapies with differing mechanisms of action expands therapeutic options for patients whose disease is inadequately controlled with DMARDs and allows for greater individualization of treatment .\",\n \"Psoriasiform exfoliative erythroderma induced by DB06674 . Golimumab is a fully human anti - tumour necrosis factor ( P01375 ) - α monoclonal antibody approved for use in the treatment of active rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis . Psoriasis induced by treatment with anti - P01375 drugs is well documented , but to our knowledge , the development of clinical features of psoriasiform exfoliative erythroderma during treatment with DB06674 has not been previously described .\",\n \"Golimumab and immunogenicity ? 2010 and beyond . Immunogenicity is a frequent adverse event observed with biological agents ' therapy . Challenges of management in patients with rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis treated with DB06674 , an anti - P01375 blocker , include limited generation of antibodies like anti - nuclear , anti - DB06674 , and anti - double stranded DNA antibodies . We conducted here a meta - analysis study in order to evaluate and compare the newly generated antibody levels after DB06674 therapy . The examination of original clinical trials revealed that their levels were neither higher nor significant . Moreover , no evident associations between the induced - antibodies and lupus - like syndromes and / or infusion site reaction were reported . The reduced patients cohort and the absence of systematic newly generated antibodies follow - up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy , and / or predicting for their worse prognosis . Hence , further studies are required to ascertain the real impact of the induced antibodies after DB06674 ' s therapy .\",\n \"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .\",\n \"Anti - P01375 agents in familial Mediterranean fever : report of three cases and review of the literature . Familial Mediterranean fever ( FMF ) is an autoinflammatory disease characterized by recurrent fever , peritonitis / pleuritis , or arthritis attacks . Patients may have FMF - associated mutations of pyrin . The role of biologics such as anti - tumor necrosis factor ( P01375 ) agents ( infliximab , etanercept , adalimumab , DB06674 ) and anakinra , canakinumab , or rilonacept in the treatment of FMF needs to be clarified . Herein we present reports of three patients ( all were positive for HLA Q8TCY5 ) with typical spondylitis associated with FMF who were successfully managed with anti - P01375 agents , along with a literature review . The patients were a 37 - year - old man with concomitant Crohn ' s disease and amyloidosis who was treated with infliximab ( P27352 , 5 mg / kg for 3 years ) and switched to adalimumab ( P00813 ) , and two female patients ( a 24 - year - old and a 31 - year - old ) with FMF who developed severe spondylitis and who were also treated with P00813 . Anti - P01375 agents can control FMF attacks quite effectively and they reveal a promising role in the treatment of FMF - associated amyloidosis and spondylitis .\",\n \"Concomitant loss of p120 - catenin and β - catenin membrane expression and oral carcinoma progression with P12830 reduction . The binding of p120 - catenin and β - catenin to the cytoplasmic domain of P12830 establishes epithelial cell - cell adhesion . Reduction and loss of catenin expression degrades P12830 - mediated carcinoma cell - cell adhesion and causes carcinomas to progress into aggressive states . Since both catenins are differentially regulated and play distinct roles when they dissociate from P12830 , evaluation of their expression , subcellular localization and the correlation with P12830 expression are important subjects . However , the same analyses are not readily performed on squamous cell carcinomas in which P12830 expression determines the disease progression . In the present study , we examined expression and subcellular localization of p120 - catenin and β - catenin in oral carcinomas ( n = 67 ) and its implications in the carcinoma progression and P12830 expression using immunohitochemistry . At the invasive front , catenin - membrane - positive carcinoma cells were decreased in the dedifferentiated ( p120 - catenin , P < 0 . 05 ; β - catenin , P < 0 . 05 ) and invasive carcinomas ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 05 ) and with the P12830 staining ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 01 ) . Carcinoma cells with β - catenin cytoplasmic and / or nuclear staining were increased at the invasive front compared to the center of tumors ( P < 0 . 01 ) . Although the p120 - catenin isoform shift from three to one associates with carcinoma progression , it was not observed after TGF - β , P01133 or P01375 - α treatments . The total amount of p120 - catenin expression was decreased upon co - treatment of TGF - β with P01133 or P01375 - α . The above data indicate that catenin membrane staining is a primary determinant for P12830 - mediated cell - cell adhesion and progression of oral carcinomas . Furthermore , it suggests that loss of p120 - catenin expression and cytoplasmic localization of β - catenin fine - tune the carcinoma progression .\",\n \"Golimumab . Inflammatory rheumatism : just another P01375 alpha antagonist , no advantage . In the absence of head - to - head comparisons with other P01375 alpha antagonists , which are perfectly feasible , there is no firm evidence that DB06674 has a better risk - benefit balance than other immunosuppressants .\",\n \"Tumour necrosis factor α antagonists in the treatment of rheumatoid arthritis : an immunological perspective . Rheumatoid arthritis ( RA ) is one of the most prevalent autoimmune conditions , affecting approximately 1 % of the adult population . It is associated with decreased quality of life and considerable morbidity and mortality . Various inflammatory cells , including macrophages , neutrophils , mast cells , natural killer cells , B and T cells and stromal cells play key pathophysiological roles in joint inflammation and RA progression . Several cytokines , including interleukin ( IL ) - 1α and / or IL - 1β , and tumour necrosis factor ( P01375 ) - α , are involved at each stage of RA pathogenesis ; namely , by augmenting autoimmunity , sustaining long - term inflammatory synovitis and promoting joint damage . Different cell types are involved in RA pathogenesis through upregulation of several cytokine and soluble pro - inflammatory mediators . As early as the late 1980s , P01375 had been identified as a potential target in RA . Five anti - P01375 drugs , infliximab , adalimumab , certolizumab pegol , etanercept and DB06674 , are now approved for the treatment of RA in various countries . All are bivalent monoclonal antibodies , with the exception of the monovalent certolizumab and etanercept , which is an engineered dimeric receptor . Although all react with and neutralise soluble P01375 in vitro , structural differences in the molecules may contribute to differences in their therapeutic effects and the occurrence of side effects . Pegylated certolizumab permits once - monthly dosing . Other mechanisms of action proposed to be important for the efficacy of anti - P01375 agents are as follows : induction of apoptosis of both monocytes and T cells ; neutralization of membrane P01375 ; antibody - dependent cell - mediated and complement - dependent cytotoxicity ; and reverse signaling via membrane P01375 .\",\n \"Golimumab for severe asthma . BACKGROUND : In severe asthma anti - P01375 therapies might be effective in improving disease control based on preclinical results and on clinical short - term data . However , the long - term efficacy and safety is not known . OBJECTIVE : To discuss the data on DB06674 , an anti - P01375 monoclonal antibody currently used in various forms of arthritis , evaluated as an add - on anti - inflammatory therapy in severe asthma . METHODS / RESULTS : Critical appraisal of the efficacy and safety clinical data . Golimumab was not found to be generally efficacious and demonstrated an unfavourable risk - benefit ratio , but in some asthma subsets its better therapeutic effects might support its use provided the long - term safety is acceptable . CONCLUSIONS : Although at first sight the safety and efficacy data of long - term use of DB06674 in severe asthma might be unsupportive , in some disease subsets it might be really effective .\",\n \"[ Fully human anti P01375 monoclonal antibodies ( adalimumab , DB06674 ) ] . A number of studies have emphasized the critical role of P01375 in the pathogenesis of rheumatoid arthritis ( RA ) . New therapeutics called \\\" bilologicals \\\" have been recently admitted for treatment of RA , including infliximab and etanercept , also in Japan . Of note , fully human anti - P01375 a monoclonal antibodies , adalimumab and DB06674 , have been developed to overcome several major problems resulting from the chimeric natures of infliximab . The efficacy and safety of adalimumab have been demonstrated in several clinical trials , as highlighted in this review . Thus , adalimumab has already been approved for treatment of RA in the United States and European Union . The clinical trials of another fully human anti - P01375 monoclonal antibody DB06674 are now under way .\",\n \"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK3___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK3___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .\",\n \"Golimumab in patients affected by moderate to severe psoriatic arthritis : an open - label study in thirty - two patients previously treated with other biologics . BACKGROUND : Clinical trials have demonstrated the efficacy of DB06674 ( GLB ) in improving the signs and symptoms of psoriatic arthritis ( PsA ) . OBJECTIVE : The aim of this study was to evaluate the efficacy of GLB in monotherapy in patients affected by PsA with cutaneous involvement unresponsive to other anti - tumor necrosis factor - α ( P01375 - α ) agents . METHODS : This study included 32 patients treated with GLB as monotherapy , at a dosage of 50 mg , subcutaneously , every 4 weeks . Patients were divided into 3 groups ( A , B , and C ) according to their number of previous anti - P01375 - α treatments ( 1 , 2 , or 3 ) . Clinical and laboratory evaluations were performed at weeks 0 , 12 , and 24 . RESULTS : All patients showed significant improvement of their clinical , inflammatory , and quality of life indexes . CONCLUSION : Data suggest that GLB can be successful and safe in patients affected by PsA with skin involvement previously treated with other anti - P01375 - α agents .\",\n \"Golimumab : clinical update on its use for ulcerative colitis . Monoclonal antibodies directed against tumor necrosis factor alpha ( anti - P01375 - α agents ) have dramatically changed the therapeutical approach to inflammatory bowel diseases , such as Crohn ' s disease and ulcerative colitis . A new anti - P01375 drug , DB06674 , has recently been approved for patients with moderate to severe ulcerative colitis . Its efficacy has been demonstrated by preclinical and clinical studies and the drug showed an efficacy and safety profile in line with the other anti - P01375 agents , such as infliximab and adalimumab . This review gives an overview on DB06674 in the treatment of moderate to severe ulcerative colitis .\",\n \"Golimumab : a new anti - P01375 agent for rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis . Rheumatoid arthritis ( RA ) is a chronic inflammatory systemic disease characterized by symmetric arthritis leading to progressive erosion of cartilage and bone . Psoriatic arthritis and ankylosing spondylitis are also inflammatory arthritides that belong to the spondyloarthritides . Disease - modifying anti - rheumatic drugs and biologic therapies including anti - P01375 agents are used in their treatment . The P01375 antagonists have shown rapid and sustained therapeutic responses . However , a substantial number of patients fail to respond to anti - P01375 agents or experience side effects . Golimumab is a human monoclonal antibody to P01375 - α requiring less frequent administration compared with current anti - P01375 products . Various trials have shown promising results in terms of efficacy and safety in methotrexate - naive and - resistant patients with RA as well as in patients previously treated with other anti - P01375 agents . The efficacy of DB06674 has also been demonstrated in patients with psoriatic arthritis and ankylosing spondylitis .\",\n \"The effect of neutralizing antibodies on the sustainable efficacy of biologic therapies : what ' s in it for African and Middle Eastern rheumatologists . Over the last decade , biologic therapeutic proteins have advanced the treatment of diseases such as rheumatoid arthritis ( RA ) . Therapeutic antibodies such as infliximab , adalimumab , rituximab , tocilizumab , DB06674 , certolizumab pegol , the receptor construct etanercept , and abatacept , an anticluster of differentiation ( CD ) 80 / anti - P42081 fusion protein , are used as treatment for RA and ankylosing spondylitis ( AS ) . DB00065 , adalimumab , DB06674 , certolizumab pegol , and etanercept are inhibitors of tumor necrosis factor ( P01375 ) , a key regulator of inflammation . Left untreated , progression of rheumatic diseases due to inflammation can lead to irreversible joint damage and serious disability . One limitation for the use of therapeutic antibodies is immunogenicity , the induction of antibodies by the adaptive immune system in response to foreign substances . The development of antidrug antibodies ( ADAs ) has a varying impact on the clinical efficacy of biologic agents for the treatment of RA and AS , depending on whether the ADAs are neutralizing or non - neutralizing . Studies have indicated that neutralizing ADAs are associated with a reduced efficacy , decreased drug survival , increased instances of dose escalation , and adverse events . Comparison studies of anti - P01375 biologics have demonstrated that each drug has a different sustained efficacy profile depending on immunogenicity . The purpose of this review is to provide rheumatologists with information regarding the effect of neutralizing antibodies on the sustainable efficacy of anti - P01375 biologic therapies . This information will be of value to practicing rheumatologists in Africa and the Middle East who should take into account the potential for changes in the efficacy and safety of biologic therapies and closely monitor patients under their care .\",\n \"Advances in the management of psoriatic arthritis . Psoriatic arthritis ( PsA ) , which affects musculoskeletal structures , skin and nails , is a heterogeneous chronic inflammatory disease with a wide clinical spectrum and variable course . Patients with PsA are more likely than healthy individuals to have metabolic syndrome or cardiovascular disease . To include these comorbidities , ' psoriatic disease ' has been suggested as an umbrella term . The management of PsA has changed tremendously over the past decade owing to early diagnosis and improvement in treatment strategies , including , early referral from dermatologists and primary - care physicians to rheumatologists , early initiation of therapy , treating to the target of remission or low disease activity , and advances in pharmacological therapy . Outcome assessment is also improving , because of validated instruments for clinical disease manifestations . The commercialization of P01375 blockers , including adalimumab , etanercept , DB06674 and infliximab , is representative of a revolution in the treatment of PsA . A new anti - P01375 agent , certolizumab pegol , and a fully human monoclonal antibody against IL - 12 and IL - 23 , ustekinumab , are approved for the treatment of active PsA . The efficacy of ustekinumab suggests that inhibiting the type 17 T helper pathway might be an alternative to blocking P01375 . PsA management must now use improved measures to predict patient outcomes and define remission , and develop better - targeted therapies .\",\n \"Current and emerging biologics for ulcerative colitis . Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy . Hence , different biological agents that target specific immunological pathways are be - ing investigated for treating ulcerative colitis . Anti - tumor necrosis factor ( P01375 ) agents were the first biologics to be used for treating inflammatory bowel disease . For example , infliximab and adalimumab , which are anti - P01375 agents , are be - ing used for treating ulcerative colitis . Recently , DB06674 , another anti - P01375 agent , and vedolizumab , an anti - adhesion therapy , have been approved for ulcerative colitis by the U . S . Food and Drug Administration . In addition , new medications such as tofacitinib , a Janus kinase inhibitor , and etrolizumab , another anti - adhesion therapy , are emerging as therapeutic agents . Therefore , there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage .\",\n \"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .\",\n \"Role of DB06674 , a P01375 inhibitor , in the treatment of the psoriatic arthritis . Psoriatic arthritis ( PsA ) is an inflammatory arthritis that affects many psoriasis patients and can often have a debilitating disease progression . Golimumab is a new tumor necrosis factor ( P01375 ) antagonist recently approved by the FDA for controlling signs and symptoms of psoriatic arthritis . In a Phase III clinical trial in patients with PsA , patients receiving DB06674 showed significant improvement in the signs and symptoms of disease . It was usually well tolerated , but adverse events generally occurred more in patients receiving DB06674 compared to placebo . Golimumab has also recently shown efficacy in slowing structural damage in PsA . This new biologic therapy provides physicians with another option in the treatment of this inflammatory arthritis while offering patients certain advantages over other P01375 antagonists .\",\n \"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK43___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK43___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .\",\n \"Current evidence in the field of the management with P01375 - α inhibitors in psoriatic arthritis and concomitant hepatitis C virus infection . INTRODUCTION : Psoriatic arthritis ( PsA ) is a chronic inflammatory condition involving the spine , enthesis and peripheral joints , which is associated with psoriasis . PsA therapy varies from use of NSAIDs to disease - modifying anti - rheumatic agents ( DMARDs ) . However , their use can represent a limitation in patients with concomitant hepatitis C virus ( HCV ) infection . In the last few decades , anti - P01375 - α therapy has opened new horizons in the treatment of PsA . Hence , the purpose of this review is to explore the efficacy and safety of anti - P01375 - α agents in PsA and concomitant HCV infection . AREAS COVERED : We reviewed the available medical literature to find all cases of PsA and concomitant HCV infection treated with P01375 - α inhibitors . We found a total of 38 cases of patients with PsA and concomitant HCV infection in therapy with anti - P01375 - α agents . EXPERT OPINION : The available literature , summarized in this review , still remains very limited . Data suggest that therapy with the anti - P01375 - α agents , mainly etanercept and adalimumab , at least with short - term use , would appear efficacious and reasonably safe in the management of PsA patients with concomitant HCV infection . With regard to infliximab , efficacy and safety have been scarcely explored , whereas in the case of DB06674 and certolizumab no report was found , may be due to their recent introduction on the market .\",\n \"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK20___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .\",\n \"Catecholamine - producing cells in the synovial tissue during arthritis : modulation of sympathetic neurotransmitters as new therapeutic target . BACKGROUND : The proinflammatory and anti - inflammatory role of the sympathetic nervous system in early and late inflammation is an unresolved paradox . A drastic loss of sympathetic nerve fibres in the synovial tissue of patients with rheumatoid arthritis ( RA ) has previously been demonstrated . The presence of tyrosine hydroxylase ( TH ) - positive cells in RA and osteoarthritis ( OA ) has been determined , but the role of these cells in inflammation is still unclear . OBJECTIVE : To characterise TH - positive cells in inflamed RA and OA synovial tissue and to study their role in inflammation . METHODS : Synovial samples were obtained from 32 patients with OA and 19 patients with RA and from 10 control patients . Synovial tissue samples were used for immunofluorescence staining . Synovial cells were isolated by tissue digestion and immediately used for cell culture . For in vivo experiments , collagen type - II arthritis in DBA / 1J mice was induced . RESULTS : TH + cells were present only in inflamed tissue and not in controls . Catecholamine - storing vesicles and vesicular monoamine transporter 2 ( Q05940 ) were identified in the synovial tissue . Experimental increase of cytoplasmic catecholamines by Q05940 blockade strongly reduced tumour necrosis factor ( P01375 ) independently of canonical extracellular β - adrenergic signalling . In addition , Q05940 blockade increased cyclic AMP ( DB02527 ) and DB02527 responsive element binding protein , responsible for P01375 inhibition . In vivo , appearance of Q05940 positive cells was confirmed . Q05940 blockade ameliorated inflammation also in vivo . CONCLUSIONS : This study demonstrates that local catecholamine - producing cells start to replace sympathetic nerve fibres around the onset of disease , and modulation of locally produced catecholamines has strong anti - inflammatory effects in vivo and in vitro .\",\n \"Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization .\",\n \"Efficacy of antitumor necrosis factor ( α ) agents on patients with ankylosing spondylitis . OBJECTIVES : This study was designed to investigate the efficacy of antitumor necrosis factor ( P01375 )( a ) agents ( etanercept , infliximab , DB06674 or adalimumab ) in ankylosing spondylitis ( AS ) . METHODS : A literature search was done using PubMed , Embaseand Cochrane databases . The reference section of all primary studies was inspected for additional references , and only those reporting the results of a randomized - controlled trial comparing etanercept , infliximab or adalimumab with placebo for patients with AS were included in this analysis . RESULTS : Eleven trials with 1851 patients were included . Compared with placebo , anti - P01375 ( α ) agents was associated with significantly higher rates of Assessment in Ankylosing Spondylitis ( ASAS ) 20 responders ( risk ratio [ RR ] : 2 . 45 , 95 % confidence interval [ CI ] : 2 . 13 - 2 . 82 ; P < 0 . 00001 ) , ASAS 50 responders ( RR : 3 . 77 , 95 % CI : 2 . 87 - 4 . 95 ; P < 0 . 00001 ) , ASAS 70 responders ( RR : 3 . 25 , 95 % CI : 1 . 97 - 5 . 35 ; P < 0 . 00001 ) and patients with partial remission ( RR : 5 . 39 , 95 % CI : 3 . 25 - 8 . 93 ; P < 0 . 00001 ) . In addition , there were more patients with at least 50 % improvement in the Bath Ankylosing Spondylitis Disease Activity Index score in the experimental groups ( RR : 3 . 07 , 95 % CI : 2 . 44 - 3 . 86 ; P < 0 . 00001 ) . Most adverse events in both treatment groups were mild or moderate in severity . CONCLUSIONS : Anti - P01375 ( a ) agents is an effective and well - tolerated treatment for reducing clinical symptoms of AS .\",\n \"Two cases of Takayasu ' s arteritis occurring under anti - P01375 therapy . Takayasu ' s arteritis is a granulomatous , large vessel vasculitis that affects the aorta , its major branches and the pulmonary arteries . Compelling evidence exists to support the notion that Takayasu ' s arteritis is a T - cell mediated process and that tumor necrosis factor alpha ( TNFa ) is an important factor in the pathogenesis of this disease . Moreover , encouraging results from recent studies support the use of anti - TNFa therapy for relapsing or resistant cases of Takayasu ' s arteritis . Here , however , we describe the case of two patients : one with seropositive rheumatoid arthritis , the other with HLA - Q8TCY5 negative spondylarthropathy , who developed Takayasu ' s arteritis during treatment with TNFa inhibitors ( adalimumab and DB06674 respectively ) . This is the first report of Takayasu ' s arteritis in rheumatic patients under TNFa blocking agents which suggests the presence of different pathogenetic mechanism in a subgroup of patients with Takayasu ' s arteritis , as well as a potential role of TNFa blockers as triggers of this disease in some cases .\",\n \"___MASK77___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK77___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .\",\n \"Immunogenicity of anti - P01375 biologic therapies for rheumatoid arthritis . Currently , five anti - P01375 biologic agents are approved for the treatment of rheumatoid arthritis ( RA ) : adalimumab , infliximab , etanercept , DB06674 and certolizumab pegol . Formation of anti - drug antibodies ( P00813 ) has been associated with all five agents . In the case of adalimumab and infliximab , immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response , but for the other three agents , data on immunogenicity are scarce , suggesting that further research would be valuable . Low P00813 levels might not influence the efficacy of anti - P01375 therapy , whereas high P00813 levels impair treatment efficacy by considerably reducing unbound drug levels . Immunogenicity is not only an issue in patients treated with anti - P01375 biologic agents ; the immunogenicity of other therapeutic proteins , such as factor VIII and interferons , is well known and has been investigated for many years . The results of such studies suggest that investigations to determine the optimal treatment regimen ( drug dosing , treatment schedule and co - medication ) required to minimize the likelihood of P00813 formation might be an effective and practical way to deal with the immunogenicity of anti - P01375 biologic agents for RA .\",\n \"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .\",\n \"Novel P01375 antagonists for the treatment of rheumatoid arthritis . IMPORTANCE OF THE FIELD : P01375 antagonists have become an integral part of the standard of care for patients with rheumatoid arthritis ( RA ) . Two additional P01375 antagonists have recently been approved in the US for this indication , and clinicians will need to understand the data on the efficacy and safety of these agents in order to properly place them into the clinical treatment algorithm . AREAS COVERED IN THIS REVIEW : This review covers the published clinical trial data on the use of certolizumab and DB06674 for RA . The literature search included manuscripts published through September 2009 and abstracts from major meetings ( P10323 and EULAR ) in 2007 - 2009 . WHAT THE READER WILL GAIN : This paper will review the efficacy and safety of DB06674 and certolizumab in the treatment of RA at various stages of disease . Use of these agents will be described in the context of other available alternatives , including other P01375 antagonists and other biologic therapies . TAKE HOME MESSAGE : Certolizumab and DB06674 have comparable efficacy and safety profiles compared with previously approved P01375 antagonists . These two agents have several unique theoretical benefits when compared to existing agents , but the available published data do not suggest a clear clinical advantage at this time .\"\n]"},"candidates":{"kind":"list like","value":["___MASK20___","___MASK3___","___MASK43___","___MASK54___","___MASK71___","___MASK73___","___MASK77___","___MASK91___","___MASK93___"],"string":"[\n \"___MASK20___\",\n \"___MASK3___\",\n \"___MASK43___\",\n \"___MASK54___\",\n \"___MASK71___\",\n \"___MASK73___\",\n \"___MASK77___\",\n \"___MASK91___\",\n \"___MASK93___\"\n]"},"answer":{"kind":"string","value":"___MASK71___"},"id":{"kind":"string","value":"MH_train_492"}}},{"rowIdx":493,"cells":{"query":{"kind":"string","value":"interacts_with DB01276?"},"supports":{"kind":"list like","value":["P09936 inhibition involved in CREB dephosphorylation in hippocampal slices . Ubiquitin C - terminal hydrolase Q9NUQ9 ( P09936 ) is abundantly expressed in the brain and is critical for the normal function of synapses . DB02527 response element binding protein ( CREB ) is a transcription factor which initiates the expression of proteins that related to the regulation of synaptic plasticity and memory function . Studies have shown that P09936 can influence the expression and activity of CREB , but the underlying mechanisms remain unclear . In this study , we used P09936 inhibitor LDN to treat mice hippocampal slices and found that P09936 inhibition caused the dephosphorylation of CREB at Ser133 site . Meanwhile , hyperphosphorylation of microtubule - associated protein tau ; increased expression of synaptic protein components of P78352 and synapsin - 1 , and decreased activity of tyrosine kinase Fyn were observed after P09936 inhibition . Moreover , all these alternations have an influence on the normal function of N - methyl - D - aspartate ( DB01221 ) receptor Q13224 subunit which is likely to result in the dephosphorylation of CREB . We also found that LDN treatment mediated protein kinase A ( PKA ) deactivation was involved in the dephosphorylation of CREB . Thus , our study introduces a novel possible mechanism for elaborating the effects of P09936 inhibition on the CREB activity and the implicated signaling pathways .","Inhibition of noradrenaline release via presynaptic P28222 receptors of the rat vena cava . In the rat inferior vena cava preincubated with 3H - noradrenaline , the effects of nine serotonin ( 5 - HT ) receptor agonists and of eight antagonists ( including two beta - adrenoceptor blocking agents ) on the electrically evoked 3H overflow were determined . 1 . 5 - HT , 5 - carboxamido - tryptamine , 5 - methoxy - 3 ( 1 , 2 , 3 , 6 - tetrahydropyridine - 4 - yl )- 1H - indole ( RU 24969 ) , 5 - methoxytryptamine , N , N - dimethyl - 5HT , tryptamine and 5 - aminotryptamine inhibited the evoked 3H overflow . The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for P28222 binding sites , but not with their affinities for P08908 , P28335 or 5 - HT2 binding sites . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , a P08908 receptor agonist , and ipsapirone , a partial agonist at these receptors , did not inhibit overflow . 2 . Cyanopindolol facilitated the evoked 3H overflow , an effect which was abolished by propranolol . The maximum inhibition of overflow obtainable with 5 - HT was diminished by cyanopindolol . 3 . The concentration - response curve for 5 - HT was shifted to the right by metitepine , metergoline , quipazine , 6 - chloro - 2 -( 1 - piperazinyl ) pyrazine ( MK 212 ) and propranolol which , given alone , did not affect 3H overflow . The apparent pA2 values of these antagonists tended to be correlated with their affinities for P28222 ( but not P08908 , P28335 or 5 - HT2 ) binding sites . Ketanserin , a 5 - HT2 receptor antagonist , and spiperone , which blocks 5 - HT2 and P08908 but not P28222 or P28335 receptors , failed to antagonize the effect of 5 - HT . ( ABSTRACT TRUNCATED AT 250 WORDS )","Suppressive effects of glucagon - like peptide - 1 on interferon - gamma - induced nitric oxide production in insulin - producing cells is mediated by inhibition of tumor necrosis factor - alpha production . During the development of Type 1 diabetes , inflammatory cytokines are known to induce the expression of inducible nitric oxide synthase ( P35228 ) in pancreatic islets , and subsequent production of nitric oxide ( NO ) contributes to beta cell destruction . Glucagon - like peptide - 1 ( P0C6A0 ) has been shown to reduce cytokine - induced apoptosis of beta cells . In this study , we investigated whether P0C6A0 affects cytokine - induced NO production , resulting in the inhibition of beta - cell apoptosis . We treated MIN6N8a mouse beta cells with interferon ( IFN ) - gamma in the presence or absence of P0C6A0 and found that P01579 treatment induced P35228 mRNA expression and NO production , which was significantly inhibited by treatment with P0C6A0 . Blocking of P43220 signaling via the cyclic AMP and phosphatidylinositol 3 - kinase pathway did not directly affect the suppressive effect of P0C6A0 on IFN - gamma - induced P35228 mRNA expression . Further studies revealed that P01579 induced the expression of P01375 mRNA and protein , which synergistically induced NO production , and P0C6A0 treatment inhibited this induction of P01375 . To examine whether the reduction of P01375 by P0C6A0 treatment plays a role in suppressing NO production , we treated MIN6N8a cells with P01579 in the presence of anti - P01375 neutralizing antibody and found that NO production was reduced . In addition , treatment of mouse islets with P0C6A0 inhibited the expression of P35228 and TNFmRNA . These results suggest that P0C6A0 inhibits P01579 - induced NO production by suppression of P01375 production .","The contribution of serotonin P28335 and melanocortin - 4 receptors to the satiety signaling of glucagon - like peptide 1 and liraglutide , a glucagon - like peptide 1 receptor agonist , in mice . Glucagon - like peptide 1 ( P0C6A0 ) , an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L - cells , and liraglutide , a P43220 ( P43220 ) agonist , induce satiety . The serotonin P28335 receptor ( 5 - HT2CR ) and melanoroctin - 4 receptor ( P32245 ) are involved in the regulation of food intake . Here we show that systemic administration of P0C6A0 ( 50 and 200μg / kg ) - induced anorexia was blunted in mice with a 5HT2CR null mutation , and was attenuated in mice with a heterozygous P32245 mutation . On the other hand , systemic administration of liraglutide ( 50 and 100μg / kg ) suppressed food intake in mice lacking 5 - HT2CR , mice with a heterozygous mutation of P32245 and wild - type mice matched for age . Moreover , once - daily consecutive intraperitoneal administration of liraglutide ( 100μg / kg ) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of P32245 as well as wild - type mice . These findings suggest that P0C6A0 and liraglutide induce anorexia via different central pathways .","___MASK13___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK13___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .","Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetic subjects . AIMS / HYPOTHESIS : P01308 resistance is related to an increased risk of diabetic retinopathy and nephropathy in type 1 diabetes . Patients with insulin resistance and / or macrovascular disease have abnormally low levels of adiponectin . The aim of this study was to investigate the relationships between adiponectin and renal and retinal diabetic complications in type 1 diabetic patients . METHODS : In this 6 - year prospective follow - up observational study , we evaluated the severity of retinopathy at baseline and determined the incident risk of microalbuminuria in 126 normoalbuminuric patients with type 1 diabetes . Each patient was age - and sex - matched to two non - diabetic control subjects . RESULTS : Plasma adiponectin concentrations were significantly higher in diabetic subjects than in control subjects ( p < 0 . 0001 ) . The adiponectin concentration was significantly higher in patients with severe diabetic retinopathy than in those without ( Q04695 +/- 14 . 0 vs 29 . 0 +/- 13 . 0 microg / ml , p = 0 . 0005 ) . The 18 patients who developed persistent microalbuminuria had higher adiponectin concentrations than the other patients ( 35 . 8 +/- 14 . 5 vs 30 . 6 +/- 13 . 7 microg / ml ) . Increased adiponectin concentrations were independently associated with the occurrence of microalbuminuria ( p = 0 . 0158 ) after adjustment for baseline urinary albumin concentration ( p = 0 . 004 ) , sex ( p = 0 . 0054 ) , blood pressure ( NS ) and metabolic control ( NS ) . CONCLUSIONS / INTERPRETATION : The elevated adiponectin concentrations observed in subjects with microvascular disease may indicate an altered regulation of this adipocytokine in patients with complications associated with type 1 diabetes .","Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .","Exendin - 4 attenuates lipopolysaccharides induced inflammatory response but does not protects H9c2 cells from apoptosis . BACKGROUND : Glucagon - like peptide - 1 ( P0C6A0 ) and its analogues are reported to exert wide - ranging cardiovascular actions in preclinical and clinical studies . We thus investigated whether the P43220 agonist , exendin - 4 , has inhibitory effects on LPS - stimulated inflammatory response in cardiomyoblasts . METHODS : H9c2 cardiomyoblasts were exposed to LPS and treated with exendin - 4 . Expressions of proinflammatory mediators were assessed using quantitative real - time PCR . Nuclear localization of NF - κB was examined using immunoblotting . mRNA expression of inducible nitric oxide synthase ( P35228 ) and nitric oxide ( NO ) production were evaluated by q PCR and NO assay . Furthermore , anti - apoptotic effect of exendin - 4 in LPS - stimulated H9c2 cells was determined using qPCR and immunoblot . RESULTS : Exposure to LPS increased mRNA expressions of P01375 - α , P35354 and P14780 in H9c2 cells . It also caused increases in P35228 mRNA expression and NF - κB nuclear translocation . Exendin - 4 dose - dependently downregulated mRNA levels of P01375 - α , P35354 and P14780 in LPS - stimulated H9c2 cells . It also reduced NF - κB nuclear translocation . Treatment with exendin - 4 showed no effect on LPS - induced apoptosis in H9c2 cells . CONCLUSIONS : Exendin - 4 exerts an effect on cardiomyoblast exposed to LPS by inhibiting mRNA expression of inflammatory mediators and suppressing NF - κB activation . These effects are consistent with some of the observed anti - inflammatory properties of exendin - 4 , as well as its beneficial actions on the cardiovascular system .","___MASK66___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK66___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK66___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .","The development of DB01276 ( exenatide ) from the venom of the Gila monster as an anti - diabetic agent . The development of DB01276 ( synthetic exendin - 4 ; exenatide ) as a treatment of diabetes arose from two , parallel lines of investigation . The development of the ' incretin concept ' which hypothesised that hormones from the gut contributed to the insulin secretion in response to meals , led to the identification of glucagon - like peptide 1 ( P0C6A0 ) as an important ' incretin ' hormone . P0C6A0 not only increases insulin secretion but increases β - cell proliferation and survival , suppresses glucagon secretion , delays gastric emptying and suppresses appetite , all of these actions contributing to a potential anti - diabetic effect . However , P0C6A0 has a very short half due to its rapid breakdown by dipeptidyl peptidase IV and ectopeptidases . A systematic investigation of the composition and activity of venom from the Gila monster , Heloderma suspectum , led to the isolation of a 39 - amino acid peptide , designated exendin - 4 , showing 53 % structural homology with P0C6A0 ( 7 - 36 ) . Exendin - 4 mimicked P0C6A0 through stimulating the P43220 . The much greater stability of exendin - 4 led to its experimental and clinical evaluation as an anti - diabetic agent and its introduction to the market in 2005 .","Exenatide twice daily : a review of its use in the management of patients with type 2 diabetes mellitus . Exenatide , administered subcutaneously twice daily ( DB01276 (®) ) , is a synthetic version of the natural peptide exendin - 4 , which is a glucagon - like peptide - 1 ( P0C6A0 ) receptor agonist ( incretin mimetic ) . Exenatide binds to the P43220 with the same affinity as P0C6A0 , but has a much longer half - life , since it is not degraded by the enzyme dipeptidyl peptidase - 4 . Exenatide twice daily enhances glucose - dependent insulin secretion , suppresses inappropriately elevated glucagon secretion , slows gastric emptying and reduces caloric intake . In well - designed clinical trials , adjunctive subcutaneous exenatide 5 or 10 μg twice daily for 16 - 52 weeks significantly and dose - dependently improved glycaemic control and reduced mean body weight compared with placebo in patients with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs ( OADs ) and / or basal insulin . The improvements in glycaemic control and reductions in body weight were stably maintained during long - term therapy ( up to 3 . 5 years ) . The efficacy of adjunctive exenatide twice daily was generally similar to that of basal , prandial or biphasic insulin , sulfonylureas , rosiglitazone and lixisenatide , and less than that of liraglutide , taspoglutide or exenatide once weekly with respect to reductions in glycated haemoglobin . Exenatide twice daily was generally well tolerated ; mild to moderate nausea and vomiting , which decreased with time on therapy , were the most common adverse events . In patients not receiving concomitant sulfonylureas or insulin , the incidence of hypoglycaemia was low ; when it did occur , it was generally mild in severity . Thus , adjunctive exenatide twice daily is a valuable option in the treatment of type 2 diabetes inadequately controlled with OADs and / or basal insulin .","Cannabinoid , melanocortin and opioid receptor expression on P21728 and P14416 subpopulations in rat striatum . The striatum harbors two neuronal populations that enable action selection . One population represents the striatonigral pathway , expresses the dopamine receptor D1 ( P21728 ) and promotes the execution of motor programs , while the other population represents the striatopallidal pathway , expresses the dopamine receptor D2 ( P14416 ) and suppresses voluntary activity . The two populations integrate distinct sensorimotor , cognitive , and emotional information streams and their combined activity enables the selection of adaptive behaviors . Characterization of these populations is critical to the understanding of their role in action selection , because it aids the identification of the molecular mechanisms that separate them . To that end , we used fluorescent in situ hybridization to quantify the percentage of striatal cells that ( co ) express dopaminergic receptors and receptors of the cannabinoid , melanocortin or opioid neurotransmitters systems . Our main findings are that the cannabinoid 1 receptor is equally expressed on both populations with a gradient from dorsal to ventral striatum , that the opioid receptors have a preference for expression with either the P21728 or P14416 and that the melanocortin 4 receptor ( P32245 ) is predominantly expressed in ventral parts of the striatum . In addition , we find that the level of P32245 expression determines its localization to either the P21728 or the P14416 population . Thereby , we provide insight into the sensitivity of the two dopaminoceptive populations to these neurotransmitters and progress the understanding of the mechanisms that enable action selection .","P04818 genotype - directed chemotherapy for patients with gastric and gastroesophageal junction cancers . BACKGROUND : Retrospective studies indicate associations between TSER ( thymidylate synthase enhancer region ) genotypes and clinical outcomes in patients receiving ___MASK75___ based chemotherapy , but well - controlled prospective validation has been lacking . METHODS : In this phase II study ( NCT00515216 registered through ClinicalTrials . gov , http :// clinicaltrials . gov / show / NCT00515216 ) , patients with \" good risk \" TSER genotypes ( at least one TSER * 2 allele ) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates ( ORR ) in patients with gastric and gastroesophageal junction ( GEJ ) cancers , compared with historical outcomes in unselected patients ( estimated 43 % ) . RESULTS : The ORR in genotype - selected patients was Q04695 % ( 9 partial responses out of 23 evaluable patients , 95 % CI , 22 . 2 to 59 . 2 ) , not achieving the primary objective of improving ORR . An encouraging disease control rate ( DCR , consisting of partial responses and stable diseases ) of 95 . 7 % was noted and patients with homozygous TSER * 2 genotype showed better tumor response . CONCLUSIONS : In this first prospective , multi - institutional study in patients with gastric or GEJ cancers , selecting patients with at least one TSER * 2 allele did not improve the ORR but led to an encouraging DCR . Further studies are needed to investigate the utility of selecting patients homozygous for the TSER * 2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers . TRIAL REGISTRATION : ClinicalTrials . gov NCT00515216 .","[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK66___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .","Genome - wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma . BACKGROUND : The molecular mechanisms of CC ( cholangiocarcinoma ) oncogenesis and progression are poorly understood . This study aimed to determine the genome - wide expression of genes related to CC oncogenesis and sarcomatous transdifferentiation . METHODS : Genes that were differentially expressed between CC cell lines or tissues and cultured normal biliary epithelial ( NBE ) cells were identified using DNA microarray technology . Expressions were validated in human CC tissues and cells . RESULTS : Using unsupervised hierarchical clustering analysis of the cell line and tissue samples , we identified a set of 342 commonly regulated ( > 2 - fold change ) genes . Of these , 53 , including tumor - related genes , were upregulated , and 289 , including tumor suppressor genes , were downregulated ( < 0 . 5 fold change ) . Expression of P10451 , P52799 , Q14209 , P78415 , O95997 , PPARγ , Q04695 , P09936 , Q16270 and P09486 proteins was immunohistochemically verified in human and hamster CC tissues . Additional unsupervised hierarchical clustering analysis of sarcomatoid CC cells compared to three adenocarcinomatous CC cell lines revealed 292 differentially upregulated genes ( > 4 - fold change ) , and 267 differentially downregulated genes ( < 0 . 25 fold change ) . The expression of 12 proteins was validated in the CC cell lines by immunoblot analysis and immunohistochemical staining . Of the proteins analyzed , we found upregulation of the expression of the epithelial - mesenchymal transition ( EMT ) - related proteins P08670 and Q15672 , and restoration of the methylation - silenced proteins P07195 , Q12983 , P09936 , and P47972 during sarcomatoid transdifferentiation of CC . CONCLUSION : The deregulation of oncogenes , tumor suppressor genes , and methylation - related genes may be useful in identifying molecular targets for CC diagnosis and prognosis .","Adipose tissue tumor necrosis factor and interleukin - 6 expression in human obesity and insulin resistance . Adipose tissue expresses tumor necrosis factor ( P01375 ) and interleukin ( IL ) - 6 , which may cause obesity - related insulin resistance . We measured P01375 and P05231 expression in the adipose tissue of 50 lean and obese subjects without diabetes . P01308 sensitivity ( S ( I ) ) was determined by an intravenous glucose tolerance test with minimal - model analysis . When lean [ body mass index ( BMI ) < 25 kg / m ( 2 ) ] and obese ( BMI 30 - 40 kg / m ( 2 ) ) subjects were compared , there was a 7 . 5 - fold increase in P01375 secretion ( P < 0 . 05 ) from adipose tissue , and the P01375 secretion was inversely related to S ( I ) ( r = - 0 . 42 , P < 0 . 02 ) . P05231 was abundantly expressed by adipose tissue . In contrast to P01375 , plasma ( rather than adipose ) P05231 demonstrated the strongest relationship with obesity and insulin resistance . Plasma P05231 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S ( I ) ( r = - 0 . 71 , P < 0 . 001 ) . To separate the effects of BMI from S ( I ) , subjects who were discordant for S ( I ) were matched for BMI , age , and gender . By use of this approach , subjects with low S ( I ) demonstrated a 3 . 0 - fold increased level of P01375 secretion from adipose tissue and a 2 . 3 - fold higher plasma P05231 level ( P < 0 . 05 ) compared with matched subjects with a high S ( I ) . Plasma P05231 was significantly associated with plasma nonesterified fatty acid levels ( r = 0 . 49 , P < 0 . 002 ) . Thus the local expression of P01375 and plasma P05231 are higher in subjects with obesity - related insulin resistance .","Glucagon - like peptide - 1 ( 1 - 37 ) inhibits chemokine - induced migration of human P01730 - positive lymphocytes . The present study examined the effect of P0C6A0 ( 1 - 37 ) on chemokine - induced P01730 - positive lymphocyte migration as an early and critical step in atherogenesis . Pretreatment with P0C6A0 ( 1 - 37 ) reduced the SDF - induced migration of isolated human P01730 - positive lymphocytes in a concentration - dependent manner . Similar effects were seen when RANTES was used as a chemokine . P0C6A0 ( 1 - 37 ) ' s effect on P01730 - positive lymphocyte migration was mediated through an early inhibition of chemokine - induced P19957 kinase activity . Downstream , P0C6A0 ( 1 - 37 ) inhibited SDF - induced phosphorylation of MLC and cofilin and limited f - actin formation as well as P32942 translocation . Furthermore , exendin - 4 inhibited SDF - induced migration of P01730 - positive lymphocytes similarly to P0C6A0 ( 1 - 37 ) , and transfection of these cells with P43220 siRNA abolished P0C6A0 ( 1 - 37 ) ' s action on chemokine - induced P32942 translocation , suggesting an effect mediated via the P43220 . Thus , P0C6A0 ( 1 - 37 ) inhibits chemokine - induced P01730 - positive lymphocyte migration by inhibition of the P19957 - kinase pathway and via the P43220 . This effect provides a potential novel mechanism for how P0C6A0 ( 1 - 37 ) may modulate vascular disease .","[ DB01276 : first once weekly P43220 agonist ( exenatide P10586 ) ] . DB01276 is a new galenic formulation ( long - acting release ) of exenatide , the first agonist of Glucagon - Like Peptide - 1 ( P0C6A0 ) receptors having been commercialized for the management of type 2 diabetes . The microsphere technology permits a prolonged absorption of exenatide from the subcutaneous depot , which allows one injection per week instead of two injections per day with the initial formulation of exenatide ( DB01276 ) . The clinical development programme DURATION showed that exenatide 2 mg once weekly more markedly reduces glycated haemoglobin ( HbA ( 1c ) ) , with a similar weight loss but a better digestive tolerance profile ( less nausea and vomiting after treatment initiation ) , compared with the twice daily 10 microg exenatide . When compared to other glucose - lowering agents , once weekly exenatide is more efficacious than sitagliptin , pioglitazone or basal insulin ( glargine or detemir ) , with the advantage of producing weight loss and lowering arterial blood pressure . It does not induce hypoglycaemia and does not necessarily require home blood glucose monitoring , two advantages compared with insulin therapy . DB01276 is currently only reimbursed in Belgium after failure of and in addition to metformin - sulfonylurea combination .","Selected P21554 polymorphisms and hyperandrogenemia as well as fat mass and fat distribution in women with polycystic ovary syndrome . The endocannabinoid system is postulated to play an important role in the etiology of obesity , insulin resistance , fat distribution and metabolic disorders . P01308 resistance associated with abdominal obesity plays a leading role in the etiology of hyperandrogenism and other clinical features of the polycystic ovary syndrome ( PCOS ) . A total of 174 women 16 - 38 years old , diagnosed with PCOS according to the Rotterdam criteria are recruited . Control group consisted of 125 healthy women 18 - 45 years old . Medical history , physical examination , anthropometric parameters and metabolic parameters were carried out . Six P21554 gene polymorphisms were diagnosed . We observed a significantly three times higher risk of GG genotype in the polymorphism rs12720071 in women with PCOS versus the control group ( p = 0 . 0344 , OR = 3 . 01 ) . A similar , significant 8 - fold higher risk ( p = 0 . 0176 , OR = 8 . 81 ) was demonstrated for genotype CC polymorphism rs806368 associated with PCOS . We observed a 3 . 6 - fold increased risk of hyperandrogenemia ( free androgen index - FAI > 7 ) in patients with GG genotype in the rs12720071 polymorphism and AA genotype in the polymorphism rs1049353 ( OR = 2 . 7 ) . Our study may indicate a role of the endocannabinoid system in the occurrence of a specific hyperandrogenemia phenotype of PCOS .","The interaction of thymidylate synthase expression with p53 - regulated signaling pathways in tumor cells . P04818 ( TS ) is a chemotherapeutic target for the fluoropyrimidine 5 - fluorouracil ( ___MASK75___ ) and antifolate tomudex ( TDX ) . Using the MCF - 7 breast cancer line , we have developed a cell line with inducible TS expression termed M7TS90 . Inducible TS expression in this line resulted in a moderate ( approximately 3 - fold ) increase in ___MASK75___ 50 % inhibitory concentration at 72 hours ( IC - 50 ( 72 h ) ) dose and a dramatic ( approximately 24 - fold ) increase in the IC - 50 ( 72 h ) dose of TDX , but did not affect chemosensitivity to cisplatin , oxaliplatin , irinotecan , and paclitaxel . In the absence of drug treatment , inducible TS expression had no effect on expression of the p53 tumor suppressor gene . However , TS induction abrogated p53 , P38936 , Fas , and Bak induction in response to TDX , but not ___MASK75___ . Similarly , downregulation of Bcl - 2 was reversed by inducible TS expression in TDX , but not ___MASK75___ - treated cells . Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX , but not ___MASK75___ .","' Neuron - specific ' protein gene product 9 . 5 ( P09936 ) is also expressed in glioma cell lines and its expression depends on cellular growth state . Protein gene product 9 . 5 ( P09936 ) , which in the normal nervous system is restricted to certain neurons , has been detected in two glioma cell lines , rat P13671 and human GL15 , by immunoblotting and immunocytochemistry . Its expression in these cells depends on the cellular growth state , being maximal between the first and second post - plating day . Only a faint P09936 immunoreactivity can be observed in glioma cells after the eleventh post - plating day , i . e . about one week after confluency has been reached . The present results suggest that P09936 in cultured glial cells is maximally expressed during the growth phase and that the protein could play a role during brain development in glial cells , in reactive gliosis , or in tumorigenesis of the glial lineage .","P10275 antagonism and an insulin sensitizer block the advancement of vaginal opening by high - fat diet in mice . Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty . In high fat - fed rodents , the timing of vaginal opening ( VO ) is advanced , suggesting that puberty begins earlier . Because obesity can increase androgens , which interfere with normal steroid feedback in adult females , we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat - fed mice . Age at VO was examined in mice fed high - fat or low - fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle ( controls ) . VO was advanced in high - fat vs . low - fat controls , and flutamide blocked this advancement . VO was also delayed in low fat - fed flutamide - treated females , suggesting involvement of androgens in the timing of normal puberty . We next investigated if high - fat diet - induced insulin resistance contributes to early VO , as elevated insulin can stimulate androgen production . VO was examined in mice on either diet treated with the insulin sensitizer metformin . Metformin blocked high - fat advancement of VO but did not alter the timing of VO in low fat - fed mice . P01308 was elevated in high fat - fed females that had undergone VO compared with age - matched low fat - fed or metformin - treated animals on either diet that had not undergone VO . Together , these data suggest a model in which metabolic changes induced by high - fat diet , including transient increased circulating insulin , act in part by increasing androgen action to influence the timing of puberty in females .","Ontogeny of expression of P09936 antigen on TcR - 1 + ( P01730 / 8 ) and TcR delta + T cells . The frequency of blood mononuclear cells expressing the 180 - kDa splice variant of the common leukocyte antigen identified by the P09936 monoclonal antibody ( a characteristic of post - thymic cells which have been through a cycle of stimulation ) rose in a logarithmic relationship to age between birth and 16 years . At birth only a low frequency of P01730 + ( negative for CD 25 ) and no CD8 + T cells expressed P09936 . The subsequent increase in P09936 expression occurred in parallel on T cells expressing alpha / beta receptors and gamma / delta receptors , suggesting that these subsets participated in post - thymic proliferation in proportion to their numbers in blood . The frequency of P09936 expression on CD8 cells was 5 - 15 % less than on P01730 cells .","P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK67___ ) in castrated male and female mice subjected to ___MASK67___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK67___ in mice CPs .","Novel P0C6A0 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain . One of the symptoms of diabetes is the progressive development of neuropathies . One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells . We have tested the effects of the novel P0C6A0 mimetics exenatide ( exendin - 4 ; DB01276 ) and liraglutide ( DB06655 ; DB06655 ) , which are already on the market as treatments for type 2 diabetes , on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes . P0C6A0 analogues were injected subcutaneously for 4 , 6 , or 10 weeks once daily in three mouse models of diabetes : ob / ob mice , db / db mice , or high - fat - diet - fed mice . Twenty - four hours before perfusion , animals were injected with 5 '- bromo - 2 '- deoxyuridine ( BrdU ) to mark dividing progenitor cells . By using immunohistochemistry and stereological methods , the number of progenitor cells or doublecortin - positive young neurons in the dentate gyrus was estimated . We found that , in all three mouse models , progenitor cell division was enhanced compared with nondiabetic controls after chronic i . p . injection of either liraglutide or exendin - 4 by 100 - 150 % ( P < 0 . 001 ) . We also found an increase in young neurons in the DG of high - fat - diet - fed mice after drug treatment ( P < 0 . 001 ) . The P43220 antagonist exendin ( 9 - 36 ) reduced progenitor cell proliferation in these mice . The results demonstrate that P0C6A0 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer ' s disease , because these novel drugs cross the blood - brain barrier and increase neuroneogenesis .","Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK49___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK49___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK49___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK49___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK49___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK49___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK49___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK49___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK49___ in the treatment of changes in hypervigilance following severe stress .","___MASK1___ induces insulin sensitization in Zucker lean and fatty rats . BACKGROUND : The 3 - hydroxy - 3 - methyl glutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors ( ' statins ' ) have been implicated in preventing new onset type 2 diabetes , whereas the mechanism of this effect is not known . We investigated the effects of an P04035 inhibitor , atorvastatin , on insulin sensitization in Zucker lean and fatty rats . METHODS AND RESULTS : In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg / kg / day ( ATORVA_50 ) and results were compared to Zucker lean and fatty rats treated with drug vehicle only ( CONT ) . Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25mg / kg / day ( ATORVA_25 ) . Treatment with atorvastatin resulted in a dose - dependent improvement in whole body insulin sensitivity in both lean and fatty rats , with an approximately two - fold increase in glucose infusion rate and glucose disposal ( Rd ) in ATORVA_50 versus CONT ( p < 0 . 01 ) . ___MASK1___ 50mg / kg / day resulted in an increase in DB08831 ( 2 - DOG ) uptake by skeletal muscles ( approximately two - fold increase in 2 - DOG uptake in quadriceps ( p = 0 . 06 ) and gastrocnemius ( p < 0 . 01 ) ) in lean Zucker rats . P01308 - stimulated phosphorylation of Akt / P31749 was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats . CONCLUSION : ___MASK1___ induces insulin sensitization in Zucker lean and fatty rats . This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans .","P16109 - and heparanase - dependent antimetastatic activity of non - anticoagulant heparins . Vascular cell adhesion molecules , P - and L - selectins , facilitate metastasis of cancer cells in mice by mediating interactions with platelets , endothelium , and leukocytes . Q9Y251 is an endoglycosidase that degrades heparan sulfate of extracellular matrix , thereby promoting tumor invasion and metastasis . ___MASK66___ is known to efficiently attenuate metastasis in different tumor models . Here we identified modified , nonanticoagulant species of heparin that specifically inhibit selectin - mediated cell - cell interactions , heparanase enzymatic activity , or both . We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC - 38 colon carcinoma and B16 - BL6 melanoma attenuates metastasis . Selectin - specific heparin derivatives attenuated metastasis of MC - 38 carcinoma , but heparanase - specific derivatives had no effect , in accordance with the virtual absence of heparanase activity in these cells . ___MASK66___ derivatives had no further effect on metastasis in mice deficient in P - and P14151 , indicating that selectins are the primary targets of heparin antimetastatic activity . Selectin - specific and heparanase - specific derivatives attenuated metastasis of B16 - BL6 melanomas to a similar extent . When mice were injected with a derivative containing both heparanase and selectin inhibitory activity , no additional attenuation of metastasis could be observed . Thus , selectin - specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase .","Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 ) at 11p15 , tyrosinase ( P14679 ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 ) at 11q22 - q23 , as well as with the c - Harvey - ras oncogene ( P01112 ) and insulin gene ( P01308 ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected - sib - pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two - point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 and P01308 excluded the 11p15 region encompassing both P21917 and TH . In agreement with the negative linkage results , affected - sib - pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 , TH , P14679 , and P14416 in the pathogenesis of bipolar illness .","P0C6A0 treatment reduces endogenous insulin resistance via activation of central P0C6A0 receptors in mice fed a high - fat diet . Glucagon - like peptide - 1 ( P0C6A0 ) improves insulin sensitivity in humans and rodents . It is currently unknown to what extent the ( metabolic ) effects of P0C6A0 treatment are mediated by central P0C6A0 receptors . We studied the impact of central P43220 ( P43220 ) antagonism on the metabolic effects of peripheral P0C6A0 administration in mice . High - fat - fed insulin - resistant C57Bl / 6 mice were treated with continuous subcutaneous infusion of P0C6A0 or saline ( PBS ) for 2 wk , whereas the P43220 antagonist exendin - 9 ( EX - 9 ) and cerebrospinal fluid ( P04141 ) were simultaneously infused in the left lateral cerebral ventricle ( icv ) . DB09341 and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp . VLDL - triglyceride ( VLDL - TG ) production was determined in hyperinsulinemic conditions . Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by P0C6A0 . Simultaneous icv infusion of EX - 9 diminished this effect by 62 % . The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by P0C6A0 . Simultaneous icv infusion of EX - 9 significantly diminished the latter effect . Central P43220 antagonism alone did not affect glucose metabolism . Also , P0C6A0 treatment reinforced the inhibitory action of insulin on VLDL - TG production . In conclusion , peripheral administration of P0C6A0 reinforces the ability of insulin to suppress endogenous glucose and VLDL - TG production ( but not lipolysis ) and boosts its capacity to stimulate glucose disposal in high - fat - fed C57Bl / 6 mice . Activation of central GLP - 1Rs contributes substantially to the inhibition of endogenous glucose production by P0C6A0 treatment in this animal model .","[ Activation of coagulation cascade in children during an idiopathic nephrotic syndrome relapse ] . The objective of this study was to assess concentrations of selected markers of coagulation in children with relapse of idiopathic nephrotic syndrome during a 6 - week therapy . Study groups : 22 subjects ( 32 relapses ) -- 14 males , 8 females ( mean age 7 . 15 +/- 1 . 5 y . ) with no thrombotic complications were included into the study . All children were clinically steroid - sensitive . METHODS : Coagulation markers ( platelet count , thrombin time , APTT , INR , fibrinogen 1 + 2 fragments ( F1 + 2 ) , thrombin - antithrombin complexes ( TAT ) , serum levels of D - dimer ( DD ) , fibrin monomers ( FM ) and antithrombin activity ( P01008 ) ) were measured three times : on admission , after 2 and 6 weeks . The control group consisted of 13 healthy children . RESULTS : Serum concentration of TAT or F1 + 2 did not differ between 3 stages ( p > 0 . 05 ) . However , values at 0 and 2 weeks were significantly higher than in control group ( p < 0 . 05 ) . We found no correlation between TAT or F1 + 2 and FBG , ALB , TCH , TG levels . [ table : see text ] CONCLUSIONS : The coagulation cascade in relapse of NS was activated during first 6 weeks of therapy whereas metabolic disturbances ( low ALB , high P02675 , TCH , TG , high platelets ) normalized . It is speculative whether it was caused by active immunological process but definitely it resulted in \" prothrombotic state \" in P01308 patients .","Neuroprotective effect of the glucagon - like peptide - 1 receptor agonist , synthetic exendin - 4 , in streptozotocin - induced diabetic rats . BACKGROUND AND PURPOSE : Glucagon - like peptide - 1 ( P0C6A0 ) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation . The aim of this study was to investigate the effect of the P0C6A0 pathway on peripheral nerves in streptozotocin - induced diabetic rats . EXPERIMENTAL APPROACH : Diabetic and nondiabetic rats were treated with the P43220 agonist , synthetic exendin - 4 ( i . p . , 1 nmol · kg (- 1 )· day (- 1 ) ) or placebo for 24 weeks , and current perception threshold values , DB02527 levels and nerve fibre size in the sciatic nerve were measured . We also investigated P43220 expression , quantitative changes in P09936 - positive intraepidermal nerve fibres and cleaved caspase 3 - stained Schwann cells by immunohistochemistry . KEY RESULTS : P43220 expression was detected in the sciatic nerve and skin . After exendin - 4 treatment , the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced . Also , the decrease in myelinated fibre size or axon / fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated . These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the DB02527 level in exendin - 4 - treated diabetic rats , compared with placebo - treated animals . CONCLUSION AND IMPLICATIONS : DB01276 may prevent peripheral nerve degeneration induced by diabetes in an animal model , supporting the hypothesis that P0C6A0 may be useful in peripheral neuropathy . The neuroprotection is probably attributable to P43220 activation , antiapoptotic effects and restoration of DB02527 content .","Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK1___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .","P01308 - induced NADPH oxidase activation promotes proliferation and matrix metalloproteinase activation in monocytes / macrophages . P01308 stimulates superoxide ( O ( 2 )(-) ) production in monocytes and macrophages . However , the mechanisms through which insulin induces O ( 2 )(-) production are not completely understood . In this study , we ( a ) characterized the enzyme and the pathways involved in insulin - stimulated O ( 2 )(-) production in human monocytes and murine macrophages , and ( b ) analyzed the consequences of insulin - stimulated O ( 2 )(-) production on the cellular phenotype in these cells . We showed that insulin stimulated O ( 2 )(-) production , and promoted p47 ( phox ) translocation to the plasma membrane . P01308 - induced O ( 2 )(-) production and p47 ( phox ) translocation were prevented in the presence of specific inhibitors of PI3K and PKC . P01308 - mediated NADPH oxidase activation stimulated P14780 activation in monocytes and cell proliferation in macrophages . The effect of insulin on these phenotypic responses was mediated through NFkappaB , p38MAPK , and P29323 1 / 2 activation . Small - interfering RNA - specific gene silencing targeted specifically against Nox2 reduced the cognate protein expression , decreased insulin - induced O ( 2 )(-) production , inhibited the turn on of NFkappaB , p38MAPK , and P29323 1 / 2 , and reduced cell proliferation in macrophages . These findings suggest a pivotal role for NADPH oxidase in insulin - induced proliferation and proteolytic activation in monocytes and macrophages , respectively , and identify a pathway that may play a pathological role in hyperinsulinemic states .","Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK67___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK67___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .","Absence of genetic variation in some obesity candidate genes ( P43220 , ASIP , P32245 , P33032 ) among Pima indians . OBJECTIVE : To examine the obesity candidate genes glucagon - like - peptide receptor ( P43220 ) , agouti signaling protein ( ASIP ) and the melanocortin receptors 4 and 5 ( P32245 and P33032 ) for DNA polymorphisms in their coding regions . SUBJECTS : Unrelated , non - diabetic Pima Indians ( 8 to 12 from each extreme of body fat ) . MEASUREMENTS : DNA sequencing within the coding regions of each gene . RESULT : Only one variant was detected , a silent substitution in exon 6 of P43220 . CONCLUSION : The exclusion of any common amino - acid polymorphisms ( allele frequency > or = 0 . 20 ) . implies that structural variants of these genes do not contribute to variation in the high level of obesity observed among the Pima Indians .","Exendin - 4 alleviates angiotensin II - induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . Vascular aging has been implicated in the progression of diabetes and age - related cardiovascular disorders . Glucagon - like peptide - 1 ( P0C6A0 ) is an incretin hormone capable of cytoprotective actions in addition to its glucose - lowering effect . The present study was undertaken to examine whether Exendin - 4 , a specific ligand for the P43220 , could prevent angiotensin ( P03950 ) II - induced premature senescence in vascular smooth muscle cells ( VSMCs ) and to determine the underlying mechanism involved . Senescence - associated β - galactosidase ( SA β - gal ) assay showed that P03950 II induced premature senescence of VSMCs . Pretreatment with Exendin - 4 significantly attenuated P03950 II - induced generation of H2O2 and the subsequent VSMC senescence . These effects were , however , reversed in the presence of exendin fragment 9 - 39 , a P43220 antagonist , or PKI14 - 22 . Moreover , a marked increase in the levels of p53 and P38936 induced by P03950 II was blunted by the treatment with Exendin - 4 . Nevertheless , Exendin - 4 failed to decrease P03950 II - induced expression of NAD ( P ) H oxidase 1 ( Nox1 ) , NAD ( P ) H oxidase 4 ( Nox4 ) , O75935 ( phox ) , or p47 ( phox ) in VSMCs . Mechanistically , Exendin - 4 blocked P03950 II - induced Rac1 activation through the DB02527 / PKA signaling cascade . Specifically , NSC23766 , a Rac1 inhibitor , abrogated the suppressive effects of Exendin - 4 on P03950 II - induced premature senescence and H2O2 generation , respectively . Thus Exendin - 4 confers resistance to P03950 II - induced superoxide anion generation from NAD ( P ) H oxidase and the resultant VSMC senescence by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . These findings demonstrate that P0C6A0 as well as its analogs ( P0C6A0 - related reagents ) may hold therapeutic potential in the treatment of diabetes with cardiovascular disease .","Role of central glucagon - like peptide - 1 in hypothalamo - pituitary - adrenocortical facilitation following chronic stress . Central glucagon - like peptide - 1 ( P0C6A0 ) regulates food intake , glucose homeostasis , and behavioral and neuroendocrine responses to acute stress . Given its pronounced role in acute stress regulation , the P0C6A0 system is a prime candidate for mediating the prolonged drive of the hypothalamo - pituitary - adrenocortical axis by chronic stress . To test this hypothesis , we evaluated the necessity and sufficiency of P0C6A0 for production of chronic stress - induced changes in Q9Y251 axis function . Exogenous P0C6A0 or the P43220 antagonist , dHG - exendin , were delivered into the 3rd ventricle of control animals or animals exposed to chronic variable stress ( CVS ) for 7 days . Animals in the CVS groups received P0C6A0 or dHG - exendin immediately prior to each stress exposure . Prior to and at the end of the 7 - day trial , chronically - stressed animals were subjected to a novel stressor to test for Q9Y251 axis facilitation . Neither P0C6A0 nor dHG - exendin affected CVS - associated increases in adrenal weight or decreases in basal plasma glucose levels . In addition , neither exogenous P0C6A0 nor dHG - exendin altered any index of Q9Y251 axis activity in unstressed rats . However , P0C6A0 enhanced CVS - induced facilitation of corticosterone ( but not DB01285 ) response to an acute stress , whereas dHG - exendin inhibited facilitation . In addition , P0C6A0 decreased body weight in chronically - stressed animals . dHG - exendin increased food intake and body weight in unstressed animals , consistent with a tonic role for P0C6A0 in body weight regulation . Overall , our data suggest that brain P0C6A0 modulates Q9Y251 axis activity within the context of chronic stress , perhaps at the level of the adrenal gland .","New insights into the role of DB02527 in the production and function of the incretin hormone glucagon - like peptide - 1 ( P0C6A0 ) . The proglucagon gene ( gcg ) encodes both glucagon and glucagon - like peptide - 1 ( P0C6A0 ) , produced in pancreatic alpha cells and intestinal endocrine L cells , respectively . The incretin hormone P0C6A0 stimulates insulin secretion and pro - insulin gene transcription . P0C6A0 also enhances pancreatic beta - cell proliferation , inhibits cell apoptosis , and has been utilized in the trans - differentiation of insulin producing cells . A long - term effective P43220 agonist , DB01276 , has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders . The expression of gcg and the production of P0C6A0 can be activated by the elevation of the second messenger cyclic AMP ( DB02527 ) . Recent studies suggest that in addition to protein kinase A ( PKA ) , exchange protein activated by DB02527 ( Epac ) , another effector of DB02527 , and the crosstalk between PKA and the Wnt signaling pathway , are involved in DB02527 - stimulated gcg transcription and P0C6A0 production as well . Finally , functions of P0C6A0 in pancreatic beta cells are also mediated by PKA , Epac , as well as the effector of the Wnt signaling pathway . Together , these novel findings bring us a new insight into the role of DB02527 in the production and function of the incretin hormone P0C6A0 .","Concurrent pharmacological modification of cannabinoid - 1 and glucagon - like peptide - 1 receptor activity affects feeding behavior and body weight in rats fed a free - choice , high - carbohydrate diet . To extend preliminary studies on the effects on food intake of the combined use of cannabinoid ( CB ) 1 and glucagon - like peptide - 1 ( P0C6A0 ) receptor agonists and antagonists , the effect of these drugs on the feeding behavior in rats maintained on a free - choice , high - carbohydrate diet was investigated over a longer period of time . Rats were fed a standard diet for 3 days and then fed with both the standard and the high - sucrose chow . After 4 days of the high - calorie diet , the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days : 1 mg / kg AM 251 ( a P21554 receptor antagonist ) or 1 mg / kg Q08050 55 , 212 - 2 ( a P21554 receptor agonist ) together with 3 µg / kg exendin - 4 ( Ex - 4 , a P43220 agonist ) or 160 µg / kg exendin ( 9 - 39 ) [ Ex ( 9 - 39 ) , a P43220 antagonist ] . The total daily caloric intake and body weight were significantly reduced in rats treated with Ex - 4 and AM 251 or Q08050 55 , 212 - 2 compared with either of the drugs injected alone and the saline - injected controls . Both drug combinations selectively inhibited ingestion of the high - sucrose chow . Although Ex ( 9 - 39 ) administration did not significantly affect food consumption , it resulted in a marked body weight gain , indicating that the P43220 antagonist caused a positive energy balance . It is concluded that AM 251 or Q08050 55 , 212 - 2 and Ex - 4 , injected together , exert additive , inhibitory effects on the consumption of high - sugar food .","Molecular physiology of glucagon - like peptide - 1 insulin secretagogue action in pancreatic β cells . P01308 secretion from pancreatic β cells is stimulated by glucagon - like peptide - 1 ( P0C6A0 ) , a blood glucose - lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e . g . , DB01276 ) and P0C6A0 analogs ( e . g . , DB06655 ) activate the β cell P43220 ( P43220 ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase - IV ( DPP - IV ) inhibitors ( e . g . , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post - prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e . g . , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac2 - mediated actions of P0C6A0 to regulate DB00171 - sensitive K ⁺ channels , voltage - dependent K ⁺ channels , O94759 cation channels , intracellular Ca ⁺ release channels , and Ca ⁺- dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM .","Improvement of psoriasis during exenatide treatment in a patient with diabetes . CONTEXT AND AIM : Psoriasis is an immune - mediated skin disorder frequently associated with obesity and type 2 diabetes ( T2D ) . This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a P43220 agonist ( exenatide ) . OBSERVATION : A 61 - year - old male patient ( BMI : 25 . 5 kg / m ( 2 ) ) with T2D treated with metformin and sulphonylureas had also complained , since 1980 , of extensive psoriasis that required multiple steroid - based treatments [ Psoriasis Area and Sensitivity Index ( PASI ) score : 11 ] . In September 2008 , his diabetes treatment was intensified with exenatide ( DB01276 (®) ) to improve poor glycaemic control . The patient , as expected , lost weight and reduced HbA ( 1c ) levels from 65 mmol / mol to 56 mmol / mol . However , after just 1 month of treatment with exenatide , the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 - year follow - up ( PASI : estimated at 3 - 4 ) . Withdrawal of exenatide was associated with weight gain , deterioration of glycaemic control and deterioration of psoriasis ( PASI : > 10 ) . After reinstating exenatide treatment , the patient again reported a prompt improvement in psoriasis ( PASI : 3 . 1 ) . CONCLUSION : There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide . A possible mechanism might be through direct modulation of the immune system by P43220 agonists .","Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug - target gene network . These genes were overrepresented in several pathways including : neuroactive ligand - receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug - gene network , we revealed a few bridge genes connected the sub - networks of the drug - gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . DB00502 was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug - gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug - gene interactions in psychosis .","P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK56___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .","[ ___MASK22___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK22___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .","Different expression of ubiquitin C - terminal hydrolase - Q9NUQ9 and αII - spectrin in ischemic and hemorrhagic stroke : Potential biomarkers in diagnosis . The two primary categories of stroke , ischemic and hemorrhagic , both have fundamentally different mechanisms and thus different treatment options . These two stroke categories were applied to rat models to identify potential biomarkers that can distinguish between them . Ischemic stroke was induced by middle cerebral artery occlusion ( MCAO ) without reperfusion while hemorrhagic stroke was induced by injecting collagenase IV into the striatum . Brain hemispheres and biofluids were collected at two time points : 3 and 6h after stroke . Known molecules were tested on the rat samples via quantitative immunoblotting ( injured brain , P04141 ) and Banyan ' s proprietary ELISA assays ( P04141 , serum ) . The injured brain quantitative analyses revealed that αII - spectrin breakdown products ( SBDP150 , SBDP145 ) were strongly increased after 6h ischemia . In P04141 , SBDP145 and ubiquitin C - terminal hydrolase - Q9NUQ9 ( P09936 ) levels were elevated after 6h ischemic stroke detected by Western blot and ELISA . In serum P09936 levels were increased after 3 and 6h of ischemia detected by ELISA . However , levels of those proteins in hemorrhagic stroke remain normal . In summary , in both the brain and the biofluids , SBDPs and P09936 were elevated after ischemic but not hemorrhagic stroke . These molecules behaved differently in the two stroke models and thus may be capable of being differentiated .","___MASK25___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients ."],"string":"[\n \"P09936 inhibition involved in CREB dephosphorylation in hippocampal slices . Ubiquitin C - terminal hydrolase Q9NUQ9 ( P09936 ) is abundantly expressed in the brain and is critical for the normal function of synapses . DB02527 response element binding protein ( CREB ) is a transcription factor which initiates the expression of proteins that related to the regulation of synaptic plasticity and memory function . Studies have shown that P09936 can influence the expression and activity of CREB , but the underlying mechanisms remain unclear . In this study , we used P09936 inhibitor LDN to treat mice hippocampal slices and found that P09936 inhibition caused the dephosphorylation of CREB at Ser133 site . Meanwhile , hyperphosphorylation of microtubule - associated protein tau ; increased expression of synaptic protein components of P78352 and synapsin - 1 , and decreased activity of tyrosine kinase Fyn were observed after P09936 inhibition . Moreover , all these alternations have an influence on the normal function of N - methyl - D - aspartate ( DB01221 ) receptor Q13224 subunit which is likely to result in the dephosphorylation of CREB . We also found that LDN treatment mediated protein kinase A ( PKA ) deactivation was involved in the dephosphorylation of CREB . Thus , our study introduces a novel possible mechanism for elaborating the effects of P09936 inhibition on the CREB activity and the implicated signaling pathways .\",\n \"Inhibition of noradrenaline release via presynaptic P28222 receptors of the rat vena cava . In the rat inferior vena cava preincubated with 3H - noradrenaline , the effects of nine serotonin ( 5 - HT ) receptor agonists and of eight antagonists ( including two beta - adrenoceptor blocking agents ) on the electrically evoked 3H overflow were determined . 1 . 5 - HT , 5 - carboxamido - tryptamine , 5 - methoxy - 3 ( 1 , 2 , 3 , 6 - tetrahydropyridine - 4 - yl )- 1H - indole ( RU 24969 ) , 5 - methoxytryptamine , N , N - dimethyl - 5HT , tryptamine and 5 - aminotryptamine inhibited the evoked 3H overflow . The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for P28222 binding sites , but not with their affinities for P08908 , P28335 or 5 - HT2 binding sites . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , a P08908 receptor agonist , and ipsapirone , a partial agonist at these receptors , did not inhibit overflow . 2 . Cyanopindolol facilitated the evoked 3H overflow , an effect which was abolished by propranolol . The maximum inhibition of overflow obtainable with 5 - HT was diminished by cyanopindolol . 3 . The concentration - response curve for 5 - HT was shifted to the right by metitepine , metergoline , quipazine , 6 - chloro - 2 -( 1 - piperazinyl ) pyrazine ( MK 212 ) and propranolol which , given alone , did not affect 3H overflow . The apparent pA2 values of these antagonists tended to be correlated with their affinities for P28222 ( but not P08908 , P28335 or 5 - HT2 ) binding sites . Ketanserin , a 5 - HT2 receptor antagonist , and spiperone , which blocks 5 - HT2 and P08908 but not P28222 or P28335 receptors , failed to antagonize the effect of 5 - HT . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"Suppressive effects of glucagon - like peptide - 1 on interferon - gamma - induced nitric oxide production in insulin - producing cells is mediated by inhibition of tumor necrosis factor - alpha production . During the development of Type 1 diabetes , inflammatory cytokines are known to induce the expression of inducible nitric oxide synthase ( P35228 ) in pancreatic islets , and subsequent production of nitric oxide ( NO ) contributes to beta cell destruction . Glucagon - like peptide - 1 ( P0C6A0 ) has been shown to reduce cytokine - induced apoptosis of beta cells . In this study , we investigated whether P0C6A0 affects cytokine - induced NO production , resulting in the inhibition of beta - cell apoptosis . We treated MIN6N8a mouse beta cells with interferon ( IFN ) - gamma in the presence or absence of P0C6A0 and found that P01579 treatment induced P35228 mRNA expression and NO production , which was significantly inhibited by treatment with P0C6A0 . Blocking of P43220 signaling via the cyclic AMP and phosphatidylinositol 3 - kinase pathway did not directly affect the suppressive effect of P0C6A0 on IFN - gamma - induced P35228 mRNA expression . Further studies revealed that P01579 induced the expression of P01375 mRNA and protein , which synergistically induced NO production , and P0C6A0 treatment inhibited this induction of P01375 . To examine whether the reduction of P01375 by P0C6A0 treatment plays a role in suppressing NO production , we treated MIN6N8a cells with P01579 in the presence of anti - P01375 neutralizing antibody and found that NO production was reduced . In addition , treatment of mouse islets with P0C6A0 inhibited the expression of P35228 and TNFmRNA . These results suggest that P0C6A0 inhibits P01579 - induced NO production by suppression of P01375 production .\",\n \"The contribution of serotonin P28335 and melanocortin - 4 receptors to the satiety signaling of glucagon - like peptide 1 and liraglutide , a glucagon - like peptide 1 receptor agonist , in mice . Glucagon - like peptide 1 ( P0C6A0 ) , an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L - cells , and liraglutide , a P43220 ( P43220 ) agonist , induce satiety . The serotonin P28335 receptor ( 5 - HT2CR ) and melanoroctin - 4 receptor ( P32245 ) are involved in the regulation of food intake . Here we show that systemic administration of P0C6A0 ( 50 and 200μg / kg ) - induced anorexia was blunted in mice with a 5HT2CR null mutation , and was attenuated in mice with a heterozygous P32245 mutation . On the other hand , systemic administration of liraglutide ( 50 and 100μg / kg ) suppressed food intake in mice lacking 5 - HT2CR , mice with a heterozygous mutation of P32245 and wild - type mice matched for age . Moreover , once - daily consecutive intraperitoneal administration of liraglutide ( 100μg / kg ) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of P32245 as well as wild - type mice . These findings suggest that P0C6A0 and liraglutide induce anorexia via different central pathways .\",\n \"___MASK13___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK13___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .\",\n \"Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetic subjects . AIMS / HYPOTHESIS : P01308 resistance is related to an increased risk of diabetic retinopathy and nephropathy in type 1 diabetes . Patients with insulin resistance and / or macrovascular disease have abnormally low levels of adiponectin . The aim of this study was to investigate the relationships between adiponectin and renal and retinal diabetic complications in type 1 diabetic patients . METHODS : In this 6 - year prospective follow - up observational study , we evaluated the severity of retinopathy at baseline and determined the incident risk of microalbuminuria in 126 normoalbuminuric patients with type 1 diabetes . Each patient was age - and sex - matched to two non - diabetic control subjects . RESULTS : Plasma adiponectin concentrations were significantly higher in diabetic subjects than in control subjects ( p < 0 . 0001 ) . The adiponectin concentration was significantly higher in patients with severe diabetic retinopathy than in those without ( Q04695 +/- 14 . 0 vs 29 . 0 +/- 13 . 0 microg / ml , p = 0 . 0005 ) . The 18 patients who developed persistent microalbuminuria had higher adiponectin concentrations than the other patients ( 35 . 8 +/- 14 . 5 vs 30 . 6 +/- 13 . 7 microg / ml ) . Increased adiponectin concentrations were independently associated with the occurrence of microalbuminuria ( p = 0 . 0158 ) after adjustment for baseline urinary albumin concentration ( p = 0 . 004 ) , sex ( p = 0 . 0054 ) , blood pressure ( NS ) and metabolic control ( NS ) . CONCLUSIONS / INTERPRETATION : The elevated adiponectin concentrations observed in subjects with microvascular disease may indicate an altered regulation of this adipocytokine in patients with complications associated with type 1 diabetes .\",\n \"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .\",\n \"Exendin - 4 attenuates lipopolysaccharides induced inflammatory response but does not protects H9c2 cells from apoptosis . BACKGROUND : Glucagon - like peptide - 1 ( P0C6A0 ) and its analogues are reported to exert wide - ranging cardiovascular actions in preclinical and clinical studies . We thus investigated whether the P43220 agonist , exendin - 4 , has inhibitory effects on LPS - stimulated inflammatory response in cardiomyoblasts . METHODS : H9c2 cardiomyoblasts were exposed to LPS and treated with exendin - 4 . Expressions of proinflammatory mediators were assessed using quantitative real - time PCR . Nuclear localization of NF - κB was examined using immunoblotting . mRNA expression of inducible nitric oxide synthase ( P35228 ) and nitric oxide ( NO ) production were evaluated by q PCR and NO assay . Furthermore , anti - apoptotic effect of exendin - 4 in LPS - stimulated H9c2 cells was determined using qPCR and immunoblot . RESULTS : Exposure to LPS increased mRNA expressions of P01375 - α , P35354 and P14780 in H9c2 cells . It also caused increases in P35228 mRNA expression and NF - κB nuclear translocation . Exendin - 4 dose - dependently downregulated mRNA levels of P01375 - α , P35354 and P14780 in LPS - stimulated H9c2 cells . It also reduced NF - κB nuclear translocation . Treatment with exendin - 4 showed no effect on LPS - induced apoptosis in H9c2 cells . CONCLUSIONS : Exendin - 4 exerts an effect on cardiomyoblast exposed to LPS by inhibiting mRNA expression of inflammatory mediators and suppressing NF - κB activation . These effects are consistent with some of the observed anti - inflammatory properties of exendin - 4 , as well as its beneficial actions on the cardiovascular system .\",\n \"___MASK66___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK66___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK66___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .\",\n \"The development of DB01276 ( exenatide ) from the venom of the Gila monster as an anti - diabetic agent . The development of DB01276 ( synthetic exendin - 4 ; exenatide ) as a treatment of diabetes arose from two , parallel lines of investigation . The development of the ' incretin concept ' which hypothesised that hormones from the gut contributed to the insulin secretion in response to meals , led to the identification of glucagon - like peptide 1 ( P0C6A0 ) as an important ' incretin ' hormone . P0C6A0 not only increases insulin secretion but increases β - cell proliferation and survival , suppresses glucagon secretion , delays gastric emptying and suppresses appetite , all of these actions contributing to a potential anti - diabetic effect . However , P0C6A0 has a very short half due to its rapid breakdown by dipeptidyl peptidase IV and ectopeptidases . A systematic investigation of the composition and activity of venom from the Gila monster , Heloderma suspectum , led to the isolation of a 39 - amino acid peptide , designated exendin - 4 , showing 53 % structural homology with P0C6A0 ( 7 - 36 ) . Exendin - 4 mimicked P0C6A0 through stimulating the P43220 . The much greater stability of exendin - 4 led to its experimental and clinical evaluation as an anti - diabetic agent and its introduction to the market in 2005 .\",\n \"Exenatide twice daily : a review of its use in the management of patients with type 2 diabetes mellitus . Exenatide , administered subcutaneously twice daily ( DB01276 (®) ) , is a synthetic version of the natural peptide exendin - 4 , which is a glucagon - like peptide - 1 ( P0C6A0 ) receptor agonist ( incretin mimetic ) . Exenatide binds to the P43220 with the same affinity as P0C6A0 , but has a much longer half - life , since it is not degraded by the enzyme dipeptidyl peptidase - 4 . Exenatide twice daily enhances glucose - dependent insulin secretion , suppresses inappropriately elevated glucagon secretion , slows gastric emptying and reduces caloric intake . In well - designed clinical trials , adjunctive subcutaneous exenatide 5 or 10 μg twice daily for 16 - 52 weeks significantly and dose - dependently improved glycaemic control and reduced mean body weight compared with placebo in patients with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs ( OADs ) and / or basal insulin . The improvements in glycaemic control and reductions in body weight were stably maintained during long - term therapy ( up to 3 . 5 years ) . The efficacy of adjunctive exenatide twice daily was generally similar to that of basal , prandial or biphasic insulin , sulfonylureas , rosiglitazone and lixisenatide , and less than that of liraglutide , taspoglutide or exenatide once weekly with respect to reductions in glycated haemoglobin . Exenatide twice daily was generally well tolerated ; mild to moderate nausea and vomiting , which decreased with time on therapy , were the most common adverse events . In patients not receiving concomitant sulfonylureas or insulin , the incidence of hypoglycaemia was low ; when it did occur , it was generally mild in severity . Thus , adjunctive exenatide twice daily is a valuable option in the treatment of type 2 diabetes inadequately controlled with OADs and / or basal insulin .\",\n \"Cannabinoid , melanocortin and opioid receptor expression on P21728 and P14416 subpopulations in rat striatum . The striatum harbors two neuronal populations that enable action selection . One population represents the striatonigral pathway , expresses the dopamine receptor D1 ( P21728 ) and promotes the execution of motor programs , while the other population represents the striatopallidal pathway , expresses the dopamine receptor D2 ( P14416 ) and suppresses voluntary activity . The two populations integrate distinct sensorimotor , cognitive , and emotional information streams and their combined activity enables the selection of adaptive behaviors . Characterization of these populations is critical to the understanding of their role in action selection , because it aids the identification of the molecular mechanisms that separate them . To that end , we used fluorescent in situ hybridization to quantify the percentage of striatal cells that ( co ) express dopaminergic receptors and receptors of the cannabinoid , melanocortin or opioid neurotransmitters systems . Our main findings are that the cannabinoid 1 receptor is equally expressed on both populations with a gradient from dorsal to ventral striatum , that the opioid receptors have a preference for expression with either the P21728 or P14416 and that the melanocortin 4 receptor ( P32245 ) is predominantly expressed in ventral parts of the striatum . In addition , we find that the level of P32245 expression determines its localization to either the P21728 or the P14416 population . Thereby , we provide insight into the sensitivity of the two dopaminoceptive populations to these neurotransmitters and progress the understanding of the mechanisms that enable action selection .\",\n \"P04818 genotype - directed chemotherapy for patients with gastric and gastroesophageal junction cancers . BACKGROUND : Retrospective studies indicate associations between TSER ( thymidylate synthase enhancer region ) genotypes and clinical outcomes in patients receiving ___MASK75___ based chemotherapy , but well - controlled prospective validation has been lacking . METHODS : In this phase II study ( NCT00515216 registered through ClinicalTrials . gov , http :// clinicaltrials . gov / show / NCT00515216 ) , patients with \\\" good risk \\\" TSER genotypes ( at least one TSER * 2 allele ) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates ( ORR ) in patients with gastric and gastroesophageal junction ( GEJ ) cancers , compared with historical outcomes in unselected patients ( estimated 43 % ) . RESULTS : The ORR in genotype - selected patients was Q04695 % ( 9 partial responses out of 23 evaluable patients , 95 % CI , 22 . 2 to 59 . 2 ) , not achieving the primary objective of improving ORR . An encouraging disease control rate ( DCR , consisting of partial responses and stable diseases ) of 95 . 7 % was noted and patients with homozygous TSER * 2 genotype showed better tumor response . CONCLUSIONS : In this first prospective , multi - institutional study in patients with gastric or GEJ cancers , selecting patients with at least one TSER * 2 allele did not improve the ORR but led to an encouraging DCR . Further studies are needed to investigate the utility of selecting patients homozygous for the TSER * 2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers . TRIAL REGISTRATION : ClinicalTrials . gov NCT00515216 .\",\n \"[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK66___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .\",\n \"Genome - wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma . BACKGROUND : The molecular mechanisms of CC ( cholangiocarcinoma ) oncogenesis and progression are poorly understood . This study aimed to determine the genome - wide expression of genes related to CC oncogenesis and sarcomatous transdifferentiation . METHODS : Genes that were differentially expressed between CC cell lines or tissues and cultured normal biliary epithelial ( NBE ) cells were identified using DNA microarray technology . Expressions were validated in human CC tissues and cells . RESULTS : Using unsupervised hierarchical clustering analysis of the cell line and tissue samples , we identified a set of 342 commonly regulated ( > 2 - fold change ) genes . Of these , 53 , including tumor - related genes , were upregulated , and 289 , including tumor suppressor genes , were downregulated ( < 0 . 5 fold change ) . Expression of P10451 , P52799 , Q14209 , P78415 , O95997 , PPARγ , Q04695 , P09936 , Q16270 and P09486 proteins was immunohistochemically verified in human and hamster CC tissues . Additional unsupervised hierarchical clustering analysis of sarcomatoid CC cells compared to three adenocarcinomatous CC cell lines revealed 292 differentially upregulated genes ( > 4 - fold change ) , and 267 differentially downregulated genes ( < 0 . 25 fold change ) . The expression of 12 proteins was validated in the CC cell lines by immunoblot analysis and immunohistochemical staining . Of the proteins analyzed , we found upregulation of the expression of the epithelial - mesenchymal transition ( EMT ) - related proteins P08670 and Q15672 , and restoration of the methylation - silenced proteins P07195 , Q12983 , P09936 , and P47972 during sarcomatoid transdifferentiation of CC . CONCLUSION : The deregulation of oncogenes , tumor suppressor genes , and methylation - related genes may be useful in identifying molecular targets for CC diagnosis and prognosis .\",\n \"Adipose tissue tumor necrosis factor and interleukin - 6 expression in human obesity and insulin resistance . Adipose tissue expresses tumor necrosis factor ( P01375 ) and interleukin ( IL ) - 6 , which may cause obesity - related insulin resistance . We measured P01375 and P05231 expression in the adipose tissue of 50 lean and obese subjects without diabetes . P01308 sensitivity ( S ( I ) ) was determined by an intravenous glucose tolerance test with minimal - model analysis . When lean [ body mass index ( BMI ) < 25 kg / m ( 2 ) ] and obese ( BMI 30 - 40 kg / m ( 2 ) ) subjects were compared , there was a 7 . 5 - fold increase in P01375 secretion ( P < 0 . 05 ) from adipose tissue , and the P01375 secretion was inversely related to S ( I ) ( r = - 0 . 42 , P < 0 . 02 ) . P05231 was abundantly expressed by adipose tissue . In contrast to P01375 , plasma ( rather than adipose ) P05231 demonstrated the strongest relationship with obesity and insulin resistance . Plasma P05231 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S ( I ) ( r = - 0 . 71 , P < 0 . 001 ) . To separate the effects of BMI from S ( I ) , subjects who were discordant for S ( I ) were matched for BMI , age , and gender . By use of this approach , subjects with low S ( I ) demonstrated a 3 . 0 - fold increased level of P01375 secretion from adipose tissue and a 2 . 3 - fold higher plasma P05231 level ( P < 0 . 05 ) compared with matched subjects with a high S ( I ) . Plasma P05231 was significantly associated with plasma nonesterified fatty acid levels ( r = 0 . 49 , P < 0 . 002 ) . Thus the local expression of P01375 and plasma P05231 are higher in subjects with obesity - related insulin resistance .\",\n \"Glucagon - like peptide - 1 ( 1 - 37 ) inhibits chemokine - induced migration of human P01730 - positive lymphocytes . The present study examined the effect of P0C6A0 ( 1 - 37 ) on chemokine - induced P01730 - positive lymphocyte migration as an early and critical step in atherogenesis . Pretreatment with P0C6A0 ( 1 - 37 ) reduced the SDF - induced migration of isolated human P01730 - positive lymphocytes in a concentration - dependent manner . Similar effects were seen when RANTES was used as a chemokine . P0C6A0 ( 1 - 37 ) ' s effect on P01730 - positive lymphocyte migration was mediated through an early inhibition of chemokine - induced P19957 kinase activity . Downstream , P0C6A0 ( 1 - 37 ) inhibited SDF - induced phosphorylation of MLC and cofilin and limited f - actin formation as well as P32942 translocation . Furthermore , exendin - 4 inhibited SDF - induced migration of P01730 - positive lymphocytes similarly to P0C6A0 ( 1 - 37 ) , and transfection of these cells with P43220 siRNA abolished P0C6A0 ( 1 - 37 ) ' s action on chemokine - induced P32942 translocation , suggesting an effect mediated via the P43220 . Thus , P0C6A0 ( 1 - 37 ) inhibits chemokine - induced P01730 - positive lymphocyte migration by inhibition of the P19957 - kinase pathway and via the P43220 . This effect provides a potential novel mechanism for how P0C6A0 ( 1 - 37 ) may modulate vascular disease .\",\n \"[ DB01276 : first once weekly P43220 agonist ( exenatide P10586 ) ] . DB01276 is a new galenic formulation ( long - acting release ) of exenatide , the first agonist of Glucagon - Like Peptide - 1 ( P0C6A0 ) receptors having been commercialized for the management of type 2 diabetes . The microsphere technology permits a prolonged absorption of exenatide from the subcutaneous depot , which allows one injection per week instead of two injections per day with the initial formulation of exenatide ( DB01276 ) . The clinical development programme DURATION showed that exenatide 2 mg once weekly more markedly reduces glycated haemoglobin ( HbA ( 1c ) ) , with a similar weight loss but a better digestive tolerance profile ( less nausea and vomiting after treatment initiation ) , compared with the twice daily 10 microg exenatide . When compared to other glucose - lowering agents , once weekly exenatide is more efficacious than sitagliptin , pioglitazone or basal insulin ( glargine or detemir ) , with the advantage of producing weight loss and lowering arterial blood pressure . It does not induce hypoglycaemia and does not necessarily require home blood glucose monitoring , two advantages compared with insulin therapy . DB01276 is currently only reimbursed in Belgium after failure of and in addition to metformin - sulfonylurea combination .\",\n \"Selected P21554 polymorphisms and hyperandrogenemia as well as fat mass and fat distribution in women with polycystic ovary syndrome . The endocannabinoid system is postulated to play an important role in the etiology of obesity , insulin resistance , fat distribution and metabolic disorders . P01308 resistance associated with abdominal obesity plays a leading role in the etiology of hyperandrogenism and other clinical features of the polycystic ovary syndrome ( PCOS ) . A total of 174 women 16 - 38 years old , diagnosed with PCOS according to the Rotterdam criteria are recruited . Control group consisted of 125 healthy women 18 - 45 years old . Medical history , physical examination , anthropometric parameters and metabolic parameters were carried out . Six P21554 gene polymorphisms were diagnosed . We observed a significantly three times higher risk of GG genotype in the polymorphism rs12720071 in women with PCOS versus the control group ( p = 0 . 0344 , OR = 3 . 01 ) . A similar , significant 8 - fold higher risk ( p = 0 . 0176 , OR = 8 . 81 ) was demonstrated for genotype CC polymorphism rs806368 associated with PCOS . We observed a 3 . 6 - fold increased risk of hyperandrogenemia ( free androgen index - FAI > 7 ) in patients with GG genotype in the rs12720071 polymorphism and AA genotype in the polymorphism rs1049353 ( OR = 2 . 7 ) . Our study may indicate a role of the endocannabinoid system in the occurrence of a specific hyperandrogenemia phenotype of PCOS .\",\n \"The interaction of thymidylate synthase expression with p53 - regulated signaling pathways in tumor cells . P04818 ( TS ) is a chemotherapeutic target for the fluoropyrimidine 5 - fluorouracil ( ___MASK75___ ) and antifolate tomudex ( TDX ) . Using the MCF - 7 breast cancer line , we have developed a cell line with inducible TS expression termed M7TS90 . Inducible TS expression in this line resulted in a moderate ( approximately 3 - fold ) increase in ___MASK75___ 50 % inhibitory concentration at 72 hours ( IC - 50 ( 72 h ) ) dose and a dramatic ( approximately 24 - fold ) increase in the IC - 50 ( 72 h ) dose of TDX , but did not affect chemosensitivity to cisplatin , oxaliplatin , irinotecan , and paclitaxel . In the absence of drug treatment , inducible TS expression had no effect on expression of the p53 tumor suppressor gene . However , TS induction abrogated p53 , P38936 , Fas , and Bak induction in response to TDX , but not ___MASK75___ . Similarly , downregulation of Bcl - 2 was reversed by inducible TS expression in TDX , but not ___MASK75___ - treated cells . Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX , but not ___MASK75___ .\",\n \"' Neuron - specific ' protein gene product 9 . 5 ( P09936 ) is also expressed in glioma cell lines and its expression depends on cellular growth state . Protein gene product 9 . 5 ( P09936 ) , which in the normal nervous system is restricted to certain neurons , has been detected in two glioma cell lines , rat P13671 and human GL15 , by immunoblotting and immunocytochemistry . Its expression in these cells depends on the cellular growth state , being maximal between the first and second post - plating day . Only a faint P09936 immunoreactivity can be observed in glioma cells after the eleventh post - plating day , i . e . about one week after confluency has been reached . The present results suggest that P09936 in cultured glial cells is maximally expressed during the growth phase and that the protein could play a role during brain development in glial cells , in reactive gliosis , or in tumorigenesis of the glial lineage .\",\n \"P10275 antagonism and an insulin sensitizer block the advancement of vaginal opening by high - fat diet in mice . Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty . In high fat - fed rodents , the timing of vaginal opening ( VO ) is advanced , suggesting that puberty begins earlier . Because obesity can increase androgens , which interfere with normal steroid feedback in adult females , we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat - fed mice . Age at VO was examined in mice fed high - fat or low - fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle ( controls ) . VO was advanced in high - fat vs . low - fat controls , and flutamide blocked this advancement . VO was also delayed in low fat - fed flutamide - treated females , suggesting involvement of androgens in the timing of normal puberty . We next investigated if high - fat diet - induced insulin resistance contributes to early VO , as elevated insulin can stimulate androgen production . VO was examined in mice on either diet treated with the insulin sensitizer metformin . Metformin blocked high - fat advancement of VO but did not alter the timing of VO in low fat - fed mice . P01308 was elevated in high fat - fed females that had undergone VO compared with age - matched low fat - fed or metformin - treated animals on either diet that had not undergone VO . Together , these data suggest a model in which metabolic changes induced by high - fat diet , including transient increased circulating insulin , act in part by increasing androgen action to influence the timing of puberty in females .\",\n \"Ontogeny of expression of P09936 antigen on TcR - 1 + ( P01730 / 8 ) and TcR delta + T cells . The frequency of blood mononuclear cells expressing the 180 - kDa splice variant of the common leukocyte antigen identified by the P09936 monoclonal antibody ( a characteristic of post - thymic cells which have been through a cycle of stimulation ) rose in a logarithmic relationship to age between birth and 16 years . At birth only a low frequency of P01730 + ( negative for CD 25 ) and no CD8 + T cells expressed P09936 . The subsequent increase in P09936 expression occurred in parallel on T cells expressing alpha / beta receptors and gamma / delta receptors , suggesting that these subsets participated in post - thymic proliferation in proportion to their numbers in blood . The frequency of P09936 expression on CD8 cells was 5 - 15 % less than on P01730 cells .\",\n \"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK67___ ) in castrated male and female mice subjected to ___MASK67___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK67___ in mice CPs .\",\n \"Novel P0C6A0 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain . One of the symptoms of diabetes is the progressive development of neuropathies . One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells . We have tested the effects of the novel P0C6A0 mimetics exenatide ( exendin - 4 ; DB01276 ) and liraglutide ( DB06655 ; DB06655 ) , which are already on the market as treatments for type 2 diabetes , on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes . P0C6A0 analogues were injected subcutaneously for 4 , 6 , or 10 weeks once daily in three mouse models of diabetes : ob / ob mice , db / db mice , or high - fat - diet - fed mice . Twenty - four hours before perfusion , animals were injected with 5 '- bromo - 2 '- deoxyuridine ( BrdU ) to mark dividing progenitor cells . By using immunohistochemistry and stereological methods , the number of progenitor cells or doublecortin - positive young neurons in the dentate gyrus was estimated . We found that , in all three mouse models , progenitor cell division was enhanced compared with nondiabetic controls after chronic i . p . injection of either liraglutide or exendin - 4 by 100 - 150 % ( P < 0 . 001 ) . We also found an increase in young neurons in the DG of high - fat - diet - fed mice after drug treatment ( P < 0 . 001 ) . The P43220 antagonist exendin ( 9 - 36 ) reduced progenitor cell proliferation in these mice . The results demonstrate that P0C6A0 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer ' s disease , because these novel drugs cross the blood - brain barrier and increase neuroneogenesis .\",\n \"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK49___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK49___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK49___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK49___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK49___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK49___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK49___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK49___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK49___ in the treatment of changes in hypervigilance following severe stress .\",\n \"___MASK1___ induces insulin sensitization in Zucker lean and fatty rats . BACKGROUND : The 3 - hydroxy - 3 - methyl glutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors ( ' statins ' ) have been implicated in preventing new onset type 2 diabetes , whereas the mechanism of this effect is not known . We investigated the effects of an P04035 inhibitor , atorvastatin , on insulin sensitization in Zucker lean and fatty rats . METHODS AND RESULTS : In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg / kg / day ( ATORVA_50 ) and results were compared to Zucker lean and fatty rats treated with drug vehicle only ( CONT ) . Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25mg / kg / day ( ATORVA_25 ) . Treatment with atorvastatin resulted in a dose - dependent improvement in whole body insulin sensitivity in both lean and fatty rats , with an approximately two - fold increase in glucose infusion rate and glucose disposal ( Rd ) in ATORVA_50 versus CONT ( p < 0 . 01 ) . ___MASK1___ 50mg / kg / day resulted in an increase in DB08831 ( 2 - DOG ) uptake by skeletal muscles ( approximately two - fold increase in 2 - DOG uptake in quadriceps ( p = 0 . 06 ) and gastrocnemius ( p < 0 . 01 ) ) in lean Zucker rats . P01308 - stimulated phosphorylation of Akt / P31749 was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats . CONCLUSION : ___MASK1___ induces insulin sensitization in Zucker lean and fatty rats . This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans .\",\n \"P16109 - and heparanase - dependent antimetastatic activity of non - anticoagulant heparins . Vascular cell adhesion molecules , P - and L - selectins , facilitate metastasis of cancer cells in mice by mediating interactions with platelets , endothelium , and leukocytes . Q9Y251 is an endoglycosidase that degrades heparan sulfate of extracellular matrix , thereby promoting tumor invasion and metastasis . ___MASK66___ is known to efficiently attenuate metastasis in different tumor models . Here we identified modified , nonanticoagulant species of heparin that specifically inhibit selectin - mediated cell - cell interactions , heparanase enzymatic activity , or both . We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC - 38 colon carcinoma and B16 - BL6 melanoma attenuates metastasis . Selectin - specific heparin derivatives attenuated metastasis of MC - 38 carcinoma , but heparanase - specific derivatives had no effect , in accordance with the virtual absence of heparanase activity in these cells . ___MASK66___ derivatives had no further effect on metastasis in mice deficient in P - and P14151 , indicating that selectins are the primary targets of heparin antimetastatic activity . Selectin - specific and heparanase - specific derivatives attenuated metastasis of B16 - BL6 melanomas to a similar extent . When mice were injected with a derivative containing both heparanase and selectin inhibitory activity , no additional attenuation of metastasis could be observed . Thus , selectin - specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase .\",\n \"Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 ) at 11p15 , tyrosinase ( P14679 ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 ) at 11q22 - q23 , as well as with the c - Harvey - ras oncogene ( P01112 ) and insulin gene ( P01308 ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected - sib - pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two - point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 and P01308 excluded the 11p15 region encompassing both P21917 and TH . In agreement with the negative linkage results , affected - sib - pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 , TH , P14679 , and P14416 in the pathogenesis of bipolar illness .\",\n \"P0C6A0 treatment reduces endogenous insulin resistance via activation of central P0C6A0 receptors in mice fed a high - fat diet . Glucagon - like peptide - 1 ( P0C6A0 ) improves insulin sensitivity in humans and rodents . It is currently unknown to what extent the ( metabolic ) effects of P0C6A0 treatment are mediated by central P0C6A0 receptors . We studied the impact of central P43220 ( P43220 ) antagonism on the metabolic effects of peripheral P0C6A0 administration in mice . High - fat - fed insulin - resistant C57Bl / 6 mice were treated with continuous subcutaneous infusion of P0C6A0 or saline ( PBS ) for 2 wk , whereas the P43220 antagonist exendin - 9 ( EX - 9 ) and cerebrospinal fluid ( P04141 ) were simultaneously infused in the left lateral cerebral ventricle ( icv ) . DB09341 and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp . VLDL - triglyceride ( VLDL - TG ) production was determined in hyperinsulinemic conditions . Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by P0C6A0 . Simultaneous icv infusion of EX - 9 diminished this effect by 62 % . The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by P0C6A0 . Simultaneous icv infusion of EX - 9 significantly diminished the latter effect . Central P43220 antagonism alone did not affect glucose metabolism . Also , P0C6A0 treatment reinforced the inhibitory action of insulin on VLDL - TG production . In conclusion , peripheral administration of P0C6A0 reinforces the ability of insulin to suppress endogenous glucose and VLDL - TG production ( but not lipolysis ) and boosts its capacity to stimulate glucose disposal in high - fat - fed C57Bl / 6 mice . Activation of central GLP - 1Rs contributes substantially to the inhibition of endogenous glucose production by P0C6A0 treatment in this animal model .\",\n \"[ Activation of coagulation cascade in children during an idiopathic nephrotic syndrome relapse ] . The objective of this study was to assess concentrations of selected markers of coagulation in children with relapse of idiopathic nephrotic syndrome during a 6 - week therapy . Study groups : 22 subjects ( 32 relapses ) -- 14 males , 8 females ( mean age 7 . 15 +/- 1 . 5 y . ) with no thrombotic complications were included into the study . All children were clinically steroid - sensitive . METHODS : Coagulation markers ( platelet count , thrombin time , APTT , INR , fibrinogen 1 + 2 fragments ( F1 + 2 ) , thrombin - antithrombin complexes ( TAT ) , serum levels of D - dimer ( DD ) , fibrin monomers ( FM ) and antithrombin activity ( P01008 ) ) were measured three times : on admission , after 2 and 6 weeks . The control group consisted of 13 healthy children . RESULTS : Serum concentration of TAT or F1 + 2 did not differ between 3 stages ( p > 0 . 05 ) . However , values at 0 and 2 weeks were significantly higher than in control group ( p < 0 . 05 ) . We found no correlation between TAT or F1 + 2 and FBG , ALB , TCH , TG levels . [ table : see text ] CONCLUSIONS : The coagulation cascade in relapse of NS was activated during first 6 weeks of therapy whereas metabolic disturbances ( low ALB , high P02675 , TCH , TG , high platelets ) normalized . It is speculative whether it was caused by active immunological process but definitely it resulted in \\\" prothrombotic state \\\" in P01308 patients .\",\n \"Neuroprotective effect of the glucagon - like peptide - 1 receptor agonist , synthetic exendin - 4 , in streptozotocin - induced diabetic rats . BACKGROUND AND PURPOSE : Glucagon - like peptide - 1 ( P0C6A0 ) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation . The aim of this study was to investigate the effect of the P0C6A0 pathway on peripheral nerves in streptozotocin - induced diabetic rats . EXPERIMENTAL APPROACH : Diabetic and nondiabetic rats were treated with the P43220 agonist , synthetic exendin - 4 ( i . p . , 1 nmol · kg (- 1 )· day (- 1 ) ) or placebo for 24 weeks , and current perception threshold values , DB02527 levels and nerve fibre size in the sciatic nerve were measured . We also investigated P43220 expression , quantitative changes in P09936 - positive intraepidermal nerve fibres and cleaved caspase 3 - stained Schwann cells by immunohistochemistry . KEY RESULTS : P43220 expression was detected in the sciatic nerve and skin . After exendin - 4 treatment , the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced . Also , the decrease in myelinated fibre size or axon / fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated . These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the DB02527 level in exendin - 4 - treated diabetic rats , compared with placebo - treated animals . CONCLUSION AND IMPLICATIONS : DB01276 may prevent peripheral nerve degeneration induced by diabetes in an animal model , supporting the hypothesis that P0C6A0 may be useful in peripheral neuropathy . The neuroprotection is probably attributable to P43220 activation , antiapoptotic effects and restoration of DB02527 content .\",\n \"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK1___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .\",\n \"P01308 - induced NADPH oxidase activation promotes proliferation and matrix metalloproteinase activation in monocytes / macrophages . P01308 stimulates superoxide ( O ( 2 )(-) ) production in monocytes and macrophages . However , the mechanisms through which insulin induces O ( 2 )(-) production are not completely understood . In this study , we ( a ) characterized the enzyme and the pathways involved in insulin - stimulated O ( 2 )(-) production in human monocytes and murine macrophages , and ( b ) analyzed the consequences of insulin - stimulated O ( 2 )(-) production on the cellular phenotype in these cells . We showed that insulin stimulated O ( 2 )(-) production , and promoted p47 ( phox ) translocation to the plasma membrane . P01308 - induced O ( 2 )(-) production and p47 ( phox ) translocation were prevented in the presence of specific inhibitors of PI3K and PKC . P01308 - mediated NADPH oxidase activation stimulated P14780 activation in monocytes and cell proliferation in macrophages . The effect of insulin on these phenotypic responses was mediated through NFkappaB , p38MAPK , and P29323 1 / 2 activation . Small - interfering RNA - specific gene silencing targeted specifically against Nox2 reduced the cognate protein expression , decreased insulin - induced O ( 2 )(-) production , inhibited the turn on of NFkappaB , p38MAPK , and P29323 1 / 2 , and reduced cell proliferation in macrophages . These findings suggest a pivotal role for NADPH oxidase in insulin - induced proliferation and proteolytic activation in monocytes and macrophages , respectively , and identify a pathway that may play a pathological role in hyperinsulinemic states .\",\n \"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK67___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK67___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .\",\n \"Absence of genetic variation in some obesity candidate genes ( P43220 , ASIP , P32245 , P33032 ) among Pima indians . OBJECTIVE : To examine the obesity candidate genes glucagon - like - peptide receptor ( P43220 ) , agouti signaling protein ( ASIP ) and the melanocortin receptors 4 and 5 ( P32245 and P33032 ) for DNA polymorphisms in their coding regions . SUBJECTS : Unrelated , non - diabetic Pima Indians ( 8 to 12 from each extreme of body fat ) . MEASUREMENTS : DNA sequencing within the coding regions of each gene . RESULT : Only one variant was detected , a silent substitution in exon 6 of P43220 . CONCLUSION : The exclusion of any common amino - acid polymorphisms ( allele frequency > or = 0 . 20 ) . implies that structural variants of these genes do not contribute to variation in the high level of obesity observed among the Pima Indians .\",\n \"Exendin - 4 alleviates angiotensin II - induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . Vascular aging has been implicated in the progression of diabetes and age - related cardiovascular disorders . Glucagon - like peptide - 1 ( P0C6A0 ) is an incretin hormone capable of cytoprotective actions in addition to its glucose - lowering effect . The present study was undertaken to examine whether Exendin - 4 , a specific ligand for the P43220 , could prevent angiotensin ( P03950 ) II - induced premature senescence in vascular smooth muscle cells ( VSMCs ) and to determine the underlying mechanism involved . Senescence - associated β - galactosidase ( SA β - gal ) assay showed that P03950 II induced premature senescence of VSMCs . Pretreatment with Exendin - 4 significantly attenuated P03950 II - induced generation of H2O2 and the subsequent VSMC senescence . These effects were , however , reversed in the presence of exendin fragment 9 - 39 , a P43220 antagonist , or PKI14 - 22 . Moreover , a marked increase in the levels of p53 and P38936 induced by P03950 II was blunted by the treatment with Exendin - 4 . Nevertheless , Exendin - 4 failed to decrease P03950 II - induced expression of NAD ( P ) H oxidase 1 ( Nox1 ) , NAD ( P ) H oxidase 4 ( Nox4 ) , O75935 ( phox ) , or p47 ( phox ) in VSMCs . Mechanistically , Exendin - 4 blocked P03950 II - induced Rac1 activation through the DB02527 / PKA signaling cascade . Specifically , NSC23766 , a Rac1 inhibitor , abrogated the suppressive effects of Exendin - 4 on P03950 II - induced premature senescence and H2O2 generation , respectively . Thus Exendin - 4 confers resistance to P03950 II - induced superoxide anion generation from NAD ( P ) H oxidase and the resultant VSMC senescence by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . These findings demonstrate that P0C6A0 as well as its analogs ( P0C6A0 - related reagents ) may hold therapeutic potential in the treatment of diabetes with cardiovascular disease .\",\n \"Role of central glucagon - like peptide - 1 in hypothalamo - pituitary - adrenocortical facilitation following chronic stress . Central glucagon - like peptide - 1 ( P0C6A0 ) regulates food intake , glucose homeostasis , and behavioral and neuroendocrine responses to acute stress . Given its pronounced role in acute stress regulation , the P0C6A0 system is a prime candidate for mediating the prolonged drive of the hypothalamo - pituitary - adrenocortical axis by chronic stress . To test this hypothesis , we evaluated the necessity and sufficiency of P0C6A0 for production of chronic stress - induced changes in Q9Y251 axis function . Exogenous P0C6A0 or the P43220 antagonist , dHG - exendin , were delivered into the 3rd ventricle of control animals or animals exposed to chronic variable stress ( CVS ) for 7 days . Animals in the CVS groups received P0C6A0 or dHG - exendin immediately prior to each stress exposure . Prior to and at the end of the 7 - day trial , chronically - stressed animals were subjected to a novel stressor to test for Q9Y251 axis facilitation . Neither P0C6A0 nor dHG - exendin affected CVS - associated increases in adrenal weight or decreases in basal plasma glucose levels . In addition , neither exogenous P0C6A0 nor dHG - exendin altered any index of Q9Y251 axis activity in unstressed rats . However , P0C6A0 enhanced CVS - induced facilitation of corticosterone ( but not DB01285 ) response to an acute stress , whereas dHG - exendin inhibited facilitation . In addition , P0C6A0 decreased body weight in chronically - stressed animals . dHG - exendin increased food intake and body weight in unstressed animals , consistent with a tonic role for P0C6A0 in body weight regulation . Overall , our data suggest that brain P0C6A0 modulates Q9Y251 axis activity within the context of chronic stress , perhaps at the level of the adrenal gland .\",\n \"New insights into the role of DB02527 in the production and function of the incretin hormone glucagon - like peptide - 1 ( P0C6A0 ) . The proglucagon gene ( gcg ) encodes both glucagon and glucagon - like peptide - 1 ( P0C6A0 ) , produced in pancreatic alpha cells and intestinal endocrine L cells , respectively . The incretin hormone P0C6A0 stimulates insulin secretion and pro - insulin gene transcription . P0C6A0 also enhances pancreatic beta - cell proliferation , inhibits cell apoptosis , and has been utilized in the trans - differentiation of insulin producing cells . A long - term effective P43220 agonist , DB01276 , has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders . The expression of gcg and the production of P0C6A0 can be activated by the elevation of the second messenger cyclic AMP ( DB02527 ) . Recent studies suggest that in addition to protein kinase A ( PKA ) , exchange protein activated by DB02527 ( Epac ) , another effector of DB02527 , and the crosstalk between PKA and the Wnt signaling pathway , are involved in DB02527 - stimulated gcg transcription and P0C6A0 production as well . Finally , functions of P0C6A0 in pancreatic beta cells are also mediated by PKA , Epac , as well as the effector of the Wnt signaling pathway . Together , these novel findings bring us a new insight into the role of DB02527 in the production and function of the incretin hormone P0C6A0 .\",\n \"Concurrent pharmacological modification of cannabinoid - 1 and glucagon - like peptide - 1 receptor activity affects feeding behavior and body weight in rats fed a free - choice , high - carbohydrate diet . To extend preliminary studies on the effects on food intake of the combined use of cannabinoid ( CB ) 1 and glucagon - like peptide - 1 ( P0C6A0 ) receptor agonists and antagonists , the effect of these drugs on the feeding behavior in rats maintained on a free - choice , high - carbohydrate diet was investigated over a longer period of time . Rats were fed a standard diet for 3 days and then fed with both the standard and the high - sucrose chow . After 4 days of the high - calorie diet , the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days : 1 mg / kg AM 251 ( a P21554 receptor antagonist ) or 1 mg / kg Q08050 55 , 212 - 2 ( a P21554 receptor agonist ) together with 3 µg / kg exendin - 4 ( Ex - 4 , a P43220 agonist ) or 160 µg / kg exendin ( 9 - 39 ) [ Ex ( 9 - 39 ) , a P43220 antagonist ] . The total daily caloric intake and body weight were significantly reduced in rats treated with Ex - 4 and AM 251 or Q08050 55 , 212 - 2 compared with either of the drugs injected alone and the saline - injected controls . Both drug combinations selectively inhibited ingestion of the high - sucrose chow . Although Ex ( 9 - 39 ) administration did not significantly affect food consumption , it resulted in a marked body weight gain , indicating that the P43220 antagonist caused a positive energy balance . It is concluded that AM 251 or Q08050 55 , 212 - 2 and Ex - 4 , injected together , exert additive , inhibitory effects on the consumption of high - sugar food .\",\n \"Molecular physiology of glucagon - like peptide - 1 insulin secretagogue action in pancreatic β cells . P01308 secretion from pancreatic β cells is stimulated by glucagon - like peptide - 1 ( P0C6A0 ) , a blood glucose - lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e . g . , DB01276 ) and P0C6A0 analogs ( e . g . , DB06655 ) activate the β cell P43220 ( P43220 ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase - IV ( DPP - IV ) inhibitors ( e . g . , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post - prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e . g . , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac2 - mediated actions of P0C6A0 to regulate DB00171 - sensitive K ⁺ channels , voltage - dependent K ⁺ channels , O94759 cation channels , intracellular Ca ⁺ release channels , and Ca ⁺- dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM .\",\n \"Improvement of psoriasis during exenatide treatment in a patient with diabetes . CONTEXT AND AIM : Psoriasis is an immune - mediated skin disorder frequently associated with obesity and type 2 diabetes ( T2D ) . This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a P43220 agonist ( exenatide ) . OBSERVATION : A 61 - year - old male patient ( BMI : 25 . 5 kg / m ( 2 ) ) with T2D treated with metformin and sulphonylureas had also complained , since 1980 , of extensive psoriasis that required multiple steroid - based treatments [ Psoriasis Area and Sensitivity Index ( PASI ) score : 11 ] . In September 2008 , his diabetes treatment was intensified with exenatide ( DB01276 (®) ) to improve poor glycaemic control . The patient , as expected , lost weight and reduced HbA ( 1c ) levels from 65 mmol / mol to 56 mmol / mol . However , after just 1 month of treatment with exenatide , the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 - year follow - up ( PASI : estimated at 3 - 4 ) . Withdrawal of exenatide was associated with weight gain , deterioration of glycaemic control and deterioration of psoriasis ( PASI : > 10 ) . After reinstating exenatide treatment , the patient again reported a prompt improvement in psoriasis ( PASI : 3 . 1 ) . CONCLUSION : There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide . A possible mechanism might be through direct modulation of the immune system by P43220 agonists .\",\n \"Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug - target gene network . These genes were overrepresented in several pathways including : neuroactive ligand - receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug - gene network , we revealed a few bridge genes connected the sub - networks of the drug - gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . DB00502 was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug - gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug - gene interactions in psychosis .\",\n \"P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK56___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .\",\n \"[ ___MASK22___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK22___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .\",\n \"Different expression of ubiquitin C - terminal hydrolase - Q9NUQ9 and αII - spectrin in ischemic and hemorrhagic stroke : Potential biomarkers in diagnosis . The two primary categories of stroke , ischemic and hemorrhagic , both have fundamentally different mechanisms and thus different treatment options . These two stroke categories were applied to rat models to identify potential biomarkers that can distinguish between them . Ischemic stroke was induced by middle cerebral artery occlusion ( MCAO ) without reperfusion while hemorrhagic stroke was induced by injecting collagenase IV into the striatum . Brain hemispheres and biofluids were collected at two time points : 3 and 6h after stroke . Known molecules were tested on the rat samples via quantitative immunoblotting ( injured brain , P04141 ) and Banyan ' s proprietary ELISA assays ( P04141 , serum ) . The injured brain quantitative analyses revealed that αII - spectrin breakdown products ( SBDP150 , SBDP145 ) were strongly increased after 6h ischemia . In P04141 , SBDP145 and ubiquitin C - terminal hydrolase - Q9NUQ9 ( P09936 ) levels were elevated after 6h ischemic stroke detected by Western blot and ELISA . In serum P09936 levels were increased after 3 and 6h of ischemia detected by ELISA . However , levels of those proteins in hemorrhagic stroke remain normal . In summary , in both the brain and the biofluids , SBDPs and P09936 were elevated after ischemic but not hemorrhagic stroke . These molecules behaved differently in the two stroke models and thus may be capable of being differentiated .\",\n \"___MASK25___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .\"\n]"},"candidates":{"kind":"list like","value":["___MASK13___","___MASK1___","___MASK22___","___MASK25___","___MASK49___","___MASK56___","___MASK66___","___MASK67___","___MASK75___"],"string":"[\n \"___MASK13___\",\n \"___MASK1___\",\n \"___MASK22___\",\n \"___MASK25___\",\n \"___MASK49___\",\n \"___MASK56___\",\n \"___MASK66___\",\n \"___MASK67___\",\n \"___MASK75___\"\n]"},"answer":{"kind":"string","value":"___MASK67___"},"id":{"kind":"string","value":"MH_train_493"}}},{"rowIdx":494,"cells":{"query":{"kind":"string","value":"interacts_with DB00921?"},"supports":{"kind":"list like","value":["[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK22___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .","Preparation of phosphorylated starch by dry - heating in the presence of pyrophosphate and its calcium - phosphate solubilizing ability . Starch was phosphorylated through dry - heating in the presence of pyrophosphate at various conditions , and the characteristics of phosphorylated starch ( PS ) were examined . Starch phosphorylation increases as the pH increases from 3 to 6 , but diminishes at pH 7 . Increased temperatures enhance phosphorylation . Data from ( 31 ) P NMR suggests that starch phosphorylation occurs mainly at the P01024 - OH and P13671 - OH of the glucose residue . The phosphate linkage is mainly due to monostarch monophosphate . Although starch had almost no calcium phosphate - solubilising capacity , this capacity was markedly enhanced by phosphorylation . X - ray diffraction analysis indicates that the crystal structure of hydroxyapatite was not present in the calcium phosphate - PS complex .","Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .","Lack of evidence for the mu - opioid receptor splice variant MOR1C in rats . We previously reported the existence of P35372 ( C ) mRNA and P35372 ( C )- immunoreactivity ( - ir ) in rats . However , the sequence that we reported for rat P35372 ( C ) appears not to be present in the rat genome . We have therefore reexamined whether P35372 ( C ) mRNA or P35372 ( C )- ir exist in rats . We used reverse - transcription polymerase chain reaction ( RT - PCR ) to attempt to amplify P35372 , P35372 ( A ) , P35372 ( B ) , the rat P35372 ( C ) sequence we previously reported , and P35372 ( C1 ) and P35372 ( P06681 ) ( which have recently been reported to exist in rats ) . In RNA extracted from rats , we were able to demonstrate PCR products representing P35372 , P35372 ( A ) , and P35372 ( B ) splice variants . All three products were confirmed as related to P35372 by Southern blot . However , we were unable to detect either the P35372 ( C ) product reported previously by us or the P35372 ( C )- like products reported to exist in rats by others . In RNA extracted from mice we were able to detect P35372 , P35372 ( A ) , P35372 ( B ) , and P35372 ( D )- like products . To test the specificity of our P35372 ( C ) antiserum , we examined P35372 ( C )- ir in control and knockout mice . P35372 ( C )- ir had a distribution in control mice similar to that previously reported in rats , including coexisting with vGLUT2 . However , although P35372 - ir was absent in P35372 knockout mice , the density and distribution of P35372 ( C )- ir were unchanged , suggesting that the antiserum crossreacts with another molecule in tissue . We find no evidence for P35372 ( C ) mRNA in rats . Furthermore , we conclude that P35372 ( C )- ir represents crossreactivity .","Neurogenetics of aggressive behavior : studies in primates . Aggressive behavior can have adaptive value in certain environmental contexts , but when extreme or executed inappropriately , can also lead to maladaptive outcomes . Neurogenetic studies performed in nonhuman primates have shown that genetic variation that impacts reward sensitivity , impulsivity , and anxiety can contribute to individual differences in aggressive behavior . Genetic polymorphisms in the coding or promoter regions of the Mu - Opioid Receptor ( P35372 ) , DB01285 Releasing Hormone ( P06850 ) , Monoamine Oxidase A ( P21397 ) , Dopamine D4 Receptor ( P21917 ) , and Serotonin Transporter ( P31645 ) genes have been shown to be functionally similar in humans and rhesus macaques and have been demonstrated to contribute to individual differences in aggression . This body of literature suggests mechanisms by which genetic variation that promotes aggressivity could simultaneously increase evolutionary success while making modern humans more vulnerable to psychopathology .","OSU - 03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood - Brain Barrier : Implications for Anti - Cancer Therapies . We examined the interaction between OSU - 03012 ( also called AR - 12 ) with phosphodiesterase 5 ( O76074 ) inhibitors to determine the role of the chaperone glucose - regulated protein ( P11021 ) / P11021 / P11021 in the cellular response . ___MASK2___ ( Viagra ) interacted in a greater than additive fashion with OSU - 03012 to kill stem - like GBM cells . Treatment of cells with OSU - 03012 / sildenafil : abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of P11021 and other HSP70 and HSP90 family chaperone proteins . Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced Q9NZJ5 - eIF2α - P18848 - P35638 signaling and was blocked by P11021 over - expression . In vivo OSU - 03012 / sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of P08183 and Q9UNQ0 in the normal brain . The combination of OSU - 03012 / sildenafil synergized with low concentrations of sorafenib to kill tumor cells , and with lapatinib to kill P00533 over - expressing tumor cells . In multiplex assays on plasma and human tumor tissue from an OSU - 03012 / sildenafil treated mouse , we noted a profound reduction in uPA signaling and identified FGF and P23458 / 2 as response biomarkers for potentially suppressing the killing response . Inhibition of FGFR signaling and to a lesser extent P23458 / 2 signaling profoundly enhanced OSU - 03012 / sildenafil lethality .","Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK80___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .","Palmitoylation and membrane cholesterol stabilize μ - opioid receptor homodimerization and G protein coupling . BACKGROUND : A cholesterol - palmitoyl interaction has been reported to occur in the dimeric interface of the β₂ - adrenergic receptor crystal structure . We sought to investigate whether a similar phenomenon could be observed with μ - opioid receptor ( P35372 ) , and if so , to assess the role of cholesterol in this class of G protein - coupled receptor ( GPCR ) signaling . RESULTS : P01024 . 55 ( 170 ) was determined to be the palmitoylation site of P35372 . Mutation of this DB00151 to Ala did not affect the binding of agonists , but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex . In addition , both attenuation of receptor palmitoylation ( by mutation of P01024 . 55 [ 170 ] to Ala ) and inhibition of cholesterol synthesis ( by treating the cells with simvastatin , a P04035 inhibitor ) impaired receptor signaling , possibly by decreasing receptor homodimerization and Gαi2 coupling ; this was demonstrated by co - immunoprecipitation , immunofluorescence colocalization and fluorescence resonance energy transfer ( FRET ) analyses . A computational model of the P35372 homodimer structure indicated that a specific cholesterol - palmitoyl interaction can facilitate P35372 homodimerization at the TMH4 - TMH4 interface . CONCLUSIONS : We demonstrate that P01024 . 55 ( 170 ) is the palmitoylation site of P35372 and identify a cholesterol - palmitoyl interaction in the P35372 complex . Our findings suggest that this interaction contributes to P35372 signaling by facilitating receptor homodimerization and G protein coupling . This conclusion is supported by computational modeling of the P35372 homodimer .","Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK68___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .","P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK10___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .","Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK75___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK75___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK75___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK75___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK75___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .","Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .","Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .","mu - Opioid receptor agonists differentially regulate the expression of miR - 190 and Q13562 . The agonists of mu - opioid receptor ( P35372 ) induce extracellular signal - regulated kinase ( P29323 ) phosphorylation through different pathways : morphine uses the protein kinase C ( PKC ) - pathway , whereas fentanyl functions in a beta - arrestin2 - dependent manner . In addition , the two pathways result in the different cellular location of phosphorylated P29323 and the activation of different sets of transcriptional factors . In the current study , the influence of the two pathways on the expression of microRNAs ( miRNAs ) was investigated . After treating the primary culture of rat hippocampal neurons and the mouse hippocampi with morphine or fentanyl for 3 days , seven miRNAs regulated by one or two of the agonists were identified . One of the identified miRNAs , miR - 190 , was down - regulated by fentanyl but not by morphine . This down - regulation was attenuated by 1 , 4 - diamino - 2 , 3 - dicyano - 1 , 4 - bis ( methylthio ) butadiene ( U0126 ) , which blocks the phosphorylation of P29323 . When fentanyl - induced but not morphine - induced P29323 phosphorylation was blocked in the primary cultures from beta - arrestin2 (-/-) mouse , fentanyl did not decrease the expression of miR - 190 . However , a PKC inhibitor that blocked morphine - induced P29323 phosphorylation specifically had no effect on the miR - 190 down - regulation . Therefore the decrease in miR - 190 expression resulted from the agonist - selective P29323 phosphorylation . In addition , the expressional changes in one of the miR - 190 targets , neurogenic differentiation 1 ( Q13562 ) , correlated with those in miR - 190 expression , suggesting the P35372 could regulate the Q13562 pathways via the control of miR - 190 expression .","Shared and unique genetic contributions to attention deficit / hyperactivity disorder and substance use disorders : a pilot study of six candidate genes . The shared genetic basis of attention deficit / hyperactivity disorder ( ADHD ) and substance use disorders ( SUDs ) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders . One hundred seven methadone maintenance treatment patients , 36 having an ADHD diagnosis , 176 adult patients with ADHD without SUDs , and 500 healthy controls were genotyped for variants in the P21917 ( exon 3 VNTR ) , P21918 ( upstream VNTR ) , P28222 ( rs6296 ) , P09172 ( rs2519152 ) , P21964 ( rs4680 ; Val158Met ) , and P35372 ( rs1799971 ; 118A > G ) genes . Association with disease was tested using logistic regression models . This pilot study was adequately powered to detect larger genetic effects ( OR ≥ 2 ) of risk alleles with a low frequency . Compared to controls , ADHD patients ( with and without SUDs ) showed significantly increased frequency of the P09172 ( rs2519152 : OR 1 . 73 ; CI 1 . 15 - 2 . 59 ; P = 0 . 008 ) and the P35372 risk genotypes ( rs1799971 : OR 1 . 71 ; CI 1 . 17 - 2 . 50 ; P = 0 . 006 ) . The P09172 risk genotype was associated with ADHD diagnosis , with the association strongest in the pure ADHD group . The P35372 risk genotype increased the risk for the combined ADHD and SUD phenotype . The present study strengthens the evidence for a shared genetic basis for ADHD and addiction . The association of P35372 with the ADHD and SUD combination could help to explain the contradictory results of previous studies . The power limitations of the study restrict the significance of these findings : replication in larger samples is warranted .","P35372 phosphorylation , desensitization , and ligand efficacy . Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways : agonist - dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation ( 1 ) . To better understand the nature of the agonist - induced mu receptor phosphorylation events , we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization . Exposure to the potent full agonists sufentanil , dihydroetorphine , etorphine , etonitazine , and [ D - Ala2 , MePhe4 , Glyol5 ] enkephalin ( DAMGO ) led to strong receptor phosphorylation , while methadone , l - alpha - acetylmethadone ( DB01227 ) , morphine , meperidine , DADL , beta - endorphin ( 1 - 31 ) , enkephalins , and dynorphin A ( 1 - 17 ) produced intermediate effects . The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation . DB00921 and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO . The rank order of opiate ligand efficacies in producing mu receptor - mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation . Interestingly , the desensitization and phosphorylation mediated by methadone and DB01227 were disproportionate to their efficacies in two distinct test systems . This generally good fit between the efficacies of opiates in mu receptor activation , phosphorylation , and desensitization supports the idea that activated receptor / agonist / G - protein complexes and / or receptor conformational changes induced by agonists are required for agonist - induced mu receptor phosphorylation . Data for methadone and DB01227 suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies .","P35372 and P00533 contribute to skin pigmentation differences between Indigenous Americans and Europeans . Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments . Previous studies have identified several genes involved in skin pigmentation differences among African , Asian , and European populations . However , none have examined skin pigmentation variation among Indigenous American populations , creating a critical gap in our understanding of skin pigmentation variation . This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans . Analysis was performed on two samples of Indigenous Americans genotyped on genome - wide SNP arrays . Using four tests for natural selection -- locus - specific branch length ( LSBL ) , ratio of heterozygosities ( lnRH ) , Tajima ' s D difference , and extended haplotype homozygosity ( EHH ) -- we identified 14 selection - nominated candidate genes ( SNCGs ) . SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground - level ultraviolet radiation . In addition to Q71RS6 and Q9UMX9 , genes previously associated with European / non - European differences in skin pigmentation , P35372 and P00533 were associated with variation in skin pigmentation in New World populations for the first time .","Pivotal role of the P06681 domain of the Smurf1 ubiquitin ligase in substrate selection . The P06681 - WW - HECT - type ubiquitin ligases Smurf1 and Smurf2 play a critical role in embryogenesis and adult bone homeostasis via regulation of bone morphogenetic protein , Wnt , and RhoA signaling pathways . The intramolecular interaction between P06681 and HECT domains autoinhibits the ligase activity of Smurf2 . However , the role of the Smurf1 P06681 domain remains elusive . Here , we show that the P06681 - HECT autoinhibition mechanism is not observed in Smurf1 , and instead its P06681 domain functions in substrate selection . The Smurf1 P06681 domain exerts a key role in localization to the plasma membrane and endows Smurf1 with differential activity toward RhoA versus Q99717 and Runx2 . Crystal structure analysis reveals that the Smurf1 P06681 domain possesses a typical anti - parallel β - sandwich fold . Examination of the sulfate - binding site analysis reveals two key lysine residues , Lys - 28 and Lys - 85 , within the P06681 domain that are important for Smurf1 localization at the plasma membrane , regulation on cell migration , and robust ligase activity toward RhoA , which further supports a Ca ( 2 +)- independent localization mechanism for Smurf1 . These findings demonstrate a previously unidentified role of the Smurf1 P06681 domain in substrate selection and cellular localization .","[ Moclobemide ( ___MASK25___ ) , the first P21397 - inhibitor : really something new ? ] .","A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men . ___MASK39___ is the major addictive substance in cigarettes , and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction . We studied six single - nucleotide polymorphisms ( SNPs ) in the P43681 gene and four SNPs in the P17787 gene with respect to nicotine dependence in a collection of 901 subjects ( 815 siblings and 86 parents ) from 222 nuclear families with multiple nicotine - addicted siblings . The subjects were assessed for addiction by both the Fagerstrom Test for ___MASK39___ Dependence ( FTND ) and the Revised Tolerance Questionnaire ( RTQ ) . Because only 5 . 8 % of female offspring were smokers , only male subjects were included in the final analyses ( 621 men from 206 families ) . Univariate ( single - marker ) family - based association tests ( FBATs ) demonstrated that variant alleles at two SNPs , rs1044396 and rs1044397 , in exon 5 of the P43681 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype ( i . e . , age - adjusted FTND and RTQ scores ) , which was consistent with the results of the global haplotype FBAT . Furthermore , the haplotype - specific FBAT showed a common ( 22 . 5 % ) P43681 haplotype , GCTATA , which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait ( Z =- 3 . 04 , P < . 005 ) and significant decreases of age - adjusted FTND ( Z =- 3 . 31 , P < . 005 ) or RTQ scores ( Z =- 2 . 73 , P =. 006 ) . Our findings provide strong evidence suggesting a common P43681 haplotype might be protective against vulnerability to nicotine addiction in men .","No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK30___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK30___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK30___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK30___ among adults with ADHD .","Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene ( P43681 ) , mu - opioid receptor gene ( P35372 ) , and ethanol - metabolizing enzyme genes with alcoholism in Korean patients . Findings obtained from several studies indicate that ethanol enhances the activity of alpha4beta2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor alpha4 subunit gene ( P43681 ) modulates enhancement of nicotinic receptor function by ethanol . To identify the association between the CfoI polymorphism of the P43681 and alcoholism , we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism ( n = 127 ) and Korean control subjects without alcoholism ( n = 185 ) with polymerase chain reaction - restriction fragment length polymorphism methods . We were able to detect the association between the CfoI polymorphism of the P43681 and alcoholism in Korean patients ( genotype P = . 023 ; allele frequency P = . 047 ) . The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes , such as alcohol metabolism - related genes [ alcohol dehydrogenase 2 ( P00325 ) , aldehyde dehydrogenase 2 ( P05091 ) , alcohol dehydrogenase 3 ( P00326 ) , and cytochrome P450 2E1 ( P05181 ) ] and mu - opioid receptor gene ( P35372 ) , were studied . The polymorphisms of P00325 , P05091 , and P05181 were significantly different in Korean patients with alcoholism and Korean control subjects without alcoholism , but P00326 and P35372 did not differ between the two groups ."],"string":"[\n \"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK22___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .\",\n \"Preparation of phosphorylated starch by dry - heating in the presence of pyrophosphate and its calcium - phosphate solubilizing ability . Starch was phosphorylated through dry - heating in the presence of pyrophosphate at various conditions , and the characteristics of phosphorylated starch ( PS ) were examined . Starch phosphorylation increases as the pH increases from 3 to 6 , but diminishes at pH 7 . Increased temperatures enhance phosphorylation . Data from ( 31 ) P NMR suggests that starch phosphorylation occurs mainly at the P01024 - OH and P13671 - OH of the glucose residue . The phosphate linkage is mainly due to monostarch monophosphate . Although starch had almost no calcium phosphate - solubilising capacity , this capacity was markedly enhanced by phosphorylation . X - ray diffraction analysis indicates that the crystal structure of hydroxyapatite was not present in the calcium phosphate - PS complex .\",\n \"Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .\",\n \"Lack of evidence for the mu - opioid receptor splice variant MOR1C in rats . We previously reported the existence of P35372 ( C ) mRNA and P35372 ( C )- immunoreactivity ( - ir ) in rats . However , the sequence that we reported for rat P35372 ( C ) appears not to be present in the rat genome . We have therefore reexamined whether P35372 ( C ) mRNA or P35372 ( C )- ir exist in rats . We used reverse - transcription polymerase chain reaction ( RT - PCR ) to attempt to amplify P35372 , P35372 ( A ) , P35372 ( B ) , the rat P35372 ( C ) sequence we previously reported , and P35372 ( C1 ) and P35372 ( P06681 ) ( which have recently been reported to exist in rats ) . In RNA extracted from rats , we were able to demonstrate PCR products representing P35372 , P35372 ( A ) , and P35372 ( B ) splice variants . All three products were confirmed as related to P35372 by Southern blot . However , we were unable to detect either the P35372 ( C ) product reported previously by us or the P35372 ( C )- like products reported to exist in rats by others . In RNA extracted from mice we were able to detect P35372 , P35372 ( A ) , P35372 ( B ) , and P35372 ( D )- like products . To test the specificity of our P35372 ( C ) antiserum , we examined P35372 ( C )- ir in control and knockout mice . P35372 ( C )- ir had a distribution in control mice similar to that previously reported in rats , including coexisting with vGLUT2 . However , although P35372 - ir was absent in P35372 knockout mice , the density and distribution of P35372 ( C )- ir were unchanged , suggesting that the antiserum crossreacts with another molecule in tissue . We find no evidence for P35372 ( C ) mRNA in rats . Furthermore , we conclude that P35372 ( C )- ir represents crossreactivity .\",\n \"Neurogenetics of aggressive behavior : studies in primates . Aggressive behavior can have adaptive value in certain environmental contexts , but when extreme or executed inappropriately , can also lead to maladaptive outcomes . Neurogenetic studies performed in nonhuman primates have shown that genetic variation that impacts reward sensitivity , impulsivity , and anxiety can contribute to individual differences in aggressive behavior . Genetic polymorphisms in the coding or promoter regions of the Mu - Opioid Receptor ( P35372 ) , DB01285 Releasing Hormone ( P06850 ) , Monoamine Oxidase A ( P21397 ) , Dopamine D4 Receptor ( P21917 ) , and Serotonin Transporter ( P31645 ) genes have been shown to be functionally similar in humans and rhesus macaques and have been demonstrated to contribute to individual differences in aggression . This body of literature suggests mechanisms by which genetic variation that promotes aggressivity could simultaneously increase evolutionary success while making modern humans more vulnerable to psychopathology .\",\n \"OSU - 03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood - Brain Barrier : Implications for Anti - Cancer Therapies . We examined the interaction between OSU - 03012 ( also called AR - 12 ) with phosphodiesterase 5 ( O76074 ) inhibitors to determine the role of the chaperone glucose - regulated protein ( P11021 ) / P11021 / P11021 in the cellular response . ___MASK2___ ( Viagra ) interacted in a greater than additive fashion with OSU - 03012 to kill stem - like GBM cells . Treatment of cells with OSU - 03012 / sildenafil : abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of P11021 and other HSP70 and HSP90 family chaperone proteins . Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced Q9NZJ5 - eIF2α - P18848 - P35638 signaling and was blocked by P11021 over - expression . In vivo OSU - 03012 / sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of P08183 and Q9UNQ0 in the normal brain . The combination of OSU - 03012 / sildenafil synergized with low concentrations of sorafenib to kill tumor cells , and with lapatinib to kill P00533 over - expressing tumor cells . In multiplex assays on plasma and human tumor tissue from an OSU - 03012 / sildenafil treated mouse , we noted a profound reduction in uPA signaling and identified FGF and P23458 / 2 as response biomarkers for potentially suppressing the killing response . Inhibition of FGFR signaling and to a lesser extent P23458 / 2 signaling profoundly enhanced OSU - 03012 / sildenafil lethality .\",\n \"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK80___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .\",\n \"Palmitoylation and membrane cholesterol stabilize μ - opioid receptor homodimerization and G protein coupling . BACKGROUND : A cholesterol - palmitoyl interaction has been reported to occur in the dimeric interface of the β₂ - adrenergic receptor crystal structure . We sought to investigate whether a similar phenomenon could be observed with μ - opioid receptor ( P35372 ) , and if so , to assess the role of cholesterol in this class of G protein - coupled receptor ( GPCR ) signaling . RESULTS : P01024 . 55 ( 170 ) was determined to be the palmitoylation site of P35372 . Mutation of this DB00151 to Ala did not affect the binding of agonists , but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex . In addition , both attenuation of receptor palmitoylation ( by mutation of P01024 . 55 [ 170 ] to Ala ) and inhibition of cholesterol synthesis ( by treating the cells with simvastatin , a P04035 inhibitor ) impaired receptor signaling , possibly by decreasing receptor homodimerization and Gαi2 coupling ; this was demonstrated by co - immunoprecipitation , immunofluorescence colocalization and fluorescence resonance energy transfer ( FRET ) analyses . A computational model of the P35372 homodimer structure indicated that a specific cholesterol - palmitoyl interaction can facilitate P35372 homodimerization at the TMH4 - TMH4 interface . CONCLUSIONS : We demonstrate that P01024 . 55 ( 170 ) is the palmitoylation site of P35372 and identify a cholesterol - palmitoyl interaction in the P35372 complex . Our findings suggest that this interaction contributes to P35372 signaling by facilitating receptor homodimerization and G protein coupling . This conclusion is supported by computational modeling of the P35372 homodimer .\",\n \"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK68___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .\",\n \"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK10___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .\",\n \"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK75___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK75___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK75___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK75___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK75___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .\",\n \"Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .\",\n \"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .\",\n \"mu - Opioid receptor agonists differentially regulate the expression of miR - 190 and Q13562 . The agonists of mu - opioid receptor ( P35372 ) induce extracellular signal - regulated kinase ( P29323 ) phosphorylation through different pathways : morphine uses the protein kinase C ( PKC ) - pathway , whereas fentanyl functions in a beta - arrestin2 - dependent manner . In addition , the two pathways result in the different cellular location of phosphorylated P29323 and the activation of different sets of transcriptional factors . In the current study , the influence of the two pathways on the expression of microRNAs ( miRNAs ) was investigated . After treating the primary culture of rat hippocampal neurons and the mouse hippocampi with morphine or fentanyl for 3 days , seven miRNAs regulated by one or two of the agonists were identified . One of the identified miRNAs , miR - 190 , was down - regulated by fentanyl but not by morphine . This down - regulation was attenuated by 1 , 4 - diamino - 2 , 3 - dicyano - 1 , 4 - bis ( methylthio ) butadiene ( U0126 ) , which blocks the phosphorylation of P29323 . When fentanyl - induced but not morphine - induced P29323 phosphorylation was blocked in the primary cultures from beta - arrestin2 (-/-) mouse , fentanyl did not decrease the expression of miR - 190 . However , a PKC inhibitor that blocked morphine - induced P29323 phosphorylation specifically had no effect on the miR - 190 down - regulation . Therefore the decrease in miR - 190 expression resulted from the agonist - selective P29323 phosphorylation . In addition , the expressional changes in one of the miR - 190 targets , neurogenic differentiation 1 ( Q13562 ) , correlated with those in miR - 190 expression , suggesting the P35372 could regulate the Q13562 pathways via the control of miR - 190 expression .\",\n \"Shared and unique genetic contributions to attention deficit / hyperactivity disorder and substance use disorders : a pilot study of six candidate genes . The shared genetic basis of attention deficit / hyperactivity disorder ( ADHD ) and substance use disorders ( SUDs ) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders . One hundred seven methadone maintenance treatment patients , 36 having an ADHD diagnosis , 176 adult patients with ADHD without SUDs , and 500 healthy controls were genotyped for variants in the P21917 ( exon 3 VNTR ) , P21918 ( upstream VNTR ) , P28222 ( rs6296 ) , P09172 ( rs2519152 ) , P21964 ( rs4680 ; Val158Met ) , and P35372 ( rs1799971 ; 118A > G ) genes . Association with disease was tested using logistic regression models . This pilot study was adequately powered to detect larger genetic effects ( OR ≥ 2 ) of risk alleles with a low frequency . Compared to controls , ADHD patients ( with and without SUDs ) showed significantly increased frequency of the P09172 ( rs2519152 : OR 1 . 73 ; CI 1 . 15 - 2 . 59 ; P = 0 . 008 ) and the P35372 risk genotypes ( rs1799971 : OR 1 . 71 ; CI 1 . 17 - 2 . 50 ; P = 0 . 006 ) . The P09172 risk genotype was associated with ADHD diagnosis , with the association strongest in the pure ADHD group . The P35372 risk genotype increased the risk for the combined ADHD and SUD phenotype . The present study strengthens the evidence for a shared genetic basis for ADHD and addiction . The association of P35372 with the ADHD and SUD combination could help to explain the contradictory results of previous studies . The power limitations of the study restrict the significance of these findings : replication in larger samples is warranted .\",\n \"P35372 phosphorylation , desensitization , and ligand efficacy . Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways : agonist - dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation ( 1 ) . To better understand the nature of the agonist - induced mu receptor phosphorylation events , we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization . Exposure to the potent full agonists sufentanil , dihydroetorphine , etorphine , etonitazine , and [ D - Ala2 , MePhe4 , Glyol5 ] enkephalin ( DAMGO ) led to strong receptor phosphorylation , while methadone , l - alpha - acetylmethadone ( DB01227 ) , morphine , meperidine , DADL , beta - endorphin ( 1 - 31 ) , enkephalins , and dynorphin A ( 1 - 17 ) produced intermediate effects . The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation . DB00921 and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO . The rank order of opiate ligand efficacies in producing mu receptor - mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation . Interestingly , the desensitization and phosphorylation mediated by methadone and DB01227 were disproportionate to their efficacies in two distinct test systems . This generally good fit between the efficacies of opiates in mu receptor activation , phosphorylation , and desensitization supports the idea that activated receptor / agonist / G - protein complexes and / or receptor conformational changes induced by agonists are required for agonist - induced mu receptor phosphorylation . Data for methadone and DB01227 suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies .\",\n \"P35372 and P00533 contribute to skin pigmentation differences between Indigenous Americans and Europeans . Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments . Previous studies have identified several genes involved in skin pigmentation differences among African , Asian , and European populations . However , none have examined skin pigmentation variation among Indigenous American populations , creating a critical gap in our understanding of skin pigmentation variation . This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans . Analysis was performed on two samples of Indigenous Americans genotyped on genome - wide SNP arrays . Using four tests for natural selection -- locus - specific branch length ( LSBL ) , ratio of heterozygosities ( lnRH ) , Tajima ' s D difference , and extended haplotype homozygosity ( EHH ) -- we identified 14 selection - nominated candidate genes ( SNCGs ) . SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground - level ultraviolet radiation . In addition to Q71RS6 and Q9UMX9 , genes previously associated with European / non - European differences in skin pigmentation , P35372 and P00533 were associated with variation in skin pigmentation in New World populations for the first time .\",\n \"Pivotal role of the P06681 domain of the Smurf1 ubiquitin ligase in substrate selection . The P06681 - WW - HECT - type ubiquitin ligases Smurf1 and Smurf2 play a critical role in embryogenesis and adult bone homeostasis via regulation of bone morphogenetic protein , Wnt , and RhoA signaling pathways . The intramolecular interaction between P06681 and HECT domains autoinhibits the ligase activity of Smurf2 . However , the role of the Smurf1 P06681 domain remains elusive . Here , we show that the P06681 - HECT autoinhibition mechanism is not observed in Smurf1 , and instead its P06681 domain functions in substrate selection . The Smurf1 P06681 domain exerts a key role in localization to the plasma membrane and endows Smurf1 with differential activity toward RhoA versus Q99717 and Runx2 . Crystal structure analysis reveals that the Smurf1 P06681 domain possesses a typical anti - parallel β - sandwich fold . Examination of the sulfate - binding site analysis reveals two key lysine residues , Lys - 28 and Lys - 85 , within the P06681 domain that are important for Smurf1 localization at the plasma membrane , regulation on cell migration , and robust ligase activity toward RhoA , which further supports a Ca ( 2 +)- independent localization mechanism for Smurf1 . These findings demonstrate a previously unidentified role of the Smurf1 P06681 domain in substrate selection and cellular localization .\",\n \"[ Moclobemide ( ___MASK25___ ) , the first P21397 - inhibitor : really something new ? ] .\",\n \"A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men . ___MASK39___ is the major addictive substance in cigarettes , and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction . We studied six single - nucleotide polymorphisms ( SNPs ) in the P43681 gene and four SNPs in the P17787 gene with respect to nicotine dependence in a collection of 901 subjects ( 815 siblings and 86 parents ) from 222 nuclear families with multiple nicotine - addicted siblings . The subjects were assessed for addiction by both the Fagerstrom Test for ___MASK39___ Dependence ( FTND ) and the Revised Tolerance Questionnaire ( RTQ ) . Because only 5 . 8 % of female offspring were smokers , only male subjects were included in the final analyses ( 621 men from 206 families ) . Univariate ( single - marker ) family - based association tests ( FBATs ) demonstrated that variant alleles at two SNPs , rs1044396 and rs1044397 , in exon 5 of the P43681 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype ( i . e . , age - adjusted FTND and RTQ scores ) , which was consistent with the results of the global haplotype FBAT . Furthermore , the haplotype - specific FBAT showed a common ( 22 . 5 % ) P43681 haplotype , GCTATA , which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait ( Z =- 3 . 04 , P < . 005 ) and significant decreases of age - adjusted FTND ( Z =- 3 . 31 , P < . 005 ) or RTQ scores ( Z =- 2 . 73 , P =. 006 ) . Our findings provide strong evidence suggesting a common P43681 haplotype might be protective against vulnerability to nicotine addiction in men .\",\n \"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK30___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK30___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK30___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK30___ among adults with ADHD .\",\n \"Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene ( P43681 ) , mu - opioid receptor gene ( P35372 ) , and ethanol - metabolizing enzyme genes with alcoholism in Korean patients . Findings obtained from several studies indicate that ethanol enhances the activity of alpha4beta2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor alpha4 subunit gene ( P43681 ) modulates enhancement of nicotinic receptor function by ethanol . To identify the association between the CfoI polymorphism of the P43681 and alcoholism , we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism ( n = 127 ) and Korean control subjects without alcoholism ( n = 185 ) with polymerase chain reaction - restriction fragment length polymorphism methods . We were able to detect the association between the CfoI polymorphism of the P43681 and alcoholism in Korean patients ( genotype P = . 023 ; allele frequency P = . 047 ) . The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes , such as alcohol metabolism - related genes [ alcohol dehydrogenase 2 ( P00325 ) , aldehyde dehydrogenase 2 ( P05091 ) , alcohol dehydrogenase 3 ( P00326 ) , and cytochrome P450 2E1 ( P05181 ) ] and mu - opioid receptor gene ( P35372 ) , were studied . The polymorphisms of P00325 , P05091 , and P05181 were significantly different in Korean patients with alcoholism and Korean control subjects without alcoholism , but P00326 and P35372 did not differ between the two groups .\"\n]"},"candidates":{"kind":"list like","value":["___MASK10___","___MASK22___","___MASK25___","___MASK2___","___MASK30___","___MASK39___","___MASK68___","___MASK75___","___MASK80___"],"string":"[\n \"___MASK10___\",\n \"___MASK22___\",\n \"___MASK25___\",\n \"___MASK2___\",\n \"___MASK30___\",\n \"___MASK39___\",\n \"___MASK68___\",\n \"___MASK75___\",\n \"___MASK80___\"\n]"},"answer":{"kind":"string","value":"___MASK25___"},"id":{"kind":"string","value":"MH_train_494"}}},{"rowIdx":495,"cells":{"query":{"kind":"string","value":"interacts_with DB01277?"},"supports":{"kind":"list like","value":["How DB01277 activates its receptor . This study presents a new model for P08069 activation in which the transmembrane domains are held apart until ligand binding brings them together in an activated state .","P08069 mRNA expression and autophosphorylation in human myometrium and leiomyoma . Uterine leiomyomas are the most common tumors of the genital tract . Growth factors seem to be implicated in the development of leiomyoma . The aim of this study was to determine insulin - like growth factor 1 receptor ( DB01277 - R ) mRNA levels and DB01277 - R tyrosine kinase activity in normal myometrium and leiomyoma . Plasma membranes of myometrium and leiomyoma of 14 women subjected to hysterectomy were prepared , and samples were incubated in the absence or presence of recombinant human DB01277 to assess the tyrosine kinase activity ( Western blot ) . Reverse - transcriptase polymerase chain reaction with specific primers for DB01277 - R was used to determine DB01277 - R mRNA levels . DB01277 - R mRNA levels in myometrium ( 0 . 8216 +/- 0 . 096 ) and in leiomyoma ( 0 . 7905 +/- 0 . 136 ) were not statistically significantly different ( p = 0 . 648 ) . The degree of DB01277 - R autophosphorylation stimulated by recombinant DB01277 was not different in myometrium ( 1 . 020 +/- 0 . 120 ) and leiomyoma ( 1 . 620 +/- 0 . 656 ) either ( p = 0 . 075 ) . There was no difference in DB01277 - R expression and DB01277 - R autophosphorylation between normal myometrium and leiomyoma .","P01308 - like growth factors and their binding proteins in the venous effluents of ovary and adrenal gland in severely hyperandrogenic women . P01308 and insulin - like growth factors ( IGF ) are thought to play an important role in the pathogenesis of excessive androgen production . To explore this question further we measured the concentrations of P05019 and - II and their binding proteins ( P08833 and - 3 ) in adrenal and ovarian vein samples of severely hyperandrogenic women ( serum testosterone > 5 nmol / l ) collected as part of their diagnostic work - up . The concentration of P01344 was slightly but not significantly higher in the ovarian vein than in the adrenal and peripheral veins . The concentrations of P05019 and IGFBP were identical in both the adrenal and ovarian veins and did not differ from those in the peripheral circulation . The concentration of P08833 was negatively correlated ( r = - 0 . 60 , P > 0 . 05 ) with insulin and P17936 showed a strong positive correlation with DB01277 ( r = 0 . 90 , P > 0 . 01 ) . These results indicate that neither the ovary nor the adrenal gland contributes significantly to the circulating pool of IGF or their binding proteins in severely hyperandrogenic subjects . Hyperinsulinaemia is associated with low circulating P08833 concentrations and P17936 seems to be an excellent indicator of the peripheral P05019 concentration . The concentrations of P05019 suggested decreased somatotrophic activity in these obese , hyperinsulinaemic subjects .","Milk consumption and the prepubertal somatotropic axis . BACKGROUND : Nutrients , hormones and growth factors in dairy foods may stimulate growth hormone ( GH ) , insulin - like growth factor I ( P05019 ) , and raise the ratio of P05019 to its binding protein , P17936 . We conducted pilot studies in Mongolia and Massachusetts to test the extent to which milk intake raised somatotropic hormone concentrations in prepubertal children . METHODS : In Ulaanbaatar , we compared plasma levels before and after introducing 710 ml daily whole milk for a month among 46 10 - 11 year old schoolchildren . In a randomized cross - over study in Boston , we compared plasma hormone levels of 28 6 - 8 year old girls after one week of drinking 710 ml low fat ( 2 % ) milk with their hormone levels after one week of consuming a macronutrient substitute for milk . RESULTS : After a month of drinking whole milk , Mongolian children had higher mean plasma levels of P05019 ( p < 0 . 0001 ) , P05019 / P17936 ( p < 0 . 0001 ) , and 75th percentile of GH levels ( p = 0 . 005 ) . After a week of drinking low fat milk , Boston girls had small and non - significant increases in DB01277 , DB01277 / P17936 and GH . CONCLUSION : Milk drinking may cause increases in somatotropic hormone levels of prepubertal girls and boys . The finding that milk intake may raise GH levels is novel , and suggests that nutrients or bioactive factors in milk may stimulate endogenous GH production .","Evaluation of the antitumor effects and mechanisms of PF00299804 , a pan - HER inhibitor , alone or in combination with chemotherapy or targeted agents in gastric cancer . Recently , P04626 - directed treatment , such as trastuzumab , has shown clinical benefit in P04626 - amplified gastric cancer . On the basis of recent studies about epidermal growth factor receptor ( P00533 ) or P04626 - targeting agents ( including gefitinib , lapatinib , and trastuzumab ) in gastric cancer , the potent effects of pan - HER inhibitors targeting the HER family are anticipated . In this study , we evaluated the activity and mechanisms of PF00299804 , an irreversible pan - HER inhibitor , in gastric cancer in vitro and in vivo models . PF00299804 showed significant growth - inhibitory effects in P04626 - amplified gastric cancer cells ( SNU216 , N87 ) , and it had lower 50 % inhibitory concentration values compared with other P00533 tyrosine kinase inhibitors , including gefitinib , lapatinib , BIBW - 2992 , and DB05424 . PF00299804 induced apoptosis and G ( 1 ) arrest and inhibited phosphorylation of receptors in the HER family and downstream signaling pathways including P40763 , AKT , and extracellular signal - regulated kinases ( P29323 ) in P04626 - amplified gastric cancer cells . PF00299804 also blocked P00533 / P04626 , P04626 / P21860 , and P21860 / Q15303 heterodimer formation as well as the association of P21860 with p85α in SNU216 cells . The combination of PF00299804 with clinically relevant chemotherapeutic agents or molecular - targeted agents including trastuzumab ( an anti - P04626 monoclonal antibody ) , CP751871 ( an P08069 inhibitor ) , PD0325901 ( an P27361 / 2 inhibitor ) , and PF04691502 ( a PI3K / P42345 inhibitor ) produced synergistic effects . These findings indicate that PF00299804 can be used as a targeted therapy for the treatment of P04626 - amplified gastric cancer through inhibition of HER family heterodimer formation and may augment antitumor efficacy of chemotherapeutic and / or molecular - targeted agents .","Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .","P08069 - mediated endocytosis in Xenopus laevis oocytes . A role for receptor tyrosine kinase activity . Equilibrium analysis of [ 125I ] DB01277 binding to Xenopus oocytes yielded curvilinear Scatchards supporting the presence of multiple binding sites . High - affinity binding displayed an apparent KD of 9 . 0 +/- 3 . 0 nM DB01277 with maximum total binding of 1 . 6 +/- 0 . 3 fmole / oocyte after 90 min at 22 degrees C . Binding of 1 nM [ 125I ] DB01277 to oocytes was competitively displaced by unlabeled DB01277 or insulin with IC50 values of 6 and 560 nM , respectively . Chemical cross - linking of [ 125I ] - DB01277 to oocyte membranes specifically labeled a single 138 - kDa protein . Using the technique of acid stripping to analyze whole - cell binding , both total and surface binding of [ 125I ] DB01277 reached a plateau after 90 min , and internalized counts surpassed surface - associated counts 20 min after hormone addition . At the 90 - min plateau , 70 - 75 % of cell - associated counts were internalized . The tyrosine kinase inhibitor , tyrphostin 47 , prevented DB01277 - stimulated oocyte maturation with an apparent IC50 of 10 . 5 +/- 2 . 5 microM and also inhibited DB01277 receptor - mediated endocytosis in micromolar concentrations . Treatment of oocyte membrane samples with 10 nM DB01277 stimulated alkali - stable phosphorylation of a protein doublet ( M ( r ) 89 and 104 kDa ) . Tyrphostin 47 also inhibited DB01277 - stimulated phosphorylation of these putative receptor beta - subunits more effectively than tyrphostin 23 or genistein . These results suggest a necessary role for receptor - mediated endocytosis in DB01277 - induced oocyte maturation and a requirement for receptor kinase activity in oocyte receptor internalization .","P17936 , hypoxia and P01375 inhibit adiponectin transcription . The thiazolidinedione rosiglitazone , an agonist ligand for the nuclear receptor P37231 , improves insulin sensitivity in part by stimulating transcription of the insulin - sensitizing adipokine adiponectin . It activates P37231 - RXR - alpha heterodimers bound to P37231 response elements in the adiponectin promoter . Rosiglitazone - stimulated adiponectin protein synthesis in 3T3 - Q9NUQ9 mouse adipocytes has been shown to be inhibited by P17936 , which can be induced by hypoxia and the proinflammatory cytokine , P01375 , two inhibitors of adiponectin transcription . The present study demonstrates that P17936 , the hypoxia - mimetic agent cobalt chloride , and P01375 inhibit rosiglitazone - induced adiponectin transcription in mouse embryo fibroblasts that stably express Q07869 - gamma2 . Native P17936 can bind RXR - alpha and inhibited rosiglitazone stimulated promoter activity , whereas an P17936 mutant that does not bind RXR - alpha did not . These results suggest that P17936 may mediate the inhibition of adiponectin transcription by hypoxia and P01375 , and that P17936 binding to RXR - alpha may be required for the observed inhibition .","___MASK72___ : kinetic and dynamic profile in the treatment of pain . ___MASK72___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK72___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK72___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK72___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .","[ Analysis of clinical manifestations and genetic mutations in a child with Laron syndrome ] . OBJECTIVE : To analyze clinical manifestations and gene mutations in a child with severe short stature , explore its molecular mechanism and further clarify the diagnostic procedure for short stature . METHOD : We observed clinical characteristics of a patient with short stature and did diagnostic examinations , assessed the function of GH - DB01277 axis , and surveyed its family members . Genomic DNA was extracted from peripheral blood , P10912 , P35858 , STAT5b and P01241 gene were amplified by PCR for sequencing , including exons and splicing areas . RESULT : The patient presented symmetrical short stature ( height - 8 . 2 SDS ) and facial features , and other congenital abnormalities . It displayed non - growth hormone deficiency . The baseline value of GH was 21 µg / L , and the peak was 57 . 9 µg / L . The value of DB01277 was less than 25 µg / L , and the P17936 less than 50 µg / L . And DB01277 generation test showed no response . There was no similar patients in the family members . Sequencing of P10912 in the patient revealed a homozygous point mutation ( c . Ivs6 + 1G > A ) , and her father and mother had the same heterozygous mutation . The same mutation was not identified for her sister . No other candidate gene was found . CONCLUSION : As the result of combined clinical characteristics and lab examinations , as well as gene detection , the case was diagnosed with Laron syndrome and P10912 gene mutation is the molecular mechanism . We should explicit the etiological diagnosis for short stature , and avoid missed diagnosis and misdiagnosis .","Spectrum of insulin - like growth factor deficiency . There are eight known genetic causes of short stature characterized by low serum DB01277 ( DB01277 deficiency , IGFD ) and normal GH secretion . One of these ( Q92847 defect ) is a form of secondary IGFD , although the GH peak in provocation tests can be normal . Bioinactive GH ( P01241 mutations ) can disturb GH secretion , but also GH binding and signaling . The remaining conditions are classified as primary IGFD ( GH insensitivity ) . The clinical phenotype of P10912 ( P10912 ) defects is variable . Of the three GH signal transduction defects , a P51692 defect is well established , but abnormalities in the MAPK pathway ( such as Q06124 mutations in Noonan syndrome ) and NF - ĸB pathway ( IĸBα mutation ) may also cause IGFD . Homozygous P35858 defects are relatively common , and lead to moderate growth failure , very low serum DB01277 and even lower P17936 , while a heterozygous P35858 mutation decreases height by 1 SD . Most cases with a homozygous IGF1 defect are very short , microcephalic , and deaf , but heterozygous mutations may also lead to short stature . IGFD can also have a digenic or oligogenic origin . The diagnostic yield of genetic testing in children with a height < - 2 . 5 SDS and a serum DB01277 < - 2 appears sufficient to perform genetic tests for known candidate genes .","A Single 60 mg Dose of ___MASK45___ Might Improve Hepatic P01308 Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women . Background . The O14788 / Q9Y6Q6 / O00300 signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis . The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation . Aim . To test whether systemic blockage of O14788 by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women . Study Design . This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test . Results . A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose , insulin , or HOMA - IR at both 4 and 12 weeks . No changes could be detected in glucose response to the glucose load , Matsuda Index , or insulinogenic index . Nonetheless , 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks . Conclusions . A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients .","Global transcriptome analysis of formalin - fixed prostate cancer specimens identifies biomarkers of disease recurrence . Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease . In an effort to identify biomarkers of recurrence , we performed global RNA sequencing on 106 formalin - fixed , paraffin - embedded prostatectomy samples from 100 patients at three independent sites , defining a 24 - gene signature panel . The 24 genes in this panel function in cell - cycle progression , angiogenesis , hypoxia , apoptosis , PI3K signaling , steroid metabolism , translation , chromatin modification , and transcription . Sixteen genes have been associated with cancer , with five specifically associated with prostate cancer ( P78543 , P17936 , Q96EB6 , P50539 , and P14324 ) . Validation was performed on an independent publicly available dataset of 140 patients , where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence . Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors , including several genes involved in the epithelial - to - mesenchymal transition and developmental pathways . Overall , this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer .","A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .","Humanins , the neuroprotective and cytoprotective peptides with antiapoptotic and anti - inflammatory properties . Q8IVG9 ( HN ) is a newly discovered 24 - amino acid peptide , which may suppress neuronal cell death . HN cDNA includes an open reading frame ( HN - ORF ) of 75 bases located 950 bases downstream of the 5 ' end of the HN cDNA . It has been demonstrated that HN cDNA is 99 % identical to the mitochondrial DNA ( mtDNA ) sequence . HN homologs have been identified as expressed sequence tags ( ESTs ) in both rats and nematodes . Certain regions that are homologous to the HN cDNA exist on human chromosomes . HN forms homodimers and multimers and this action seems to be essential for peptide function . HN acts as a ligand for formyl peptide receptor - like 1 ( P25090 ) and 2 ( P25089 ) . It has been demonstrated that HN plays a protective role through its antiapoptotic activity that interferes with Bax activation , which suppresses Bax - dependent apoptosis . HN has also been shown to suppress the c - Jun N - terminal kinase ( JNK ) and ASK / JNK - mediated neuronal cell death . Several studies have also confirmed that HN could be important in the prevention of angiopathy - associated Alzheimer ' s disease dementia , diseases related to mitochondrial dysfunction ( MELAS ) , and other types of β - amyloid accumulation - associated neurodegeneration . Avery recent study demonstrated a pluripotent cytoprotective effect and mechanisms of HNs in cells not from the CNS , such as germ cells or pancreatic β - cells , and the potent physiological consequences that result from HN interaction with P17936 and P40763 . In vivo studies suggest that HN may also protect against cognitive impairment due to ischemia / reperfusion injury .","DB01277 pathway mutations and protein expression in resected non - small cell lung cancer . The purpose of this study was to characterize the prevalence of insulin - like growth factor 1 receptor ( P08069 ) mutations , single nucleotide polymorphisms ( SNP ) , and protein overexpression in surgically resected non - small cell lung cancers in relation to patient characteristics and prognosis . This retrospective study was conducted on 304 patients with non - small cell lung cancers who underwent curative pulmonary resection ( median follow - up for surviving patients , 3 . 6 years ) . P08069 gene alterations ( n = 304 ) and protein expression ( n = 181 ) were evaluated by polymerase chain reaction - based assays and immunohistochemistry , respectively . Membranous and cytoplasmic staining were analyzed separately . In an exploratory analysis , 1 silent mutation in exon 16 and 3 mutations in introns of the P08069 gene comprising the tyrosine kinase domain were detected . Moreover , evaluating selected P08069 SNPs , patients with adenocarcinomas and homozygous for the rs8038415 T - allele had a significantly better survival ( P = . 025 ) but no different disease - free survival . Regarding expression , membranous but not cytoplasmic P08069 staining was higher in squamous cell carcinomas versus other histologies ( P < . 0001 ) and showed a trend to longer survival ( P = . 08 ) . No association between SNP variations and protein expression was found . Membranous P08069 protein expression is higher in squamous cell versus other histologies but does not correlate with prognosis . SNPs and mutations can be detected and may harbor prognostic value . These alterations may be of interest when evaluating the P08069 as potential therapeutic target and should receive further research .","Specific Biomarkers Are Associated with Docetaxeland Gemcitabine - Resistant NSCLC Cell Lines . Five - year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non - small cell lung cancer cell lines . Therefore , we checked - in the control condition as well as after short - term pharmacological treatment with either docetaxel or gemcitabine - the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness - related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug - related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness - related genes were downregulated in the control condition but became upregulated in docetaxel - resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance .","Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .","Growth response of Egyptian children with idiopathic short stature during four years of growth hormone therapy . BACKGROUND : Multiple factors affect the growth response to recombinant human growth hormone ( rhGH ) in children with idiopathic short stature ( ISS ) . AIM : To evaluate the growth responses of children with ISS treated with rhGH , aiming to identify the predictors of growth response . MATERIALS AND METHODS : We studied 120 cases , 90 males ( 75 % ) , with a mean age of 13 . 8 ± 2 . 7 years and 30 females ( 25 % ) , with a mean age of 12 . 3 ± 2 . 5 years . All patients received rhGH with a standard dose of 20 IU / m ( 2 )/ week . The calculated dose per week was divided into six days and given subcutaneous at night . RESULTS : A significant positive trend was detected in the delta changes of all anthropometric data . For the first year , the growth response was positively correlated to CA and BA delay and negatively correlated to height , weight and DB01277 SDSs . For the second year , the growth response was correlated positively to first year growth velocity , BA , triceps skin fold thickness SDS and deviation from target height , and negatively correlated to weight , P17936 SDS and target height SDS . For the third year , the growth response was positively correlated to five variables namely target height , 2 ( nd ) year growth velocity , DB01277 SDS , weight SDS and triceps skin fold thickness SDS . For the fourth year , growth response was positively correlated to 2 ( nd ) and 3 ( rd ) year growth velocity , BA , deviation from target height and weight / height SDS . CONCLUSION : Our study showed multiplicity of predictors that is responsible for response in ISS children treated with rhGH , and BA was an important predictor .","Disturbances in growth hormone secretion and action in adolescents with anorexia nervosa . Women in whom anorexia nervosa develops during adolescence have failure of linear growth associated with low levels of insulin - like growth factor I ( DB01277 ) . To investigate the pathophysiology of growth retardation in adolescents with anorexia nervosa , we measured basal growth hormone ( GH ) , growth hormone - binding protein ( P30043 ) , DB01277 , and insulin - like growth factor binding protein - 3 ( P17936 ) in three groups of patients : ( 1 ) 28 recently hospitalized female adolescents with anorexia nervosa , ( 2 ) 23 of the same patients after partial weight restoration , and ( 3 ) 28 healthy control subjects matched for age , sex , and pubertal stage . Fasting GH levels in group 1 did not differ significantly from those in group 3 . In contrast , serum P30043 ( p < 0 . 001 ) , DB01277 ( p < 0 . 001 ) , and P17936 ( p < 0 . 01 ) were significantly lower in group 1 than in group 3 . Serum P30043 and P17936 levels were positively correlated with body mass index . Serum P30043 levels were low in patients in all five pubertal stages and even in those shown to have adequate GH secretion . In group 2 ( after refeeding ) the serum DB01277 concentration increased significantly and P30043 and P17936 returned to normal . We conclude that patients with anorexia nervosa have diminished GH action resulting in decreased secretion of DB01277 . The positive correlation with body mass index and the reversibility with refeeding suggest that these changes are secondary to malnutrition . Altered GH function that occurs during the years of active growth can explain the growth retardation seen in anorexia nervosa .","___MASK45___ for joints and bones . ___MASK45___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK45___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK45___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .","Myocardial insulin - like growth factor - 1 and insulin - like growth factor binding protein - 3 gene expression in failing hearts harvested from patients undergoing cardiac transplantation . P01308 - like growth factor - 1 ( DB01277 ) and insulin - like growth factor binding proteins ( IGFBPs ) might play a pathogenic role in heart failure . We showed significantly increased myocardial P17936 expression ( investigated by real - time polymerase chain reaction ) and apoptosis ( detected by flow cytometry ) in 23 failing hearts from patients undergoing cardiac transplantation for end - stage dilated or ischemic cardiomyopathy , when compared with 10 controls . Higher DB01277 mRNA levels were shown only in end - stage dilated cardiomyopathy .","DB01277 and DB01686 levels are inversely correlated in nondiabetic ankylosing spondylitis patients undergoing anti - P01375 therapy . Like rheumatoid arthritis , ankylosing spondylitis ( AS ) is also an inflammatory disease associated with accelerated atherosclerosis and the presence of metabolic syndrome ( MeS ) features . AS patients often display osteoporosis as well as new bone formation . DB01277 ( DB01277 ) is a protein involved in both inflammation and bone metabolism . In the present study we assessed whether disease activity , systemic inflammation , MeS features , adipokines , and biomarkers of endothelial activation were associated with DB01277 and insulin - like growth factor binding protein - 3 ( P17936 ) levels in a series of 30 nondiabetic AS patients without CV disease undergoing P01375 - α antagonist - infliximab therapy . All determinations were made in the fasting state , immediately before an infliximab infusion . Although no association of DB01277 and P17936 levels with angiopoietin - 2 or osteopontin was found , an inverse correlation between DB01277 levels and asymmetric dimethylarginine ( DB01686 ) , an endogenous endothelial nitric oxide synthase inhibitor that impairs nitric oxide production and secretion promoting endothelial dysfunction , was found ( r =- 0 . 397 ; P = 0 . 04 ) . However , no significant association was found between DB01277 and P17936 levels and disease activity , systemic inflammation , metabolic syndrome features , or adipokines . In conclusion , in nondiabetic patients with AS undergoing periodic anti - P01375 - α therapy , DB01277 and DB01686 are inversely correlated .","Increased low density lipoprotein receptor expression mediated through the insulin - like growth factor - I receptor in cultured fibroblasts . Plasma insulin - like growth factor - I ( P05019 ) levels are inversely correlated with apolipoprotein B and low density lipoprotein ( LDL ) cholesterol in humans . To identify a molecular basis for this observation , the effects of P05019 on P01130 expression in fibroblasts were studied . P05019 increased LDL receptors in cultured human skin fibroblasts at concentrations greater than 25 ng / ml . However , P05019 effects were not easily quantitated due to secretion of inhibitory IGF - binding proteins by the cells . To circumvent this difficulty , QAYL , an P05019 analog that binds to the P08069 but not to IGF - binding proteins , was used . QAYL increased P01130 number 56 - 72 % with half - maximum effect at 0 . 6 ng / ml . alpha - IR3 , a monoclonal antibody directed toward the P08069 , blocked this effect . QAYL treatment increased synthesis of P01130 protein without increasing P01130 mRNA levels or altering protein stability . Both QAYL and P05019 increased LDL receptors prominently in cells that had been treated with physiological amounts of LDL cholesterol . P05019 , acting through the P08069 and modulated by IGF - binding proteins , may contribute to the regulation of LDL metabolism by increasing translation of P01130 message .","Prostate carcinoma cells that have resided in bone have an upregulated P05019 axis . BACKGROUND : Prostate cancer ( PC ) has a propensity to metastasize to the skeleton , inducing an osteoblastic response in the host . Recent epidemiological studies have suggested that circulating P05019 may be important for both the pathogenesis and dissemination of PC . We have postulated that tumor secreted P05019 in conjunction with endogenous P05019 contributes to the osteoblastic phenotype characteristic of metastatic PC . METHODS : To test this thesis we studied the established LNCaP PC progression model consisting of three genetically related human PC cell lines . RESULTS : Using RIA , we found serum - free conditioned media ( CM ) of LNCaP and C4 - 2 had no measurable P05019 , whereas P05019 was easily detected in CM from C4 - 2B cells at 24 hr ( i . e . , 1 . 8 +/- 0 . 53 ng / mg cell protein ) . Real - time PCR of P05019 mRNA showed that C4 - 2B expressed 100 - fold more P05019 mRNA than LNCaP cells . In addition , C4 - 2B expression of P05019 mRNA was substantially increased in the presence of exogenous P05019 to nearly twofold . While P17936 and P08833 were not detectable in the CM of any PC line , all cells secreted P18065 . C4 - 2B cells produced 40 % more P18065 than LNCaP or C4 - 2 cells ( C4 - 2B at 167 +/- 43 ng / mg cell protein ) . O14788 , a product of bone stromal cells , was also differentially expressed : LNCaP had threefold higher O14788 mRNA compared to C4 - 2 and C4 - 2B and at least equivalent protein expression . CONCLUSIONS : Our results suggest that PC cells that have metastasized to bone have an upregulated P05019 regulatory system . This suggests an activated P05019 axis contributes to the host - PC interaction in promoting osteoblastic metastases .","Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK65___ and Tissue P00747 Activator in Occluded Arteries .","Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .","Differential expression of IGF components and insulin receptor isoforms in human seminoma versus normal testicular tissue . P01308 - like growth factors ( IGF ) have mitogenic and antiapoptotic functions , and may be involved in tumor growth . The purpose of the study was to investigate the role of IGF components in seminoma compared to normal testis . Normal testicular tissues from autopsy cases and seminoma from surgery cases were obtained for microarray and real - time reverse transcription polymerase chain reaction ( RT - PCR ) analysis of DB01277 , IGF - 2 , IGF receptor type 1 ( IGF - Q96GN5 ) , IGF - R2 , insulin receptor isoforms A ( IR - A ) and B ( IR - B ) , and IGF - binding proteins ( IGFBP ) 1 - 6 . IGF - 2 was localized by immunohistochemistry . P24593 protein expression was evaluated by Western blot analysis . mRNA expression in microarray and real - time RT - PCR showed similar tendencies : DB01277 , IGF - Q96GN5 , IGF - R2 , IR - A , and P18065 were not different in both groups . IGF - 2 , IR - B , P08833 , P22692 , and P24592 mRNA were downregulated in seminoma . P17936 tended to be upregulated in pT1 seminoma , but downregulated in pT2 stages . P24593 and IGF - 2 protein expression correlated with mRNA expression . In conclusion , downregulation of mainly inhibiting IGFBPs may allow a stimulated tumor growth . The downregulated IGF - 2 does not seem to be involved in the growth regulation of seminoma . Constantly expressed genes ( e . g . , DB01277 , IGF - Q96GN5 , IR - A , and P18065 ) may reflect an involvement in spermatogenesis , but may also play a major role in tumor growth as their expression is not downregulated despite the lack of spermatogenesis in tumor tissue .","Metabolic effect and receptor signalling profile of a non - metabolisable insulin glargine analogue . CONTEXT : P01308 glargine ( GLA ) is rapidly metabolized in vivo to metabolite M1 , which has in vitro metabolic and mitogenic profiles comparable with human insulin ( HI ) . OBJECTIVE : To investigate the pharmacologic and signalling profiles of a non - metabolizable analogue ( A21Gly , DiD - DB00125 ) insulin ( D - GLA ) . METHODS : Rats were injected s . c . with 1 , 12 . 5 or 200 U / kg of GLA or D - GLA ; blood glucose and phosphorylation status of the insulin receptor ( IR ) , Akt and DB01277 receptor ( P08069 ) in tissue samples were investigated after 1 h . Plasma samples were analysed for insulin by LC - MS / MS . RESULTS : Blood glucose lowering was prolonged with D - GLA . D - GLA comprised ≥ 98 % of insulin after D - GLA injection ; M1 comprised 76 - 92 % after GLA injection . IR and Akt phosphorylation were comparable with GLA and D - GLA . Neither analogue stimulated P08069 phosphorylation . CONCLUSIONS : Suprapharmacological doses of D - GLA did not activate P08069 in vivo . Mitogenic effects of insulin and insulin analogues might be solely based on IR growth - promoting activity .","Growth hormone , insulin - like growth factor - 1 , and the insulin - like growth factor binding proteins in rats maintaining reduced body protein following lesions of the lateral hypothalamus . Rats with lesions of the lateral hypothalamus ( LH ) maintain a reduced body protein mass that they effectively defend when challenged by under - or over - nutrition . The two studies reported here evaluate the potential contributions of growth hormone ( GH ) , insulin - like growth factor - 1 ( DB01277 ) , and the insulin - like growth factor - binding ( IGFBP ) to this persistent maintenance of a reduced body protein mass by LH rats . At 18 weeks postlesion , it was found that the serum levels of GH , DB01277 , total IGFBP , and P17936 of LH rats maintaining reduced body protein were not different from those of age - matched controls . However , closer to the time of surgery , at which time the lesion - induced body protein adjustments are known to occur , altered hormone and binding protein levels were observed . Specifically , at 3 weeks after lesioning , the IGF - binding proteins of LH rats were significantly elevated , whereas their GH levels were lower than those of controls . Because the GH , DB01277 , and IGF - binding proteins of LH rats were comparable to those of controls at 18 weeks after lesioning , none apparently underlie the chronically reduced body protein mass that LH rats display . Closer to the time of lesioning , however , altered GH and IGF binding protein levels may contribute to the postlesion adjustments by which the body protein mass of LH rats is lowered to its reduced level .","Hepatic osteodystrophy : does the osteoprotegerin / receptor activator of nuclear factor - kB ligand system play a role ? Multiple factors can contribute to the development of osteodystrophy in patients with chronic liver disease ( CLD ) . Recently , two new cytokines , osteoprotegerin ( O00300 ) and the receptor activator of nuclear factor - kB ligand ( O14788 ) , have been implicated in the pathogenesis of postmenopausal osteoporosis and other metabolic bone diseases . Therefore , the aim of our study was to evaluate bone metabolism , bone mineral density ( BMD ) and O00300 / O14788 system in 65 male patients with CLD and in 65 healthy controls . Our patients showed lower BMD values than controls both at lumbar and femoral levels . Moreover , they had an unbalanced bone turnover with an increased resorption phase , as shown by high levels of urinary deoxypyridinoline and a decreased formation phase , as shown by the slightly , but significant , low levels of bone - alkaline phosphatase . Patients showed lower plasma levels of free - testosterone than controls and higher - although not significantly so - plasma levels of 17 beta - estradiol . Furthermore , patients with CLD had higher levels of sex hormone - binding globulin and O00300 , and lower levels of 25 - hydroxyvitamin D ( 25 - Q9BPY8 ) and P05019 than the control group , while O14788 levels were similar in the two groups . In conclusion , our data do not confirm the hypothesis that the O00300 / O14788 system could exert a key role in the pathogenesis of hepatic osteodystrophy , but rather that the observed increase in O00300 levels may represent either the result of the inflammatory process per se or a compensation for the observed enhanced bone resorption .","___MASK100___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK100___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK100___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK100___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK100___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .","Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK79___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .","Apparent growth hormone deficiency in children with cerebral palsy . Ten children with cerebral palsy ( CP ) and growth failure underwent assessment of the growth hormone ( GH ) axis , including spontaneous GH secretion , GH secretion in response to pharmacological stimulation , and circulating levels of insulin - like growth factor - 1 ( DB01277 ) and IGF binding protein - 3 ( P17936 ) . Six of the children had subnormal GH secretion consistent with GH deficiency . Subnormal growth velocity was the best clinical predictor of GH deficiency . The large percentage of these children with apparent GH deficiency is surprising . Possible mechanisms include anatomic abnormalities of the hypothalamic - pituitary axis , psychosocial deprivation , and an interaction between suboptimal nutritional status and an abnormal central nervous system .","Influence of genetic polymorphisms on the pharmacokinetics and pharmaco - dynamics of sulfonylurea drugs . Sulfonylurea drugs including chlorpropamide , gliclazide , tolbutamide , glipizide , glibenclamide ( glyburide ) and glimepiride are the most widely used oral hypoglycaemic agents in people with type 2 diabetes . This review investigates the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of sulfonylurea drugs . P11712 is the major enzyme involved in sulfonylurea drug metabolism . P11712 variant allele carriers have significant lower apparent clearance of these medicines . P33261 genotype is more influential for gliclazide pharmacokinetics when compared to P11712 . Sulfonylurea pharmacodynamics is affected by several genes . Q09428 ( Q09428 , Q09428 gene ) and K + inward rectifier Kir6 . 2 ( Q14654 ) have been correlated to significant variation in sulfonylurea response . Diabetics with the Q09428 exon 33 G allele are more sensitive to gliclazide and the rs5210 variant of the Q14654 gene was associated with improved clinical efficacy of gliclazide . Carriers of Q9NQB0 ( Q9NQB0 ) variants are more likely to fail sulfonylurea therapy . On the other hand , patients with HNF - 1alpha mutations had a significant greater response to gliclazide when compared to those with type 2 diabetes . The Arg972 polymorphism of insulin receptor substrate 1 ( P35568 ) may lead to secondary failure of sulfonylurea therapy . Calpain 10 gene ( Q9HC96 ) polymorphism has also been linked to sulfonylurea drug response . Despite the available evidence , larger population studies that investigate the pharmacokinetics and pharmacodynamics of sulfonylurea drugs are needed to investigate the influence of key SNPs amidst all potential contributing factors to variability in response to these which inturn will provide information to optimise sulfonylurea use in people with diabetes .","[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK65___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .","Associations of proinflammatory cytokine levels with lipid profiles , growth , and body composition in HIV - infected children initiating or changing antiretroviral therapy . OBJECTIVES : To measure proinflammatory cytokines ( PIC ) in HIV - infected children beginning or changing antiretroviral therapy ( O00253 ) , evaluating associations with virologic , immunologic , serum lipid , growth , and body composition measures , markers of growth hormone action and glucose metabolism . METHODS : Forty - nine prepubertal HIV - infected children had measurements of viral load ( VL ) , P01730 lymphocyte count and percentage , serum lipids , apolipoprotein AI / B , DB01277 , P08833 , and P17936 , anthropometry , bioelectrical impedance analysis , P01375 - α , IL - 1 β , and P05231 at baseline and 48 weeks of O00253 . RESULTS : Baseline levels were detectable ( > 0 . 1 pg / mL ) for IL - 1 β in 28 of 48 , and for P01375 - α and Il - 6 in all 49 children . P01375 - α decreased with O00253 ( P < 0 . 001 ) and P05231 demonstrated a similar trend ( P = 0 . 065 ) . Children with 48 - week VL < 400 copies / mL had greater declines in P01375 - α ( mean 45 % ) than subjects with higher VL ( 5 % ; P = 0 . 009 ) . Each 10 % improvement in P01730 % was associated with 26 % lower P01375 - α ( P = 0 . 002 ) and 31 % lower P05231 ( P = 0 . 016 ) . Greater reductions in P01375 - α were associated with lower total / HDL cholesterol ratio ( P = 0 . 003 ) at week 48 . CONCLUSIONS : In HIV - infected children initiating or changing O00253 , PIC were detectable at baseline and decreased over 48 weeks . Better immunologic responses were associated with greater reductions in P01375 - α and P05231 . Reductions in P01375 - α were associated with improved total / HDL cholesterol ratio .","Phenotypic characterization of human chondrocyte cell line C - 20 / A4 : a comparison between monolayer and alginate suspension culture . DNA microarray analysis was used to investigate the molecular phenotype of one of the first human chondrocyte cell lines , C - 20 / A4 , derived from juvenile costal chondrocytes by immortalization with origin - defective simian virus 40 large T antigen . Clontech Human Cancer Arrays 1 . 2 and quantitative PCR were used to examine gene expression profiles of C - 20 / A4 cells cultured in the presence of serum in monolayer and alginate beads . In monolayer cultures , genes involved in cell proliferation were strongly upregulated compared to those expressed by human adult articular chondrocytes in primary culture . Of the cell cycle - regulated genes , only two , the CDK regulatory subunit and histone H4 , were downregulated after culture in alginate beads , consistent with the ability of these cells to proliferate in suspension culture . In contrast , the expression of several genes that are involved in pericellular matrix formation , including P50281 , P12109 , fibronectin , biglycan and decorin , was upregulated when the C - 20 / A4 cells were transferred to suspension culture in alginate . Also , nexin - 1 , vimentin , and P17936 , which are known to be expressed by primary chondrocytes , were differentially expressed in our study . Consistent with the proliferative phenotype of this cell line , few genes involved in matrix synthesis and turnover were highly expressed in the presence of serum . These results indicate that immortalized chondrocyte cell lines , rather than substituting for primary chondrocytes , may serve as models for extending findings on chondrocyte function not achievable by the use of primary chondrocytes .","P01308 - like growth factors ( IGFs ) and IGF - binding proteins in nephrotic syndrome children on glucocorticoid . Growth failure is often seen in nephrotic children who fail to respond to glucocorticoid therapy or are glucocorticoid dependent . The underlying mechanism responsible for such growth defect remains poorly understood although long - term glucocorticoid use or nephrotic syndrome ( NS ) has been indicated to independently affect growth . Recent clinical evidence has suggested that changes in the serum levels of insulin - like growth factors ( IGFs ) and IGF - binding proteins ( IGFBPs ) among these children . The loss of insulin - like growth factor - I ( DB01277 ) and P17936 found in nephrotic children may directly prompt growth defect and retardation . In addition , glucocorticoid is believed to be associated with overt elevation of serum P05019 levels suggesting potential development of IGF resistance , one of the main factors responsible for persistent growth retardation . Growth hormone therapy has been shown to effectively reconcile this IGF resistance . The present review will discuss the complex relationship among IGF , IGFBPs , and glucocorticoid in children with NS .","Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .","Expression of a protease - resistant insulin - like growth factor - binding protein - 4 inhibits tumour growth in a murine model of breast cancer . BACKGROUND : DB01277 ( IGF1 ) promotes breast cancer and disease progression . Bioavailability of IGF1 is modulated by IGF - binding proteins ( IGFBPs ) . P22692 inhibits IGF1 activity but cleavage by pregnancy - associated plasma protein - A ( Q13219 ) protease releases active IGF1 . METHODS : Expression of IGF pathway components and Q13219 was assessed by western blot or RT - PCR . P22692 ( dBP4 ) resistant to Q13219 cleavage , but retaining IGF - binding capacity , was used to block IGF activity in vivo . 4T1 . 2 mouse mammary adenocarcinoma cells transfected with empty vector , vector expressing wild - type P22692 or vector expressing dBP4 were implanted in the mammary fat pad of BALB / c mice and tumour growth was assessed . Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry . RESULTS : 4T1 . 2 cells expressed the P08069 receptor and P22692 . Q13219 was expressed within mammary tumours but not by 4T1 . 2 cells . Proliferation and vascular endothelial growth factor ( P15692 ) production by 4T1 . 2 cells was increased by IGF1 ( E3R ) ( recombinant IGF1 resistant to binding by IGFBPs ) but not by wild - type IGF1 . IGF1 - stimulated microvascular endothelial cell proliferation was blocked by recombinant P22692 . 4T1 . 2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild - type P22692 . Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis . CONCLUSION : Protease - resistant P22692 blocks IGF activity , tumour growth and angiogenesis .","Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 or Q09428 genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long - term follow - up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 , Q14654 , or Q09428 genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow - up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 and Q09428 genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .","Gene expression of malignant rhabdoid tumor cell lines by reverse transcriptase - polymerase chain reaction . Malignant rhabdoid tumors ( MRT ) are characterized by unique neoplastic cells demonstrating phenotypic diversity . By using the reverse transcriptase - polymerase chain reaction , we have detected expression of various genes before and after differentiation induction with four different agents in four established MRT cell lines ( TM87 - 16 , STM91 - 01 , TTC642 , and TTC549 ) . The agents used in this study were all - trans retinoic acid ( RA ) , 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) , interleukin - 3 , or interferon - gamma . Before and after induction , c - myc , P01344 , P08069 , and P11717 were constitutively expressed by all four cell lines . The neurofilament medium - size ( P07197 ) was constitutively expressed by the TM87 - 16 and TTC642 , and the S100 protein alpha subunit was expressed by TM87 - 16 , TTC642 , and TTC549 . Chromogranin A was expressed by TM87 - 16 only after treatment with either TPA or RA . MyoD , N - myc , tyrosine hydroxylase , N - P62158 , trkA , and the S100 protein beta subunit were not expressed by any cell line before or after induction with these agents . All the MRT cell lines in this study except TM87 - 16 were highly resistant to differentiation induction . The proliferating cells in TM87 - 16 and TTC642 expressed mRNA profiles characteristic of neuroectoderm .","Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK63___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK63___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .","Two new substrates in insulin signaling , Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 . We have identified two new human genes that encode proteins with tandem pleckstrin homology - phosphotyrosine binding ( PH - PTB ) domains at their amino termini . Because the other known PH - PTB proteins ( insulin receptor substrates : P35568 , Q9Y4H2 , P41252 - 3 , and O14654 , and the downstream of kinases : DOK - 1 , DOK - 2 , and DOK - 3 ) are substrates of insulin and insulin - like growth factor ( IGF ) - 1 receptors , we asked whether these new proteins , termed Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 , might also have roles in insulin and DB01277 signaling . Northern analyses indicate that Q8TEW6 / Q8TEW6 is ubiquitously expressed but most abundant in kidney and liver . Q9P104 / Q9P104 expression is highest in skeletal muscle . Both proteins are tyrosine - phosphorylated in response to insulin and DB01277 in transfected cells , although the kinetics differ . P06213 - phosphorylated Q8TEW6 / Q8TEW6 associates with P20936 , Crk , Src , and Fyn , but not phosphatidylinositol 3 - kinase p85 , Grb2 , Q06124 , Nck , or phospholipase Cgamma Src homology 2 domains , and activates MAPK in cells . Q9P104 / Q9P104 neither associates with these Src homology 2 domains nor activates MAPK . Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 represent two new signaling proteins with potential roles in insulin and DB01277 action .","Hormone stability in human whole blood . OBJECTIVE : To determine whether significant changes in the plasma concentrations of 17 hormones occur when human whole blood is held at 4 or 24 degrees C for up to 24 h before separation of the plasma fraction . DESIGN AND METHODS : Blood samples ( DB00974 ) from healthy human volunteers were held at 4 degrees C or 24 degrees C for 0 . 5 , 6 or 24 h before separation . Plasma concentrations of DB01285 , aldosterone , gonadotrophin alpha - subunits , AVP , C - peptide , estradiol , DB00094 , GH , glucagon , DB01277 , P17936 , insulin , leptin , LH , prolactin , PTH and P01282 were measured and the results compared to baseline values . Nonlinear regression was used to test for a significant mean rate of change . The time interval for median concentrations to change by 10 % was determined . RESULTS : Significant changes were observed for DB01285 ( decrease at 18 . 6 hr , 4 degrees C ; 17 . 5 hr , 24 degrees C ) ; AVP ( increase at 2 . 6 h , 24 degrees C ) ; insulin ( decrease at 16 . 8 hr , 4 degrees C ; 16 . 9 hr , 24 degrees C ) and P01282 ( increase at 18 . 6 h , 24 degrees C ) . No changes were detected for the remaining analytes . B CONCLUSIONS : The measurement of some hormones is compromised by a delay in plasma separation from normal human blood . While many hormones appear stable in normal whole blood , we recommend that processing occurs without delay .","Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK58___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .","Treatment of growth hormone - deficient adults with recombinant human growth hormone increases the concentration of growth hormone in the cerebrospinal fluid and affects neurotransmitters . In a double - blind , placebo - controlled trial , the effects of recombinant human growth hormone were studied on cerebrospinal fluid concentrations of growth hormone , insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor binding protein - 3 ( P17936 ) , monoamine metabolites , neuropeptides and endogenous opioid peptides . Twenty patients , 10 patients in each of 2 groups , with adult - onset , growth hormone deficiency were treated for 1 month with recombinant human growth hormone ( 0 . 25 U / kg / week ) or placebo . All the patients received the appropriate thyroid , adrenal and gonadal hormone replacement . In cerebrospinal fluid , the mean concentration of growth hormone increased from 13 . 3 +/- 4 . 4 to 149 . 3 +/- 22 . 2 muU / l ( p = 0 . 002 ) , during recombinant human growth hormone treatment . The cerebrospinal fluid P05019 concentration increased from 0 . 67 +/- 0 . 04 to 0 . 99 +/- 0 . 10 micrograms / l ( p = 0 . 005 ) and the P17936 concentration rose from 13 . 4 +/- 1 . 25 to 17 . 5 +/- 1 . 83 micrograms / l ( p = 0 . 002 ) . The dopamine metabolite homovanillic acid decreased from 282 . 1 +/- 36 . 0 to 234 . 3 +/- 26 . 5 nmol / l ( p = 0 . 02 ) and the vasoactive intestinal peptide decreased from 4 . 1 +/- 0 . 6 to 3 . 7 +/- 0 . 4 pmol / l ( p = 0 . 03 ) . Cerebrospinal fluid immunoreactive beta - endorphin increased from 24 . 4 +/- 1 . 8 to 29 . 9 +/- 2 . 1 pmol / l ( p = 0 . 002 ) . There were no significant changes compared to baseline in the cerebrospinal fluid concentrations of enkephalins , dynorphin A , the norepinephrine metabolite 3 - methoxy - 4 - hydroxyphenyl - ethyleneglycol , the serotonin metabolite 5 - hydroxyindoleacetic acid , gamma - aminobutyric acid , somatostatin or DB05394 . ( ABSTRACT TRUNCATED AT 250 WORDS )","___MASK26___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .","Short stature caused by a natural growth hormone antagonist . Severe short stature in a male child due to a single mutation in the GH - 1 gene was first reported in 1996 by Takahashi et al . [ N Engl J Med 1996 ; 334 : 432 - 436 ] . This missense mutation was predicted to convert codon 77 from arginine ( R ) to cysteine ( C ) . The child ' s chronological age was 4 years and 11 months , and his bone age 2 years and 6 months , i . e . , equal to only 51 % of his chronological age . Body proportions were normal except for the prominent forehead and saddle nose . Pituitary size was normal on magnetic resonance imaging examinations . Serum DB01277 , P17936 and P30043 were all decreased or at the lower limit of the normal range . Nocturnal urinary growth hormone ( GH ) excretion was high . Isoelectric focusing analysis revealed the presence of an abnormal GH peak in addition to the normal one . The R77C mutant GH possessed a 6 times greater affinity to P30043 than the wild - type GH , and inhibited tyrosine phosphorylation in IM - 9 cells 10 times more potently than the wild - type GH , showing an antagonistic or a dominant negative action . In agreement with the antagonistic property of the mutant GH exhibited , the child did not show any increase in serum DB01277 levels after exogenous hGH administration . It should be noted that the child in this study is not a typical case of Kowarski syndrome in which endogenous GH is found to be simply bioinactive , as in the patient we recently described elsewhere . Therefore , this patient ' s condition should be categorized as a new syndrome of short stature caused by a natural GH antagonist .","Interleukin 10 blocks matrix metalloproteinase - 2 and membrane type 1 - matrix metalloproteinase synthesis in primary human prostate tumor lines . P01308 - like growth factor ( IGF ) I has been shown previously to up - regulate matrix metalloproteinase - 2 ( P08253 ) production , whereas the interleukin ( IL ) 10 / P22301 receptor axis has been found to down - regulate P08253 synthesis in tumor cells . In this paper , we showed that P22301 activation of the P22301 receptor blocked P08253 and membrane type 1 ( MT1 ) - MMP transcription and protein synthesis in nonimmortalized primary human prostate cell strains ( i . e . , P84074 - 10a and P84074 - 10c ) derived from high - grade cancer . Northern blots , Western blots , and ELISAs showed that P22301 suppressed P05019 induction of P08253 and P50281 mRNA synthesis in these cell strains ( P < 0 . 001 ) . Inhibition studies with P22301 and P08069 antibodies plus transfections experiments with P22301 sense , and P08069 antisense constructs confirmed these results . Finally , transient transfection experiments and chloramphenicol acetyltransferase assays with different regions of the 5 ' promoter region of the P08253 gene ( - 1659 to - 555 bp ) additionally showed that P05019 stimulated p53 - dependent plasmid catecholamine acetyltransferase activity and that P22301 blocked P05019 - induced plasmid catecholamine acetyltransferase activity . Electrophoretic mobility shift assays revealed that P22301 induced protein ( s ) binding to a putative \" silencer element \" ( - 1309 to - 555 fragment ) downstream of the p53 binding site ( - 1649 to - 1640 ) . The data show that P22301 blocks P05019 activation of P08253 and P50281 mRNA expression and protein synthesis in primary prostate cell strains .","8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .","Development of an absolute quantification method targeting growth hormone biomarkers using liquid chromatography coupled to isotope dilution mass spectrometry . A method to perform absolute quantification of two biomarkers ( DB01277 and P17936 ) of growth hormone abuse has been developed . Isotope dilution is used with synthetically labelled peptides as internal standards . Peptide selection and multiple reaction monitoring design are discussed . A simple sample preparation based on the reduction and alkylation of cysteine residues followed by tryptic digestion provides a sufficient digestion of proteins . Serum samples fortified with increasing amounts of target proteins are analysed by liquid chromatography - tandem mass spectrometry ( LC - MS / MS ) on a triple quadrupole mass spectrometer . Specificity is ensured by the selection of sequences with no homology in BLAST , as well as retention time deviation check , and ion ratio monitoring . Linearity is studied in terms of calibration curves . These curves for P17936 and DB01277 are generated with mean slopes of 0 . 055 and 0 . 065 , intercepts of 0 . 107 and - 0 . 011 , and with coefficients of correlation of 0 . 95 and 0 . 98 , respectively . These curves result from the addition of proteins to the serum . Risks of variations related to potential matrix effects are therefore reduced , as well as probable variations related to the digestion steps . The working concentration ranges are 4 - 10 ng / microl for P17936 and 2 - 8 ng / microl for DB01277 . Preliminary data regarding repeatability show that relative standard deviations ( RSDs ) range between 13 and 32 % for P17936 and between 7 and 29 % for DB01277 .","DB00133 phosphorylation of the insulin - like growth factor I ( DB01277 ) receptor C - terminal tail restrains kinase activity and cell growth . P08069 ( IGF - 1R ) signaling is essential for cell , organ , and animal growth . The C - terminal tail of the IGF - 1R exhibits regulatory function , but the mechanism is unknown . Here , we show that mutation of DB00133 - 1248 ( S1248A ) enhances IGF - 1R in vitro kinase activity , autophosphorylation , Akt / mammalian target of rapamycin activity , and cell growth . DB00133 - 1248 phosphorylation is mediated by GSK - 3β in a mechanism that involves a priming phosphorylation on DB00133 - 1252 . GSK - 3β knock - out cells exhibit reduced IGF - 1R cell surface expression , enhanced IGF - 1R kinase activity , and signaling . Examination of crystallographic structures of the IGF - 1R kinase domain revealed that the ( 1248 ) SFYYS ( 1252 ) motif adopts a conformation tightly packed against the kinase C - lobe when DB00133 - 1248 is in the unphosphorylated state that favors kinase activity . S1248A mutation is predicted to lock the motif in this position . In contrast , phosphorylation of DB00133 - 1248 will drive profound structural transition of the sequence , critically affecting connection of the C terminus as well as exposing potential protein docking sites . Decreased kinase activity of a phosphomimetic S1248E mutant and enhanced kinase activity in mutants of its predicted target residue Lys - 1081 support this auto - inhibitory model . Thus , the SFYYS motif controls the organization of the IGF - 1R C terminus relative to the kinase domain . Its phosphorylation by GSK - 3β restrains kinase activity and regulates receptor trafficking and signaling .","Nonalcoholic fatty liver disease is associated with increased P30043 and reduced GH / P05019 levels . INTRODUCTION : Nonalcoholic fatty liver disease ( NAFLD ) has been described in adult GH deficiency syndrome . Furthermore , chronic liver disease can be associated with significant changes in levels of P05019 , GH - binding protein ( P30043 ) , IGF - binding proteins ( IGFBPs ) and acid - labile subunit ( P35858 ) . However , the effect of liver steatosis on the P30043 production has not been investigated yet . AIM OF THE STUDY : To explore whether GH secretion and / or levels of P05019 , P17936 , P35858 and P30043 could be altered in obese patients in relation to the presence of liver steatosis . MATERIALS AND METHODS : A total of 115 obese patients ( BMI > 30 ) were enrolled in the protocol ( 65 patients with liver steatosis and 50 age - and BMI - matched controls ) . In all patients , the following parameters were studied : serum levels of glucose , insulin , the HOMA index , P05019 , P30043 , P17936 , P35858 and GH after P01286 and arginine stimulation test . RESULTS : As expected , patients with NAFLD had blood glucose , insulin , HOMA - R significantly higher than controls , indicating a more severe insulin - resistance state in NAFLD . Furthermore , patients with NAFLD had higher levels of P30043 and P17936 and lower GH peak and P05019 levels as compared to controls . No difference was found in P35858 levels between the groups . In a multivariate analysis , P30043 was positively associated with hepatic steatosis while DB01277 was negatively associated with hepatic steatosis . CONCLUSIONS : This study demonstrates that in patients with NAFLD , the P30043 levels are increased , and that the GH / P05019 axis is significantly altered probably leading to reduced P05019 bioavailability at tissue level .","Duodenal mucosal protection by bicarbonate secretion and its mechanisms . Proximal portion of duodenum is exposed to intermittent pulses of gastric H (+) discharged by the stomach . This review summarizes the mechanisms of duodenal mucosal integrity , mainly the role of mucus - alkaline secretion and the mucous barrier protecting surface epithelium against gastric H (+) . The mucous barrier protects the leaky duodenal epithelium against each pulse of gastric H (+) , which penetrates this barrier and diffuses into duodenocytes , but fails to damage them due to ; a ) an enhanced expression of cyclooxygenase - 1 ( P23219 ) , with release of protective prostaglandins ( PG ) and of nitric oxide ( NO ) synthase ( NOS ) with , however , production of NO , stimulating duodenal HCO ( 3 )(-) secretion and b ) the release of several neurotransmitters also stimulating HCO ( 3 )(-) secretion such as vasoactive intestinal peptide ( P01282 ) , pituitary adenylate - cyclase activating polypeptide ( PACAP ) , acetylcholine , melatonin , leptin and ghrelin released by enteric nerves and mucosal cells . At the apical duodenocyte membrane at least two HCO ( 3 )(-)/ Cl (-) anion exchangers operate in response to luminal H (+) to provide adequate extrusion of HCO ( 3 )(-) into duodenal lumen . In the basolateral portion of duodenocyte membrane , both non - electrogenic ( NBC ) and electrogenic ( NBC ( n ) ) Na (+) HCO ( 3 )(-) cotransporters are activated by the exposure to duodenal acidification , causing inward movement of HCO ( 3 )(-) from extracellular fluid to duodenocytes . There are also at least three Na (+)/ H (+) ( P19634 - 3 ) amiloride - sensitive exchangers , eliminating H (+) which diffused into these cells . The Helicobacter pylori ( Hp ) infection and gastric metaplasia in the duodenum with bacterium inoculating metaplastic mucosa and inhibiting HCO ( 3 )(-) secretion by its endogenous inhibitor , asymmetric dimethyl arginine ( DB01686 ) , may result in duodenal ulcerogenesis .","Serum insulin - like growth factor - 1 ( DB01277 ) and insulin - like growth factor binding protein - 3 ( P17936 ) in healthy Thai children and adolescents : relation to age , sex , and stage of puberty . The authors studied the serum concentrations of insulin - like growth factor - 1 ( DB01277 ) and IGF - binding protein - 3 ( P17936 ) in 260 healthy children and adolescents ( 115 males , 145 females ) aged 5 - 20 years . The subjects were divided into 12 groups according to age and sex . The serum DB01277 and P17936 concentrations increased with age and peaked at age 13 - 15 years in males , and 11 - 13 years in females . After the peak concentration , DB01277 and P17936 levels declined significantly in males , but were still high in females . Comparing between sexes , the concentrations of DB01277 and P17936 were greater in females than males in all age groups . However , when subjects were divided according to the stage of puberty , the different concentrations between sexes were not significant , except for children within Tanner stage V where concentrations of DB01277 and P17936 were significantly greater in females than males . Multiple regression analysis demonstrated the age , sex , and stage of puberty - dependent of DB01277 concentration , and only the age and sex - dependent of P17936 concentration .","P00747 activator system : implications for mammary cell growth and involution . Several tissue remodeling events that require extracellular proteolysis are thought to be mediated by plasminogen activators that convert the inactive proenzyme plasminogen to active plasmin . The involvement of plasminogen activator in many biological phenomena reflects the ubiquitous presence of plasminogen and the ability of numerous cell types to synthesize plasminogen activator in a highly regulated manner . Increased plasmin and plasminogen activator in bovine milk are correlated with gradual involution ( the declining phase of lactation ) . Treatment with bST prevented the increase in plasmin during gradual involution , indicating that bST interferes with conversion of plasminogen to plasmin . Concentrations of plasminogen activator in mammary tissue are high after cessation of milking . These results reinforce the association of the plasmin - plasminogen system with gradual involution postlactation . Recently , a role has been proposed for plasminogen activator in cell proliferation in several cellular systems . P01308 and P05019 increased synthesis of urokinase plasminogen activator and enhanced proliferation of cultured bovine mammary epithelial cells . In contrast , phorbol myristate acetate , which increased expression of urokinase plasminogen activator mRNA by mammary epithelial and myoepithelial cells , stimulated proliferation of myoepithelial cells , but not epithelial cells . Thus , expression of plasminogen activator is not simply related to mitogenesis but is likely to serve multiple functions in bovine mammary epithelial cells .","Q9H244 receptor signalling towards P31749 proceeds through P08069 cross - talk and requires activation of Src , Pyk2 and Rap1 . Previously it was shown that stimulation of the Q9H244 receptor activates P31749 signalling in P13671 glioma cells [ K . Van Kolen and H . Slegers , J . Neurochem . 89 , 442 . ] . In the present study , the mechanisms involved in this response were further elucidated . In cells transfected with the Gbetagamma - scavenger beta - O14965 / P25098 or Rap1GAPII , stimulation with 2MeSADP failed to enhance P31749 phosphorylation demonstrating that the signalling proceeds through Gbetagamma - subunits and Rap1 . Moreover , Rap1 - GTP pull - down assays revealed that Q9H244 receptor stimulation induced a rapid activation of Rap1 . Treatment of cells with the Ca2 + chelator BAPTA - AM and inhibition of Src and O14939 with Q99463 or 1 - butanol , respectively , abrogated Q9H244 receptor - mediated activation of Rap1 and P31749 . In addition inhibition of PKCzeta decreased basal and 2MeSADP - stimulated phosphorylation of P31749 indicating a role for this PKC isoform in P31749 signalling . Although the increased P31749 phosphorylation was abolished in the presence of the P08069 tyrosine kinase inhibitor AG 1024 , 2MeSADP did not significantly increase receptor phosphorylation . Nevertheless , phosphorylation of a 120 kDa P08069 - associated protein was observed . The latter protein was identified by MALDI - TOF / TOF - MS as the proline - rich tyrosine kinase 2 ( Pyk2 ) that co - operates with Src in a O14939 - dependent manner . Consistent with the signalling towards Rap1 and P31749 , activation of Pyk2 was abrogated by Ca2 + chelation , inhibition of O14939 and P08069 tyrosine kinase activity . In conclusion , the data reveal a novel type of cross - talk between Q9H244 and P05019 receptors that proceeds through Gbetagamma - , Ca2 +- and O14939 - dependent activation of the Pyk2 / Src pathway resulting in GTP - loading of Rap1 required for an increased P31749 phosphorylation .","Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK94___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK94___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .","Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .","P00749 and insulin - like growth factor - binding protein 3 mRNA expression in endometriotic lesions and eutopic endometrium : implications for the pathophysiology of endometriosis . The peritoneal fluid of women with endometriosis contains an increased insulin - like growth factor 1 ( DB01277 ) bioavailability , which is produced by limited hydrolysis of urokinase - type plasminogen activator ( uPA ) on P17936 ( P17936 ) . Recently , DB01277 was shown to inhibit apoptosis of endometrial - like cells in vitro , suggesting that a microenvironment of increased DB01277 bioavailability can optimize the survival of endometrial cells grown ectopically . Here the expression of mRNA of P17936 and uPA in tissue biopsies from eutopic endometrium and endometriotic lesions obtained at laparoscopy from women with endometriosis have been analyzed , and it is documented that both P17936 and uPA mRNA expression are increased from 3 - to 10 - fold in endometriotic lesions versus eutopic endometrium . Consequently , the necessary components ( uPA and P17936 expression ) of endocrine / autocrine / paracrine enhancement of local IGF bioavailability mediated by uPA hydrolysis of the P17936 were present in endometriotic lesions . These data possibly explain the origin of the increased content of uPA activity , DB01277 bioavailability , and NH ( 2 )- truncated forms of P17936 in the peritoneal fluid of women with endometriosis ."],"string":"[\n \"How DB01277 activates its receptor . This study presents a new model for P08069 activation in which the transmembrane domains are held apart until ligand binding brings them together in an activated state .\",\n \"P08069 mRNA expression and autophosphorylation in human myometrium and leiomyoma . Uterine leiomyomas are the most common tumors of the genital tract . Growth factors seem to be implicated in the development of leiomyoma . The aim of this study was to determine insulin - like growth factor 1 receptor ( DB01277 - R ) mRNA levels and DB01277 - R tyrosine kinase activity in normal myometrium and leiomyoma . Plasma membranes of myometrium and leiomyoma of 14 women subjected to hysterectomy were prepared , and samples were incubated in the absence or presence of recombinant human DB01277 to assess the tyrosine kinase activity ( Western blot ) . Reverse - transcriptase polymerase chain reaction with specific primers for DB01277 - R was used to determine DB01277 - R mRNA levels . DB01277 - R mRNA levels in myometrium ( 0 . 8216 +/- 0 . 096 ) and in leiomyoma ( 0 . 7905 +/- 0 . 136 ) were not statistically significantly different ( p = 0 . 648 ) . The degree of DB01277 - R autophosphorylation stimulated by recombinant DB01277 was not different in myometrium ( 1 . 020 +/- 0 . 120 ) and leiomyoma ( 1 . 620 +/- 0 . 656 ) either ( p = 0 . 075 ) . There was no difference in DB01277 - R expression and DB01277 - R autophosphorylation between normal myometrium and leiomyoma .\",\n \"P01308 - like growth factors and their binding proteins in the venous effluents of ovary and adrenal gland in severely hyperandrogenic women . P01308 and insulin - like growth factors ( IGF ) are thought to play an important role in the pathogenesis of excessive androgen production . To explore this question further we measured the concentrations of P05019 and - II and their binding proteins ( P08833 and - 3 ) in adrenal and ovarian vein samples of severely hyperandrogenic women ( serum testosterone > 5 nmol / l ) collected as part of their diagnostic work - up . The concentration of P01344 was slightly but not significantly higher in the ovarian vein than in the adrenal and peripheral veins . The concentrations of P05019 and IGFBP were identical in both the adrenal and ovarian veins and did not differ from those in the peripheral circulation . The concentration of P08833 was negatively correlated ( r = - 0 . 60 , P > 0 . 05 ) with insulin and P17936 showed a strong positive correlation with DB01277 ( r = 0 . 90 , P > 0 . 01 ) . These results indicate that neither the ovary nor the adrenal gland contributes significantly to the circulating pool of IGF or their binding proteins in severely hyperandrogenic subjects . Hyperinsulinaemia is associated with low circulating P08833 concentrations and P17936 seems to be an excellent indicator of the peripheral P05019 concentration . The concentrations of P05019 suggested decreased somatotrophic activity in these obese , hyperinsulinaemic subjects .\",\n \"Milk consumption and the prepubertal somatotropic axis . BACKGROUND : Nutrients , hormones and growth factors in dairy foods may stimulate growth hormone ( GH ) , insulin - like growth factor I ( P05019 ) , and raise the ratio of P05019 to its binding protein , P17936 . We conducted pilot studies in Mongolia and Massachusetts to test the extent to which milk intake raised somatotropic hormone concentrations in prepubertal children . METHODS : In Ulaanbaatar , we compared plasma levels before and after introducing 710 ml daily whole milk for a month among 46 10 - 11 year old schoolchildren . In a randomized cross - over study in Boston , we compared plasma hormone levels of 28 6 - 8 year old girls after one week of drinking 710 ml low fat ( 2 % ) milk with their hormone levels after one week of consuming a macronutrient substitute for milk . RESULTS : After a month of drinking whole milk , Mongolian children had higher mean plasma levels of P05019 ( p < 0 . 0001 ) , P05019 / P17936 ( p < 0 . 0001 ) , and 75th percentile of GH levels ( p = 0 . 005 ) . After a week of drinking low fat milk , Boston girls had small and non - significant increases in DB01277 , DB01277 / P17936 and GH . CONCLUSION : Milk drinking may cause increases in somatotropic hormone levels of prepubertal girls and boys . The finding that milk intake may raise GH levels is novel , and suggests that nutrients or bioactive factors in milk may stimulate endogenous GH production .\",\n \"Evaluation of the antitumor effects and mechanisms of PF00299804 , a pan - HER inhibitor , alone or in combination with chemotherapy or targeted agents in gastric cancer . Recently , P04626 - directed treatment , such as trastuzumab , has shown clinical benefit in P04626 - amplified gastric cancer . On the basis of recent studies about epidermal growth factor receptor ( P00533 ) or P04626 - targeting agents ( including gefitinib , lapatinib , and trastuzumab ) in gastric cancer , the potent effects of pan - HER inhibitors targeting the HER family are anticipated . In this study , we evaluated the activity and mechanisms of PF00299804 , an irreversible pan - HER inhibitor , in gastric cancer in vitro and in vivo models . PF00299804 showed significant growth - inhibitory effects in P04626 - amplified gastric cancer cells ( SNU216 , N87 ) , and it had lower 50 % inhibitory concentration values compared with other P00533 tyrosine kinase inhibitors , including gefitinib , lapatinib , BIBW - 2992 , and DB05424 . PF00299804 induced apoptosis and G ( 1 ) arrest and inhibited phosphorylation of receptors in the HER family and downstream signaling pathways including P40763 , AKT , and extracellular signal - regulated kinases ( P29323 ) in P04626 - amplified gastric cancer cells . PF00299804 also blocked P00533 / P04626 , P04626 / P21860 , and P21860 / Q15303 heterodimer formation as well as the association of P21860 with p85α in SNU216 cells . The combination of PF00299804 with clinically relevant chemotherapeutic agents or molecular - targeted agents including trastuzumab ( an anti - P04626 monoclonal antibody ) , CP751871 ( an P08069 inhibitor ) , PD0325901 ( an P27361 / 2 inhibitor ) , and PF04691502 ( a PI3K / P42345 inhibitor ) produced synergistic effects . These findings indicate that PF00299804 can be used as a targeted therapy for the treatment of P04626 - amplified gastric cancer through inhibition of HER family heterodimer formation and may augment antitumor efficacy of chemotherapeutic and / or molecular - targeted agents .\",\n \"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .\",\n \"P08069 - mediated endocytosis in Xenopus laevis oocytes . A role for receptor tyrosine kinase activity . Equilibrium analysis of [ 125I ] DB01277 binding to Xenopus oocytes yielded curvilinear Scatchards supporting the presence of multiple binding sites . High - affinity binding displayed an apparent KD of 9 . 0 +/- 3 . 0 nM DB01277 with maximum total binding of 1 . 6 +/- 0 . 3 fmole / oocyte after 90 min at 22 degrees C . Binding of 1 nM [ 125I ] DB01277 to oocytes was competitively displaced by unlabeled DB01277 or insulin with IC50 values of 6 and 560 nM , respectively . Chemical cross - linking of [ 125I ] - DB01277 to oocyte membranes specifically labeled a single 138 - kDa protein . Using the technique of acid stripping to analyze whole - cell binding , both total and surface binding of [ 125I ] DB01277 reached a plateau after 90 min , and internalized counts surpassed surface - associated counts 20 min after hormone addition . At the 90 - min plateau , 70 - 75 % of cell - associated counts were internalized . The tyrosine kinase inhibitor , tyrphostin 47 , prevented DB01277 - stimulated oocyte maturation with an apparent IC50 of 10 . 5 +/- 2 . 5 microM and also inhibited DB01277 receptor - mediated endocytosis in micromolar concentrations . Treatment of oocyte membrane samples with 10 nM DB01277 stimulated alkali - stable phosphorylation of a protein doublet ( M ( r ) 89 and 104 kDa ) . Tyrphostin 47 also inhibited DB01277 - stimulated phosphorylation of these putative receptor beta - subunits more effectively than tyrphostin 23 or genistein . These results suggest a necessary role for receptor - mediated endocytosis in DB01277 - induced oocyte maturation and a requirement for receptor kinase activity in oocyte receptor internalization .\",\n \"P17936 , hypoxia and P01375 inhibit adiponectin transcription . The thiazolidinedione rosiglitazone , an agonist ligand for the nuclear receptor P37231 , improves insulin sensitivity in part by stimulating transcription of the insulin - sensitizing adipokine adiponectin . It activates P37231 - RXR - alpha heterodimers bound to P37231 response elements in the adiponectin promoter . Rosiglitazone - stimulated adiponectin protein synthesis in 3T3 - Q9NUQ9 mouse adipocytes has been shown to be inhibited by P17936 , which can be induced by hypoxia and the proinflammatory cytokine , P01375 , two inhibitors of adiponectin transcription . The present study demonstrates that P17936 , the hypoxia - mimetic agent cobalt chloride , and P01375 inhibit rosiglitazone - induced adiponectin transcription in mouse embryo fibroblasts that stably express Q07869 - gamma2 . Native P17936 can bind RXR - alpha and inhibited rosiglitazone stimulated promoter activity , whereas an P17936 mutant that does not bind RXR - alpha did not . These results suggest that P17936 may mediate the inhibition of adiponectin transcription by hypoxia and P01375 , and that P17936 binding to RXR - alpha may be required for the observed inhibition .\",\n \"___MASK72___ : kinetic and dynamic profile in the treatment of pain . ___MASK72___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK72___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK72___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK72___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .\",\n \"[ Analysis of clinical manifestations and genetic mutations in a child with Laron syndrome ] . OBJECTIVE : To analyze clinical manifestations and gene mutations in a child with severe short stature , explore its molecular mechanism and further clarify the diagnostic procedure for short stature . METHOD : We observed clinical characteristics of a patient with short stature and did diagnostic examinations , assessed the function of GH - DB01277 axis , and surveyed its family members . Genomic DNA was extracted from peripheral blood , P10912 , P35858 , STAT5b and P01241 gene were amplified by PCR for sequencing , including exons and splicing areas . RESULT : The patient presented symmetrical short stature ( height - 8 . 2 SDS ) and facial features , and other congenital abnormalities . It displayed non - growth hormone deficiency . The baseline value of GH was 21 µg / L , and the peak was 57 . 9 µg / L . The value of DB01277 was less than 25 µg / L , and the P17936 less than 50 µg / L . And DB01277 generation test showed no response . There was no similar patients in the family members . Sequencing of P10912 in the patient revealed a homozygous point mutation ( c . Ivs6 + 1G > A ) , and her father and mother had the same heterozygous mutation . The same mutation was not identified for her sister . No other candidate gene was found . CONCLUSION : As the result of combined clinical characteristics and lab examinations , as well as gene detection , the case was diagnosed with Laron syndrome and P10912 gene mutation is the molecular mechanism . We should explicit the etiological diagnosis for short stature , and avoid missed diagnosis and misdiagnosis .\",\n \"Spectrum of insulin - like growth factor deficiency . There are eight known genetic causes of short stature characterized by low serum DB01277 ( DB01277 deficiency , IGFD ) and normal GH secretion . One of these ( Q92847 defect ) is a form of secondary IGFD , although the GH peak in provocation tests can be normal . Bioinactive GH ( P01241 mutations ) can disturb GH secretion , but also GH binding and signaling . The remaining conditions are classified as primary IGFD ( GH insensitivity ) . The clinical phenotype of P10912 ( P10912 ) defects is variable . Of the three GH signal transduction defects , a P51692 defect is well established , but abnormalities in the MAPK pathway ( such as Q06124 mutations in Noonan syndrome ) and NF - ĸB pathway ( IĸBα mutation ) may also cause IGFD . Homozygous P35858 defects are relatively common , and lead to moderate growth failure , very low serum DB01277 and even lower P17936 , while a heterozygous P35858 mutation decreases height by 1 SD . Most cases with a homozygous IGF1 defect are very short , microcephalic , and deaf , but heterozygous mutations may also lead to short stature . IGFD can also have a digenic or oligogenic origin . The diagnostic yield of genetic testing in children with a height < - 2 . 5 SDS and a serum DB01277 < - 2 appears sufficient to perform genetic tests for known candidate genes .\",\n \"A Single 60 mg Dose of ___MASK45___ Might Improve Hepatic P01308 Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women . Background . The O14788 / Q9Y6Q6 / O00300 signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis . The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation . Aim . To test whether systemic blockage of O14788 by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women . Study Design . This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test . Results . A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose , insulin , or HOMA - IR at both 4 and 12 weeks . No changes could be detected in glucose response to the glucose load , Matsuda Index , or insulinogenic index . Nonetheless , 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks . Conclusions . A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients .\",\n \"Global transcriptome analysis of formalin - fixed prostate cancer specimens identifies biomarkers of disease recurrence . Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease . In an effort to identify biomarkers of recurrence , we performed global RNA sequencing on 106 formalin - fixed , paraffin - embedded prostatectomy samples from 100 patients at three independent sites , defining a 24 - gene signature panel . The 24 genes in this panel function in cell - cycle progression , angiogenesis , hypoxia , apoptosis , PI3K signaling , steroid metabolism , translation , chromatin modification , and transcription . Sixteen genes have been associated with cancer , with five specifically associated with prostate cancer ( P78543 , P17936 , Q96EB6 , P50539 , and P14324 ) . Validation was performed on an independent publicly available dataset of 140 patients , where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence . Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors , including several genes involved in the epithelial - to - mesenchymal transition and developmental pathways . Overall , this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer .\",\n \"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .\",\n \"Humanins , the neuroprotective and cytoprotective peptides with antiapoptotic and anti - inflammatory properties . Q8IVG9 ( HN ) is a newly discovered 24 - amino acid peptide , which may suppress neuronal cell death . HN cDNA includes an open reading frame ( HN - ORF ) of 75 bases located 950 bases downstream of the 5 ' end of the HN cDNA . It has been demonstrated that HN cDNA is 99 % identical to the mitochondrial DNA ( mtDNA ) sequence . HN homologs have been identified as expressed sequence tags ( ESTs ) in both rats and nematodes . Certain regions that are homologous to the HN cDNA exist on human chromosomes . HN forms homodimers and multimers and this action seems to be essential for peptide function . HN acts as a ligand for formyl peptide receptor - like 1 ( P25090 ) and 2 ( P25089 ) . It has been demonstrated that HN plays a protective role through its antiapoptotic activity that interferes with Bax activation , which suppresses Bax - dependent apoptosis . HN has also been shown to suppress the c - Jun N - terminal kinase ( JNK ) and ASK / JNK - mediated neuronal cell death . Several studies have also confirmed that HN could be important in the prevention of angiopathy - associated Alzheimer ' s disease dementia , diseases related to mitochondrial dysfunction ( MELAS ) , and other types of β - amyloid accumulation - associated neurodegeneration . Avery recent study demonstrated a pluripotent cytoprotective effect and mechanisms of HNs in cells not from the CNS , such as germ cells or pancreatic β - cells , and the potent physiological consequences that result from HN interaction with P17936 and P40763 . In vivo studies suggest that HN may also protect against cognitive impairment due to ischemia / reperfusion injury .\",\n \"DB01277 pathway mutations and protein expression in resected non - small cell lung cancer . The purpose of this study was to characterize the prevalence of insulin - like growth factor 1 receptor ( P08069 ) mutations , single nucleotide polymorphisms ( SNP ) , and protein overexpression in surgically resected non - small cell lung cancers in relation to patient characteristics and prognosis . This retrospective study was conducted on 304 patients with non - small cell lung cancers who underwent curative pulmonary resection ( median follow - up for surviving patients , 3 . 6 years ) . P08069 gene alterations ( n = 304 ) and protein expression ( n = 181 ) were evaluated by polymerase chain reaction - based assays and immunohistochemistry , respectively . Membranous and cytoplasmic staining were analyzed separately . In an exploratory analysis , 1 silent mutation in exon 16 and 3 mutations in introns of the P08069 gene comprising the tyrosine kinase domain were detected . Moreover , evaluating selected P08069 SNPs , patients with adenocarcinomas and homozygous for the rs8038415 T - allele had a significantly better survival ( P = . 025 ) but no different disease - free survival . Regarding expression , membranous but not cytoplasmic P08069 staining was higher in squamous cell carcinomas versus other histologies ( P < . 0001 ) and showed a trend to longer survival ( P = . 08 ) . No association between SNP variations and protein expression was found . Membranous P08069 protein expression is higher in squamous cell versus other histologies but does not correlate with prognosis . SNPs and mutations can be detected and may harbor prognostic value . These alterations may be of interest when evaluating the P08069 as potential therapeutic target and should receive further research .\",\n \"Specific Biomarkers Are Associated with Docetaxeland Gemcitabine - Resistant NSCLC Cell Lines . Five - year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non - small cell lung cancer cell lines . Therefore , we checked - in the control condition as well as after short - term pharmacological treatment with either docetaxel or gemcitabine - the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness - related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug - related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness - related genes were downregulated in the control condition but became upregulated in docetaxel - resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance .\",\n \"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .\",\n \"Growth response of Egyptian children with idiopathic short stature during four years of growth hormone therapy . BACKGROUND : Multiple factors affect the growth response to recombinant human growth hormone ( rhGH ) in children with idiopathic short stature ( ISS ) . AIM : To evaluate the growth responses of children with ISS treated with rhGH , aiming to identify the predictors of growth response . MATERIALS AND METHODS : We studied 120 cases , 90 males ( 75 % ) , with a mean age of 13 . 8 ± 2 . 7 years and 30 females ( 25 % ) , with a mean age of 12 . 3 ± 2 . 5 years . All patients received rhGH with a standard dose of 20 IU / m ( 2 )/ week . The calculated dose per week was divided into six days and given subcutaneous at night . RESULTS : A significant positive trend was detected in the delta changes of all anthropometric data . For the first year , the growth response was positively correlated to CA and BA delay and negatively correlated to height , weight and DB01277 SDSs . For the second year , the growth response was correlated positively to first year growth velocity , BA , triceps skin fold thickness SDS and deviation from target height , and negatively correlated to weight , P17936 SDS and target height SDS . For the third year , the growth response was positively correlated to five variables namely target height , 2 ( nd ) year growth velocity , DB01277 SDS , weight SDS and triceps skin fold thickness SDS . For the fourth year , growth response was positively correlated to 2 ( nd ) and 3 ( rd ) year growth velocity , BA , deviation from target height and weight / height SDS . CONCLUSION : Our study showed multiplicity of predictors that is responsible for response in ISS children treated with rhGH , and BA was an important predictor .\",\n \"Disturbances in growth hormone secretion and action in adolescents with anorexia nervosa . Women in whom anorexia nervosa develops during adolescence have failure of linear growth associated with low levels of insulin - like growth factor I ( DB01277 ) . To investigate the pathophysiology of growth retardation in adolescents with anorexia nervosa , we measured basal growth hormone ( GH ) , growth hormone - binding protein ( P30043 ) , DB01277 , and insulin - like growth factor binding protein - 3 ( P17936 ) in three groups of patients : ( 1 ) 28 recently hospitalized female adolescents with anorexia nervosa , ( 2 ) 23 of the same patients after partial weight restoration , and ( 3 ) 28 healthy control subjects matched for age , sex , and pubertal stage . Fasting GH levels in group 1 did not differ significantly from those in group 3 . In contrast , serum P30043 ( p < 0 . 001 ) , DB01277 ( p < 0 . 001 ) , and P17936 ( p < 0 . 01 ) were significantly lower in group 1 than in group 3 . Serum P30043 and P17936 levels were positively correlated with body mass index . Serum P30043 levels were low in patients in all five pubertal stages and even in those shown to have adequate GH secretion . In group 2 ( after refeeding ) the serum DB01277 concentration increased significantly and P30043 and P17936 returned to normal . We conclude that patients with anorexia nervosa have diminished GH action resulting in decreased secretion of DB01277 . The positive correlation with body mass index and the reversibility with refeeding suggest that these changes are secondary to malnutrition . Altered GH function that occurs during the years of active growth can explain the growth retardation seen in anorexia nervosa .\",\n \"___MASK45___ for joints and bones . ___MASK45___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK45___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK45___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .\",\n \"Myocardial insulin - like growth factor - 1 and insulin - like growth factor binding protein - 3 gene expression in failing hearts harvested from patients undergoing cardiac transplantation . P01308 - like growth factor - 1 ( DB01277 ) and insulin - like growth factor binding proteins ( IGFBPs ) might play a pathogenic role in heart failure . We showed significantly increased myocardial P17936 expression ( investigated by real - time polymerase chain reaction ) and apoptosis ( detected by flow cytometry ) in 23 failing hearts from patients undergoing cardiac transplantation for end - stage dilated or ischemic cardiomyopathy , when compared with 10 controls . Higher DB01277 mRNA levels were shown only in end - stage dilated cardiomyopathy .\",\n \"DB01277 and DB01686 levels are inversely correlated in nondiabetic ankylosing spondylitis patients undergoing anti - P01375 therapy . Like rheumatoid arthritis , ankylosing spondylitis ( AS ) is also an inflammatory disease associated with accelerated atherosclerosis and the presence of metabolic syndrome ( MeS ) features . AS patients often display osteoporosis as well as new bone formation . DB01277 ( DB01277 ) is a protein involved in both inflammation and bone metabolism . In the present study we assessed whether disease activity , systemic inflammation , MeS features , adipokines , and biomarkers of endothelial activation were associated with DB01277 and insulin - like growth factor binding protein - 3 ( P17936 ) levels in a series of 30 nondiabetic AS patients without CV disease undergoing P01375 - α antagonist - infliximab therapy . All determinations were made in the fasting state , immediately before an infliximab infusion . Although no association of DB01277 and P17936 levels with angiopoietin - 2 or osteopontin was found , an inverse correlation between DB01277 levels and asymmetric dimethylarginine ( DB01686 ) , an endogenous endothelial nitric oxide synthase inhibitor that impairs nitric oxide production and secretion promoting endothelial dysfunction , was found ( r =- 0 . 397 ; P = 0 . 04 ) . However , no significant association was found between DB01277 and P17936 levels and disease activity , systemic inflammation , metabolic syndrome features , or adipokines . In conclusion , in nondiabetic patients with AS undergoing periodic anti - P01375 - α therapy , DB01277 and DB01686 are inversely correlated .\",\n \"Increased low density lipoprotein receptor expression mediated through the insulin - like growth factor - I receptor in cultured fibroblasts . Plasma insulin - like growth factor - I ( P05019 ) levels are inversely correlated with apolipoprotein B and low density lipoprotein ( LDL ) cholesterol in humans . To identify a molecular basis for this observation , the effects of P05019 on P01130 expression in fibroblasts were studied . P05019 increased LDL receptors in cultured human skin fibroblasts at concentrations greater than 25 ng / ml . However , P05019 effects were not easily quantitated due to secretion of inhibitory IGF - binding proteins by the cells . To circumvent this difficulty , QAYL , an P05019 analog that binds to the P08069 but not to IGF - binding proteins , was used . QAYL increased P01130 number 56 - 72 % with half - maximum effect at 0 . 6 ng / ml . alpha - IR3 , a monoclonal antibody directed toward the P08069 , blocked this effect . QAYL treatment increased synthesis of P01130 protein without increasing P01130 mRNA levels or altering protein stability . Both QAYL and P05019 increased LDL receptors prominently in cells that had been treated with physiological amounts of LDL cholesterol . P05019 , acting through the P08069 and modulated by IGF - binding proteins , may contribute to the regulation of LDL metabolism by increasing translation of P01130 message .\",\n \"Prostate carcinoma cells that have resided in bone have an upregulated P05019 axis . BACKGROUND : Prostate cancer ( PC ) has a propensity to metastasize to the skeleton , inducing an osteoblastic response in the host . Recent epidemiological studies have suggested that circulating P05019 may be important for both the pathogenesis and dissemination of PC . We have postulated that tumor secreted P05019 in conjunction with endogenous P05019 contributes to the osteoblastic phenotype characteristic of metastatic PC . METHODS : To test this thesis we studied the established LNCaP PC progression model consisting of three genetically related human PC cell lines . RESULTS : Using RIA , we found serum - free conditioned media ( CM ) of LNCaP and C4 - 2 had no measurable P05019 , whereas P05019 was easily detected in CM from C4 - 2B cells at 24 hr ( i . e . , 1 . 8 +/- 0 . 53 ng / mg cell protein ) . Real - time PCR of P05019 mRNA showed that C4 - 2B expressed 100 - fold more P05019 mRNA than LNCaP cells . In addition , C4 - 2B expression of P05019 mRNA was substantially increased in the presence of exogenous P05019 to nearly twofold . While P17936 and P08833 were not detectable in the CM of any PC line , all cells secreted P18065 . C4 - 2B cells produced 40 % more P18065 than LNCaP or C4 - 2 cells ( C4 - 2B at 167 +/- 43 ng / mg cell protein ) . O14788 , a product of bone stromal cells , was also differentially expressed : LNCaP had threefold higher O14788 mRNA compared to C4 - 2 and C4 - 2B and at least equivalent protein expression . CONCLUSIONS : Our results suggest that PC cells that have metastasized to bone have an upregulated P05019 regulatory system . This suggests an activated P05019 axis contributes to the host - PC interaction in promoting osteoblastic metastases .\",\n \"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK65___ and Tissue P00747 Activator in Occluded Arteries .\",\n \"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .\",\n \"Differential expression of IGF components and insulin receptor isoforms in human seminoma versus normal testicular tissue . P01308 - like growth factors ( IGF ) have mitogenic and antiapoptotic functions , and may be involved in tumor growth . The purpose of the study was to investigate the role of IGF components in seminoma compared to normal testis . Normal testicular tissues from autopsy cases and seminoma from surgery cases were obtained for microarray and real - time reverse transcription polymerase chain reaction ( RT - PCR ) analysis of DB01277 , IGF - 2 , IGF receptor type 1 ( IGF - Q96GN5 ) , IGF - R2 , insulin receptor isoforms A ( IR - A ) and B ( IR - B ) , and IGF - binding proteins ( IGFBP ) 1 - 6 . IGF - 2 was localized by immunohistochemistry . P24593 protein expression was evaluated by Western blot analysis . mRNA expression in microarray and real - time RT - PCR showed similar tendencies : DB01277 , IGF - Q96GN5 , IGF - R2 , IR - A , and P18065 were not different in both groups . IGF - 2 , IR - B , P08833 , P22692 , and P24592 mRNA were downregulated in seminoma . P17936 tended to be upregulated in pT1 seminoma , but downregulated in pT2 stages . P24593 and IGF - 2 protein expression correlated with mRNA expression . In conclusion , downregulation of mainly inhibiting IGFBPs may allow a stimulated tumor growth . The downregulated IGF - 2 does not seem to be involved in the growth regulation of seminoma . Constantly expressed genes ( e . g . , DB01277 , IGF - Q96GN5 , IR - A , and P18065 ) may reflect an involvement in spermatogenesis , but may also play a major role in tumor growth as their expression is not downregulated despite the lack of spermatogenesis in tumor tissue .\",\n \"Metabolic effect and receptor signalling profile of a non - metabolisable insulin glargine analogue . CONTEXT : P01308 glargine ( GLA ) is rapidly metabolized in vivo to metabolite M1 , which has in vitro metabolic and mitogenic profiles comparable with human insulin ( HI ) . OBJECTIVE : To investigate the pharmacologic and signalling profiles of a non - metabolizable analogue ( A21Gly , DiD - DB00125 ) insulin ( D - GLA ) . METHODS : Rats were injected s . c . with 1 , 12 . 5 or 200 U / kg of GLA or D - GLA ; blood glucose and phosphorylation status of the insulin receptor ( IR ) , Akt and DB01277 receptor ( P08069 ) in tissue samples were investigated after 1 h . Plasma samples were analysed for insulin by LC - MS / MS . RESULTS : Blood glucose lowering was prolonged with D - GLA . D - GLA comprised ≥ 98 % of insulin after D - GLA injection ; M1 comprised 76 - 92 % after GLA injection . IR and Akt phosphorylation were comparable with GLA and D - GLA . Neither analogue stimulated P08069 phosphorylation . CONCLUSIONS : Suprapharmacological doses of D - GLA did not activate P08069 in vivo . Mitogenic effects of insulin and insulin analogues might be solely based on IR growth - promoting activity .\",\n \"Growth hormone , insulin - like growth factor - 1 , and the insulin - like growth factor binding proteins in rats maintaining reduced body protein following lesions of the lateral hypothalamus . Rats with lesions of the lateral hypothalamus ( LH ) maintain a reduced body protein mass that they effectively defend when challenged by under - or over - nutrition . The two studies reported here evaluate the potential contributions of growth hormone ( GH ) , insulin - like growth factor - 1 ( DB01277 ) , and the insulin - like growth factor - binding ( IGFBP ) to this persistent maintenance of a reduced body protein mass by LH rats . At 18 weeks postlesion , it was found that the serum levels of GH , DB01277 , total IGFBP , and P17936 of LH rats maintaining reduced body protein were not different from those of age - matched controls . However , closer to the time of surgery , at which time the lesion - induced body protein adjustments are known to occur , altered hormone and binding protein levels were observed . Specifically , at 3 weeks after lesioning , the IGF - binding proteins of LH rats were significantly elevated , whereas their GH levels were lower than those of controls . Because the GH , DB01277 , and IGF - binding proteins of LH rats were comparable to those of controls at 18 weeks after lesioning , none apparently underlie the chronically reduced body protein mass that LH rats display . Closer to the time of lesioning , however , altered GH and IGF binding protein levels may contribute to the postlesion adjustments by which the body protein mass of LH rats is lowered to its reduced level .\",\n \"Hepatic osteodystrophy : does the osteoprotegerin / receptor activator of nuclear factor - kB ligand system play a role ? Multiple factors can contribute to the development of osteodystrophy in patients with chronic liver disease ( CLD ) . Recently , two new cytokines , osteoprotegerin ( O00300 ) and the receptor activator of nuclear factor - kB ligand ( O14788 ) , have been implicated in the pathogenesis of postmenopausal osteoporosis and other metabolic bone diseases . Therefore , the aim of our study was to evaluate bone metabolism , bone mineral density ( BMD ) and O00300 / O14788 system in 65 male patients with CLD and in 65 healthy controls . Our patients showed lower BMD values than controls both at lumbar and femoral levels . Moreover , they had an unbalanced bone turnover with an increased resorption phase , as shown by high levels of urinary deoxypyridinoline and a decreased formation phase , as shown by the slightly , but significant , low levels of bone - alkaline phosphatase . Patients showed lower plasma levels of free - testosterone than controls and higher - although not significantly so - plasma levels of 17 beta - estradiol . Furthermore , patients with CLD had higher levels of sex hormone - binding globulin and O00300 , and lower levels of 25 - hydroxyvitamin D ( 25 - Q9BPY8 ) and P05019 than the control group , while O14788 levels were similar in the two groups . In conclusion , our data do not confirm the hypothesis that the O00300 / O14788 system could exert a key role in the pathogenesis of hepatic osteodystrophy , but rather that the observed increase in O00300 levels may represent either the result of the inflammatory process per se or a compensation for the observed enhanced bone resorption .\",\n \"___MASK100___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK100___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK100___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK100___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK100___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .\",\n \"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK79___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .\",\n \"Apparent growth hormone deficiency in children with cerebral palsy . Ten children with cerebral palsy ( CP ) and growth failure underwent assessment of the growth hormone ( GH ) axis , including spontaneous GH secretion , GH secretion in response to pharmacological stimulation , and circulating levels of insulin - like growth factor - 1 ( DB01277 ) and IGF binding protein - 3 ( P17936 ) . Six of the children had subnormal GH secretion consistent with GH deficiency . Subnormal growth velocity was the best clinical predictor of GH deficiency . The large percentage of these children with apparent GH deficiency is surprising . Possible mechanisms include anatomic abnormalities of the hypothalamic - pituitary axis , psychosocial deprivation , and an interaction between suboptimal nutritional status and an abnormal central nervous system .\",\n \"Influence of genetic polymorphisms on the pharmacokinetics and pharmaco - dynamics of sulfonylurea drugs . Sulfonylurea drugs including chlorpropamide , gliclazide , tolbutamide , glipizide , glibenclamide ( glyburide ) and glimepiride are the most widely used oral hypoglycaemic agents in people with type 2 diabetes . This review investigates the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of sulfonylurea drugs . P11712 is the major enzyme involved in sulfonylurea drug metabolism . P11712 variant allele carriers have significant lower apparent clearance of these medicines . P33261 genotype is more influential for gliclazide pharmacokinetics when compared to P11712 . Sulfonylurea pharmacodynamics is affected by several genes . Q09428 ( Q09428 , Q09428 gene ) and K + inward rectifier Kir6 . 2 ( Q14654 ) have been correlated to significant variation in sulfonylurea response . Diabetics with the Q09428 exon 33 G allele are more sensitive to gliclazide and the rs5210 variant of the Q14654 gene was associated with improved clinical efficacy of gliclazide . Carriers of Q9NQB0 ( Q9NQB0 ) variants are more likely to fail sulfonylurea therapy . On the other hand , patients with HNF - 1alpha mutations had a significant greater response to gliclazide when compared to those with type 2 diabetes . The Arg972 polymorphism of insulin receptor substrate 1 ( P35568 ) may lead to secondary failure of sulfonylurea therapy . Calpain 10 gene ( Q9HC96 ) polymorphism has also been linked to sulfonylurea drug response . Despite the available evidence , larger population studies that investigate the pharmacokinetics and pharmacodynamics of sulfonylurea drugs are needed to investigate the influence of key SNPs amidst all potential contributing factors to variability in response to these which inturn will provide information to optimise sulfonylurea use in people with diabetes .\",\n \"[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK65___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .\",\n \"Associations of proinflammatory cytokine levels with lipid profiles , growth , and body composition in HIV - infected children initiating or changing antiretroviral therapy . OBJECTIVES : To measure proinflammatory cytokines ( PIC ) in HIV - infected children beginning or changing antiretroviral therapy ( O00253 ) , evaluating associations with virologic , immunologic , serum lipid , growth , and body composition measures , markers of growth hormone action and glucose metabolism . METHODS : Forty - nine prepubertal HIV - infected children had measurements of viral load ( VL ) , P01730 lymphocyte count and percentage , serum lipids , apolipoprotein AI / B , DB01277 , P08833 , and P17936 , anthropometry , bioelectrical impedance analysis , P01375 - α , IL - 1 β , and P05231 at baseline and 48 weeks of O00253 . RESULTS : Baseline levels were detectable ( > 0 . 1 pg / mL ) for IL - 1 β in 28 of 48 , and for P01375 - α and Il - 6 in all 49 children . P01375 - α decreased with O00253 ( P < 0 . 001 ) and P05231 demonstrated a similar trend ( P = 0 . 065 ) . Children with 48 - week VL < 400 copies / mL had greater declines in P01375 - α ( mean 45 % ) than subjects with higher VL ( 5 % ; P = 0 . 009 ) . Each 10 % improvement in P01730 % was associated with 26 % lower P01375 - α ( P = 0 . 002 ) and 31 % lower P05231 ( P = 0 . 016 ) . Greater reductions in P01375 - α were associated with lower total / HDL cholesterol ratio ( P = 0 . 003 ) at week 48 . CONCLUSIONS : In HIV - infected children initiating or changing O00253 , PIC were detectable at baseline and decreased over 48 weeks . Better immunologic responses were associated with greater reductions in P01375 - α and P05231 . Reductions in P01375 - α were associated with improved total / HDL cholesterol ratio .\",\n \"Phenotypic characterization of human chondrocyte cell line C - 20 / A4 : a comparison between monolayer and alginate suspension culture . DNA microarray analysis was used to investigate the molecular phenotype of one of the first human chondrocyte cell lines , C - 20 / A4 , derived from juvenile costal chondrocytes by immortalization with origin - defective simian virus 40 large T antigen . Clontech Human Cancer Arrays 1 . 2 and quantitative PCR were used to examine gene expression profiles of C - 20 / A4 cells cultured in the presence of serum in monolayer and alginate beads . In monolayer cultures , genes involved in cell proliferation were strongly upregulated compared to those expressed by human adult articular chondrocytes in primary culture . Of the cell cycle - regulated genes , only two , the CDK regulatory subunit and histone H4 , were downregulated after culture in alginate beads , consistent with the ability of these cells to proliferate in suspension culture . In contrast , the expression of several genes that are involved in pericellular matrix formation , including P50281 , P12109 , fibronectin , biglycan and decorin , was upregulated when the C - 20 / A4 cells were transferred to suspension culture in alginate . Also , nexin - 1 , vimentin , and P17936 , which are known to be expressed by primary chondrocytes , were differentially expressed in our study . Consistent with the proliferative phenotype of this cell line , few genes involved in matrix synthesis and turnover were highly expressed in the presence of serum . These results indicate that immortalized chondrocyte cell lines , rather than substituting for primary chondrocytes , may serve as models for extending findings on chondrocyte function not achievable by the use of primary chondrocytes .\",\n \"P01308 - like growth factors ( IGFs ) and IGF - binding proteins in nephrotic syndrome children on glucocorticoid . Growth failure is often seen in nephrotic children who fail to respond to glucocorticoid therapy or are glucocorticoid dependent . The underlying mechanism responsible for such growth defect remains poorly understood although long - term glucocorticoid use or nephrotic syndrome ( NS ) has been indicated to independently affect growth . Recent clinical evidence has suggested that changes in the serum levels of insulin - like growth factors ( IGFs ) and IGF - binding proteins ( IGFBPs ) among these children . The loss of insulin - like growth factor - I ( DB01277 ) and P17936 found in nephrotic children may directly prompt growth defect and retardation . In addition , glucocorticoid is believed to be associated with overt elevation of serum P05019 levels suggesting potential development of IGF resistance , one of the main factors responsible for persistent growth retardation . Growth hormone therapy has been shown to effectively reconcile this IGF resistance . The present review will discuss the complex relationship among IGF , IGFBPs , and glucocorticoid in children with NS .\",\n \"Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .\",\n \"Expression of a protease - resistant insulin - like growth factor - binding protein - 4 inhibits tumour growth in a murine model of breast cancer . BACKGROUND : DB01277 ( IGF1 ) promotes breast cancer and disease progression . Bioavailability of IGF1 is modulated by IGF - binding proteins ( IGFBPs ) . P22692 inhibits IGF1 activity but cleavage by pregnancy - associated plasma protein - A ( Q13219 ) protease releases active IGF1 . METHODS : Expression of IGF pathway components and Q13219 was assessed by western blot or RT - PCR . P22692 ( dBP4 ) resistant to Q13219 cleavage , but retaining IGF - binding capacity , was used to block IGF activity in vivo . 4T1 . 2 mouse mammary adenocarcinoma cells transfected with empty vector , vector expressing wild - type P22692 or vector expressing dBP4 were implanted in the mammary fat pad of BALB / c mice and tumour growth was assessed . Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry . RESULTS : 4T1 . 2 cells expressed the P08069 receptor and P22692 . Q13219 was expressed within mammary tumours but not by 4T1 . 2 cells . Proliferation and vascular endothelial growth factor ( P15692 ) production by 4T1 . 2 cells was increased by IGF1 ( E3R ) ( recombinant IGF1 resistant to binding by IGFBPs ) but not by wild - type IGF1 . IGF1 - stimulated microvascular endothelial cell proliferation was blocked by recombinant P22692 . 4T1 . 2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild - type P22692 . Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis . CONCLUSION : Protease - resistant P22692 blocks IGF activity , tumour growth and angiogenesis .\",\n \"Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 or Q09428 genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long - term follow - up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 , Q14654 , or Q09428 genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow - up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 and Q09428 genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .\",\n \"Gene expression of malignant rhabdoid tumor cell lines by reverse transcriptase - polymerase chain reaction . Malignant rhabdoid tumors ( MRT ) are characterized by unique neoplastic cells demonstrating phenotypic diversity . By using the reverse transcriptase - polymerase chain reaction , we have detected expression of various genes before and after differentiation induction with four different agents in four established MRT cell lines ( TM87 - 16 , STM91 - 01 , TTC642 , and TTC549 ) . The agents used in this study were all - trans retinoic acid ( RA ) , 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) , interleukin - 3 , or interferon - gamma . Before and after induction , c - myc , P01344 , P08069 , and P11717 were constitutively expressed by all four cell lines . The neurofilament medium - size ( P07197 ) was constitutively expressed by the TM87 - 16 and TTC642 , and the S100 protein alpha subunit was expressed by TM87 - 16 , TTC642 , and TTC549 . Chromogranin A was expressed by TM87 - 16 only after treatment with either TPA or RA . MyoD , N - myc , tyrosine hydroxylase , N - P62158 , trkA , and the S100 protein beta subunit were not expressed by any cell line before or after induction with these agents . All the MRT cell lines in this study except TM87 - 16 were highly resistant to differentiation induction . The proliferating cells in TM87 - 16 and TTC642 expressed mRNA profiles characteristic of neuroectoderm .\",\n \"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK63___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK63___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .\",\n \"Two new substrates in insulin signaling , Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 . We have identified two new human genes that encode proteins with tandem pleckstrin homology - phosphotyrosine binding ( PH - PTB ) domains at their amino termini . Because the other known PH - PTB proteins ( insulin receptor substrates : P35568 , Q9Y4H2 , P41252 - 3 , and O14654 , and the downstream of kinases : DOK - 1 , DOK - 2 , and DOK - 3 ) are substrates of insulin and insulin - like growth factor ( IGF ) - 1 receptors , we asked whether these new proteins , termed Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 , might also have roles in insulin and DB01277 signaling . Northern analyses indicate that Q8TEW6 / Q8TEW6 is ubiquitously expressed but most abundant in kidney and liver . Q9P104 / Q9P104 expression is highest in skeletal muscle . Both proteins are tyrosine - phosphorylated in response to insulin and DB01277 in transfected cells , although the kinetics differ . P06213 - phosphorylated Q8TEW6 / Q8TEW6 associates with P20936 , Crk , Src , and Fyn , but not phosphatidylinositol 3 - kinase p85 , Grb2 , Q06124 , Nck , or phospholipase Cgamma Src homology 2 domains , and activates MAPK in cells . Q9P104 / Q9P104 neither associates with these Src homology 2 domains nor activates MAPK . Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 represent two new signaling proteins with potential roles in insulin and DB01277 action .\",\n \"Hormone stability in human whole blood . OBJECTIVE : To determine whether significant changes in the plasma concentrations of 17 hormones occur when human whole blood is held at 4 or 24 degrees C for up to 24 h before separation of the plasma fraction . DESIGN AND METHODS : Blood samples ( DB00974 ) from healthy human volunteers were held at 4 degrees C or 24 degrees C for 0 . 5 , 6 or 24 h before separation . Plasma concentrations of DB01285 , aldosterone , gonadotrophin alpha - subunits , AVP , C - peptide , estradiol , DB00094 , GH , glucagon , DB01277 , P17936 , insulin , leptin , LH , prolactin , PTH and P01282 were measured and the results compared to baseline values . Nonlinear regression was used to test for a significant mean rate of change . The time interval for median concentrations to change by 10 % was determined . RESULTS : Significant changes were observed for DB01285 ( decrease at 18 . 6 hr , 4 degrees C ; 17 . 5 hr , 24 degrees C ) ; AVP ( increase at 2 . 6 h , 24 degrees C ) ; insulin ( decrease at 16 . 8 hr , 4 degrees C ; 16 . 9 hr , 24 degrees C ) and P01282 ( increase at 18 . 6 h , 24 degrees C ) . No changes were detected for the remaining analytes . B CONCLUSIONS : The measurement of some hormones is compromised by a delay in plasma separation from normal human blood . While many hormones appear stable in normal whole blood , we recommend that processing occurs without delay .\",\n \"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK58___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .\",\n \"Treatment of growth hormone - deficient adults with recombinant human growth hormone increases the concentration of growth hormone in the cerebrospinal fluid and affects neurotransmitters . In a double - blind , placebo - controlled trial , the effects of recombinant human growth hormone were studied on cerebrospinal fluid concentrations of growth hormone , insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor binding protein - 3 ( P17936 ) , monoamine metabolites , neuropeptides and endogenous opioid peptides . Twenty patients , 10 patients in each of 2 groups , with adult - onset , growth hormone deficiency were treated for 1 month with recombinant human growth hormone ( 0 . 25 U / kg / week ) or placebo . All the patients received the appropriate thyroid , adrenal and gonadal hormone replacement . In cerebrospinal fluid , the mean concentration of growth hormone increased from 13 . 3 +/- 4 . 4 to 149 . 3 +/- 22 . 2 muU / l ( p = 0 . 002 ) , during recombinant human growth hormone treatment . The cerebrospinal fluid P05019 concentration increased from 0 . 67 +/- 0 . 04 to 0 . 99 +/- 0 . 10 micrograms / l ( p = 0 . 005 ) and the P17936 concentration rose from 13 . 4 +/- 1 . 25 to 17 . 5 +/- 1 . 83 micrograms / l ( p = 0 . 002 ) . The dopamine metabolite homovanillic acid decreased from 282 . 1 +/- 36 . 0 to 234 . 3 +/- 26 . 5 nmol / l ( p = 0 . 02 ) and the vasoactive intestinal peptide decreased from 4 . 1 +/- 0 . 6 to 3 . 7 +/- 0 . 4 pmol / l ( p = 0 . 03 ) . Cerebrospinal fluid immunoreactive beta - endorphin increased from 24 . 4 +/- 1 . 8 to 29 . 9 +/- 2 . 1 pmol / l ( p = 0 . 002 ) . There were no significant changes compared to baseline in the cerebrospinal fluid concentrations of enkephalins , dynorphin A , the norepinephrine metabolite 3 - methoxy - 4 - hydroxyphenyl - ethyleneglycol , the serotonin metabolite 5 - hydroxyindoleacetic acid , gamma - aminobutyric acid , somatostatin or DB05394 . ( ABSTRACT TRUNCATED AT 250 WORDS )\",\n \"___MASK26___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .\",\n \"Short stature caused by a natural growth hormone antagonist . Severe short stature in a male child due to a single mutation in the GH - 1 gene was first reported in 1996 by Takahashi et al . [ N Engl J Med 1996 ; 334 : 432 - 436 ] . This missense mutation was predicted to convert codon 77 from arginine ( R ) to cysteine ( C ) . The child ' s chronological age was 4 years and 11 months , and his bone age 2 years and 6 months , i . e . , equal to only 51 % of his chronological age . Body proportions were normal except for the prominent forehead and saddle nose . Pituitary size was normal on magnetic resonance imaging examinations . Serum DB01277 , P17936 and P30043 were all decreased or at the lower limit of the normal range . Nocturnal urinary growth hormone ( GH ) excretion was high . Isoelectric focusing analysis revealed the presence of an abnormal GH peak in addition to the normal one . The R77C mutant GH possessed a 6 times greater affinity to P30043 than the wild - type GH , and inhibited tyrosine phosphorylation in IM - 9 cells 10 times more potently than the wild - type GH , showing an antagonistic or a dominant negative action . In agreement with the antagonistic property of the mutant GH exhibited , the child did not show any increase in serum DB01277 levels after exogenous hGH administration . It should be noted that the child in this study is not a typical case of Kowarski syndrome in which endogenous GH is found to be simply bioinactive , as in the patient we recently described elsewhere . Therefore , this patient ' s condition should be categorized as a new syndrome of short stature caused by a natural GH antagonist .\",\n \"Interleukin 10 blocks matrix metalloproteinase - 2 and membrane type 1 - matrix metalloproteinase synthesis in primary human prostate tumor lines . P01308 - like growth factor ( IGF ) I has been shown previously to up - regulate matrix metalloproteinase - 2 ( P08253 ) production , whereas the interleukin ( IL ) 10 / P22301 receptor axis has been found to down - regulate P08253 synthesis in tumor cells . In this paper , we showed that P22301 activation of the P22301 receptor blocked P08253 and membrane type 1 ( MT1 ) - MMP transcription and protein synthesis in nonimmortalized primary human prostate cell strains ( i . e . , P84074 - 10a and P84074 - 10c ) derived from high - grade cancer . Northern blots , Western blots , and ELISAs showed that P22301 suppressed P05019 induction of P08253 and P50281 mRNA synthesis in these cell strains ( P < 0 . 001 ) . Inhibition studies with P22301 and P08069 antibodies plus transfections experiments with P22301 sense , and P08069 antisense constructs confirmed these results . Finally , transient transfection experiments and chloramphenicol acetyltransferase assays with different regions of the 5 ' promoter region of the P08253 gene ( - 1659 to - 555 bp ) additionally showed that P05019 stimulated p53 - dependent plasmid catecholamine acetyltransferase activity and that P22301 blocked P05019 - induced plasmid catecholamine acetyltransferase activity . Electrophoretic mobility shift assays revealed that P22301 induced protein ( s ) binding to a putative \\\" silencer element \\\" ( - 1309 to - 555 fragment ) downstream of the p53 binding site ( - 1649 to - 1640 ) . The data show that P22301 blocks P05019 activation of P08253 and P50281 mRNA expression and protein synthesis in primary prostate cell strains .\",\n \"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .\",\n \"Development of an absolute quantification method targeting growth hormone biomarkers using liquid chromatography coupled to isotope dilution mass spectrometry . A method to perform absolute quantification of two biomarkers ( DB01277 and P17936 ) of growth hormone abuse has been developed . Isotope dilution is used with synthetically labelled peptides as internal standards . Peptide selection and multiple reaction monitoring design are discussed . A simple sample preparation based on the reduction and alkylation of cysteine residues followed by tryptic digestion provides a sufficient digestion of proteins . Serum samples fortified with increasing amounts of target proteins are analysed by liquid chromatography - tandem mass spectrometry ( LC - MS / MS ) on a triple quadrupole mass spectrometer . Specificity is ensured by the selection of sequences with no homology in BLAST , as well as retention time deviation check , and ion ratio monitoring . Linearity is studied in terms of calibration curves . These curves for P17936 and DB01277 are generated with mean slopes of 0 . 055 and 0 . 065 , intercepts of 0 . 107 and - 0 . 011 , and with coefficients of correlation of 0 . 95 and 0 . 98 , respectively . These curves result from the addition of proteins to the serum . Risks of variations related to potential matrix effects are therefore reduced , as well as probable variations related to the digestion steps . The working concentration ranges are 4 - 10 ng / microl for P17936 and 2 - 8 ng / microl for DB01277 . Preliminary data regarding repeatability show that relative standard deviations ( RSDs ) range between 13 and 32 % for P17936 and between 7 and 29 % for DB01277 .\",\n \"DB00133 phosphorylation of the insulin - like growth factor I ( DB01277 ) receptor C - terminal tail restrains kinase activity and cell growth . P08069 ( IGF - 1R ) signaling is essential for cell , organ , and animal growth . The C - terminal tail of the IGF - 1R exhibits regulatory function , but the mechanism is unknown . Here , we show that mutation of DB00133 - 1248 ( S1248A ) enhances IGF - 1R in vitro kinase activity , autophosphorylation , Akt / mammalian target of rapamycin activity , and cell growth . DB00133 - 1248 phosphorylation is mediated by GSK - 3β in a mechanism that involves a priming phosphorylation on DB00133 - 1252 . GSK - 3β knock - out cells exhibit reduced IGF - 1R cell surface expression , enhanced IGF - 1R kinase activity , and signaling . Examination of crystallographic structures of the IGF - 1R kinase domain revealed that the ( 1248 ) SFYYS ( 1252 ) motif adopts a conformation tightly packed against the kinase C - lobe when DB00133 - 1248 is in the unphosphorylated state that favors kinase activity . S1248A mutation is predicted to lock the motif in this position . In contrast , phosphorylation of DB00133 - 1248 will drive profound structural transition of the sequence , critically affecting connection of the C terminus as well as exposing potential protein docking sites . Decreased kinase activity of a phosphomimetic S1248E mutant and enhanced kinase activity in mutants of its predicted target residue Lys - 1081 support this auto - inhibitory model . Thus , the SFYYS motif controls the organization of the IGF - 1R C terminus relative to the kinase domain . Its phosphorylation by GSK - 3β restrains kinase activity and regulates receptor trafficking and signaling .\",\n \"Nonalcoholic fatty liver disease is associated with increased P30043 and reduced GH / P05019 levels . INTRODUCTION : Nonalcoholic fatty liver disease ( NAFLD ) has been described in adult GH deficiency syndrome . Furthermore , chronic liver disease can be associated with significant changes in levels of P05019 , GH - binding protein ( P30043 ) , IGF - binding proteins ( IGFBPs ) and acid - labile subunit ( P35858 ) . However , the effect of liver steatosis on the P30043 production has not been investigated yet . AIM OF THE STUDY : To explore whether GH secretion and / or levels of P05019 , P17936 , P35858 and P30043 could be altered in obese patients in relation to the presence of liver steatosis . MATERIALS AND METHODS : A total of 115 obese patients ( BMI > 30 ) were enrolled in the protocol ( 65 patients with liver steatosis and 50 age - and BMI - matched controls ) . In all patients , the following parameters were studied : serum levels of glucose , insulin , the HOMA index , P05019 , P30043 , P17936 , P35858 and GH after P01286 and arginine stimulation test . RESULTS : As expected , patients with NAFLD had blood glucose , insulin , HOMA - R significantly higher than controls , indicating a more severe insulin - resistance state in NAFLD . Furthermore , patients with NAFLD had higher levels of P30043 and P17936 and lower GH peak and P05019 levels as compared to controls . No difference was found in P35858 levels between the groups . In a multivariate analysis , P30043 was positively associated with hepatic steatosis while DB01277 was negatively associated with hepatic steatosis . CONCLUSIONS : This study demonstrates that in patients with NAFLD , the P30043 levels are increased , and that the GH / P05019 axis is significantly altered probably leading to reduced P05019 bioavailability at tissue level .\",\n \"Duodenal mucosal protection by bicarbonate secretion and its mechanisms . Proximal portion of duodenum is exposed to intermittent pulses of gastric H (+) discharged by the stomach . This review summarizes the mechanisms of duodenal mucosal integrity , mainly the role of mucus - alkaline secretion and the mucous barrier protecting surface epithelium against gastric H (+) . The mucous barrier protects the leaky duodenal epithelium against each pulse of gastric H (+) , which penetrates this barrier and diffuses into duodenocytes , but fails to damage them due to ; a ) an enhanced expression of cyclooxygenase - 1 ( P23219 ) , with release of protective prostaglandins ( PG ) and of nitric oxide ( NO ) synthase ( NOS ) with , however , production of NO , stimulating duodenal HCO ( 3 )(-) secretion and b ) the release of several neurotransmitters also stimulating HCO ( 3 )(-) secretion such as vasoactive intestinal peptide ( P01282 ) , pituitary adenylate - cyclase activating polypeptide ( PACAP ) , acetylcholine , melatonin , leptin and ghrelin released by enteric nerves and mucosal cells . At the apical duodenocyte membrane at least two HCO ( 3 )(-)/ Cl (-) anion exchangers operate in response to luminal H (+) to provide adequate extrusion of HCO ( 3 )(-) into duodenal lumen . In the basolateral portion of duodenocyte membrane , both non - electrogenic ( NBC ) and electrogenic ( NBC ( n ) ) Na (+) HCO ( 3 )(-) cotransporters are activated by the exposure to duodenal acidification , causing inward movement of HCO ( 3 )(-) from extracellular fluid to duodenocytes . There are also at least three Na (+)/ H (+) ( P19634 - 3 ) amiloride - sensitive exchangers , eliminating H (+) which diffused into these cells . The Helicobacter pylori ( Hp ) infection and gastric metaplasia in the duodenum with bacterium inoculating metaplastic mucosa and inhibiting HCO ( 3 )(-) secretion by its endogenous inhibitor , asymmetric dimethyl arginine ( DB01686 ) , may result in duodenal ulcerogenesis .\",\n \"Serum insulin - like growth factor - 1 ( DB01277 ) and insulin - like growth factor binding protein - 3 ( P17936 ) in healthy Thai children and adolescents : relation to age , sex , and stage of puberty . The authors studied the serum concentrations of insulin - like growth factor - 1 ( DB01277 ) and IGF - binding protein - 3 ( P17936 ) in 260 healthy children and adolescents ( 115 males , 145 females ) aged 5 - 20 years . The subjects were divided into 12 groups according to age and sex . The serum DB01277 and P17936 concentrations increased with age and peaked at age 13 - 15 years in males , and 11 - 13 years in females . After the peak concentration , DB01277 and P17936 levels declined significantly in males , but were still high in females . Comparing between sexes , the concentrations of DB01277 and P17936 were greater in females than males in all age groups . However , when subjects were divided according to the stage of puberty , the different concentrations between sexes were not significant , except for children within Tanner stage V where concentrations of DB01277 and P17936 were significantly greater in females than males . Multiple regression analysis demonstrated the age , sex , and stage of puberty - dependent of DB01277 concentration , and only the age and sex - dependent of P17936 concentration .\",\n \"P00747 activator system : implications for mammary cell growth and involution . Several tissue remodeling events that require extracellular proteolysis are thought to be mediated by plasminogen activators that convert the inactive proenzyme plasminogen to active plasmin . The involvement of plasminogen activator in many biological phenomena reflects the ubiquitous presence of plasminogen and the ability of numerous cell types to synthesize plasminogen activator in a highly regulated manner . Increased plasmin and plasminogen activator in bovine milk are correlated with gradual involution ( the declining phase of lactation ) . Treatment with bST prevented the increase in plasmin during gradual involution , indicating that bST interferes with conversion of plasminogen to plasmin . Concentrations of plasminogen activator in mammary tissue are high after cessation of milking . These results reinforce the association of the plasmin - plasminogen system with gradual involution postlactation . Recently , a role has been proposed for plasminogen activator in cell proliferation in several cellular systems . P01308 and P05019 increased synthesis of urokinase plasminogen activator and enhanced proliferation of cultured bovine mammary epithelial cells . In contrast , phorbol myristate acetate , which increased expression of urokinase plasminogen activator mRNA by mammary epithelial and myoepithelial cells , stimulated proliferation of myoepithelial cells , but not epithelial cells . Thus , expression of plasminogen activator is not simply related to mitogenesis but is likely to serve multiple functions in bovine mammary epithelial cells .\",\n \"Q9H244 receptor signalling towards P31749 proceeds through P08069 cross - talk and requires activation of Src , Pyk2 and Rap1 . Previously it was shown that stimulation of the Q9H244 receptor activates P31749 signalling in P13671 glioma cells [ K . Van Kolen and H . Slegers , J . Neurochem . 89 , 442 . ] . In the present study , the mechanisms involved in this response were further elucidated . In cells transfected with the Gbetagamma - scavenger beta - O14965 / P25098 or Rap1GAPII , stimulation with 2MeSADP failed to enhance P31749 phosphorylation demonstrating that the signalling proceeds through Gbetagamma - subunits and Rap1 . Moreover , Rap1 - GTP pull - down assays revealed that Q9H244 receptor stimulation induced a rapid activation of Rap1 . Treatment of cells with the Ca2 + chelator BAPTA - AM and inhibition of Src and O14939 with Q99463 or 1 - butanol , respectively , abrogated Q9H244 receptor - mediated activation of Rap1 and P31749 . In addition inhibition of PKCzeta decreased basal and 2MeSADP - stimulated phosphorylation of P31749 indicating a role for this PKC isoform in P31749 signalling . Although the increased P31749 phosphorylation was abolished in the presence of the P08069 tyrosine kinase inhibitor AG 1024 , 2MeSADP did not significantly increase receptor phosphorylation . Nevertheless , phosphorylation of a 120 kDa P08069 - associated protein was observed . The latter protein was identified by MALDI - TOF / TOF - MS as the proline - rich tyrosine kinase 2 ( Pyk2 ) that co - operates with Src in a O14939 - dependent manner . Consistent with the signalling towards Rap1 and P31749 , activation of Pyk2 was abrogated by Ca2 + chelation , inhibition of O14939 and P08069 tyrosine kinase activity . In conclusion , the data reveal a novel type of cross - talk between Q9H244 and P05019 receptors that proceeds through Gbetagamma - , Ca2 +- and O14939 - dependent activation of the Pyk2 / Src pathway resulting in GTP - loading of Rap1 required for an increased P31749 phosphorylation .\",\n \"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK94___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK94___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .\",\n \"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .\",\n \"P00749 and insulin - like growth factor - binding protein 3 mRNA expression in endometriotic lesions and eutopic endometrium : implications for the pathophysiology of endometriosis . The peritoneal fluid of women with endometriosis contains an increased insulin - like growth factor 1 ( DB01277 ) bioavailability , which is produced by limited hydrolysis of urokinase - type plasminogen activator ( uPA ) on P17936 ( P17936 ) . Recently , DB01277 was shown to inhibit apoptosis of endometrial - like cells in vitro , suggesting that a microenvironment of increased DB01277 bioavailability can optimize the survival of endometrial cells grown ectopically . Here the expression of mRNA of P17936 and uPA in tissue biopsies from eutopic endometrium and endometriotic lesions obtained at laparoscopy from women with endometriosis have been analyzed , and it is documented that both P17936 and uPA mRNA expression are increased from 3 - to 10 - fold in endometriotic lesions versus eutopic endometrium . Consequently , the necessary components ( uPA and P17936 expression ) of endocrine / autocrine / paracrine enhancement of local IGF bioavailability mediated by uPA hydrolysis of the P17936 were present in endometriotic lesions . These data possibly explain the origin of the increased content of uPA activity , DB01277 bioavailability , and NH ( 2 )- truncated forms of P17936 in the peritoneal fluid of women with endometriosis .\"\n]"},"candidates":{"kind":"list like","value":["___MASK100___","___MASK26___","___MASK45___","___MASK58___","___MASK63___","___MASK65___","___MASK72___","___MASK79___","___MASK94___"],"string":"[\n \"___MASK100___\",\n \"___MASK26___\",\n \"___MASK45___\",\n \"___MASK58___\",\n \"___MASK63___\",\n \"___MASK65___\",\n \"___MASK72___\",\n \"___MASK79___\",\n \"___MASK94___\"\n]"},"answer":{"kind":"string","value":"___MASK63___"},"id":{"kind":"string","value":"MH_train_495"}}},{"rowIdx":496,"cells":{"query":{"kind":"string","value":"interacts_with DB01229?"},"supports":{"kind":"list like","value":["A phase I - II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin - cyclophosphamide in locally advanced breast cancer . Histone deacetylases ( HDACs ) are a family of enzymes that regulate chromatin remodeling and gene transcription . ___MASK36___ is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing Q9UBN7 and Hsp90 client proteins . Fifty - five patients with clinical stage IIA - IIIC breast cancer received 12 weekly doses of paclitaxel ( 80 mg / m ( 2 ) ) plus vorinostat ( 200 - 300 mg PO P55957 ) on days 1 - 3 of each paclitaxel dose plus trastuzumab ( for Her2 / neu positive disease only ) , followed by doxorubicin / cyclophosphamide ( 60 / 600 mg / m ( 2 ) every 2 weeks plus pegfilgrastim ) . The primary study endpoint was pathologic complete response ( pCR ). pCR occurred in 13 of 24 evaluable patients with Her2 - positive disease ( 54 , 95 % confidence intervals [ CI ] 35 - 72 % ) , which met the prespecified study endpoint . pCR occurred in 4 of 15 patients with triple negative disease ( 27 , 95 % CI 11 - 52 % ) and none of 12 patients with ER - positive , Her2 / neu negative disease ( 0 , 95 % CI 0 - 24 % ) , which did not meet the prespecified endpoint . ER - positive tumors exhibited lower Ki67 and higher Hsp70 expression , and Q9UBN7 , Hsp70 , P38936 , and p27 expression were not predictive of response . ___MASK36___ increased acetylation of Hsp90 and alpha tubulin , and reduced expression of Hsp90 client proteins and Q9UBN7 in the primary tumor . Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin - cyclophosphamide is associated with a high pCR rate in locally advanced Her2 / neu positive breast cancer . Consistent with cell line and xenograft data , vorinostat increased acetylation of Hsp90 and alpha tubulin , and decreased Hsp90 client protein and Q9UBN7 expression in human breast cancers in vivo .","Recombinant human prothrombin kringle - 2 induces bovine capillary endothelial cell cycle arrest at G0 - P55008 phase through inhibition of cyclin D1 / P11802 complex : modulation of reactive oxygen species generation and up - regulation of cyclin - dependent kinase inhibitors . P00734 is a plasma glycoprotein involved in blood coagulation and , as we have previously reported , prothrombin kringles inhibit BCE ( bovine capillary endothelial ) cell proliferation . To reveal the mechanism , we investigated the influence of rk - 2 ( recombinant human prothrombin kringle - 2 ) on the BCE cell cycle progression and ROS ( reactive oxygen species ) generation using FACS ( fluorescence - activated cell sorter ) analysis . Cell cycle analysis showed a decrease of G ( 1 ) phase cells in cells treated with P09038 ( basic fibroblast growth factor ) and an increase in cells treated with rk - 2 , as compared with the control cells . But , the portion of the S phase was reversed . In Western blot analysis , P09038 induced cytoplasmic translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) and phosphorylation of p27 ( Kip1 ) but rk - 2 treatment inhibited translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) from nucleus to cytoplasm and phosphorylation of p27 ( Kip1 ) . Also , rk - 2 induced up - regulation of p53 and nuclear P38936 ( Waf1 / Cip1 ) and inhibited the cyclin D1 / P11802 ( cyclin - dependent kinase 4 ) complex . The ROS level of rk - 2 - treated BCE cells was increased 2 - fold when compared with the control , but treatment with Q9C000 ( N - Acetyl - L : - cysteine ) , an anti - oxidant , decreased ROS generation about 55 % as compared with the rk - 2 treatment . Q9C000 treatment also restored cell cycle progression inhibited by rk - 2 and down - regulated p53 and nuclear P38936 ( Waf1 / Cip1 ) expression induced by rk - 2 . These data suggest that rk - 2 induces the BCE cell cycle arrest at G ( 0 )- G ( 1 ) phase through inhibition of the cyclin D1 / P11802 complex caused by increase of ROS generation and nuclear cyclin - dependent kinase inhibitors .","Molecular response of HL - 60 cells to mitotic inhibitors vincristine and taxol visualized with apoptosis - related gene expressions , including the new member Q9HB09 . DB01229 and vincristine belong to a group of anticancer drugs that target microtubules , subsequently arresting cells at the mitotic phase of the cell cycle and inducing programmed cell death . The P10415 ( bcl - 2 ) family of genes is of known implication in apoptosis induced by various stimuli , among which Q9HB09 , a new member of the family , cloned by our group . For further insights into the mechanisms and molecular targets implicated and modified as a result of apoptosis induced by these two mitosis - arresting drugs , we studied the possible alterations , at the mRNA level , of various apoptosis - related genes ( P10415 , Q07812 , Q9HB09 , CASPASE - 3 , FAS ) after leukemia cell ( HL - 60 ) treatment with these drugs . The kinetics of cell toxicity were evaluated by the MTT [ 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide ] method , trypan blue staining , and cell proliferation efficiency ; apoptosis induction was assayed by endonucleosomal cleavage of DNA ( DNA laddering ) ; and the expression levels of the genes were analysed by RT - PCR , using gene - specific primers . The percentage of nonviable cells was upregulated with increasing cell exposure time and drug concentrations to both taxol and vincristine . Distinct modulations of apoptosis - related genes at the mRNA level were also observed , mainly concerning P10415 and Q9HB09 along apoptosis induction . Our results indicate and support the hypothesis that the apoptosis - related genes P10415 and Q9HB09 respond similarly to treatment of the human , acute , myelocytic leukemia HL60 cells with the anticancer drugs vincristine and taxol though in a drug - specific and time - dependent manner .","Production of paired helical filament , tau - like proteins by PC12 cells : a model of neurofibrillary degeneration . Neuron - like cells derived from a rat pheochromocytoma cell line ( PC12 ) and differentiated with nerve growth factor produce a paired helical filament ( PHF ) - like antigen when they are subjected to heat shock ( Wallace et al . : Mol Brain Res 19 : 149 - 155 , 1993 ) . It accumulates in a localized region of the perinuclear cytoplasm and reacts with monoclonal antitau antibodies , which identify epitopes in the N - and C - terminal halves and the microtubule - binding domain of tau protein . The observed profile of immunoreactivity suggests the presence of full - length and C - terminally truncated tau in a region of perinuclear cytoplasm in which no structurally intact PHFs could be demonstrated by conventional transmission electron microscopy . The accumulated tau protein colocalized with antibodies raised against mitochondrial outer membrane proteins and was associated with the presence of numerous mitochondrial profiles that were demonstrated with electron microscopy . Because differentiated PC12 cells pretreated with colcemid or DB01229 prior to heat shock fail to exhibit perinuclear PHF - like immunoreactivity , the reported response to heat shock appears to require an intact system of intracellular microtubules . This PC12 system provides a model in which the metabolic and molecular biological underpinnings of neuronal degeneration in Alzheimer ' s disease can be manipulated . The system may eventually be applicable to the development of pharmaceutical agents that interfere with formation and / or degeneration of P10636 in Alzheimer ' s disease .","Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK97___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .","Tyrosine kinase inhibition facilitates autophagic P37840 / α - synuclein clearance . The effects of P00519 / P00519 inhibition on clearance of P37840 / α - synuclein were evaluated in animal models of α - synucleinopathies . Parkinson disease ( PD ) is a movement disorder characterized by death of dopaminergic substantia nigra ( SN ) neurons and brain accumulation of P37840 . The tyrosine kinase P00519 is activated in several neurodegenerative diseases . An increase in P00519 activity is detected in human postmortem PD brains . Lentiviral expression of P37840 in the mouse SN activates P00519 via phosphorylation , while lentiviral Abl expression increases P37840 levels . Administration of the brain - penetrant tyrosine kinase inhibitor DB04868 decreases Abl activity and facilitates autophagic clearance of P37840 in transgenic and lentiviral gene transfer models . Subcellular fractionation demonstrates accumulation of P37840 and hyperphosphorylated P10636 / Tau ( p - P10636 ) in autophagic vacuoles in P37840 - expressing brains , while DB04868 treatment leads to protein deposition into the lysosomes , suggesting enhanced autophagic clearance . These data suggest that DB04868 may be a therapeutic strategy to degrade P37840 in PD and other α - synucleinopathies .","Induction of G2 / M arrest and inhibition of cyclooxygenase - 2 activity by curcumin in human bladder cancer T24 cells . Curcumin , a polyphenol compound derived from Curcuma longa Linn , has been recognized as a promising anti - cancer drug due to its multiple properties including anti - inflammatory , anti - oxidant and anti - carcinogenic activities . To elucidate the mechanisms by which curcumin inhibits human bladder carcinoma T24 cell proliferation , we tested the effects of curcumin on specific cell cycle pathways and on the expression of cyclooxygenases ( COXs ) . Curcumin inhibited the growth of T24 cells and induced G2 / M arrest in a concentration - dependent manner , effects associated with the down - regulation of cyclin A and up - regulation of cyclin - dependent kinase ( Cdk ) inhibitor P38936 ( P38936 / CIP1 ) . However , other G2 / M regulatory molecules , such as cyclin A , Cdc2 , Cdk2 , Wee1 and Cdc25C , were not modulated by curcumin treatment . Furthermore , curcumin decreased the levels of P35354 mRNA and protein expression without significant changes in the levels of P23219 , which correlated with a decrease in prostaglandin E2 ( DB00917 ) synthesis . These observations suggest that curcumin may have therapeutic potential for bladder cancer patients .","___MASK53___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK53___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .","Q03135 tyrosine phosphorylation enhances paclitaxel - mediated cytotoxicity . Q03135 ( Q03135 ) , a highly conserved membrane - associated protein , is a putative regulator of cellular transformation . Q03135 is localized in the plasmalemma , secretory vesicles , Golgi , mitochondria , and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton . Taxanes such as paclitaxel ( DB01229 ) are potent anti - tumor agents that repress the dynamic instability of microtubules and arrest cells in the G ( 2 )/ M phase . Src phosphorylation of DB00135 - 14 on Q03135 regulates its cellular localization and function . We report that phosphorylation of Q03135 on DB00135 - 14 regulates paclitaxel - mediated apoptosis in MCF - 7 breast cancer cells . Befitting its role as a multitasking molecule , we show that Q03135 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules P10415 , p53 , and P38936 . We demonstrate that phosphorylated Q03135 triggers apoptosis by inactivating P10415 and increasing mitochondrial permeability more efficiently than non - phosphorylated Q03135 . Furthermore , expression of P38936 , which correlates with taxane sensitivity , is regulated by Q03135 phosphorylation in a p53 - dependent manner . Collectively , our findings underscore the importance of Q03135 phosphorylation in apoptosis and suggest that events that negate Q03135 tyrosine phosphorylation may contribute to anti - microtubule drug resistance .","P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK25___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .","Neuroprotective gene expression profiles in ischemic cortical cultures preconditioned with DB01277 or P09038 . The mechanisms underlying growth factor preconditioning of neurons are only partially elucidated , and no studies have been conducted in this area using a gene profiling approach . We used cDNA microarrays to compare the transcriptional profiles of cells preconditioned either with insulin - like growth factor I ( DB01277 ) or basic fibroblast growth factor ( P09038 ) , to identify differentially regulated genes that may function in growth factor signaling , response to oxygen - glucose deprivation ( OGD ) , and most importantly , cell survival . Primary rat cortical cultures were treated with P09038 or DB01277 for 2 , 24 , or 24 h followed by OGD for 90 min , and compared with cells that were subject to OGD without growth factor pretreatment . Although the majority of surveyed genes were unchanged in all experimental treatments , 175 genes ( 10 % of the cDNAs on the chip ) were found to be differentially regulated in at least one of the treatment conditions . Hierarchical clustering of these 175 genes was used to identify four expression clusters : DB01277 regulated , P09038 regulated , OGD regulated , and putative neuroprotective genes . Further analysis using realtime RT - PCR confirmed that we had identified genes that are regulated by single growth factors , as well as several more that are co - regulated by both DB01277 and P09038 . These genes can influence neuronal survival by affecting diverse pathways such as growth factor signal transduction ( P16070 , Q99075 , Q16828 , Q12929 , P17936 ) , DNA repair and transcription ( Q92949 ) , metabolic homeostasis ( P20936 , P34897 ) , cytoskeletal stability ( P26038 , P10636 ) and cholesterol biosynthesis ( P37268 , P14324 ) .","[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK49___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .","Histone carbonylation occurs in proliferating cells . Chromatin is a dynamic structure formed mainly by DNA and histones , and chemical modifications on these elements regulate its compaction . Histone posttranslational modifications ( PTMs ) have a direct impact on chromatin conformation , controlling important cellular events such as cell proliferation and differentiation . Redox - related posttranslational modifications may have important effects on chromatin structure and function , offering a new intriguing area of research termed \" redox epigenetics . \" Little is known about histone carbonylation , a PTM that may be related to modifications in the cellular redox environment . The aim of our study was to determine the carbonylation of the various histones during cell proliferation , a moment in cell life during which important redox changes take place . Here , we describe changes in histone carbonylation during cell proliferation in NIH3T3 fibroblasts . In addition , we have studied the variations of poly ( ADP - ribosyl ) ation and phospho - P16104 at the same time , because both modifications are related to DNA damage responses . High levels of carbonylation on specific histones ( H1 , H1 ( 0 ) , and H3 . 1 dimers ) were found when cells were in an active phase of DNA synthesis . The modification decreased when nuclear proteasome activity was activated . However , these results did not correlate completely with poly ( ADP - ribosyl ) ation and phospho - P16104 levels . Therefore , histone carbonylation may represent a specific event during cell proliferation . We describe a new methodology named oxy - 2D - P10636 Western blot that allowed us to separate and analyze the carbonylation patterns of the histone variants . In addition we offer a new role for histone carbonylation and its implication in redox epigenetics . Our results suggest that histone carbonylation is involved in histone detoxification during DNA synthesis .","P23219 and - 2 expressions in sex - related organs of neonatally estrogen - treated rats and in activated and nonactivated macrophage RAW264 . 7 cells with phytoestrogen . Cyclooxygenase ( P36551 ) - 2 is an inducible isoform , expressed in inflamed leukocytes and cancer cells . It is known that estrogen causes prostate dysplasia , but little is known about P35354 expression and its influence on male reproductivity . In this study , we show that P35354 was abolished in the distal end of the vas deferens in neonatally estrogenized ( diethylstilbestrol , NeoDES ) Sprague - Dawley ( SD ) rats at age of 15 mo , but the control normal rats were found to remain constitutive expression at the same age , while the levels of P23219 in these rats remained intact . Furthermore , Q07812 , an indicator of sperm quality , was observed in the endothelium of vas deferens and sperm of the aged rats . However , P35354 was not detected in the inflamed lesions of NeoDES rat ' s prostate by immunohistochemistry . In addition to estrogen , hydroxymatairesinol ( P22736 ) , a phytoestrogen , was analyzed in vitro for possible regulation on P35354 . Through Western blot analysis , P22736 was shown to have no inhibitory affect on P35354 expression . These results indicated that estrogen treatment strongly influences the expression of P35354 that is associated with fertility , but no induction of P35354 by estrogen may not exclude P35354 ' s role in prostatitis , and the anti - tumor mechanism of P22736 largely remains elusive .","Prevention and treatment of pancreatic cancer by curcumin in combination with omega - 3 fatty acids . Pancreatic cancer BxPC - 3 cells were exposed to curcumin , docosahexaenoic acid ( DB01708 ) , or combinations of both and analyzed for proliferation and apoptosis . Pancreatic tumor xenografts were established by injecting BxPC - 3 cells into each flank of nude mice . After the tumors reached a size of approximately 190 - 200 mm ( 3 ) , animals were fed diets with or without 2 , 000 ppm curcumin in 18 % corn oil or 15 % fish oil + 3 % corn oil for 6 more wk before assessing the tumor volume and expression of inducible nitric oxide synthase ( P35228 ) , cyclooxygeanse - 2 ( P35354 ) , 5 - lipoxinase ( 5 - P28300 ) , and P38936 . A synergistic effect was observed on induction of apoptosis ( approximately sixfold ) and inhibition of cell proliferation ( approximately 70 % ) when cells were treated with curcumin ( 5 microM ) together with the DB01708 ( 25 microM ) . Mice fed fish oil and curcumin showed a significantly reduced tumor volume , 25 % ( P < 0 . 04 ) and 43 % ( P < 0 . 005 ) , respectively , and importantly , a combination of curcumin and fish oil diet showed > 72 % ( P < 0 . 0001 ) tumor volume reduction . Expression and activity of P35228 , P35354 , and 5 - P28300 are downregulated , and P38936 is upregulated in tumor xenograft fed curcumin combined with fish oil diet when compared to individual diets . The preceding results evidence for the first time that curcumin combined with omega - 3 fatty acids provide synergistic pancreatic tumor inhibitory properties .","Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK65___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .","Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK1___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .","P62942 , the 12 - kDa FK506 - binding protein , is a physiologic regulator of the cell cycle . P62942 , the 12 - kDa FK506 - binding protein , is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506 , binds tightly to intracellular calcium release channels and to the transforming growth factor beta ( TGF - beta ) type I receptor . We now demonstrate that cells from P62942 - deficient ( P62942 (-/-) ) mice manifest cell cycle arrest in G ( 1 ) phase and that these cells can be rescued by P62942 transfection . This arrest is mediated by marked augmentation of P38936 ( P38936 / CIP1 ) levels , which can not be further augmented by TGF - beta1 . The P38936 up - regulation and cell cycle arrest derive from the overactivity of TGF - beta receptor signaling , which is normally inhibited by P62942 . Cell cycle arrest is prevented by transfection with a dominant - negative TGF - beta receptor construct . TGF - beta receptor signaling to gene expression can be mediated by SMAD , p38 , and P29323 / Q96HU1 kinase ( extracellular signal - regulated kinase / mitogen - activated protein kinase ) pathways . SMAD signaling is down - regulated in P62942 (-/-) cells . Inhibition of P29323 / Q96HU1 kinase fails to affect P38936 up - regulation . By contrast , activated phosphorylated p38 is markedly augmented in P62942 (-/-) cells and the P38936 up - regulation is prevented by an inhibitor of p38 . Thus , P62942 is a physiologic regulator of cell cycle acting by normally down - regulating TGF - beta receptor signaling .","Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer ' s disease animal model . Harboring the behavioral and histopathological signatures of Alzheimer ' s disease ( AD ) , senescence accelerated mouse - prone 8 ( SAMP8 ) mice are currently considered a robust model for studying AD . However , the underlying mechanisms , prioritized pathways and genes in SAMP8 mice linked to AD remain unclear . In this study , we provide a biological interpretation of the molecular underpinnings of SAMP8 mice . Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age - matched SAMR1 mice at 2 , 6 , and 12 months of age using cDNA microarray analysis . On the basis of PPI , MetaCore and the co - expression network , we constructed a distinct genetic sub - network in the brains of SAMP8 mice . Next , we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice . We found abnormal gene expression of P04049 , P10636 , P35354 , CDKN2A , Q9UQM7 , Q16620 , Q15109 , P25098 , O60318 , and Q9UNE7 , which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice . Specifically , we found microRNAs , including miR - 20a , miR - 17 , miR - 34a , miR - 155 , miR - 18a , miR - 22 , miR - 26a , miR - 101 , miR - 106b , and miR - 125b , that might regulate the expression of nodes in the sub - network . Taken together , these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro - pathogenesis in SAMP8 mice from a systems perspective .","___MASK40___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK40___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK40___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK40___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK40___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK40___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .","Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .","___MASK97___ ( FK506 ) increases neuronal expression of P20936 - 43 and improves functional recovery after spinal cord injury in rats . ___MASK97___ ( FK506 ) , a widely used immunosuppressant drug , has neurite - promoting activity in cultured PC12 cells and peripheral neurons . The present study investigated whether tacrolimus affects the expression of the neuronal growth - associated protein , P20936 - 43 , as well as functional recovery after photothrombotic spinal cord injury in the rat . In injured animals receiving tacrolimus , the number of neurons expressing P20936 - 43 mRNA and protein approximately doubled compared to that in injured animals receiving vehicle alone . This increase in P20936 - 43 - positive cells was paralleled by a significant improvement in neurological function evaluated by open - field and inclined plane tests . Another P62942 ligand ( V - 10 , 367 ) had similar effects on P20936 - 43 expression and functional outcome , indicating that the observed effects of tacrolimus do not involve inhibition of the phosphatase calcineurin . Thus , tacrolimus , a drug which is already approved for use in humans , as well as other P62942 ligands which do not inhibit calcineurin , could potentially enhance functional outcome after CNS injury in humans .","Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .","Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc - dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan - HDAC inhibitor ___MASK36___ ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil - tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down - regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and ___MASK36___ . Tubacin in combination with ___MASK36___ or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan - caspase inhibitor Z - VAD - fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 , an early marker of DNA double - strand breaks . Tubacin enhances DNA damage induced by etoposide or ___MASK36___ as indicated by increased accumulation of γ P16104 and activation of the checkpoint kinase Chk2 . Tubacin induces the expression of P35638 ( P35638 / P35638 ) , a transcription factor up - regulated in response to cellular stress . P35638 induction is further increased when tubacin is combined with ___MASK36___ . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti - cancer agents in transformed cells .","Stress response genes are suppressed in mouse preimplantation embryos by granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) . BACKGROUND : P04141 ( GM - P04141 ) is known to promote the development and survival of human and mouse preimplantation embryos ; however , the mechanism of action of GM - P04141 in embryos is not defined . METHODS : Mouse blastocysts were cultured from zygote stage in vitro with and without recombinant mouse GM - P04141 ( rmGM - P04141 ) , and in vivo developed blastocysts were flushed from Csf2 null mutant and wild - type mice . The effect of GM - P04141 on blastocyst expression of stress response and apoptosis genes was evaluated by microarray , qPCR and immunochemistry . RESULTS : Microarray analysis of the gene transcription profile showed suppression of stress response and apoptosis gene pathways in blastocysts exposed to rmGM - P04141 in vitro . qPCR analysis confirmed that rmGM - P04141 inhibited expression of heat shock protein ( HSP ) and apoptosis pathway genes Cbl , Hspa5 , Hsp90aa1 , Hsp90ab1 and Gas5 in in vitro blastocysts . Immunocytochemical analysis of HSP 1 ( P0DMV8 / 1B ; HSP70 ) , Q07812 , P10415 and TRP53 ( p53 ) in in vitro blastocysts showed that P0DMV8 / 1B and P10415 proteins were less abundant when embryos were cultured with rmGM - P04141 . Q07812 and TRP53 were unchanged at the protein level , but Bax mRNA expression was reduced after GM - P04141 treatment . In in vivo developed blastocysts , Csf2 null mutation caused elevated expression of Hsph1 but not other stress response genes . CONCLUSIONS : We conclude that GM - P04141 inhibits the cellular stress response and apoptosis pathways to facilitate embryo growth and survival , and the protective effects of GM - P04141 are particularly evident in in vitro culture media , whereas in vivo other cytokines can partly compensate for absence of GM - P04141 .","Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 .","Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK36___ ( ___MASK36___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK36___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK36___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .","Biological differences between in vitro produced bovine embryos and parthenotes . Parthenotes may represent an alternate ethical source of stem cells , once biological differences between parthenotes and embryos can be understood . In this study , we analyzed development , trophectoderm ( TE ) differentiation , apoptosis / necrosis , and ploidy in parthenotes and in vitro produced bovine embryos . Subsequently , using real - time PCR , we analyzed the expression of genes expected to underlie the observed differences at the blastocyst stage . In vitro matured oocytes were either fertilized or activated with ionomycin + 6 - DMAP and cultured in simple medium . Parthenotes showed enhanced blastocyst development and diploidy and reduced TE cell counts . Apoptotic and necrotic indexes did not vary , but parthenotes evidenced a higher relative proportion of apoptotic cells between inner cell mass and TE . The pluripotence - related Q01860 and the methylation Q9Y6K1 genes were downregulated in parthenotes . Among pregnancy recognition genes , TP - 1 was upregulated in parthenotes , while O00264 and PLAC8 did not change . Expression of p66 ( shc ) and Q07812 / P10415 ratio were higher , and p53 lower , in parthenotes . Among metabolism genes , P11166 was downregulated , while P15121 , P35354 , O95479 , and P10599 were upregulated in parthenotes , and P22732 did not differ . Among genes involved in compaction / blastulation , P17302 was downregulated in parthenotes , but no differences were detected within P05023 and CDH1 . Within parthenotes , the expression levels of P11166 , TP - 1 , and O95479 , and possibly P15121 , resemble patterns described in female embryos . The pro - apoptotic profile is more pronounced in parthenotes than in embryos , which may differ in their way to channel apoptotic stimuli , through p66 ( shc ) and p53 respectively , and in their mechanisms to control pluripotency and de novo methylation .","Tau hyperphosphorylation and increased P56817 and RAGE levels in the cortex of PPARβ / δ - null mice . The role of peroxisome proliferator activator receptor ( Q07869 ) β / δ in the pathogenesis of Alzheimer ' s disease has only recently been explored through the use of PPARβ / δ agonists . Here we evaluated the effects of PPARβ / δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation . PPARβ / δ - null mice showed cognitive impairment in the object recognition task , accompanied by enhanced DNA - binding activity of NF - κB in the cortex and increased expression of P05231 . In addition , two NF - κB - target genes involved in β - amyloid ( Aβ ) synthesis and deposition , the β site P05067 cleaving enzyme 1 ( Bace1 ) and the receptor for advanced glycation endproducts ( Rage ) , respectively , increased in PPARβ / δ - null mice compared to wild type animals . The protein levels of glial fibrillary acidic protein ( P14136 ) increased in the cortex of PPARβ / δ - null mice , which would suggest the presence of astrogliosis . Finally , tau hyperphosphorylation at Ser199 and enhanced levels of P10636 were associated with increased levels of the tau kinases Q00535 and phospho - P27361 / 2 in the cortex of PPARβ / δ (-/-) mice . Collectively , our findings indicate that PPARβ / δ deficiency results in cognitive impairment associated with enhanced inflammation , astrogliosis and tau hyperphosphorylation in the cortex .","Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .","Linkage of cytokine genes to rheumatoid arthritis . Evidence of genetic heterogeneity . OBJECTIVE : To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis ( RA ) in affected sibling pair families stratified for specific clinical features . METHOD : Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from : P27352 alpha , P27352 gamma , P27352 beta , IL1 alpha , IL1 beta , P14778 , P60568 , P05231 , Q01344 , IL8R , P10415 , P29965 , NOS3 , P49279 , alpha 1 anti - trypsin , and alpha 1 anti - chymotrypsin , using fluorescence based automated technology . Linkage was examined by defining allele sharing sibling pairs . This was assessed by maximum likelihood - inheritance by descent methods . RESULTS : An increase in allele sharing was seen for Q01344 in female sibling pairs ( LOD 0 . 91 , p = 0 . 03 ) , for P27352 gamma in sibling pairs with an affected male ( LOD 0 . 96 , p = 0 . 03 ) and most significantly for P60568 in sibling pairs where one or both were persistently seronegative ( LOD 1 . 05 , p = 0 . 02 ) . CONCLUSION : Weak evidence of linkage of RA to Q01344 , IFN gamma , and P60568 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease .","P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .","c - P05412 promotes P11274 - P00519 - induced lymphoid leukemia by inhibiting methylation of the 5 ' region of Cdk6 . The transcription factor c - P05412 and its upstream kinase P45983 have been implicated in P11274 - P00519 - induced leukemogenesis . P45983 has been shown to regulate P10415 expression , thereby altering leukemogenesis , but the impact of c - P05412 remained unclear . In this study , we show that P45983 and c - P05412 promote leukemogenesis via separate pathways , because lack of c - P05412 impairs proliferation of p185 ( P11274 - P00519 )- transformed cells without affecting their viability . The decreased proliferation of c - Jun ( Δ / Δ ) cells is associated with the loss of cyclin - dependent kinase 6 ( Q00534 ) expression . In c - Jun ( Δ / Δ ) cells , Q00534 expression becomes down - regulated upon P11274 - P00519 - induced transformation , which correlates with CpG island methylation within the 5 ' region of Cdk6 . We verified the impact of Cdk6 deficiency using Cdk6 (-/-) mice that developed P11274 - P00519 - induced B - lymphoid leukemia with significantly increased latency and an attenuated disease phenotype . In addition , we show that reexpression of Q00534 in P11274 - P00519 - transformed c - Jun ( Δ / Δ ) cells reconstitutes proliferation and tumor formation in Nu / Nu mice . In summary , our study reveals a novel function for the activating protein 1 ( AP - 1 ) transcription factor c - P05412 in leukemogenesis by antagonizing promoter methylation . Moreover , we identify Q00534 as relevant and critical target of AP - 1 - regulated DNA methylation on P11274 - P00519 - induced transformation , thereby accelerating leukemogenesis .","Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK40___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .","An acidic pH environment increases cell death and pro - inflammatory cytokine release in osteoblasts : the involvement of Q07812 inhibitor - 1 . Q07812 Inhibitor - 1 ( P55061 ) , a transmembrane protein on the endoplasmic reticulum , has been studied previously in various physio / pathological conditions , but not in bone cells . In this study , using the MG63 osteoblast cell line and osteoblasts differentiated from stem cells , the role of P55061 was studied . First , expression of P55061 was confirmed in osteoblasts , as well as osteoclasts , in mouse tibiae bone immunohistochemistry . For evaluation of a recently published property of P55061 , an acidic pH - dependent Ca² ⁺ channel - like effect in osteoblasts , acidic pH - associated cell death , and pro - inflammatory cytokine release were examined . In MG63 osteoblasts , acidic pH induced a pH - dependent increase in cell death and ER stress , as determined by elevated expression of P11021 , P35638 , phospho - eIF2α , IRE - 1α , spliced P17861 , and phospho - JNK . In osteoblasts , mitochondrial Ca² ⁺ also showed a strong pH - dependent increase . P55061 knock - down using siRNA protected cells against acidic pH , regulating mitochondrial Ca² ⁺ accumulation , possibly via the acidic pH - dependent Ca² ⁺ channel - like effect of P55061 . P55061 knock - down also resulted in inhibition of acidic pH - induced release of pro - inflammatory cytokines , including IL - 1β , P05231 , and P01375 - α . In addition , bone marrow stem cells were differentiated into human osteoblasts , which showed increased expression of P55061 mRNA and protein . In differentiated primary human osteoblasts , acidic pH - associated cell death , mitochondrial Ca² ⁺ accumulation , and pro - inflammatory cytokine release were more significant than in non - differentiated stem cells . In summary , endogenous expression of P55061 is associated with acidic pH - induced Ca² ⁺ release , cell death , and pro - inflammatory cytokine release in human osteoblasts .","Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .","JTT - 705 blocks cell proliferation and angiogenesis through p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways . The excessive proliferation and migration of vascular smooth muscle cells ( SMCs ) participate in the growth and instability of atherosclerotic plaque . We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein , JTT - 705 , on SMC proliferation and angiogenesis in endothelial cells ( ECs ) . JTT - 705 inhibited human coronary artery SMC proliferation . JTT - 705 induced the phosphorylation of p38 mitogen - activated protein kinase ( MAPK ) and extracellular - signal - regulated kinases ( P29323 ) in SMCs . In addition , the anti - proliferative effects of JTT - 705 in SMCs were blocked by p38 MAPK inhibitor . JTT - 705 induced the upregulation of p - P38936 ( waf1 ) , and this effect was blocked by dominant - negative Ras ( N17 ) , but not by inhibitors of p38 MAPK or P29323 . In addition , JTT - 705 also induced the upregulation of p27 ( kip1 ) , and this effect was blocked by p38 MAPK inhibitor . Interestingly , culture medium from JTT - 705 - treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor ( P15692 ) from SMCs and directly via an anti - proliferative effect in ECs . JTT - 705 blocked the proliferation of SMCs through the activation of p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways , and simultaneously blocked EC tube formation associated with a decrease in P15692 production from SMCs and an anti - proliferative effect in ECs . Our results indicate that JTT - 705 may induce a direct anti - atherogenic effect in addition to its inhibitory effect of P11597 activity .","Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration . BACKGROUND : Mutations in the progranulin gene ( PGRN ) were identified as the causal mechanism underlying frontotemporal lobar degeneration ( FTLD ) . Most of these mutations are predicted to create null alleles leading to a 50 % loss of progranulin transcript . METHODS : Patients underwent clinical and neurologic examination at the Memory Clinic of the IRCCS S . Giovanni di Dio - Fatebenefratelli , Brescia , Italy . We enrolled affected ( n = 6 ) and unaffected at risk members ( n = 73 ) of families carrying the FTLD associated progranulin Leu271LeufsX10 mutation ; additionally , we included subjects affected by sporadic / familial FTLD ( n = 65 ) , controls ( n = 75 ) , and a family carrying the tau P301L mutation . The presence of mutations in PGRN and P10636 genes was investigated by direct sequencing of exonic and flanking intronic regions . Progranulin plasma and P04141 levels were measured using ELISA . RESULTS : We demonstrated that progranulin protein is strongly reduced ( up to 3 . 93 - fold ) both in plasma and P04141 of affected and unaffected subjects carrying mutations in progranulin gene ( PGRN Leu271LeufsX10 and Q341X ) . We established a plasma progranulin protein cutoff level of 74 . 4 ng / mL that identifies , with specificity and sensitivity of 100 % , mutation carriers among unaffected subjects . In FTLD , values < or = 110 . 9 ng / mL give a specificity of 92 . 8 % and a sensitivity of 100 % for PGRN mutations . CONCLUSIONS : We propose the dosage of plasma progranulin as a useful tool for a quick and inexpensive large - scale screening of carriers of progranulin mutations and for monitoring future treatments that might boost the level of this protein .","Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection . Accelerated coronary atherosclerosis in cardiac transplants ( cardiac allograft vasculopathy , Q03135 ) is characterized by coronary intimal hyperplasia . P05230 ( P05230 ) is a potent mitogen for vascular smooth muscle cells and endothelial cells , and its expression is increased in cardiac allografts , suggesting it may play a role in the pathogenesis of Q03135 . The activity of P05230 is dependent on binding to transmembrane receptors . To investigate whether receptors for P05230 are also induced after transplantation , polymerase chain reaction , in situ hybridization , and immunohistochemistry were used to analyze expression of four receptors for P05230 ( P11362 - P22455 ) . Expression of mRNA encoding extracellular immunoglobulin - like domains of P11362 was increased 35 - fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures . Alternatively spliced mRNA that encodes transmembrane forms of P11362 , which contain the signal - transducing tyrosine kinase domains , was induced in allografts during rejection , in infiltrating cells , vascular structures , and myocytes . In vitro experiments showed that differential expression of FGF receptor isoforms was induced by P05230 , and also by P05231 and TGF - beta , which are expressed in cardiac allografts during rejection . The results show that expression of both P05230 and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of Q03135 .","[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK38___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK38___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .","Assessment of Alzheimer ' s disease case - control associations using family - based methods . The genetics of Alzheimer ' s disease ( AD ) is heterogeneous and remains only ill - defined . We have recently created a freely available and continuously updated online database ( AlzGene ; http :// www . alzgene . org ) for which we collect all published genetic association studies in AD and perform systematic meta - analyses on all polymorphisms with sufficient genotype data . In this study , we tested 27 genes ( P12821 , P23560 , O95992 , P17787 , P01034 , P07339 , P53355 , Q9UBC7 , hCG2039140 , P01584 , P02545 , LOC439999 , LOC651924 , P10636 , P42898 , Q9UKX3 , P35558 , Q96JS3 , PRNP , P49768 , Q8WY21 , Q92673 , TF , Q00059 , Q13470 , GWA_14q32 . 13 , and GWA_7p15 . 2 ) , all showing significant association with AD risk in the AlzGene meta - analyses , in a large collection of family - based samples comprised of 4 , 180 subjects from over 1 , 300 pedigrees . Overall , we observe significant association with risk for AD and polymorphisms in P12821 , P17787 , TF , and an as yet uncharacterized locus on chromosome 7p15 . 2 [ rs1859849 ] . For all four loci , the association was observed with the same alleles as in the AlzGene meta - analyses . The convergence of case - control and family - based findings suggests that these loci currently represent the most promising AD gene candidates . Further fine - mapping and functional analyses are warranted to elucidate the potential biochemical mechanisms and epidemiological relevance of these genes .","Methylation of the nonhomologous end joining repair pathway genes does not explain the increase of translocations with aging . Chromosome translocations are especially frequent in human lymphomas and leukemias but are insufficient to drive carcinogenesis . Indeed , several of the so - called tumor specific translocations have been detected in peripheral blood of healthy individuals , finding a higher frequency of some of them with aging . The inappropriate repair of DNA double strand breaks by the nonhomologous end joining ( NHEJ ) pathway is one of the reasons for a translocation to occur . Moreover , fidelity of this pathway has been shown to decline with age . Although the mechanism underlying this inefficacy is unknown , other repair pathways are inactivated by methylation with aging . In this study , we analyzed the implication of NHEJ genes methylation in the increase of translocations with the age . To this aim , we determined the relationship between translocations and aging in 565 Spanish healthy individuals and correlated these data with the methylation status of 11 NHEJ genes . We found higher frequency of P10415 - JH and P11274 - P00519 ( major ) translocations with aging . In addition , we detected that two NHEJ genes ( P49917 and P12956 ) presented age - dependent promoter methylation changes . However , we did not observe a correlation between the increase of translocations and methylation , indicating that other molecular mechanisms are involved in the loss of NHEJ fidelity with aging .","Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK97___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation ."],"string":"[\n \"A phase I - II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin - cyclophosphamide in locally advanced breast cancer . Histone deacetylases ( HDACs ) are a family of enzymes that regulate chromatin remodeling and gene transcription . ___MASK36___ is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing Q9UBN7 and Hsp90 client proteins . Fifty - five patients with clinical stage IIA - IIIC breast cancer received 12 weekly doses of paclitaxel ( 80 mg / m ( 2 ) ) plus vorinostat ( 200 - 300 mg PO P55957 ) on days 1 - 3 of each paclitaxel dose plus trastuzumab ( for Her2 / neu positive disease only ) , followed by doxorubicin / cyclophosphamide ( 60 / 600 mg / m ( 2 ) every 2 weeks plus pegfilgrastim ) . The primary study endpoint was pathologic complete response ( pCR ). pCR occurred in 13 of 24 evaluable patients with Her2 - positive disease ( 54 , 95 % confidence intervals [ CI ] 35 - 72 % ) , which met the prespecified study endpoint . pCR occurred in 4 of 15 patients with triple negative disease ( 27 , 95 % CI 11 - 52 % ) and none of 12 patients with ER - positive , Her2 / neu negative disease ( 0 , 95 % CI 0 - 24 % ) , which did not meet the prespecified endpoint . ER - positive tumors exhibited lower Ki67 and higher Hsp70 expression , and Q9UBN7 , Hsp70 , P38936 , and p27 expression were not predictive of response . ___MASK36___ increased acetylation of Hsp90 and alpha tubulin , and reduced expression of Hsp90 client proteins and Q9UBN7 in the primary tumor . Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin - cyclophosphamide is associated with a high pCR rate in locally advanced Her2 / neu positive breast cancer . Consistent with cell line and xenograft data , vorinostat increased acetylation of Hsp90 and alpha tubulin , and decreased Hsp90 client protein and Q9UBN7 expression in human breast cancers in vivo .\",\n \"Recombinant human prothrombin kringle - 2 induces bovine capillary endothelial cell cycle arrest at G0 - P55008 phase through inhibition of cyclin D1 / P11802 complex : modulation of reactive oxygen species generation and up - regulation of cyclin - dependent kinase inhibitors . P00734 is a plasma glycoprotein involved in blood coagulation and , as we have previously reported , prothrombin kringles inhibit BCE ( bovine capillary endothelial ) cell proliferation . To reveal the mechanism , we investigated the influence of rk - 2 ( recombinant human prothrombin kringle - 2 ) on the BCE cell cycle progression and ROS ( reactive oxygen species ) generation using FACS ( fluorescence - activated cell sorter ) analysis . Cell cycle analysis showed a decrease of G ( 1 ) phase cells in cells treated with P09038 ( basic fibroblast growth factor ) and an increase in cells treated with rk - 2 , as compared with the control cells . But , the portion of the S phase was reversed . In Western blot analysis , P09038 induced cytoplasmic translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) and phosphorylation of p27 ( Kip1 ) but rk - 2 treatment inhibited translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) from nucleus to cytoplasm and phosphorylation of p27 ( Kip1 ) . Also , rk - 2 induced up - regulation of p53 and nuclear P38936 ( Waf1 / Cip1 ) and inhibited the cyclin D1 / P11802 ( cyclin - dependent kinase 4 ) complex . The ROS level of rk - 2 - treated BCE cells was increased 2 - fold when compared with the control , but treatment with Q9C000 ( N - Acetyl - L : - cysteine ) , an anti - oxidant , decreased ROS generation about 55 % as compared with the rk - 2 treatment . Q9C000 treatment also restored cell cycle progression inhibited by rk - 2 and down - regulated p53 and nuclear P38936 ( Waf1 / Cip1 ) expression induced by rk - 2 . These data suggest that rk - 2 induces the BCE cell cycle arrest at G ( 0 )- G ( 1 ) phase through inhibition of the cyclin D1 / P11802 complex caused by increase of ROS generation and nuclear cyclin - dependent kinase inhibitors .\",\n \"Molecular response of HL - 60 cells to mitotic inhibitors vincristine and taxol visualized with apoptosis - related gene expressions , including the new member Q9HB09 . DB01229 and vincristine belong to a group of anticancer drugs that target microtubules , subsequently arresting cells at the mitotic phase of the cell cycle and inducing programmed cell death . The P10415 ( bcl - 2 ) family of genes is of known implication in apoptosis induced by various stimuli , among which Q9HB09 , a new member of the family , cloned by our group . For further insights into the mechanisms and molecular targets implicated and modified as a result of apoptosis induced by these two mitosis - arresting drugs , we studied the possible alterations , at the mRNA level , of various apoptosis - related genes ( P10415 , Q07812 , Q9HB09 , CASPASE - 3 , FAS ) after leukemia cell ( HL - 60 ) treatment with these drugs . The kinetics of cell toxicity were evaluated by the MTT [ 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide ] method , trypan blue staining , and cell proliferation efficiency ; apoptosis induction was assayed by endonucleosomal cleavage of DNA ( DNA laddering ) ; and the expression levels of the genes were analysed by RT - PCR , using gene - specific primers . The percentage of nonviable cells was upregulated with increasing cell exposure time and drug concentrations to both taxol and vincristine . Distinct modulations of apoptosis - related genes at the mRNA level were also observed , mainly concerning P10415 and Q9HB09 along apoptosis induction . Our results indicate and support the hypothesis that the apoptosis - related genes P10415 and Q9HB09 respond similarly to treatment of the human , acute , myelocytic leukemia HL60 cells with the anticancer drugs vincristine and taxol though in a drug - specific and time - dependent manner .\",\n \"Production of paired helical filament , tau - like proteins by PC12 cells : a model of neurofibrillary degeneration . Neuron - like cells derived from a rat pheochromocytoma cell line ( PC12 ) and differentiated with nerve growth factor produce a paired helical filament ( PHF ) - like antigen when they are subjected to heat shock ( Wallace et al . : Mol Brain Res 19 : 149 - 155 , 1993 ) . It accumulates in a localized region of the perinuclear cytoplasm and reacts with monoclonal antitau antibodies , which identify epitopes in the N - and C - terminal halves and the microtubule - binding domain of tau protein . The observed profile of immunoreactivity suggests the presence of full - length and C - terminally truncated tau in a region of perinuclear cytoplasm in which no structurally intact PHFs could be demonstrated by conventional transmission electron microscopy . The accumulated tau protein colocalized with antibodies raised against mitochondrial outer membrane proteins and was associated with the presence of numerous mitochondrial profiles that were demonstrated with electron microscopy . Because differentiated PC12 cells pretreated with colcemid or DB01229 prior to heat shock fail to exhibit perinuclear PHF - like immunoreactivity , the reported response to heat shock appears to require an intact system of intracellular microtubules . This PC12 system provides a model in which the metabolic and molecular biological underpinnings of neuronal degeneration in Alzheimer ' s disease can be manipulated . The system may eventually be applicable to the development of pharmaceutical agents that interfere with formation and / or degeneration of P10636 in Alzheimer ' s disease .\",\n \"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK97___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .\",\n \"Tyrosine kinase inhibition facilitates autophagic P37840 / α - synuclein clearance . The effects of P00519 / P00519 inhibition on clearance of P37840 / α - synuclein were evaluated in animal models of α - synucleinopathies . Parkinson disease ( PD ) is a movement disorder characterized by death of dopaminergic substantia nigra ( SN ) neurons and brain accumulation of P37840 . The tyrosine kinase P00519 is activated in several neurodegenerative diseases . An increase in P00519 activity is detected in human postmortem PD brains . Lentiviral expression of P37840 in the mouse SN activates P00519 via phosphorylation , while lentiviral Abl expression increases P37840 levels . Administration of the brain - penetrant tyrosine kinase inhibitor DB04868 decreases Abl activity and facilitates autophagic clearance of P37840 in transgenic and lentiviral gene transfer models . Subcellular fractionation demonstrates accumulation of P37840 and hyperphosphorylated P10636 / Tau ( p - P10636 ) in autophagic vacuoles in P37840 - expressing brains , while DB04868 treatment leads to protein deposition into the lysosomes , suggesting enhanced autophagic clearance . These data suggest that DB04868 may be a therapeutic strategy to degrade P37840 in PD and other α - synucleinopathies .\",\n \"Induction of G2 / M arrest and inhibition of cyclooxygenase - 2 activity by curcumin in human bladder cancer T24 cells . Curcumin , a polyphenol compound derived from Curcuma longa Linn , has been recognized as a promising anti - cancer drug due to its multiple properties including anti - inflammatory , anti - oxidant and anti - carcinogenic activities . To elucidate the mechanisms by which curcumin inhibits human bladder carcinoma T24 cell proliferation , we tested the effects of curcumin on specific cell cycle pathways and on the expression of cyclooxygenases ( COXs ) . Curcumin inhibited the growth of T24 cells and induced G2 / M arrest in a concentration - dependent manner , effects associated with the down - regulation of cyclin A and up - regulation of cyclin - dependent kinase ( Cdk ) inhibitor P38936 ( P38936 / CIP1 ) . However , other G2 / M regulatory molecules , such as cyclin A , Cdc2 , Cdk2 , Wee1 and Cdc25C , were not modulated by curcumin treatment . Furthermore , curcumin decreased the levels of P35354 mRNA and protein expression without significant changes in the levels of P23219 , which correlated with a decrease in prostaglandin E2 ( DB00917 ) synthesis . These observations suggest that curcumin may have therapeutic potential for bladder cancer patients .\",\n \"___MASK53___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK53___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .\",\n \"Q03135 tyrosine phosphorylation enhances paclitaxel - mediated cytotoxicity . Q03135 ( Q03135 ) , a highly conserved membrane - associated protein , is a putative regulator of cellular transformation . Q03135 is localized in the plasmalemma , secretory vesicles , Golgi , mitochondria , and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton . Taxanes such as paclitaxel ( DB01229 ) are potent anti - tumor agents that repress the dynamic instability of microtubules and arrest cells in the G ( 2 )/ M phase . Src phosphorylation of DB00135 - 14 on Q03135 regulates its cellular localization and function . We report that phosphorylation of Q03135 on DB00135 - 14 regulates paclitaxel - mediated apoptosis in MCF - 7 breast cancer cells . Befitting its role as a multitasking molecule , we show that Q03135 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules P10415 , p53 , and P38936 . We demonstrate that phosphorylated Q03135 triggers apoptosis by inactivating P10415 and increasing mitochondrial permeability more efficiently than non - phosphorylated Q03135 . Furthermore , expression of P38936 , which correlates with taxane sensitivity , is regulated by Q03135 phosphorylation in a p53 - dependent manner . Collectively , our findings underscore the importance of Q03135 phosphorylation in apoptosis and suggest that events that negate Q03135 tyrosine phosphorylation may contribute to anti - microtubule drug resistance .\",\n \"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK25___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .\",\n \"Neuroprotective gene expression profiles in ischemic cortical cultures preconditioned with DB01277 or P09038 . The mechanisms underlying growth factor preconditioning of neurons are only partially elucidated , and no studies have been conducted in this area using a gene profiling approach . We used cDNA microarrays to compare the transcriptional profiles of cells preconditioned either with insulin - like growth factor I ( DB01277 ) or basic fibroblast growth factor ( P09038 ) , to identify differentially regulated genes that may function in growth factor signaling , response to oxygen - glucose deprivation ( OGD ) , and most importantly , cell survival . Primary rat cortical cultures were treated with P09038 or DB01277 for 2 , 24 , or 24 h followed by OGD for 90 min , and compared with cells that were subject to OGD without growth factor pretreatment . Although the majority of surveyed genes were unchanged in all experimental treatments , 175 genes ( 10 % of the cDNAs on the chip ) were found to be differentially regulated in at least one of the treatment conditions . Hierarchical clustering of these 175 genes was used to identify four expression clusters : DB01277 regulated , P09038 regulated , OGD regulated , and putative neuroprotective genes . Further analysis using realtime RT - PCR confirmed that we had identified genes that are regulated by single growth factors , as well as several more that are co - regulated by both DB01277 and P09038 . These genes can influence neuronal survival by affecting diverse pathways such as growth factor signal transduction ( P16070 , Q99075 , Q16828 , Q12929 , P17936 ) , DNA repair and transcription ( Q92949 ) , metabolic homeostasis ( P20936 , P34897 ) , cytoskeletal stability ( P26038 , P10636 ) and cholesterol biosynthesis ( P37268 , P14324 ) .\",\n \"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK49___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .\",\n \"Histone carbonylation occurs in proliferating cells . Chromatin is a dynamic structure formed mainly by DNA and histones , and chemical modifications on these elements regulate its compaction . Histone posttranslational modifications ( PTMs ) have a direct impact on chromatin conformation , controlling important cellular events such as cell proliferation and differentiation . Redox - related posttranslational modifications may have important effects on chromatin structure and function , offering a new intriguing area of research termed \\\" redox epigenetics . \\\" Little is known about histone carbonylation , a PTM that may be related to modifications in the cellular redox environment . The aim of our study was to determine the carbonylation of the various histones during cell proliferation , a moment in cell life during which important redox changes take place . Here , we describe changes in histone carbonylation during cell proliferation in NIH3T3 fibroblasts . In addition , we have studied the variations of poly ( ADP - ribosyl ) ation and phospho - P16104 at the same time , because both modifications are related to DNA damage responses . High levels of carbonylation on specific histones ( H1 , H1 ( 0 ) , and H3 . 1 dimers ) were found when cells were in an active phase of DNA synthesis . The modification decreased when nuclear proteasome activity was activated . However , these results did not correlate completely with poly ( ADP - ribosyl ) ation and phospho - P16104 levels . Therefore , histone carbonylation may represent a specific event during cell proliferation . We describe a new methodology named oxy - 2D - P10636 Western blot that allowed us to separate and analyze the carbonylation patterns of the histone variants . In addition we offer a new role for histone carbonylation and its implication in redox epigenetics . Our results suggest that histone carbonylation is involved in histone detoxification during DNA synthesis .\",\n \"P23219 and - 2 expressions in sex - related organs of neonatally estrogen - treated rats and in activated and nonactivated macrophage RAW264 . 7 cells with phytoestrogen . Cyclooxygenase ( P36551 ) - 2 is an inducible isoform , expressed in inflamed leukocytes and cancer cells . It is known that estrogen causes prostate dysplasia , but little is known about P35354 expression and its influence on male reproductivity . In this study , we show that P35354 was abolished in the distal end of the vas deferens in neonatally estrogenized ( diethylstilbestrol , NeoDES ) Sprague - Dawley ( SD ) rats at age of 15 mo , but the control normal rats were found to remain constitutive expression at the same age , while the levels of P23219 in these rats remained intact . Furthermore , Q07812 , an indicator of sperm quality , was observed in the endothelium of vas deferens and sperm of the aged rats . However , P35354 was not detected in the inflamed lesions of NeoDES rat ' s prostate by immunohistochemistry . In addition to estrogen , hydroxymatairesinol ( P22736 ) , a phytoestrogen , was analyzed in vitro for possible regulation on P35354 . Through Western blot analysis , P22736 was shown to have no inhibitory affect on P35354 expression . These results indicated that estrogen treatment strongly influences the expression of P35354 that is associated with fertility , but no induction of P35354 by estrogen may not exclude P35354 ' s role in prostatitis , and the anti - tumor mechanism of P22736 largely remains elusive .\",\n \"Prevention and treatment of pancreatic cancer by curcumin in combination with omega - 3 fatty acids . Pancreatic cancer BxPC - 3 cells were exposed to curcumin , docosahexaenoic acid ( DB01708 ) , or combinations of both and analyzed for proliferation and apoptosis . Pancreatic tumor xenografts were established by injecting BxPC - 3 cells into each flank of nude mice . After the tumors reached a size of approximately 190 - 200 mm ( 3 ) , animals were fed diets with or without 2 , 000 ppm curcumin in 18 % corn oil or 15 % fish oil + 3 % corn oil for 6 more wk before assessing the tumor volume and expression of inducible nitric oxide synthase ( P35228 ) , cyclooxygeanse - 2 ( P35354 ) , 5 - lipoxinase ( 5 - P28300 ) , and P38936 . A synergistic effect was observed on induction of apoptosis ( approximately sixfold ) and inhibition of cell proliferation ( approximately 70 % ) when cells were treated with curcumin ( 5 microM ) together with the DB01708 ( 25 microM ) . Mice fed fish oil and curcumin showed a significantly reduced tumor volume , 25 % ( P < 0 . 04 ) and 43 % ( P < 0 . 005 ) , respectively , and importantly , a combination of curcumin and fish oil diet showed > 72 % ( P < 0 . 0001 ) tumor volume reduction . Expression and activity of P35228 , P35354 , and 5 - P28300 are downregulated , and P38936 is upregulated in tumor xenograft fed curcumin combined with fish oil diet when compared to individual diets . The preceding results evidence for the first time that curcumin combined with omega - 3 fatty acids provide synergistic pancreatic tumor inhibitory properties .\",\n \"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK65___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .\",\n \"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK1___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .\",\n \"P62942 , the 12 - kDa FK506 - binding protein , is a physiologic regulator of the cell cycle . P62942 , the 12 - kDa FK506 - binding protein , is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506 , binds tightly to intracellular calcium release channels and to the transforming growth factor beta ( TGF - beta ) type I receptor . We now demonstrate that cells from P62942 - deficient ( P62942 (-/-) ) mice manifest cell cycle arrest in G ( 1 ) phase and that these cells can be rescued by P62942 transfection . This arrest is mediated by marked augmentation of P38936 ( P38936 / CIP1 ) levels , which can not be further augmented by TGF - beta1 . The P38936 up - regulation and cell cycle arrest derive from the overactivity of TGF - beta receptor signaling , which is normally inhibited by P62942 . Cell cycle arrest is prevented by transfection with a dominant - negative TGF - beta receptor construct . TGF - beta receptor signaling to gene expression can be mediated by SMAD , p38 , and P29323 / Q96HU1 kinase ( extracellular signal - regulated kinase / mitogen - activated protein kinase ) pathways . SMAD signaling is down - regulated in P62942 (-/-) cells . Inhibition of P29323 / Q96HU1 kinase fails to affect P38936 up - regulation . By contrast , activated phosphorylated p38 is markedly augmented in P62942 (-/-) cells and the P38936 up - regulation is prevented by an inhibitor of p38 . Thus , P62942 is a physiologic regulator of cell cycle acting by normally down - regulating TGF - beta receptor signaling .\",\n \"Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer ' s disease animal model . Harboring the behavioral and histopathological signatures of Alzheimer ' s disease ( AD ) , senescence accelerated mouse - prone 8 ( SAMP8 ) mice are currently considered a robust model for studying AD . However , the underlying mechanisms , prioritized pathways and genes in SAMP8 mice linked to AD remain unclear . In this study , we provide a biological interpretation of the molecular underpinnings of SAMP8 mice . Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age - matched SAMR1 mice at 2 , 6 , and 12 months of age using cDNA microarray analysis . On the basis of PPI , MetaCore and the co - expression network , we constructed a distinct genetic sub - network in the brains of SAMP8 mice . Next , we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice . We found abnormal gene expression of P04049 , P10636 , P35354 , CDKN2A , Q9UQM7 , Q16620 , Q15109 , P25098 , O60318 , and Q9UNE7 , which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice . Specifically , we found microRNAs , including miR - 20a , miR - 17 , miR - 34a , miR - 155 , miR - 18a , miR - 22 , miR - 26a , miR - 101 , miR - 106b , and miR - 125b , that might regulate the expression of nodes in the sub - network . Taken together , these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro - pathogenesis in SAMP8 mice from a systems perspective .\",\n \"___MASK40___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK40___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK40___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK40___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK40___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK40___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .\",\n \"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .\",\n \"___MASK97___ ( FK506 ) increases neuronal expression of P20936 - 43 and improves functional recovery after spinal cord injury in rats . ___MASK97___ ( FK506 ) , a widely used immunosuppressant drug , has neurite - promoting activity in cultured PC12 cells and peripheral neurons . The present study investigated whether tacrolimus affects the expression of the neuronal growth - associated protein , P20936 - 43 , as well as functional recovery after photothrombotic spinal cord injury in the rat . In injured animals receiving tacrolimus , the number of neurons expressing P20936 - 43 mRNA and protein approximately doubled compared to that in injured animals receiving vehicle alone . This increase in P20936 - 43 - positive cells was paralleled by a significant improvement in neurological function evaluated by open - field and inclined plane tests . Another P62942 ligand ( V - 10 , 367 ) had similar effects on P20936 - 43 expression and functional outcome , indicating that the observed effects of tacrolimus do not involve inhibition of the phosphatase calcineurin . Thus , tacrolimus , a drug which is already approved for use in humans , as well as other P62942 ligands which do not inhibit calcineurin , could potentially enhance functional outcome after CNS injury in humans .\",\n \"Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .\",\n \"Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc - dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan - HDAC inhibitor ___MASK36___ ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil - tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down - regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and ___MASK36___ . Tubacin in combination with ___MASK36___ or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan - caspase inhibitor Z - VAD - fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 , an early marker of DNA double - strand breaks . Tubacin enhances DNA damage induced by etoposide or ___MASK36___ as indicated by increased accumulation of γ P16104 and activation of the checkpoint kinase Chk2 . Tubacin induces the expression of P35638 ( P35638 / P35638 ) , a transcription factor up - regulated in response to cellular stress . P35638 induction is further increased when tubacin is combined with ___MASK36___ . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti - cancer agents in transformed cells .\",\n \"Stress response genes are suppressed in mouse preimplantation embryos by granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) . BACKGROUND : P04141 ( GM - P04141 ) is known to promote the development and survival of human and mouse preimplantation embryos ; however , the mechanism of action of GM - P04141 in embryos is not defined . METHODS : Mouse blastocysts were cultured from zygote stage in vitro with and without recombinant mouse GM - P04141 ( rmGM - P04141 ) , and in vivo developed blastocysts were flushed from Csf2 null mutant and wild - type mice . The effect of GM - P04141 on blastocyst expression of stress response and apoptosis genes was evaluated by microarray , qPCR and immunochemistry . RESULTS : Microarray analysis of the gene transcription profile showed suppression of stress response and apoptosis gene pathways in blastocysts exposed to rmGM - P04141 in vitro . qPCR analysis confirmed that rmGM - P04141 inhibited expression of heat shock protein ( HSP ) and apoptosis pathway genes Cbl , Hspa5 , Hsp90aa1 , Hsp90ab1 and Gas5 in in vitro blastocysts . Immunocytochemical analysis of HSP 1 ( P0DMV8 / 1B ; HSP70 ) , Q07812 , P10415 and TRP53 ( p53 ) in in vitro blastocysts showed that P0DMV8 / 1B and P10415 proteins were less abundant when embryos were cultured with rmGM - P04141 . Q07812 and TRP53 were unchanged at the protein level , but Bax mRNA expression was reduced after GM - P04141 treatment . In in vivo developed blastocysts , Csf2 null mutation caused elevated expression of Hsph1 but not other stress response genes . CONCLUSIONS : We conclude that GM - P04141 inhibits the cellular stress response and apoptosis pathways to facilitate embryo growth and survival , and the protective effects of GM - P04141 are particularly evident in in vitro culture media , whereas in vivo other cytokines can partly compensate for absence of GM - P04141 .\",\n \"Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 .\",\n \"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK36___ ( ___MASK36___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK36___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK36___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .\",\n \"Biological differences between in vitro produced bovine embryos and parthenotes . Parthenotes may represent an alternate ethical source of stem cells , once biological differences between parthenotes and embryos can be understood . In this study , we analyzed development , trophectoderm ( TE ) differentiation , apoptosis / necrosis , and ploidy in parthenotes and in vitro produced bovine embryos . Subsequently , using real - time PCR , we analyzed the expression of genes expected to underlie the observed differences at the blastocyst stage . In vitro matured oocytes were either fertilized or activated with ionomycin + 6 - DMAP and cultured in simple medium . Parthenotes showed enhanced blastocyst development and diploidy and reduced TE cell counts . Apoptotic and necrotic indexes did not vary , but parthenotes evidenced a higher relative proportion of apoptotic cells between inner cell mass and TE . The pluripotence - related Q01860 and the methylation Q9Y6K1 genes were downregulated in parthenotes . Among pregnancy recognition genes , TP - 1 was upregulated in parthenotes , while O00264 and PLAC8 did not change . Expression of p66 ( shc ) and Q07812 / P10415 ratio were higher , and p53 lower , in parthenotes . Among metabolism genes , P11166 was downregulated , while P15121 , P35354 , O95479 , and P10599 were upregulated in parthenotes , and P22732 did not differ . Among genes involved in compaction / blastulation , P17302 was downregulated in parthenotes , but no differences were detected within P05023 and CDH1 . Within parthenotes , the expression levels of P11166 , TP - 1 , and O95479 , and possibly P15121 , resemble patterns described in female embryos . The pro - apoptotic profile is more pronounced in parthenotes than in embryos , which may differ in their way to channel apoptotic stimuli , through p66 ( shc ) and p53 respectively , and in their mechanisms to control pluripotency and de novo methylation .\",\n \"Tau hyperphosphorylation and increased P56817 and RAGE levels in the cortex of PPARβ / δ - null mice . The role of peroxisome proliferator activator receptor ( Q07869 ) β / δ in the pathogenesis of Alzheimer ' s disease has only recently been explored through the use of PPARβ / δ agonists . Here we evaluated the effects of PPARβ / δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation . PPARβ / δ - null mice showed cognitive impairment in the object recognition task , accompanied by enhanced DNA - binding activity of NF - κB in the cortex and increased expression of P05231 . In addition , two NF - κB - target genes involved in β - amyloid ( Aβ ) synthesis and deposition , the β site P05067 cleaving enzyme 1 ( Bace1 ) and the receptor for advanced glycation endproducts ( Rage ) , respectively , increased in PPARβ / δ - null mice compared to wild type animals . The protein levels of glial fibrillary acidic protein ( P14136 ) increased in the cortex of PPARβ / δ - null mice , which would suggest the presence of astrogliosis . Finally , tau hyperphosphorylation at Ser199 and enhanced levels of P10636 were associated with increased levels of the tau kinases Q00535 and phospho - P27361 / 2 in the cortex of PPARβ / δ (-/-) mice . Collectively , our findings indicate that PPARβ / δ deficiency results in cognitive impairment associated with enhanced inflammation , astrogliosis and tau hyperphosphorylation in the cortex .\",\n \"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .\",\n \"Linkage of cytokine genes to rheumatoid arthritis . Evidence of genetic heterogeneity . OBJECTIVE : To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis ( RA ) in affected sibling pair families stratified for specific clinical features . METHOD : Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from : P27352 alpha , P27352 gamma , P27352 beta , IL1 alpha , IL1 beta , P14778 , P60568 , P05231 , Q01344 , IL8R , P10415 , P29965 , NOS3 , P49279 , alpha 1 anti - trypsin , and alpha 1 anti - chymotrypsin , using fluorescence based automated technology . Linkage was examined by defining allele sharing sibling pairs . This was assessed by maximum likelihood - inheritance by descent methods . RESULTS : An increase in allele sharing was seen for Q01344 in female sibling pairs ( LOD 0 . 91 , p = 0 . 03 ) , for P27352 gamma in sibling pairs with an affected male ( LOD 0 . 96 , p = 0 . 03 ) and most significantly for P60568 in sibling pairs where one or both were persistently seronegative ( LOD 1 . 05 , p = 0 . 02 ) . CONCLUSION : Weak evidence of linkage of RA to Q01344 , IFN gamma , and P60568 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease .\",\n \"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \\\" normal \\\" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .\",\n \"c - P05412 promotes P11274 - P00519 - induced lymphoid leukemia by inhibiting methylation of the 5 ' region of Cdk6 . The transcription factor c - P05412 and its upstream kinase P45983 have been implicated in P11274 - P00519 - induced leukemogenesis . P45983 has been shown to regulate P10415 expression , thereby altering leukemogenesis , but the impact of c - P05412 remained unclear . In this study , we show that P45983 and c - P05412 promote leukemogenesis via separate pathways , because lack of c - P05412 impairs proliferation of p185 ( P11274 - P00519 )- transformed cells without affecting their viability . The decreased proliferation of c - Jun ( Δ / Δ ) cells is associated with the loss of cyclin - dependent kinase 6 ( Q00534 ) expression . In c - Jun ( Δ / Δ ) cells , Q00534 expression becomes down - regulated upon P11274 - P00519 - induced transformation , which correlates with CpG island methylation within the 5 ' region of Cdk6 . We verified the impact of Cdk6 deficiency using Cdk6 (-/-) mice that developed P11274 - P00519 - induced B - lymphoid leukemia with significantly increased latency and an attenuated disease phenotype . In addition , we show that reexpression of Q00534 in P11274 - P00519 - transformed c - Jun ( Δ / Δ ) cells reconstitutes proliferation and tumor formation in Nu / Nu mice . In summary , our study reveals a novel function for the activating protein 1 ( AP - 1 ) transcription factor c - P05412 in leukemogenesis by antagonizing promoter methylation . Moreover , we identify Q00534 as relevant and critical target of AP - 1 - regulated DNA methylation on P11274 - P00519 - induced transformation , thereby accelerating leukemogenesis .\",\n \"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK40___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .\",\n \"An acidic pH environment increases cell death and pro - inflammatory cytokine release in osteoblasts : the involvement of Q07812 inhibitor - 1 . Q07812 Inhibitor - 1 ( P55061 ) , a transmembrane protein on the endoplasmic reticulum , has been studied previously in various physio / pathological conditions , but not in bone cells . In this study , using the MG63 osteoblast cell line and osteoblasts differentiated from stem cells , the role of P55061 was studied . First , expression of P55061 was confirmed in osteoblasts , as well as osteoclasts , in mouse tibiae bone immunohistochemistry . For evaluation of a recently published property of P55061 , an acidic pH - dependent Ca² ⁺ channel - like effect in osteoblasts , acidic pH - associated cell death , and pro - inflammatory cytokine release were examined . In MG63 osteoblasts , acidic pH induced a pH - dependent increase in cell death and ER stress , as determined by elevated expression of P11021 , P35638 , phospho - eIF2α , IRE - 1α , spliced P17861 , and phospho - JNK . In osteoblasts , mitochondrial Ca² ⁺ also showed a strong pH - dependent increase . P55061 knock - down using siRNA protected cells against acidic pH , regulating mitochondrial Ca² ⁺ accumulation , possibly via the acidic pH - dependent Ca² ⁺ channel - like effect of P55061 . P55061 knock - down also resulted in inhibition of acidic pH - induced release of pro - inflammatory cytokines , including IL - 1β , P05231 , and P01375 - α . In addition , bone marrow stem cells were differentiated into human osteoblasts , which showed increased expression of P55061 mRNA and protein . In differentiated primary human osteoblasts , acidic pH - associated cell death , mitochondrial Ca² ⁺ accumulation , and pro - inflammatory cytokine release were more significant than in non - differentiated stem cells . In summary , endogenous expression of P55061 is associated with acidic pH - induced Ca² ⁺ release , cell death , and pro - inflammatory cytokine release in human osteoblasts .\",\n \"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .\",\n \"JTT - 705 blocks cell proliferation and angiogenesis through p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways . The excessive proliferation and migration of vascular smooth muscle cells ( SMCs ) participate in the growth and instability of atherosclerotic plaque . We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein , JTT - 705 , on SMC proliferation and angiogenesis in endothelial cells ( ECs ) . JTT - 705 inhibited human coronary artery SMC proliferation . JTT - 705 induced the phosphorylation of p38 mitogen - activated protein kinase ( MAPK ) and extracellular - signal - regulated kinases ( P29323 ) in SMCs . In addition , the anti - proliferative effects of JTT - 705 in SMCs were blocked by p38 MAPK inhibitor . JTT - 705 induced the upregulation of p - P38936 ( waf1 ) , and this effect was blocked by dominant - negative Ras ( N17 ) , but not by inhibitors of p38 MAPK or P29323 . In addition , JTT - 705 also induced the upregulation of p27 ( kip1 ) , and this effect was blocked by p38 MAPK inhibitor . Interestingly , culture medium from JTT - 705 - treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor ( P15692 ) from SMCs and directly via an anti - proliferative effect in ECs . JTT - 705 blocked the proliferation of SMCs through the activation of p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways , and simultaneously blocked EC tube formation associated with a decrease in P15692 production from SMCs and an anti - proliferative effect in ECs . Our results indicate that JTT - 705 may induce a direct anti - atherogenic effect in addition to its inhibitory effect of P11597 activity .\",\n \"Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration . BACKGROUND : Mutations in the progranulin gene ( PGRN ) were identified as the causal mechanism underlying frontotemporal lobar degeneration ( FTLD ) . Most of these mutations are predicted to create null alleles leading to a 50 % loss of progranulin transcript . METHODS : Patients underwent clinical and neurologic examination at the Memory Clinic of the IRCCS S . Giovanni di Dio - Fatebenefratelli , Brescia , Italy . We enrolled affected ( n = 6 ) and unaffected at risk members ( n = 73 ) of families carrying the FTLD associated progranulin Leu271LeufsX10 mutation ; additionally , we included subjects affected by sporadic / familial FTLD ( n = 65 ) , controls ( n = 75 ) , and a family carrying the tau P301L mutation . The presence of mutations in PGRN and P10636 genes was investigated by direct sequencing of exonic and flanking intronic regions . Progranulin plasma and P04141 levels were measured using ELISA . RESULTS : We demonstrated that progranulin protein is strongly reduced ( up to 3 . 93 - fold ) both in plasma and P04141 of affected and unaffected subjects carrying mutations in progranulin gene ( PGRN Leu271LeufsX10 and Q341X ) . We established a plasma progranulin protein cutoff level of 74 . 4 ng / mL that identifies , with specificity and sensitivity of 100 % , mutation carriers among unaffected subjects . In FTLD , values < or = 110 . 9 ng / mL give a specificity of 92 . 8 % and a sensitivity of 100 % for PGRN mutations . CONCLUSIONS : We propose the dosage of plasma progranulin as a useful tool for a quick and inexpensive large - scale screening of carriers of progranulin mutations and for monitoring future treatments that might boost the level of this protein .\",\n \"Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection . Accelerated coronary atherosclerosis in cardiac transplants ( cardiac allograft vasculopathy , Q03135 ) is characterized by coronary intimal hyperplasia . P05230 ( P05230 ) is a potent mitogen for vascular smooth muscle cells and endothelial cells , and its expression is increased in cardiac allografts , suggesting it may play a role in the pathogenesis of Q03135 . The activity of P05230 is dependent on binding to transmembrane receptors . To investigate whether receptors for P05230 are also induced after transplantation , polymerase chain reaction , in situ hybridization , and immunohistochemistry were used to analyze expression of four receptors for P05230 ( P11362 - P22455 ) . Expression of mRNA encoding extracellular immunoglobulin - like domains of P11362 was increased 35 - fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures . Alternatively spliced mRNA that encodes transmembrane forms of P11362 , which contain the signal - transducing tyrosine kinase domains , was induced in allografts during rejection , in infiltrating cells , vascular structures , and myocytes . In vitro experiments showed that differential expression of FGF receptor isoforms was induced by P05230 , and also by P05231 and TGF - beta , which are expressed in cardiac allografts during rejection . The results show that expression of both P05230 and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of Q03135 .\",\n \"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK38___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK38___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .\",\n \"Assessment of Alzheimer ' s disease case - control associations using family - based methods . The genetics of Alzheimer ' s disease ( AD ) is heterogeneous and remains only ill - defined . We have recently created a freely available and continuously updated online database ( AlzGene ; http :// www . alzgene . org ) for which we collect all published genetic association studies in AD and perform systematic meta - analyses on all polymorphisms with sufficient genotype data . In this study , we tested 27 genes ( P12821 , P23560 , O95992 , P17787 , P01034 , P07339 , P53355 , Q9UBC7 , hCG2039140 , P01584 , P02545 , LOC439999 , LOC651924 , P10636 , P42898 , Q9UKX3 , P35558 , Q96JS3 , PRNP , P49768 , Q8WY21 , Q92673 , TF , Q00059 , Q13470 , GWA_14q32 . 13 , and GWA_7p15 . 2 ) , all showing significant association with AD risk in the AlzGene meta - analyses , in a large collection of family - based samples comprised of 4 , 180 subjects from over 1 , 300 pedigrees . Overall , we observe significant association with risk for AD and polymorphisms in P12821 , P17787 , TF , and an as yet uncharacterized locus on chromosome 7p15 . 2 [ rs1859849 ] . For all four loci , the association was observed with the same alleles as in the AlzGene meta - analyses . The convergence of case - control and family - based findings suggests that these loci currently represent the most promising AD gene candidates . Further fine - mapping and functional analyses are warranted to elucidate the potential biochemical mechanisms and epidemiological relevance of these genes .\",\n \"Methylation of the nonhomologous end joining repair pathway genes does not explain the increase of translocations with aging . Chromosome translocations are especially frequent in human lymphomas and leukemias but are insufficient to drive carcinogenesis . Indeed , several of the so - called tumor specific translocations have been detected in peripheral blood of healthy individuals , finding a higher frequency of some of them with aging . The inappropriate repair of DNA double strand breaks by the nonhomologous end joining ( NHEJ ) pathway is one of the reasons for a translocation to occur . Moreover , fidelity of this pathway has been shown to decline with age . Although the mechanism underlying this inefficacy is unknown , other repair pathways are inactivated by methylation with aging . In this study , we analyzed the implication of NHEJ genes methylation in the increase of translocations with the age . To this aim , we determined the relationship between translocations and aging in 565 Spanish healthy individuals and correlated these data with the methylation status of 11 NHEJ genes . We found higher frequency of P10415 - JH and P11274 - P00519 ( major ) translocations with aging . In addition , we detected that two NHEJ genes ( P49917 and P12956 ) presented age - dependent promoter methylation changes . However , we did not observe a correlation between the increase of translocations and methylation , indicating that other molecular mechanisms are involved in the loss of NHEJ fidelity with aging .\",\n \"Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK97___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .\"\n]"},"candidates":{"kind":"list like","value":["___MASK1___","___MASK25___","___MASK36___","___MASK38___","___MASK40___","___MASK49___","___MASK53___","___MASK65___","___MASK97___"],"string":"[\n \"___MASK1___\",\n \"___MASK25___\",\n \"___MASK36___\",\n \"___MASK38___\",\n \"___MASK40___\",\n \"___MASK49___\",\n \"___MASK53___\",\n \"___MASK65___\",\n \"___MASK97___\"\n]"},"answer":{"kind":"string","value":"___MASK97___"},"id":{"kind":"string","value":"MH_train_496"}}},{"rowIdx":497,"cells":{"query":{"kind":"string","value":"interacts_with DB01022?"},"supports":{"kind":"list like","value":["Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK78___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK78___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .","___MASK50___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK50___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK50___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK50___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .","[ Construction of mammalian cell expression vector for pAcGFP - bFADD fusion protein and its expression in CHO - P04264 cell ] . Fas - associated death domain ( Q13158 ) is a signal connection protein in Fas / P48023 apoptotic path which might play a key role on apoptosis by transferring apoptotic signal . To reveal the intracellular signal transduction molecules involved in the procedure of follicular development in bovine ovary , we cloned Q13158 gene in bovine ovary tissue with RT - PCR , deleted the termination codon in its cDNA and directionally cloned the amplified Q13158 gene into eukaryotic expression vector pAcGFP - N1 including AcGFP , successfully constructed the fusion protein recombinant plasmid . After identifying by restrictive enzyme Bgl II / EcoR I and sequencing , transfected pAcGFP - bFADD into CHO - P04264 cell mediated by Lipofectamine 2000 , observed the expression of AcGFP and detected the transcription and expression of Q13158 by RT - PCR and Western blotting . The results showed that the cattle Q13158 was successfully cloned , the pAcGFP - bFADD fusion protein recombinant plasmid was successfully constructed by introducing Bgl II , EcoR I cloning site at two ends of Q13158 open reading frame and inserting a Kozak sequence before start codon . AcGFP expression was detected as early as 24 h after transfection . The percentage of AcGFP positive cells reached about 65 % after 24 h . A 654 bp transcription was amplified by RT - PCR , and 51 . 4 kD target protein was detected by Western blotting . Construction of pAcGFP - bFADD recombinant plasmid should be helpful for further understanding the mechanism of regulation of Q13158 on bovine oocytes formation and development .","Agonist - promoted down - regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor . We recently reported two naturally occurring polymorphisms of the human serotonin1A ( P08908 ) receptor : glycine22 --> serine ( Ser22 ) and isoleucine28 --> valine ( Val28 ) in the putative aminoterminal domain of the receptor . To investigate the regulatory properties of these variants , the wild type ( WT ) and variant P08908 receptors were stably expressed in CHO - P04264 cells . WT , Ser22 , and Val28 displayed similar high - affinity binding to [ 3H ] - 8 - OH - DPAT . Competition experiments with P08908 agonists and antagonists demonstrated similar pharmacological profiles . Receptor agonist - promoted down - regulation was tested by exposure to 100 mumol / L 8 - OH - DPAT . After 24 - h exposure , WT and Val28 underwent 59 . 3 +/- 3 . 9 % and 59 . 5 +/- 1 . 4 % reduction in receptor density respectively , whereas the degree of down - regulation was significantly lower for Ser22 ( 21 . 4 +/- 4 . 2 % ) . Cell treatment for 24 h with 100 mumol / L 8 - OH - DPAT reduced the 5 - HT - induced inhibition of DB02527 accumulation by 24 . 9 +/- 5 . 1 % for WT and 16 . 4 +/- 0 . 8 % for Val28 , but only by 4 . 8 +/- 3 % for Ser22 . We conclude that the Ser22 variant is capable of attenuating agonist - mediated receptor down - regulation and desensitization .","The revised human liver cytochrome P450 \" Pie \" : absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics . The CYP4F subfamily of enzymes has been identified recently to be involved in the metabolism of endogenous compounds ( arachidonic acid and leukotriene B4 ) , nutrients ( vitamins P04264 and E ) , and xenobiotics ( pafuramidine and fingolimod ) . P78329 and CYP4F3B are reported to be expressed in the human liver . However , absolute concentrations of these enzymes in human liver microsomes ( HLMs ) and their interindividual variability have yet to be determined because of the lack of specific antibodies . Here , an liquid chromatography with tandem mass spectrometry ( LC - MS / MS ) - based targeted quantitative proteomic approach was employed to determine the absolute protein concentrations of P78329 and CYP4F3B compared with CYP3A in two panels of HLMs ( n = 31 ) . As a result , the human hepatic cytochrome P450 ( P450 ) \" pie \" has been revised to include the contribution of CYP4F enzymes , which amounts to 15 % of the total hepatic cytochrome P450 enzymes . CYP4F3B displayed low interindividual variability ( 3 . 3 - fold ) in the HLM panels whereas P78329 displayed large variability ( 21 - fold ) . However , P78329 variability decreased to 3 . 4 - fold if the two donors with the lowest expression were excluded . In contrast , CYP3A exhibited 29 - fold interindividual variability in the same HLM panels . The proposed marker reaction for CYP4F enzymes pafuramidine / DB289 M1 formation did not correlate with CYP4F protein content , suggesting alternate metabolic pathways for DB289 M1 formation in HLMs . In conclusion , CYP4F enzymes are highly expressed in the human liver and their physiologic and pharmacologic roles warrant further investigation .","Developmental expression of CLC - P04264 in the postnatal rat kidney . CLC - P04264 , a kidney - specific chloride channel , has been demonstrated to be involved in the urine concentration mechanism . Here , we investigated the developmental expression of CLC - P04264 in the rat kidney . Using immunohistochemistry , we showed that CLC - P04264 was not present in the thin ascending limb of Henle ' s loop during the early prenatal stages but was significantly expressed during the adult stage . CLC - P04264 started to appear at day 5 and its expression increased during further development . In developing rats this increase coincided with the increase in the urine - concentrating capacity as the animals matured . We also investigated the expressions of other channels and transporters , including Q13621 , P29972 , and P41181 . Q13621 was strongly expressed throughout the inner medulla in neonatal rat kidneys but was entirely undetectable at the adult stage . The decline in its expression took the form of a gradual recession from the inner medulla together with reciprocal increases in the expression of CLC - P04264 . P29972 was weakly expressed in the inner medulla during early development and showed a rapid increase in expression at a later stage . The collecting duct cells significantly expressed P41181 even at birth and maintained its expression throughout the development . These results suggest that CLC - P04264 expression is one of the major determinants of the urine - concentrating capacity of the developing rat kidney .","Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK97___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .","[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK91___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .","5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK4___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .","Direct binding of recombinant plasminogen kringle 1 - 3 to angiogenin inhibits angiogenin - induced angiogenesis in the chick embryo P62158 . P03950 is one of the most potent angiogenesis - inducing proteins . Angiostatin is one of the most potent angiogenesis inhibitors , and it contains the first four kringle domains of plasminogen ( P04264 - 4 ) . Recombinant human plasminogen kringle 1 - 3 ( rK1 - 3 ) was expressed in Escherichia coli and purified to homogeneity . The binding of t - 4 - aminomethylcyclohexanecarboxylic acid with the purified kringle 1 - 3 was determined by changes in intrinsic fluorescence . rK1 - 3 exhibits comparable ligand - binding properties as native human plasminogen kringle 1 - 3 . The purified rK1 - 3 inhibits neovascularization in the chick embryo chorioallantoic membrane ( P62158 ) assay . Interaction of angiogenin with rK1 - 3 was examined by immunological binding assay and surface plasmon resonance kinetic analysis , and the equilibrium dissociation constants for the complex , Kd , are 0 . 89 and 0 . 18 microM , respectively . rK1 - 3 inhibits angiogenin - induced angiogenesis in the chick embryo P62158 in a concentration - dependent manner . These results indicate that rK1 - 3 directly binds to angiogenin and thus rK1 - 3 inhibits the angiogenic activity of angiogenin .","___MASK19___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK19___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .","Alcohols inhibit N - methyl - D - aspartate receptors via a site exposed to the extracellular environment . N - Methyl - D - aspartate ( DB01221 ) receptors are important CNS target sites of alcohols , but the site and mechanism of action of alcohols on DB01221 receptors remains unclear . In CHO - P04264 cells transfected with Q9UHB4 / Q13224 DB01221 receptor subunits , ethanol inhibited DB01221 - activated current with an IC ( 50 ) of 138 mM . Truncation of the intracellular C - terminal domain of the Q9UHB4 subunit ( NR1T ) did not alter ethanol sensitivity when combined with the Q13224 subunit , but a similar truncation of the Q13224 subunit ( NR2BT ) slightly enhanced ethanol sensitivity of receptors formed from coexpression with either Q9UHB4 or NR1T subunits . 1 - Pentanol applied externally inhibited DB01221 receptors with an IC ( 50 ) of 9 . 9 mM , but intracellular application of 1 - pentanol ( 25 mM ) did not alter DB01221 receptor inhibition by externally applied ethanol or 1 - pentanol . In addition , the amplitude of DB01221 - activated current did not decrease during the time required for 1 - pentanol ( 25 mM ) to diffuse throughout the cytoplasm . DB00898 did not inhibit DB01221 receptors when bath - applied in cell - attached patches or when applied to the cytoplasmic face of inside - out membrane patches . These results appear to be best explained by an action of alcohols on the DB01221 receptor - channel protein , at a site located in a domain exposed to , or only accessible from , the extracellular environment .","Characterization of a thyroiditis - inducing thyroglobulin - specific T - cell clone restricted by the H - 2 molecule of a low responder mouse strain . We established a thyroglobulin ( Tg ) - specific , thyroiditis - inducing T - cell clone , B12G , from B6C3F1 mice by the immunization of mouse Tg with lipopolysaccharide ( LPS ) from Klebsiella strain LEN ( O3 : P04264 ) . B12G was Thy - 1 . 2 + , CD3 + , P01730 + , P05107 + , and CD8 - , and could transfer thyroiditis to recipient mice after in vitro stimulation with mouse or bovine Tg . Histological examination showed severe thyroiditis with predominant infiltrations of polymorphonuclear cells ; few mononuclear cells were observed . B12G proliferated in response to bovine , mouse , porcine , and rat Tg in the presence of irradiated spleen cells , but did not respond to chicken or human Tg . H - 2b , a low - responder haplotype of experimental autoimmune thyroiditis , governed the response of the clone to Tg . B12G produced interleukin - 4 ( P05112 ) and P05231 , but not P60568 or interferon - gamma ( P01579 ) , on stimulation with mouse Tg . These findings were different from characteristics of previously reported Tg - specific T - cell clones from high - responder mice in terms of epitope specificity and cytokine production pattern , raising the possibility that the specificities and functions of T cells involved in the development of autoimmune thyroiditis in low - responder mice differ from those in high responders .","Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK8___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .","Serial changes in serum vitamin P04264 , triglyceride , cholesterol , osteocalcin and 25 - hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis . Serum vitamin P04264 concentrations were measured at presentation ( just before surgery ) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur ( FON , n = 13 ) or total hip replacement for osteoarthritis of the hip ( OA , n = 16 ) . In comparison with healthy elderly volunteers ( n = 25 ) , serum vitamin P04264 concentrations were significantly lower in both groups at presentation , and fell significantly within 24 h after surgery to concentrations approaching non - detectable , subsequently returning to pre - operative values within 3 weeks . Serum vitamin P04264 tended to be lower in the fracture group both before and after operation , although calculation of a vitamin P04264 - triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group . P02818 concentrations were similar and fell significantly after operation in both groups , returning to pre - operative levels within 7 days . No differences in the two forms of osteocalcin ( carboxylated and undercarboxylated ) were observed either before or after operation in either group . DB00146 concentrations were not significantly different between the two groups at any time . DB01022 status may be lower than desirable in certain groups of the elderly population , and supplementation should be considered as prophylactic therapy .","___MASK58___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK58___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .","Q01094 - mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product . Previous studies have shown that the carboxyl - terminal region of Q01094 ( residues 368 - 437 ) can support transcriptional activation when linked to the DNA - binding domain of the yeast transcription factor GAL4 . This region also contains an 18 - residue retinoblastoma ( RB ) - binding sequence , raising the possibility that RB binding might inhibit the ability of Q01094 to form protein - protein contacts required for activation . Here we report a further analysis of the Q01094 activation domain . In addition , we show that overexpression of RB , but not the RB mutant , RBd22 , can inhibit GAL4 / Q01094 activity in vivo . Moreover , expression of the simian virus 40 large tumor antigen ( T antigen ) , but not the RB - binding defective T antigen point mutant , P04264 , can overcome this repression . Three different GAL4 / Q01094 mutants that activate transcription , but fail to bind to RB , are not significantly affected by overexpression of RB . These findings support a model wherein RB suppresses Q01094 - mediated transcriptional activation through direct physical association .","P29323 , Akt , and P42229 are Differentially Activated by the Two Growth Hormone Receptor Subtypes of a Teleost Fish ( Oncorhynchus Mykiss ) . Previously , we found that the teleost fish , rainbow trout , possesses two growth hormone receptor ( P10912 ) subtypes that display distinct ligand - binding and agonist - induced regulation features . In this study , we used Chinese hamster ovary - P04264 cells stably transfected individually with the two trout P10912 subtypes , GHR1 and GHR2 , to elucidate receptor - effector pathway linkages . Growth hormone ( GH ) stimulated rapid ( 5 - 10 min ) phosphorylation of P29323 , Akt , JAk2 , and P42229 in both GHR1 - and GHR2 - expressing cells ; however ; P42229 was activated to a greater extent through GHR1 than through GHR2 , whereas P29323 and Akt were activated to a greater through GHR2 than through GHR1 . Although blockade of the P29323 pathway had no effect on the activation of Akt , inhibition of PI3K - Akt partially prevented activation of P29323 , suggesting cross - talk between the P29323 and PI3K - Akt pathways . O60674 inhibition completely blocked activation of P29323 , Akt , and P42229 , suggesting that all of these pathways link to GHR1 and GHR2 via O60674 . These findings establish important receptor - effector pathway linkages and suggest that the P10912 subtypes of teleost fish may be functionally distinct .","17 ___MASK73___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis ."],"string":"[\n \"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK78___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK78___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .\",\n \"___MASK50___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK50___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK50___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK50___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .\",\n \"[ Construction of mammalian cell expression vector for pAcGFP - bFADD fusion protein and its expression in CHO - P04264 cell ] . Fas - associated death domain ( Q13158 ) is a signal connection protein in Fas / P48023 apoptotic path which might play a key role on apoptosis by transferring apoptotic signal . To reveal the intracellular signal transduction molecules involved in the procedure of follicular development in bovine ovary , we cloned Q13158 gene in bovine ovary tissue with RT - PCR , deleted the termination codon in its cDNA and directionally cloned the amplified Q13158 gene into eukaryotic expression vector pAcGFP - N1 including AcGFP , successfully constructed the fusion protein recombinant plasmid . After identifying by restrictive enzyme Bgl II / EcoR I and sequencing , transfected pAcGFP - bFADD into CHO - P04264 cell mediated by Lipofectamine 2000 , observed the expression of AcGFP and detected the transcription and expression of Q13158 by RT - PCR and Western blotting . The results showed that the cattle Q13158 was successfully cloned , the pAcGFP - bFADD fusion protein recombinant plasmid was successfully constructed by introducing Bgl II , EcoR I cloning site at two ends of Q13158 open reading frame and inserting a Kozak sequence before start codon . AcGFP expression was detected as early as 24 h after transfection . The percentage of AcGFP positive cells reached about 65 % after 24 h . A 654 bp transcription was amplified by RT - PCR , and 51 . 4 kD target protein was detected by Western blotting . Construction of pAcGFP - bFADD recombinant plasmid should be helpful for further understanding the mechanism of regulation of Q13158 on bovine oocytes formation and development .\",\n \"Agonist - promoted down - regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor . We recently reported two naturally occurring polymorphisms of the human serotonin1A ( P08908 ) receptor : glycine22 --> serine ( Ser22 ) and isoleucine28 --> valine ( Val28 ) in the putative aminoterminal domain of the receptor . To investigate the regulatory properties of these variants , the wild type ( WT ) and variant P08908 receptors were stably expressed in CHO - P04264 cells . WT , Ser22 , and Val28 displayed similar high - affinity binding to [ 3H ] - 8 - OH - DPAT . Competition experiments with P08908 agonists and antagonists demonstrated similar pharmacological profiles . Receptor agonist - promoted down - regulation was tested by exposure to 100 mumol / L 8 - OH - DPAT . After 24 - h exposure , WT and Val28 underwent 59 . 3 +/- 3 . 9 % and 59 . 5 +/- 1 . 4 % reduction in receptor density respectively , whereas the degree of down - regulation was significantly lower for Ser22 ( 21 . 4 +/- 4 . 2 % ) . Cell treatment for 24 h with 100 mumol / L 8 - OH - DPAT reduced the 5 - HT - induced inhibition of DB02527 accumulation by 24 . 9 +/- 5 . 1 % for WT and 16 . 4 +/- 0 . 8 % for Val28 , but only by 4 . 8 +/- 3 % for Ser22 . We conclude that the Ser22 variant is capable of attenuating agonist - mediated receptor down - regulation and desensitization .\",\n \"The revised human liver cytochrome P450 \\\" Pie \\\" : absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics . The CYP4F subfamily of enzymes has been identified recently to be involved in the metabolism of endogenous compounds ( arachidonic acid and leukotriene B4 ) , nutrients ( vitamins P04264 and E ) , and xenobiotics ( pafuramidine and fingolimod ) . P78329 and CYP4F3B are reported to be expressed in the human liver . However , absolute concentrations of these enzymes in human liver microsomes ( HLMs ) and their interindividual variability have yet to be determined because of the lack of specific antibodies . Here , an liquid chromatography with tandem mass spectrometry ( LC - MS / MS ) - based targeted quantitative proteomic approach was employed to determine the absolute protein concentrations of P78329 and CYP4F3B compared with CYP3A in two panels of HLMs ( n = 31 ) . As a result , the human hepatic cytochrome P450 ( P450 ) \\\" pie \\\" has been revised to include the contribution of CYP4F enzymes , which amounts to 15 % of the total hepatic cytochrome P450 enzymes . CYP4F3B displayed low interindividual variability ( 3 . 3 - fold ) in the HLM panels whereas P78329 displayed large variability ( 21 - fold ) . However , P78329 variability decreased to 3 . 4 - fold if the two donors with the lowest expression were excluded . In contrast , CYP3A exhibited 29 - fold interindividual variability in the same HLM panels . The proposed marker reaction for CYP4F enzymes pafuramidine / DB289 M1 formation did not correlate with CYP4F protein content , suggesting alternate metabolic pathways for DB289 M1 formation in HLMs . In conclusion , CYP4F enzymes are highly expressed in the human liver and their physiologic and pharmacologic roles warrant further investigation .\",\n \"Developmental expression of CLC - P04264 in the postnatal rat kidney . CLC - P04264 , a kidney - specific chloride channel , has been demonstrated to be involved in the urine concentration mechanism . Here , we investigated the developmental expression of CLC - P04264 in the rat kidney . Using immunohistochemistry , we showed that CLC - P04264 was not present in the thin ascending limb of Henle ' s loop during the early prenatal stages but was significantly expressed during the adult stage . CLC - P04264 started to appear at day 5 and its expression increased during further development . In developing rats this increase coincided with the increase in the urine - concentrating capacity as the animals matured . We also investigated the expressions of other channels and transporters , including Q13621 , P29972 , and P41181 . Q13621 was strongly expressed throughout the inner medulla in neonatal rat kidneys but was entirely undetectable at the adult stage . The decline in its expression took the form of a gradual recession from the inner medulla together with reciprocal increases in the expression of CLC - P04264 . P29972 was weakly expressed in the inner medulla during early development and showed a rapid increase in expression at a later stage . The collecting duct cells significantly expressed P41181 even at birth and maintained its expression throughout the development . These results suggest that CLC - P04264 expression is one of the major determinants of the urine - concentrating capacity of the developing rat kidney .\",\n \"Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK97___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .\",\n \"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK91___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .\",\n \"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK4___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .\",\n \"Direct binding of recombinant plasminogen kringle 1 - 3 to angiogenin inhibits angiogenin - induced angiogenesis in the chick embryo P62158 . P03950 is one of the most potent angiogenesis - inducing proteins . Angiostatin is one of the most potent angiogenesis inhibitors , and it contains the first four kringle domains of plasminogen ( P04264 - 4 ) . Recombinant human plasminogen kringle 1 - 3 ( rK1 - 3 ) was expressed in Escherichia coli and purified to homogeneity . The binding of t - 4 - aminomethylcyclohexanecarboxylic acid with the purified kringle 1 - 3 was determined by changes in intrinsic fluorescence . rK1 - 3 exhibits comparable ligand - binding properties as native human plasminogen kringle 1 - 3 . The purified rK1 - 3 inhibits neovascularization in the chick embryo chorioallantoic membrane ( P62158 ) assay . Interaction of angiogenin with rK1 - 3 was examined by immunological binding assay and surface plasmon resonance kinetic analysis , and the equilibrium dissociation constants for the complex , Kd , are 0 . 89 and 0 . 18 microM , respectively . rK1 - 3 inhibits angiogenin - induced angiogenesis in the chick embryo P62158 in a concentration - dependent manner . These results indicate that rK1 - 3 directly binds to angiogenin and thus rK1 - 3 inhibits the angiogenic activity of angiogenin .\",\n \"___MASK19___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK19___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .\",\n \"Alcohols inhibit N - methyl - D - aspartate receptors via a site exposed to the extracellular environment . N - Methyl - D - aspartate ( DB01221 ) receptors are important CNS target sites of alcohols , but the site and mechanism of action of alcohols on DB01221 receptors remains unclear . In CHO - P04264 cells transfected with Q9UHB4 / Q13224 DB01221 receptor subunits , ethanol inhibited DB01221 - activated current with an IC ( 50 ) of 138 mM . Truncation of the intracellular C - terminal domain of the Q9UHB4 subunit ( NR1T ) did not alter ethanol sensitivity when combined with the Q13224 subunit , but a similar truncation of the Q13224 subunit ( NR2BT ) slightly enhanced ethanol sensitivity of receptors formed from coexpression with either Q9UHB4 or NR1T subunits . 1 - Pentanol applied externally inhibited DB01221 receptors with an IC ( 50 ) of 9 . 9 mM , but intracellular application of 1 - pentanol ( 25 mM ) did not alter DB01221 receptor inhibition by externally applied ethanol or 1 - pentanol . In addition , the amplitude of DB01221 - activated current did not decrease during the time required for 1 - pentanol ( 25 mM ) to diffuse throughout the cytoplasm . DB00898 did not inhibit DB01221 receptors when bath - applied in cell - attached patches or when applied to the cytoplasmic face of inside - out membrane patches . These results appear to be best explained by an action of alcohols on the DB01221 receptor - channel protein , at a site located in a domain exposed to , or only accessible from , the extracellular environment .\",\n \"Characterization of a thyroiditis - inducing thyroglobulin - specific T - cell clone restricted by the H - 2 molecule of a low responder mouse strain . We established a thyroglobulin ( Tg ) - specific , thyroiditis - inducing T - cell clone , B12G , from B6C3F1 mice by the immunization of mouse Tg with lipopolysaccharide ( LPS ) from Klebsiella strain LEN ( O3 : P04264 ) . B12G was Thy - 1 . 2 + , CD3 + , P01730 + , P05107 + , and CD8 - , and could transfer thyroiditis to recipient mice after in vitro stimulation with mouse or bovine Tg . Histological examination showed severe thyroiditis with predominant infiltrations of polymorphonuclear cells ; few mononuclear cells were observed . B12G proliferated in response to bovine , mouse , porcine , and rat Tg in the presence of irradiated spleen cells , but did not respond to chicken or human Tg . H - 2b , a low - responder haplotype of experimental autoimmune thyroiditis , governed the response of the clone to Tg . B12G produced interleukin - 4 ( P05112 ) and P05231 , but not P60568 or interferon - gamma ( P01579 ) , on stimulation with mouse Tg . These findings were different from characteristics of previously reported Tg - specific T - cell clones from high - responder mice in terms of epitope specificity and cytokine production pattern , raising the possibility that the specificities and functions of T cells involved in the development of autoimmune thyroiditis in low - responder mice differ from those in high responders .\",\n \"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK8___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .\",\n \"Serial changes in serum vitamin P04264 , triglyceride , cholesterol , osteocalcin and 25 - hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis . Serum vitamin P04264 concentrations were measured at presentation ( just before surgery ) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur ( FON , n = 13 ) or total hip replacement for osteoarthritis of the hip ( OA , n = 16 ) . In comparison with healthy elderly volunteers ( n = 25 ) , serum vitamin P04264 concentrations were significantly lower in both groups at presentation , and fell significantly within 24 h after surgery to concentrations approaching non - detectable , subsequently returning to pre - operative values within 3 weeks . Serum vitamin P04264 tended to be lower in the fracture group both before and after operation , although calculation of a vitamin P04264 - triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group . P02818 concentrations were similar and fell significantly after operation in both groups , returning to pre - operative levels within 7 days . No differences in the two forms of osteocalcin ( carboxylated and undercarboxylated ) were observed either before or after operation in either group . DB00146 concentrations were not significantly different between the two groups at any time . DB01022 status may be lower than desirable in certain groups of the elderly population , and supplementation should be considered as prophylactic therapy .\",\n \"___MASK58___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK58___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .\",\n \"Q01094 - mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product . Previous studies have shown that the carboxyl - terminal region of Q01094 ( residues 368 - 437 ) can support transcriptional activation when linked to the DNA - binding domain of the yeast transcription factor GAL4 . This region also contains an 18 - residue retinoblastoma ( RB ) - binding sequence , raising the possibility that RB binding might inhibit the ability of Q01094 to form protein - protein contacts required for activation . Here we report a further analysis of the Q01094 activation domain . In addition , we show that overexpression of RB , but not the RB mutant , RBd22 , can inhibit GAL4 / Q01094 activity in vivo . Moreover , expression of the simian virus 40 large tumor antigen ( T antigen ) , but not the RB - binding defective T antigen point mutant , P04264 , can overcome this repression . Three different GAL4 / Q01094 mutants that activate transcription , but fail to bind to RB , are not significantly affected by overexpression of RB . These findings support a model wherein RB suppresses Q01094 - mediated transcriptional activation through direct physical association .\",\n \"P29323 , Akt , and P42229 are Differentially Activated by the Two Growth Hormone Receptor Subtypes of a Teleost Fish ( Oncorhynchus Mykiss ) . Previously , we found that the teleost fish , rainbow trout , possesses two growth hormone receptor ( P10912 ) subtypes that display distinct ligand - binding and agonist - induced regulation features . In this study , we used Chinese hamster ovary - P04264 cells stably transfected individually with the two trout P10912 subtypes , GHR1 and GHR2 , to elucidate receptor - effector pathway linkages . Growth hormone ( GH ) stimulated rapid ( 5 - 10 min ) phosphorylation of P29323 , Akt , JAk2 , and P42229 in both GHR1 - and GHR2 - expressing cells ; however ; P42229 was activated to a greater extent through GHR1 than through GHR2 , whereas P29323 and Akt were activated to a greater through GHR2 than through GHR1 . Although blockade of the P29323 pathway had no effect on the activation of Akt , inhibition of PI3K - Akt partially prevented activation of P29323 , suggesting cross - talk between the P29323 and PI3K - Akt pathways . O60674 inhibition completely blocked activation of P29323 , Akt , and P42229 , suggesting that all of these pathways link to GHR1 and GHR2 via O60674 . These findings establish important receptor - effector pathway linkages and suggest that the P10912 subtypes of teleost fish may be functionally distinct .\",\n \"17 ___MASK73___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .\"\n]"},"candidates":{"kind":"list like","value":["___MASK19___","___MASK4___","___MASK50___","___MASK58___","___MASK73___","___MASK78___","___MASK8___","___MASK91___","___MASK97___"],"string":"[\n \"___MASK19___\",\n \"___MASK4___\",\n \"___MASK50___\",\n \"___MASK58___\",\n \"___MASK73___\",\n \"___MASK78___\",\n \"___MASK8___\",\n \"___MASK91___\",\n \"___MASK97___\"\n]"},"answer":{"kind":"string","value":"___MASK97___"},"id":{"kind":"string","value":"MH_train_497"}}},{"rowIdx":498,"cells":{"query":{"kind":"string","value":"interacts_with DB01235?"},"supports":{"kind":"list like","value":["Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .","CXC chemokine receptor 4 expression and function in human astroglioma cells . Chemokines constitute a superfamily of proteins that function as chemoattractants and activators of leukocytes . Astrocytes , the major glial cell type in the CNS , are a source of chemokines within the diseased brain . Specifically , we have shown that primary human astrocytes and human astroglioma cell lines produce the CXC chemokines P01579 - inducible protein - 10 and P10145 and the CC chemokines monocyte chemoattractant protein - 1 and RANTES in response to stimuli such as P01375 , IL - 1beta , and P01579 . In this study , we investigated chemokine receptor expression and function on human astroglioma cells . Enhancement of CXC chemokine receptor 4 ( P61073 ) mRNA expression was observed upon treatment with the cytokines P01375 and IL - 1beta . The peak of P61073 expression in response to P01375 and IL - 1beta was 8 and 4 h , respectively . P61073 protein expression was also enhanced upon treatment with P01375 and IL - 1beta ( 2 - to 3 - fold ) . To study the functional relevance of P61073 expression , stable astroglioma transfectants expressing high levels of P61073 were generated . Stimulation of cells with the ligand for P61073 , stromal cell - derived factor - 1alpha ( SDF - 1alpha ) , resulted in an elevation in intracellular Ca ( 2 +) concentration and activation of the mitogen - activated protein kinase cascade , specifically , extracellular signal - regulated kinase 2 ( P28482 ) mitogen - activated protein kinase . Of most interest , SDF - 1alpha treatment induced expression of the chemokines monocyte chemoattractant protein - 1 , P10145 , and P01579 - inducible protein - 10 . SDF - 1alpha - induced chemokine expression was abrogated upon inclusion of U0126 , a pharmacological inhibitor of P27361 / 2 , indicating that the P29323 signaling cascade is involved in this response . Collectively , these data suggest that P61073 - mediated signaling pathways in astroglioma cells may be another mechanism for these cells to express chemokines involved in angiogenesis and inflammation .","Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK87___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .","[ ___MASK39___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .","Role of everolimus in pancreatic neuroendocrine tumors . Survival from pancreatic neuroendocrine tumors has not improved over the past two decades and , until recently , streptozocin was the last therapeutic agent approved for this malignancy . ___MASK9___ blocks P42345 , which plays an integral role in cell growth , mitosis and angiogenesis . Abnormal PI3K - Akt / P31749 - P42345 pathway signaling has been implicated in the pathogenesis of pancreatic neuroendocrine tumors . In a Phase III study , patients with low - and intermediate - grade advanced pancreatic neuroendocrine tumors were randomized to receive everolimus 10 mg / day or placebo . Median progression - free survival was significantly greater in patients treated with everolimus than placebo - 11 versus 4 . 6 months - and drug - related adverse events were consistent with the known side - effect profile of everolimus . ___MASK9___ represents a significant treatment development for pancreatic neuroendocrine tumors .","P21728 , but not dopamine D2 receptor , is a critical regulator for acute cocaine - enhanced gene expression . OBJECTIVE : The aim of present study is to investigate the roles of dopamine receptor subfamilies and their subsequent molecular events in cocaine - enhanced gene expression in striatum . METHODS : Acute cocaine - treated mice models were build to address this issue . Specific antagonists for dopamine D1 and D2 receptors ( P35240 23390 and raclopride , respectively ) and specific inhibitor for extracellular signal - regulated protein kinase 1 / 2 ( P27361 / 2 ) kinase were pretreated . Immunofluorescence was used to detect the expressions of c - Fos , phosphorylated DB02527 response element binding ( p - CREB ) and phosphorylated Elk - 1 ( p - Elk - 1 ) in striatum . RESULTS : Acute cocaine injection significantly enhanced expressions of c - Fos , p - CREB and p - Elk - 1 in the striatum . Notably , these enhancements were totally blocked to normal level by P35240 23390 pre - treatment , while no changes occurred in the presence of raclopride . Moreover , we found that dopamine D1 receptor was involved in acute cocaine - induced activation of P27361 / 2 in the striatum . Blockade of this dopamine D1 receptor - dependent P27361 / 2 activation by SL 327 could reduce cocaine - enhanced expressions of c - Fos , p - CREB and p - Elk - 1 in the striatum . DISCUSSION : These results suggest that dopamine D1 receptor , but not dopamine D2 receptor , plays a critical role in regulating acute cocaine - enhanced gene expression in the striatum , and P27361 / 2 pathway may contribute to this regulation .","Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells . Histone deacetylase inhibitors are promising anti - tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies . However , little is known about any effects of these drugs on the central nervous system . The aim of the present study was to analyze the effects of trichostatin A ( P32119 ) -- a broad - spectrum histone deacetylase inhibitor -- on the transcriptional regulation of several genes involved in dopamine - and serotonergic neurotransmission . To this end , short - term parallel cultures of SK - NF - I neuroblastoma cells were treated with P32119 either alone or in combination with hypoxia , and mRNA levels of dopamine receptor D3 ( P35462 ) and D4 ( P21917 ) , dopamine transporter ( Q01959 ) , dopamine hydroxylase ( P09172 ) , dopamine receptor regulating factor ( DRRF ) , catechol - O - methyltransferase ( P21964 ) , serotonin receptor 1A ( P08908 ) , monoamino oxidase A ( P21397 ) , serotonin transporter ( P31645 ) and tryptophan hydroxylase 2 ( Q8IWU9 ) were determined by quantitative PCR . We found that P32119 did not antagonize the hypoxia - induced activation of D3 and D4 dopamine receptor genes , implying that induction of these genes is not mediated directly by hypoxia inducible factor - 1alpha . On the other hand , P32119 dramatically upregulated the expression of Q01959 and P31645 ( 45 - fold and 15 - fold , respectively ) , while transcript levels of P21397 and P21964 were significantly reduced ( by 70 % and by more than 90 % , respectively ) . Induction of Q01959 protein expression was detected by western blotting . These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons .","Bacterial superantigens bypass Lck - dependent T cell receptor signaling by activating a Galpha11 - dependent , P98160 - beta - mediated pathway . The paradigm to explain antigen - dependent T cell receptor ( TCR ) signaling is based on the activation of the P01730 or CD8 coreceptor - associated kinase Lck . It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens . However , these bacterial toxins can activate human T cells lacking Lck , suggesting the existence of an additional pathway of TCR signaling . Here we showed that this alternative pathway operates in the absence of Lck - dependent tyrosine - phosphorylation events and was initiated by the TCR - dependent activation of raft - enriched heterotrimeric Galpha11 proteins . This event , in turn , activated a phospholipase C - beta and protein kinase C - mediated cascade that turned on the mitogen - activated protein kinases P27361 and P28482 , triggered Ca ( 2 +) influx , and translocated the transcription factors NF - AT and NF - kappaB to the nucleus , ultimately inducing the production of interleukin - 2 in Lck - deficient T cells . The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein - coupled receptor as a coreceptor on T cells .","Dopamine receptor D4 polymorphism predicts the effect of DB01235 on gambling behavior . BACKGROUND : There is ample evidence that a subgroup of Parkinson ' s disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling . The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors . These are potentially of genetic origin , since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 ( P21917 ) gene . Using a pharmacogenetic approach , we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects . METHODS : We administered 300 mg of L - dihydroxyphenylalanine ( DB01235 ) or placebo to 200 healthy male subjects who were all genotyped for their P21917 polymorphism . Subjects played a gambling task 60 minutes after DB01235 administration . RESULTS : Without considering genetic information , DB01235 administration did not lead to an increase in gambling propensity compared with placebo . As expected , however , an individual ' s P21917 polymorphism accounted for variation in gambling behavior after the administration of DB01235 . Subjects who carry at least one copy of the 7 - repeat allele showed an increased gambling propensity after dopaminergic stimulation . CONCLUSIONS : These findings demonstrate that genetic variation in the P21917 gene determines an individual ' s gambling behavior in response to a dopaminergic drug challenge . They may have implications for the treatment of Parkinson ' s disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior .","___MASK9___ ( RAD001 ) : an P42345 inhibitor for the treatment of metastatic renal cell carcinoma . The recent introduction of drugs that inhibit angiogenesis or the P42345 has provided new options for the treatment of metastatic renal cell carcinoma , a disease which often has a poor prognosis . Chemotherapy and cytokine therapy are largely ineffective . The 5 - year survival rate is under 10 % . ___MASK9___ , an immunosuppressive drug widely used for the prevention of allograft rejection and an P42345 inhibitor , is one of the latest drugs undergoing clinical trials in metastatic renal cell carcinoma . It has been tested in patients with progressive disease after therapy with tyrosine kinase receptor inhibitors ( sunitinib , sorafenib or both ) , which interfere with signaling pathways , such as the P15692 pathway . Clinical efficacy results ( progression - free survival ) for everolimus are promising and the safety profile is good .","Q9UD71 as a marker for D - 1 dopaminoceptive cells in the rat brain : prenatal development and presence in glial elements ( tanycytes ) in the basal hypothalamus . The present article reviews some aspects of the localization of a dopamine - and cyclic AMP - regulated phosphoprotein , Q9UD71 , which is assumed to be present in D - 1 dopaminoceptive neurons . Its prenatal development starts at day 14 of gestation , is to a large extent complete at birth and seems to be independent of ingrowing dopamine - containing afferents . Rearrangements occur in certain areas , and in some systems Q9UD71 appears to be only transiently expressed . The presence of Q9UD71 in glial structures , the tanycytes , in the arcuate nucleus - median eminence complex in the mediobasal hypothalamus , has given further support to the hypothesis that dopamine , by controlling the shape of the tanycytes and the extension of their processes , can regulate P01148 release by a ' mechanical mechanism ' . This hypothesis is now being examined in some experimental paradigms .","Shared and unique genetic contributions to attention deficit / hyperactivity disorder and substance use disorders : a pilot study of six candidate genes . The shared genetic basis of attention deficit / hyperactivity disorder ( ADHD ) and substance use disorders ( SUDs ) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders . One hundred seven methadone maintenance treatment patients , 36 having an ADHD diagnosis , 176 adult patients with ADHD without SUDs , and 500 healthy controls were genotyped for variants in the P21917 ( exon 3 VNTR ) , P21918 ( upstream VNTR ) , P28222 ( rs6296 ) , P09172 ( rs2519152 ) , P21964 ( rs4680 ; Val158Met ) , and P35372 ( rs1799971 ; 118A > G ) genes . Association with disease was tested using logistic regression models . This pilot study was adequately powered to detect larger genetic effects ( OR ≥ 2 ) of risk alleles with a low frequency . Compared to controls , ADHD patients ( with and without SUDs ) showed significantly increased frequency of the P09172 ( rs2519152 : OR 1 . 73 ; CI 1 . 15 - 2 . 59 ; P = 0 . 008 ) and the P35372 risk genotypes ( rs1799971 : OR 1 . 71 ; CI 1 . 17 - 2 . 50 ; P = 0 . 006 ) . The P09172 risk genotype was associated with ADHD diagnosis , with the association strongest in the pure ADHD group . The P35372 risk genotype increased the risk for the combined ADHD and SUD phenotype . The present study strengthens the evidence for a shared genetic basis for ADHD and addiction . The association of P35372 with the ADHD and SUD combination could help to explain the contradictory results of previous studies . The power limitations of the study restrict the significance of these findings : replication in larger samples is warranted .","P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .","DB01235 - treatment in primates disrupts the expression of A ( 2A ) adenosine - CB ( 1 ) cannabinoid - P14416 heteromers in the caudate nucleus . The molecular basis of priming for DB01235 - induced dyskinesias in Parkinson ' s disease ( PD ) , which depends on the indirect pathway of motor control , is not known . In rodents , the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A ( 2A ) adenosine , CB ( 1 ) cannabinoid and D ( 2 ) dopamine receptors that regulate dopaminergic neurotransmission . The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson ' s disease and to determine whether their expression and pharmacological properties are altered upon DB01235 treatment . By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint , we discovered a regional distribution of A ( 2A )/ CB ( 1 ) / D ( 2 ) receptor heteromers that predicts differential D ( 2 )- mediated neurotransmission in the caudate - putamen of Macaca fascicularis . Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP - treated monkeys , DB01235 treatment blunted the biochemical fingerprint and led to weak heteromer expression . These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A ( 2A )- CB ( 1 ) - D ( 2 ) receptor heteromers may be successful to either normalize basal ganglia output or prevent DB01235 - induced side effects .","P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK77___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .","Interaction between serotonin transporter gene , catechol - O - methyltransferase gene and stressful life events in mood disorders . It is well established that stress is a risk factor for onset of mood disorders . Emerging evidence suggests that genetic vulnerability may also moderate individual responsiveness to stress . The most compelling evidence regards the polymorphism within the promoter region of the serotonin transporter gene ( SERTPR ) , which has been reported to moderate the risk for depression , in conjunction with life stressors . In the present paper we analysed SERTPR in the onset of mood disorders , along with adverse life events , and other candidate genes : the serotonin receptor 1A ( P08908 ) , the dopamine receptor D4 ( P21917 ) and the catechol - O - methyltransferase ( P21964 ) . The sample was composed of 686 Italian subjects , affected by major depression and bipolar disorder . Patients were asked to report about life stressors within the year preceding onset of their first mood - disorder episode and genotyped . A ' case - only ' design was employed to investigate the interaction between genes and stressors . P21964 was associated with depression following exposure to stressors ( chi2 = 13 . 05 , d . f .= 2 , p = 0 . 0015 ) and SERTPR also showed a positive association ( chi2 = 6 . 70 , d . f .= 2 , p = 0 . 035 ) , mainly among women and among major depressives . The interaction between P21964 and SERTPR was also significant ( p = 0 . 0005 ) . In our retrospective study SERTPR is hypothesized to lead to the onset of major depression via its influence on reaction to adversities , particularly in females . Moreover , P21964 was risk factor for onset of both major depression and bipolar disorder , in conjunction with adversities .","Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK42___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .","Radiation hybrid map of 13 loci on the long arm of chromosome 5 . Radiation hybrid mapping was used in conjunction with a natural deletion mapping panel to predict the order of and distance between 13 loci in the distal portion of the long arm of human chromosome 5 . A panel of irradiation hybrids containing fragments of 5q was generated from an P00492 + Chinese hamster - human cell hybrid containing a derivative chromosome 5 [ der ( 5 ) t ( 4 ; 5 ) ( 5qter ---- 5p15 . 1 :: 4p15 . 1 ---- 4pter ) ] as its only human DNA . One hundred nine radiation hybrids containing human DNA were screened with polymerase chain reaction primer sets representing nine genes encoding growth factors , growth factor receptors , or hormone receptors ( P08700 , P05112 , P05113 , P07333 , P05230 , P07550 , GRL , P14867 , and P21728 ) as well as four other loci ( P16591 , P09486 , P62263 , and P08571 ) to generate a radiation hybrid map of the area 5q21 - q35 . A physical map predicting the order of and distance between the 13 loci was constructed based on segregation of the 13 loci in hybrid clones . The radiation hybrid panel will be useful as a mapping tool for determining the location and order of other genes and polymorphic loci in this region as well as for generating new DNA probes from specific regions .","P00797 - angiotensin system revisited . New components and functions of the renin - angiotensin system ( DB01367 ) are still being unravelled . The classical DB01367 as it looked in the middle 1970s consisted of circulating renin , acting on angiotensinogen to produce angiotensin I , which in turn was converted into angiotensin II ( Ang II ) by angiotensin - converting enzyme ( P12821 ) . Ang II , still considered the main effector of DB01367 was believed to act only as a circulating hormone via angiotensin receptors , AT1 and P50052 . Since then , an expanded view of DB01367 has gradually emerged . Local tissue DB01367 systems have been identified in most organs . Recently , evidence for an intracellular DB01367 has been reported . The new expanded view of DB01367 therefore covers both endocrine , paracrine and intracrine functions . Other peptides of DB01367 have been shown to have biological actions ; angiotensin 2 - 8 heptapeptide ( Ang III ) has actions similar to those of Ang II . Further , the angiotensin 3 - 8 hexapeptide ( Ang IV ) exerts its actions via insulin - regulated amino peptidase receptors . Finally , angiotensin 1 - 7 ( Ang 1 - 7 ) acts via mas receptors . The discovery of another Q9BYF1 was an important complement to this picture . The recent discovery of renin receptors has made our view of DB01367 unexpectedly complex and multilayered . The importance of DB01367 in cardiovascular disease has been demonstrated by the clinical benefits of P12821 inhibitors and AT1 receptor blockers . Great expectations are now generated by the introduction of renin inhibitors . Indeed , DB01367 regulates much more and diverse physiological functions than previously believed .","Sustained increase of PKA activity in the postcommissural putamen of dyskinetic monkeys . Levodopa - induced dyskinesias ( LID ) are a frequent complication of Parkinson ' s disease pharmacotherapy that causes significant disability and narrows the therapeutic window . Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood . Here , our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication . We examined the expression and downstream activity of dopamine receptors ( DR ) in the striatum of 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 tetrahydropiridine ( MPTP ) - lesioned monkeys with and without DB01235 treatment . Four monkeys were made dyskinetic and other four received a shorter course of DB01235 and did not develop LID . Our results show that DB01235 treatment induces an increase in P14416 and P35462 expression in the postcommissural putamen , but only P35462 is correlated with the severity of LID . Dyskinetic monkeys show a hyperactivation of the canonical P21728 - signaling pathway , measured by an increased phosphorylation of protein kinase A ( PKA ) and its substrates , particularly Q9UD71 . In contrast , activation of the P14416 - signaling pathway , visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9 , is associated with DB01235 treatment , independently of the presence of dyskinesias . Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the P35462 receptor and the P21728 pathway with a sustained increase of PKA activity in the postcommissural putamen . Importantly , we found that all signaling changes related to long - term DB01235 administration are exquisitely restricted to the postcommissural putamen , which may be related to the recurrent failure of pharmacological approaches .","The interleukin 10 promoter haplotype ACA and the long - form variant of the P21917 uVNTR polymorphism are associated with vulnerability to schizophrenia . A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin - 10 ( P22301 ) promoter and P21917 uVNTR polymorphisms . P21917 long - form variants ( namely , those with ≥ 5 repeats ) , homozygosity for the 4 - repeat allele , and the P22301 haplotype ACA were associated with schizophrenia , respectively . No obvious interactions among the potential polymorphisms were found , which suggests that P22301 and P21917 confer vulnerability to schizophrenia independently .","A genomic insight into diversity among tribal and nontribal population groups of Manipur , India . Twenty autosomal markers , including linked markers at two gene markers , are used to understand the genomic similarity and diversity among three tribal ( Paite , Thadou , and Kom ) and one nontribal communities of Manipur ( Northeast India ) . Two of the markers ( P01730 and HB9 ) are monomorphic in Paite and one ( the P01730 marker ) in Kom . Data suggest the Meitei ( nontribal groups ) stand apart from the three tribal groups with respect to higher heterozygosity ( 0 . 366 ) and presence of the highest ancestor haplotypes of P14416 markers ( 0 . 228 ) ; this is also supported by principal co - ordinate analysis . These populations are found to be genomically closer to the Chinese population than to other Indian populations .","Q9UD71 increases interactions between epidermal growth factor receptor and P21860 to promote tumor resistance to gefitinib . BACKGROUND & AIMS : Dopamine and adenosine 3 ', 5 '- cyclic monophosphate - regulated phosphoprotein , Mr 32000 ( Q9UD71 ) , is overexpressed during gastric carcinogenesis . Gastric tumors can become resistant to gefitinib , an inhibitor of the epidermal growth factor receptor ( P00533 ) . We investigated the role of Q9UD71 in gastric tumor resistance to gefitinib . METHODS : Cell survival was determined by clonogenic survival and DB00171 - Glo Viability Assays . Apoptosis was assessed by Annexin - V and immunoblot analyses . The association between Q9UD71 and P00533 was evaluated by immunofluorescence and co - immunoprecipitation assays . Findings were validated in mice with gastric xenograft tumors . Q9UD71 expression was reduced using small hairpin RNAs in the human gastric cancer cell lines SNU - 16 and MKN - 45 cells . RESULTS : Overexpression of Q9UD71 in MKN - 28 cells , which do not normally express Q9UD71 , blocked gefitinib - induced apoptosis and increased the drug ' s IC ( 50 ) 10 - fold , compared to that of control cells ( P < . 01 ) . Reduced expression of Q9UD71 in SNU - 16 cells increased the sensitivity to gefitinib ( P < . 01 ) . Q9UD71 activated phosphatidylinositol - 3 - kinase - AKT signaling , increased stability of the P00533 , and suppressed P01133 - or gefitinib - induced degradation of the P00533 . Q9UD71 colocalized with P00533 on the cell membrane in a complex with P00533 and the P01133 receptor P21860 . Q9UD71 - mediated resistance to gefitinib resulted from increased phosphorylation of and interaction between P00533 and P21860 , which led to phosphorylation of AKT ( at serine 473 ) . Knockdown of Q9UD71 in gastric cancer cells reduced the mean size of tumors in mice and increased their response to gefitinib . CONCLUSIONS : Q9UD71 promotes resistance of gastric cancer cells to gefitinib by promoting interaction between P00533 and P21860 and activating phosphatidylinositol - 3 - kinase - AKT signaling .","Expression profile of genes associated with the dopamine pathway in vitiligo skin biopsies and blood sera . BACKGROUND : Dopamine has been proven to be toxic for melanocytes . In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed . METHODS : With the use of quantitative real - time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway ( PAH , P61457 , TH , DDC , P09172 , PNMT , P07203 , P21397 , P27338 , P21964 , P21728 - P21918 , P54219 and Q05940 ) was observed in vitiligo patients ' and control subjects ' skin and blood . RESULTS : The mRNA expression of P07203 , DDC , P21397 , P21728 and P21918 differs in vitiligo skin and the protein level of DDC , P21397 , P27338 , P21728 and P21918 is changed in vitiligo patients ' skin and / or blood sera . CONCLUSIONS : The dopamine pathway probably influences melanogenesis directly or through the melanocortin pathway . We provide new data about changes of expression profile of the dopamine - synthesizing enzyme DDC , the dopamine - degrading enzymes P21397 and P27338 and the D1 - like family dopamine receptors in vitiligo skin and blood sera .","Dopamine receptor agonists reverse behavioral abnormalities of alpha - synuclein transgenic mouse , a new model of Parkinson ' s disease . Parkinson ' s disease ( PD ) is characterized by loss of nigral dopaminergic ( DAergic ) neurons and presence of Lewy bodies , whose major component is alpha - synuclein . We had previously generated transgenic mice termed Syn130m that express truncated human alpha - synuclein ( amino acid residues 1 - 130 ) in DAergic neurons . Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta . Subsequently , the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly . In the present study , we investigated behavioral responses of Syn130m mice to DB01235 and DA receptor agonists . Administration of DB01235 dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice . Similarly , D ( 2 ) agonists , quinpirole and talipexole , and a D1 / D2 agonist , pergolide , were effective against the reduction . Syn130m mice also showed significant reduction in exploratory behavior compared with non - Tg littermates when they were placed in a novel environment , but this abnormality was ameliorated by treatment with pergolide . These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content . On the other hand , the expression of postsynaptic D ( 2 )- like receptors ( P14416 ) in the striatum was not increased in Syn130m mice , although the low striatal DA level is known to induce compensatory expression of P14416 . Because the abnormalities could be rectified by treatment with DA receptor agonists , it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease .","___MASK53___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK53___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK53___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK53___ inhibits activated T cells . We show that in vitro , ___MASK53___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK53___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK53___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK53___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK53___ to treat chronic inflammatory disease .","P22301 - inducing adjuvants enhance sublingual immunotherapy efficacy in a murine asthma model . BACKGROUND : P22301 - inducing adjuvants could enhance the efficacy of allergy vaccines in establishing allergen - specific tolerance . The aim of this study was to identify such adjuvants using in vitro cultures of human and murine cells and to evaluate them in a therapeutic murine model of sublingual immunotherapy ( SLIT ) . METHODS : Adjuvants stimulating P22301 gene expression by human or murine immune cells were tested sublingually in BALB / c mice sensitized to ovalbumin ( OVA ) , assessing the reduction in airway hyperresponsiveness ( P35869 ) by whole - body plethysmography . The induction of regulatory T cells ( T ( reg ) ) was evaluated using phenotypic and functional assays . T - cell proliferation in cervical lymph nodes ( LNs ) was assessed following intravenous transfer of CFSE - labelled OVA - specific T cells and FACS analysis . RESULTS : A combination of 1 , 25 - dihydroxyvitamin D3 plus dexamethasone ( VitD3 / DB00514 ) as well as Lactobacillus plantarum were found to induce P22301 production by human and murine dendritic cells ( DCs ) . The former inhibits LPS - induced DC maturation , whereas L . plantarum induces DC maturation . Following stimulation with VitD3 / DB00514 - pretreated DCs , P01730 + naïve T cells exhibit a T ( reg ) profile . In contrast , a Th1 / T ( reg ) pattern of differentiation is observed in the presence of DCs treated with L . plantarum . Both adjuvants significantly enhance SLIT efficacy in mice , in association with either induction of Foxp3 + T ( reg ) cells ( for VitD3 / DB00514 ) or proliferation of OVA - specific T cells in cervical LNs ( for L . plantarum ) . CONCLUSIONS : Both VitD3 / DB00514 and L . plantarum polarize naïve T cells towards P22301 - expressing T cells , through distinct mechanisms . As adjuvants , they both enhance SLIT efficacy in a murine asthma model .","Adrenal and gonadal function in hypothyroid adult male rats . The functional relationship between thyroid , adrenal and gonadal hormones was investigated using adult male rats . Hypothyroidism was produced by the administration of 4 - methyl - 2 - thiouracil ( thiouracil ) in the drinking water for 2 weeks . Plasma concentrations of DB00024 dramatically increased , whereas plasma concentrations of tri - iodothyronine and thyroxine decreased in thiouraciltreated rats as compared with euthyroid rats . Hypothyroidism increased basal levels of plasma DB01285 and pituitary content of DB01285 . The pituitary responsiveness to P06850 for DB01285 release markedly increased , whereas the adrenal responsiveness to DB01285 for corticosterone release decreased . These results indicated that hypothyroidism causes adrenal dysfunction in adult male rats . Pituitary contents of LH and prolactin decreased in hypothyroid rats as compared with euthyroid rats . In addition , hypothyroidism lowered pituitary LH responsiveness to P01148 . Testicular responsiveness to human chorionic gonadotrophin for testosterone release , however , was not different between euthyroid and hypothyroid animals . These results indicated that hypothyroidism causes adrenal dysfunction and results in hypersecretion of DB01285 from the pituitary gland . Adrenal dysfunction may contribute to the inhibition of P01148 secretion from the hypothalamus , possibly mediated by excess P06850 .","P14416 - induced heterologous sensitization of adenylyl cyclase requires Galphas : characterization of Galphas - insensitive mutants of adenylyl cyclase V . Whereas acute stimulation of Galphai / o - coupled receptors inhibits the activity of adenylyl cyclase , a delayed consequence of persistent activation of the receptors is heterologous sensitization , an enhanced responsiveness of adenylyl cyclase to activators such as forskolin or agonists of Galphas - coupled receptors . Galphas - insensitive mutants of adenylyl cyclase type V were used to test the hypothesis that heterologous sensitization requires Galphas - dependent activation of adenylyl cyclase . When adenylyl cyclase was stably expressed in human embryonic kidney ( P29320 ) 293 cells with the D2L dopamine receptor , basal , forskolin - stimulated , and isoproterenol - stimulated cyclic AMP accumulation were all enhanced by 2 - h pretreatment with the D2 receptor agonist quinpirole . Transient expression of wild - type adenylyl cyclase and three Galphas - insensitive mutants ( F379L , R1021Q , and F1093S ) in HEK293 cells stably expressing the D2L receptor demonstrated that all three mutants had little or no responsiveness to beta - adrenergic receptor - mediated activation of Galphas but that the mutants retained sensitivity to forskolin and to D2L receptor - mediated inhibition . Transiently expressed adenylyl cyclase V was robustly sensitized by 2 - h pretreatment with quinpirole . In contrast , the Galphas - insensitive mutants displayed no sensitization of forskolin - stimulated cyclic AMP accumulation , indicating that responsiveness to Galphas is required for the expression of heterologous sensitization .","Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .","P12821 inhibitors could be therapeutic for antisocial personality disorder . Antisocial personality traits are an important topic for research . The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes . Catecholamine genes are being studied to facilitate this understanding , and some tentative findings are being reached about several of these genes . It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious . One conclusion that could be drawn from the current research findings is that DA2 like receptors ( P14416 , P35462 , P21917 ) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors . DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition . When these receptors are less active by genetically decreased density , lower affinity , or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state . Peripheral metabolism is increased and behavioral activation is noted . P00797 is disinhibited in this setting thus allowing sympathetic nervous system activation . The fight or flight behaviors thus produced , in the extreme , would be the setting of antisocial behavior . Research validates this hypothesis . Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others . P12821 inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders .","P21728 behavioral responsitivity following selective lesions of the striatal patch compartment during development . The behavioral effects of selective destruction of the dopamine ( DA ) input to the patch compartment of rat striatum early in development was investigated . Rat pups were given bilateral intrastriatal ( i . s . ) injections of the neurotoxin 6 - hydroxydopamine ( 6 - OHDA ) on day of birth ( P0 ) or postnatal day 1 ( P1 ) , which resulted in selective behavioral alterations following DA agonist treatment in adulthood . Neonatally - lesioned rats exhibited self - biting behavior following treatment with the DA precursor L - dihydroxyphenylalanine ( DB01235 ) . In response to treatment with the selective D1 agonist SKF38393 , there was an increased incidence of abnormal perioral movements . The cataleptogenic effects of the D1 antagonist SCH23390 and the D2 antagonist haloperidol were also studied . Neonatally - lesioned rats were significantly less cataleptic compared to control rats following D1 antagonist treatment , but not following D2 antagonist treatment . Autoradiographs of [ 3H ] mazindol binding to DA uptake sites ( a measure of DA terminal density ) showed a ' patchy ' loss of approx . 40 - 50 % in striatal tissue sections derived from the i . s . lesioned rats . These data suggest that injections of 6 - OHDA into the striatum during this early postnatal period cause a DA lesion that results in long - term effects on a D1 receptor system .","___MASK30___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .","Blockade of globus pallidus adenosine A ( 2A ) receptors displays antiparkinsonian activity in 6 - hydroxydopamine - lesioned rats treated with D ( 1 ) or P14416 agonists . We have recently demonstrated how antagonism of adenosine A ( 2A ) receptors within the globus pallidus ( GP ) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor DB01235 in 6 - hydroxydopamine - lesioned hemiparkinsonian rats . To further characterize the influence of pallidal A ( 2A ) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation , hemiparkinsonian rats were infused with the water - soluble A ( 2A ) antagonist P35240 BT2 in the GP , alone or in combination with systemic administration of either SKF 38393 or quinpirole , to stimulate dopamine D ( 1 ) or D ( 2 ) receptors , respectively . P35240 BT2 alone ( 5 mug / 1 mul ) neither altered motor behavior nor produced postural asymmetry . In contrast , the contralateral rotations elicited by SKF 38393 ( 1 . 5 mg / kg ) as well as quinpirole ( 0 . 05 mg / kg ) were potentiated by the concomitant intrapallidal infusion of P35240 BT2 . The results of this study demonstrate that blockade of pallidal A ( 2A ) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D ( 1 ) or D ( 2 ) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A ( 2A ) receptor antagonists .","Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .","Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .","Genetic basis of delay discounting in frequent gamblers : examination of a priori candidates and exploration of a panel of dopamine - related loci . INTRODUCTION : Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards . It has been consistently linked to pathological gambling and other forms of addictive behavior , and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders ( i . e . , an endophenotype ) . Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission . The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine - related variants in a sample of frequent gamblers . METHODS : Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva . RESULTS : In a priori tests , two loci previously associated with delayed reward discounting ( rs1800497 and rs4680 ) were not replicated , however , the long form of P21917 VNTR was significantly associated with lower discounting of delayed rewards . Exploratory analysis of the dopamine - related panel revealed 11 additional significant associations in genes associated with dopamine synthesis , breakdown , reuptake , and receptor function ( P35462 , Q01959 , DDC , P09172 , and Q05940 ) . An aggregate genetic risk score from the nominally significant loci accounted for 17 % of the variance in discounting . Mediational analyses largely supported the presence of indirect effects between the associated loci , delay discounting , and pathological gambling severity . CONCLUSIONS : These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting .","Single - nucleotide polymorphisms of the dopamine D2 receptor increase inflammation and fibrosis in human renal proximal tubule cells . The dopamine D2 receptor ( D2R ) negatively regulates inflammation in mouse renal proximal tubule cells ( RPTCs ) , and lack or downregulation of the receptor in mice increases the vulnerability to renal inflammation independent of blood pressure . Some common single - nucleotide polymorphisms ( SNPs ; rs6276 , rs6277 , and rs1800497 ) in the human P14416 gene are associated with decreased D2R expression and function , as well as high blood pressure . We tested the hypothesis that human RPTCs ( hRPTCs ) expressing these SNPs have increased expression of inflammatory and injury markers . We studied immortalized hRPTCs carrying D2R SNPs and compared them with cells carrying no D2R SNPs . RPTCs with D2R SNPs had decreased D2R expression and function . The expressions of the proinflammatory tumor necrosis factor - α and the profibrotic transforming growth factor - β1 and its signaling targets P84022 and Snail1 were increased in hRPTC with D2R SNPs . These cells also showed induction of epithelial mesenchymal transition and production of extracellular matrix proteins , assessed by increased vimentin , fibronectin 1 , and collagen I a1 . To test the specificity of these D2R SNP effects , hRPTC with D2R SNPs were transfected with a plasmid encoding wild - type P14416 . The expression of D2R was increased and that of transforming growth factor - β1 , P84022 , Snail1 , vimentin , fibronectin 1 , and collagen I a1 was decreased in hRPTC with D2R SNPs transfected with wild - type P14416 compared with hRPTC - D2R SNP transfected with empty vector . These data support the hypothesis that D2R function has protective effects in hRPTCs and suggest that carriers of these SNPs may be prone to chronic renal disease and high blood pressure .","Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK21___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .","Neurogenetics of aggressive behavior : studies in primates . Aggressive behavior can have adaptive value in certain environmental contexts , but when extreme or executed inappropriately , can also lead to maladaptive outcomes . Neurogenetic studies performed in nonhuman primates have shown that genetic variation that impacts reward sensitivity , impulsivity , and anxiety can contribute to individual differences in aggressive behavior . Genetic polymorphisms in the coding or promoter regions of the Mu - Opioid Receptor ( P35372 ) , DB01285 Releasing Hormone ( P06850 ) , Monoamine Oxidase A ( P21397 ) , Dopamine D4 Receptor ( P21917 ) , and Serotonin Transporter ( P31645 ) genes have been shown to be functionally similar in humans and rhesus macaques and have been demonstrated to contribute to individual differences in aggression . This body of literature suggests mechanisms by which genetic variation that promotes aggressivity could simultaneously increase evolutionary success while making modern humans more vulnerable to psychopathology .","Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .","P35462 stimulation underlies the development of DB01235 - induced dyskinesia in animal models of Parkinson ' s disease . Development of DB01235 - induced dyskinesia ( LID ) remains a major problem in the long - term treatment of Parkinson ' s disease ( PD ) . Sensitization to DB01235 correlates with ectopic expression of D3 dopamine receptors in the striatum , implicating D3 receptors in development of LID . We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP - lesioned marmosets without effecting the anti - parkinsonian actions of DB01235 . Furthermore , following a 14 day washout , when challenged with DB01235 in the absence of S33084 , these animals continued to exhibit reduced LID . In the 6 - OHDA - lesioned rat , S33084 similarly attenuated development of behavioural sensitization to DB01235 . Additionally , DB01235 - induced elevations in striatal pre - proenkephalin - A ( PPE - A ) ( but not PPE - B , phospho [ DB00156 ( 34 )] Q9UD71 , D1 , and D2 receptor mRNA or D3 receptor levels ) were reduced in S33084 treated animals . Our data suggest a role for D3 receptors in the development of LID and suggest that initiating DB01235 treatment with a D3 antagonist may reduce the development of LID in PD .","D3 dopamine receptor activates phospholipase D through a pertussis toxin - insensitive pathway . Within the dopamine receptor family , the P35462 ' s function remains inadequately described . The D ( 3 ) receptor has been shown to couple to inhibition of adenylyl cyclase , stimulation of mitogenesis , and regulation of K (+) and Ca ( 2 +) currents , all in a pertussis toxin ( PTX ) - sensitive manner . Here we report D ( 3 ) receptor activation of the phospholipase D ( PLD ) enzyme in P29320 293 cells heterologously expressing the human D ( 3 ) receptor . Activation by agonist is dose dependent and displays the pharmacology expected of the D ( 3 ) receptor . The D ( 3 ) receptor specific antagonists AJ - 76 and U99194A ablated the increase in activity by the preferring D ( 3 ) agonist ( + ) 7 - OH DPAT . In addition , the D ( 3 ) receptor - mediated activation of PLD is not mediated by G - proteins of the G ( i )/ G ( o ) family , as pretreatment with PTX had no effect . PLD activation is a novel finding for the D ( 3 ) receptor , and is the first example of an effector system where D ( 3 ) signals without G ( i )/ G ( o ) protein intermediates .","The Akt / mTor signaling cascade is modified during placentation in the porcine uterine tissue . Recently we showed that essential components for the initiation of protein synthesis , namely the eukaryotic initiation factor 4E ( P06730 , mRNA - cap - binding protein ) and its repressors Q13541 as well as Q13542 , are proteolytically processed in the porcine endometrium during implantation . Here , the situation during placentation was compared with ovariectomized ( OVX ) animals and animals on pregnancy day 1 ( PD1 ) . Furthermore , the research was extended to factors which phosphorylate P06730 and 4E - BPs and regulate their activities . These are the protein kinase B / mammalian target of rapamycin kinase ( Akt / mTor ) with the regulators Q8N122 and Rictor as well as the mitogen activated protein kinases ( MAPKs ) : extra cellular - signal regulated kinase 1 and 2 ( P27361 and P28482 ) . Striking differences in the placentation site ( PS ) and the areas aside from PS ( peri - PS ) were observed . P06730 and Q13542 truncation as well as Q13541 degradation took place in the endometrium of the peri - PS on PD24 . Accompanied by a fragmentation of Akt / mTor , no expression of Rictor was observed , whereas the abundance of Q8N122 was not altered . On the contrary , MAPKs expression and phosphorylation remained almost stable in the peri - PS . In conclusion , the results indicated that on PD24 the translational regulation was shifted to Q13542 control . Furthermore , the Akt / mTor signaling cascade seemed to be down regulated which suggest reduced phosphorylation of Q13542 . Whereas Akt was proteolyzed , the observed mTor fragments represented most likely splicing variants . The results indicate that translational control of gene expression is an important feature in the porcine endometrium during early pregnancy .","The role of the subthalamic nucleus in DB01235 induced dyskinesia in 6 - hydroxydopamine lesioned rats . DB01235 is the most effective treatment for Parkinson ' s disease ( PD ) , but prolonged use leads to disabling motor complications including dyskinesia . Strong evidence supports a role of the subthalamic nucleus ( Q05639 ) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy . Here , we investigated the involvement of Q05639 in dyskinesia , using single - unit extracellular recording , behavioural and molecular approaches in hemi - parkinsonian rats rendered dyskinetic by chronic DB01235 administration . Our results show that chronic DB01235 treatment does not modify the abnormal Q05639 activity induced by the 6 - hydroxydopamine lesion of the nigrostriatal pathway in this model . Likewise , we observed a loss of Q05639 responsiveness to a single DB01235 dose both in lesioned and sham animals that received daily DB01235 treatment . We did not find any correlation between the abnormal involuntary movement ( AIM ) scores and the electrophysiological parameters of Q05639 neurons recorded 24 h or 20 - 120 min after the last DB01235 injection , except for the axial subscores . Nonetheless , unilateral chemical ablation of the Q05639 with ibotenic acid resulted in a reduction in global AIM scores and peak - severity of dyskinesia . In addition , Q05639 lesion decreased the anti - dyskinetogenic effect of buspirone in a reciprocal manner . Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB , phosphoDARPP - 32 , dopamine receptor ( DR ) D3 and P14416 / P21728 ratio . The Q05639 lesion attenuated the striatal molecular changes and normalized the P14416 / P21728 ratio . Taken together , our results show that the Q05639 plays a role , if modest , in the physiopathology of dyskinesias .","Synergistic activity of activin A and basic fibroblast growth factor on tyrosine hydroxylase expression through P84022 and P27361 / P28482 MAPK signaling pathways . Activin has previously been shown to act as a nerve cell survival factor and to have neurotrophic effects on neurons . However , the role of activin in regulating neurotransmitter expression in the central nervous system and the exact mechanisms involved in this process are poorly understood . In the present study , we report that activin A and basic fibroblast growth factor ( P09038 ) synergistically increased the protein level of tyrosine hydroxylase ( TH ) , and also greatly increased the TH mRNA level , in both mouse Q14207 striatal primary cell cultures and the hippocampal neuronal cell line HT22 . Activin A and P09038 cooperatively stimulated nuclear translocation of P84022 and specifically activated P27361 / 2 , but not p38 or JNK . Interestingly , a specific inhibitor for MEK , U0126 , efficiently blocked the induction of TH promoter activity by activin A and P09038 , indicating that activin A collaborated with P09038 signaling to induce the TH gene through selective activation of P29323 - type Q96HU1 kinase in mouse striatal and HT22 cells . These data suggest that activin A may act in concert with P09038 for the development of TH - positive neurons .","Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic - pituitary - gonadal axis , including gonadotrophin - releasing hormone - I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor - 1 ( VIPR - 1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker - trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR - 1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR - 1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T - C1715301T haplotypes of VIPR - 1 and EN300 . H1H3 had the highest EN300 . Four PCR - RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C - G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3 - domain P62993 - like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR - 1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 .","P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .","Task - dependent interactions between dopamine D2 receptor polymorphisms and DB01235 in patients with Parkinson ' s disease . Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning . In the current study , we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with DB01235 during motor tasks in patients with Parkinson ' s disease ( PD ) . Forty - five PD patients were genotyped for the P14416 polymorphism ( rs 1076560 , G > T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 states . For motor sequence learning , P14416 genotype mediated DB01235 effects such that DB01235 associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 =- 2 . 71 , p = 0 . 022 ) , whereas G homozygotes showed no performance change with DB01235 . For the grooved pegboard test , performance improved with DB01235 independent of patients ' P14416 genotype . Collectively these results demonstrate that common P14416 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .","Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK39___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .","Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .","The leukocytes expressing Q9UD71 are reduced in patients with schizophrenia and bipolar disorder . Bipolar disorder ( BPD ) and schizophrenia ( SCZ ) are severe disorders representing an enormous social , familiar and individual burden , being SCZ the most disabling psychiatric disorder characterized by psychosis and cognitive impairment . It is well known that SCZ and BPD are associated with abnormalities in dopamine signaling pathway . Recent data in the literature have demonstrated altered expression levels of some proteins involved in the modulation of this pathway in both brain and peripheral tissues . It was shown that protein and mRNA levels of dopamine and DB02527 regulated phosphoprotein ( Q9UD71 ) were downregulated in dorsolateral prefrontal cortex ( DLPFC ) of patients with SCZ or BPD when compared to controls . Due to the difficulty to access brain tissue and the absence of objective laboratory tests for bio - markers , we measured Q9UD71 expression in blood cell sub - populations ( P01730 + T lymphocytes , CD56 + NK cells , P15391 + B lymphocytes and P08571 + monocytes ) taking advantage of the close relation of nervous and immune systems . Using flow cytometry as the analytical method , our results have shown that the Q9UD71 expression was diminished in P01730 + T lymphocytes , P15391 + B lymphocytes and P08571 + monocytes of BPD patients and was also decreased in P01730 + T lymphocytes and CD56 + NK cells of SCZ patients . These results showed that Q9UD71 expression in immune cells agrees with reports of reduced Q9UD71 protein in the DLPFC of BPD or SCZ patients . Our data suggest that Q9UD71 expression in PBMC could be used as a source of bio - markers to help in the treatment response of neuropsychiatry disorders as a window to the changes in the brain of those patients .","Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK9___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .","The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK53___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .","___MASK77___ : An orally active renin inhibitor . P00797 inhibitors are antihypertensive drugs that block the first step in the renin - angiotensin system . Their mechanism of action differs from that of the angiotensin - converting enzyme inhibitors and angiotensin - receptor antagonists , but like these drugs , renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion . The renin - angiotensin - aldosterone system ( RAAS ) has long been recognized to play a significant role in hypertension pathophysiology . Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes . Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug . ___MASK77___ is the first of a new class of antihypertensive agents . ___MASK77___ is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once - daily oral dosing . In short - term studies , it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide , and had a low incidence of serious adverse effects . It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives . Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin - receptor blocker . The most common adverse effects reported in clinical trials were headache , fatigue , dizziness , diarrhea , and nasopharyngitis . ___MASK77___ has not been studied in patients with moderate renal dysfunction ; as an RAAS - acting drug , it should be prescribed for such patients only with caution .","Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re - validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague - Dawley rats were treated with chronic DB01235 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 ( the D ( 1 ) and P14416 antagonists , P35240 - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti - dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .","P21728 - mediated inhibition of NADPH oxidase activity in human kidney cells occurs via protein kinase A - protein kinase C cross talk . Dopamine cellular signaling via the D ( 1 ) receptor ( D ( 1 ) R ) involves both protein kinase A ( PKA ) and protein kinase C ( PKC ) , but the PKC isoform involved has not been determined . Therefore , we tested the hypothesis that the D ( 1 ) R - mediated inhibition of NADPH oxidase activity involves cross talk between PKA and a specific PKC isoform ( s ) . In P29320 - 293 cells heterologously expressing human D ( 1 ) R ( P29320 - hD ( 1 ) ) , fenoldopam , a D ( 1 ) R agonist , and phorbol 12 - myristate 13 - acetate ( PMA ) , a PKC activator , inhibited oxidase activity in a time - and concentration - dependent manner . The D ( 1 ) R - mediated inhibition of oxidase activity ( 68 . 1 ± 3 . 6 % ) was attenuated by two PKA inhibitors , H89 ( 10μmol / L ; 88 ± 8 . 1 % ) and Rp - DB02527 ( 10μmol / L ; 97 . 7 ± 6 . 7 % ) , and two PKC inhibitors , bisindolylmaleimide I ( 1μmol / L ; 94 ± 6 % ) and staurosporine ( 10nmol / L ; 93 ± 8 % ) , which by themselves had no effect ( n = 4 - 8 / group ) . The inhibitory effect of PMA ( 1μmol / L ) on oxidase activity ( 73 ± 3 . 2 % ) was blocked by H89 ( 100 ± 7 . 8 % ; n = 5 or 6 / group ) . The PMA - mediated inhibition of NADPH oxidase activity was accompanied by an increase in PKCθ ( S676 ) , an effect that was also blocked by H89 . Fenoldopam ( 1μmol / L ) also increased PKCθ ( S676 ) in P29320 - hD ( 1 ) and human renal proximal tubule ( RPT ) cells . Knockdown of PKCθ with siRNA in RPT cells prevented the inhibitory effect of fenoldopam on NADPH oxidase activity . Our studies demonstrate for the first time that cross talk between PKA and PKCθ plays an important role in the D ( 1 ) R - mediated negative regulation of NADPH oxidase activity in human kidney cells .","Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms . Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level . A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour , but only limited genetic evidence for positive selection has been presented . To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset , studying single nucleotide polymorphisms ( SNPs ) , and analyzed 55 genes in detail . We identified eight genes that are associated with the melanin pathway ( Q9UMX9 , Q04671 , P17643 , P40126 , P21583 , P00533 , P14416 and Q03181 ) and presented significant differences in genetic variation between Europeans , Africans and Asians . In six of these genes we detected , by means of the EHH test , variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( Q04671 , P17643 and P21583 ) and in Asians ( Q04671 , P40126 , P21583 , P00533 and P14416 ) , whereas signals were scarce in Africans ( P40126 , P00533 and P14416 ) . Furthermore , a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed . Overall , our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians , whereas dark skin color seems of unique origin , reflecting the ancestral state in humans .","Dopamine selectively reduces GABA ( B ) transmission onto dopaminergic neurones by an unconventional presynaptic action . The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement . In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine ( DA ) release in the brain . Here , we report a concentration - dependent depressant action of dopamine on the GABA ( B ) IPSPs intracellularly recorded from dopaminergic neurones . Such effect was observed in spite of the presence of D ( 1 )/ P14416 antagonists . A reduction of the GABA ( B ) IPSPs was also caused by noradrenaline ( norepinephrine ) and by L - beta - 3 , 4 - dihydroxyphenylalanine ( DB01235 ) , which is metabolically transformed into DA . The DA - induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine . DA did not change the postsynaptic effects of the GABA ( B ) agonist baclofen , suggesting a presynaptic site of action . Furthermore , DA did not modulate the GABA ( A )- mediated IPSP . The DA - induced depression of the GABA ( B ) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists . The DA - and 5 - HT - induced depression of the GABA ( B ) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals . These results describe an unconventional presynaptic , D ( 1 ) and D ( 2 ) independent action of DA on the GABA ( B ) IPSP . This might have a principal role in determining therapeutic / side effects of DB01235 and antipsychotics and could be also involved in drug abuse .","The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L - amino acid decarboxylase in healthy subjects . The A1 allele of the TaqI restriction fragment length polymorphism ( RFLP ) of the human dopamine D2 receptor gene ( P14416 ) is associated with a low density of D2 dopamine receptors in the striatum . Because of the important role of D2 autoreceptors in regulating dopamine synthesis , we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain . We also studied the effects of two other P14416 polymorphisms , C957 T and -- 141C Ins / Del , which have been suggested to affect D2 receptor levels in brain . The relationships between the TaqIA RFLP , C957 T and -- 141C Ins / Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18F ] fluorodopa ( [ 18F ] FDOPA ) , a radiolabelled analog of the dopamine precursor DB01235 . Heterozygous carriers of the A1 allele ( A1 / A2 ; 10 subjects ) had significantly higher ( 18 % ) [ 18F ] FDOPA uptake in the putamen than subjects without the A1 allele ( A2 / A2 ; 23 subjects ) . C957 T and -- 141C Ins / Del polymorphisms did not significantly affect [ 18F ] FDOPA Ki values . These results demonstrate that the A1 allele of P14416 gene is associated with increased striatal activity of aromatic L - amino acid decarboxylase , the final enzyme in the biosynthesis of dopamine and the rate - limiting enzyme for trace amine ( e . g . beta - phenylethylamine ) synthesis . The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function , and suggests that dopamine and / or trace amine synthesis rate is increased in the brains of A1 allele carriers .","Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK38___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .","Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .","Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy ."],"string":"[\n \"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .\",\n \"CXC chemokine receptor 4 expression and function in human astroglioma cells . Chemokines constitute a superfamily of proteins that function as chemoattractants and activators of leukocytes . Astrocytes , the major glial cell type in the CNS , are a source of chemokines within the diseased brain . Specifically , we have shown that primary human astrocytes and human astroglioma cell lines produce the CXC chemokines P01579 - inducible protein - 10 and P10145 and the CC chemokines monocyte chemoattractant protein - 1 and RANTES in response to stimuli such as P01375 , IL - 1beta , and P01579 . In this study , we investigated chemokine receptor expression and function on human astroglioma cells . Enhancement of CXC chemokine receptor 4 ( P61073 ) mRNA expression was observed upon treatment with the cytokines P01375 and IL - 1beta . The peak of P61073 expression in response to P01375 and IL - 1beta was 8 and 4 h , respectively . P61073 protein expression was also enhanced upon treatment with P01375 and IL - 1beta ( 2 - to 3 - fold ) . To study the functional relevance of P61073 expression , stable astroglioma transfectants expressing high levels of P61073 were generated . Stimulation of cells with the ligand for P61073 , stromal cell - derived factor - 1alpha ( SDF - 1alpha ) , resulted in an elevation in intracellular Ca ( 2 +) concentration and activation of the mitogen - activated protein kinase cascade , specifically , extracellular signal - regulated kinase 2 ( P28482 ) mitogen - activated protein kinase . Of most interest , SDF - 1alpha treatment induced expression of the chemokines monocyte chemoattractant protein - 1 , P10145 , and P01579 - inducible protein - 10 . SDF - 1alpha - induced chemokine expression was abrogated upon inclusion of U0126 , a pharmacological inhibitor of P27361 / 2 , indicating that the P29323 signaling cascade is involved in this response . Collectively , these data suggest that P61073 - mediated signaling pathways in astroglioma cells may be another mechanism for these cells to express chemokines involved in angiogenesis and inflammation .\",\n \"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK87___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .\",\n \"[ ___MASK39___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .\",\n \"Role of everolimus in pancreatic neuroendocrine tumors . Survival from pancreatic neuroendocrine tumors has not improved over the past two decades and , until recently , streptozocin was the last therapeutic agent approved for this malignancy . ___MASK9___ blocks P42345 , which plays an integral role in cell growth , mitosis and angiogenesis . Abnormal PI3K - Akt / P31749 - P42345 pathway signaling has been implicated in the pathogenesis of pancreatic neuroendocrine tumors . In a Phase III study , patients with low - and intermediate - grade advanced pancreatic neuroendocrine tumors were randomized to receive everolimus 10 mg / day or placebo . Median progression - free survival was significantly greater in patients treated with everolimus than placebo - 11 versus 4 . 6 months - and drug - related adverse events were consistent with the known side - effect profile of everolimus . ___MASK9___ represents a significant treatment development for pancreatic neuroendocrine tumors .\",\n \"P21728 , but not dopamine D2 receptor , is a critical regulator for acute cocaine - enhanced gene expression . OBJECTIVE : The aim of present study is to investigate the roles of dopamine receptor subfamilies and their subsequent molecular events in cocaine - enhanced gene expression in striatum . METHODS : Acute cocaine - treated mice models were build to address this issue . Specific antagonists for dopamine D1 and D2 receptors ( P35240 23390 and raclopride , respectively ) and specific inhibitor for extracellular signal - regulated protein kinase 1 / 2 ( P27361 / 2 ) kinase were pretreated . Immunofluorescence was used to detect the expressions of c - Fos , phosphorylated DB02527 response element binding ( p - CREB ) and phosphorylated Elk - 1 ( p - Elk - 1 ) in striatum . RESULTS : Acute cocaine injection significantly enhanced expressions of c - Fos , p - CREB and p - Elk - 1 in the striatum . Notably , these enhancements were totally blocked to normal level by P35240 23390 pre - treatment , while no changes occurred in the presence of raclopride . Moreover , we found that dopamine D1 receptor was involved in acute cocaine - induced activation of P27361 / 2 in the striatum . Blockade of this dopamine D1 receptor - dependent P27361 / 2 activation by SL 327 could reduce cocaine - enhanced expressions of c - Fos , p - CREB and p - Elk - 1 in the striatum . DISCUSSION : These results suggest that dopamine D1 receptor , but not dopamine D2 receptor , plays a critical role in regulating acute cocaine - enhanced gene expression in the striatum , and P27361 / 2 pathway may contribute to this regulation .\",\n \"Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells . Histone deacetylase inhibitors are promising anti - tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies . However , little is known about any effects of these drugs on the central nervous system . The aim of the present study was to analyze the effects of trichostatin A ( P32119 ) -- a broad - spectrum histone deacetylase inhibitor -- on the transcriptional regulation of several genes involved in dopamine - and serotonergic neurotransmission . To this end , short - term parallel cultures of SK - NF - I neuroblastoma cells were treated with P32119 either alone or in combination with hypoxia , and mRNA levels of dopamine receptor D3 ( P35462 ) and D4 ( P21917 ) , dopamine transporter ( Q01959 ) , dopamine hydroxylase ( P09172 ) , dopamine receptor regulating factor ( DRRF ) , catechol - O - methyltransferase ( P21964 ) , serotonin receptor 1A ( P08908 ) , monoamino oxidase A ( P21397 ) , serotonin transporter ( P31645 ) and tryptophan hydroxylase 2 ( Q8IWU9 ) were determined by quantitative PCR . We found that P32119 did not antagonize the hypoxia - induced activation of D3 and D4 dopamine receptor genes , implying that induction of these genes is not mediated directly by hypoxia inducible factor - 1alpha . On the other hand , P32119 dramatically upregulated the expression of Q01959 and P31645 ( 45 - fold and 15 - fold , respectively ) , while transcript levels of P21397 and P21964 were significantly reduced ( by 70 % and by more than 90 % , respectively ) . Induction of Q01959 protein expression was detected by western blotting . These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons .\",\n \"Bacterial superantigens bypass Lck - dependent T cell receptor signaling by activating a Galpha11 - dependent , P98160 - beta - mediated pathway . The paradigm to explain antigen - dependent T cell receptor ( TCR ) signaling is based on the activation of the P01730 or CD8 coreceptor - associated kinase Lck . It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens . However , these bacterial toxins can activate human T cells lacking Lck , suggesting the existence of an additional pathway of TCR signaling . Here we showed that this alternative pathway operates in the absence of Lck - dependent tyrosine - phosphorylation events and was initiated by the TCR - dependent activation of raft - enriched heterotrimeric Galpha11 proteins . This event , in turn , activated a phospholipase C - beta and protein kinase C - mediated cascade that turned on the mitogen - activated protein kinases P27361 and P28482 , triggered Ca ( 2 +) influx , and translocated the transcription factors NF - AT and NF - kappaB to the nucleus , ultimately inducing the production of interleukin - 2 in Lck - deficient T cells . The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein - coupled receptor as a coreceptor on T cells .\",\n \"Dopamine receptor D4 polymorphism predicts the effect of DB01235 on gambling behavior . BACKGROUND : There is ample evidence that a subgroup of Parkinson ' s disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling . The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors . These are potentially of genetic origin , since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 ( P21917 ) gene . Using a pharmacogenetic approach , we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects . METHODS : We administered 300 mg of L - dihydroxyphenylalanine ( DB01235 ) or placebo to 200 healthy male subjects who were all genotyped for their P21917 polymorphism . Subjects played a gambling task 60 minutes after DB01235 administration . RESULTS : Without considering genetic information , DB01235 administration did not lead to an increase in gambling propensity compared with placebo . As expected , however , an individual ' s P21917 polymorphism accounted for variation in gambling behavior after the administration of DB01235 . Subjects who carry at least one copy of the 7 - repeat allele showed an increased gambling propensity after dopaminergic stimulation . CONCLUSIONS : These findings demonstrate that genetic variation in the P21917 gene determines an individual ' s gambling behavior in response to a dopaminergic drug challenge . They may have implications for the treatment of Parkinson ' s disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior .\",\n \"___MASK9___ ( RAD001 ) : an P42345 inhibitor for the treatment of metastatic renal cell carcinoma . The recent introduction of drugs that inhibit angiogenesis or the P42345 has provided new options for the treatment of metastatic renal cell carcinoma , a disease which often has a poor prognosis . Chemotherapy and cytokine therapy are largely ineffective . The 5 - year survival rate is under 10 % . ___MASK9___ , an immunosuppressive drug widely used for the prevention of allograft rejection and an P42345 inhibitor , is one of the latest drugs undergoing clinical trials in metastatic renal cell carcinoma . It has been tested in patients with progressive disease after therapy with tyrosine kinase receptor inhibitors ( sunitinib , sorafenib or both ) , which interfere with signaling pathways , such as the P15692 pathway . Clinical efficacy results ( progression - free survival ) for everolimus are promising and the safety profile is good .\",\n \"Q9UD71 as a marker for D - 1 dopaminoceptive cells in the rat brain : prenatal development and presence in glial elements ( tanycytes ) in the basal hypothalamus . The present article reviews some aspects of the localization of a dopamine - and cyclic AMP - regulated phosphoprotein , Q9UD71 , which is assumed to be present in D - 1 dopaminoceptive neurons . Its prenatal development starts at day 14 of gestation , is to a large extent complete at birth and seems to be independent of ingrowing dopamine - containing afferents . Rearrangements occur in certain areas , and in some systems Q9UD71 appears to be only transiently expressed . The presence of Q9UD71 in glial structures , the tanycytes , in the arcuate nucleus - median eminence complex in the mediobasal hypothalamus , has given further support to the hypothesis that dopamine , by controlling the shape of the tanycytes and the extension of their processes , can regulate P01148 release by a ' mechanical mechanism ' . This hypothesis is now being examined in some experimental paradigms .\",\n \"Shared and unique genetic contributions to attention deficit / hyperactivity disorder and substance use disorders : a pilot study of six candidate genes . The shared genetic basis of attention deficit / hyperactivity disorder ( ADHD ) and substance use disorders ( SUDs ) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders . One hundred seven methadone maintenance treatment patients , 36 having an ADHD diagnosis , 176 adult patients with ADHD without SUDs , and 500 healthy controls were genotyped for variants in the P21917 ( exon 3 VNTR ) , P21918 ( upstream VNTR ) , P28222 ( rs6296 ) , P09172 ( rs2519152 ) , P21964 ( rs4680 ; Val158Met ) , and P35372 ( rs1799971 ; 118A > G ) genes . Association with disease was tested using logistic regression models . This pilot study was adequately powered to detect larger genetic effects ( OR ≥ 2 ) of risk alleles with a low frequency . Compared to controls , ADHD patients ( with and without SUDs ) showed significantly increased frequency of the P09172 ( rs2519152 : OR 1 . 73 ; CI 1 . 15 - 2 . 59 ; P = 0 . 008 ) and the P35372 risk genotypes ( rs1799971 : OR 1 . 71 ; CI 1 . 17 - 2 . 50 ; P = 0 . 006 ) . The P09172 risk genotype was associated with ADHD diagnosis , with the association strongest in the pure ADHD group . The P35372 risk genotype increased the risk for the combined ADHD and SUD phenotype . The present study strengthens the evidence for a shared genetic basis for ADHD and addiction . The association of P35372 with the ADHD and SUD combination could help to explain the contradictory results of previous studies . The power limitations of the study restrict the significance of these findings : replication in larger samples is warranted .\",\n \"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .\",\n \"DB01235 - treatment in primates disrupts the expression of A ( 2A ) adenosine - CB ( 1 ) cannabinoid - P14416 heteromers in the caudate nucleus . The molecular basis of priming for DB01235 - induced dyskinesias in Parkinson ' s disease ( PD ) , which depends on the indirect pathway of motor control , is not known . In rodents , the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A ( 2A ) adenosine , CB ( 1 ) cannabinoid and D ( 2 ) dopamine receptors that regulate dopaminergic neurotransmission . The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson ' s disease and to determine whether their expression and pharmacological properties are altered upon DB01235 treatment . By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint , we discovered a regional distribution of A ( 2A )/ CB ( 1 ) / D ( 2 ) receptor heteromers that predicts differential D ( 2 )- mediated neurotransmission in the caudate - putamen of Macaca fascicularis . Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP - treated monkeys , DB01235 treatment blunted the biochemical fingerprint and led to weak heteromer expression . These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A ( 2A )- CB ( 1 ) - D ( 2 ) receptor heteromers may be successful to either normalize basal ganglia output or prevent DB01235 - induced side effects .\",\n \"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK77___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .\",\n \"Interaction between serotonin transporter gene , catechol - O - methyltransferase gene and stressful life events in mood disorders . It is well established that stress is a risk factor for onset of mood disorders . Emerging evidence suggests that genetic vulnerability may also moderate individual responsiveness to stress . The most compelling evidence regards the polymorphism within the promoter region of the serotonin transporter gene ( SERTPR ) , which has been reported to moderate the risk for depression , in conjunction with life stressors . In the present paper we analysed SERTPR in the onset of mood disorders , along with adverse life events , and other candidate genes : the serotonin receptor 1A ( P08908 ) , the dopamine receptor D4 ( P21917 ) and the catechol - O - methyltransferase ( P21964 ) . The sample was composed of 686 Italian subjects , affected by major depression and bipolar disorder . Patients were asked to report about life stressors within the year preceding onset of their first mood - disorder episode and genotyped . A ' case - only ' design was employed to investigate the interaction between genes and stressors . P21964 was associated with depression following exposure to stressors ( chi2 = 13 . 05 , d . f .= 2 , p = 0 . 0015 ) and SERTPR also showed a positive association ( chi2 = 6 . 70 , d . f .= 2 , p = 0 . 035 ) , mainly among women and among major depressives . The interaction between P21964 and SERTPR was also significant ( p = 0 . 0005 ) . In our retrospective study SERTPR is hypothesized to lead to the onset of major depression via its influence on reaction to adversities , particularly in females . Moreover , P21964 was risk factor for onset of both major depression and bipolar disorder , in conjunction with adversities .\",\n \"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK42___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .\",\n \"Radiation hybrid map of 13 loci on the long arm of chromosome 5 . Radiation hybrid mapping was used in conjunction with a natural deletion mapping panel to predict the order of and distance between 13 loci in the distal portion of the long arm of human chromosome 5 . A panel of irradiation hybrids containing fragments of 5q was generated from an P00492 + Chinese hamster - human cell hybrid containing a derivative chromosome 5 [ der ( 5 ) t ( 4 ; 5 ) ( 5qter ---- 5p15 . 1 :: 4p15 . 1 ---- 4pter ) ] as its only human DNA . One hundred nine radiation hybrids containing human DNA were screened with polymerase chain reaction primer sets representing nine genes encoding growth factors , growth factor receptors , or hormone receptors ( P08700 , P05112 , P05113 , P07333 , P05230 , P07550 , GRL , P14867 , and P21728 ) as well as four other loci ( P16591 , P09486 , P62263 , and P08571 ) to generate a radiation hybrid map of the area 5q21 - q35 . A physical map predicting the order of and distance between the 13 loci was constructed based on segregation of the 13 loci in hybrid clones . The radiation hybrid panel will be useful as a mapping tool for determining the location and order of other genes and polymorphic loci in this region as well as for generating new DNA probes from specific regions .\",\n \"P00797 - angiotensin system revisited . New components and functions of the renin - angiotensin system ( DB01367 ) are still being unravelled . The classical DB01367 as it looked in the middle 1970s consisted of circulating renin , acting on angiotensinogen to produce angiotensin I , which in turn was converted into angiotensin II ( Ang II ) by angiotensin - converting enzyme ( P12821 ) . Ang II , still considered the main effector of DB01367 was believed to act only as a circulating hormone via angiotensin receptors , AT1 and P50052 . Since then , an expanded view of DB01367 has gradually emerged . Local tissue DB01367 systems have been identified in most organs . Recently , evidence for an intracellular DB01367 has been reported . The new expanded view of DB01367 therefore covers both endocrine , paracrine and intracrine functions . Other peptides of DB01367 have been shown to have biological actions ; angiotensin 2 - 8 heptapeptide ( Ang III ) has actions similar to those of Ang II . Further , the angiotensin 3 - 8 hexapeptide ( Ang IV ) exerts its actions via insulin - regulated amino peptidase receptors . Finally , angiotensin 1 - 7 ( Ang 1 - 7 ) acts via mas receptors . The discovery of another Q9BYF1 was an important complement to this picture . The recent discovery of renin receptors has made our view of DB01367 unexpectedly complex and multilayered . The importance of DB01367 in cardiovascular disease has been demonstrated by the clinical benefits of P12821 inhibitors and AT1 receptor blockers . Great expectations are now generated by the introduction of renin inhibitors . Indeed , DB01367 regulates much more and diverse physiological functions than previously believed .\",\n \"Sustained increase of PKA activity in the postcommissural putamen of dyskinetic monkeys . Levodopa - induced dyskinesias ( LID ) are a frequent complication of Parkinson ' s disease pharmacotherapy that causes significant disability and narrows the therapeutic window . Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood . Here , our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication . We examined the expression and downstream activity of dopamine receptors ( DR ) in the striatum of 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 tetrahydropiridine ( MPTP ) - lesioned monkeys with and without DB01235 treatment . Four monkeys were made dyskinetic and other four received a shorter course of DB01235 and did not develop LID . Our results show that DB01235 treatment induces an increase in P14416 and P35462 expression in the postcommissural putamen , but only P35462 is correlated with the severity of LID . Dyskinetic monkeys show a hyperactivation of the canonical P21728 - signaling pathway , measured by an increased phosphorylation of protein kinase A ( PKA ) and its substrates , particularly Q9UD71 . In contrast , activation of the P14416 - signaling pathway , visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9 , is associated with DB01235 treatment , independently of the presence of dyskinesias . Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the P35462 receptor and the P21728 pathway with a sustained increase of PKA activity in the postcommissural putamen . Importantly , we found that all signaling changes related to long - term DB01235 administration are exquisitely restricted to the postcommissural putamen , which may be related to the recurrent failure of pharmacological approaches .\",\n \"The interleukin 10 promoter haplotype ACA and the long - form variant of the P21917 uVNTR polymorphism are associated with vulnerability to schizophrenia . A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin - 10 ( P22301 ) promoter and P21917 uVNTR polymorphisms . P21917 long - form variants ( namely , those with ≥ 5 repeats ) , homozygosity for the 4 - repeat allele , and the P22301 haplotype ACA were associated with schizophrenia , respectively . No obvious interactions among the potential polymorphisms were found , which suggests that P22301 and P21917 confer vulnerability to schizophrenia independently .\",\n \"A genomic insight into diversity among tribal and nontribal population groups of Manipur , India . Twenty autosomal markers , including linked markers at two gene markers , are used to understand the genomic similarity and diversity among three tribal ( Paite , Thadou , and Kom ) and one nontribal communities of Manipur ( Northeast India ) . Two of the markers ( P01730 and HB9 ) are monomorphic in Paite and one ( the P01730 marker ) in Kom . Data suggest the Meitei ( nontribal groups ) stand apart from the three tribal groups with respect to higher heterozygosity ( 0 . 366 ) and presence of the highest ancestor haplotypes of P14416 markers ( 0 . 228 ) ; this is also supported by principal co - ordinate analysis . These populations are found to be genomically closer to the Chinese population than to other Indian populations .\",\n \"Q9UD71 increases interactions between epidermal growth factor receptor and P21860 to promote tumor resistance to gefitinib . BACKGROUND & AIMS : Dopamine and adenosine 3 ', 5 '- cyclic monophosphate - regulated phosphoprotein , Mr 32000 ( Q9UD71 ) , is overexpressed during gastric carcinogenesis . Gastric tumors can become resistant to gefitinib , an inhibitor of the epidermal growth factor receptor ( P00533 ) . We investigated the role of Q9UD71 in gastric tumor resistance to gefitinib . METHODS : Cell survival was determined by clonogenic survival and DB00171 - Glo Viability Assays . Apoptosis was assessed by Annexin - V and immunoblot analyses . The association between Q9UD71 and P00533 was evaluated by immunofluorescence and co - immunoprecipitation assays . Findings were validated in mice with gastric xenograft tumors . Q9UD71 expression was reduced using small hairpin RNAs in the human gastric cancer cell lines SNU - 16 and MKN - 45 cells . RESULTS : Overexpression of Q9UD71 in MKN - 28 cells , which do not normally express Q9UD71 , blocked gefitinib - induced apoptosis and increased the drug ' s IC ( 50 ) 10 - fold , compared to that of control cells ( P < . 01 ) . Reduced expression of Q9UD71 in SNU - 16 cells increased the sensitivity to gefitinib ( P < . 01 ) . Q9UD71 activated phosphatidylinositol - 3 - kinase - AKT signaling , increased stability of the P00533 , and suppressed P01133 - or gefitinib - induced degradation of the P00533 . Q9UD71 colocalized with P00533 on the cell membrane in a complex with P00533 and the P01133 receptor P21860 . Q9UD71 - mediated resistance to gefitinib resulted from increased phosphorylation of and interaction between P00533 and P21860 , which led to phosphorylation of AKT ( at serine 473 ) . Knockdown of Q9UD71 in gastric cancer cells reduced the mean size of tumors in mice and increased their response to gefitinib . CONCLUSIONS : Q9UD71 promotes resistance of gastric cancer cells to gefitinib by promoting interaction between P00533 and P21860 and activating phosphatidylinositol - 3 - kinase - AKT signaling .\",\n \"Expression profile of genes associated with the dopamine pathway in vitiligo skin biopsies and blood sera . BACKGROUND : Dopamine has been proven to be toxic for melanocytes . In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed . METHODS : With the use of quantitative real - time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway ( PAH , P61457 , TH , DDC , P09172 , PNMT , P07203 , P21397 , P27338 , P21964 , P21728 - P21918 , P54219 and Q05940 ) was observed in vitiligo patients ' and control subjects ' skin and blood . RESULTS : The mRNA expression of P07203 , DDC , P21397 , P21728 and P21918 differs in vitiligo skin and the protein level of DDC , P21397 , P27338 , P21728 and P21918 is changed in vitiligo patients ' skin and / or blood sera . CONCLUSIONS : The dopamine pathway probably influences melanogenesis directly or through the melanocortin pathway . We provide new data about changes of expression profile of the dopamine - synthesizing enzyme DDC , the dopamine - degrading enzymes P21397 and P27338 and the D1 - like family dopamine receptors in vitiligo skin and blood sera .\",\n \"Dopamine receptor agonists reverse behavioral abnormalities of alpha - synuclein transgenic mouse , a new model of Parkinson ' s disease . Parkinson ' s disease ( PD ) is characterized by loss of nigral dopaminergic ( DAergic ) neurons and presence of Lewy bodies , whose major component is alpha - synuclein . We had previously generated transgenic mice termed Syn130m that express truncated human alpha - synuclein ( amino acid residues 1 - 130 ) in DAergic neurons . Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta . Subsequently , the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly . In the present study , we investigated behavioral responses of Syn130m mice to DB01235 and DA receptor agonists . Administration of DB01235 dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice . Similarly , D ( 2 ) agonists , quinpirole and talipexole , and a D1 / D2 agonist , pergolide , were effective against the reduction . Syn130m mice also showed significant reduction in exploratory behavior compared with non - Tg littermates when they were placed in a novel environment , but this abnormality was ameliorated by treatment with pergolide . These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content . On the other hand , the expression of postsynaptic D ( 2 )- like receptors ( P14416 ) in the striatum was not increased in Syn130m mice , although the low striatal DA level is known to induce compensatory expression of P14416 . Because the abnormalities could be rectified by treatment with DA receptor agonists , it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease .\",\n \"___MASK53___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK53___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK53___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK53___ inhibits activated T cells . We show that in vitro , ___MASK53___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK53___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK53___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK53___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK53___ to treat chronic inflammatory disease .\",\n \"P22301 - inducing adjuvants enhance sublingual immunotherapy efficacy in a murine asthma model . BACKGROUND : P22301 - inducing adjuvants could enhance the efficacy of allergy vaccines in establishing allergen - specific tolerance . The aim of this study was to identify such adjuvants using in vitro cultures of human and murine cells and to evaluate them in a therapeutic murine model of sublingual immunotherapy ( SLIT ) . METHODS : Adjuvants stimulating P22301 gene expression by human or murine immune cells were tested sublingually in BALB / c mice sensitized to ovalbumin ( OVA ) , assessing the reduction in airway hyperresponsiveness ( P35869 ) by whole - body plethysmography . The induction of regulatory T cells ( T ( reg ) ) was evaluated using phenotypic and functional assays . T - cell proliferation in cervical lymph nodes ( LNs ) was assessed following intravenous transfer of CFSE - labelled OVA - specific T cells and FACS analysis . RESULTS : A combination of 1 , 25 - dihydroxyvitamin D3 plus dexamethasone ( VitD3 / DB00514 ) as well as Lactobacillus plantarum were found to induce P22301 production by human and murine dendritic cells ( DCs ) . The former inhibits LPS - induced DC maturation , whereas L . plantarum induces DC maturation . Following stimulation with VitD3 / DB00514 - pretreated DCs , P01730 + naïve T cells exhibit a T ( reg ) profile . In contrast , a Th1 / T ( reg ) pattern of differentiation is observed in the presence of DCs treated with L . plantarum . Both adjuvants significantly enhance SLIT efficacy in mice , in association with either induction of Foxp3 + T ( reg ) cells ( for VitD3 / DB00514 ) or proliferation of OVA - specific T cells in cervical LNs ( for L . plantarum ) . CONCLUSIONS : Both VitD3 / DB00514 and L . plantarum polarize naïve T cells towards P22301 - expressing T cells , through distinct mechanisms . As adjuvants , they both enhance SLIT efficacy in a murine asthma model .\",\n \"Adrenal and gonadal function in hypothyroid adult male rats . The functional relationship between thyroid , adrenal and gonadal hormones was investigated using adult male rats . Hypothyroidism was produced by the administration of 4 - methyl - 2 - thiouracil ( thiouracil ) in the drinking water for 2 weeks . Plasma concentrations of DB00024 dramatically increased , whereas plasma concentrations of tri - iodothyronine and thyroxine decreased in thiouraciltreated rats as compared with euthyroid rats . Hypothyroidism increased basal levels of plasma DB01285 and pituitary content of DB01285 . The pituitary responsiveness to P06850 for DB01285 release markedly increased , whereas the adrenal responsiveness to DB01285 for corticosterone release decreased . These results indicated that hypothyroidism causes adrenal dysfunction in adult male rats . Pituitary contents of LH and prolactin decreased in hypothyroid rats as compared with euthyroid rats . In addition , hypothyroidism lowered pituitary LH responsiveness to P01148 . Testicular responsiveness to human chorionic gonadotrophin for testosterone release , however , was not different between euthyroid and hypothyroid animals . These results indicated that hypothyroidism causes adrenal dysfunction and results in hypersecretion of DB01285 from the pituitary gland . Adrenal dysfunction may contribute to the inhibition of P01148 secretion from the hypothalamus , possibly mediated by excess P06850 .\",\n \"P14416 - induced heterologous sensitization of adenylyl cyclase requires Galphas : characterization of Galphas - insensitive mutants of adenylyl cyclase V . Whereas acute stimulation of Galphai / o - coupled receptors inhibits the activity of adenylyl cyclase , a delayed consequence of persistent activation of the receptors is heterologous sensitization , an enhanced responsiveness of adenylyl cyclase to activators such as forskolin or agonists of Galphas - coupled receptors . Galphas - insensitive mutants of adenylyl cyclase type V were used to test the hypothesis that heterologous sensitization requires Galphas - dependent activation of adenylyl cyclase . When adenylyl cyclase was stably expressed in human embryonic kidney ( P29320 ) 293 cells with the D2L dopamine receptor , basal , forskolin - stimulated , and isoproterenol - stimulated cyclic AMP accumulation were all enhanced by 2 - h pretreatment with the D2 receptor agonist quinpirole . Transient expression of wild - type adenylyl cyclase and three Galphas - insensitive mutants ( F379L , R1021Q , and F1093S ) in HEK293 cells stably expressing the D2L receptor demonstrated that all three mutants had little or no responsiveness to beta - adrenergic receptor - mediated activation of Galphas but that the mutants retained sensitivity to forskolin and to D2L receptor - mediated inhibition . Transiently expressed adenylyl cyclase V was robustly sensitized by 2 - h pretreatment with quinpirole . In contrast , the Galphas - insensitive mutants displayed no sensitization of forskolin - stimulated cyclic AMP accumulation , indicating that responsiveness to Galphas is required for the expression of heterologous sensitization .\",\n \"Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .\",\n \"P12821 inhibitors could be therapeutic for antisocial personality disorder . Antisocial personality traits are an important topic for research . The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes . Catecholamine genes are being studied to facilitate this understanding , and some tentative findings are being reached about several of these genes . It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious . One conclusion that could be drawn from the current research findings is that DA2 like receptors ( P14416 , P35462 , P21917 ) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors . DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition . When these receptors are less active by genetically decreased density , lower affinity , or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state . Peripheral metabolism is increased and behavioral activation is noted . P00797 is disinhibited in this setting thus allowing sympathetic nervous system activation . The fight or flight behaviors thus produced , in the extreme , would be the setting of antisocial behavior . Research validates this hypothesis . Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others . P12821 inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders .\",\n \"P21728 behavioral responsitivity following selective lesions of the striatal patch compartment during development . The behavioral effects of selective destruction of the dopamine ( DA ) input to the patch compartment of rat striatum early in development was investigated . Rat pups were given bilateral intrastriatal ( i . s . ) injections of the neurotoxin 6 - hydroxydopamine ( 6 - OHDA ) on day of birth ( P0 ) or postnatal day 1 ( P1 ) , which resulted in selective behavioral alterations following DA agonist treatment in adulthood . Neonatally - lesioned rats exhibited self - biting behavior following treatment with the DA precursor L - dihydroxyphenylalanine ( DB01235 ) . In response to treatment with the selective D1 agonist SKF38393 , there was an increased incidence of abnormal perioral movements . The cataleptogenic effects of the D1 antagonist SCH23390 and the D2 antagonist haloperidol were also studied . Neonatally - lesioned rats were significantly less cataleptic compared to control rats following D1 antagonist treatment , but not following D2 antagonist treatment . Autoradiographs of [ 3H ] mazindol binding to DA uptake sites ( a measure of DA terminal density ) showed a ' patchy ' loss of approx . 40 - 50 % in striatal tissue sections derived from the i . s . lesioned rats . These data suggest that injections of 6 - OHDA into the striatum during this early postnatal period cause a DA lesion that results in long - term effects on a D1 receptor system .\",\n \"___MASK30___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .\",\n \"Blockade of globus pallidus adenosine A ( 2A ) receptors displays antiparkinsonian activity in 6 - hydroxydopamine - lesioned rats treated with D ( 1 ) or P14416 agonists . We have recently demonstrated how antagonism of adenosine A ( 2A ) receptors within the globus pallidus ( GP ) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor DB01235 in 6 - hydroxydopamine - lesioned hemiparkinsonian rats . To further characterize the influence of pallidal A ( 2A ) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation , hemiparkinsonian rats were infused with the water - soluble A ( 2A ) antagonist P35240 BT2 in the GP , alone or in combination with systemic administration of either SKF 38393 or quinpirole , to stimulate dopamine D ( 1 ) or D ( 2 ) receptors , respectively . P35240 BT2 alone ( 5 mug / 1 mul ) neither altered motor behavior nor produced postural asymmetry . In contrast , the contralateral rotations elicited by SKF 38393 ( 1 . 5 mg / kg ) as well as quinpirole ( 0 . 05 mg / kg ) were potentiated by the concomitant intrapallidal infusion of P35240 BT2 . The results of this study demonstrate that blockade of pallidal A ( 2A ) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D ( 1 ) or D ( 2 ) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A ( 2A ) receptor antagonists .\",\n \"Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .\",\n \"Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .\",\n \"Genetic basis of delay discounting in frequent gamblers : examination of a priori candidates and exploration of a panel of dopamine - related loci . INTRODUCTION : Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards . It has been consistently linked to pathological gambling and other forms of addictive behavior , and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders ( i . e . , an endophenotype ) . Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission . The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine - related variants in a sample of frequent gamblers . METHODS : Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva . RESULTS : In a priori tests , two loci previously associated with delayed reward discounting ( rs1800497 and rs4680 ) were not replicated , however , the long form of P21917 VNTR was significantly associated with lower discounting of delayed rewards . Exploratory analysis of the dopamine - related panel revealed 11 additional significant associations in genes associated with dopamine synthesis , breakdown , reuptake , and receptor function ( P35462 , Q01959 , DDC , P09172 , and Q05940 ) . An aggregate genetic risk score from the nominally significant loci accounted for 17 % of the variance in discounting . Mediational analyses largely supported the presence of indirect effects between the associated loci , delay discounting , and pathological gambling severity . CONCLUSIONS : These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting .\",\n \"Single - nucleotide polymorphisms of the dopamine D2 receptor increase inflammation and fibrosis in human renal proximal tubule cells . The dopamine D2 receptor ( D2R ) negatively regulates inflammation in mouse renal proximal tubule cells ( RPTCs ) , and lack or downregulation of the receptor in mice increases the vulnerability to renal inflammation independent of blood pressure . Some common single - nucleotide polymorphisms ( SNPs ; rs6276 , rs6277 , and rs1800497 ) in the human P14416 gene are associated with decreased D2R expression and function , as well as high blood pressure . We tested the hypothesis that human RPTCs ( hRPTCs ) expressing these SNPs have increased expression of inflammatory and injury markers . We studied immortalized hRPTCs carrying D2R SNPs and compared them with cells carrying no D2R SNPs . RPTCs with D2R SNPs had decreased D2R expression and function . The expressions of the proinflammatory tumor necrosis factor - α and the profibrotic transforming growth factor - β1 and its signaling targets P84022 and Snail1 were increased in hRPTC with D2R SNPs . These cells also showed induction of epithelial mesenchymal transition and production of extracellular matrix proteins , assessed by increased vimentin , fibronectin 1 , and collagen I a1 . To test the specificity of these D2R SNP effects , hRPTC with D2R SNPs were transfected with a plasmid encoding wild - type P14416 . The expression of D2R was increased and that of transforming growth factor - β1 , P84022 , Snail1 , vimentin , fibronectin 1 , and collagen I a1 was decreased in hRPTC with D2R SNPs transfected with wild - type P14416 compared with hRPTC - D2R SNP transfected with empty vector . These data support the hypothesis that D2R function has protective effects in hRPTCs and suggest that carriers of these SNPs may be prone to chronic renal disease and high blood pressure .\",\n \"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK21___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .\",\n \"Neurogenetics of aggressive behavior : studies in primates . Aggressive behavior can have adaptive value in certain environmental contexts , but when extreme or executed inappropriately , can also lead to maladaptive outcomes . Neurogenetic studies performed in nonhuman primates have shown that genetic variation that impacts reward sensitivity , impulsivity , and anxiety can contribute to individual differences in aggressive behavior . Genetic polymorphisms in the coding or promoter regions of the Mu - Opioid Receptor ( P35372 ) , DB01285 Releasing Hormone ( P06850 ) , Monoamine Oxidase A ( P21397 ) , Dopamine D4 Receptor ( P21917 ) , and Serotonin Transporter ( P31645 ) genes have been shown to be functionally similar in humans and rhesus macaques and have been demonstrated to contribute to individual differences in aggression . This body of literature suggests mechanisms by which genetic variation that promotes aggressivity could simultaneously increase evolutionary success while making modern humans more vulnerable to psychopathology .\",\n \"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .\",\n \"P35462 stimulation underlies the development of DB01235 - induced dyskinesia in animal models of Parkinson ' s disease . Development of DB01235 - induced dyskinesia ( LID ) remains a major problem in the long - term treatment of Parkinson ' s disease ( PD ) . Sensitization to DB01235 correlates with ectopic expression of D3 dopamine receptors in the striatum , implicating D3 receptors in development of LID . We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP - lesioned marmosets without effecting the anti - parkinsonian actions of DB01235 . Furthermore , following a 14 day washout , when challenged with DB01235 in the absence of S33084 , these animals continued to exhibit reduced LID . In the 6 - OHDA - lesioned rat , S33084 similarly attenuated development of behavioural sensitization to DB01235 . Additionally , DB01235 - induced elevations in striatal pre - proenkephalin - A ( PPE - A ) ( but not PPE - B , phospho [ DB00156 ( 34 )] Q9UD71 , D1 , and D2 receptor mRNA or D3 receptor levels ) were reduced in S33084 treated animals . Our data suggest a role for D3 receptors in the development of LID and suggest that initiating DB01235 treatment with a D3 antagonist may reduce the development of LID in PD .\",\n \"D3 dopamine receptor activates phospholipase D through a pertussis toxin - insensitive pathway . Within the dopamine receptor family , the P35462 ' s function remains inadequately described . The D ( 3 ) receptor has been shown to couple to inhibition of adenylyl cyclase , stimulation of mitogenesis , and regulation of K (+) and Ca ( 2 +) currents , all in a pertussis toxin ( PTX ) - sensitive manner . Here we report D ( 3 ) receptor activation of the phospholipase D ( PLD ) enzyme in P29320 293 cells heterologously expressing the human D ( 3 ) receptor . Activation by agonist is dose dependent and displays the pharmacology expected of the D ( 3 ) receptor . The D ( 3 ) receptor specific antagonists AJ - 76 and U99194A ablated the increase in activity by the preferring D ( 3 ) agonist ( + ) 7 - OH DPAT . In addition , the D ( 3 ) receptor - mediated activation of PLD is not mediated by G - proteins of the G ( i )/ G ( o ) family , as pretreatment with PTX had no effect . PLD activation is a novel finding for the D ( 3 ) receptor , and is the first example of an effector system where D ( 3 ) signals without G ( i )/ G ( o ) protein intermediates .\",\n \"The Akt / mTor signaling cascade is modified during placentation in the porcine uterine tissue . Recently we showed that essential components for the initiation of protein synthesis , namely the eukaryotic initiation factor 4E ( P06730 , mRNA - cap - binding protein ) and its repressors Q13541 as well as Q13542 , are proteolytically processed in the porcine endometrium during implantation . Here , the situation during placentation was compared with ovariectomized ( OVX ) animals and animals on pregnancy day 1 ( PD1 ) . Furthermore , the research was extended to factors which phosphorylate P06730 and 4E - BPs and regulate their activities . These are the protein kinase B / mammalian target of rapamycin kinase ( Akt / mTor ) with the regulators Q8N122 and Rictor as well as the mitogen activated protein kinases ( MAPKs ) : extra cellular - signal regulated kinase 1 and 2 ( P27361 and P28482 ) . Striking differences in the placentation site ( PS ) and the areas aside from PS ( peri - PS ) were observed . P06730 and Q13542 truncation as well as Q13541 degradation took place in the endometrium of the peri - PS on PD24 . Accompanied by a fragmentation of Akt / mTor , no expression of Rictor was observed , whereas the abundance of Q8N122 was not altered . On the contrary , MAPKs expression and phosphorylation remained almost stable in the peri - PS . In conclusion , the results indicated that on PD24 the translational regulation was shifted to Q13542 control . Furthermore , the Akt / mTor signaling cascade seemed to be down regulated which suggest reduced phosphorylation of Q13542 . Whereas Akt was proteolyzed , the observed mTor fragments represented most likely splicing variants . The results indicate that translational control of gene expression is an important feature in the porcine endometrium during early pregnancy .\",\n \"The role of the subthalamic nucleus in DB01235 induced dyskinesia in 6 - hydroxydopamine lesioned rats . DB01235 is the most effective treatment for Parkinson ' s disease ( PD ) , but prolonged use leads to disabling motor complications including dyskinesia . Strong evidence supports a role of the subthalamic nucleus ( Q05639 ) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy . Here , we investigated the involvement of Q05639 in dyskinesia , using single - unit extracellular recording , behavioural and molecular approaches in hemi - parkinsonian rats rendered dyskinetic by chronic DB01235 administration . Our results show that chronic DB01235 treatment does not modify the abnormal Q05639 activity induced by the 6 - hydroxydopamine lesion of the nigrostriatal pathway in this model . Likewise , we observed a loss of Q05639 responsiveness to a single DB01235 dose both in lesioned and sham animals that received daily DB01235 treatment . We did not find any correlation between the abnormal involuntary movement ( AIM ) scores and the electrophysiological parameters of Q05639 neurons recorded 24 h or 20 - 120 min after the last DB01235 injection , except for the axial subscores . Nonetheless , unilateral chemical ablation of the Q05639 with ibotenic acid resulted in a reduction in global AIM scores and peak - severity of dyskinesia . In addition , Q05639 lesion decreased the anti - dyskinetogenic effect of buspirone in a reciprocal manner . Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB , phosphoDARPP - 32 , dopamine receptor ( DR ) D3 and P14416 / P21728 ratio . The Q05639 lesion attenuated the striatal molecular changes and normalized the P14416 / P21728 ratio . Taken together , our results show that the Q05639 plays a role , if modest , in the physiopathology of dyskinesias .\",\n \"Synergistic activity of activin A and basic fibroblast growth factor on tyrosine hydroxylase expression through P84022 and P27361 / P28482 MAPK signaling pathways . Activin has previously been shown to act as a nerve cell survival factor and to have neurotrophic effects on neurons . However , the role of activin in regulating neurotransmitter expression in the central nervous system and the exact mechanisms involved in this process are poorly understood . In the present study , we report that activin A and basic fibroblast growth factor ( P09038 ) synergistically increased the protein level of tyrosine hydroxylase ( TH ) , and also greatly increased the TH mRNA level , in both mouse Q14207 striatal primary cell cultures and the hippocampal neuronal cell line HT22 . Activin A and P09038 cooperatively stimulated nuclear translocation of P84022 and specifically activated P27361 / 2 , but not p38 or JNK . Interestingly , a specific inhibitor for MEK , U0126 , efficiently blocked the induction of TH promoter activity by activin A and P09038 , indicating that activin A collaborated with P09038 signaling to induce the TH gene through selective activation of P29323 - type Q96HU1 kinase in mouse striatal and HT22 cells . These data suggest that activin A may act in concert with P09038 for the development of TH - positive neurons .\",\n \"Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic - pituitary - gonadal axis , including gonadotrophin - releasing hormone - I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor - 1 ( VIPR - 1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker - trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR - 1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR - 1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T - C1715301T haplotypes of VIPR - 1 and EN300 . H1H3 had the highest EN300 . Four PCR - RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C - G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3 - domain P62993 - like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR - 1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 .\",\n \"P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .\",\n \"Task - dependent interactions between dopamine D2 receptor polymorphisms and DB01235 in patients with Parkinson ' s disease . Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning . In the current study , we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with DB01235 during motor tasks in patients with Parkinson ' s disease ( PD ) . Forty - five PD patients were genotyped for the P14416 polymorphism ( rs 1076560 , G > T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 states . For motor sequence learning , P14416 genotype mediated DB01235 effects such that DB01235 associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 =- 2 . 71 , p = 0 . 022 ) , whereas G homozygotes showed no performance change with DB01235 . For the grooved pegboard test , performance improved with DB01235 independent of patients ' P14416 genotype . Collectively these results demonstrate that common P14416 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .\",\n \"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK39___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .\",\n \"Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .\",\n \"The leukocytes expressing Q9UD71 are reduced in patients with schizophrenia and bipolar disorder . Bipolar disorder ( BPD ) and schizophrenia ( SCZ ) are severe disorders representing an enormous social , familiar and individual burden , being SCZ the most disabling psychiatric disorder characterized by psychosis and cognitive impairment . It is well known that SCZ and BPD are associated with abnormalities in dopamine signaling pathway . Recent data in the literature have demonstrated altered expression levels of some proteins involved in the modulation of this pathway in both brain and peripheral tissues . It was shown that protein and mRNA levels of dopamine and DB02527 regulated phosphoprotein ( Q9UD71 ) were downregulated in dorsolateral prefrontal cortex ( DLPFC ) of patients with SCZ or BPD when compared to controls . Due to the difficulty to access brain tissue and the absence of objective laboratory tests for bio - markers , we measured Q9UD71 expression in blood cell sub - populations ( P01730 + T lymphocytes , CD56 + NK cells , P15391 + B lymphocytes and P08571 + monocytes ) taking advantage of the close relation of nervous and immune systems . Using flow cytometry as the analytical method , our results have shown that the Q9UD71 expression was diminished in P01730 + T lymphocytes , P15391 + B lymphocytes and P08571 + monocytes of BPD patients and was also decreased in P01730 + T lymphocytes and CD56 + NK cells of SCZ patients . These results showed that Q9UD71 expression in immune cells agrees with reports of reduced Q9UD71 protein in the DLPFC of BPD or SCZ patients . Our data suggest that Q9UD71 expression in PBMC could be used as a source of bio - markers to help in the treatment response of neuropsychiatry disorders as a window to the changes in the brain of those patients .\",\n \"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK9___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .\",\n \"The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK53___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .\",\n \"___MASK77___ : An orally active renin inhibitor . P00797 inhibitors are antihypertensive drugs that block the first step in the renin - angiotensin system . Their mechanism of action differs from that of the angiotensin - converting enzyme inhibitors and angiotensin - receptor antagonists , but like these drugs , renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion . The renin - angiotensin - aldosterone system ( RAAS ) has long been recognized to play a significant role in hypertension pathophysiology . Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes . Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug . ___MASK77___ is the first of a new class of antihypertensive agents . ___MASK77___ is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once - daily oral dosing . In short - term studies , it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide , and had a low incidence of serious adverse effects . It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives . Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin - receptor blocker . The most common adverse effects reported in clinical trials were headache , fatigue , dizziness , diarrhea , and nasopharyngitis . ___MASK77___ has not been studied in patients with moderate renal dysfunction ; as an RAAS - acting drug , it should be prescribed for such patients only with caution .\",\n \"Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re - validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague - Dawley rats were treated with chronic DB01235 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 ( the D ( 1 ) and P14416 antagonists , P35240 - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti - dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .\",\n \"P21728 - mediated inhibition of NADPH oxidase activity in human kidney cells occurs via protein kinase A - protein kinase C cross talk . Dopamine cellular signaling via the D ( 1 ) receptor ( D ( 1 ) R ) involves both protein kinase A ( PKA ) and protein kinase C ( PKC ) , but the PKC isoform involved has not been determined . Therefore , we tested the hypothesis that the D ( 1 ) R - mediated inhibition of NADPH oxidase activity involves cross talk between PKA and a specific PKC isoform ( s ) . In P29320 - 293 cells heterologously expressing human D ( 1 ) R ( P29320 - hD ( 1 ) ) , fenoldopam , a D ( 1 ) R agonist , and phorbol 12 - myristate 13 - acetate ( PMA ) , a PKC activator , inhibited oxidase activity in a time - and concentration - dependent manner . The D ( 1 ) R - mediated inhibition of oxidase activity ( 68 . 1 ± 3 . 6 % ) was attenuated by two PKA inhibitors , H89 ( 10μmol / L ; 88 ± 8 . 1 % ) and Rp - DB02527 ( 10μmol / L ; 97 . 7 ± 6 . 7 % ) , and two PKC inhibitors , bisindolylmaleimide I ( 1μmol / L ; 94 ± 6 % ) and staurosporine ( 10nmol / L ; 93 ± 8 % ) , which by themselves had no effect ( n = 4 - 8 / group ) . The inhibitory effect of PMA ( 1μmol / L ) on oxidase activity ( 73 ± 3 . 2 % ) was blocked by H89 ( 100 ± 7 . 8 % ; n = 5 or 6 / group ) . The PMA - mediated inhibition of NADPH oxidase activity was accompanied by an increase in PKCθ ( S676 ) , an effect that was also blocked by H89 . Fenoldopam ( 1μmol / L ) also increased PKCθ ( S676 ) in P29320 - hD ( 1 ) and human renal proximal tubule ( RPT ) cells . Knockdown of PKCθ with siRNA in RPT cells prevented the inhibitory effect of fenoldopam on NADPH oxidase activity . Our studies demonstrate for the first time that cross talk between PKA and PKCθ plays an important role in the D ( 1 ) R - mediated negative regulation of NADPH oxidase activity in human kidney cells .\",\n \"Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms . Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level . A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour , but only limited genetic evidence for positive selection has been presented . To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset , studying single nucleotide polymorphisms ( SNPs ) , and analyzed 55 genes in detail . We identified eight genes that are associated with the melanin pathway ( Q9UMX9 , Q04671 , P17643 , P40126 , P21583 , P00533 , P14416 and Q03181 ) and presented significant differences in genetic variation between Europeans , Africans and Asians . In six of these genes we detected , by means of the EHH test , variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( Q04671 , P17643 and P21583 ) and in Asians ( Q04671 , P40126 , P21583 , P00533 and P14416 ) , whereas signals were scarce in Africans ( P40126 , P00533 and P14416 ) . Furthermore , a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed . Overall , our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians , whereas dark skin color seems of unique origin , reflecting the ancestral state in humans .\",\n \"Dopamine selectively reduces GABA ( B ) transmission onto dopaminergic neurones by an unconventional presynaptic action . The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement . In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine ( DA ) release in the brain . Here , we report a concentration - dependent depressant action of dopamine on the GABA ( B ) IPSPs intracellularly recorded from dopaminergic neurones . Such effect was observed in spite of the presence of D ( 1 )/ P14416 antagonists . A reduction of the GABA ( B ) IPSPs was also caused by noradrenaline ( norepinephrine ) and by L - beta - 3 , 4 - dihydroxyphenylalanine ( DB01235 ) , which is metabolically transformed into DA . The DA - induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine . DA did not change the postsynaptic effects of the GABA ( B ) agonist baclofen , suggesting a presynaptic site of action . Furthermore , DA did not modulate the GABA ( A )- mediated IPSP . The DA - induced depression of the GABA ( B ) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists . The DA - and 5 - HT - induced depression of the GABA ( B ) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals . These results describe an unconventional presynaptic , D ( 1 ) and D ( 2 ) independent action of DA on the GABA ( B ) IPSP . This might have a principal role in determining therapeutic / side effects of DB01235 and antipsychotics and could be also involved in drug abuse .\",\n \"The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L - amino acid decarboxylase in healthy subjects . The A1 allele of the TaqI restriction fragment length polymorphism ( RFLP ) of the human dopamine D2 receptor gene ( P14416 ) is associated with a low density of D2 dopamine receptors in the striatum . Because of the important role of D2 autoreceptors in regulating dopamine synthesis , we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain . We also studied the effects of two other P14416 polymorphisms , C957 T and -- 141C Ins / Del , which have been suggested to affect D2 receptor levels in brain . The relationships between the TaqIA RFLP , C957 T and -- 141C Ins / Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18F ] fluorodopa ( [ 18F ] FDOPA ) , a radiolabelled analog of the dopamine precursor DB01235 . Heterozygous carriers of the A1 allele ( A1 / A2 ; 10 subjects ) had significantly higher ( 18 % ) [ 18F ] FDOPA uptake in the putamen than subjects without the A1 allele ( A2 / A2 ; 23 subjects ) . C957 T and -- 141C Ins / Del polymorphisms did not significantly affect [ 18F ] FDOPA Ki values . These results demonstrate that the A1 allele of P14416 gene is associated with increased striatal activity of aromatic L - amino acid decarboxylase , the final enzyme in the biosynthesis of dopamine and the rate - limiting enzyme for trace amine ( e . g . beta - phenylethylamine ) synthesis . The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function , and suggests that dopamine and / or trace amine synthesis rate is increased in the brains of A1 allele carriers .\",\n \"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK38___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .\",\n \"Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .\",\n \"Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy .\"\n]"},"candidates":{"kind":"list like","value":["___MASK21___","___MASK30___","___MASK38___","___MASK39___","___MASK42___","___MASK53___","___MASK77___","___MASK87___","___MASK9___"],"string":"[\n \"___MASK21___\",\n \"___MASK30___\",\n \"___MASK38___\",\n \"___MASK39___\",\n \"___MASK42___\",\n \"___MASK53___\",\n \"___MASK77___\",\n \"___MASK87___\",\n \"___MASK9___\"\n]"},"answer":{"kind":"string","value":"___MASK77___"},"id":{"kind":"string","value":"MH_train_498"}}},{"rowIdx":499,"cells":{"query":{"kind":"string","value":"interacts_with DB00674?"},"supports":{"kind":"list like","value":["P01308 suppresses IKs ( P51787 / P15382 ) currents , which require β - subunit P15382 . Abnormal QT prolongation in diabetic patients has become a clinical problem because it increases the risk of lethal ventricular arrhythmia . In an animal model of type 1 diabetes mellitus , several ion currents , including the slowly activating delayed rectifier potassium current ( IKs ) , are altered . The IKs channel is composed of P51787 and P15382 subunits , whose genetic mutations are well known to cause long QT syndrome . Although insulin is known to affect many physiological and pathophysiological events in the heart , acute effects of insulin on cardiac ion channels are poorly understood at present . This study was designed to investigate direct electrophysiological effects of insulin on IKs ( P51787 / P15382 ) currents . P51787 and P15382 were co - expressed in Xenopus oocytes , and whole cell currents were measured by a two - microelectrode voltage - clamp method . Acute application of insulin suppressed the P51787 / P15382 currents and phosphorylated Akt and extracellular signal - regulated kinase ( P29323 ) , the two major downstream effectors , in a concentration - dependent manner . Wortmannin ( 10 (- 6 ) M ) , a phosphoinositide 3 - kinase ( PI3K ) inhibitor , attenuated the suppression of the currents and phosphorylation of Akt by insulin , whereas U0126 ( 10 (- 5 ) M ) , a mitogen - activated protein kinase kinase ( MEK ) inhibitor , had no effect on insulin - induced suppression of the currents . In addition , insulin had little effect on P51787 currents without P15382 , which indicated an essential role of P15382 in the acute suppressive effects of insulin . Mutagenesis studies revealed amino acid residues 111 - 118 within the distal third C - terminus of P15382 as an important region . P01308 has direct electrophysiological effects on IKs currents , which may affect cardiac excitability .","DB00674 ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine : involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic - P27361 / 2 systems . DB00674 , a drug used to treat Alzheimer ' s disease , inhibits acetylcholinesterase ( P22303 ) and allosterically modulates nicotinic acetylcholine receptors ( nAChRs ) resulting in stimulation of catecholamine neurotransmission . In this study , we investigated whether galantamine exerts cognitive - improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine ( Meth ) psychosis . The mice treated with Meth ( 1 mg / kg . d ) for 7 d showed memory impairment in a novel object recognition test . DB00674 ( 3 mg / kg ) ameliorated the memory impairment , and it increased the extracellular dopamine release in the prefrontal cortex ( P27918 ) of Meth - treated mice . Donepezil , an P22303 inhibitor ( 1 mg / kg ) increased the extracellular ACh release in the P27918 , whereas it had no effect on the memory impairment in Meth - treated mice . The nAChR antagonist , mecamylamine , and dopamine D1 receptor antagonist , P35240 23390 , blocked the ameliorating effect of galantamine on Meth - induced memory impairment , whereas the muscarinic AChR antagonist , scopolamine , had no effect . The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine . DB00674 attenuated the defect of the novelty - induced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . The ameliorating effect of galantamine on recognition memory in Meth - treated mice was negated by microinjection of an P29323 inhibitor , PD98059 , into the P27918 . These results suggest that the ameliorating effect of galantamine on Meth - induced memory impairment is associated with indirect activation of dopamine D1 receptor - P27361 / 2 following augmentation with dopaminergic neurotransmission in the P27918 through the allosteric activation of nAChRs . DB00674 could be a useful therapeutic agent for treating cognitive deficits in schizophrenia / Meth psychosis , as well as Alzheimer ' s disease .","Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .","Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK65___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .","___MASK100___ improves hippocampal neurogenesis and depression - like behaviors via P08908 receptor stimulation in olfactory bulbectomized mice . ___MASK100___ is a non - competitive inhibitor of both acetylcholinesterase ( P22303 ) and butylcholinesterase ( BuChE ) used to treat mild to moderate dementia in Alzheimer ' s disease ( AD ) patients . Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients , its ability to improve Behavioral and Psychological Symptoms of Dementia ( BPSD ) remains unclear . To determine whether rivastigmine treatment antagonizes depression - like behaviors , we chronically administered rivastigmine ( 0 . 1 - 1 . 0mg / kg ) to olfactory bulbectomized ( OBX ) mice once a day for 2weeks , starting 2weeks after bulbectomy . Chronic treatment at 0 . 3 or 1 . 0mg / kg dose dependently and significantly improved depression - like behaviors , as assessed by tail suspension ( Q16762 ) , forced swim ( P19883 ) , locomotion and novelty - suppressed feeding ( NSFT ) tests . Importantly , co - administration with WAY - 100635 ( 1 . 0mg / kg ) , a P08908 receptor antagonist , but not ketanserin ( 1 . 0mg / kg , ) , a 5 - Q13049 receptor antagonist , completely blocked rivastigmine - induced anti - depressive effects , suggesting that P08908 receptor stimulation mediates this activity . Consistent with this observation , rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a P08908 receptor - dependent manner . Furthermore , enhanced protein kinase B ( Akt ) and extracellular signal - regulated kinase ( P29323 ) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis . These effects were blocked by WAY - 100635 but not ketanserin treatment . Finally , we confirmed that P08908 but not 5 - Q13049 receptor stimulation by specific agonists mimicked rivastigmine - induced anti - depression activity and promoted hippocampal neurogenesis . We conclude that , in addition to enhancing the cholinergic system , rivastigmine treatment restores normal function of the hippocampal serotonergic system , an activity that likely ameliorates depressive behaviors in AD patients .","Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .","The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK26___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .","Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK43___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .","Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .","Somatostatin preserved blood brain barrier against cytokine induced alterations : possible role in multiple sclerosis . Multiple sclerosis ( MS ) is an inflammatory neurological disorder associated with demyelination , impaired blood brain barrier ( BBB ) , axonal damage and neuronal loss . In the present study , we measured somatostatin ( P61278 ) and tumor necrosis factor - α ( P01375 - α ) like immunoreactivity in P04141 samples from MS and non - MS patients . We also examined the role of P61278 in cytokines and lipopolysaccharide ( LPS ) - induced damage to the BBB using human brain endothelial cells in culture . Most of the cerebrospinal fluid ( P04141 ) samples studied from definite MS patients exhibited lower somatostatin ( P61278 ) - like immunoreactivity and higher expression of P01375 - α in comparison to non - MS patients . Treatment of cells with cytokines and LPS blocked P61278 secretion and decreased P61278 expression . Human brain endothelial cells expressed all five somatostatin receptors ( SSTRs ) with increased expression of P30874 and 4 upon treatment with cytokines and LPS . Cytokines and LPS - induced disruption of the tight junction proteins Zonula occludens ( ZO - 1 ) organization was restored in presence of P61278 , P30874 or P31391 selective agonists . Furthermore , inflammation induced changes in extracellular signal - regulated kinases ( P27361 / 2 and Q13164 ) signaling and altered expression of endothelial and inducible nitric oxide synthase are modulated in presence of P61278 . These data indicate that decreased levels of P61278 contribute to failure of the BBB in MS .","Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .","Different cholinesterase inhibitor effects on P04141 cholinesterases in Alzheimer patients . BACKGROUND : The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) activities and protein levels , in the cerebrospinal fluid ( P04141 ) of Alzheimer disease ( AD ) patients . METHODS AND FINDINGS : AD patients aged 50 - 85 years were randomized to open - label treatment with oral rivastigmine , donepezil or galantamine for 13 weeks . P22303 and BuChE activities were assayed by Ellman ' s colorimetric method . Protein levels were assessed by enzyme - linked immunosorbent assay ( ELISA ) . Primary analyses were based on the Completer population ( randomized patients who completed Week 13 assessments ) . 63 patients were randomized to treatment . ___MASK100___ was associated with decreased P22303 activity by 42 . 6 % and decreased P22303 protein levels by 9 . 3 % , and decreased BuChE activity by 45 . 6 % and decreased BuChE protein levels by 21 . 8 % . DB00674 decreased P22303 activity by 2 . 1 % and BuChE activity by 0 . 5 % , but increased P22303 protein levels by 51 . 2 % and BuChE protein levels by 10 . 5 % . Donepezil increased P22303 and BuChE activities by 11 . 8 % and 2 . 8 % , respectively . Donepezil caused a 215 . 2 % increase in P22303 and 0 . 4 % increase in BuChE protein levels . Changes in mean P22303 - Readthrough / Synaptic ratios , which might reflect underlying neurodegenerative processes , were 1 . 4 , 0 . 6 , and 0 . 4 for rivastigmine , donepezil and galantamine , respectively . CONCLUSION : The findings suggest pharmacologically - induced differences between rivastigmine , donepezil and galantamine . ___MASK100___ provides sustained inhibition of P22303 and BuChE , while donepezil and galantamine do not inhibit BuChE and are associated with increases in P04141 P22303 protein levels . The clinical implications require evaluation .","___MASK7___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .","The dopamine metabolite 3 - methoxytyramine is a neuromodulator . Dopamine ( 3 - hydroxytyramine ) is a well - known catecholamine neurotransmitter involved in multiple physiological functions including movement control . Here we report that the major extracellular metabolite of dopamine , 3 - methoxytyramine ( 3 - MT ) , can induce behavioral effects in a dopamine - independent manner and these effects are partially mediated by the trace amine associated receptor 1 ( Q96RJ0 ) . Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3 - MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine . In normal mice , the central administration of 3 - MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements . Furthermore , 3 - MT induced significant P29323 and CREB phosphorylation in the mouse striatum , signaling events generally related to PKA - mediated DB02527 accumulation . In mice lacking Q96RJ0 , both behavioral and signaling effects of 3 - MT were partially attenuated , consistent with the ability of 3 - MT to activate Q96RJ0 receptors and cause DB02527 accumulation as well as P29323 and CREB phosphorylation in cellular assays . Thus , 3 - MT is not just an inactive metabolite of DA , but a novel neuromodulator that in certain situations may be involved in movement control . Further characterization of the physiological functions mediated by 3 - MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission , such as Parkinson ' s disease , dyskinesia and schizophrenia .","A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK95___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK95___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .","P50406 mediates defective brain development in monoamine oxidase A - deficient mouse embryos . Monoamine oxidases A and B ( P21397 and P27338 ) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines . In the adult central nervous system , MAOs have important functions for neurotransmitter homeostasis . Expression of MAO isoforms has been detected in the developing embryo . However , suppression of P27338 does not induce developmental alterations . In contrast , targeted inhibition and knockdown of P21397 expression ( E7 . 5 - E10 . 5 ) caused structural abnormalities in the brain . Here we explored the molecular mechanisms underlying defective brain development induced by P21397 knockdown during in vitro embryogenesis . The developmental alterations were paralleled by diminished apoptotic activity in the affected neuronal structures . Moreover , dysfunctional P21397 expression led to elevated levels of embryonic serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) , and we found that knockdown of serotonin receptor - 6 ( 5 - Htr6 ) expression or pharmacologic inhibition of 5 - Htr6 activity rescued the P21397 knockdown phenotype and restored apoptotic activity in the developing brain . Our data suggest that excessive 5 - Htr6 activation reduces activation of caspase - 3 and - 9 of the intrinsic apoptotic pathway and enhances expression of antiapoptotic proteins Bcl - 2 and Bcl - XL . Moreover , we found that elevated 5 - HT levels in P21397 knockdown embryos coincided with an enhanced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) and a reduction of proliferating cell numbers . In summary , our findings suggest that excessive 5 - HT in P21397 - deficient mouse embryos triggers cellular signaling cascades via 5 - Htr6 , which suppresses developmental apoptosis in the brain and thus induces developmental retardations .","Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK1___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .","___MASK20___ binding to human and rat dopamine and 5 - HT receptors . ___MASK20___ ( ___MASK20___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK20___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK20___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK20___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .","Fibrinolytic activity in the inner ear of human beings and guinea pigs . Fibrinolytic activity in the inner ear of human beings and guinea pigs was assayed qualitatively and quantitatively . It was found that fibrinolytic activity of the stria vascularis was caused by a conversion of plasminogen to plasmin by tissue plasminogen activator and was moderate in degree compared with that of other organs in both species . In human beings , endolymph showed higher plasminogen activator activity than that of P04141 . P00747 activator activity was not detected in either endolymph or perilymph of guinea pigs . Thrombin infusion diminished plasminogen activator activity in the stria vascularis of guinea pigs .","P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK11___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )"],"string":"[\n \"P01308 suppresses IKs ( P51787 / P15382 ) currents , which require β - subunit P15382 . Abnormal QT prolongation in diabetic patients has become a clinical problem because it increases the risk of lethal ventricular arrhythmia . In an animal model of type 1 diabetes mellitus , several ion currents , including the slowly activating delayed rectifier potassium current ( IKs ) , are altered . The IKs channel is composed of P51787 and P15382 subunits , whose genetic mutations are well known to cause long QT syndrome . Although insulin is known to affect many physiological and pathophysiological events in the heart , acute effects of insulin on cardiac ion channels are poorly understood at present . This study was designed to investigate direct electrophysiological effects of insulin on IKs ( P51787 / P15382 ) currents . P51787 and P15382 were co - expressed in Xenopus oocytes , and whole cell currents were measured by a two - microelectrode voltage - clamp method . Acute application of insulin suppressed the P51787 / P15382 currents and phosphorylated Akt and extracellular signal - regulated kinase ( P29323 ) , the two major downstream effectors , in a concentration - dependent manner . Wortmannin ( 10 (- 6 ) M ) , a phosphoinositide 3 - kinase ( PI3K ) inhibitor , attenuated the suppression of the currents and phosphorylation of Akt by insulin , whereas U0126 ( 10 (- 5 ) M ) , a mitogen - activated protein kinase kinase ( MEK ) inhibitor , had no effect on insulin - induced suppression of the currents . In addition , insulin had little effect on P51787 currents without P15382 , which indicated an essential role of P15382 in the acute suppressive effects of insulin . Mutagenesis studies revealed amino acid residues 111 - 118 within the distal third C - terminus of P15382 as an important region . P01308 has direct electrophysiological effects on IKs currents , which may affect cardiac excitability .\",\n \"DB00674 ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine : involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic - P27361 / 2 systems . DB00674 , a drug used to treat Alzheimer ' s disease , inhibits acetylcholinesterase ( P22303 ) and allosterically modulates nicotinic acetylcholine receptors ( nAChRs ) resulting in stimulation of catecholamine neurotransmission . In this study , we investigated whether galantamine exerts cognitive - improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine ( Meth ) psychosis . The mice treated with Meth ( 1 mg / kg . d ) for 7 d showed memory impairment in a novel object recognition test . DB00674 ( 3 mg / kg ) ameliorated the memory impairment , and it increased the extracellular dopamine release in the prefrontal cortex ( P27918 ) of Meth - treated mice . Donepezil , an P22303 inhibitor ( 1 mg / kg ) increased the extracellular ACh release in the P27918 , whereas it had no effect on the memory impairment in Meth - treated mice . The nAChR antagonist , mecamylamine , and dopamine D1 receptor antagonist , P35240 23390 , blocked the ameliorating effect of galantamine on Meth - induced memory impairment , whereas the muscarinic AChR antagonist , scopolamine , had no effect . The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine . DB00674 attenuated the defect of the novelty - induced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . The ameliorating effect of galantamine on recognition memory in Meth - treated mice was negated by microinjection of an P29323 inhibitor , PD98059 , into the P27918 . These results suggest that the ameliorating effect of galantamine on Meth - induced memory impairment is associated with indirect activation of dopamine D1 receptor - P27361 / 2 following augmentation with dopaminergic neurotransmission in the P27918 through the allosteric activation of nAChRs . DB00674 could be a useful therapeutic agent for treating cognitive deficits in schizophrenia / Meth psychosis , as well as Alzheimer ' s disease .\",\n \"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .\",\n \"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK65___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \\\" neurological dose \\\" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .\",\n \"___MASK100___ improves hippocampal neurogenesis and depression - like behaviors via P08908 receptor stimulation in olfactory bulbectomized mice . ___MASK100___ is a non - competitive inhibitor of both acetylcholinesterase ( P22303 ) and butylcholinesterase ( BuChE ) used to treat mild to moderate dementia in Alzheimer ' s disease ( AD ) patients . Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients , its ability to improve Behavioral and Psychological Symptoms of Dementia ( BPSD ) remains unclear . To determine whether rivastigmine treatment antagonizes depression - like behaviors , we chronically administered rivastigmine ( 0 . 1 - 1 . 0mg / kg ) to olfactory bulbectomized ( OBX ) mice once a day for 2weeks , starting 2weeks after bulbectomy . Chronic treatment at 0 . 3 or 1 . 0mg / kg dose dependently and significantly improved depression - like behaviors , as assessed by tail suspension ( Q16762 ) , forced swim ( P19883 ) , locomotion and novelty - suppressed feeding ( NSFT ) tests . Importantly , co - administration with WAY - 100635 ( 1 . 0mg / kg ) , a P08908 receptor antagonist , but not ketanserin ( 1 . 0mg / kg , ) , a 5 - Q13049 receptor antagonist , completely blocked rivastigmine - induced anti - depressive effects , suggesting that P08908 receptor stimulation mediates this activity . Consistent with this observation , rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a P08908 receptor - dependent manner . Furthermore , enhanced protein kinase B ( Akt ) and extracellular signal - regulated kinase ( P29323 ) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis . These effects were blocked by WAY - 100635 but not ketanserin treatment . Finally , we confirmed that P08908 but not 5 - Q13049 receptor stimulation by specific agonists mimicked rivastigmine - induced anti - depression activity and promoted hippocampal neurogenesis . We conclude that , in addition to enhancing the cholinergic system , rivastigmine treatment restores normal function of the hippocampal serotonergic system , an activity that likely ameliorates depressive behaviors in AD patients .\",\n \"Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .\",\n \"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK26___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .\",\n \"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK43___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .\",\n \"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .\",\n \"Somatostatin preserved blood brain barrier against cytokine induced alterations : possible role in multiple sclerosis . Multiple sclerosis ( MS ) is an inflammatory neurological disorder associated with demyelination , impaired blood brain barrier ( BBB ) , axonal damage and neuronal loss . In the present study , we measured somatostatin ( P61278 ) and tumor necrosis factor - α ( P01375 - α ) like immunoreactivity in P04141 samples from MS and non - MS patients . We also examined the role of P61278 in cytokines and lipopolysaccharide ( LPS ) - induced damage to the BBB using human brain endothelial cells in culture . Most of the cerebrospinal fluid ( P04141 ) samples studied from definite MS patients exhibited lower somatostatin ( P61278 ) - like immunoreactivity and higher expression of P01375 - α in comparison to non - MS patients . Treatment of cells with cytokines and LPS blocked P61278 secretion and decreased P61278 expression . Human brain endothelial cells expressed all five somatostatin receptors ( SSTRs ) with increased expression of P30874 and 4 upon treatment with cytokines and LPS . Cytokines and LPS - induced disruption of the tight junction proteins Zonula occludens ( ZO - 1 ) organization was restored in presence of P61278 , P30874 or P31391 selective agonists . Furthermore , inflammation induced changes in extracellular signal - regulated kinases ( P27361 / 2 and Q13164 ) signaling and altered expression of endothelial and inducible nitric oxide synthase are modulated in presence of P61278 . These data indicate that decreased levels of P61278 contribute to failure of the BBB in MS .\",\n \"Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .\",\n \"Different cholinesterase inhibitor effects on P04141 cholinesterases in Alzheimer patients . BACKGROUND : The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) activities and protein levels , in the cerebrospinal fluid ( P04141 ) of Alzheimer disease ( AD ) patients . METHODS AND FINDINGS : AD patients aged 50 - 85 years were randomized to open - label treatment with oral rivastigmine , donepezil or galantamine for 13 weeks . P22303 and BuChE activities were assayed by Ellman ' s colorimetric method . Protein levels were assessed by enzyme - linked immunosorbent assay ( ELISA ) . Primary analyses were based on the Completer population ( randomized patients who completed Week 13 assessments ) . 63 patients were randomized to treatment . ___MASK100___ was associated with decreased P22303 activity by 42 . 6 % and decreased P22303 protein levels by 9 . 3 % , and decreased BuChE activity by 45 . 6 % and decreased BuChE protein levels by 21 . 8 % . DB00674 decreased P22303 activity by 2 . 1 % and BuChE activity by 0 . 5 % , but increased P22303 protein levels by 51 . 2 % and BuChE protein levels by 10 . 5 % . Donepezil increased P22303 and BuChE activities by 11 . 8 % and 2 . 8 % , respectively . Donepezil caused a 215 . 2 % increase in P22303 and 0 . 4 % increase in BuChE protein levels . Changes in mean P22303 - Readthrough / Synaptic ratios , which might reflect underlying neurodegenerative processes , were 1 . 4 , 0 . 6 , and 0 . 4 for rivastigmine , donepezil and galantamine , respectively . CONCLUSION : The findings suggest pharmacologically - induced differences between rivastigmine , donepezil and galantamine . ___MASK100___ provides sustained inhibition of P22303 and BuChE , while donepezil and galantamine do not inhibit BuChE and are associated with increases in P04141 P22303 protein levels . The clinical implications require evaluation .\",\n \"___MASK7___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .\",\n \"The dopamine metabolite 3 - methoxytyramine is a neuromodulator . Dopamine ( 3 - hydroxytyramine ) is a well - known catecholamine neurotransmitter involved in multiple physiological functions including movement control . Here we report that the major extracellular metabolite of dopamine , 3 - methoxytyramine ( 3 - MT ) , can induce behavioral effects in a dopamine - independent manner and these effects are partially mediated by the trace amine associated receptor 1 ( Q96RJ0 ) . Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3 - MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine . In normal mice , the central administration of 3 - MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements . Furthermore , 3 - MT induced significant P29323 and CREB phosphorylation in the mouse striatum , signaling events generally related to PKA - mediated DB02527 accumulation . In mice lacking Q96RJ0 , both behavioral and signaling effects of 3 - MT were partially attenuated , consistent with the ability of 3 - MT to activate Q96RJ0 receptors and cause DB02527 accumulation as well as P29323 and CREB phosphorylation in cellular assays . Thus , 3 - MT is not just an inactive metabolite of DA , but a novel neuromodulator that in certain situations may be involved in movement control . Further characterization of the physiological functions mediated by 3 - MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission , such as Parkinson ' s disease , dyskinesia and schizophrenia .\",\n \"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK95___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK95___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .\",\n \"P50406 mediates defective brain development in monoamine oxidase A - deficient mouse embryos . Monoamine oxidases A and B ( P21397 and P27338 ) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines . In the adult central nervous system , MAOs have important functions for neurotransmitter homeostasis . Expression of MAO isoforms has been detected in the developing embryo . However , suppression of P27338 does not induce developmental alterations . In contrast , targeted inhibition and knockdown of P21397 expression ( E7 . 5 - E10 . 5 ) caused structural abnormalities in the brain . Here we explored the molecular mechanisms underlying defective brain development induced by P21397 knockdown during in vitro embryogenesis . The developmental alterations were paralleled by diminished apoptotic activity in the affected neuronal structures . Moreover , dysfunctional P21397 expression led to elevated levels of embryonic serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) , and we found that knockdown of serotonin receptor - 6 ( 5 - Htr6 ) expression or pharmacologic inhibition of 5 - Htr6 activity rescued the P21397 knockdown phenotype and restored apoptotic activity in the developing brain . Our data suggest that excessive 5 - Htr6 activation reduces activation of caspase - 3 and - 9 of the intrinsic apoptotic pathway and enhances expression of antiapoptotic proteins Bcl - 2 and Bcl - XL . Moreover , we found that elevated 5 - HT levels in P21397 knockdown embryos coincided with an enhanced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) and a reduction of proliferating cell numbers . In summary , our findings suggest that excessive 5 - HT in P21397 - deficient mouse embryos triggers cellular signaling cascades via 5 - Htr6 , which suppresses developmental apoptosis in the brain and thus induces developmental retardations .\",\n \"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK1___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .\",\n \"___MASK20___ binding to human and rat dopamine and 5 - HT receptors . ___MASK20___ ( ___MASK20___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK20___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK20___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK20___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .\",\n \"Fibrinolytic activity in the inner ear of human beings and guinea pigs . Fibrinolytic activity in the inner ear of human beings and guinea pigs was assayed qualitatively and quantitatively . It was found that fibrinolytic activity of the stria vascularis was caused by a conversion of plasminogen to plasmin by tissue plasminogen activator and was moderate in degree compared with that of other organs in both species . In human beings , endolymph showed higher plasminogen activator activity than that of P04141 . P00747 activator activity was not detected in either endolymph or perilymph of guinea pigs . Thrombin infusion diminished plasminogen activator activity in the stria vascularis of guinea pigs .\",\n \"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK11___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )\"\n]"},"candidates":{"kind":"list like","value":["___MASK100___","___MASK11___","___MASK1___","___MASK20___","___MASK26___","___MASK43___","___MASK65___","___MASK7___","___MASK95___"],"string":"[\n \"___MASK100___\",\n \"___MASK11___\",\n \"___MASK1___\",\n \"___MASK20___\",\n \"___MASK26___\",\n \"___MASK43___\",\n \"___MASK65___\",\n \"___MASK7___\",\n \"___MASK95___\"\n]"},"answer":{"kind":"string","value":"___MASK11___"},"id":{"kind":"string","value":"MH_train_499"}}}],"truncated":false,"partial":false},"paginationData":{"pageIndex":4,"numItemsPerPage":100,"numTotalItems":1620,"offset":400,"length":100}},"jwt":"eyJhbGciOiJFZERTQSJ9.eyJyZWFkIjp0cnVlLCJwZXJtaXNzaW9ucyI6eyJyZXBvLmNvbnRlbnQucmVhZCI6dHJ1ZX0sImlhdCI6MTc2NTU0MDkzMCwic3ViIjoiL2RhdGFzZXRzL2NvbW11bml0eS1kYXRhc2V0cy9xYW5nYXJvbyIsImV4cCI6MTc2NTU0NDUzMCwiaXNzIjoiaHR0cHM6Ly9odWdnaW5nZmFjZS5jbyJ9.UCQX4811dbaz6h-7zrV72ABKgyFgpcd3wWFQC6i493b5bobUnVNs0cJbddOxz7mQWaM7J8J64LqMBiuLrxTOCQ","displayUrls":true,"splitSizeSummaries":[{"config":"masked_medhop","split":"train","numRows":1620,"numBytesParquet":50027308},{"config":"masked_medhop","split":"validation","numRows":342,"numBytesParquet":8774415},{"config":"masked_wikihop","split":"train","numRows":43738,"numBytesParquet":187716381},{"config":"masked_wikihop","split":"validation","numRows":5129,"numBytesParquet":23586614},{"config":"medhop","split":"train","numRows":1620,"numBytesParquet":49190527},{"config":"medhop","split":"validation","numRows":342,"numBytesParquet":8647233},{"config":"wikihop","split":"train","numRows":43738,"numBytesParquet":179876427},{"config":"wikihop","split":"validation","numRows":5129,"numBytesParquet":22578535}]},"discussionsStats":{"closed":6,"open":0,"total":6},"fullWidth":true,"hasGatedAccess":true,"hasFullAccess":true,"isEmbedded":false,"savedQueries":{"community":[],"user":[]}}">
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[
"Signalling mechanisms in sphingosine 1 - phosphate - promoted mesangial cell proliferation . BACKGROUND : The bioactive sphingolipid sphingosine 1 - phosphate ( Q14703 ) is formed by the activation of sphingosine kinase ( Q9NYA1 ) in diverse stimuli , such as platelet - derived growth factor ( PDGF ) . Q14703 acts not only as an extracellular mediator but also as an intracellular second messenger , resulting in the proliferation of various different types of cells . However , the signal transduction mechanism in Q14703 - induced proliferation of mesangial cells is poorly known . RESULTS : We examined the signalling mechanisms by which Q14703 and dihydro - Q14703 ( DHS1P ) , another Q14703 receptor agonist , induce mesangial cell proliferation . We first observed that exogenous Q14703 / DHS1P had additive effects on the PDGF - promoted proliferation of mesangial cells . Treatment of mesangial cells with pertussis toxin almost completely inhibited Q14703 - and DHS1P - induced , and slightly inhibited PDGF - induced cell proliferation . Additionally , the P29323 kinase inhibitor PD98059 partially blocked the proliferation of mesangial cells induced by all these ligands . N , N - dimethylsphingosine , a competitive inhibitor of Q9NYA1 , reduced PDGF - induced mesangial cell proliferation , whereas over - expression of Q9NYA1 promoted it . We also revealed that PDGF induces Q9NYA1 mRNA expression and Q9NYA1 activity , suggesting that Q9NYA1 , which links the PDGF to the Q14703 signalling cascade , is , at least in part , involved in PDGF - induced mesangial cell proliferation . Moreover , we found that extracellular Q14703 stimulates two Q14703 receptors , Q99500 and O95136 , which leads to cell proliferation and survival . CONCLUSIONS : The data show that Q14703 - induced mesangial cell proliferation is mediated by EDG - dependent and - independent signalling pathways . Q14703 may cooperate with PDGF to increase the proliferation of mesangial cells during pathophysiological processes .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK5___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK61___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .",
"DB08868 : direct CNS effects of sphingosine 1 - phosphate ( Q14703 ) receptor modulation and implications in multiple sclerosis therapy . DB08868 is the first oral disease - modifying therapy approved for relapsing forms of multiple sclerosis ( MS ) . Following phosphorylation in vivo , the active agent , fingolimod phosphate ( fingolimod - P ) , acts as a sphingosine 1 - phosphate ( Q14703 ) receptor modulator , binding with high affinity to four of the five known Q14703 receptors ( P21453 , Q99500 , O95977 and Q9H228 ) . The mechanism of action of fingolimod in MS has primarily been considered as immunomodulatory , whereby fingolimod - P modulates P21453 on lymphocytes , selectively retaining autoreactive lymphocytes in lymph nodes to reduce damaging infiltration into the central nervous system ( CNS ) . However , emerging evidence indicates that fingolimod has direct effects in the CNS in MS . For example , in the MS animal model of experimental autoimmune encephalomyelitis ( EAE ) , fingolimod is highly efficacious in both a prophylactic and therapeutic setting , yet becomes ineffective in animals selectively deficient for P21453 on astrocytes , despite maintained normal immunologic receptor expression and functions , and Q14703 - mediated immune activities . Here we review Q14703 signaling effects relevant to MS in neural cell types expressing Q14703 receptors , including astrocytes , oligodendrocytes , neurons , microglia and dendritic cells . The direct effects of fingolimod on these CNS cells observed in preclinical studies are discussed in view of the functional consequences of reducing neurodegenerative processes and promoting myelin preservation and repair . The therapeutic implications of Q14703 modulation in the CNS are considered in terms of the clinical outcomes of MS , such as reducing MS - related brain atrophy , and other CNS disorders . Additionally , we briefly outline other existing and investigational MS therapies that may also have effects in the CNS .",
"Synthesis and evaluation of fluorinated fingolimod ( FTY720 ) analogues for sphingosine - 1 - phosphate receptor molecular imaging by positron emission tomography . DB03203 - 1 - phosphate ( Q14703 ) is a lysophospholipid that evokes a variety of biological responses via stimulation of a set of cognate G - protein coupled receptors ( GPCRs ) : P21453 - Q9H228 . Q14703 and its receptors ( S1PRs ) play important roles in the immune , cardiovascular , and central nervous systems and have also been implicated in carcinogenesis . Recently , the Q14703 analogue DB08868 ( FTY720 ) has been approved for the treatment of patients with relapsing multiple sclerosis . This work presents the synthesis of various fluorinated structural analogues of FTY720 , their in vitro and in vivo biological testing , and their development and application as [( 18 ) F ] radiotracers for the study of S1PR biodistribution and imaging in mice using small - animal positron emission tomography ( PET ) .",
"DB08868 ( FTY720 ) enhances remyelination following demyelination of organotypic cerebellar slices . Remyelination , which occurs subsequent to demyelination , contributes to functional recovery and is mediated by oligodendrocyte progenitor cells ( OPCs ) that have differentiated into myelinating cells . Therapeutics that impact remyelination in the CNS could be critical determinants of long - term functional outcome in multiple sclerosis ( MS ) . DB08868 is a Q14703 receptor modulator in MS clinical trials due to systemic anti - inflammatory properties , yet may impact cells within the CNS by crossing the blood - brain barrier . Previous studies using isolated dissociated cultures indicate that neural cells express Q14703 receptors and respond to receptor engagement . Our objective was to assess the effects of fingolimod on myelin - related processes within a multicellular environment that maintains physiological cell - cell interactions , using organotypic cerebellar slice cultures . DB08868 treatment had no impact on myelin under basal conditions . DB08868 treatment subsequent to lysolecithin - induced demyelination enhanced remyelination and process extension by OPCs and mature oligodendrocytes , while increasing microglia numbers and immunoreactivity for the astrocytic marker glial fibrillary acidic protein . The number of phagocytosing microglia was not increased by fingolimod . Using Q14703 receptor specific agonists and antagonists , we determined that fingolimod - induced effects on remyelination and astrogliosis were mediated primarily through Q99500 and Q9H228 , whereas enhanced microgliosis was mediated through P21453 and Q9H228 . Taken together , these data demonstrate that fingolimod modulates multiple neuroglial cell responses , resulting in enhanced remyelination in organotypic slice cultures that maintain the complex cellular interactions of the mammalian brain .",
"___MASK27___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK27___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK27___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK27___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"P01308 protects apoptotic cardiomyocytes from hypoxia / reoxygenation injury through the sphingosine kinase / sphingosine 1 - phosphate axis . OBJECTIVE : Experimental and clinical studies have shown that administration of insulin during reperfusion is cardioprotective , but the mechanisms underlying this effect are still unknown . In this study , the ability of insulin to protect apoptotic cardiomyocytes from hypoxia / reoxygenation injury using the sphingosine kinase / sphingosine 1 - phosphate axis was investigated . METHODS AND RESULTS : Rat cardiomyocytes were isolated and subjected to hypoxia and reoxygenation . [ γ - 32P ] DB00171 was used to assess sphingosine kinase activity . P01308 was found to increase sphingosine kinase activity . Immunocytochemistry and Western blot analysis showed changes in the subcellular location of sphingosine kinase 1 from cytosol to the membrane in cardiomyocytes . P01308 caused cardiomyocytes to accumulate of Q14703 in a dose - dependent manner . FRET efficiency showed that insulin also transactivates the P21453 receptor . TUNEL staining showed that administration of insulin during reoxygenation could to reduce the rate of reoxygenation - induced apoptosis , which is a requirement for SphK 1 activity . It also reduced the rate of activation of the Q14703 receptor and inhibited hypoxia / reoxygenation - induced cell death in cardiomyocytes . CONCLUSION : The sphingosine kinase 1 / sphingosine 1 - phosphate / Q14703 receptor axis is one pathway through which insulin protects rat cardiomyocytes from apoptosis induced by hypoxia / reoxygenation injury .",
"DB03203 - 1 - phosphate inhibits interleukin - 1β - induced inflammation in human articular chondrocytes . DB03203 - 1 - phosphate ( Q14703 ) is a pluripotent lipid mediator that transmits signals through a family of G - protein - coupled receptors ( GPCRs ) to control diverse biological processes including inflammation and wound - healing . In this study , a novel biological activity of Q14703 in articular chondrocytes was identified . Human primary chondrocytes were cultured in a monolayer . Reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting were performed to detect genes and proteins involved in inflammation and cartilage degradation when human primary chondrocytes were stimulated by interleukin ( IL ) - 1β . Matrix metalloproteinase ( MMP ) - 2 and P14780 activity was evaluated by gelatin zymography . Glycosaminoglycan ( GAG ) degradation was evaluated using the dimethylene blue method . DB00917 ( DB00917 ) was measured by enzyme - linked immunosorbent assay ( ELISA ) . By using the P21453 receptor agonist and antagonist , we discovered the key role played by P21453 in the Q14703 - dependent inhibition of IL - 1β - induced inflammation in human chondrocytes . Q14703 dose - dependently inhibited IL - 1β - induced NF - κB p65 , cyclooxygenase ( P36551 ) - 2 , P03956 , P08254 , P45452 and P50281 mRNA expression in human chondrocytes and IL - 1β - induced DB00917 synthesis and GAG degradation in human cartilage explants . W146 , a known P21453 receptor antagonist , inhibited the active form of NF - κB p65 and P35354 expression induced by IL - 1β . The anti - inflammatory action of the P21453 receptor agonist SEW2871 was similar to that of Q14703 . This study demonstrates that Q14703 has anti - inflammatory effects on chondrocytes via the P21453 receptor . Our data suggest that targeting Q14703 and P21453 may be a potential therapy for arthritis .",
"___MASK90___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK90___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"___MASK51___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .",
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK25___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .",
"Identification of B cells participated in the mechanism of postmenopausal women osteoporosis using microarray analysis . To further understand the molecular mechanism of lymphocytes B cells in postmenopausal women osteoporosis . Microarray data ( GSE7429 ) were downloaded from Gene Expression Omnibus , in which B cells were separated from the whole blood of postmenopausal women , including 10 with high bone mineral density ( BMD ) and 10 with low BMD . Differentially expressed genes ( DEGs ) between high and low BMD women were identified by Student ' s t - test , and P < 0 . 01 was used as the significant criterion . Functional enrichment analysis was performed for up - and down - regulated DEGs using KEGG , REACTOME , and Gene Ontology ( GO ) databases . Protein - protein interaction network ( PPI ) of up - and down - regulated DEGs was respectively constructed by Cytoscape software using the STRING data . Total of 169 up - regulated and 69 down - regulated DEGs were identified . Functional enrichment analysis indicated that the genes ( Q9BY32 , P31939 , P11172 , P00492 , Q12887 and Q7KZN9 ) might participate in metabolic pathways , Q02779 and P80192 might participate in the activation of P45985 activity , Q12887 and Q7KZN9 might involve in mitochondrial electron transport , and P31939 , P11172 and P00492 might involve in transferase activity . P27361 , Q9BY32 , P31939 , P11172 and P00492 with a higher degree in PPI network were identified . P27361 , Q02779 , P80192 , Q12887 , Q7KZN9 , P31939 , P11172 and P00492 might participate in the pathogenesis of osteoporosis .",
"Functional consequences of Q14703 receptor modulation in rat oligodendroglial lineage cells . DB08868 ( FTY720 ) and its phosphorylated form FTY720P are modulators of sphingosine - 1 - phosphate ( Q14703 ) receptors , which are G - protein coupled receptors linked to cell migration and vascular maturation . The efficacy of FTY720 in autoimmune diseases such as multiple sclerosis and its animal models has been attributed to its inhibition of lymphocyte trafficking to target organs . In this study , we examined the role of Q14703 receptors in cultured rat oligodendrocytes ( OLGs ) and OLG progenitor cells ( OPCs ) using the active phosphorylated form of FTY720 . We found that ( 1 ) FTY720P improves the survival of neonatal rat OLGs during serum withdrawal , which is associated with the phosphorylation of extracellular signal regulated kinases ( P27361 / 2 ) and Akt ; ( 2 ) FTY720P regulates OPC differentiation into OLGs in a concentration - dependent manner ; and ( 3 ) Q14703 receptors are differentially modulated by platelet - derived growth factor ( PDGF ) resulting in downregulation of Q9H228 and upregulation of P21453 in OPCs . In addition , siRNA studies revealed that P21453 participates in PDGF - induced OPC mitogenesis . We conclude that P21453 and Q9H228 serve different functions during oligodendroglial development , and possibly during remyelination .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK43___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK99___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK99___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK99___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"DB03203 1 - phosphate ( Q14703 ) induced interleukin - 8 ( P10145 ) release is mediated by O95136 and nuclear factor κB in BEAS - 2B cells . The airway epithelium may release pro - inflammatory cytokines and chemokines in the asthmatic airway . DB03203 1 - phosphate ( Q14703 ) is a bioactive lipid , increased in the airways of asthmatics , that may trigger the release of the potent neutrophil chemoattractant P10145 ( P10145 ) by epithelial cells . Q14703 is a ligand for 5 G protein - coupled receptors , P21453 - 5 . We wished to explore the mechanisms of Q14703 induced P10145 secretion with regard to the receptor ( s ) and downstream signaling events involved . Our results indicate that Q14703 induced P10145 release is mediated by O95136 and the transcription factor NF - κB . Since the Epidermal Growth Factor Receptor ( P00533 ) and reactive oxygen species ( ROS ) have been implicated in P10145 release in response to activation of other G protein - coupled receptors , we examined their importance in Q14703 induced P10145 release and established that they are not involved . This study reveals O95136 and NF - κB as potential therapeutic targets in neutrophilic airway diseases such as severe asthma .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"Interferon - gamma - induced dephosphorylation of P40763 and apoptosis are dependent on the P42345 pathway . Interferon - gamma ( P01579 ) exhibits diverse biological activities , including control of cell growth and tumor suppression . Here , we report that the treatment of M12 cells , a human metastatic prostate cancer cell line , with P01579 , resulted in marked inhibition of cell proliferation and induced apoptosis . These effects were not seen with either IFN - alpha or IFN - beta . M12 cells , like many other human cancer cells , contain constitutively activated signal transducer and activator of transcription 3 ( P40763 ) . The basal levels of both Akt and P27361 / 2 phosphorylation are also markedly elevated in M12 cells . Strikingly , P01579 - induced apoptosis and growth inhibition of M12 cells were associated with persistent suppression of the constitutive tyrosine - phosphorylated P40763 ( pY - P40763 ) . The P01579 - induced dephosphorylation of pY - P40763 , however , was inhibited when the P42345 pathway was specifically blocked by rapamycin . Inhibition of PI - 3K with low - dose LY294002 , or MAPK with PD98059 also suppressed the P42345 / P08133 S6k pathway , and correlated with the blockage of P01579 - induced dephosphorylation of pY - P40763 . Simultaneously , treatment with LY294002 , PD98059 , or rapamycin abolished P01579 - induced apoptosis in M12 cells . The inhibition of the P42345 pathway , however , did not affect P01579 - induced activation of P42224 pathway , and suppression of P42224 expression by siRNA had no effect on P01579 - induced dephosphorylation of pY - P40763 . Taken together , these results demonstrate that an intact P42345 pathway is critical for P01579 - induced suppression of pY - P40763 and apoptosis . Our study thus provides novel insights into the contributions of signaling pathways other than the classical JAK / P42224 pathway in the anti - proliferative , proapoptotic actions of P01579 .",
"Q96RP3 is expressed in human pregnant myometrial cells and regulates myosin light chain phosphorylation : potential role of the type - 2 corticotropin - releasing hormone receptor in the control of myometrial contractility . The family of P06850 - related peptides are suggested to play important roles in the control of myometrial contractility during pregnancy and labor . In this study we investigated the expression of urocortin II ( P55089 II ) in human myometrium and its ability to phosphorylate intracellular components that can be involved in modulating myometrial contractility . Using RT - PCR and fluorescent in situ hybridization , we demonstrated that P55089 II and type - 2 P06850 receptor ( Q13324 ) mRNAs were expressed in human nonpregnant and pregnant myometrium . Immunofluorescent studies confirmed protein expression of P55089 II in human pregnant myometrial cells , whereas chemical cross - linking studies with radiolabeled P55089 II confirmed the presence of Q13324 sites with an apparent molecular mass of 50 kDa . Treatment of primary human myometrial cells with P55089 II to specifically activate Q13324 resulted in a dose - dependent increase of myosin light chain ( MLC ( 20 ) ) phosphorylation . Activation of protein kinase C ( PKC ) and P27361 / 2 was required for the P55089 II - induced activation of MLC ( 20 ) , because treatment of myometrial cells with inhibitors of MAPK kinase 1 ( U0126 ) and PKC ( bisindolylmaleimide ) inhibited the P55089 II - induced phosphorylation of MLC ( 20 ) . Furthermore , the P55089 II effect on MLC ( 20 ) was dependent on RhoA translocation to the membrane and subsequent activation of RhoA - associated kinase , as shown by the use of the specific inhibitors exoenzyme P01024 and Y27632 . Collectively , our data suggest a distinctive role for Q13324 - specific agonists like P55089 II in the control of myometrial contractility during human pregnancy involving sequential activation of PKC , MAPK kinase 1 , P27361 / 2 , RhoA , and RhoA - associated kinase , leading to the MLC ( 20 ) phosphorylation .",
"Molecular mechanisms involved in the growth stimulation of breast cancer cells by leptin . Obesity is a risk factor for breast cancer in postmenopausal women . Leptin , an adipocyte - derived cytokine , elicits proliferative effects in some cell types and potentially stimulates the growth of mammary epithelium . Here we show that leptin induced time - and dose - dependent signal transducer and activator of transcription 3 ( P40763 ) phosphorylation and extracellular signal - regulated kinase ( P29323 ) 1 / 2 kinase activation in breast carcinoma cells . Blocking P40763 phosphorylation with a specific inhibitor , AG490 , abolished leptin - induced proliferation of MCF - 7 cells , whereas blocking P27361 / 2 activation by a specific P27361 / 2 kinase inhibitor , U0126 , did not result in any significant changes in leptin - induced cell proliferation . Our experiments also showed that one member of the P52701 family of steroid receptor coactivators , steroid receptor coactivator ( P12931 ) - 1 , but not glucocorticoid receptor interacting protein 1 ( GRIP1 ) or amplified in breast cancer 1 ( Q9Y6Q9 ) , also functioned in gene transactivation in response to leptin treatment . O60760 pull - down experiments showed that Q15788 physically interacted with the activation domain of P40763 and that chromatin immunoprecipitation experiments detected the occupancy of Q15788 , but not GRIP1 or Q9Y6Q9 , on the promoter of P40763 target genes . Our experiments collectively showed that Q15788 is involved in P40763 signaling pathway that is implicated in leptin - stimulated cell growth .",
"DB03203 1 - phosphate in amniotic fluid modulates cyclooxygenase - 2 expression in human amnion - derived Q9NZQ3 cells . The metabolism of arachidonic acid , in particular the generation of prostaglandins ( PGs ) , has been proposed to play a key role in the regulation of labor . Moreover , several extracellular proteins have been reported to modulate PG synthesis in amnion cells . In this study , we found that lipid components dissolved in the amniotic fluid modulate PG synthesis in Q9NZQ3 human amnion cells and identified one of these components as a sphingosine 1 - phosphate ( Q14703 ) . Q9NZQ3 cells express several Q14703 receptors including P21453 , O95136 , and Q99500 . When Q9NZQ3 cells were stimulated with Q14703 , DB00917 synthesis increased in a concentration - dependent manner , showing maximal activity at around 100 nM . Q14703 treatment also caused the up - regulation of cyclooxygenase - 2 ( P35354 ) mRNA and protein , which was apparent within 3 - 12 h of stimulation . In terms of the intracellular signaling pathway of Q14703 - induced Q9NZQ3 cell activation , we found that Q14703 stimulated two kinds of MAPK , P29323 , and p38 kinase . We examined the roles of these two MAPKs in Q14703 - induced P35354 expression . Q14703 - induced P35354 expression was blocked completely by PD - 98059 but not by SB - 203580 , suggesting that P29323 has a critical role in the process . Transfection of P21453 or Q99500 but not of O95136 antisense oligonucleotide inhibited Q14703 - induced P35354 expression and DB00917 production in Q9NZQ3 cells , indicating the involvements of P21453 and Q99500 in the processes . This study demonstrates the physiological role of Q14703 in amniotic fluid and its effect on the modulation of P35354 expression and PGs synthesis in Q9NZQ3 cells .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"___MASK55___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients ."
] |
[
"___MASK25___",
"___MASK27___",
"___MASK43___",
"___MASK51___",
"___MASK55___",
"___MASK5___",
"___MASK61___",
"___MASK90___",
"___MASK99___"
] |
___MASK51___
|
MH_train_400
|
interacts_with DB01064?
|
[
"DB01064 inhibits fibroblast growth factor - 2 - induced growth of renal epithelial cells . The signal transduction pathways modulating P09038 effects in renal tubular epithelial cells ( RTEc ) are not completely understood . Since the DB02527 and the mitogen - activated protein kinase ( MAPK ) pathways can modulate the growth of RTEc , we studied whether two DB02527 elevating agents , isoproterenol and 8 - bromo - DB02527 , would modulate basic fibroblast growth factor ( P09038 ) induction of MAPK activity ( P28482 ) and cell proliferation in human renal proximal tubular epithelial cells ( RPTEc ) and Madin - Darby canine kidney cells ( MDCK clone EI1 ) . DB01064 , but not P09038 , stimulated DB02527 production in RPTEc and MDCKEI1 cells . P09038 , isoproterenol , and 8 - bromo - DB02527 alone increased P28482 activity in both cell types . However , isoproterenol and 8 - bromo - DB02527 partially inhibited the P09038 induction of P28482 activity , but only isoproterenol inhibited the proliferation of both cell types . PD098059 ( 25 microM ) , an inhibitor of MAPK kinase ( Q02750 / 2 ) , blocked the P09038 mitogenic effects , but did not affect the 8 - bromo - DB02527 - induced mitogenic effects in MDCKEI1 cells . These findings suggest that activation of P28482 is required but not sufficient for mitogenesis in RTEc . We conclude that isoproterenol inhibits the growth - promoting effects of P09038 in RTEc via MEK - dependent and - independent pathways .",
"P10275 expression induces P09038 , FGF - binding protein production , and P09038 release in prostate carcinoma cells : role of P09038 in growth , survival , and androgen receptor down - modulation . BACKGROUND : Alterations in fibroblast growth factors ( FGFs ) production and / or FGF receptors expression have been described to play key roles in prostate tumor progression , particularly in androgen - independent tumors . However , the role of androgen receptor ( AR ) in altering FGF - mediated growth and survival of prostatic neoplastic cells has not been completely defined . In this study , we investigated the alterations in P09038 production and utilization by the PC3 cell line , after transfection with a full - length AR . METHODS : P05230 , 2 , 7 , FGF - binding protein ( Q14512 ) production and FGF receptor ( FGFR ) 1 - 4 expression were investigated by polymerase chain reaction ( PCR ) and Western blot analysis . RESULTS : De novo AR expression by PC3 cells restores P21802 IIIb isoform expression and sensitivity to P21781 and P09038 . Androgen stimulation induces AR + PC3 clones to secrete Q14512 , likely responsible for activation and mobilization from the extracellular matrix of the high amounts of P09038 produced by the same cells . In addition to the effects on cell proliferation , P09038 maintains the survival of AR + PC3 clones through a positive modulation of the Bcl - 2 protein and down - modulates AR protein expression , allowing the escape of selected clones from androgen regulation . CONCLUSION : In the presence of an active AR , the combined production of P09038 and Q14512 may play an important role in the progression of prostate cancer through the selection of AR - clones expressing high levels of Bcl - 2 .",
"P00734 kringle - 2 induces death of mesencephalic dopaminergic neurons in vivo and in vitro via microglial activation . We have shown that prothrombin kringle - 2 ( pKr - 2 ) , a domain of human prothrombin distinct from thrombin could activate cultured rat brain microglia in vitro . However , little is known whether pKr - 2 - induced microglial activation could cause neurotoxicity on dopaminergic ( DA ) neurons in vivo . To address this question , pKr - 2 was injected into the rat substantia nigra ( SN ) . Tyrosine hydroxylase ( TH ) immunohistochemistry experiments demonstrate significant loss of DA neurons seven days after injection of pKr - 2 . In parallel , pKr - 2 - activated microglia were detected in the SN with OX - 42 and OX - 6 immunohistochemistry . Reverse transcription PCR and double - label immunohistochemistry revealed that activated microglia in vivo exhibit early and transient expression of inducible nitric oxide synthase ( P35228 ) , cyclooxygenase - 2 ( P35354 ) and several proinflammatory cytokines . The pKr - 2 - induced loss of SN DA neurons was partially inhibited by the NOS inhibitor N ( G )- nitro - L - arginine methyl ester hydrochloride , and the P35354 inhibitor DuP - 697 . P27361 / 2 , c - Jun N - terminal kinase and p38 mitogen - activated protein kinase were activated in the SN as early as 1 hr after pKr - 2 injection , and localized within microglia . Inhibition of these kinases led to attenuation of mRNA expression of P35228 , P35354 and several proinflammatory cytokines , and rescue of DA neurons in the SN . Intriguingly , following treatment with pKr - 2 in vitro , neurotoxicity was detected exclusively in co - cultures of mesencephalic neurons and microglia , but not microglia - free neuron - enriched mesencephalic cultures , indicating that microglia are required for pKr - 2 neurotoxicity . Our results strongly suggest that microglia activated by endogenous compound ( s ) , such as pKr - 2 , are implicated in the DA neuronal cell death in the SN .",
"Angiotensin II and basic fibroblast growth factor mitogenic pathways in human fetal mesangial cells . Angiotensin II ( Ang II ) and basic fibroblast growth factor ( P09038 / P09038 ) play relevant roles in renal development . Since the signaling pathways modulating the mitogenic effects of Ang II and P09038 in human fetal mesangial cells ( HFMc ) are not clearly defined , we carried out experiments to determine whether they would exert their mitogenic effects by modulating the activity of the mitogen - activated protein kinases ( MAPK ) [ extracellular signal - regulated kinase - 2 ( P28482 ) ] and DB02527 signaling pathways . In confluent HFMc , P09038 ( 20 ng / mL ) induced a significant 4 - fold increase in P28482 activity and [ 3H ] - thymidine incorporation ( 6 - fold ) . In contrast , under similar tissue culture conditions , Ang II ( 10 (- 6 ) M ) induced a more modest increase in P28482 activity ( 2 - fold ) and [ 3H ] - thymidine incorporation ( 35 +/- 4 % ) . The mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) inhibitor PD098059 ( 25 microM ) almost completely abolished the P09038 - induced proliferation in HFMc but did not significantly affect Ang II proliferative effects . In the presence of the DB02527 elevating agent isoproterenol , Ang II and P09038 induced opposite changes in DB02527 accumulation and cell growth . DB01064 inhibited the basal and P09038 - induced proliferation of HFMc through a MEK - 1 / 2 - independent pathway that included the accumulation of DB02527 . In contrast , isoproterenol increased Ang II mitogenic effects in correlation with a reduction in DB02527 accumulation . We conclude that Ang II and P09038 modulate the proliferation of HFMc through the stimulation of different MEK - 1 / 2 - dependent and independent signaling pathways . Activation of MEK - 1 / 2 is required but not sufficient for mitogenesis in HFMc . The accumulation of DB02527 in HFMc counteracts the mitogenic effects of P09038 by a MEK - 1 / 2 - independent pathway .",
"Multiple pathways of apolipoprotein E signaling in primary neurons . P02649 is a genetic risk factor for Alzheimer ' s disease , and the apoE protein is associated with beta - amyloid deposits in Alzheimer ' s disease brain . We examined signaling pathways stimulated by apoE in primary neurons in culture . ApoE and an apoE - derived peptide activated several intracellular kinases , including prominently extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . P27361 / 2 activation by apoE was blocked by an inhibitor of the low - density lipoprotein receptor family , the specific DB01221 glutamate receptor antagonist MK 801 and other calcium channel blockers . Activation of apoE receptors also induced tyrosine phosphorylation of Dab1 , an adaptor protein of apoE receptors , but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for P29323 activation . In contrast , apoE treatment of primary neurons decreased activation of c - Jun N - terminal kinase , a kinase that interacts with another apoE receptor adaptor protein , c - Jun N - terminal kinase - interacting protein . This change also depended on interactions with the low - density lipoprotein receptor family but was independent of calcium channels . c - Jun N - terminal kinase deactivation by apoE was blocked by gamma - secretase inhibitors and pertussis toxin . These results demonstrate that apoE affects several signaling cascades in neurons : increased disabled phosphorylation , activation of the P27361 / 2 pathway ( dependent on calcium influx via the DB01221 receptor ) and inhibition of the P45983 / 2 pathway ( dependent on gamma - secretase and G proteins ) .",
"Regulatory roles of sex hormones in cutaneous biology and immunology . Recent studies have revealed that sex hormones manifest a variety of biological and immunological effects in the skin . Pregnancy , menstruation and the menopause modulate the natural course of psoriasis , indicating a female hormone - induced regulation of skin inflammation . Estrogen in vitro down - regulates the production of the neutrophil , type 1 T cell and macrophage - attracting chemokines , P10145 , P02778 , P13501 , by keratinocytes , and suppresses IL - 12 production and antigen - presenting capacity while enhancing anti - inflammatory P22301 production by dendritic cells . These data indicate that estrogen may attenuate inflammation in psoriatic lesions . Estrogen , alone or together with progesterone , prevents or reverses skin atrophy , dryness and wrinkles associated with chronological or photo - aging . Estrogen and progesterone stimulate proliferation of keratinocytes while estrogen suppresses apoptosis and thus prevents epidermal atrophy . Estrogen also enhances collagen synthesis , and estrogen and progesterone suppress collagenolysis by reducing matrix metalloproteinase activity in fibroblasts , thereby maintaining skin thickness . Estrogen maintains skin moisture by increasing acid mucopolysaccharide or hyaluronic acid levels in the dermis . Progesterone increases sebum secretion . Estrogen accelerates cutaneous wound healing stimulating P01138 production in macrophages , GM - P04141 production in keratinocytes and P09038 and TGF - beta1 production in fibroblasts , leading to the enhancement of wound re - innervation , re - epithelialization and granulation tissue formation . In contrast , androgens prolong inflammation , reduce deposition of extracellular matrix in wounds , and reduce the rate of wound healing . Estrogen enhances P15692 production in macrophages , an effect that is antagonized by androgens and which may be related to the development of granuloma pyogenicum during pregnancy . These regulatory effects of sex steroids may be manipulated as therapeutic or prophylactic measures in psoriasis , aging , chronic wounds or granuloma pyogenicum .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"P02649 : a potent inhibitor of endothelial and tumor cell proliferation . Recombinant human apolipoprotein E3 ( apoE ) , purified from E . coli , inhibited the proliferation of several cell types , including endothelial cells and tumor cells in a dose - and time - dependent manner . ApoE inhibited both de novo DNA synthesis and proliferation as assessed by an increase in cell number . Maximal inhibition of cell growth by apoE was achieved under conditions where proliferation was dependent on heparin - binding growth factors . Thus , at low serum concentrations ( 0 - 2 . 5 % ) basic fibroblast growth factor ( P09038 ) stimulated the proliferation of bovine aortic endothelial ( BAE ) cells severalfold . The P09038 - dependent proliferation was dramatically inhibited by apoE with an IC50 approximately 50 nM . Under conditions where cell proliferation was mainly serum - dependent , apoE also suppressed growth but required higher concentrations to be effective ( IC50 approximately 500 nM ) . ApoE also inhibited growth of bovine corneal endothelial cells , human melanoma cells , and human breast carcinoma cells . The IC50 values obtained with these cells were generally 3 - 5 times higher than with BAE cells . Inhibition of cell proliferation by apoE was reversible and dependent on the time of apoE addition to the culture . In addition , apoE inhibited the chemotactic response of endothelial cells that were induced to migrate by a gradient of soluble P09038 . Inhibition of cell proliferation by apoE may be mediated both by competition for growth factor binding to proteoglycans and by an antiadhesive activity of apoE . The present results demonstrate that apoE is a potent inhibitor of proliferation of several cell types and suggest that apoE may be effective in modulating angiogenesis , tumor cell growth , and metastasis .",
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK25___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .",
"Lessons learned from the irinotecan metabolic pathway . ___MASK10___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK10___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK10___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK34___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"Synergism between bosutinib ( ___MASK26___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"Antiangiogenic property of human thrombin . Using protein chromatography , we purified and identified human prothrombin from human plasma as antiangiogenic . P00734 significantly inhibited endothelial cell tube formation in vitro at 10 microg / ml . Importantly , it also inhibited P09038 - induced angiogenesis in Matrigel - plug assays performed in mice . The proteolytic activity of thrombin appeared to be critical for the antiangiogenic activity of prothrombin . For example , thrombin exhibited inhibitory effects on endothelial cell tube formation in vitro at 10 U / ml . Addition of lepirudin , a specific inhibitor of thrombin , completely blocked prothrombin ' s and thrombin ' s antiangiogenic effects in vitro . We also assessed the importance of thrombin receptors in angiogenesis . Using small peptides that activate different protease - activated receptors ( PARs ) , we showed that activation of P25116 led to inhibition of endothelial cell tube formation in vitro and P09038 - induced angiogenesis in vivo . Collectively , our data suggest that thrombin ' s proteolytic activity can be antiangiogenic .",
"GNAS mutation as an alternative mechanism of activation of the Wnt / β - catenin signaling pathway in gastric adenocarcinoma of the fundic gland type . Gastric adenocarcinoma of the fundic gland type ( GAFG ) is a rare variant of gastric tumor . We have recently reported the frequent accumulation of β - catenin in GAFGs and showed that approximately half of the cases studied harbored at least 1 mutation in P35222 / AXINs / P25054 , leading to the constitutive activation of the Wnt / β - catenin pathway . However , the mechanisms of Wnt signaling activation in the remaining cases are unknown . Accumulating evidence showed that the activating mutation in GNAS promotes tumorigenesis via the activation of the Wnt / β - catenin pathway or the P27361 / 2 MAPK pathway . Therefore , we analyzed the mutations in GNAS ( exons 8 and 9 ) and in P01116 ( exon 2 ) in 26 GAFGs . Immunohistochemistry revealed nuclear β - catenin expression in 22 of 26 GAFGs , and 10 ( 38 . 5 % ) of 26 cases harbored at least 1 mutation in P35222 / AXINs / P25054 . Activating mutations in GNAS were found in 5 ( 19 . 2 % ) of 26 GAFGs , all of which harbored R201C mutations . Activating mutations in P01116 were found in 2 ( 7 . 7 % ) of 26 GAFGs , and both of these also contained GNAS activating mutations . Four of 5 cases with GNAS mutation showed nuclear β - catenin expression , and presence of GNAS mutation was associated with β - catenin nuclear expression ( P = . 01 ) . Furthermore , 3 of these 4 cases did not harbor mutations in P35222 , P25054 , or AXINs , suggesting that mutations in the Wnt component genes and those in GNAS occur almost exclusively . These results suggest that GNAS mutation might occur in a small subset of GAFG as an alternative mechanism of activating the Wnt / β - catenin signaling pathway .",
"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK9___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK9___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .",
"Somatostatin preserved blood brain barrier against cytokine induced alterations : possible role in multiple sclerosis . Multiple sclerosis ( MS ) is an inflammatory neurological disorder associated with demyelination , impaired blood brain barrier ( BBB ) , axonal damage and neuronal loss . In the present study , we measured somatostatin ( P61278 ) and tumor necrosis factor - α ( P01375 - α ) like immunoreactivity in P04141 samples from MS and non - MS patients . We also examined the role of P61278 in cytokines and lipopolysaccharide ( LPS ) - induced damage to the BBB using human brain endothelial cells in culture . Most of the cerebrospinal fluid ( P04141 ) samples studied from definite MS patients exhibited lower somatostatin ( P61278 ) - like immunoreactivity and higher expression of P01375 - α in comparison to non - MS patients . Treatment of cells with cytokines and LPS blocked P61278 secretion and decreased P61278 expression . Human brain endothelial cells expressed all five somatostatin receptors ( SSTRs ) with increased expression of P30874 and 4 upon treatment with cytokines and LPS . Cytokines and LPS - induced disruption of the tight junction proteins Zonula occludens ( ZO - 1 ) organization was restored in presence of P61278 , P30874 or P31391 selective agonists . Furthermore , inflammation induced changes in extracellular signal - regulated kinases ( P27361 / 2 and Q13164 ) signaling and altered expression of endothelial and inducible nitric oxide synthase are modulated in presence of P61278 . These data indicate that decreased levels of P61278 contribute to failure of the BBB in MS .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK2___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK2___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"Interleukin 6 destabilizes atherosclerotic plaques by downregulating prolyl - 4 - hydroxylase α1 via a mitogen - activated protein kinase and c - Jun pathway . Interleukin 6 ( P05231 ) is a pivotal cytokine that regulates extracellular matrix metabolism by ameliorating the modification of collagen content , important in fibrous caps of atherosclerotic plaque . Prolyl - 4 - hydroxylase α1 ( P4Hα1 ) is a key intracellular enzyme required for synthesis of collagen in animals . We investigated the relationship of P05231 and P4Hα1 in atherosclerosis - prone mice and human aortic smooth muscle cells ( HASMCs ) . P02649 ( ApoE ) -/- mice were fed a high - fat diet and a perivascular constrictive silica collar was placed on the right common carotid artery to induce atherosclerotic lesions , then mice were divided into two groups for transfection with empty lentivirus or P05231 lentivirus . HASMCs were transfected with small interfering RNA or treated with recombinant human P05231 . P05231 significantly downregulated collagen , P4Hα1 and smooth muscle cell contents in atherosclerotic mouse arteries . Macrophage and lipid contents in the atherosclerotic area were significantly increased with P05231 treatment . P05231 significantly downregulated P4Hα1 expression in HASMCs through an RAF - Q02750 / 2 - P27361 / 2 mitogen - activated protein kinase ( MAPK ) pathway , and c - Jun was involved in the process . Our findings highlight P05231 destabilize atherosclerotic plaques in mice by downregulating P4Hα1 via an RAF - Q02750 / 2 - P27361 / 2 MAPK and c - Jun pathway .",
"Growth advantage and vascularization induced by basic fibroblast growth factor overexpression in endometrial O14777 - 1 - B cells : an export - dependent mechanism of action . The human endometrial adenocarcinoma O14777 - 1 - B cell line was transfected with an expression vector harboring the human basic fibroblast growth factor ( P09038 ) cDNA under the control of the human beta - actin gene promoter . Stable transfectants were obtained in which a constitutive , limited overexpression of M ( r ) 24 , 000 , 22 , 000 , and 18 , 000 P09038 isoforms was observed . When transfectants were screened for the capacity to release the growth factor , significant amounts of P09038 were present in the conditioned medium and extracellular matrix of the P09038 - B9 clone but not of the P09038 - Q92854 clone , even though both cell lines produced similar levels of intracellular P09038 . When compared to parental cells , P09038 - B9 cells showed down - regulation of tyrosine kinase fibroblast growth factor receptors along with up - regulation of urokinase - type plasminogen activator expression which was abolished by incubation of the cell cultures with neutralizing anti - P09038 antibody . In vivo , P09038 - B9 cells formed highly vascularized tumors growing faster than parental cells when injected s . c . in nude mice . Also , they were more potent than nontransfected cells in inducing an angiogenic response in the rabbit cornea assay . In contrast , the P09038 - Q92854 cell phenotype was indistinguishable from parental cells both in vitro and in vivo . In conclusion , clonal differences exist within the O14777 - 1 - B cell line in the capacity to release P09038 . P09038 export by human endometrial adenocarcinoma cells results in autocrine and paracrine effects that confer a growth advantage in vivo associated with increased neovascularization .",
"___MASK18___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK18___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK56___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .",
"___MASK9___ interacts with P00533 / MAPK signalling and modulates P00533 levels in androgen receptor - positive LNCaP prostate cancer cells . P10275 ( AR ) signalling plays a pivotal role in prostate cancer pathogenesis and progression . However , androgen - mediated AR signalling is yet to be fully understood . P00533 and Q96HU1 kinase signalling pathways play predominant roles in AR function . Therefore , we investigated the interaction of P00533 signalling and AR activity in AR - positive LNCaP cells . We found that 5alpha - dihydrotestosterone ( ___MASK9___ ) and P01133 had a synergistic effect on AR activity as detected by a luciferase reporter system , although P01133 alone did not activate AR . Both P27361 / 2 and p38 were involved in ___MASK9___ and ___MASK9___ / P01133 - induced AR activation as detected by specific MEK and p38 inhibitors . Furthermore , 24 - h treatment of the cells with ___MASK9___ resulted in ubiquitination and down - regulation of the P00533 . This effect could be inhibited by the anti - androgen flutamide , suggesting an androgen - dependent mechanism . On the other hand , ___MASK9___ - treatment strongly increased AR levels in LNCaP cells . These data suggest a complex regulatory loop between activated AR and P00533 . In conclusion , activation of AR by both ___MASK9___ and P01133 / ___MASK9___ involves the Q96HU1 kinase pathway . Long - term activation of AR results in increase of AR levels , which through so far unknown regulatory mechanisms results in ubiquitination and degradation of the P00533 .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK92___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"Role of the phosphatidylinositol 3 kinase - Akt pathway in the regulation of P22301 and IL - 12 by Porphyromonas gingivalis lipopolysaccharide . Stimulation of the P25054 by Porphyromonas gingivalis LPS has been shown to result in the production of certain pro - and anti - inflammatory cytokines . However , the signaling pathways that regulate these processes are currently unknown . In the present study , the role of the phosphatidylinositol 3 kinase ( PI3K ) - Akt pathway in regulating P . gingivalis LPS - induced production of P22301 , IL - 12 p40 , and IL - 12 P08133 by human monocytes was investigated . P . gingivalis LPS selectively activates the PI3K - Akt pathway via O60603 , and inhibition of this pathway results in an abrogation of extracellular signal - regulated kinase 1 / 2 phosphorylation , whereas the activation of p38 and P45983 / 2 kinases were unaffected . Analysis of cytokine production following stimulation of monocytes with P . gingivalis LPS revealed that inhibition of the PI3K pathway differentially regulated P22301 and IL - 12 synthesis . P22301 production was suppressed , whereas IL - 12 levels were enhanced . Inhibition of P . gingivalis LPS - mediated activation of the PI3K - Akt pathway resulted in a pronounced augmentation of NF - kappaB p65 that was independent of IkappaB - alpha degradation . Furthermore , the ability of the PI3K - Akt pathway to modulate P22301 and IL - 12 production appears to be mediated by the selective suppression of extracellular signal - regulated kinase 1 / 2 activity , as the Q02750 inhibitor PD98059 closely mimicked the effects of wortmannin and LY294002 to differentially regulate P22301 and IL - 12 production by P . gingivalis LPS - stimulated monocytes . These studies provide new insight into how engagement of the PI3K - Akt pathway by P . gingivalis LPS affects the induction of key immunoregulatory cytokines that control both qualitative and quantitative aspects of innate and adaptive immunity .",
"Phosphorylation of beta - arrestin2 regulates its function in internalization of beta ( 2 )- adrenergic receptors . Beta - arrestins mediate agonist - dependent desensitization and internalization of G protein - coupled receptors . Previously , we have shown that phosphorylation of beta - arrestin1 by ERKs at DB00133 - 412 regulates its association with clathrin and its function in promoting clathrin - mediated internalization of the receptor . In this paper we report that beta - arrestin2 is also phosphorylated , predominantly at residues DB00156 - 383 and DB00133 - 361 . DB01064 stimulation of the beta ( 2 )- adrenergic receptor promotes dephosphorylation of beta - arrestin2 . Mutation of beta - arrestin2 phosphorylation sites to aspartic acid decreases the association of beta - arrestin2 with clathrin , thereby reducing its ability to promote internalization of the beta ( 2 )- adrenergic receptor . Its ability to bind and desensitize the beta ( 2 )- adrenergic receptor is , however , unaltered . These results suggest that , analogous to beta - arrestin1 , phosphorylation / dephosphorylation of beta - arrestin2 regulates clathrin - mediated internalization of the beta ( 2 )- adrenergic receptor . In contrast to beta - arrestin1 , which is phosphorylated by P27361 and P28482 , phosphorylation of beta - arrestin2 at DB00156 - 383 is shown to be mediated by casein kinase II . Recently , it has been reported that phosphorylation of visual arrestin at DB00133 - 366 prevents its binding to clathrin . Thus it appears that the function of all arrestin family members in mediating internalization of G protein - coupled receptors is regulated by distinct phosphorylation / dephosphorylation mechanisms .",
"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .",
"Proangiogenesis action of the thyroid hormone analog 3 , 5 - diiodothyropropionic acid ( DITPA ) is initiated at the cell surface and is integrin mediated . We have recently described the proangiogenesis effects of thyroid hormone in the chick chorioallantoic membrane ( P62158 ) model . Generation of new blood vessels from existing vessels was promoted 2 - to 3 - fold by either T ( 4 ) or T ( 3 ) at 10 (- 8 )- 10 (- 7 ) M total hormone concentrations . In the present studies , nanomolar concentrations of 3 , 5 - diiodothyropropionic acid ( DITPA ) , a thyroid hormone analog with inotropic but not chronotropic properties , exhibited potent proangiogenic activity that was comparable to that obtained with T ( 3 ) and T ( 4 ) in both the P62158 model and in an in vitro three - dimensional human microvascular endothelial sprouting assay . The proangiogenesis effect of DITPA was inhibited by tetraiodothyroacetic acid , a thyroid hormone analog that competes with T ( 4 ) and T ( 3 ) for a novel cell surface hormone receptor site on integrin alphavbeta3 . The thyroid hormone analogs DITPA , T ( 4 ) , and T ( 4 )- agarose , as well as basic fibroblast growth factor ( b - FGF ) and vascular endothelial cell growth factor , demonstrated comparable proangiogenic effects in the P62158 model and in the three - dimensional human microvascular endothelial sprouting model . The proangiogenesis effect of either DITPA or b - FGF was blocked by PD 98059 , an inhibitor of the P27361 / 2 signal transduction cascade . Additionally , a specific integrin alphavbeta3 small molecule antagonist , XT199 , effectively inhibited the proangiogenesis effect of DITPA and b - FGF . Thus , the proangiogenesis actions of thyroid hormone and its analog DITPA are initiated at the plasma membrane , apparently at integrin alphavbeta3 , and are MAPK dependent .",
"Knockdown of cyclophilin A reverses paclitaxel resistance in human endometrial cancer cells via suppression of MAPK kinase pathways . PURPOSE : Paclitaxel resistance remains to be a major obstacle to the chemotherapy of endometrial cancer . Using proteomic - based approach , we used to identify cyclophilin A ( CypA ) as a potential therapeutic target for endometrial cancer . As a natural continuation , this study aimed to reveal the correlation between CypA and paclitaxel resistance and evaluate the possibility of CypA as a therapeutic target for reversal of resistance . METHODS : Two paclitaxel - resistant endometrial cancer cell sublines O14777 - 1 - B / TAX and AN3CA / TAX were generated , and expressions of CypA , P - gp , MRP - 2 and survivin were demonstrated by Western blotting . CypA was knocked down by RNA interference , and the subsequent effects on the alteration of paclitaxel resistance were examined by MTT , flow cytometry and migratory / invasive transwell assays . MAPK kinases activities were examined by Western blotting . RESULTS : CypA knockdown led to significant inhibition of cell proliferation , induction of apoptosis and suppression of migratory / invasive capacity in O14777 - 1 - B / TAX and AN3CA / TAX cells when exposed to paclitaxel . CypA knockdown led to reductions in total and phosphorylated MAPK kinases , including Akt , P27361 / 2 , p38 MAPK and JNK , in O14777 - 1 - B / TAX cells . Furthermore , pretreatment with MAPK kinase inhibitors exhibited a synergistic effect in combination with CypA knockdown . CONCLUSIONS : These results demonstrated that CypA expression was up - regulated in paclitaxel - resistant cancer cells , and knockdown of CypA could reverse the paclitaxel resistance through , at least partly , suppression of MAPK kinase pathways , presenting a possibility of CypA serving as a therapeutic target to overcome paclitaxel resistance .",
"Traditional Korean Herbal Formula Samsoeum Attenuates Adipogenesis by Regulating the Phosphorylation of P27361 / 2 in 3T3 - Q9NUQ9 Cells . Adipogenesis is the cell differentiation process from preadipocytes into adipocytes and the critical action in the development of obesity . In the present study , we conducted in vitro analyses to investigate the inhibitory effects of Samsoeum ( SSE ) , a traditional herbal decoction . SSE had no significant cytotoxic effect against either the undifferentiated or differentiated 3T3 - Q9NUQ9 cells . Oil Red O staining results showed that SSE significantly inhibited fat accumulation in adipocytes . SSE treatment consistently reduced the intracellular triglyceride content in the cells . SSE significantly inactivated glycerol - 3 - phosphate dehydrogenase ( GPDH ) , a major link between carbohydrate and lipid metabolisms in 3T3 - Q9NUQ9 adipocytes , and markedly inhibited the production of leptin , an important adipokine , in differentiated cells . SSE markedly suppressed the mRNA expression of the adipogenesis - related genes peroxisome proliferator - activated receptor - gamma ( Q07869 - γ ) , CCAAT / enhancer binding protein - alpha ( C / EBP - α ) , fatty acid synthase ( FAS ) , lipoprotein lipase ( P06858 ) , and fatty acid binding protein 4 ( P15090 ) . Importantly , SSE increased the phosphorylation of P27361 / 2 , but not p38 MAPK and JNK , in adipose cells . Overall , our results indicate that SSE exerts antiadipogenic activity and modulates expressions of adipogenesis - related genes and P27361 / 2 activation in adipocytes .",
"P28482 , but not P27361 , mediates acquired and \" de novo \" resistance to imatinib mesylate : implication for CML therapy . Resistance to Imatinib Mesylate ( IM ) is a major problem in Chronic Myelogenous Leukaemia management . Most of the studies about resistance have focused on point mutations on P11274 / P00519 . However , other types of resistance that do not imply mutations in P11274 / P00519 have been also described . In the present report we aim to study the role of several MAPK in IM resistance not associate to P11274 / P00519 mutations . Therefore we used an experimental system of resistant cell lines generated by co - culturing with IM ( K562 , Lama 84 ) as well as primary material from resistant and responder patient without P11274 / P00519 mutations . Here we demonstrate that Erk5 and p38MAPK signaling pathways are not implicated in the acquired resistance phenotype . However , Erk2 , but not Erk1 , is critical for the acquired resistance to IM . In fact , Bcr / Abl activates preferentially Erk2 in transient transfection in a dose dependent fashion through the c - Abl part of the chimeric protein . Finally , we present evidences demonstrating how constitutive activation of Erk2 is a de novo mechanism of resistance to IM . In summary our data support the use of therapeutic approaches based on Erk2 inhibition , which could be added to the therapeutic armamentarium to fight CML , especially when IM resistance develops secondary to Erk2 activation .",
"Effects of leptin and adiponectin on proliferation and protein metabolism of porcine myoblasts . The aim of this study was to show the abundance of leptin and adiponectin receptors ( LEPR , Q96A54 , Q86V24 ) and to determine the direct effects of leptin and adiponectin on the in vitro growth of porcine skeletal muscle cells . Q96A54 and Q86V24 were abundant at mRNA and protein level in proliferating and differentiating myoblast cultures derived from semimembranosus and semitendinosus muscles of newborn piglets , whereas LEPR expression was close to the detection limit . Q15848 ( 10 , 20 , 40 μg / ml ) attenuated the proliferation of porcine myoblasts , measured as [ ( 3 ) H ] - thymidine incorporation and real - time monitoring of the cells in response to 24 - and 48 - h exposure , in a dose - dependent manner . This effect resulted from suppressed basic fibroblast growth factor ( P09038 ) - mediated stimulation of DNA synthesis in serum - free medium ( SFM ) containing P09038 . No effects of leptin ( 5 , 10 , 20 , 40 , 80 ng / ml ) on myoblast proliferation in SFM were detectable . Neither leptin nor adiponectin altered protein synthesis and degradation in differentiating porcine myoblasts cultured in SFM . The results on receptor abundance suggest that porcine skeletal muscle cells may be sensitive to adiponectin and leptin . However , except via inhibitory interaction of adiponectin with P09038 , these adipokines appear not to affect in vitro proliferation and protein metabolism of porcine muscle cells directly under serum - free culture conditions .",
"Pancreatic cancer : the potential clinical relevance of alterations in growth factors and their receptors . Molecular alterations play a key role in the pathogenesis of gastrointestinal cancers . In the present paper we describe relevant molecular alterations in human pancreatic adenocarcinomas . Overexpression of growth factor receptors ( P01133 receptor , c - erbB2 , c - erbB3 , TGF beta receptor I - III ) , growth factors ( P01133 , TGF alpha , TGF beta - 1 - 3 , P05230 , P09038 ) , adhesion molecules ( P05362 , P16581 ) and gene mutations ( p53 , K - ras , P43146 , P25054 ) are present in a significant number of these tumors . These changes stimulate tumor growth and enhance the metastatic behavior of pancreatic cancer cells and thereby may contribute to shorter postoperative survival following tumor resection ."
] |
[
"___MASK10___",
"___MASK18___",
"___MASK25___",
"___MASK26___",
"___MASK2___",
"___MASK34___",
"___MASK56___",
"___MASK92___",
"___MASK9___"
] |
___MASK34___
|
MH_train_401
|
interacts_with DB00275?
|
[
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK33___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK33___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK73___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK25___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"AT1 receptor subtype mediates the inhibitory effect of central angiotensin II on cerebrospinal fluid formation in the rat . The effect of central administration of angiotensin II ( AII ) on cerebrospinal fluid ( P04141 ) formation was studied in pentobarbital - anesthetized , artificially - ventilated rats . P04141 production was measured by the ventriculocisternal perfusion method with Blue DB09255 2000 as the indicator . Baseline value of P04141 production was 3 . 35 +/- 0 . 08 microliters / min . Intracerebroventricular ( i . c . v . ) infusion of AII at rates of 0 . 5 and 5 pg / min significantly lowered ( P < 0 . 01 ) P04141 formation by 23 % and 16 % , respectively . In comparison , high peptide doses ( 50 and 500 pg / min ) did not alter this parameter . The inhibitory effect of low AII doses on P04141 formation was blocked by the i . c . v . AT1 receptor subtype antagonists , losartan and SK & F 108566 ( 2 . 4 and 2 . 7 ng / min , respectively ) , but not by the P50052 receptor subtype - specific agent , PD 123319 ( 3 . 8 ng / min ) . Peptide AII antagonists , [ Sar1 , Ile8 ] AII ( 5 ng / min ) , which binds to both AT1 and P50052 receptors , had a similar effect to those of AT1 - specific blockers . It is concluded that AII , by controlling P04141 formation , may influence the water and electrolyte balance in the brain .",
"Antenatal maternally - administered phosphodiesterase type 5 inhibitors normalize P29474 expression in the fetal lamb model of congenital diaphragmatic hernia . PURPOSE : Pulmonary hypertension ( pHTN ) , a main determinant of survival in congenital diaphragmatic hernia ( Q8NE62 ) , results from in utero vascular remodeling . Phosphodiesterase type 5 ( O76074 ) inhibitors have never been used antenatally to treat pHTN . The purpose of this study is to determine if antenatal O76074 inhibitors can prevent pHTN in the fetal lamb model of Q8NE62 . METHODS : Q8NE62 was created in pregnant ewes . Postoperatively , pregnant ewes received oral placebo or tadalafil , a O76074 inhibitor , until delivery . Near term gestation , lambs underwent resuscitations , and lung tissue was snap frozen for protein analysis . RESULTS : Mean cGMP levels were 0 . 53 ± 0 . 11 in placebo - treated fetal lambs and 1 . 73 ± 0 . 21 in tadalafil - treated fetal lambs ( p = 0 . 002 ) . Normalized expression of P29474 was 82 % ± 12 % in Normal - Placebo , 61 % ± 5 % in Q8NE62 - Placebo , 116 % ± 6 % in Normal - ___MASK52___ , and 86 % ± 8 % in Q8NE62 - ___MASK52___ lambs . Normalized expression of β - sGC was 105 % ± 15 % in Normal - Placebo , 82 % ± 3 % in Q8NE62 - Placebo , 158 % ± 16 % in Normal - ___MASK52___ , and 86 % ± 8 % in Q8NE62 - ___MASK52___ lambs . P29474 and β - sGC were significantly decreased in Q8NE62 ( p = 0 . 0007 and 0 . 01 for P29474 and β - sGC , respectively ) , and tadalafil significantly increased P29474 expression ( p = 0 . 0002 ) . CONCLUSIONS : O76074 inhibitors can cross the placental barrier . β - sGC and P29474 are downregulated in fetal lambs with Q8NE62 . Antenatal O76074 inhibitors normalize P29474 and may prevent in utero vascular remodeling in Q8NE62 .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK84___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK93___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK93___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK93___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK93___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK93___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK93___ increased the protein expression of hepatic P05181 and ___MASK93___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK93___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK93___ and RFP - induced hepatotoxicity .",
"___MASK52___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK52___ , in the USA in 2003 .",
"The regulation of NHE₁ and NHE₃ activity by angiotensin II is mediated by the activation of the angiotensin II type I receptor / phospholipase C / calcium / calmodulin pathway in distal nephron cells . Angiotensin II ( Ang II ) , acting via the AT1 receptor , induces an increase in intracellular calcium [ Ca ( 2 +)] i that then interacts with calmodulin ( P62158 ) . The Ca ( 2 +)/ P62158 complex directly or indirectly activates sodium hydrogen exchanger 1 ( P19634 ) and phosphorylates calmodulin kinase II ( CaMKII ) , which then regulates sodium hydrogen exchanger 3 ( P48764 ) activity . In this study , we investigated the cellular signaling pathways responsible for Ang II - mediated regulation of P19634 and P48764 in Madin - Darby canine kidney ( MDCK ) cells . The P19634 - and P48764 - dependent pHi recovery rates were evaluated by fluorescence microscopy using the fluorescent probe BCECF / AM , messenger RNA was evaluated with the reverse transcription polymerase chain reaction ( RT - PCR ) , and protein expression was evaluated by immunoblot . We demonstrated that treatment with Ang II ( 1pM or 1 nM ) for 30 min induced , via the AT1 but not the P50052 receptor , an equal increase in P19634 and P48764 activity that was reduced by the specific inhibitors HOE 694 and S3226 , respectively . Ang II ( 1 nM ) did not change the total expression of P19634 , P48764 or calmodulin , but it induced CaMKII , P04049 - 1 , Erk1 / 2 and p90 ( RSK ) phosphorylation . The stimulatory effects of Ang II ( 1 nM ) on P19634 or P48764 activity or protein abundance was reduced by ophiobolin - A ( P62158 inhibitor ) , KN93 ( CaMKII inhibitor ) or PD98059 ( Mek inhibitor ) . These results indicate that after 30 min , Ang II treatment may activate G protein - dependent pathways , including the AT1 / P98160 / Ca ( 2 +)/ P62158 pathway , which induces CaMKII phosphorylation to stimulate P48764 and induces P04049 - 1 / Mek / Erk1 / 2 / p90 ( RSK ) activity to stimulate P19634 .",
"P30556 antagonist attenuates LPS - induced acute lung injury . Angiotensin II is able to trigger inflammatory responses through an angiotensin II type 1 ( AT1 ) receptor . The role of AT1 receptor in acute lung injury ( ALI ) is poorly understood . Mice were randomly divided into three groups ( n = 40 each groups ) : NS group ; LPS group ( 2mg / kg LPS intratracheally ) ; and LPS + ZD 7155 group , 10mg / kg ZD 7155 ( an AT1 receptor antagonist ) intraperitoneally 30 min prior to LPS exposure . Samples from the lung were isolated and assayed for histopathology analyses or proinflammatory gene expressions , angiotensin II receptors expressions and nuclear factors activities . LPS exposure resulted in severe ALI , elevated levels of P01375 and P01584 mRNA expressions , and increased activities of NF - kappaB and activated protein ( AP ) - 1 . Upregulation of AT1 receptor and down - regulation of P50052 receptor were also observed after LPS challenge . Pretreatment with ZD 7155 significantly inhibited the increase of AT1 receptor expression and upregulated P50052 receptor expression . ZD 7155 also reduced the mRNA expression of P01375 and P01584 , inhibited the activation of NF - kappaB and AP - 1 , and improved lung histopathology . These findings suggest that antagonism of AT1 receptor inhibits the activation of NF - kappaB and AP - 1 in the lung , which may mediate the release of P01375 and P01584 and contribute to LPS - induced ALI .",
"[ Association study of renin - angiotensin system genes and hemostasis system genes with ischemic stroke among Russians of Central Russia ] . The analysis of alleles and genotypes frequencies of 14 SNP in genes of rennin - angiotensin system ( REN , AGT , P30556 , P50052 , P30411 , P07550 ) and hemostasis system ( P02675 , F2 , P12259 , P08709 , P05106 , P05121 , P42898 ) , as well as P12821 insertion - deletion polymorphism in patients with stroke comparing to healthy controls matched by age , sex and ethnicity has been carried out . The genotyping procedure included the amplification of selected gene sequences following by hybridization of fluorescently labeled fragments with SNP - specific DNA probes . The analysis of allele frequencies of each gene separately revealed no statistically significant differences between groups of patients with stroke and healthy donors . Also the complex study has been performed to estimate the contribution of rennin - angiotensin system and hemostasis system genes to the genetic susceptibility to ischemic stroke among Russians from Central Russia using method MDR ( Multifactor Dimensionality Reduction ) . The combination with increased risk for development of ischemic stroke was presented by complex genotype P02675 G /- x P12821 I /- x P42898 C /- x P05121 5G / 5G ( p = 0 . 03 , OR = 2 . 4 , 95 % CI 1 . 1 - 5 . 3 ) , which frequency was statistically significant higher in patients with stroke compared to healthy control .",
"Expression of renin - angiotensin system components in the early bovine embryo . The renin - angiotensin system ( DB01367 ) , mainly associated with the regulation of blood pressure , has been recently investigated in female reproductive organs and the developing foetus . Angiotensin II ( Ang II ) influences oviductal gamete movements and foetal development , but there is no information about DB01367 in the early embryo . The aim of this study was to determine whether DB01367 components are present in the pre - implantation embryo , to determine how early they are expressed and to investigate their putative role at this stage of development . Bovine embryos produced in vitro were used for analysis of DB01367 transcripts ( RT - PCR ) and localisation of the receptors P30556 and P50052 ( immunofluorescent labelling ) . We also investigated the effects of Ang II , DB00275 ( P30556 antagonist ) and PD123319 ( P50052 antagonist ) on oocyte cleavage , embryo expansion and hatching . Pre - implanted embryos possessed P30556 and P50052 but not the other DB01367 components . Both receptors were present in the trophectoderm and in the inner cell mass of the blastocyst . P30556 was mainly localised in granular - like structures in the cytoplasm , suggesting its internalisation into clathrin - coated vesicles , and P50052 was found mainly in the nuclear membrane and in the mitotic spindle of dividing trophoblastic cells . Treating embryos with PD123319 increased the proportion of hatched embryos compared with the control . These results , the first on DB01367 in the early embryo , suggest that the pre - implanted embryo responds to Ang II from the mother rather than from the embryo itself . This may be a route by which the maternal DB01367 influences blastocyst hatching and early embryonic development .",
"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK48___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .",
"Postnatal early overnutrition dysregulates the intrarenal renin - angiotensin system and extracellular matrix - linked molecules in juvenile male rats . Overnutrition during the perinatal period has been associated with susceptibility to obesity and related comorbidities . We examined the effects of postnatal early overnutrition on the development of juvenile obesity and the associated renal pathophysiological changes . Three or 10 pups per mother from rat pup litters were assigned to either the overnutrition or control groups during the first 21 days of life . The effects of overfeeding were measured at 28 days . The smaller male litter pups were heavier than the controls between 4 and 28 days after birth ( P < . 05 ) . By 28 days of age , the kidney weight per body weight ratio decreased in the small litter group ( P < . 05 ) . Circulating leptin levels increased in the small litter rats ( P < . 05 ) . Overnutrition had no effect on renal cell proliferation , apoptosis , macrophages and glomerulosclerosis . In the immunoblots and immunohistochemistry , renin and angiotensin II type ( AT ) 2 receptor expression increased in the overfed rats ( P < . 05 ) . By contrast , the plasminogen activator inhibitor ( P05121 ) - 1 and matrix metalloproteinase ( MMP ) - 9 expression decreased in the overnutrition group ( P < . 05 ) . The AT 1 receptor , tissue inhibitor of P03956 , monocyte chemoattractant protein - 1 , tumor necrosis factor - α , osteopontin and adiponectin expression was not changed . Our data showed that postnatal early overfeeding led to hyperleptinemia , juvenile obesity and the acquired reset of renal maturation . Up - regulation of renin and P50052 and down - regulation of P05121 and P14780 might contribute to abnormal programming of renal growth in rats exposed to postnatal early overnutrition .",
"Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case - control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population - based case - control study . We examined nutrient density - adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0 . 026 ) , cooked by pan - frying ( trend P = 0 . 035 ) , and cooked until well - done ( trend P = 0 . 013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0 . 023 ) . A gene - by - diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0 . 008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK6___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"Program death - 1 engagement upon TCR activation has distinct effects on costimulation and cytokine - driven proliferation : attenuation of Q9Y6W8 , P05112 , and Q9HBE4 , but not P10747 , P13232 , and P40933 responses . The program death 1 ( P18621 ) receptor and its ligands , P18621 ligand ( PD - L ) 1 and Q9BQ51 , define a novel regulatory pathway with potential inhibitory effects on T , B , and monocyte responses . In the present study , we show that human P01730 (+) T cells express P18621 , Q9NZQ7 , and Q9BQ51 upon activation , and Abs to the receptor can be agonists or antagonists of the pathway . Under optimal conditions of stimulation , Q9Y6W8 but not P10747 costimulation can be prevented by P18621 engagement . P60568 levels induced by costimulation are critical in determining the outcome of the P18621 engagement . Thus , low to marginal P60568 levels produced upon Q9Y6W8 costimulation account for the greater sensitivity of this pathway to P18621 - mediated inhibition . Interestingly , exogenous P60568 , P13232 , and P40933 but not P05112 and Q9HBE4 can rescue P18621 inhibition , suggesting that among these cytokines only those that activate P42229 can rescue P18621 inhibition . As P42229 has been implicated in the maintenance of IL - 2Ralpha expression , these results suggest that P13232 and P40933 restore proliferation under conditions of P18621 engagement by enhancing high - affinity IL - 2R expression and hence , P60568 responsiveness .",
"DB01645 prevents myocardial hypertrophy in 2 - kidney 1 - clip renal hypertensive rats by restoring P29474 pathway . DB01645 has been shown to increase nitric oxide ( NO ) production derived from endothelial nitric oxide synthase ( P29474 ) . This study was to investigate whether genistein could prevent myocardial hypertrophy in the 2 - kidney 1 - clip ( 2K1C ) renohypertensive rat through the NO pathway and to clarify the underlying mechanisms . After the 2K1C operation , plasma angiotensin II increased , and the rats developed significant left ventricular hypertrophy ( LVH ) and increased collagen I expression . Phosphorylated P29474 , NOS activity , NO production and cGMP contents were markedly decreased in ventricular tissues of 2K1C rats . Chronic administration of genistein to 2K1C rats restored NO , NOS activity , phosphorylated P29474 expression , cGMP in ventricular tissues , and the restoration was parallel with the improvement of LVH and attenuated the excessive ventricular collagen I expression . DB01645 also elevated angiotensin II type 2 receptor ( P50052 ) expression , and the effects of genistein on LVH could be completely abolished by an P50052 antagonist , PD123319 . The antagonist also reversed the increase in P29474 activity , NO and cGMP restored by genistein in hypertensive rats . We further explored the mechanisms by which genistein restored NO in hypertension and found that genistein significantly enhanced phosphorylated P29474 but left relatively unchanged total P29474 and the P29474 dimer / monomer ratio . In addition , genistein decreased the binding of P29474 with caveolin 3 and simultaneously promoted its binding with calmodulin and heat shock protein 90 . We conclude that the preventive effects of genistein on cardiac remodeling induced by 2K1C hypertension are mediated by P50052 - dependent NO production .",
"[ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out - such as the renin - angiotensin - aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance - , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR = 3 . 0 ; p = 0 . 023 ) ; P21728 , rs686 ( OR = 0 . 38 ; p = 0 . 012 ) and P07550 , rs1042718 ( OR = 10 . 0 ; p = 0 . 008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure .",
"Comparison of effects of olmesartan and telmisartan on blood pressure and metabolic parameters in Japanese early - stage type - 2 diabetics with hypertension . P30556 blockers ( ARBs ) are regarded as first - line treatments for type - 2 diabetes with hypertension . Despite the availability of various types of ARBs , there are no comparative studies of their effects on patients with diabetes . In this open - label prospective crossover study , we compared the effects of olmesartan ( 20 mg / day ) and telmisartan ( 40 mg / day ) . Twenty Japanese early - stage type - 2 diabetes patients with hypertension treated with valsartan ( 80 mg / day ) for at least 8 weeks were recruited to this study . At study entry , valsartan was changed to olmesartan ( 20 mg / day ) or telmisartan ( 40 mg / day ) and administered for 8 weeks . The drugs were then switched and treatment was continued for another 8 weeks . We analyzed the blood pressure lowering effects of each drug by 24 - h ambulatory blood pressure monitoring at 0 , 8 , and 16 weeks . Simultaneously , we measured metabolic parameters and inflammation markers . DB00275 lowered mean systolic and diastolic blood pressure more significantly than did telmisartan . While there were no differences between the groups in metabolic parameters , including HbA1c and adiponectin , the decreases in serum interleukin - 6 and highly sensitive P02741 were more significant by olmesartan treatment . Our results indicate that olmesartan has more potent arterial blood pressure lowering and anti - inflammatory effects than telmisartan .",
"Angiotensin II blockers in obstructive pulmonary disease : a randomised controlled trial . In chronic obstructive pulmonary disease ( P48444 ) , the sympathetic nervous system , as well as the renin - angiotensin system , is activated with possible negative systemic effects on skeletal muscles . P30556 blockers inhibit the sympathetic and renin - angiotensin systems and might improve skeletal and respiratory muscle strength in patients in whom these systems are activated . The effects of the angiotensin receptor blocker irbesartan given over 4 months was evaluated in 60 patients with P48444 and a forced expiratory volume in one second of < 50 % of the predicted value and without obvious cardiovascular disease that would necessitate the administration of an angiotensin - converting enzyme inhibitor or an angiotensin receptor blocker . Irbesartan was well tolerated , but did not exert a significant effect on the primary end - point maximum inspiratory pressure . Spirometric results were not affected , but total lung capacity was reduced . Irbesartan led to a significant decrease in haematocrit ( 46 . 4 +/- 3 . 6 to 43 . 9 +/- 4 . 3 % versus 47 . 5 +/- 2 . 4 to 48 . 7 +/- 3 . 0 % with placebo ) . In conclusion , respiratory muscle strength in chronic obstructive pulmonary disease patients was not influenced by angiotensin II receptor blockade . However , the changes in haematocrit and total lung capacity following irbesartan raise the possibility that well - known cardiovascular drugs can produce unanticipated beneficial effects in chronic obstructive pulmonary disease patients .",
"Blockade of P30556 reduces oxidative stress in adipose tissue and ameliorates adipocytokine dysregulation . Dysregulated production of adipocytokines may be involved in the development of atherosclerotic cardiovascular disease in metabolic syndrome and chronic kidney disease ( CKD ) associated with metabolic syndrome . The aim of this study was to determine the effects of treatment with angiotensin II ( Ang II ) type - 1 receptor blocker ( ARB ) on the regulation of adipocytokines . DB00275 , an ARB , significantly blunted the age - and body weight - associated falls in plasma adiponectin both in genetically and diet - induced obese mice , without affecting body weight , but had no effect on plasma adiponectin levels in lean mice . DB00275 also ameliorated dysregulation of adipocytokines in obesity , such as tumor necrosis factor - alpha , plasminogen activator inhibitor - 1 , monocyte chemotactic protein - 1 , and serum amyloid A3 . DB00275 significantly reduced reactive oxygen species originating from accumulated fat and attenuated the expression of nicotinamide adenine dinucleotide phospho hydrogenase oxidase subunits in adipose tissue . In cultured adipocytes , olmesartan acted as an antioxidant and improved adipocytokine dysregulation . Our results indicate that blockade of Ang II receptor ameliorates adipocytokine dysregulation and that such action is mediated , at least in part , by targeting oxidative stress in obese adipose tissue . Ang II signaling and subsequent oxidative stress in adipose tissue may be potential targets for the prevention of atherosclerotic cardiovascular disease in metabolic syndrome and also in metabolic syndrome - based CKD .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK44___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Association of a polymorphism of the apolipoprotein E gene with chronic kidney disease in Japanese individuals with metabolic syndrome . The purpose of the present study was to identify genetic variants that confer susceptibility to chronic kidney disease ( CKD ) in Japanese individuals with metabolic syndrome . The study population comprised 2150 Japanese individuals with metabolic syndrome , including 411 subjects with CKD [ estimated glomerular filtration rate ( eGFR ) < 50 mL / min / 1 . 73m ( 2 ) ] and 1739 controls ( eGFR >/= 60 mL / min / 1 . 73m ( 2 ) ) . The genotypes for 100 polymorphisms of 80 candidate genes were determined . The chi - square test , multivariable logistic regression analysis with adjustment for covariates , as well as a stepwise forward selection procedure revealed that nine polymorphisms of P02649 , O95477 , P23219 , P01375 , Q96IY4 , P30556 , Q8NGZ3 , and P16520 were associated ( P < 0 . 05 ) with the prevalence of CKD . Among these polymorphisms , the - 219G --> T polymorphism of P02649 ( rs405509 ) was most significantly associated with CKD in Japanese individuals with metabolic syndrome .",
"Genomic profiling of 766 cancer - related genes in archived esophageal normal and carcinoma tissues . We employed the BeadArraytrade mark technology to perform a genetic analysis in 33 formalin - fixed , paraffin - embedded ( FFPE ) human esophageal carcinomas , mostly squamous - cell - carcinoma ( ESCC ) , and their adjacent normal tissues . A total of 1 , 432 single nucleotide polymorphisms ( SNPs ) derived from 766 cancer - related genes were genotyped with partially degraded genomic DNAs isolated from these samples . This directly targeted genomic profiling identified not only previously reported somatic gene amplifications ( e . g . , P24385 ) and deletions ( e . g . , CDKN2A and P42772 ) but also novel genomic aberrations . Among these novel targets , the most frequently deleted genomic regions were chromosome 3p ( including tumor suppressor genes Q9BXW9 and P35222 ) and chromosome 5 ( including tumor suppressor gene P25054 ) . The most frequently amplified genomic region was chromosome 3q ( containing Q92997 , P58340 , O15440 , P41182 , P30556 and known oncogenes Q07912 , P50591 , P61328 ) . The chromosome 3p deletion and 3q amplification occurred coincidently in nearly all of the affected cases , suggesting a molecular mechanism for the generation of somatic chromosomal aberrations . We also detected significant differences in germline allele frequency between the esophageal cohort of our study and normal control samples from the International HapMap Project for 10 genes ( P09603 , Q5TCX8 , P60568 , P54278 , Q92985 , P36888 , Q16620 , P80192 , P04626 and P10644 ) , suggesting that they might play roles in esophageal cancer susceptibility and / or development . Taken together , our results demonstrated the utility of the BeadArray technology for high - throughput genetic analysis in FFPE tumor tissues and provided a detailed genetic profiling of cancer - related genes in human esophageal cancer .",
"Pharmacological effects of lipid - lowering drugs recapitulate with a larger amplitude the phenotypic effects of common variants within their target genes . BACKGROUND : A major expectation underlying the search for novel susceptibility genes for common diseases using genome - wide association studies ( GWAS ) is that these discoveries will lead to new drug targets . This claim has not been verified yet . Here , we tested the hypothesis that common single nucleotide polymorphisms ( SNPs ) within drug target genes are associated with the corresponding phenotypes , using a population - based GWAS dataset and lipid - lowering drugs as a test case . METHODS : We examined the association between 36 genotyped and 193 imputed SNPs within four lipid - lowering drug target genes ( P04035 , Q07869 , Q8TDS4 / Q8TDS4 and P11597 ) and four non - lipid drug target genes ( P12821 , P30556 , Q9H244 , and P51164 ) and lipid phenotypes , blood pressure , and coronary artery disease in 5635 adult participants of the Lausanne , Switzerland , CoLaus study , genotyped using the Affymetrix 500K SNP chip technology . RESULTS : The phenotypes associated with SNPs within drug target genes recapitulated to a certain extent the pharmacological effects of the drug . The amplitude of the SNP effect was about 10 times smaller than the pharmacological effect of the corresponding drug . In particular , several P11597 SNPs were associated with an elevation in HDL - cholesterol levels , yet a lower diastolic blood pressure , providing evidence that the blood pressure elevation induced by the P11597 inhibitor torcetrapib is more likely compound specific than class specific . CONCLUSION : Pharmacological modulation of lipid - lowering drug targets recapitulates , and markedly amplifies , the phenotypic effects of common SNPs within these target genes . This data provides indirect evidence that , with certain limitations , large - scale GWAS represent a new tool for the discovery and the development of innovative drugs ."
] |
[
"___MASK25___",
"___MASK33___",
"___MASK44___",
"___MASK48___",
"___MASK52___",
"___MASK6___",
"___MASK73___",
"___MASK84___",
"___MASK93___"
] |
___MASK52___
|
MH_train_402
|
interacts_with DB00470?
|
[
"Glucocorticoids enhance regeneration of murine olfactory epithelium . CONCLUSION : Glucocorticoid ( GC ) administration enhanced apoptotic changes in mature olfactory receptor neurons ( ORNs ) . GC administration may enhance regeneration of olfactory epithelium ( OE ) . OBJECTIVES : The mechanism underlying olfactory epithelial cells turnover involves apoptosis replaced by new ORNs . On regeneration of OE , we evaluated the apoptotic changes in OE . Our aim was to corroborate the enhancement of apoptosis of ORNs induced by GCs that are generally administered locally or systemically to patients with olfactory dysfunction . MATERIALS AND METHODS : For the in vitro study , we established cultured murine ORNs . ___MASK93___ acetonide was added to culture supernatants . ORNs were then cultured for another 2 weeks . In the in vivo study , triamcinolone acetonide was administered to mice 5 or 10 times . The mice were dissected 3 days after the final injection , and the olfactory regions were removed and embedded in paraffin . All samples were examined by immunohistochemical staining and the TdT - mediated dUTP - biotin nick - end labeling ( TUNEL ) method . RESULTS : P04150 ( GR ) expression of cultured murine ORNs was observed among ORNs at the mature stage . Expression of GRs by murine OE was localized on mature ORNs and supporting cells . Administration of GC to both cultured ORNs and mice resulted in proportions of apoptotic cells that were significantly higher than those in the control groups .",
"Direct modulation of the outer mitochondrial membrane channel , voltage - dependent anion channel 1 ( P21796 ) by cannabidiol : a novel mechanism for cannabinoid - induced cell death . DB09061 ( DB09061 ) is a non - psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells . It is not an agonist of the classical P21554 / CB2 cannabinoid receptors and the mechanism by which it functions is unknown . Here , we studied the effects of DB09061 on various mitochondrial functions in BV - 2 microglial cells . Our findings indicate that DB09061 treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death . Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of DB09061 with protein markers of mitochondria . Single - channel recordings of the outer - mitochondrial membrane protein , the voltage - dependent anion channel 1 ( P21796 ) functioning in cell energy , metabolic homeostasis and apoptosis revealed that DB09061 markedly decreases channel conductance . Finally , using microscale thermophoresis , we showed a direct interaction between purified fluorescently labeled P21796 and DB09061 . Thus , P21796 seems to serve as a novel mitochondrial target for DB09061 . The inhibition of P21796 by DB09061 may be responsible for the immunosuppressive and anticancer effects of DB09061 .",
"The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide - activated enzyme . The effects of cannabinoids on ketogenesis in primary cultures of rat astrocytes were studied . Delta9 - DB00470 ( THC ) , the major active component of marijuana , produced a malonyl - DB01992 - independent stimulation of carnitine palmitoyltransferase I ( CPT - I ) and ketogenesis from [ 14C ] palmitate . The THC - induced stimulation of ketogenesis was mimicked by the synthetic cannabinoid HU - 210 and was prevented by pertussis toxin and the P21554 cannabinoid receptor antagonist SR141716 . Experiments performed with different cellular modulators indicated that the THC - induced stimulation of ketogenesis was independent of cyclic AMP , Ca2 + , protein kinase C , and mitogen - activated protein kinase ( MAPK ) . The possible involvement of ceramide in the activation of ketogenesis by cannabinoids was subsequently studied . THC produced a P21554 receptor - dependent stimulation of sphingomyelin breakdown that was concomitant to an elevation of intracellular ceramide levels . Addition of exogenous sphingomyelinase to the astrocyte culture medium led to a MAPK - independent activation of ketogenesis that was quantitatively similar and not additive to that exerted by THC . Furthermore , ceramide activated CPT - I in astrocyte mitochondria . Results thus indicate that cannabinoids stimulate ketogenesis in astrocytes by a mechanism that may rely on P21554 receptor activation , sphingomyelin hydrolysis , and ceramide - mediated activation of CPT - I .",
"Molecular basis of the structural stability of a Top7 - based scaffold at extreme pH and temperature conditions . The development of stable biomolecular scaffolds that can tolerate environmental extremes has considerable potential for industrial and defense - related applications . However , most natural proteins are not sufficiently stable to withstand non - physiological conditions . We have recently engineered the de novo designed Top7 protein to specifically recognize the glycoprotein P01730 by insertion of an eight - residue loop . The engineered variant exhibited remarkable stability under chemical and thermal denaturation conditions . In the present study , far - UV CD spectroscopy and explicit - solvent MD simulations are used to investigate the structural stability of Top7 and the engineered variant under extreme conditions of temperature and pH . Circular dichroism measurements suggest that the engineered variant Top7 ( P21554 ) , like Top7 , retains its structure at high temperatures . Changes in CD spectra suggest that there are minor structural rearrangements between neutral and acidic environments for both proteins but that these do not make the proteins less stable at high temperatures . The anti - parallel beta - sheet is well conserved within the timescale simulated whereas there is a decrease of helical content when low pH and high - temperature conditions are combined . Concerted alanine mutations along the alpha - helices of the engineered Top7 variant did not revert this trend when at pH 2 and 400K . The structural resilience of the anti - parallel beta - sheet suggests that the protein scaffold can accommodate varying sequences . The robustness of the Top7 scaffold under extreme conditions of pH and temperature and its amenability to production in inexpensive bacterial expression systems reveal great potential for novel biotechnological applications .",
"Genomic organization , expression and evolution of porcine Q15648 , 2 , and 3 . Recently we identified and characterized porcine calcitonin receptor - stimulating peptide ( CRSP ) 1 , O60244 and Q9ULK4 as members of the calcitonin / calcitonin gene - related peptide ( CT / P80511 ) family . In the present study , the genomic sequences and organization of Q15648 , 2 , and 3 were determined , and the expression of the genes in the porcine brain was investigated using in situ hybridization . Analysis of 5 '- upstream regions of the three CRSPs demonstrated that Q15648 and O60244 have almost identical sequences ( > 98 % similarity ) and high sequence similarities including functional transcription binding sites with the corresponding region of human CALCA ( CT / alpha P80511 ) , whereas Q9ULK4 retains less similarity with the above genes . RH mapping of CRSPs demonstrated that they resided in a region of swine chromosome 2 ( Q9NXB9 ) . The arrangement of the genes in the region was found to be conserved in corresponding human and mouse regions . In situ hybridization demonstrated sense transcripts of the three genes in cerebrum , hippocampus , hypothalamus , pons / midbrain , and thalamus of 3 - month - old pigs , and O60244 sense transcripts additionally in tractus opticus . The sense transcripts of alpha P80511 and P10092 ( beta P80511 ) were detected in cerebrum , hippocampus , and pons / midbrain of newborn mice , and to a lesser extent in pons / midbrain of 8 - week - old mice . These results taken together with the chromosomal conservation and phylogenetic clustering of CT / P80511 family indicate that Q15648 , 2 , and 3 may be functionally different from alpha P80511 and beta P80511 , though they are indicated to have a common progenitor gene .",
"Incorporating age at onset of smoking into genetic models for nicotine dependence : evidence for interaction with multiple genes . ___MASK9___ dependence is moderately heritable , but identified genetic associations explain only modest portions of this heritability . We analyzed 3369 SNPs from 349 candidate genes and investigated whether incorporation of SNP - by - environment interaction into association analyses might bolster gene discovery efforts and prediction of nicotine dependence . Specifically , we incorporated the interaction between allele count and age at onset of regular smoking ( AOS ) into association analyses of nicotine dependence . Subjects were from the Collaborative Genetic Study of ___MASK9___ Dependence and included 797 cases ascertained for Fagerström nicotine dependence and 811 non - nicotine - dependent smokers as controls , all of European descent . Compared with main effect models , SNP x AOS interaction models resulted in higher numbers of nominally significant tests , increased predictive utility at individual SNPs and higher predictive utility in a multi - locus model . Some SNPs previously documented in main effect analyses exhibited improved fits in the joint analysis , including rs16969968 from P30532 and rs2314379 from Q9Y6R4 . P30532 exhibited larger effects in later - onset smokers , in contrast with a previous report that suggested the opposite interaction ( Weiss et al . 2008 ) . However , a number of SNPs that did not emerge in main effect analyses were among the strongest findings in the interaction analyses . These include SNPs located in Q13224 ( P = 1 . 5 x 10 (- 5 ) ) , which encodes a subunit of the N - methyl - D - aspartate receptor channel , a key molecule in mediating age - dependent synaptic plasticity . Incorporation of logically chosen interaction parameters , such as AOS , into genetic models of substance use disorders may increase the degree of explained phenotypic variation and constitutes a promising avenue for gene discovery .",
"Imatinib triggers mesenchymal - like conversion of CML cells associated with increased aggressiveness . Chronic myelogenous leukemia ( CML ) is a cytogenetic disorder resulting from the expression of p210BCR - P00519 . Imatinib , an inhibitor of P11274 - P00519 , has emerged as the leading compound to treat CML patients . Despite encouraging clinical results , resistance to imatinib represents a major drawback for therapy , as a substantial proportion of patients are refractory to this treatment . Recent publications have described the existence of a small cancer cell population with the potential to exhibit the phenotypic switch responsible for chemoresistance . To investigate the existence of such a chemoresistant cellular subpopulation in CML , we used a two - step approach of pulse and continuous selection by imatinib in different CML cell lines that allowed the emergence of a subpopulation of adherent cells ( IM - R Adh ) displaying an epithelial - mesenchymal transition ( EMT ) - like phenotype . Overexpression of several EMT markers was observed in this CML subpopulation , as well as in P28906 (+) CML primary cells from patients who responded poorly to imatinib treatment . In response to imatinib , this P16070 ( high )/ P25063 ( low ) IM - R Adh subpopulation exhibited increased adhesion , transmigration and invasion in vitro and in vivo through specific overexpression of the αVβ3 receptor . Q05397 / Akt pathway activation following integrin β3 ( ITGβ3 ) engagement mediated the migration and invasion of IM - R Adh cells , whereas persistent activation of P29323 counteracted P11274 - P00519 inhibition by imatinib , promoting cell adhesion - mediated resistance .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK69___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"Biophysical and pharmacological characterization of hypotonically activated chloride currents in cortical astrocytes . Rat cortical astrocytes regulate their cell volume in response to hypotonic challenge . This regulation is believed to depend largely on the release of chloride or organic osmolytes through anion channels . Using whole - cell recordings , we identified weakly outwardly rectifying chloride currents that could be activated in response to hypotonic challenge . These currents exhibited the following permeability sequence upon replacement of chloride in the bathing solution with various anions : I - > NO3 - > Cl - > Gluc - > or = MeS - > Ise - . Interestingly , extracellular I - , albeit showing the greatest permeability , blocked the currents with an IC50 of approximately 50 mM . Currents were almost completely inhibited by 123 microM P16860 and partially inhibited by 200 microM niflumic acid or 200 microM DIDS . Additionally , the total number of Cl - ions effluxed through the hypotonically activated channels was markedly similar to the total solute efflux during volume regulation . We therefore propose the hypotonically activated chloride channel as a major contributor to volume regulation of astrocytes . To examine potential candidate chloride channel genes expressed by astrocytes , we employed RT - PCR to demonstrate the presence of transcripts for P51788 , 3 , 4 , 5 , and 7 , as well as for P21796 and P13569 in cultured astrocytes . Moreover , we performed immunostaining with antibodies against each of these channels and showed the strongest expression of P51788 and P51790 , strong expression of P51795 and P21796 , weak expression of P51798 and very weak expression of P51793 and P13569 . Intriguingly , although we found at least seven Cl - channel proteins from three different gene families in astrocytes , none appeared to be active in resting cells .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK56___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"Some cannabinoid receptor ligands and their distomers are direct - acting openers of Q09428 K ( DB00171 ) channels . Here , we examined the chronic effects of two cannabinoid receptor - 1 ( P21554 ) inverse agonists , rimonabant and ibipinabant , in hyperinsulinemic Zucker rats to determine their chronic effects on insulinemia . DB06155 and ibipinabant ( 10 mg · kg ⁻ ¹ · day ⁻ ¹ ) elicited body weight - independent improvements in insulinemia and glycemia during 10 wk of chronic treatment . To elucidate the mechanism of insulin lowering , acute in vivo and in vitro studies were then performed . Surprisingly , chronic treatment was not required for insulin lowering . In acute in vivo and in vitro studies , the P21554 inverse agonists exhibited acute K channel opener ( KCO ; e . g . , diazoxide and NN414 ) - like effects on glucose tolerance and glucose - stimulated insulin secretion ( GSIS ) with approximately fivefold better potency than diazoxide . Followup studies implied that these effects were inconsistent with a P21554 - mediated mechanism . Thus effects of several P21554 agonists , inverse agonists , and distomers during GTTs or GSIS studies using perifused rat islets were unpredictable from their known P21554 activities . In vivo rimonabant and ibipinabant caused glucose intolerance in P21554 but not Q09428 - KO mice . Electrophysiological studies indicated that , compared with diazoxide , 3 μM rimonabant and ibipinabant are partial agonists for K channel opening . Partial agonism was consistent with data from radioligand binding assays designed to detect Q09428 K ( DB00171 ) KCOs where rimonabant and ibipinabant allosterically regulated ³H - glibenclamide - specific binding in the presence of MgATP , as did diazoxide and NN414 . Our findings indicate that some P21554 ligands may directly bind and allosterically regulate Kir6 . 2 / Q09428 K ( DB00171 ) channels like other KCOs . This mechanism appears to be compatible with and may contribute to their acute and chronic effects on GSIS and insulinemia .",
"Interactions between A - 9THC and capsaicin on isolated lamb bladder detrusor . A number of studies have demonstrated that capsaicin , a capsicum alkaloid , can affect isolated bladder tissue with either a relaxation or a contraction , depending on the species , by acting on Q8NER1 receptors . In a previous work on isolated lamb detrusor , we demonstrated that capsaicin generally produces a relaxation of the tissue ; this relaxation seems to be mediated by P80511 . Endogenous cannabinoids , such as anandamide , produce some of their actions by stimulating Q8NER1 receptors and this seems to cause the release of peptides , e . g . P80511 . The aim of this work was to ascertain whether a cannabinoid , DB00470 ( delta - 9THC ) , was able to interfere with the response of the isolated lamb detrusor to capsaicin . A - 9THC , at concentrations between 1 . 6 x 10 (- 7 ) and 1 . 3 x 10 (- 6 ) M , displayed no activity on tissues . Instead , following delta - 9THC , most of the tissues responded to capsaicin with a contraction that was abolished by atropine ( 9 . 0 x 10 (- 7 ) M ) . It has been reported that cannabinoids can inhibit the release of P80511 by stimulation of P21554 and CB2 cannabinoid receptors . Delta - 9THC could act stimulating these receptors and thus inhibiting P80511 release and vesical relaxation . The muscle relaxing component removal could favour the contracting component , usually not active .",
"Chronic administration of AM251 improves albuminuria and renal tubular structure in obese rats . Modulation of the endocannabinoid system as an anti - obesity therapeutic is well established ; however , the direct effects of cannabinoid receptor 1 ( P21554 ) antagonism on renal function and structure in a model of diet - induced obesity ( DIO ) are unknown . The aim of this study was to characterise the renal effects of the P21554 antagonist AM251 in a model of DIO . Male Sprague - Dawley rats were fed a low - or high - fat diet ( HFD : 40 % digestible energy from lipids ) for 10 weeks to elicit DIO ( n = 9 ) . In a different cohort , rats were fed a HFD for 15 weeks . After 9 weeks consuming a HFD , rats were injected daily for 6 weeks with 3 mg / kg AM251 ( n = 9 ) or saline via i . p . injection ( n = 9 ) . After 10 weeks consuming a HFD , P21554 and megalin protein expression were significantly increased in the kidneys of obese rats . Antagonism of P21554 with AM251 significantly reduced weight gain , systolic blood pressure , plasma leptin , and reduced albuminuria and plasma creatinine levels in obese rats . Importantly , there was a significant reduction in tubular cross - section diameter in the obese rats treated with AM251 . An improvement in albuminuria was likely due to the reduction in tubular size , reduced leptinaemia and maintenance of megalin expression levels . In obese rats , AM251 did not alter diastolic blood pressure , sodium excretion , creatinine clearance or expression of the fibrotic proteins P15692 , P01137 and collagen IV in the kidney . This study demonstrates that treatment with P21554 antagonist AM251 improves renal outcomes in obese rats .",
"Molecular cloning , expression and function of the murine CB2 peripheral cannabinoid receptor . We have cloned the peripheral cannabinoid receptor , mCB2 , from a mouse splenocyte cDNA library . The 3 . 7 kb sequence contains an open reading frame encoding a protein of 347 residues sharing 82 % overall identity with the only other known peripheral receptor , human CB2 ( P34972 ) and shorter than P34972 by 13 amino acids at the carboxyl terminus . Binding experiments with membranes from COS - 3 cells transiently expressing mCB2 showed that the synthetic cannabinoid Q08050 55212 - 2 had a 6 - fold lower affinity for mCB2 than for P34972 , whereas both receptors showed similar affinities for the agonists CP 55 , 940 , DB00470 and anandamide and almost no affinity for the central receptor - ( P21554 ) specific antagonist SR 141716A . Both P34972 and mCB2 mediate agonist - stimulated inhibition of forskolin - induced DB02527 production in CHO cell lines permanently expressing the receptors . SR 141716A failed to antagonize this activity in either cell line , confirming its specificity for P21554 .",
"Beneficial effects of cannabinoids ( CB ) in a murine model of allergen - induced airway inflammation : role of P21554 / CB2 receptors . The endocannabinoid system ( ECS ) consists of two cannabinoid ( CB ) receptors , namely CB ( 1 ) and CB ( 2 ) receptor , and their endogenous ( endocannabinoids ) and exogenous ( cannabinoids , e . g . DB00470 ( THC ) ) ligands which bind to these receptors . Based on studies suggesting a role of THC and the ECS in inflammation , the objective of this study was to examine their involvement in type I hypersensitivity using a murine model of allergic airway inflammation . THC treatment of C57BL / 6 wildtype mice dramatically reduced airway inflammation as determined by significantly reduced total cell counts in bronchoalveolar lavage ( BAL ) . These effects were greatest when mice were treated during both , the sensitization and the challenge phase . Furthermore , systemic immune responses were significantly suppressed in mice which received THC during sensitization phase . To investigate a role of CB ( 1 / 2 ) receptors in this setting , we used pharmacological blockade of CB ( 1 ) and / or CB ( 2 ) receptors by the selective antagonists and moreover CB ( 1 )/ CB ( 2 ) receptor double - knockout mice ( CB ( 1 )(-/-)/ CB ( 2 )(-/-) ) and found neither significant changes in the cell patterns in BAL nor in immunoglobulin levels as compared to wildtype mice . Our results indicate that the activation of the ECS by applying the agonist THC is involved in the development of type I allergies . However , CB ( 1 )/ CB ( 2 ) receptor - independent signalling seems likely in the observed results .",
"Actions of DB00470 in cannabis : relation to use , abuse , dependence . Cannabis use disorders have been recently identified as a relevant clinical issue : a subset of cannabis smokers seeks treatment for their cannabis use , yet few succeed in maintaining long - term abstinence . The rewarding and positive reinforcing effects of the primary psychoactive component of smoked cannabis , DB00470 ( THC ) are mediated by the cannabinoid P21554 receptor . The P21554 receptor has also been shown to mediate cannabinoid dependence and expression of withdrawal upon cessation of drug administration , a phenomenon verified across species . This paper will review findings implicating the P21554 receptor in the behavioural effects of exogenous cannabinoids with a focus on cannabinoid dependence and reinforcement , factors that contribute to the maintenance of chronic cannabis smoking despite negative consequences . Opioidergic modulation of these effects is also discussed .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK67___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK67___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"Modular competition driven by DB01221 receptor subtypes in spike - timing - dependent plasticity . N - methyl - d - aspartate receptors ( NMDARs ) play a critical role in transducing neuronal activity patterns into changes in synaptic strength . However , how they mediate this transduction in response to physiological stimuli has remained elusive . In particular , it has been debated whether different NMDAR subtypes play opposing signaling roles in synaptic plasticity . Using perforated patch - clamp recordings from pairs of synaptically connected glutamatergic neurons in dissociated hippocampal culture , we found that spike - timing - dependent potentiation induced by pairing pre - and postsynaptic spikes required the activation of a fast component of NMDAR current that is likely to be mediated by Q12879 - containing NMDARs ( Q12879 - NRs ) . In contrast , spike - timing - dependent depression required a slow component of NMDAR current carried by Q13224 - containing NMDARs ( Q13224 - NRs ) . CV analysis showed that the locus of this depression was primarily presynaptic in pairs of cells making strong synaptic connections , whereas weaker synapses showed no clear preference for pre - or postsynaptic expression . This depression was not significantly reduced by antagonism of the P21554 receptor , in contrast to spike - timing - dependent depression in the neocortex that requires presynaptic P21554 signaling . With blockade of Q13224 - NRs , spike triplets that contained both potentiating and depressing spike - timing components induced net potentiation . However , when the putative Q12879 - NR population is inhibited , these spike triplets resulted in either depression or no net change , depending on the temporal order of the spike - timing components . These results imply a dynamic competition between signaling modules that can be biased by differentially antagonizing NMDAR subtypes during the induction of spike - timing - dependent plasticity . Using a simple model , we show that such a modular competition recapitulates our observations .",
"123I - labeled AM251 : a radioiodinated ligand which binds in vivo to mouse brain cannabinoid P21554 receptors . We have investigated the binding of 123I - labeled N -( piperidin - 1 - yl )- 5 -( 4 - iodophenyl )- 1 -( 2 , 4 - dichlorophenyl )- 4 - methy l - 1 H - pyrazole - 3 - carboxamide ( AM251 ) , an analog of the cannabinoid receptor antagonist SR141716A [ N -( piperidin - 1 - yl )- 5 -( 4 - chlorophenyl )- 1 -( 2 , 4 - dichlorophenyl )- 4 - me thyl - 1 H - pyrazole - 3 - carboxamide ] in the mouse brain . Following intravenous injection , the peak whole - brain uptake of about 1 % of the administered activity occurred at about 2 h . By 8 h radioactivity in brain had declined to about half its peak value . High - performance liquid chromatographic analysis showed that > 70 % of radioactivity extracted from brain at 2 h was still present as [ 123I ] AM251 . Co - injection of SR141716A inhibited the in vivo brain binding of [ 123I ] AM251 dose dependently . At 2 mg / kg , the highest dose that could be tested , inhibition was 50 % at 2 h post - administration . The ED50 value calculated assuming that 2 mg / kg gave near - maximal inhibition was about 0 . 1 mg / kg . In contrast to the brain , radioactivity in other major organs ( blood , liver , kidney , heart and lung ) was little affected by SR141716A . The regional binding of [ 123I ] AM251 in the brain was consistent with the published distribution of cannabinoid receptors in rat brain , in that the order was hippocampus , striatum > cerebellum > brain stem . delta 9 - DB00470 co - administered intravenously at 10 mg / kg , a dose which induced catalepsy and decreased locomotor activity , decreased the 2 h brain uptake of [ 123I ] AM251 by 10 % , but this was not significant ( P = 0 . 08 ) . In in vitro binding assays with mouse hippocampal membranes , tetrahydrocannabinol inhibited binding of [ 123I ] AM251 with an IC50 value of about 700 nM , compared with about 0 . 2 nM for SR141716A .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK7___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK7___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK70___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .",
"Cannabinoid P21554 receptor activation mediates the opposing effects of amphetamine on impulsive action and impulsive choice . It is well known that acute challenges with psychostimulants such as amphetamine affect impulsive behavior . We here studied the pharmacology underlying the effects of amphetamine in two rat models of impulsivity , the 5 - choice serial reaction time task ( 5 - CSRTT ) and the delayed reward task ( P29323 ) , providing measures of inhibitory control , an aspect of impulsive action , and impulsive choice , respectively . We focused on the role of cannabinoid P21554 receptor activation in amphetamine - induced impulsivity as there is evidence that acute challenges with psychostimulants activate the endogenous cannabinoid system , and P21554 receptor activity modulates impulsivity in both rodents and humans . Results showed that pretreatment with either the P21554 receptor antagonist / inverse agonist SR141716A or the neutral P21554 receptor antagonist O - 2050 dose - dependently improved baseline inhibitory control in the 5 - CSRTT . Moreover , both compounds similarly attenuated amphetamine - induced inhibitory control deficits , suggesting that P21554 receptor activation by endogenously released cannabinoids mediates this aspect of impulsive action . Direct P21554 receptor activation by Δ9 - DB00470 ( Δ9 - THC ) did , however , not affect inhibitory control . Although neither SR141716A nor O - 2050 affected baseline impulsive choice in the P29323 , both ligands completely prevented amphetamine - induced reductions in impulsive decision making , indicating that P21554 receptor activity may decrease this form of impulsivity . Indeed , acute Δ9 - THC was found to reduce impulsive choice in a P21554 receptor - dependent way . Together , these results indicate an important , though complex role for cannabinoid P21554 receptor activity in the regulation of impulsive action and impulsive choice as well as the opposite effects amphetamine has on both forms of impulsive behavior .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK61___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK64___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"Cannabis - induced cytotoxicity in leukemic cell lines : the role of the cannabinoid receptors and the MAPK pathway . Delta9 - DB00470 ( THC ) is the active metabolite of cannabis . THC causes cell death in vitro through the activation of complex signal transduction pathways . However , the role that the cannabinoid 1 and 2 receptors ( P21554 - R and CB2 - R ) play in this process is less clear . We therefore investigated the role of the CB - Rs in mediating apoptosis in 3 leukemic cell lines and performed microarray and immunoblot analyses to establish further the mechanism of cell death . We developed a novel flow cytometric technique of measuring the expression of functional receptors and used combinations of selective P21554 - R and CB2 - R antagonists and agonists to determine their individual roles in this process . We have shown that THC is a potent inducer of apoptosis , even at 1 x IC ( 50 ) ( inhibitory concentration 50 % ) concentrations and as early as 6 hours after exposure to the drug . These effects were seen in leukemic cell lines ( CEM , HEL - 92 , and HL60 ) as well as in peripheral blood mononuclear cells . Additionally , THC did not appear to act synergistically with cytotoxic agents such as cisplatin . One of the most intriguing findings was that THC - induced cell death was preceded by significant changes in the expression of genes involved in the mitogen - activated protein kinase ( MAPK ) signal transduction pathways . Both apoptosis and gene expression changes were altered independent of p53 and the CB - Rs .",
"Conditional ablation of mediator subunit MED1 ( MED1 / Q15648 ) gene in mouse liver attenuates glucocorticoid receptor agonist dexamethasone - induced hepatic steatosis . P04150 ( GR ) agonist dexamethasone ( DB00514 ) induces hepatic steatosis and enhances constitutive androstane receptor ( CAR ) expression in the liver . CAR is known to worsen hepatic injury in nonalcoholic hepatic steatosis . Because transcription coactivator MED1 / Q15648 gene is required for GR - and CAR - mediated transcriptional activation , we hypothesized that disruption of MED1 / Q15648 gene in liver cells would result in the attenuation of DB00514 - induced hepatic steatosis . Here we show that liver - specific disruption of MED1 gene ( MED1 ( delta Liv ) ) improves DB00514 - induced steatotic phenotype in the liver . In wild - type mice DB00514 induced severe hepatic steatosis and caused reduction in medium - and short - chain acyl - DB01992 dehydrogenases that are responsible for mitochondrial beta - oxidation . In contrast , DB00514 did not induce hepatic steatosis in mice conditionally null for hepatic MED1 , as it failed to inhibit fatty acid oxidation enzymes in the liver . MED1 ( delta Liv ) livers had lower levels of GR - regulated CAR mRNA compared to wild - type mouse livers . Microarray gene expression profiling showed that absence of MED1 affects the expression of the GR - regulated genes responsible for energy metabolism in the liver . These results establish that absence of MED1 in the liver diminishes DB00514 - induced hepatic steatosis by altering the GR - and CAR - dependent gene functions .",
"Anti - inflammatory activity of topical THC in DNFB - mediated mouse allergic contact dermatitis independent of P21554 and CB2 receptors . BACKGROUND : ∆( 9 ) - DB00470 ( THC ) , the active constituent of Cannabis sativa , exerts its biological effects in part through the G - protein - coupled P21554 and CB2 receptors , which were initially discovered in brain and spleen tissue , respectively . However , THC also has P21554 / 2 receptor - independent effects . Because of its immune - inhibitory potential , THC and related cannabinoids are being considered for the treatment of inflammatory skin diseases . Here we investigated the mechanism of the anti - inflammatory activity of THC and the role of P21554 and CB2 receptors . METHODS : We evaluated the impact of topically applied THC on DNFB - mediated allergic contact dermatitis in wild - type and P21554 / 2 receptor - deficient mice . We performed immunohistochemical analyses for infiltrating immune cells and studied the influence of THC on the interaction between T cells , keratinocytes and myeloid immune cells in vitro . RESULTS : Topical THC application effectively decreased contact allergic ear swelling and myeloid immune cell infiltration not only in wild - type but also in P21554 / 2 receptor - deficient mice . We found that THC ( 1 ) inhibited the production of IFNγ by T cells , ( 2 ) decreased the production of P13500 and of IFNγ - induced P80075 and CXL10 by epidermal keratinocytes and ( 3 ) thereby limited the recruitment of myeloid immune cells in vitro in a P21554 / 2 receptor - independent manner . CONCLUSIONS : Topically applied THC can effectively attenuate contact allergic inflammation by decreasing keratinocyte - derived pro - inflammatory mediators that orchestrate myeloid immune cell infiltration independent of P21554 / 2 receptors . This has important implications for the future development of strategies to harness cannabinoids for the treatment of inflammatory skin diseases .",
"Pharmacological , behavioural and mechanistic analysis of HIV - 1 gp120 induced painful neuropathy . A painful neuropathy is frequently observed in people living with human immunodeficiency virus type 1 ( HIV - 1 ) . The HIV coat protein , glycoprotein 120 ( gp120 ) , implicated in the pathogenesis of neurological disorders associated with HIV , is capable of initiating neurotoxic cascades via an interaction with the P61073 and / or P51681 chemokine receptors , which may underlie the pathogenesis of HIV - associated peripheral neuropathic pain . In order to elucidate the mechanisms underlying HIV - induced painful peripheral neuropathy , we have characterised pathological events in the peripheral and central nervous system following application of HIV - 1 gp120 to the rat sciatic nerve . Perineural HIV - 1 gp120 treatment induced a persistent mechanical hypersensitivity ( 44 % decrease from baseline ) , but no alterations in sensitivity to thermal or cold stimuli , and thigmotactic ( anxiety - like ) behaviour in the open field . The mechanical hypersensitivity was sensitive to systemic treatment with gabapentin , morphine and the cannabinoid Q08050 55 , 212 - 2 , but not with amitriptyline . Immunohistochemical studies reveal : decreased intraepidermal nerve fibre density , macrophage infiltration into the peripheral nerve at the site of perineural HIV - 1 gp120 ; changes in sensory neuron phenotype including expression of activating transcription factor 3 ( P18847 ) in 27 % of cells , caspase - 3 in 25 % of cells , neuropeptide Y ( P01303 ) in 12 % of cells and galanin in 13 % of cells and a spinal gliosis . These novel findings suggest that this model is not only useful for the elucidation of mechanisms underlying HIV - 1 - related peripheral neuropathy but may prove useful for preclinical assessment of drugs for the treatment of HIV - 1 related peripheral neuropathic pain ."
] |
[
"___MASK56___",
"___MASK61___",
"___MASK64___",
"___MASK67___",
"___MASK69___",
"___MASK70___",
"___MASK7___",
"___MASK93___",
"___MASK9___"
] |
___MASK67___
|
MH_train_403
|
interacts_with DB00205?
|
[
"Synthesis and in vitro evaluation of potential anti - leishmanial targeted drugs of pyrimethamine . DB00205 , an antimalarial drug , was found to be able to inhibit both enzymes ( P00374 - TS and PTR1 ) of the leishmanial folate pathway , although this effect in vivo appears only in relatively high concentrations . To reach the parasites inside macrophage cells , where they are sheltered , targeted drugs of pyrimethamine , carboxymethyldextran - thiomannopyranoside - pyrimethamine ( CMD - P ) , and succinyldextran - thiomannopyranoside - pyrimethamine ( SD - P ) , were synthesized and assayed against L .( L .) amazonensis amastigotes . CMD - P has 2 . 43 % and SD - P has 2 . 58 % of pyrimethamine attached . At a CMD - P dose of 200 microg / mL ( 4 . 86 microg / mL pyrimethamine ) , the results were very promising , with a destruction of approximately 50 % of the intracellular amastigotes , with no detectable toxicity to macrophage cells . SD - P in similar doses did not show good results , probably due to different patterns of drug release . These results open the possibility of treating leishmaniasis with a safe targeted drug of pyrimethamine released directly inside the macrophage cells , reducing the host systemic toxicity .",
"___MASK53___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"DB00563 gamma - hydroxamate derivatives as potential dual target antitumor drugs . A series of new aminopteroyl - based hydroxamate derivatives were synthesized and tested in vitro in cell culture models as potential dual target drugs . These compounds were designed to target two families of enzymes , matrix metalloproteinases ( MMP ) and a folate enzyme , dihydrofolate reductase ( P00374 ) . These enzymes are the components of two unrelated cellular pathways and they are often over - expressed in metastasizing tumors . In addition to the synthesis and full structural characterization of the hybrid molecules , we describe their inhibitory activities against a series of MMPs ( P08253 , P09237 , P14780 , P50281 ) and P00374 , as well as their antiproliferative activity in three cancer cell lines . The new hydroxamate derivatives of MTX proved to be effective inhibitors of MMPs and P00374 in the micromolar and nanomolar range , respectively . Furthermore , they showed strong antiproliferative activity against A549 cells ( non - small cell lung carcinoma ) , and PPC - 1 and Tsu - Pr1 prostate cancer cell lines . Therefore , based on the present results , these bi - functional drugs may be good candidates to target specific tumors in animal models due to potential combined effects on two pathways crucial for tumor development .",
"Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK11___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK11___ peptide content within the pituitary , and plasma ___MASK11___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK11___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK11___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK11___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .",
"Plasmodium falciparum dihydrofolate reductase alleles and pyrimethamine use in pregnant Ghanaian women . Drug resistance in Plasmodium falciparum affects prevention of malaria in pregnancy . In a cross - sectional study of 530 pregnant Ghanaian women , P . falciparum dihydrofolate reductase ( P00374 ) gene mutations linked with pyrimethamine resistance were assessed and associations with pyrimethamine intake were analyzed . P . falciparum infected 69 % of women without pyrimethamine use , 59 % of those who had a history of pyrimethamine consumption but a negative urine test , and 53 % of individuals with a positive urine test . Eighty - one percent , 43 % , and 74 % of the isolates contained the mutations DB00174 - 108 , DB00167 - 51 , and DB00125 - 59 , respectively . DB00156 - 108 occurred in 8 % . DB00205 use was associated with increased frequencies of DB00174 - 108 and DB00125 - 59 but not of DB00167 - 51 or DB00156 - 108 . In women with prophylaxis , wild - type parasites were absent and anemia tended to be more common with an increasing number of P00374 gene mutations . DB00205 appears to be not adequately effective in this part of Ghana , most likely due to the predominance of resistant parasites . Selection for resistance following insufficient prophylaxis could possibly affect the efficacy of future intermittent sulfadoxine - pyrimethamine treatment .",
"Q9Y251 1 : a key participant of inner root sheath differentiation program and hair follicle homeostasis . Q9Y251 is a heparan sulphate endo - glycosidase which was previously detected in the outer root sheath of murine hair follicles . Q9Y251 overexpression was reported to improve mouse hair ( re ) growth . In this study , we investigated its involvement in human hair biology . Immunofluorescence detection was used to explore heparanase distribution in both anagen and catagen hair follicles . Q9Y251 functionality was assessed in in vitro cultured hair follicles , in the presence of a heparanase activity inhibitor . Our results showed that heparanase expression was ( i ) primarily located in the inner root sheath ( P41252 ) of human hair follicle , and there ( ii ) restricted to anagen phase . Furthermore , inhibition of heparanase in in vitro cultured hair follicles induced a catagen - like process . Hair shaft retreat upward was accompanied by a decrease in Ki67 - positive cells , the formation of an epithelial strand as evidenced by P02533 keratin expression , and the loss of P41252 as assessed by transglutaminase 1 and desmoglein labelling . P41252 distribution of heparanase and the induction of catagen - like involution of hair follicles when a potent heparanase inhibitor is added suggest that heparanase is a key actor of P41252 differentiation and hair homeostasis .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"Functional interactions between ubiquitin E2 enzymes and Q6PIZ9 proteins . The Q6PIZ9 ( tripartite motif ) family of proteins is characterized by the presence of the tripartite motif module , composed of a RING domain , one or two B - box domains and a coiled - coil region . Q6PIZ9 proteins are involved in many cellular processes and represent the largest subfamily of RING - containing putative ubiquitin E3 ligases . Whereas their role as E3 ubiquitin ligases has been presumed , and in several cases established , little is known about their specific interactions with the ubiquitin - conjugating E2 enzymes or UBE2s . In the present paper , we report a thorough screening of interactions between the Q6PIZ9 and P41226 families . We found a general preference of the Q6PIZ9 proteins for the D and E classes of P41226 enzymes , but we also revealed very specific interactions between Q9C026 and P60604 , and Q13049 and Q13404 / 2 . Furthermore , we demonstrated that the Q6PIZ9 E3 activity is only manifest with the P41226 with which they interact . For most specific interactions , we could also observe subcellular co - localization of the Q6PIZ9 involved and its cognate P41226 enzyme , suggesting that the specific selection of Q6PIZ9 - P41226 pairs has physiological relevance . Our findings represent the basis for future studies on the specific reactions catalysed by the Q6PIZ9 E3 ligases to determine the fate of their targets .",
"DB00563 induces apoptosis through p53 / P38936 - dependent pathway and increases P12830 expression through downregulation of HDAC / Q15910 . DB00563 ( MTX ) is a dihydrofolate reductase ( P00374 ) inhibitor widely used as an anticancer drug in different kinds of human cancers . Here we investigated the anti - tumor mechanism of MTX against non - small cell lung cancer ( NSCLC ) A549 cells . MTX not only inhibited in vitro cell growth via induction of apoptosis , but also inhibited tumor formation in animal xenograft model . RNase protection assay ( RPA ) and RT - PCR demonstrated its induction of p53 target genes including DR5 , P38936 , Puma and Noxa . Moreover , MTX promoted p53 phosphorylation at Ser15 and acetylaion at Lys373 / 382 , which increase its stability and expression . The apoptosis and inhibition of cell viability induced by MTX were dependent on p53 and , partially , on P38936 . In addition , MTX also increased P12830 expression through inhibition of histone deacetylase ( HDAC ) activity and downregulation of polycomb group protein enhancer of zeste homologue 2 ( Q15910 ) . Therefore , the anticancer mechanism of MTX acts through initiation of p53 - dependent apoptosis and restoration of P12830 expression by downregulation of HDAC / Q15910 .",
"Persistence of Sulfadoxine - DB00205 Resistance Despite Reduction of Drug Pressure in Malawi . BACKGROUND : In 2007 , Malawi replaced sulfadoxine - pyrimethamine ( SP ) with an artemisinin - based combination therapy as the first - line treatment for uncomplicated Plasmodium falciparum malaria in response to failing SP efficacy . Here we estimate the effect of reduced SP pressure on the prevalence of SP - resistant parasites and the characteristics of the associated selective sweeps flanking the resistance loci . METHODS : Samples obtained from individuals with clinical malaria during a period of high SP use ( 1999 - 2001 ) , a transitional period ( 2007 - 2008 ) , and a period of low SP use ( 2012 ) were genotyped for resistance markers at pfdhfr - ts codons 51 , 59 , and 108 and pfdhps codons 437 , 540 , and 581 . Expected heterozygosity was estimated to evaluate the genetic diversity flanking pfdhfr - ts and pfdhps . RESULTS : An increase in the prevalence of the resistance haplotypes P00374 51I / 59R / 108N and P49366 437G / 540E occurred under sustained drug pressure , with no change in haplotype prevalence 5 years after reduction in SP pressure . The P49366 437G / 540E / 581G haplotype was observed in 2007 and increased in prevalence during a period of reduced SP pressure . Changes to the sweep characteristics flanking pfdhfr - ts and pfdhps were minimal . CONCLUSIONS : In contrast to the rapid and complete return of chloroquine - susceptible falciparum malaria after chloroquine was withdrawn from Malawi , a reemergence of SP efficacy is unlikely in the near future .",
"___MASK49___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK49___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"Functional characterization of agonists at recombinant human 5 - Q13049 , P41595 and P28335 receptors in CHO - P04264 cells . 1 . The goal of this study was to characterize the agonist pharmacology of human 5 - Q13049 , P41595 and P28335 ( VSV ) receptors expressed in CHO - P04264 ( Chinese hamster ovary ) cells . 2 . We used a fluorometric imaging plate reader ( FLIPR ) which allows rapid detection of rises in intracellular calcium levels upon the addition of agonists . 3 . Stimulation of all three receptors by 5 - HT caused a robust concentration dependent increase in intracellular calcium levels . No such effect was observed from non - transfected control CHO - P04264 cells . 4 . The rank order of potency of agonists at the different receptor subtypes varied . Tryptamines , BW - 723C86 , d - norfenfluramine , Ro 60 - 0175 and LSD exhibited the following rank order of potency ; P41595 > P28335 > 5 - Q13049 . Piperazines such as m - Chlorophenylpiperazine ( mCPP ) , ORG - 12962 , MK - 212 and also ORG - 37684 exhibited a rank order of potency of P28335 > P41595 > 5 - Q13049 . The phenylisopropylamines DOI and DOB had a rank order of 5 - Q13049 > P41595 > P28335 . 5 . Many agonists tested had partial agonist actions when compared to 5 - HT , and a wide range of relative efficacies were exhibited , which was cell line dependent . For example , mCPP had a relative efficacy of 65 % at P28335 receptors but < 25 % at either 5 - Q13049 or P41595 receptors . 6 . Interpretation of literature values of functional assays using different cell lines , different receptor expression levels and different receptor isoforms , is complex . Species differences and the previous use of antagonist radioligands to characterize agonist potency in binding assays emphasizes the importance of studying agonists in the same experiment using the same assay conditions and parental cell lines .",
"DB00205 - resistant dihydrofolate reductase enzymes of Plasmodium falciparum are not enzymatically compromised in vitro . Plasmodium falciparum , the protozoan that causes the most lethal form of human malaria , has been controlled principally by two safe , affordable drugs , chloroquine and sulfadoxine - pyrimethamine ( SP ) . Studies in the laboratory and in the field have demonstrated that resistance to SP depends on non - synonymous point mutations in the dihydrofolate reductase ( P00374 ) , and dihydropteroate synthase ( P49366 ) coding regions . Parasites that carry dhfr genes with 3 or 4 point mutations ( 51I / 59R / 108N triple mutation or 51I / 59R / 108N / 164L quadruple mutation ) are resistant to pyrimethamine in vitro and patients infected with these parasites respond poorly to SP treatment . The wide spread of these pyrimethamine - resistant alleles demonstrates the increased fitness over drug - sensitive alleles in the presence of the drug . However , it is not clear whether these alleles might reduce the fitness of parasites in the absence of drug pressure . As a first step , we compared the kinetic properties of the wild type , and three mutant alleles to determine whether the native P00374 - thymidylate synthase form of the mutant proteins showed compromised activity in vitro . The mutant enzymes had K ( m ) values for their substrate , dihydrofolate that were significantly lower than the wild type , k ( cat ) values in the same range as the wild type enzyme , and k ( cat )/ K ( m ) values higher than wild type . In contrast , the K ( m ) values for the NADPH cofactor were higher than wild type for the mutant enzymes . These observations suggest that the fitness of these parasites may not be compromised relative to those that carry the wild type allele , even without sustained SP drug pressure .",
"Implants of encapsulated human P26441 - producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington ' s disease . Delivery of neurotrophic molecules to the CNS has gained considerable attention as a potential treatment strategy for neurological disorders . In the present study , a P00374 - based expression vector containing the human ciliary neurotrophic factor ( hCNTF ) was transfected into a baby hamster kidney fibroblast cell line ( BHK ) . Using a polymeric device , encapsulated BHK - control cells and those secreting hCNTF ( BHK - hCNTF ) were transplanted unilaterally into the rat lateral ventricle . Twelve days later , the same animals received unilateral injections of quinolinic acid ( QA ; 225 nmol ) into the ipsilateral striatum . After surgery , animals were behaviorally tested for apomorphine - induced rotation behavior and for skilled forelimb function using the staircase test . Rats receiving BHK - hCNTF cells rotated significantly less than animals receiving BHK - control cells . No behavioral effects of hCNTF were observed on the staircase test . Nissl - stained sections demonstrated that BHK - hCNTF cells significantly reduced the extent of striatal damage produced by QA . Quantitative analysis of striatal neurons further demonstrated that both choline acetyltransferase - and Q99259 - immunoreactive neurons were protected by BHK - hCNTF implants . In contrast , a similar loss of NADPH - diaphorase - positive cells was observed in the striatum of both implant groups . Analysis of retrieved capsules revealed numerous viable and mitotically active BHK cells that continued to secrete hCNTF . These results support the concepts that implants of polymer - encapsulated hCNTF - releasing cells can be used to protect striatal neurons from excitotoxic damage and that this strategy may ultimately prove relevant for the treatment of Huntington ' s disease .",
"Estrogen response element - dependent regulation of transcriptional activation of estrogen receptors alpha and beta by coactivators and corepressors . One mechanism by which ligand - activated estrogen receptors alpha and beta ( ERalpha and ERbeta ) stimulate gene transcription is through direct ER interaction with specific DNA sequences , estrogen response elements ( EREs ) . ERE - bound ER recruits coactivators that stimulate gene transcription . Binding of ER to natural and synthetic EREs with different nucleotide sequences alters ER binding affinity , conformation , and transcriptional activity , indicating that the ERE sequence is an allosteric effector of ER action . Here we tested the hypothesis that alterations in ER conformation induced by binding to different ERE sequences modulates ER interaction with coactivators and corepressors . CHO - P04264 cells transfected with ERalpha or ERbeta show ERE sequence - dependent differences in the functional interaction of ERalpha and ERbeta with coactivators steroid receptor coactivator 1 ( Q15788 ) , P12931 - 2 ( glucocorticoid receptor interacting protein 1 ( GRIP1 ) ) , Q9Y6Q9 amplified in breast cancer 1 ( Q9Y6Q9 ) and Q9Y6Q9 , cyclic AMP binding protein ( CBP ) , and steroid receptor RNA activator ( SRA ) , corepressors nuclear receptor co - repressor ( NCoR ) and silencing mediator for retinoid and thyroid hormone receptors ( Q9Y618 ) , and secondary coactivators coactivator associated arginine methyltransferase 1 ( Q86X55 ) and protein arginine methyltransferase 1 ( Q99873 ) . We note both ligand - independent as well estradiol - and 4 - hydroxytamoxifen - dependent differences in ER - coregulator activity . In vitro ER - ERE binding assays using receptor interaction domains of these coregulators failed to recapitulate the cell - based results , substantiating the importance of the full - length proteins in regulating ER activity . These data demonstrated that the ERE sequence impacts estradiol - and 4 - hydroxytamoxifen - occupied ERalpha and ERbeta interaction with coregulators as measured by transcriptional activity in mammalian cells .",
"Reporter gene expression in cell culture stages and oocysts of Eimeria nieschulzi ( Coccidia , Apicomplexa ) . The rat parasite Eimeria nieschulzi is a suitable model for transfection studies and was used as an additional model organism for the genus Eimeria . We describe the transfection of this apicomplexan parasites and the cultivation of transformed stages in cell culture and in vivo . The beta - galactosidase or yellow fluorescent protein was expressed in all parasitic stages up to the second merozoite generation in vitro under control of the heterologous promoter region of Eimeria tenella mic1 gene previously described for E . tenella transfection . DB00205 resistant E . nieschulzi parasites were obtained in vitro after transfection with a plasmid encoding the Toxoplasma gondii dhfr / ts - m2m3 gene . Co - transfection experiments with an YFP - plasmid resulted in pyrimethamine resistant and fluorescent parasitic stages . Infection of rats with transfected E . nieschulzi sporozoites directed to expression of beta - galactosidase or YFP in oocysts . Co - transfection with YFP / P00374 - TS allowed selection of resistant parasites in vivo . Excreted transgenic oocysts showed arrangement of YFP expression which lead to questions about meiotic recombination frequency and mechanisms .",
"DB00205 and proguanil resistance - conferring mutations in Plasmodium falciparum dihydrofolate reductase : polymerase chain reaction methods for surveillance in Africa . As chloroquine resistance spreads across Africa , the dihydrofolate reductase ( P00374 ) inhibitors pyrimethamine and proguanil are being used as alternative first - line drugs for the treatment and prevention of Plasmodium falciparum malaria . Resistance to these drugs is conferred by point mutations in parasite P00374 . These point mutations can be detected by polymerase chain reaction ( PCR ) assays , but better methods for sample collection , DNA extraction , and a diagnostic PCR are needed to make these assays useful in malaria - endemic areas . Here we report methods for collecting fingerstick blood onto filter paper strips that are air - dried , then stored and transported at room temperature . Cell lysis and DNA extraction are accomplished by boiling in Chelex - 100 . We also report a nested PCR technique that has improved sensitivity and specificity . These procedures readily detect mixed infections of parasites with both sensitive and resistant genotypes ( confirmed by direct sequencing ) and are reliable at parasite densities less than 250 / mm3 in field surveys .",
"The role of serotonin receptor subtypes in the behavioural effects of neuroleptic drugs . A paw test study in rats . The present study was designed to evaluate the roles of serotonin P08908 and 5 - HT2 receptors in the effects of neuroleptic drugs in the paw test . This behavioural test has been shown to model both the antipsychotic efficacy as well as the extrapyramidal side - effect liability of neuroleptic drugs . Whereas the P08908 receptor agonist 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OHDPAT ) reduced the effects of the classical neuroleptic haloperidol , it increased the effects of the atypical neuroleptic clozapine . The 5 - HT2 receptor antagonist ketanserin as well as the P28335 / 5 - HT2 receptor antagonist ritanserin , on the other hand reduced the effects of haloperidol , whereas the P28335 / 5 - HT2 receptor agonist 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane ( DOI ) reduced the effects of clozapine . The most important finding , however , was that the behavioural effects of different ( putative ) neuroleptics ( fluphenazine , P35240 - 39166 , remoxipride , prothipendyl , thioridazine and risperidone ) were differentially influenced by both 8 - OHDPAT and DOI , suggesting that there are important differences between the neuronal mechanisms underlying the behavioural effects of these neuroleptic drugs , even within the subclasses of classical and atypical neuroleptics .",
"DB00205 - sulfadoxine efficacy and selection for mutations in Plasmodium falciparum dihydrofolate reductase and dihydropteroate synthase in Mali . To assess pyrimethamine - sulfadoxine ( PS ) efficacy in Mali , and the role of mutations in Plasmodium falciparum dihydrofolate reductase ( P00374 ) and dihydropteroate synthase ( P49366 ) in in vivo PS resistance , 190 patients with uncomplicated P . falciparum malaria were treated with PS and monitored for 56 days . Mutation - specific polymerase chain reactions and digestion with restriction endonucleases were used to detect P00374 and P49366 mutations on filter paper blood samples from pretreatment and post - treatment infections . Only one case each of RI and RII level resistance and no cases of RIII resistance or therapeutic failure were observed . Post - PS treatment infections had significantly higher rates of P00374 mutations at codons 108 and 59 . No significant selection for P49366 mutations was seen . DB00205 - sulfadoxine is highly efficacious in Mali , and while the low level of resistance precludes assessing the utility of molecular assays for in vivo PS resistance , rapid selection of P00374 mutations supports their role in PS failure .",
"Unimpeded skin carcinogenesis in P02533 - HPV16 transgenic mice deficient for plasminogen activator inhibitor . Angiogenesis , extracellular matrix remodeling and cell migration are associated with cancer progression and involve at least , the plasminogen activating system and its main physiological inhibitor , the plasminogen activator inhibitor - 1 ( P05121 ) . Considering the recognized importance of P05121 in the regulation of tumor angiogenesis and invasion in murine models of skin tumor transplantation , we explored the functional significance of P05121 during early stages of neoplastic progression in the transgenic mouse model of multistage epithelial carcinogenesis ( P02533 - HPV16 mice ) . We have studied the effect of genetic deletion of P05121 on inflammation , angiogenesis , lymphangiogenesis and tumor progression . In this model , P05121 deficiency neither impaired keratinocyte hyperproliferation or tumor development nor affected the infiltration of inflammatory cells and development of angiogenic or lymphangiogenic vasculature . We are reporting evidence for concomitant lymphangiogenic and angiogenic switches independent to P05121 status . Taken together , these data indicate that P05121 is not rate limiting for neoplastic progression and vascularization during premalignant progression , or that there is a functional redundancy between P05121 and other tumor regulators , masking the effect of P05121 deficiency in this long - term model of multistage epithelial carcinogenesis .",
"Fitness effects of P00374 - TS mutations associated with pyrimethamine resistance in apicomplexan parasites . DB00205 resistance in the malaria parasite Plasmodium falciparum is characterized by specific point mutations in the dihydrofolate reductase ( P00374 ) domain of the bifunctional dihydrofolate reductase - thymidylate synthase ( P00374 - TS ) gene . We have previously explored the effect of these mutations by engineering homologous alleles of Toxoplasma gondii P00374 - TS , which can readily be expressed as recombinant protein for enzymatic studies , or as allelic replacements in transgenic parasites . In order to directly assess the costs of pyrimethamine - resistance in vivo , we have carried out competition studies between mixtures of T . gondii tachyzoites harbouring wild - type or mutant P00374 - TS alleles , both in tissue culture and in mice . Arg59 + Asn108 mutants ( using the P . falciparum numbering system ) exhibit no significant fitness defects in vitro , but a fitness defect of 1 . 8 % per generation in mice . Arg59 + Ser223 mutants exhibit fitness defects of > 2 . 8 % per generation both in vitro and in vivo , which may explain why this highly pyrimethamine - resistant allele has not been observed in the field . It is important to note that long - term propagation of parasites in vitro or in vivo can produce adaptations affecting fitness by > 3 . 7 % per generation , necessitating careful attention to background in head - to - head competition studies . A sensitive PCR - based assay permits different growth rates to be assessed even in the absence of a drug resistance marker that can be scored by plaque assay .",
"DB00205 resistant Plasmodium falciparum : overproduction of dihydrofolate reductase by a gene duplication . The accumulation of [ 3H ] pyrimethamine by pyrimethamine - resistant ( Pyrr ) mutants of the Plasmodium falciparum strain FCR3 was examined by measuring the accumulation of drug in infected red blood cells . [ 3H ] DB00205 was stage specifically accumulated in trophozoites and schizont infected red blood cells . The mutant parasites accumulated drug as efficiently as FCR3 . DB00205 was associated with a high molecular weight protein that eluted from a Sephadex G200 column exactly as [ 3H ] fluorodeoxyuridinemonophosphate ( FdUMP ) labeled parasite dihydrofolate reductase - thymidylate synthetase ( P00374 - TS ) enzyme . These results suggested that the pyrimethamine resistance was not associated with decreased drug permeability of the membrane . P00374 - TS -[ 3H ] FdUMP enzyme complex of all the Pyrr mutants and FCR3 had a monomer of 70 kDa as measured by sodium dodecyl sulfate - polyacrylamide gel electrophoresis . One highly resistant mutant , FCR3 - D7 , exhibited a 5 - 10 fold higher uptake of pyrimethamine and a proportionately higher amount of P00374 - TS protein than FCR3 but only a normal level of P00374 activity . The genomic DNA of FCR3 - D7 was shown to contain at least twice as much P00374 - TS specific DNA than either FCR3 - P41226 , another Pyrr mutant , or FCR3 . Preliminary results suggested some of the P00374 - TS genetic material in FCR3 - D7 is associated with a gene duplication .",
"Development of 2 , 4 - diaminopyrimidines as antimalarials based on inhibition of the S108N and C59R + S108N mutants of dihydrofolate reductase from pyrimethamine - resistant Plasmodium falciparum . The reduced binding of pyrimethamine to Ser108Asn ( S108N ) mutants of parasite dihydrofolate reductase ( P00374 ) , which forms the basis of resistance of Plasmodium falciparum to pyrimethamine , is largely due to steric constraint imposed by the bulky side chain of N108 on Cl of the 5 - p - Cl - phenyl group . This and other S108 mutants with bulky side chains all showed reduced binding to pyrimethamine and cycloguanil . Less effect on binding to some bulky mutants was observed for trimethoprim , with greater flexibility for the 5 - substituent . S108N P00374 also binds poorly with other pyrimethamine derivatives with bulky groups in place of the p - Cl , and the binding was generally progressively poorer for the double ( C59R + S108N ) mutant . Removal of the p - Cl or replacement with m - Cl led to better binding with the mutant DHFRs . DB00205 analogues with unbranched hydrophobic 6 - substituents showed generally good binding with the mutant DHFRs . A number of compounds were identified with high affinities for both wild - type and mutant DHFRs , with very low to no affinity to human P00374 . Some of these compounds show good antimalarial activities against pyrimethamine - resistant P . falciparum containing the mutant DHFRs with low cytotoxicity to three mammalian cell lines .",
"Tyrosine phosphorylation of Shc proteins and formation of Shc / Grb2 complex correlate to the transformation of NIH3T3 cells mediated by the point - mutation activated neu . P98160 - gamma , ras - P20936 and Shc have been proposed to be in vivo substrates for the neu - encoded p185neu receptor tyrosine kinases . We compared the tyrosine phosphorylation levels of P98160 - gamma , ras - P20936 and Shc in two NIH3T3 derived cell lines , transformed B104 - 1 - 1 and non - transformed P00374 / Q9UBA6 cells in which point - mutation activated and normal rat neu genes were transfected and expressed , respectively . We found that tyrosine phosphorylation of Shc and formation of Shc / Grb2 complex were more significant in B104 - 1 - 1 cells than in P00374 / Q9UBA6 cells , while no obvious difference could be detected for the tyrosine phosphorylation levels of ras - P20936 and P98160 - gamma between these two cell lines . Furthermore , we observed that association with Shc was severely impaired by deletion of most of the major autophosphorylation sites of the point - mutated neu . The truncated neu product , however , fully retained its ability to transform NIH3T3 cells , induce Shc tyrosine phosphorylation and Shc / Grb2 complex formation . Our results suggest that tyrosine phosphorylation of Shc which allows formation of Shc / Grb2 complex may play an important role for cell transformation induced by the point mutation - activated neu , and that stable binding to mutant p185neu may not be necessary for Shc to mediate this signaling pathway .",
"Rational drug design approach for overcoming drug resistance : application to pyrimethamine resistance in malaria . DB00205 acts by selectively inhibiting malarial dihydrofolate reductase - thymidylate synthase ( P00374 - TS ) . Resistance in the most important human parasite , Plasmodium falciparum , initially results from an S108N mutation in the P00374 domain , with additional mutation ( most commonly C59R or N51I or both ) imparting much greater resistance . From a homology model of the 3 - D structure of P00374 - TS , rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance . Compared to pyrimethamine ( Ki 1 . 5 nM ) with purified recombinant P00374 fromP . falciparum , the Ki value of the m - methoxy analogue of pyrimethamine was 1 . 07 nM , but against the P00374 bearing the double mutation ( C59R + S108N ) , the Ki values for pyrimethamine and the m - methoxy analogue were 71 . 7 and 14 . 0 nM , respectively . The m - chloro analogue of pyrimethamine was a stronger inhibitor of both wild - type P00374 ( with Ki 0 . 30 nM ) and the doubly mutant ( C59R + S108N ) purified enzyme ( with Ki 2 . 40 nM ) . Growth of parasite cultures of P . falciparum in vitro was also strongly inhibited by these compounds with 50 % inhibition of growth occurring at 3 . 7 microM for the m - methoxy and 0 . 6 microM for the m - chloro compounds with the P04264 parasite line bearing the double mutation ( S108N + C59R ) , compared to 10 . 2 microM for pyrimethamine . These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P . berghei - infected mice .",
"Atrial natriuretic peptide binds to P01160 - Q96GN5 receptors in neuroblastoma cells or is degraded extracellularly at the DB00133 - DB00120 bond . P01160 - Q96GN5 receptors for atrial natriuretic peptide ( P01160 ) showed the following rank order of affinity in intact human neuroblastoma cells NB - OK - 1 : human P01160 -( 99 - 126 ) approximately human P01160 -( 102 - 126 ) approximately rat P01160 -( 99 - 126 ) ( P04264 17 - 32 pM ) > human P01160 -( 103 - 126 ) > porcine brain natriuretic peptide ( DB04899 ) . Analogues truncated at the C - terminal extremity or devoid of a disulphide bridge , such as rat P01160 -( 103 - 123 ) , rat C - P01160 -( 102 - 121 ) , rat P01160 -( 111 - 126 ) , rat P01160 -( 99 - 109 ) and rat [ desCys105 , Cys121 ] P01160 -( 104 - 126 ) and chicken P23582 , were not recognized . The occupancy of these high affinity P01160 - Q96GN5 receptors led to marked cyclic GMP accumulation in the presence of 3 - isobutyl 1 - methylxanthine . An ectoenzymic activity , partly shed in the incubation medium , provoked the stepwise release of DB00120 - DB00125 -[ 125I ] DB00135 , DB00125 -[ 125I ] DB00135 and [ 125I ] DB00135 from rat [ 125I ] P01160 -( 99 - 126 ) , at an optimal pH of 7 . 0 . Its inhibition by 1 , 10 - phenanthroline , DB00974 and bacitracin but not by thiorphan suggests the contribution of at least one neutral metalloendopeptidase , distinct from EC 3 . 4 . 24 . 11 , for which P01160 showed high affinity .",
"P02786 and P60709 as the best reference genes to quantify DB00013 P00747 Activator in breast cancer . BACKGROUND : Biomedical researchers have long looked for ways to diagnose and treat cancer patients at the early stages through biomarkers . Although conventional techniques are routinely applied in the detection of biomarkers , attitudes towards using Real - Time PCR techniques in detection of many biomarkers are increasing . Normalization of quantitative Real - Time PCR is necessary to validate non - biological alteration occurring during the steps of RNA quantification . Selection of variably expressed housekeeping genes ( HKs ) will affect the validity of the data . The aim of the present study was to identify uniformly expressed housekeeping genes in order to use in the breast cancer gene expression studies . DB00013 P00747 Activator was used as a gene of interest . FINDINGS : The expression of six HKs ( P02786 , P08236 , P04406 , P60709 , P00492 and P05388 ) was investigated using geNorm and NormFinder softwares in forty breast tumor , four normal and eight adjacent tissues . P05388 and P04406 revealed maximum M value , while P02786 demonstrated lowest M value . CONCLUSIONS : In the present study the most and the least stable genes were P02786 and P05388 respectively . P02786 and P60709 were verified as the best combination of two genes for breast cancer quantification . The result of this study shows that in each gene expression analysis HKs selection should be done based on experiment conditions .",
"Construction , expression and characterization of tissue - type plasminogen activator mutants . Three tissue - type plasminogen activator ( t - PA ) mutants were constructed by recombinant and site - directed mutagenesis techniques . They are del ( 296 - 302 ) with deletion of P05121 binding site , N117Q / N184Q with deglycosylation of P04264 and K2 domains , and their combination mutant designated as GGI . Then these three mutants were successfully transiently expressed in COS - 7 cells , and GGI was further stably expressed in CHO cells . The biological characterization of the expression products indicated that del ( 296 - 302 ) and GGI possessed the resistance to inhibition by P05121 . In addition , the specific activity of GGI was increased by about 46 % , the plasma half - life was prolonged by about one fold , while its affinity for fibrin was not affected .",
"Uptake , cytotoxicity and metabolism of m - azidopyrimethamine and related lipophilic antifolates in SV - P02533 human keratinocytes in vivo . The growth - inhibitory properties of a series of lipophilic diaminopyrimidine antifolates were evaluated in comparison with methotrexate ( MTX ) against SV - P02533 human keratinocytes in vitro under folate - dependent and folate - independent conditions . Under folate - dependent conditions metoprine ( DDMP ) proved more cytotoxic than MTX , despite the greater inhibitory activity of the latter compound against mammalian dihydrofolate reductase ( P00374 ) , possibly reflecting differences in cellular accumulation . The significantly lower activity of both compounds under folate - independent conditions indicated P00374 as the primary target . DB00205 ( Q9BRP8 ) , m - azidopyrimethamine ( MZP ) and m - aminopyrimethamine ( Q96HU1 ) , a metabolite of MZP , were approximately equiactive but less cytotoxic than MTX or DDMP . The unexpected activity of Q96HU1 , an inferior P00374 inhibitor , suggests differences in the mechanism of action or cellular transport of the drug , although the reduction of cytotoxicity observed under folate - independent conditions indicate folate metabolism as the cytotoxic locus . In contrast , the cytotoxicity of Q9BRP8 or MZP was not reduced under folate - independent conditions implying an alternative mechanism of action . The uptake of 2 -[ 14C ] pyrimethamine by SV - P02533 keratinocytes was rapid with steady - state intracellular concentrations being observed after approximately 100 min , partition of drug into the plasma membrane preceding redistribution and extensive accumulation within the particulate cell components . The previously reported NADPH - dependent metabolism of MZP to Q96HU1 by murine liver microsome preparations was not observed with SV - P02533 keratinocytes nor with murine skin homogenates in the present study .",
"High - level synthesis of recombinant murine endostatin in Chinese hamster ovary cells . Endostatin , a carboxy - terminal fragment of collagen XVIII , has been shown to act as an anti - angiogenic agent that specifically inhibits proliferation of endothelial cells and growth of various primary tumors . Here , we describe the expression by Chinese hamster ovary ( CHO ) cells of murine endostatin and of a tagged - fusion protein , ( his ) 6 - met - endostatin . A dicistronic mRNA expression vector was utilized in which endostatin cDNA was inserted upstream of the amplifiable marker gene , dihydrofolate reductase ( P00374 ) . After transfection of the expression vectors , stepwise increments in methotrexate levels in the culture medium were applied , promoting gene amplification and increasing expression levels of the proteins of interest . The expression level of secreted native endostatin was about 78 microg / mL while the one for secreted ( his ) 6 - met - endostatin was about 114 microg / mL , for the best expressing clones . Characterization of physico - chemical and immunological activities of the proteins was performed using SDS - PAGE and Western blotting . The biological activities of recombinant endostatins were tested with a cow pulmonary artery endothelial ( C - PAE ) cell proliferation assay . Both recombinant endostatin and ( his ) 6 - met - endostatin inhibited , in a dose - dependent fashion , growth of C - PAE cells stimulated by basic fibroblast growth factor ( P09038 ) .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK83___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"Transmitter neurochemistry of the efferent neuron system innervating the labyrinth . It is likely that several mechanisms contribute to the efferent control of cochlear and vestibular function . Different effects are probably mediated by different neuronal transmitters . In spite of a number of transmitter candidates , it is still widely assumed that the entire efferent system can be globally characterized as cholinergic . We attempted to label retrogradely identified efferent neurons in the brainstem with a monoclonal antibody against choline acetyltransferase ( P28329 ) , the acetylcholine ( ACh ) synthesizing enzyme . Only a portion of the vestibular efferents could thus be shown to be cholinergic in the rat . Medial cochlear efferents , terminating under outer hair cells , may also be cholinergic since they stain intensely for acetylcholine esterase ( P22303 ) after pre - treatment with the P22303 inhibitor diisopropylfluorophosphate ( ___MASK84___ ) . The lateral cochlear efferents terminating under inner hair cells , as well as more than half of the vestibular efferent neuron population , reacted negatively with either method designed to identify cholinergic neurons . Half of the lateral olivo - cochlear neuron population filled retrogradely with tritiated gamma - amino butyric acid [ ( 3H ] - GABA ) . These cells were similar in size and distribution to neurons staining for the GABA synthesizing enzyme glutamic acid decarboxylase ( Q99259 ) . Retrograde transport of [ 3H ] - aspartate from the inner ear to the brainstem was seen in half of the lateral olivocochlear population , as well as in part of the efferent vestibular population in group E and in the caudal pontine reticular nucleus ( P16435 ) . Since various peptides have also been located in efferent neurons , this system is chemically diversified . Several distinct mechanisms of efferent control with presumably differing functions must , therefore , exist .",
"Genome comparison of progressively drug resistant Plasmodium falciparum lines derived from drug sensitive clone . Chloroquine has been the mainstay of malaria chemotherapy for the past five decades , but resistance is now widespread . DB00205 or proguanil form an important component of some alternate drug combinations being used for treatment of uncomplicated Plasmodium falciparum infections in areas of chloroquine resistance . Both pyrimethamine and proguanil are dihydrofolate reductase ( P00374 ) inhibitors , the proguanil acting primarily through its major metabolite cycloguanil . Resistance to these drugs arises due to specific point mutations in the dhfr gene . Cross resistance between cycloguanil and pyrimethamine is not absolute . It is , therefore , important to investigate mutation rates in P . falciparum for pyrimethamine and proguanil so that P00374 inhibitor with less mutation rate is favored in drug combinations . Hence , we have compared mutation rates in P . falciparum genome for pyrimethamine and cycloguanil . Using erythrocytic stages of P . falciparum cultures , progressively drug resistant lines were selected in vitro and comparing their RFLP profile with a repeat sequence . Our finding suggests that pyrimethamine has higher mutation rate compared to cycloguanil . It enhances the degree of genomic polymorphism leading to diversity of natural parasite population which in turn is predisposes the parasites for faster selection of resistance to some other antimalarial drugs .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK34___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Novel biologically active bibenzyls from Bauhinia saccocalyx Pierre . Four new bibenzyls , bauhinols A - D ( 1 - 4 ) , together with the two known bibenzyls 5 and 6 , were isolated from the roots of Bauhinia saccocalyx , and their structures were elucidated by analyses of spectroscopic data . Bauhinol A ( 1 ) exhibits significant cytotoxicity towards NCI - H187 ( small - cell lung cancer ) , BC ( breast cancer ) , and KB ( oral - cavity cancer ) cell lines , with IC50 values of 2 . 7 - 4 . 5 microg / ml . Bauhinol B ( 2 ) is cytotoxic against NCI - H187 ( IC50 = 1 . 1 microg / ml ) and BC ( IC50 = 9 . 7 microg / ml ) cell lines , but inactive toward the KB cell line ( at 20 microg / ml ) . Compound 2 also is mildly antifungal towards Candia albicans ( IC50 = 28 . 9 microg / ml ) . Bibenzyl 6 is active against NCI - H187 ( IC50 = 14 . 1 microg / ml ) and BC ( IC50 = 4 . 0 microg / ml ) cells , but inactive ( at 20 microg / ml ) toward the KB cell line . Compounds 1 , 2 , and 6 show mild antimycobacterial activities , with MIC values of 25 - 50 microg / ml , but are inactive at 20 microg / ml against the P04264 malarial parasite strain ( Plasmodium falciparum ) . While bauhinol A ( 1 ) is inactive against cyclooxygenase 1 ( P23219 ) and cyclooxygenase 2 ( P35354 ) , compounds 2 and 6 inhibit both P23219 and P35354 , with IC50 values comparable to those of the standard drug , aspirin ( Table 3 ) .",
"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK57___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .",
"Discovery and structure - activity relationship of ( 1R ) - 8 - chloro - 2 , 3 , 4 , 5 - tetrahydro - 1 - methyl - 1H - 3 - benzazepine ( ___MASK61___ ) , a selective serotonin P28335 receptor agonist for the treatment of obesity . The synthesis and SAR of a novel 3 - benzazepine series of P28335 agonists is described . Compound 7d ( lorcaserin , APD356 ) was identified as one of the more potent and selective compounds in vitro ( pEC50 values in functional assays measuring [( 3 ) H ] phosphoinositol turnover : P28335 = 8 . 1 ; 5 - Q13049 = 6 . 8 ; P41595 = 6 . 1 ) and was potent in an acute in vivo rat food intake model upon oral administration ( ED50 at 6 h = 18 mg / kg ) . ___MASK61___ was further characterized in a single - dose pharmacokinetic study in rat ( t1 / 2 = 3 . 7 h ; F = 86 % ) and a 28 - day model of weight gain in growing Sprague - Dawley rat ( 8 . 5 % decrease in weight gain observed at 36 mg / kg b . i . d . ) . ___MASK61___ was selected for further evaluation in clinical trials for the treatment of obesity .",
"Clinical trials in thrombolytic therapy , Part 2 : The open - artery hypothesis and RAPID - 1 and RAPID - 2 . The open - artery hypothesis as supported by thrombolytic study results is discussed . The open - artery hypothesis states that survival after acute myocardial infarction ( AMI ) is maximized by achieving early and sustained patency of the infarct - related artery . However , two large multicenter trials did not detect any difference in mortality between patients given alteplase and patients given streptokinase , despite previous evidence that alteplase led to earlier recanalization of infarct - related arteries . The Global Utilization of DB00086 and Tissue P00747 Activator for Occluded Coronary Arteries ( GUSTO - 1 ) trial suggested that early and complete patency is essential for short - term survival after AMI . Subsequent observations indicated that an open infarct - related artery at the time of hospital discharge is associated with improved long - term survival . In the ___MASK34___ Angiographic Phase II International Dose - Finding ( RAPID - 1 ) trial , complete patency was more frequent in patients who received a double - bolus regimen of reteplase than in patients who received standard - dose alteplase . Similar results were obtained in the ___MASK34___ versus DB00009 Patency Investigation during Myocardial Infarction ( RAPID - 2 ) trial , which compared the same double - bolus reteplase regimen with an accelerated regimen of alteplase . In both RAPID studies , mortality was lower and other outcomes were more favorable in reteplase recipients . ___MASK34___ seems more likely to produce normal blood flow soon after AMI than either standard - dose or accelerated alteplase and may be associated with a lower mortality rate . This lends further support to the open - artery hypothesis .",
"DB00205 resistant mutations in Plasmodium falciparum . Three mutations in Plasmodium falciparum yielding increased resistance to pyrimethamine were obtained following treatment with chemical mutagens and selection in presence of pyrimethamine . From parasite clone TM4 / 8 . 2 a mutant , TM4 / 8 . 2 / 4 . 1 , was produced which raised pyrimethamine resistance about 500 times and was found to involve an amino acid change in the P00374 - TS enzyme molecule from Ser108 to Asn108 . A clone of another isolate , P02786 / 94 , yielded a mutant , P02786 / 94 / 300 . 300 , raising pyrimethamine resistance about 10 times and involving an amino acid change from Ile164 to Met164 . However , another mutant from P02786 / 94 , P02786 / 94 / M1 - 1 ( b3 ) , although it raised the pyrimethamine resistance 100 times , did not involve any changes in the coding sequence of the P00374 - TS gene , but resulted in the production of about twice as much P00374 - TS enzyme as the original clone P02786 / 94 . No amplification of the P00374 - TS gene was detected . It is concluded that changes in pyrimethamine resistance of malaria parasites may arise in at least 2 ways : ( 1 ) by structural changes in the P00374 domain of the P00374 - TS gene ( as previously found by other workers ) ; ( 2 ) by other changes , possibly affecting the expression of the P00374 - TS gene . The relative importance of these 2 mechanisms in causing resistance in wild populations of P . falciparum is discussed .",
"Crystal structure of dihydrofolate reductase from Plasmodium vivax : pyrimethamine displacement linked with mutation - induced resistance . DB00205 ( Pyr ) targets dihydrofolate reductase of Plasmodium vivax ( PvDHFR ) as well as other malarial parasites , but its use as antimalarial is hampered by the widespread high resistance . Comparison of the crystal structures of PvDHFR from wild - type and the Pyr - resistant ( SP21 , DB00133 - 58 --> DB00125 + DB00133 - 117 --> DB00174 ) strain as complexes with NADPH and Pyr or its analog lacking p - Cl ( Pyr20 ) clearly shows that the steric conflict arising from the side chain of DB00174 - 117 in the mutant enzyme , accompanied by the loss of binding to DB00133 - 120 , is mainly responsible for the reduction in binding of Pyr . Pyr20 still effectively inhibits both the wild - type and SP21 proteins , and the x - ray structures of these complexes show how Pyr20 fits into both active sites without steric strain . These structural insights suggest a general approach for developing new generations of antimalarial P00374 inhibitors that , by only occupying substrate space of the active site , would retain binding affinity with the mutant enzymes .",
"The transcriptional coactivator DRIP / mediator complex is involved in vitamin D receptor function and regulates keratinocyte proliferation and differentiation . Mediator is a multisubunit coactivator complex that facilitates transcription of nuclear receptors . We investigated the role of the mediator complex as a coactivator for vitamin D receptor ( P11473 ) in keratinocytes . Using P11473 affinity beads , the vitamin D receptor interacting protein ( DRIP ) / mediator complex was purified from primary keratinocytes , and its subunit composition was determined by mass spectrometry . The complex included core subunits , such as Q15648 / MED1 ( MED1 ) , that directly binds to P11473 . Additional subunits were identified that are components of the RNA polymerase II complex . The functions of different mediator components were investigated by silencing its subunits . The core subunit MED1 facilitates P11473 activity and regulating keratinocyte proliferation and differentiation . A newly described subunit Q13503 also has a role in promoting keratinocyte proliferation and differentiation , whereas Q9BTT4 has an inhibitory role . Blocking MED1 / Q13503 expression caused hyperproliferation of keratinocytes , accompanied by increases in mRNA expression of the cell cycle regulator cyclin D1 and / or glioma - associated oncogene homolog . Blocking MED1 or Q13503 expression also resulted in defects in calcium - induced keratinocyte differentiation , as indicated by decreased expression of differentiation markers and decreased translocation of P12830 to the membrane . These results show that keratinocytes use the transcriptional coactivator mediator to regulate P11473 functions and control keratinocyte proliferation and differentiation .",
"[ Postoperative pulmonary embolism ] . Post - operative thrombo - embolic disease remains a frequent occurrence in spite of advances in their prophylaxis . Evaluation of 60 case - reports of this disease which often includes peripheral manifestations and always pulmonary manifestations , enables to specify the role of the procedure itself ( mostly orthopaedic surgery 60 % ) , pelvic surgery 20 % , the chronology of events ( possibility of early embolism between D1 and D3 and usual occurrence of manifestations between P41226 and D18 , and the importance of the background , whether investigated or not : deficiencies in anti - thrombin III , protein C and S : 4 cases . The diagnosis is based on clinical signs ( non - specific ) and the laboratory tests , especially scintigraphy ( screening ) and angiography , absolutely necessary for the diagnosis and evaluation of the amputation coefficient ( Miller index ) . With a diagnosis of pulmonary embolism , it is always necessary to look for a proximal venous thrombosis . The treatment , calls for heparin ( quite seldom ) , thrombolytics ( DB00013 , P00747 in our experience ) , the indication of which must take into consideration the delays and the nature of the previous procedure , and finally surgery ( massive forms where thrombolytics are contraindicated ) . The thrombo - embolic manifestations with thrombogenic thrombopenia secondary to heparin are quite frequent , in a surgical environment ( 10 cases ) and difficult to treat .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"Prevalence of the dihydrofolate reductase DB00174 - 108 mutation as the basis for pyrimethamine - resistant falciparum malaria in the Brazilian Amazon . DB00205 resistance in cultivated laboratory isolates of Plasmodium falciparum is linked to the dihydrofolate reductase mutation DB00174 - 108 , a mutation that acts by interrupting drug binding within the active site of the enzyme . To determine the prevalence of this mutation in endemic regions harboring pyrimethamine - resistant malaria , we used a mutation - specific polymerase chain reaction assay to survey P . falciparum strains from a wide section of the Brazilian Amazon . Mutations were identified directly from blood samples without intervening steps of in vitro cultivation . Of 42 samples collected from four states in Brazil , 38 ( 90 % ) contained the DB00174 - 108 codon AAC that confers pyrimethamine resistance , four samples contained only the wild - type DB00133 - 108 codon AGC , and none contained the DB00156 - 108 codon ACC found in cycloguanil - resistant pyrimethamine - sensitive strains . These findings indicate that a very high incidence of the DB00174 - 108 P00374 mutation is responsible for pyrimethamine resistance in the Amazon , and they are consistent with recent failure rates reported for Fansidar ( pyrimethamine - sulfadoxine ) . We suggest that limited use of proguanil be evaluated as an alternative to pyrimethamine .",
"Exposure to an organophosphate ( ___MASK84___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK84___ ( ___MASK84___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK84___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK84___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK84___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .",
"Comparison of the effects of cytoprotective drugs on human plasma adrenocorticotropic hormone and cortisol levels with continual stress exposure . Cetraxate hydrochloride ( cetraxate ) , ecabet sodium ( ecabet ) , and sulpiride , which are cytoprotective drugs , have been used to treat peptic ulcers and acute or chronic gastritis . They are reported to improve mucosal blood flow in the stomach . One of the most important factors believed to cause gastric ulcers is mental and / or physiological stress . When people feel stress , the hypothalamo - pituitary - adrenal ( Q9Y251 ) axis is activated . Therefore , corticotropin - releasing hormone ( P06850 ) , adrenocorticotropic hormone ( ___MASK11___ ) , and cortisol can be indicators of stress . We examined the effects of cetraxate , ecabet and sulpiride on the plasma levels of ___MASK11___ and cortisol under stress conditions by repetitive blood sampling . Venous blood samples were taken before and 20 - 240 min after a single administration of the drugs or a placebo . A single dose of ecabet caused significant suppression of increases in plasma ___MASK11___ - like immunoreactive substance ( IS ) levels at 90 to 120 min and cortisol levels at 240 min , compared with the response to placebo . DB00391 only suppressed increases in plasma cortisol levels at 180 to 240 min , compared with the response to placebo . A single dose of cetraxate had no effect on plasma ___MASK11___ - IS and cortisol levels . Ecabet may have a modulatory effect on the Q9Y251 axis while sulpiride may have a partial modulatory effect on the Q9Y251 axis . These effects might be beneficial in stress - related disease .",
"Changes in enzyme activity and expression of P00374 of Toxoplasma gondii by antifolates . The responses to antifolates of Toxoplasma gondii were investigated by measuring the dihydrofolate reductase ( P00374 ) activity , quantity of P00374 mRNA , and single - strand conformational polymorphism ( SSCP ) pattern . DB00205 ( Q9BRP8 ) and methotrexate ( MTX ) were tested as antifolates . When T . gondii was treated with Q9BRP8 , the viability was decreased by the increasing concentration of Q9BRP8 , P00374 activity tended to increase as the passage proceeded , and the quantity of mRNA expressed was also increased according to passages . The viability of T . gondii was decreased by the increasing concentration of MTX , but it was maintained over 40 % up to 100 microM MTX . P00374 activity was 77 . 4 % in the 1st passage ( 1 microM ) . 82 . 2 % in the 4th passage ( 10 microM ) , and 141 . 3 % in the 7th passage ( 100 microM ) . But no changes were detected in SSCP pattern of T . gondii exposed to Q9BRP8 and MTX , both . These results suggested that the response of T . gondii to Q9BRP8 was regulated by transcriptional level and that , in MTX , the viability of T . gondii was derived from increasing P00374 activity .",
"DB00205 and WR99210 exert opposing selection on dihydrofolate reductase from Plasmodium vivax . Plasmodium vivax is a major public health problem in Asia and South and Central America where it is most prevalent . Until very recently , the parasite has been effectively treated with chloroquine , but resistance to this drug has now been reported in several areas . Affordable alternative treatments for vivax malaria are urgently needed . DB00205 - sulfadoxine is an inhibitor of dihydrofolate reductase ( P00374 ) that has been widely used to treat chloroquine - resistant Plasmodium falciparum malaria . P00374 inhibitors have not been considered for treatment of vivax malaria , because initial trials showed poor efficacy against P . vivax . P . vivax can not be grown in culture ; the reason for its resistance to P00374 inhibitors is unknown . We show that , like P . falciparum , point mutations in the dhfr gene can cause resistance to pyrimethamine in P . vivax . WR99210 is a novel inhibitor of P00374 , effective even against the most pyrimethamine - resistant P . falciparum strains . We have found that it is also an extremely effective inhibitor of the P . vivax P00374 , and mutations that confer high - level resistance to pyrimethamine render the P . vivax enzyme exquisitely sensitive to WR99210 . These data suggest that pyrimethamine and WR99210 would exert opposing selective forces on the P . vivax population . If used in combination , these two drugs could greatly slow the selection of parasites resistant to both drugs . If that is the case , this novel class of P00374 inhibitors could provide effective and affordable treatment for chloroquine - and pyrimethamine - resistant vivax and falciparum malaria for many years to come .",
"Roles of glutamatergic and serotonergic mechanisms in reflex control of the external urethral sphincter in urethane - anesthetized female rats . This study was conducted to examine reflex mechanisms that mediate urinary bladder and external urethral sphincter ( EUS ) coordination in urethane - anesthetized female Sprague - Dawley rats . We investigated the properties of EUS reflexes elicited by electrical stimulation of pelvic nerve afferent axons ( pelvic - EUS reflex ) . The changes in the reflexes induced by bladder distension and administration of agonists or antagonists for glutamatergic or serotonergic receptors were examined . The reflexes consisted of an early response ( ER , 18 - to 22 - ms latency ) and a late , long - duration ( > 100 - ms latency ) response ( LR ) , which consisted of bursts of activity at 20 - to 160 - ms interburst intervals . In a few experiments , a reflex with an intermediate ( 40 - to 70 - ms ) latency was also identified . With the bladder empty , the ER , but not the LR , was detected in the majority of experiments . The LR was markedly enhanced when the bladder was distended . The ER remained , but the LR was abolished , after spinal cord transection at T8 - P02786 . The ER and LR were significantly decreased 75 and 35 % , respectively , by the N - methyl - D - aspartate receptor antagonist MK - 801 ( 0 . 3 mg / kg iv ) , but only decreased 18 and 14 % , respectively , by the alpha - amino - 5 - methylisoxazole - 4 - propionate receptor antagonist LY - 215490 ( 3 mg / kg iv ) . The serotonin ( P08908 ) receptor agonist 8 - hydroxy - 2 -( di - n - propylamino )- tetralin ( 1 mg / kg iv ) enhanced spontaneous EUS activity and the pelvic - EUS reflex . WAY - 100635 ( 0 . 1 - 1 mg / kg iv ) , a P08908 antagonist , reversed the effect of 8 - hydroxy - 2 -( di - n - propylamino )- tetralin and suppressed EUS activity and the pelvic - EUS reflex . These results indicate that glutamatergic and serotonergic mechanisms are important in the reflex pathways underlying bladder - sphincter coordination in rats .",
"Novel mechanism of steroid action in skin through glucocorticoid receptor monomers . Glucocorticoids ( GCs ) , important regulators of epidermal growth , differentiation , and homeostasis , are used extensively in the treatment of skin diseases . Using keratin gene expression as a paradigm of epidermal physiology and pathology , we have developed a model system to study the molecular mechanism of GCs action in skin . Here we describe a novel mechanism of suppression of transcription by the glucocorticoid receptor ( GR ) that represents an example of customizing a device for transcriptional regulation to target a specific group of genes within the target tissue , in our case , epidermis . We have shown that GCs repress the expression of the basal - cell - specific keratins P13647 and P02533 and disease - associated keratins K6 , P08779 , and Q04695 but not the differentiation - specific keratins K3 and P13645 or the simple epithelium - specific keratins K8 , P05783 , and P08727 . We have identified the negative recognition elements ( nGREs ) in all five regulated keratin gene promoters . Detailed footprinting revealed that the function of nGREs is to instruct the GR to bind as four monomers . Furthermore , using cotransfection and antisense technology we have found that , unlike Q15788 and Q9Y3R0 , which are not involved in the GR complex that suppresses keratin genes , histone acetyltransferase and CBP are . In addition , we have found that GR , independently from GREs , blocks the induction of keratin gene expression by P05412 . We conclude that GR suppresses keratin gene expression through two independent mechanisms : directly , through interactions of keratin nGREs with four GR monomers , as well as indirectly , by blocking the P05412 induction of keratin gene expression .",
"In vitro susceptibility of various genotypic strains of Toxoplasma gondii to pyrimethamine , sulfadiazine , and atovaquone . Sulfadiazine , pyrimethamine , and atovaquone are widely used for the treatment of severe toxoplasmosis . Their in vitro activities have been almost exclusively demonstrated on laboratory strains belonging to genotype I . We determined the in vitro activities of these drugs against 17 strains of Toxoplasma gondii belonging to various genotypes and examined the correlations among 50 % inhibitory concentrations ( IC50s ) , growth kinetics , strain genotypes , and mutations on drug target genes . Growth kinetics were determined in THP - 1 cell cultures using real - time PCR . IC50s were determined in MRC - 5 cell cultures using a T . gondii - specific enzyme - linked immunosorbent assay performed on cultures . Mutations in dihydrofolate reductase ( P00374 ) , dihydropteroate synthase ( P49366 ) , and cytochrome b genes were determined by sequencing . DB00205 IC50s ranged between 0 . 07 and 0 . 39 mg / liter , with no correlation with the strain genotype but a significant correlation with growth kinetics . Several mutations found on the P00374 gene were not linked to lower susceptibility . DB01117 IC50s were in a narrow range of concentrations ( mean , 0 . 06 +/- 0 . 02 mg / liter ) ; no mutation was found on the cytochrome b gene . IC50s for sulfadiazine ranged between 3 and 18 . 9 mg / liter for 13 strains and were > 50 mg / liter for three strains . High IC50s were not correlated to strain genotypes or growth kinetics . A new mutation of the P49366 gene was demonstrated in one of these strains . In conclusion , we found variability in the susceptibilities of T . gondii strains to pyrimethamine and atovaquone , with no evidence of drug resistance . A higher variability was found for sulfadiazine , with a possible resistance of three strains . No relationship was found between drug susceptibility and strain genotype .",
"Pituitary - specific and hormonally regulated gene expression directed by the rat proopiomelanocortin promoter in transgenic mice . All aspects of P01189 biosynthesis exhibit tissue - specific regulation . The single copy gene is highly expressed in anterior lobe ( AL ) corticotrophs and intermediate lobe ( IL ) melanotrophs of the pituitary gland and in the arcuate nucleus of the hypothalamus . P01189 gene transcription in corticotrophs is induced by hypothalamic P06850 and vasopressin and inhibited by adrenal glucocorticoids , while in melanotrophs it is predominantly regulated by beta - adrenergic neural input and dopamine . To identify the rat P01189 ( rPOMC ) gene sequences necessary and sufficient to target expression and hormonal regulation in corticotrophs and melanotrophs , we generated 13 transgenic mice carrying rPOMC fusion genes . The genes consisted of 706 or 480 basepairs of rPOMC 5 ' flanking sequences ligated to either the E . coli LacZ gene encoding beta - galactosidase or the P04264 mutant of the SV40 large T - antigen gene . Overall , half of the transgenic lines had reporter gene expression in their AL and IL in a pattern indistinguishable from ___MASK11___ immunohistochemistry . In three of these lines , beta - galactosidase or P04264 T - antigen was localized by double immunofluorescence exclusively to ___MASK11___ - positive corticotrophs and melanotrophs . Transcriptional regulation of the rPOMC - LacZ fusion gene in response to hormonal manipulation was quantified by a fluorescence assay for beta - galactosidase enzyme activity in pituitary extracts . There was a 15 - fold increase in AL enzyme activity after adrenalectomy and a 3 - fold increase in IL activity after haloperidol treatment . X - gal histochemistry of pituitaries from hormonally treated mice confirmed the cellular specificity of these effects . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain . The perinatal brain requires a tightly regulated iron transport system . DB01592 regulatory proteins ( IRPs ) 1 and 2 are cytosolic proteins that regulate the stability of mRNA for the two major cellular iron transporters , transferrin receptor ( P02786 ) and divalent metal transporter - 1 ( P49281 ) . We studied the localization of IRPs , their change in expression during perinatal development , and their relationship to P02786 and P49281 in rat brain between postnatal days ( P01160 ) 5 and 15 . Twelve - micron frozen coronal sections of fixed brain tissue were obtained from iron - sufficient Sprague - Dawley rat pups on P01160 5 , 10 , and 15 , and were visualized at 20 to 1 , 000x light microscopy for diaminobenzidine activity after incubation with specific primary P09544 - 1 , P09544 - 2 , P49281 , and P02786 antibodies and a universal biotinylated secondary and tertiary antibody system . P09544 and transport protein expression increased in parallel over time . P21399 , P48200 , and P49281 were partially expressed in the choroid plexus epithelial cells at P01160 5 and 10 , and fully expressed at P01160 15 . The cerebral blood vessels and ependymal cells strongly expressed P21399 , P48200 , and P49281 as early as P01160 5 . Substantive P02786 staining was not seen in the choroid plexus or ependyma until P01160 15 . Glial and neuronal expression of P21399 , P48200 , P49281 , and P02786 in cortex , hippocampal subareas and striatum increased over time , but showed variability in cell number and intensity of expression based on brain region , cell type , and age . These developmental changes in P09544 and transporter expression suggest potentially different time periods of brain structure vulnerability to iron deficiency or iron overload .",
"DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . DB00563 ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .",
"5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .",
"P00374 hysteresis and its effect of inhibitor binding analyses . Escherichia coli dihydrofolate reductase was shown to follow slow transient kinetics ( hysteresis ) . Nonlinear reaction velocities were detected during the enzyme assay and required 10 - 15 min to reach a steady - state rate . The degree of hysteresis was influenced by the enzyme concentration and the order of substrate addition . Incubation of the enzyme with NADPH before addition of dihydrofolate resulted in slow initial velocities that increased up to 2 - fold during the course of the assay . Increasing the enzyme concentration from 0 . 2 to 1 nM resulted in diminished hysteresis . NADPH - initiated reactions were linear at all enzyme concentrations tested . Certain drugs had profound effects on hysteresis . DB00205 practically eliminated the hysteresis of dihydrofolate - started reactions , whereas trimethoprime augmented the non - linearities in the sense that hysteresis was detected in both enzyme - and NADPH - started reactions . The shape of these reaction tracings makes trimethoprim is not a slow - binding inhibitor when assayed under conditions that eliminate hysteresis . Contrary to this , sulfamethoxazole did not affect hysteresis or augment inhibition of the enzyme by trimethoprim . Sulfamethoxazole alone ( at 6 mM ) did not inhibit the hysteresis and allow reliable determinations of Ki values of both weak and tight binding inhibitors . For example , Ki values for pyrimethamine , trimethoprim , and methotrexate were found to be 214 nM , 1 . 3 nM , and 0 . 021 nM , respectively .",
"In vitro selection of Plasmodium falciparum lines resistant to dihydrofolate - reductase inhibitors and cross resistance studies . A cloned Plasmodium falciparum line was subjected to in vitro drug pressure , by employing a relapse protocol , to select progressively resistant falciparum lines to pyrimethamine and cycloguanil , the two dihydrofolate - reductase ( P00374 ) inhibitor antimalarial drugs . The falciparum lines resistant to pyrimethamine were selected much faster than those resistant to cycloguanil . In 348 days of selection / cultivation , there was 2 , 400 - fold increase in IC50 value to pyrimethamine , whereas only about 75 - fold decrease in sensitivity to cycloguanil was registered in 351 days . DB00205 - resistant parasites acquired a degree of cross resistance to cycloguanil and methotrexate , another P00374 inhibitor , but did not show any cross resistance to some other groups of antimalarial drugs . The highly pyrimethamine - resistant line was not predisposed for faster selection to cycloguanil resistance . Resistance acquired to pyrimethamine was stable . The series of resistant lines obtained form a good material to study the ' evolution ' of resistance more meaningfully at molecular level .",
"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK61___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK61___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK61___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK61___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .",
"Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum . DB00205 and cycloguanil are competitive inhibitors of the Plasmodium enzyme dihydrofolate reductase ( P00374 ) . They have been effective treatments for malaria , but rapid selection of populations of the parasite resistant to these drugs has compromised their effectiveness . Parasites resistant to either drug usually have point mutations in the dhfr gene , but the frequency of these mutations is unknown . To study drug resistance more effectively , we transferred the P00374 domain of the dhfr - thymidylate synthase gene from a drug - sensitive line of P . falciparum to a strain of the budding yeast , Saccharomyces cerevisiae , that lacks endogenous P00374 activity . Expression of the P . falciparum dhfr is controlled by the yeast dhfr 5 ' and 3 ' regulatory regions and the heterologous enzyme provided all of the functions of the yeast dhfr gene . These yeast were susceptible to pyrimethamine and cycloguanil at low concentrations that inhibit P . falciparum ( IC50 about 10 (- 8 ) and 10 (- 7 ) M , respectively ) . Yeast expressing constructs with dhfr alleles from pyrimethamine - resistant strains were resistant to both pyrimethamine and cycloguanil ( IC50 > 10 (- 6 ) M ) ; resistance of the yeast depended on the dhfr allele they expressed . The experimental drug WR99210 efficiently killed all three yeast strains ( IC50 about 10 (- 8 ) M ) but the pyrR strains showed collateral hypersensitivity to drug . The yeast transformants carrying the drug - sensitive allele can now be screened quickly and quantitatively to identify new drugs or combinations of drugs and determine which drugs select resistant parasites least efficiently . Such compounds would be excellent candidates for development of treatments with a longer life in clinical practice .",
"In - vitro activity of atovaquone , sulphamethoxazole and dapsone alone and combined with inhibitors of dihydrofolate reductase and macrolides against Pneumocystis carinii . The anti - Pneumocystis carinii activity of atovaquone , dapsone and sulphamethoxazole alone and combined with dihydrofolate reductase ( P00374 ) inhibitors and macrolides was investigated against five clinical isolates of P . carinii . The susceptibility tests were performed by inoculation of the organisms on to cell monolayer and parasite count after 72 h incubation at 37 degrees C . Culture plates were added to Dulbecco ' s modified Eagle ' s medium containing serial dilutions of atovaquone , dapsone and sulphamethoxazole alone or in combination with diaveridine , pyrimethamine , trimethoprim , azithromycin , clarithromycin and roxithromycin . DB01117 , dapsone and sulphamethoxazole were found to be effective at levels well below the concentrations that could be achieved clinically , while P00374 inhibitors were shown to combine effectively with dapsone and sulphamethoxazole . No synergy could be demonstrated between atovaquone and P00374 inhibitors or macrolides . A mild synergic effect was noted when macrolides were combined with dapsone and sulphamethoxazole . DB00205 ( 0 . 5 mg / L ) combined with dapsone and trimethoprim ( 0 . 5 mg / L ) combined with sulphamethoxazole exerted the strongest inhibitory effect .",
"Effects of retroviral - mediated P08183 expression on hematopoietic stem cell self - renewal and differentiation in culture . Ex vivo expansion of hematopoietic stem cells would be useful for bone marrow transplantation and gene therapy applications . Toward this goal , we have investigated whether retrovirally - transduced murine stem cells could be expanded in culture with hematopoietic cytokines . Bone marrow cells were transduced with retroviral vectors expressing either the human multidrug resistance 1 gene ( HaMDR1 ) , a variant of human dihydrofolate reductase ( HaDHFR ) , or both P08183 and P00374 in an internal ribosomal entry site ( IRES ) - containing bicistronic vector ( HaMID ) . Cells were then expanded for 15 days in cultures stimulated with interleukin ( IL ) - 3 , P05231 , and stem cell factor . When very low marrow volumes were injected into lethally irradiated recipient mice , long - term reconstitution with 100 % donor cells was seen in all mice injected with HaMDR1 - or HaMID - transduced cells . By contrast , engraftment with HaDHFR - or mock - transduced cells ranged from partial to undetectable despite injection of significantly larger marrow volumes . In addition , mice transplanted with expanded HaMDR1 - or HaMID - transduced stem cells developed a myeloproliferative disorder that was characterized by an increase in abnormal peripheral blood leukocytes . These results show that P08183 - transduced stem cells can be expanded in vitro with hematopoietic cytokines , but indicate that an increased stem cell division frequency can lead to stem cell damage .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK42___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK42___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK42___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy ."
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___MASK57___
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MH_train_404
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interacts_with DB08916?
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[
"Strategies for overcoming resistance to P00533 family tyrosine kinase inhibitors . The first - generation epidermal growth factor receptor tyrosine kinase inhibitors erlotinib and gefitinib have been incorporated into treatment paradigms for patients with advanced non - small cell lung cancer . These agents are particularly effective in a subset of patients whose tumors harbor activating epidermal growth factor receptor mutations . However , most patients do not respond to these tyrosine kinase inhibitors , and those who do will eventually acquire resistance that typically results from a secondary epidermal growth factor receptor mutation ( e . g . , T790M ) , mesenchymal - epithelial transition factor amplification , or activation of other signaling pathways . For patients whose tumors have wild - type epidermal growth factor receptor , there are several known mechanisms of initial resistance ( e . g . , Kirsten rat sarcoma viral oncogene homolog mutations ) but these do not account for all cases , suggesting that unknown mechanisms also contribute . To potentially overcome the issue of resistance , next - generation tyrosine kinase inhibitors are being developed , which irreversibly block multiple epidermal growth factor receptor family members ( e . g . , afatinib [ DB08916 ] and PF - 00299804 ) and / or vascular endothelial growth factor receptor pathways ( e . g . , BMS - 690514 and DB05007 ) . In addition , drugs that block parallel signaling pathways or signaling molecules downstream of the epidermal growth factor receptor , such as the insulin - like growth factor - 1 receptor and the mammalian target of rapamycin , are undergoing clinical evaluation . As drug resistance appears to be pleomorphic , combinations of drugs or drugs with multiple targets may be more effective in circumventing resistance .",
"Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .",
"DB08916 , erlotinib and gefitinib in the first - line therapy of P00533 mutation - positive lung adenocarcinoma : a review . Non - small cell lung cancer ( NSCLC ) consists of several histomorphologically defined phenotypes that display an enormous genetic variability . In recent years , epidermal growth factor receptor ( P00533 ) mutation - positive lung adenocarcinoma has emerged as a unique subset of NSCLC in terms of etiopathogenesis and tumor biology . Since the introduction of the reversible P00533 tyrosine kinase inhibitors ( TKIs ) erlotinib and gefitinib , patients with metastatic P00533 mutation - positive lung cancer can be offered a therapeutic alternative that has proven its superiority over standard platinum - based chemotherapy . However , primary or acquired resistance limits the therapeutic success of these targeted agents . Irreversible inhibitors targeting all ErbB family receptor tyrosine kinases , such as afatinib and dacomitinib , have been developed to confer sustained disease control in ErbB - dependent cancers . The large LUX - Lung 3 phase III trial recently reported afatinib to be clearly superior over the most effective platinum doublet in patients with P00533 mutation - positive lung cancer . To fully exploit the clinical activity of afatinib , proactive management of its gastrointestinal and dermatologic toxicities is advised .",
"DB08916 for the treatment of advanced non - small - cell lung cancer . INTRODUCTION : The inhibition of the epidermal growth factor receptor ( P00533 ) through tyrosine kinase inhibitors ( TKIs ) represents an effective strategy for P00533 - mutated NSCLC . DB08916 is an irreversible erythroblastosis oncogene B ( ErbB ) family blocker , able to inhibit the kinase domains of P00533 , P04626 and Q15303 , and the transphosphorylation of ErbB3 that has recently been approved in the United States for the first - line treatment of P00533 - mutated NSCLC and in Europe and Japan for the treatment of P00533 - mutated TKI - naive patients . AREAS COVERED : The authors analyzed the pharmacology and the clinical activity of afatinib in NSCLC through a review of the literature . Trials exploring different settings have been reported , including LUX - Lung 3 and LUX - Lung 6 , where the drug achieved better outcomes in terms of response rate , progression - free survival and quality of life compared with chemotherapy . The main toxicities of afatinib are gastrointestinal and skin - related adverse events . EXPERT OPINION : DB08916 showed remarkable efficacy as a first - line treatment in the presence of common P00533 mutations . DB08916 showed some activity in NSCLC with acquired resistance to P00533 TKIs , although , currently , its efficacy after the failure of erlotinib or gefitinib has not been clearly stated . Direct clinical data comparing the activity and tolerability of different inhibitors are still needed .",
"Significance of interleukin - 6 signaling in the resistance of pharyngeal cancer to irradiation and the epidermal growth factor receptor inhibitor . PURPOSE : Tumor eradication by chemoradiotherapy for pharyngeal cancer has not been particularly successful . Targeting epithelial growth factor receptor ( P00533 ) could be a potential treatment strategy providing additional benefits , but only a subset of these tumors gives a clinically significant response to P00533 inhibitors . The aim has been to identify the role of interleukin - 6 ( P05231 ) signaling and its predictive power in the treatment response of pharyngeal cancer . METHODS AND MATERIALS : Human pharyngeal cancer cell lines , including the hypopharyngeal cancer cell line FaDu and its derived cell line FaDu - C225 - R , were selected . Changes in tumor growth , response to treatment , and responsible signaling pathway were investigated in vitro . Furthermore , 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining , and correlations were made between levels of P05231 , P05231 receptor ( IL - 6R ) , p - AKT , and p - P40763 expression and the clinical outcome of patients . RESULTS : In vitro , either extrinsic P05231 stimulation of cancer cells or intrinsically activated P05231 signaling detected in FADu - C225 - R cells results in resistance to irradiation and P00533 inhibitor . Blocking P05231 signaling attenuated aggressive tumor behavior and sensitized the cells to treatments . The responsible mechanisms included decreased p - P40763 , less nuclear translocation of P00533 , and subsequently attenuated epithelial - mesenchymal transition . Regarding clinical data , staining of p - P40763 and P05231 was significantly linked with lower response rates to treatments and shorter survival in pharyngeal cancer patients . CONCLUSIONS : P05231 and p - P40763 may be significant predictors of pharyngeal carcinoma , and regulating P05231 signaling can be considered a promising therapeutic approach .",
"Next generation tyrosine kinase inhibitor ( TKI ) : afatinib . DB08916 is a recently introduced new tyrosine kinase inhibitor , approved by the USFDA on July 12 , 2013 . DB08916 is marketed under the trade name Gilotrif and developed by Boehringer Ingelheim GmbH . It is indicated for the first - line treatment of patients with metastatic non - small cell lung cancer ( NSCLC ) carrying P00533 exon 19 deletions or exon 21 ( L858R ) mutations . DB08916 is a covalent , irreversible inhibitor of epidermal growth factor receptor ( P00533 ) , human epidermal growth factor receptor 2 ( P04626 ) and Q15303 . Chemically afatinib is a 4 - anilinoquinazoline derivative , having an acrylamide warhead . Gilotrif is the formulation of DB08916 di - meleate salt . Presently , afatinib has been approved in the USA , the European Union , Taiwan and Mexico . In this review , we have summarized the chemical characterization of afatinib , its synthesis , patent status , marketed formulation , available crystalline form and current clinical trials .",
"Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre - RT ) , at the fourth week of RT ( mid - RT ) , and 1 month after RT completion ( post - RT ) . Two serial punch biopsies were performed at pre - and mid - RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) - 2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre - RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid - RT ( P30518 ) was greater than 0 . 5 , seven ( 100 % , p = 0 . 0515 ) and five ( 71 . 4 % , p = 0 . 3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre - RT were associated with P30518 ( p = 0 . 0782 ) . For the mid - RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0 . 5 ( p = 0 . 2222 ) . CONCLUSION : The poor mid - RT tumor response was associated with the coexpression of P35354 and P00533 .",
"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK2___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .",
"P21554 cannabinoid receptor deficiency promotes cardiac remodeling induced by pressure overload in mice . BACKGROUND : The endocannabinoid system is known to play a role in regulating myocardial contractility , but the influence of cannabinoid receptor 1 ( P21554 ) deficiency on chronic heart failure ( CHF ) remains unclear . In this study we attempted to investigate the effect of P21554 deficiency on CHF induced by pressure overload and the possible mechanisms involved . METHODS AND RESULTS : A CHF model was created by transverse aortic constriction ( TAC ) in both P21554 knockout mice and wild - type mice . P21554 knockout mice showed a marked increase of mortality due to CHF from 4 to 8 weeks after TAC ( p = 0 . 021 ) . Five weeks after TAC , in contrast to wild - type mice , P21554 knockout mice had a higher left ventricular ( LV ) end - diastolic pressure , lower rate of LV pressure change ( ± dp / dt max ) , lower LV contractility index , and a larger heart weight to body weight ratio and lung weight to body weight ratio compared with wild - type mice ( all p < 0 . 05 - 0 . 001 ) . Phosphorylation of the epidermal growth factor receptor ( P00533 ) and mitogen - activated protein kinases ( O75791 and P29323 ) was higher in P21554 knockout mice than that in wild - type mice . In cultured neonatal rat cardiomyocytes , a P21554 agonist reduced DB02527 production stimulated by isoproterenol or forskolin , and suppressed phosphorylation of the P00533 , O75791 , and P29323 , while the inhibitory effect of a P21554 agonist on P00533 phosphorylation was abrogated by P21554 knockdown . CONCLUSION : These findings indicate that cannabinoid receptor 1 inactivation promotes cardiac remodeling by enhancing the activity of the epidermal growth factor receptor and mitogen - activated protein kinases .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK51___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"DB08916 : first global approval . DB08916 , an irreversible inhibitor of the ErbB family of tyrosine kinases , is under development with Boehringer Ingelheim for the once - daily , oral treatment of cancer . DB08916 downregulates ErbB signalling by covalently binding to epidermal growth factor receptor ( P00533 ) , human epidermal growth factor receptor ( HER ) 2 and Q15303 , irreversibly inhibiting tyrosine kinase autophosphorylation . It also inhibits transphosphorylation of P21860 . Oral afatinib ( Gilotrif ™ ) has been approved in the US for the first - line treatment of patients with metastatic non - small - cell lung cancer ( NSCLC ) who have tumours with P00533 exon 19 deletions or exon 21 ( L858R ) substitution mutations as detected by a US FDA - approved test . DB08916 has also been approved in Taiwan for the first - line treatment of patients with P00533 mutation - positive NSCLC . In addition , the European Medicines Agency ' s Committee for Medicinal Products for Human Use has recommended the approval of afatinib ( Giotrif ® ) for the treatment of patients with locally advanced or metastatic NSCLC with activating P00533 mutations who are P00533 tyrosine kinase inhibitor naïve . DB08916 is also under regulatory review in Canada , Japan and other Asian countries . This article summarizes the milestones in the development of afatinib , leading to this first approval in patients with metastatic NSCLC .",
"Second - generation irreversible epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKIs ) : a better mousetrap ? A review of the clinical evidence . The discovery of activating epidermal growth factor receptor ( P00533 ) mutations in non - small cell lung cancer ( NSCLC ) in 2004 heralded the era of molecular targeted therapy in NSCLC . First - generation small molecule , reversible tyrosine kinase inhibitors ( TKIs ) of P00533 , gefitinib and erlotinib , had been approved for second - or third - line treatment of NSCLC prior to the knowledge of these mutations . However , resistance to gefitinib and erlotinib invariably develops after prolonged clinical use . Two second - generation irreversible P00533 TKIs , afatinib ( DB08916 ) and dacomitinib ( PF - 00299804 ) , that can potentially overcome the majority of these resistances are in late stage clinical development . Here I will review the clinical data of P00533 TKIs and discuss the appropriate future role of afatinib and dacomitinib in NSCLC : whether as replacement of erlotinib or gefitinib or only after erlotinib or gefitinib failure and whether different subgroups would benefit from different approaches .",
"DB08916 for Erlotinib Refractory Brain Metastases in a Patient with P00533 - Mutant Non - Small - Cell Lung Cancer : Can High - Affinity TKI Substitute for High - Dose TKI ?",
"Influences of apolipoprotein E polymorphism on the risk for breast cancer and P04626 / neu status in Taiwan . P02649 ( P02649 ) polymorphism plays an important role in lipid metabolism . Preliminary evidence suggests that P02649 genotype appears to be a risk factor for not only cardiovascular disease , but also Alzheimer ' s disease and cancer . We screened the P02649 genotype in 290 breast cancer patients and 232 non - cancer controls and determined the relationship between P02649 gene polymorphism and breast cancer in Taiwan . We found risk for breast cancer was associated with the P02649 genotype ( xi ( 2 ) = 8 . 652 , p = 0 . 013 ) . Carriers of the epsilon4 allele were more common in breast cancer cases than carriers of epsilon3 allele ( p = 0 . 004 , OR = 1 . 786 , 95 % CI : 1 . 197 - 2 . 664 ) . In addition , the epsilon4 allele is also associated with P04626 / neu negative status in breast cancer patients ( p = 0 . 006 , OR = 0 . 277 , 95 % CI : 0 . 111 - 0 . 693 ) . No significant associations between P02649 genotype and tumor grade , TN classification , progesterone receptor , estrogen receptor , lymphatic invasion , or recurrence of breast cancer were in evidence . These results suggest that the P02649 epsilon4 allele may be a risk factor for breast cancer and correlates with P04626 / neu negative status .",
"P00533 inhibitors enhanced the susceptibility to NK cell - mediated lysis of lung cancer cells . As quercetin , which can inhibit phosphatidylinositol 3 - kinase , nuclear factor - kappa B , and protein kinase C ( PKC ) pathways , induced expression of natural killer group 2 , member D ( P26718 ) ligands on cancer cells and made the cells sensitive to NK - cell - mediated killing ; inhibition of epidermal growth factor receptor ( P00533 ) pathway might lead to induction of P26718 ligands . In this study , it was investigated whether P00533 inhibitors , including erlotinib or gefitinib , could regulate expression of P26718 ligands in various lung cancer cells including A549 , NCI - H23 , and SW - 900 . The P00533 inhibitors predominantly increased transcription and surface expression of Q9BZM6 , and subsequently increased susceptibility of the cancer cells to NK - 92 cells . When the selective inhibitors of nuclear factor - kappa B , phosphatidylinositol 3 - kinase , mitogen - activated protein kinases , and PKC were treated to discriminate downstream signaling of P00533 pathway , expression of Q9BZM6 in the cancer cells was induced by inhibition of PKC . Treatment with phorbol 12 - myristate 13 - acetate restored the P00533 inhibitor - induced Q9BZM6 transcription . Binding activity to Q9BZM6 promoter region of AP - 2α , which suggested as suppressor of expression of Q9BZM6 , was decreased by treatment with P00533 inhibitors , and restored by pretreatment with phorbol 12 - myristate 13 - acetate in A549 and SW - 900 . Rottlerin , a PKCδ inhibitor , also decreased the binding activity of AP - 2α in dose - dependent manner . This study suggests that P00533 inhibitors enhanced the susceptibility to NK cell - mediated lysis of lung cancer cells by induction of Q9BZM6 by inhibition of PKC pathway and therapeutic efficacy of P00533 inhibitors in lung cancer may be mediated in part by increased susceptibility to NK cell - mediated cytotoxicity .",
"A phase I dose escalation study of DB08916 , an irreversible dual inhibitor of epidermal growth factor receptor 1 ( P00533 ) and 2 ( P04626 ) tyrosine kinase in a 2 - week on , 2 - week off schedule in patients with advanced solid tumours . To assess tolerability , pharmacokinetics ( PK ) , pharmacodynamics ( PD ) and clinical activity of the dual epidermal growth factor receptor ( P00533 ) 1 and 2 ( P04626 ) tyrosine kinase inhibitor DB08916 . An escalating schedule of once - daily ( OD ) DB08916 for 14 days followed by 14 days off medication was explored . Thirty - eight patients were enrolled . Dose levels were 10 , 20 , 30 , 45 , 70 , 85 , and 100 mg . At 100 mg dose - limiting toxicity ( DLT ) ( common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide ) occurred in two patients . In the next - lower dose of 70 mg , DLT ( grade 3 fatigue and ALAT elevation ) occurred in one of six patients . An intermediate dose level of 85 mg was studied . Here DLT occurred in two patients ( grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment ) . An additional 12 patients were treated at 70 mg . DB08916 PK after single and multiple doses revealed moderately fast absorption , and no deviation from dose proportionality . Pharmacodynamics analysis in skin biopsies did not show significant changes in P00533 - associated biomarkers . However , a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed . No partial or complete responses were observed , stable disease lasting more than four cycles was seen in seven patients . The recommended dose for studies with DB08916 for 14 days followed by 14 days off medication is 70 mg OD .",
"First report of warfarin dose requirements in patients possessing the P11712 * 12 allele . BACKGROUND : ___MASK76___ is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S - warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S - warfarin . Numerous variant alleles of P11712 have been identified . The P11712 * 12 ( rs9332239 ) allele harbors a P489S substitution in P11712 which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 , Q9BQB6 and P02649 variant alleles . None of the four patients carried the common P11712 variant alleles ( * 2 , * 3 , * 5 , * 6 , * 7 , * 8 , * 9 , * 11 , * 13 ) despite a relatively low MWWD ( 23 . 4 ± 7 . 94 mg ) compared to 208 patients carrying the CYP29C9 * 1 genotype ( 32 . 2 ± 12 . 65 mg ) . Given that P11712 * 12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 * 12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 genotypes also demonstrated lower dose requirements in the patients that possessed P11712 * 12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 substrates . This is the first report of patients with the rare P11712 * 12 genotype and lower warfarin dose requirements .",
"P00533 inhibitors in non - small cell lung cancer ( NSCLC ) : the emerging role of the dual irreversible P00533 / P04626 inhibitor DB08916 . Non - small cell lung cancer ( NSCLC ) is one of the most lethal types of cancer and is associated with significant mortality and morbidity worldwide . Despite improvements in conventional treatment for NSCLC , survival remains poor and improvements in patient outcome are warranted . Over recent years , basic scientific research has dramatically increased our knowledge of the pathogenesis of lung cancer and allowed us to uncover and understand the cellular pathways involved in this process . This has led to the development of therapies to selectively target these pathways . Among these , the epidermal growth factor receptor ( P00533 ) tyrosine kinase family and related downstream pathways play a critical role in cancer development and over recent years have become a validated target in NSCLC . The development of monoclonal antibodies and first - generation tyrosine kinase inhibitors ( TKIs ) targeted towards P00533 has had a considerable impact on patient outcomes . However , despite dramatic and sustained responses and the discovery of specific patient subgroups that may derive clinical benefit , resistance to first - generation P00533 TKIs inevitably develops . A new generation of agents have been developed to provide superior potency of target inhibition and further individualize the treatment of NSCLC . This article reviews P00533 - targeted therapies currently available for use and undergoing clinical development for the treatment of NSCLC , specifically focusing on next generation agents including DB08916 , an irreversible dual inhibitor of P00533 and P04626 kinases .",
"Curcumin and epigallocatechin gallate inhibit the cancer stem cell phenotype via down - regulation of P40763 - NFκB signaling . BACKGROUND / AIM : The cancer stem cell ( CSC ) model postulates the existence of a small proportion of cancer cells capable of sustaining tumor formation , self - renewal and differentiation . Signal Transducer and Activator of Transcription 3 ( P40763 ) signaling is known to be selectively activated in breast CSC populations . However , it is yet to be determined which molecular mechanisms regulate P40763 signaling in CSCs and what chemopreventive agents are effective for suppressing CSC growth . The aim of this study was to examine the potential efficacy of curcumin and epigallocatechin gallate ( EGCG ) against CSC and to uncover the molecular mechanisms of their anticancer effects . MATERIALS AND METHODS : To suppress the CSC phenotype , two breast cancer cell lines ( MDA - MB - 231 cells and MCF7 cells transfected with P04626 ) were treated with curcumin ( 10 μM ) with or without EGCG ( 10 μM ) for 48 h . We used tumor - sphere formation and wound - healing assays to determine CSC phenotype . To quantify CSC populations , Fluorescence - activated cell sorting profiling was monitored . P40763 phosphorylation and interaction with Nuclear Factor - kB ( NFkB ) were analyzed by performing western blot and immunoprecipitation assays . RESULTS : Combined curcumin and EGCG treatment reduced the cancer stem - like Cluster of differentiation 44 ( P16070 ) - positive cell population . Western blot and immunoprecipitation analyses revealed that curcumin and EGCG specifically inhibited P40763 phosphorylation and P40763 - NFkB interaction was retained . CONCLUSION : This study suggests that curcumin and EGCG function as antitumor agents for suppressing breast CSCs . P40763 and NFκB signaling pathways could serve as targets for reducing CSCs leading to novel targeted - therapy for treating breast cancer .",
"DB08916 : A first - line treatment for selected patients with metastatic non - small - cell lung cancer . PURPOSE : The pharmacology , pharmacokinetics , clinical efficacy , safety , adverse effects , dosage and administration , and role in therapy of afatinib in the management of non - small - cell lung cancer ( NSCLC ) are reviewed . SUMMARY : DB08916 ( Gilotrif , Boehringer Ingelheim ) is a novel oral tyrosine kinase inhibitor ( TKI ) recently approved for the first - line treatment of patients with NSCLC whose tumors are driven by activating mutations of genes coding for epidermal growth factor receptor ( P00533 ) . DB08916 is also an inhibitor of a specific P00533 mutation ( T790M ) that causes resistance to first - generation P00533 - targeted TKIs in about half of patients receiving those drugs . The recommended dosage is 40 mg once daily . In a Phase III trial completed last year , patients with P00533 - mutated NSCLC who were treated with afatinib had a twofold higher response rate than those receiving standard combination chemotherapy ( 56 % versus 23 % ) and significantly longer progression - free survival ( 11 . 0 months versus 5 . 6 months ) . Other studies indicated that afatinib may offer advantages over standard chemotherapy for NSCLC in terms of enhanced symptom control and quality of life and is modestly effective in cases involving EGFRT790M - related acquired resistance to the TKIs erlotinib and gefitinib . Among clinical trial participants , afatinib was generally well tolerated , with the most common grade I or II adverse events being diarrhea and rash or acne ; grade III or IV events were infrequent . CONCLUSION : DB08916 is a novel TKI that is efficacious and well tolerated in patients with NSCLC associated with activating P00533 mutations , including cases involving the T790M resistance mutation . It has possible applications in other P00533 mutation - positive cancers .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK57___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .",
"Substance P promotes expansion of human mesenteric preadipocytes through proliferative and antiapoptotic pathways . White adipose tissue is intimately involved in the regulation of immunity and inflammation . We reported that human mesenteric preadipocytes express the DB05875 ( SP ) - mediated neurokinin - 1 receptor ( P25103 ) , which signals proinflammatory responses . Here we tested the hypothesis that SP promotes proliferation and survival of human mesenteric preadipocytes and investigated responsible mechanism ( s ) . Preadipocytes were isolated from mesenteric fat biopsies during gastric bypass surgery . Proliferative and antiapoptotic responses were delineated in 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 5 -( 3 - carboxymethoxyphenyl )- 2 -( 4 - sulfophenyl )- 2H - tetrazolium ( MTS ) , bromodeoxyuridine ( BrdU ) , caspase - 3 , and TUNEL assays , as well as Western immunoanalysis . SP ( 10 (- 7 ) M ) increased MTS and proliferation ( BrdU ) and time dependently ( 15 - 30 min ) induced Akt , P01133 receptor , IGF receptor , integrin alphaVbeta3 , phosphatidylinositol 3 - kinase , and PKC - theta phosphorylation . Furthermore , pharmacological antagonism of Akt and PKC - theta activation significantly attenuated SP - induced preadipocyte proliferation . Exposure of preadipocytes to the proapoptotic P48023 ( P48023 , 100 microM ) resulted in nuclear DNA fragmentation ( TUNEL assay ) , as well as increased cleaved poly ( ADP - ribose ) polymerase , cleaved caspase - 7 , and caspase - 3 expression . Cotreatment with SP almost completely abolished these responses in a P25103 - dependent fashion . SP ( 10 (- 7 ) M ) also time dependently stimulated expression 4E binding protein 1 and phosphorylation of P08133 S6 kinase , which increased protein translation efficiency . SP increases preadipocyte viability , reduces apoptosis , and stimulates proliferation , possibly via cell cycle upregulation and increased protein translation efficiency . SP - induced proliferative and antiapoptotic pathways in fat depots may contribute to development of the creeping fat and inflammation characteristic of Crohn ' s disease .",
"Irreversible P00533 inhibitors in the treatment of advanced NSCLC . The epidermal growth factor receptor ( P00533 ) is among the most important targets in the treatment of advanced non - small cell lung cancer ( NSCLC ) . Erlotinib and gefitinib , two small molecules , are reversible P00533 tyrosine kinase inhibitors ( TKIs ) . Non - small cell lung cancers with P00533 mutations , are characterized by excellent responses when treated with the P00533 - TKIs gefitinib and erlotinib . However , all the patients with tumors harbouring P00533 mutations experience disease progression after a median of 10 to 14 months of treatment with gefitinib or erlotinib . A group of new generation P00533 - TKIs irreversibly inhibit P00533 - TK and represent one of the strategies that may potentially overcome the acquired resistance to gefitinib and erlotinib or achieve better outcomes than reversible inhibitors in the first - line treatment of P00533 mutant lung cancers . DB08916 ( DB08916 ) and PF299804 are the irreversible P00533 - TKIs with the most relevant data in the treatment of advanced NSCLC , as primary P00533 - targeted therapy and after resistance to reversible P00533 - TKIs . However , to date , the role of irreversible P00533 inhibitors remains to be defined .",
"Temporal molecular and biological assessment of an erlotinib - resistant lung adenocarcinoma model reveals markers of tumor progression and treatment response . Patients with lung cancer with activating mutations in the P01133 receptor ( P00533 ) kinase , who are treated long - term with tyrosine kinase inhibitors ( TKI ) , often develop secondary mutations in P00533 associated with resistance . Mice engineered to develop lung adenocarcinomas driven by the human P00533 T790M resistance mutation are similarly resistant to the P00533 TKI erlotinib . By tumor volume endpoint analysis , these mouse tumors respond to DB08916 ( an irreversible P00533 / P04626 TKI ) and rapamycin combination therapy . To correlate P00533 - driven changes in the lung with response to drug treatment , we conducted an integrative analysis of global transcriptome and metabolite profiling compared with quantitative imaging and histopathology at several time points during tumor progression and treatment . Responses to single - drug treatments were temporary , whereas combination therapy elicited a sustained response . During tumor development , metabolomic signatures indicated a shift to high anabolic activity and suppression of antitumor programs with 11 metabolites consistently present in both lung tissue and blood . Combination drug treatment reversed many of the molecular changes found in tumored lung . Data integration linking cancer signaling networks with metabolic activity identified key pathways such as glutamine and glutathione metabolism that signified response to single or dual treatments . Results from combination drug treatment suggest that metabolic transcriptional control through C - MYC and SREBP , as well as ELK1 , NRF1 , and Q16236 , depends on both P00533 and mTORC1 signaling . Our findings establish the importance of kinetic therapeutic studies in preclinical assessment and provide in vivo evidence that TKI - mediated antiproliferative effects also manifest in specific metabolic regulation .",
"Monitoring afatinib treatment in P04626 - positive gastric cancer with DB09150 and 89Zr - trastuzumab PET . We evaluated the ability of the PET imaging agent ( 89 ) Zr - trastuzumab to delineate P04626 - positive gastric cancer and to monitor the pharmacodynamic effects of the epidermal growth factor receptor ( P00533 ) / human epidermal growth factor receptor 2 ( P04626 ) tyrosine kinase inhibitor afatinib . METHODS : Using ( 89 ) Zr - trastuzumab , ( 18 ) F - DB09150 , or 3 '- deoxy - 3 '-( 18 ) F - fluorothymidine ( ( 18 ) F - P17948 PET ) , we imaged P04626 - positive NCI - N87 and P04626 - negative MKN74 gastric cancer xenografts in mice . Next , we examined the pharmacodynamic effects of afatinib in NCI - N87 xenografts using ( 89 ) Zr - trastuzumab and ( 18 ) F - DB09150 PET and comparing imaging results to changes in tumor size and in protein expression as monitored by Western blot and histologic studies . RESULTS : Although ( 18 ) F - DB09150 uptake in NCI - N87 tumors did not change , a decrease in ( 89 ) Zr - trastuzumab uptake was observed in the afatinib - treated versus control groups ( 3 . 0 ± 0 . 0 percentage injected dose per gram ( % ID / g ) vs . 21 . 0 ± 3 . 4 % ID / g , respectively ; P < 0 . 05 ) . ( 89 ) Zr - trastuzumab PET results corresponded with tumor reduction , apoptosis , and downregulation of P04626 observed on treatment with afatinib . Downregulation of total P04626 , phosphorylated ( p )- P04626 , and p - P00533 occurred within 24 h of the first dose of afatinib , with a sustained effect over 21 d of treatment . CONCLUSION : DB08916 demonstrated antitumor activity in P04626 - positive gastric cancer in vivo . ( 89 ) Zr - trastuzumab PET specifically delineated P04626 - positive gastric cancer and can be used to measure the pharmacodynamic effects of afatinib .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Anti - P04626 cancer therapy and cardiotoxicity . A significant milestone in the treatment of breast cancer is the identification of the P04626 receptor as a drug target for cancer therapies . DB00072 ( Herceptin ) , a monoclonal antibody that blocks the P04626 receptor , is among the first of such drugs approved by the US Food and Drug Administration for targeted cancer therapy . Clinical studies have shown that DB00072 significantly improves the overall survival of breast cancer patients . However , an unforeseen significant side - effect of cardiotoxicity manifested as left ventricular dysfunction and heart failure . Concurrent studies have demonstrated the essential role of the P04626 receptor in cardiac development and maintaining the physiological function of an adult heart . The P04626 receptor , therefore , has become a critical link between the oncology and cardiology fields . In addition to DB00072 , new drugs targeting the P04626 receptor , such as ___MASK3___ , DB06366 and DB08916 , are either approved or being evaluated in clinical trials for cancer therapy . With the concern of cardiotoxicity caused by P04626 inhibition , it becomes clear that new therapeutic strategies for preventing such cardiac side effects need to be developed . It is the intent of this paper to review the potential cardiac impact of anti - P04626 cancer therapy .",
"DB08916 circumvents multidrug resistance via dually inhibiting DB00171 binding cassette subfamily G member 2 in vitro and in vivo . Multidrug resistance ( MDR ) to chemotherapeutic drugs is a formidable barrier to the success of cancer chemotherapy . Expressions of DB00171 - binding cassette ( DB01048 ) transporters contribute to clinical MDR phenotype . In this study , we found that afatinib , a small molecule tyrosine kinase inhibitor ( TKI ) targeting P00533 , HER - 2 and HER - 4 , reversed the chemoresistance mediated by Q9UNQ0 in vitro , but had no effect on that mediated by multidrug resistance protein P08183 and P33527 . In addition , afatinib , in combination with topotecan , significantly inhibited the growth of Q9UNQ0 - overexpressing cell xenograft tumors in vivo . Mechanistic investigations exhibited that afatinib significantly inhibited ATPase activity of Q9UNQ0 and downregulated expression level of Q9UNQ0 , which resulted in the suppression of efflux activity of Q9UNQ0 in parallel to the increase of intracellular accumulation of Q9UNQ0 substrate anticancer agents . Taken together , our findings may provide a new and useful combinational therapeutic strategy of afatinib with chemotherapeutical drug for the patients with Q9UNQ0 overexpressing cancer cells .",
"Targeted treatment of advanced and metastaticbreast cancer with lapatinib . Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER - 2 and P00533 . ___MASK3___ is a potent dual inhibitor of HER - 2 and P00533 . Preclinical and phase I studies have shown activity with lapatinib in a number of cancers , including breast cancer , and the drug is well tolerated . The main known drug interactions are with paclitaxel and irinotecan . The most significant side - effects of lapatinib are diarrhea and adverse skin events . Rates of cardiotoxicity compare favorably with trastuzumab , a monoclonal antibody against HER - 2 . This paper focuses on lapatinib in advanced and metastatic breast cancer , which remains an important therapeutic challenge . Phase II and III studies show activity as monotherapy , and in combination with chemotherapy or hormonal agents . Results from these studies suggest that the main benefit from lapatinib is in the HER - 2 positive breast cancer population . Combinations of lapatinib and trastuzumab are also being studied and show encouraging results , particularly in trastuzumab - refractory metastatic breast cancer . ___MASK3___ may have a specific role in treating HER - 2 positive CNS metastases . The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated .",
"An update on molecularly targeted therapies in second - and third - line treatment in non - small cell lung cancer : focus on P00533 inhibitors and anti - angiogenic agents . DB01248 , pemetrexed and epidermal growth factor receptor tyrosine kinase inhibitors ( gefitinib and erlotinib ) are recommended second - line therapy for advanced non - small cell lung cancer ( NSCLC ) patients with disease progression . Although erlotinib is the only recommended third - line therapy , several drugs are being used in the clinic . Recent studies have focused on combining targeted agents with approved therapies , including broad - spectrum multikinase inhibitors targeting multiple ErbB Family receptors and multitargeted anti - angiogenic agents targeting the vascular endothelial growth factor receptor , platelet - derived growth factor receptor and fibroblast growth factor receptor pathways . Here , we review targeted therapies that are being evaluated in second - and third - line settings in NSCLC , including the ErbB Family Blocker afatinib ( DB08916 ) , multityrosine kinase inhibitors ( pelitinib [ Q9Y259 - 56 ] ) , neratinib [ HKI - 272 ] , canertinib [ DB05424 ] , lapatinib [ GW - 572016 ] , dacomitinib [ PF - 299804 ] ) and multitargeted anti - angiogenic agents ( vandetanib [ DB05294 ] , sunitinib [ SU11248 ] , sorafenib [ BAY43 - 9006 ] , nintedanib [ BIBF1120 ] , axitinib [ AG - 013736 ] , cediranib [ DB04849 ] , motesanib [ Q99217 706 ] , linifanib [ ABT869 ] and pazopanib [ DB06589 ] ) .",
"Targeted therapies : DB08916 -- new therapy option for P00533 - mutant lung cancer .",
"Targeting epidermal growth factor receptor / human epidermal growth factor receptor 2 signalling pathway by a dual receptor tyrosine kinase inhibitor afatinib for radiosensitisation in murine bladder carcinoma . Given the promising control of bladder cancer achieved by combined chemotherapy / radiotherapy with selective transurethral resection , obstacles remain to the treatment of unresectable bladder cancer . The aim of this study was to determine whether targeting epidermal growth factor receptor ( P00533 ) / human epidermal growth factor receptor 2 ( P04626 ) can radiosensitise a murine bladder tumour ( MBT - 2 ) cell line . Cell survival , expression of signal proteins and cell cycle changes in MBT - 2 cells treated in vitro and in vivo with afatinib , an irreversible P00533 / P04626 inhibitor , plus radiotherapy were investigated by colony formation assay , Western blot assay and flow cytometry , respectively . Ectopic xenografts were established by subcutaneous injection of MBT - 2 cells in C3H / HeN mice . Mice were randomised into 4 groups to receive afatinib ( 10mg / kg / day on day 1 - 7 ) and / or radiotherapy ( 15Gy on day 4 ) . Positron emission tomography ( PET ) on day 8 was used to evaluate the early treatment response . DB08916 ( 200 - 1000nM ) increased cell killing by radiation ( 0 - 10Gy ) . Pre - treatment of irradiated cells with afatinib inhibited radiation - activated P04626 and P00533 phosphorylation . As compared to either treatment alone , the combination increased the level of the cleavage form of poly ( ADP - ribose ) polymerase , the expression of phospho - γ P16104 and the percentage of cells in subG1 phase ( indicating enhanced induction of apoptosis ) , and decreased tumour metabolism and inhibited tumour growth by 64 % . DB08916 has therapeutic value as a radiosensitiser of murine bladder cancer cells . The synergism between afatinib and radiation likely enhances DNA damage , leading to increased cell apoptosis .",
"The effect of acquired cisplatin resistance on sensitivity to P00533 tyrosine kinase inhibitors in P00533 mutant lung cancer cells . Although epidermal growth factor receptor tyrosine kinase inhibitors ( P00533 TKIs ) are used as first - line agents for treating nonsquamous cell lung cancer with P00533 mutation , there are many patients who have to receive these drugs following platinum - based chemotherapy . This study was designed to define whether exposure to cisplatin could affect the sensitivity to P00533 TKIs because conflicting results have been presented . We established sublines that are resistant to cisplatin from P00533 wild - type cells ( A549 and H460 ) and P00533 mutant cells ( PC - 9 and HCC827 ) . The P00533 - related signals were examined by Western blotting . MTT assay and the trypan blue exclusion method were used for the in vitro study , while tumor size and the SUV of the 18FDG - PET scans were measured in animal models . The IC50 value and apoptotic fractions after exposure to P00533 TKIs , such as gefitinib , erlotinib , and DB08916 , were almost the same in the cisplatin - resistant sublines compared to that of the parent cells . Although the baseline P60484 expression was reduced in the resistant cells , as was indicated in a previous study , the P00533 - related signals similarly responded to the P00533 TKIs . Furthermore , the reduced tumor size and SUV of the 18FDG - PET of the implanted tumor in nude mice according to erlotinib treatment were not different between the resistant sublines and the parent cells . In conclusion , the acquired resistance to cisplatin did not affect the sensitivity to P00533 TKIs in the P00533 mutant lung cancer cells , and this should abrogate any concerns about the use of P00533 TKIs following platinum - based chemotherapy .",
"DB08916 : emerging next - generation tyrosine kinase inhibitor for NSCLC . The discovery of epidermal growth - factor receptor ( P00533 ) - activating mutations and the introduction of oral P00533 tyrosine kinase inhibitors ( P00533 - TKIs ) have expanded the treatment options for patients with non - small cell lung cancer . The first two reversible P00533 - TKIs , erlotinib and gefitinib , are approved for use in the first - line setting in patients with known P00533 - activating mutations and in the second - and third - line settings for all NSCLC patients . These first - generation P00533 - TKIs improve progression - free survival when compared to chemotherapy in patients with P00533 - activating mutations in the first - line setting . However , nearly all patients develop resistance to P00533 - directed agents . There is a need for further therapy options for patients with disease progression after treatment with reversible P00533 - TKIs . DB08916 is an irreversible ErbB family blocker that inhibits P00533 , P04626 , and Q15303 . In vitro and in vivo , afatinib have shown increased inhibition of the common P00533 - activating mutations as well as the T790M resistance mutation when compared to erlotinib and gefitinib . Clinically , afatinib has been evaluated in the LUX - Lung series of trials , with improvement in progression - free survival reported in patients with P00533 - activating mutations in both first - and second -/ third - line settings when compared to chemotherapy . Further investigation is needed to determine the precise role that afatinib will play in the treatment of patients with non - small cell lung cancer and P00533 - activating mutations .",
"P05121 Regulates the Invasive Phenotype in Human Cutaneous Squamous Cell Carcinoma . The emergence of highly aggressive subtypes of human cutaneous squamous cell carcinoma ( SCC ) often reflects increased autocrine / paracrine TGF - beta synthesis and epidermal growth factor receptor ( P00533 ) amplification . Cooperative TGF - beta / P00533 signaling promotes cell migration and induces expression of both proteases and protease inhibitors that regulate stromal remodeling resulting in the acquisition of an invasive phenotype . In one physiologically relevant model of human cutaneous SCC progression , TGF - beta1 + P01133 stimulation increases the production of several matrix metalloproteinases ( MMPs ) , among the most prominent of which is P09238 - an MMP known to be elevated in SCC in situ . Activation of stromal plasminogen appears to be critical in triggering downstream MMP activity . Paradoxically , P05121 , the major physiological inhibitor of plasmin generation , is also upregulated under these conditions and is an early event in progression of incipient epidermal SCC . One testable hypothesis proposes that TGF - beta1 + P01133 - dependent P09238 elevation directs focalized matrix remodeling events that promote epithelial cell plasticity and tissue invasion . Increased P05121 expression serves to temporally and spatially modulate plasmin - initiated pericellular proteolysis , further facilitating epithelial invasive potential . Defining the complex signaling and transcriptional mechanisms that maintain this delicate balance is critical to developing targeted therapeutics for the treatment of human cutaneous malignancies .",
"Dermatologic adverse events associated with afatinib : an oral ErbB family blocker . Dermatologic adverse events ( AEs ) are frequently observed in patients receiving P01133 receptor ( P00533 ; also known as ErbB1 ) tyrosine kinase inhibitor therapy . The impact of these AEs goes beyond cosmesis to the discomfort from itching , pain and secondary infections , all of which may significantly impact on patient well - being , adherence and clinical outcomes . DB08916 is a potent , irreversible , oral , ErbB family blocker , inhibiting P00533 ( ErbB1 ) , P04626 ( ErbB2 ) and ErbB4 receptor kinases . It also inhibits transphosphorylation of ErbB3 . Similar to P00533 inhibitors , dermatologic AEs have been frequently observed in patients treated with afatinib . Papulopustular ( acneiform ) rash , pruritus , xerosis , paronychia and alopecia will require patient education and proactive treatment interventions . This article summarizes current data on the dermatologic AEs associated with afatinib treatment across the clinical trial program , and provides strategies for their effective management .",
"LUX - Lung 3 : redundancy , toxicity or a major step forward ? DB08916 as front - line therapy for patients with metastatic P00533 - mutated lung cancer . Mutant P01133 receptor ( P00533 ) is an attractive therapeutic target in patients with metastatic non - small cell lung cancer ( NSCLC ) . A new paradigm has been defined using DB00171 - competitive P00533 tyrosine kinase inhibitors ( TKIs ) , gefitinib and erlotinib , as the most effective first - line treatment . However , clinical benefit of P00533 - TKI is only transient and limited by primary or acquired resistance . DB08916 has been developed as a highly potent , irreversible inhibitor of P00533 , P04626 and ErbB4 , as well as transphosphorylation of ErbB3 . The clinical activity of afatinib in lung cancer has been extensively studied in the LUX - Lung series of trials . LUX - Lung 3 was a pivotal randomized Phase III study that recently led to the approval of afatinib ( Gilotrif ) in several countries for treatment of patients with metastatic NSCLC harboring somatic P00533 gene mutations . Here , we review the rationale , study design including end points , results and implications of this trial for current and future P00533 genotype - directed lung cancer therapies .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK80___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"DB08916 enhances the efficacy of conventional chemotherapeutic agents by eradicating cancer stem - like cells . Cancer stem cells ( CSC ) have garnered significant attention as a therapeutic focus , based on evidence that they may represent an etiologic root of treatment - resistant cells . Indeed , expression of the multidrug resistance protein DB00171 - binding cassette subfamily G member 2 ( Q9UNQ0 ) confers chemoresistance to CSCs , where it serves as a potential biomarker and therapeutic target . Here , we show that afatinib , a small - molecule inhibitor of the tyrosine kinases P00533 , P04626 , and Q15303 , preferentially eliminated side population cells with CSC character , in both cell lines and patient - derived leukemia cells , by decreasing Q9UNQ0 expression . In these cells , afatinib also acted in parallel to suppress self - renewal capacity and tumorigenicity . Combining afatinib with the DNA - damaging drug topotecan enhanced the antitumor effect of topotecan in vitro and in vivo . Mechanistic investigations suggested that Q9UNQ0 suppression by afatinib did not proceed by proteolysis through the ubiquitin - dependent proteosome , lysosome , or calpain . Instead , we found that afatinib increased DNA methyltransferase activity , thereby leading to methylation of the Q9UNQ0 promoter and to a decrease in Q9UNQ0 message level . Taken together , our results advocate the use of afatinib in combination with conventional chemotherapeutic drugs to improve efficacy by improving CSC eradication .",
"[ Hange - Shashin - to for preventing diarrhea during afatinib therapy ] . DB08916 is an epidermal growth factor receptor - tyrosine kinase inhibitor ( P00533 - TKI ) . In a randomized phase III study ( Lux - Lung 3 study ) employing patients harboring P00533 mutations , patients administered afatinib show a significantly longer progression free survival time ( PFS ) than those administeredcombination chemotherapy comprising cisplatin andpemetrexed . However , most of the patients ( 95 . 2 % ) treatedwith afatinib experiencedd iarrhea . In the present report , 16 patients with P00533 mutations were treatedby afatinib at our institution from May 2014 to December 2014 . Twelve patients were administered a diarrhea prevention herbal medicine , Hange - shashin - to . Seven of 12 patients ( 58 % ) had no diarrhea during the 28 days of therapy . All 4 of the patients who did not receive Hange - shashin - to experienced diarrhea above Grade 1 within 6 days of starting therapy . The rate of diarrhea differed significantly between the patients receiving and not receiving Hangeshashin - to . In conclusion , preventive administration of Hange - shashin - to may reduce the occurrence of diarrhea during afatinib treatment .",
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK3___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .",
"Polymorphisms of human histamine receptor H4 gene are associated with breast cancer in Chinese Han population . Previous investigations indicated that histamine receptor H4 ( Q9H3N8 ) played important roles in many aspects of breast cancer pathogenesis , and that the polymorphisms of Q9H3N8 gene may result in expression and functional changes of Q9H3N8 proteins . However , the relationship between polymorphisms of Q9H3N8 and breast cancer risk and malignant degree is unclear . In the present study , we conducted a case - control investigation among 185 Chinese Han breast cancer patients and 199 ethnicity - matched health controls . Four tag - SNPs ( i . e . rs623590 , rs16940762 , rs11662595 and rs1421125 ) of Q9H3N8 were genotyped and association analysis was performed . Odds ratios ( ORs ) with 95 % confidence intervals ( CI ) were used to assess the association . We found that the T allele of rs623590 had a decreased risk of breast cancer ( adjusted OR , 0 . 667 ; 95 % CI , 0 . 486 - 0 . 913 ; P = 0 . 012 ) while the A allele of rs1421125 had an increased risk ( adjusted OR , 1 . 653 ; 95 % CI , 1 . 139 - 2 . 397 ; P = 0 . 008 ) . Further haplotype analysis showed that the CAA haplotype of rs623590 - rs11662595 - rs1421125 was more frequent among patients with breast cancer ( adjusted OR , 1 . 856 ; 95 % CI , 1 . 236 - 2 . 787 ; P = 0 . 003 ) . Additionally , polymorphisms of rs623590 and rs11662595 were also correlated with clinical stages , lymph node involvement , and P04626 status . These findings indicated that the variants of rs623590 , rs11662595 and rs1421125 genotypes of Q9H3N8 gene were significantly associated with the risk and malignant degree of breast cancer in Chinese Han populations , which may provide us novel insight into the pathogenesis of breast cancer although further studies with larger participants worldwide are still needed for conclusion validation .",
"Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with P00533 - mutant lung adenocarcinoma . PURPOSE : Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor ( P00533 ) gene are associated with sensitivity of lung adenocarcinomas to the P00533 tyrosine kinase inhibitors , gefitinib and erlotinib . Acquired drug resistance is frequently associated with a secondary somatic mutation that leads to the substitution of methionine for threonine at position 790 ( T790M ) . We aimed to identify additional second - site alterations associated with acquired resistance . EXPERIMENTAL DESIGN : Tumor samples were obtained from 48 patients with acquired resistance . Tumor cell DNA was analyzed for P00533 kinase domain mutations . Molecular analyses were then done to characterize the biological properties of a novel mutant P00533 allele . RESULTS : A previously unreported mutation in exon 21 of P00533 , which leads to substitution of alanine for threonine at position 854 ( T854A ) , was identified in one patient with a drug - sensitive P00533 L858R - mutant lung adenocarcinoma after long - term treatment with tyrosine kinase inhibitors . The T854A mutation was not detected in a pretreatment tumor sample . The crystal structure analyses of P00533 suggest that the T854 side chain is within contact distance of gefitinib and erlotinib . Surrogate kinase assays show that the P00533 T854A mutation abrogates the inhibition of tyrosine phosphorylation by erlotinib . Such resistance seems to be overcome by a new irreversible dual P00533 / P04626 inhibitor , DB08916 . CONCLUSIONS : The T854A mutation is the second reported second - site acquired resistance mutation that is within contact distance of gefitinib and erlotinib . These data suggest that acquired resistance to DB00171 - mimetic P00533 kinase inhibitors may often be associated with amino acid substitutions that alter drug contact residues in the P00533 DB00171 - binding pocket .",
"DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .",
"Development of [ 18F ] afatinib as new TKI - PET tracer for P00533 positive tumors . INTRODUCTION : DB08916 is an irreversible ErbB family blocker that was approved for the treatment of P00533 mutated non - small cell lung cancer in 2013 . Positron emission tomography ( PET ) with fluorine - 18 labeled afatinib provides a means to obtain improved understanding of afatinib tumor disposition in vivo . PET imaging with [( 18 ) F ] afatinib may also provide a method to select treatment responsive patients . The aim of this study was to label afatinib with fluorine - 18 and evaluate its potential as TKI - PET tracer in tumor bearing mice . METHODS : A radiochemically novel coupling , using peptide coupling reagent BOP , was explored and optimized to synthesize [( 18 ) F ] afatinib , followed by a metabolite analysis and biodistribution studies in two clinically relevant lung cancer cell lines , xenografted in nude mice . RESULTS : A reliable [( 18 ) F ] afatinib radiosynthesis was developed and the tracer could be produced in yields of 17 . 0 ± 2 . 5 % calculated from [( 18 ) F ] F (-) and > 98 % purity . The identity of the product was confirmed by co - injection on HPLC with non - labeled afatinib . Metabolite analysis revealed a moderate rate of metabolism , with > 80 % intact tracer in plasma at 45 min p . i . Biodistribution studies revealed rapid tumor accumulation and good retention for a period of at least 2 hours , while background tissues showed rapid clearance of the tracer . CONCLUSION : We have developed a method to synthesize [( 18 ) F ] afatinib and related fluorine - 18 labeled 4 - anilinoquinazolines . [( 18 ) F ] DB08916 showed good stability in vivo , justifying further evaluation as a TKI - PET tracer .",
"Clinical and comparative utility of afatinib in non - small cell lung cancer . The first targeted agents approved for non - small cell lung cancer ( NSCLC ) treatment , the epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKIs ) gefitinib and erlotinib , have an impressive activity in the presence of activating mutations of the P00533 gene . However , all patients develop acquired resistance principally through secondary mutations ( T790M ) , P04626 amplification , MET amplification , and other molecular aberrations . An attempt to overcome P00533 TKI resistance has been through the development of irreversible blockers . DB08916 is an irreversible inhibitor of the tyrosine kinase activity of all members of the HER family . The pharmacologic properties of afatinib ( formation of covalent bonds , inhibition of other family members , and in vitro and in vivo activity on T790M mutation positive tumors ) made this drug particularly appealing to study in clinic . Therefore , an intense program of clinical research ( LUX - Lung program ) was started and clinical results have shown very encouraging activity profiles in patients harboring P00533 activating mutations and in those with acquired resistance to reversible TKIs .",
"DB08916 monotherapy in P00533 - mutant lung adenocarcinoma .",
"[ A new perspective in the treatment of non - small - cell lung cancer ( NSCLC ). Role of afatinib : An oral and irreversible ErbB family blocker ] . Tyrosine kinase inhibitors ( TKI ) that block epidermal growth factor receptor ( P00533 ) pathway have demonstrated a clinical benefit for patients with non - small - cell lung cancer ( NSCLC ) harboring P00533 mutations . The currently available TKI ( gefitinib and erlotinib ) are P00533 reversible inhibitors . DB08916 is an oral , irreversible ErbB family blocker that covalently binds and blocks signaling from P00533 ( ErbB1 ) , P04626 ( ErbB2 ) and ErbB4 . The compound inhibits also the transphosphorylation of ErbB3 . With this mode of action , afatinib is thought to have a mechanistic advantage over P00533 blockade alone , in that it provides a sustained , covalent inhibition of ErbB homo - and hetero - dimers . In the pivotal LUX - Lung 3 study , afatinib demonstrated a prolonged progression free survival over standard pemetrexed plus cisplatin chemotherapy ( 11 . 1 versus 6 . 9 months ; HR = 0 . 58 , 95 % CI : 0 . 43 - 0 . 78 ; P = 0 . 001 ) in P00533 mutation positive NSCLC patients . The compound has recently been granted a marketing authorization ( MA ) for the treatment of patients with locally advanced or metastatic NSCLC with activating P00533 mutation ( s ) and P00533 TKI - naive . In this paper are summarized the efficacy and safety data in this indication .",
"Expression Enhancement in DB00072 Therapeutic Monoclonal Antibody Production using Genomic Amplification with ___MASK2___ . BACKGROUND : DB00072 ( Herceptin ) is a humanized monoclonal antibody ( mAb ) which is used for specific treatment of metastatic breast cancer in patients with overexpression of P04626 / neu receptor . In this study , we have attempted to develop a biosimilar version of trastuzumab mAb . METHODS : According to in silico studies , the heavy and light chains of trastuzumab mAb were designed and constructed . The recombinant constructs were co - transfected in CHO DG44 cell line . Stable transformants were selected on a semi solid medium . Genomic amplification with methotrexate was achieved for heavy chain gene amplification . Biological activity of produced antibody in comparison with Herceptin was tested by flow cytometry method . RESULTS : Three folds of amplification were obtained after seven rounds of methotrexate treatments . The results indicated the equal expression level of heavy and light chains . The yield of purified mAb was between 50 to 60 mg / l / day . According to the results , the produced mAb had similar affinity to P04626 (+) tumor cells to that of Herceptin . CONCLUSION : High - level recombinant protein expression can be achieved by amplification of the recombinant gene with a selectable marker , such as Dihydrofolate Reductase ( P00374 ) . It is usually accepted that P00374 gene can be amplified in P00374 (－) CHO cells , which consequently leads to amplification of the co - linked target gene , and finally amplification of recombinant protein . In this research , with the aim of producing a biosimilar version of herceptin , the effect of genomic amplification was investigated on the increasing the gene copy number using quantitative real - time PCR .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK37___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK88___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"A comprehensive review of the preclinical efficacy profile of the ErbB family blocker afatinib in cancer . DB08916 ( also known as DB08916 ) has recently been approved in several countries for the treatment of a distinct type of epidermal growth factor receptor ( P00533 ) - mutated non - small cell lung cancer . This manuscript comprehensively reviews the preclinical data on afatinib , an irreversible inhibitor of the tyrosine kinase activity of members of the epidermal growth factor receptor family ( ErbB ) including P00533 , P04626 and ErbB4 . DB08916 covalently binds to cysteine 797 of the P00533 and the corresponding cysteines 805 and 803 in P04626 and ErbB4 , respectively . Such covalent binding irreversibly inhibits the tyrosine kinase activity of these receptors , resulting in reduced auto - and transphosphorylation within the ErbB dimers and inhibition of important steps in the signal transduction of all ErbB receptor family members . DB08916 inhibits cellular growth and induces apoptosis in a wide range of cells representative for non - small cell lung cancer , breast cancer , pancreatic cancer , colorectal cancer , head and neck squamous cell cancer and several other cancer types exhibiting abnormalities of the ErbB network . This translates into tumour shrinkage in a variety of in vivo rodent models of such cancers . DB08916 retains inhibitory effects on signal transduction and in vitro and in vivo cancer cell growth in tumours resistant to reversible P00533 inhibitors , such as those exhibiting the T790M mutations . Several combination treatments have been explored to prevent and / or overcome development of resistance to afatinib , the most promising being those with P00533 - or P04626 - targeted antibodies , other tyrosine kinase inhibitors or inhibitors of downstream signalling molecules .",
"DB08916 ( DB08916 ) development in non - small - cell lung cancer . DB08916 ( DB08916 ) , a novel aniline - quinazoline derivative , irreversibly and equipotently targets the intrinsic kinase activity of all active ErbB receptor family members . Preclinical results show that afatinib is effective in lung cancer models , including those with P01133 receptor ( P00533 ) mutations resistant to reversible first - generation P00533 inhibitors . DB08916 is being investigated in the LUX - Lung program , which will evaluate afatinib as a first - line treatment in patients with P00533 - activating mutations ( LUX - Lung 2 , 3 and 6 ) and as a second - or third - line treatment in patients that have acquired resistance to gefitinib and / or erlotinib ( LUX - Lung 1 , 4 and 5 ) . LUX - Lung 1 and 2 have demonstrated , within their respective target groups , a significant increase in the disease control rate of 58 and 86 % , respectively , and significant prolongation of progression - free survival . Further Phase III clinical trials are currently ongoing to assess afatinib in combination with paclitaxel ( LUX - Lung 5 ) , and compared with cisplatin / pemetrexed ( LUX - Lung 3 ) or cisplatin / gemcitabine ( LUX - Lung 6 ) .",
"DB08916 and lung cancer . P00533 tyrosine kinase inhibitors ( P00533 - TKI ) have an established role in the treatment of non - small - cell lung cancer ( NSCLC ) . First - generation reversible DB00171 - competitive P00533 - TKIs are approved for the initial treatment of patients with P00533 mutation - positive advanced NSCLC . DB08916 is an irreversible second - generation P00533 - TKI with potent preclinical activity against P00533 ( wild type and mutant ) , P04626 , Q15303 and P00533 - mutant NSCLC with acquired resistance to reversible P00533 - TKI . LUX - Lung 3 trial demonstrated superiority of afatinib to cisplatin and pemetrexed in the frontline treatment of treatment - naïve patients with advanced adenocarcinoma of the lung and P00533 mutation . Based on these results , afatinib was recently approved for the first - line treatment of NSCLC patients with P00533 mutation . This article summarizes current status of preclinical and clinical development of afatinib in NSCLC .",
"The LUX - Lung clinical trial program of afatinib for non - small - cell lung cancer . P00533 ( P00533 ) - mutant non - small - cell lung cancer ( NSCLC ) represents a distinct disease entity whose molecular phenotype predicts exquisite sensitivity to the reversible P00533 - tyrosine kinase inhibitors ( TKIs ) gefitinib or erlotinib . However , primary or acquired resistance to these agents remains a major clinical problem . DB08916 is a novel dual irreversible P00533 / P04626 TKI that has been shown in preclinical studies to potentially prevent , delay or overcome resistance to reversible P00533 - TKIs . On this basis , the LUX - Lung clinical trial program has been recently launched for testing this molecule in advanced NSCLC patients . Notably , early results from the randomized LUX - Lung 1 trial indicate that afatinib significantly prolongs progression - free survival compared with placebo in pretreated patients with clinically acquired resistance to gefitinib or erlotinib . On the other hand , the LUX - Lung 2 trial shows that afatinib is highly active in the P00533 - mutant subgroup of patients . While these preliminary data open a new exciting scenario for the future development of anti - P00533 therapies in NSCLC , ongoing afatinib trials will definitively establish a role for this molecule in the treatment of advanced NSCLC .",
"Convergent and divergent cellular responses by ErbB4 isoforms in mammary epithelial cells . Associations of ErbB4 ( Q15303 / Q15303 ) , the fourth member of the P00533 family , with cancer are variable , possibly as a result of structural diversity of this receptor . There are multiple structural isoforms of Q15303 arising by alternative mRNA splicing , and a subset undergo proteolysis that releases membrane - anchored and soluble isoforms that associate with transcription factors and coregulators to modulate transcription . To compare the differential and common signaling activities of full - length ( FL ) and soluble intracellular isoforms of Q15303 , four JM - a isoforms ( FL and soluble intracellular domain ( ICD ) CYT - 1 and CYT - 2 ) were expressed in isogenic MCF10A cells and their biologic activities were analyzed . Both FL and ICD CYT - 2 promoted cell proliferation and invasion , and CYT - 1 suppressed cell growth . Transcriptional profiling revealed several new and underexplored Q15303 - regulated transcripts , including : proteases / protease inhibitors ( P08254 and P07093 ) , the YAP / Hippo pathway ( P29279 , O00622 , and P09486 ) , the mevalonate / cholesterol pathway ( P04035 , Q01581 , P01130 , and Q9UBM7 ) , and cytokines ( P10145 , P78556 , and P09341 ) . Many of these transcripts were subsequently validated in a luminal breast cancer cell line that normally expresses Q15303 . Furthermore , ChIP - seq experiments identified O75689 , P02649 , P09486 , P16949 , and Q05195 as novel molecular targets of Q15303 . These findings clarify the diverse biologic activities of Q15303 isoforms , and reveal new and divergent functions . IMPLICATIONS : ErbB4 as a regulator of Hippo and mevalonate pathways provides new insight into milk production and anabolic processes in normal mammary epithelia and cancer .",
"Current and emerging targeted therapies for metastatic breast cancer . The success of endocrine therapies for hormone receptor - positive breast cancer and trastuzumab and lapatinib for targeting human epidermal growth factor receptor 2 ( P04626 ) - positive tumors has paved the way for the clinical development of several other metastatic breast cancer ( MBC ) - targeted therapies . Although the benefit of the anti - P15692 ( vascular endothelial growth factor ) monoclonal antibody bevacizumab in the MBC setting has become a topic of debate , clinical trial results are accumulating , and phase 3 evaluations are ongoing for newer P04626 - targeted agents ( pertuzumab and trastuzumab - maytansine immunoconjugate ) and P15692 - targeted agents ( aflibercept ) , as well as dual , epidermal growth factor receptor / P04626 - targeted agents ( afatinib [ DB08916 ] and neratinib ) , multitargeted tyrosine kinase inhibitors ( sunitinib and pazopanib ) , and mammalian target of rapamycin ( everolimus ) and poly ( ADP - ribose ) polymerase 1 inhibitors ( iniparib , olaparib ) . These agents as well as other novel classes of anticancer agents are being tested in clinical trials with the potential of addressing unmet therapeutic needs in the MBC patient population .",
"Substance P autocrine signaling contributes to persistent P04626 activation that drives malignant progression and drug resistance in breast cancer . P00533 receptor transmodulation by heterologous G - protein - coupled receptors ( GPCR ) generates functional diversity in signal transduction . Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs . In this work , we found that the pain - associated tachykinin Substance P ( SP ) contributes to persistent transmodulation of the P00533 receptors , P00533 and P04626 , in breast cancer , acting to enhance malignancy and therapeutic resistance . SP and its high - affinity receptor P25103 were highly expressed in P04626 (+) primary breast tumors ( relative to the luminal and triple - negative subtypes ) and were overall correlated with poor prognosis factors . In breast cancer cell lines and primary cultures derived from breast cancer samples , we found that SP could activate P04626 . Conversely , RNA interference - mediated attenuation of P25103 , or its chemical inhibition , or suppression of overall GPCR - mediated signaling , all strongly decreased steady - state expression of P00533 and P04626 , establishing that their basal activity relied upon transdirectional activation by GPCR . Thus , SP exposure affected cellular responses to anti - P00533 therapies . Our work reveals an important oncogenic cooperation between P25103 and P04626 , thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored .",
"A phase II study of afatinib ( DB08916 ) , an irreversible ErbB family blocker , in patients with P04626 - positive metastatic breast cancer progressing after trastuzumab . DB08916 is an oral , ErbB family blocker , which covalently binds and irreversibly blocks all kinase - competent ErbB family members . This phase II , open - label , single - arm study explored afatinib activity in human epidermal growth factor receptor 2 ( P04626 ) - positive breast cancer patients progressing after trastuzumab treatment . Patients had stage IIIB / IV P04626 - positive metastatic breast cancer , with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group ( ECOG ) performance status of 0 - 2 . Patients received 50 mg afatinib once - daily until disease progression . Primary endpoint was objective response rate ( Response Evaluation Criteria in Solid Tumors 1 . 0 ) , with tumor assessments every 8 weeks . Forty - one patients were treated . Patients had received a median of three prior chemotherapy lines ( range , 0 - 15 ) and 68 . 3 % had received trastuzumab for > 1 year . Four patients ( 10 % of 41 treated ; 11 % of evaluable patients ) had partial response . Fifteen patients ( 37 % of 41 ) had stable disease as best response and 19 ( 46 % of 41 ) achieved clinical benefit . Median progression - free survival was 15 . 1 weeks ( 95 % confidence interval [ CI ] : 8 . 1 - 16 . 7 ) ; median overall survival was 61 . 0 weeks ( 95 % CI : 56 . 7 - not evaluable ) . Most frequent common terminology criteria for adverse events grade 3 treatment - related adverse events were diarrhea ( 24 . 4 % ) and rash ( 9 . 8 % ) . DB08916 monotherapy was associated with promising clinical activity in extensively pretreated P04626 - positive breast cancer patients who had progressed following trastuzumab treatment .",
"Phase II Study of DB08916 as Third - Line Treatment for Patients in Korea With Stage IIIB / IV Non - Small Cell Lung Cancer Harboring Wild - Type P00533 .",
"___MASK65___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK65___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK65___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK65___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK65___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"DB08916 in the treatment of head and neck squamous cell carcinoma . INTRODUCTION : Head and neck squamous cell carcinoma ( HNSCC ) is the sixth most common cause of cancer death in the United States . Treatment of locally advanced disease is associated with significant acute side effects and can lead to chronic disabilities , while the prognosis of recurrent or metastatic disease is very poor . This highlights the need for better therapeutic options . P00533 is overexpressed in 90 % of HNSCC patients and is an attractive therapeutic target in this patient population . DB08916 is a potent , irreversible pan - ErbB inhibitor . Preliminary studies in HNSCC show promising activity . AREAS COVERED : This article reviews the current data evaluating small molecules inhibitors of the ErbB family in the treatment of HNSCC with a specific emphasis on afatinib , a second - generation , irreversible , pan - ErbB inhibitor . It also provides a description of afatinib ' s drug characteristics , pharmacokinetics and toxicity profile as well as details of the published and ongoing clinical trials evaluating its efficacy in HNSCC patients . EXPERT OPINION : Phase II trials in HNSCC show that daily oral treatment with afatinib is tolerable . Most common toxicities are skin rash and diarrhea . DB08916 has clinical activity as a single agent in a subset of refractory and / or metastatic HNSCC patients . It is thought that ongoing Phase III trials should better clarify the role of this compound in the treatment of HNSCC .",
"Potential of afatinib in the treatment of patients with P04626 - positive breast cancer . In the absence of treatment , overexpression of the human epidermal growth factor receptor 2 ( P04626 ) predicts a poor prognosis in breast cancer . In the last decade , monoclonal antibodies and small molecule tyrosine kinase inhibitors have significantly improved the outcome of P04626 - positive breast cancer patients . However , tumor resistance and toxicities often limit the use of these therapies . For this reason , there is a compelling need for further investigation of new targeted therapies , such as afatinib , an oral irreversible pan inhibitor of the epidermal growth factor receptor ( P00533 ) family . This compound covalently interacts with tyrosine kinase domains , which are deeply involved in signal transduction leading to cell proliferation and protection from apoptosis . DB08916 has been studied in several Phase I clinical trials in advanced solid tumors . These trials have shown encouraging clinical activity and manageable side effects when afatinib is used either as a single agent or in combination with chemotherapy , with cutaneous adverse events and diarrhea being the most frequently observed toxicities . This review will focus on afatinib ' s clinical activity and will discuss ongoing clinical studies in P04626 - positive breast cancer patients . In the scenario of the different P04626 - targeted therapies , it will be important to define the best specific clinical and \" molecular \" setting for afatinib use , trying to identify predictors of resistance and response . Moreover , afatinib , which has the ability to cross the blood - brain barrier , could play a role in patients with brain metastases from breast cancer ."
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___MASK3___
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MH_train_405
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interacts_with DB08896?
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"Antagonism of endothelin action normalizes altered levels of P15692 and its signaling in the brain of stroke - prone spontaneously hypertensive rat . Stroke - prone spontaneously hypertensive rats ( SHRSP ) often suffer from spontaneous stroke , in part , due to abnormalities in the cerebrovasculature . Here , we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age - dependent stages of hypertension . The profile of P15692 and its receptor , Flk - 1 , was dependent on age and stage of hypertension ( i . e . , down regulated at pre - hypertensive and malignant hypertensive stages , but up regulated at typical hypertensive stage ) , while that of its downstream components , pAkt and P29474 , were down regulated in a time - dependent manner in the frontal cortex of SHRSP compared to age - matched genetic control , normotensive WKY rats . On the other hand , the expression of endothelin - 1 and its type A receptor ( endothelin P25101 receptor ) were up regulated , depending on age and stage of hypertension . In contrast , levels of endothelin type B receptor were down regulated . The regional cerebral blood flow decreased during the development of malignant hypertension . Thus , subsequent experiments were designed to investigate whether endothelin - 1 receptor antagonism , using endothelin - A /- B dual receptor antagonist SB209670 , could normalize the molecular profile of these factors in SHRSP brain . Interestingly , blockage of endothelin - 1 receptor restored to normal , levels of cerebral endothelin - 1 , endothelin P25101 receptor and endothelin ETB receptor ; P15692 and Flk - 1 ; endothelial nitric oxide synthase ( P29474 ) and pAkt , in SHRSP , compared to age - matched WKY . Endothelin receptor blocker might be important to prevent the progression in the defect in P15692 and its angiogenic signaling cascade in the pathogenesis of hypertension - induced vascular remodeling in frontal cortex of SHRSP rats .",
"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK82___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK82___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .",
"P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .",
"Altered endothelin receptor expression and affinity in spontaneously hypertensive rat cerebral and coronary arteries . BACKGROUND : Hypertension is associated with arterial hyperreactivity , and endothelin ( ET ) receptors are involved in vascular pathogenesis . The present study was performed to examine the hypothesis that ET receptors were altered in cerebral and coronary arteries of spontaneously hypertensive rats ( SHR ) . METHODOLOGY / PRINCIPAL FINDINGS : Cerebral and coronary arteries were removed from SHR . Vascular contraction was recorded using a sensitive myograph system . Real - time PCR and Western blotting were used to quantify mRNA and protein expression of receptors and essential MAPK pathway molecules . The results demonstrated that both P25101 and ETB receptor - mediated contractile responses in SHR cerebral arteries were shifted to the left in a nonparallel manner with increased maximum contraction compared with Wistar - Kyoto ( WKY ) rats . In SHR coronary arteries , the P25101 receptor - mediated contraction curve was shifted to the left in parallel with an increased pEC50 compared with the arteries in WKY rats . There was no significant increase in ETB receptor - mediated contraction in SHR coronary arteries . P25101 receptor mRNA and protein expression was increased in SHR cerebral arteries compared with the arteries in WKY rats . However , P25101 receptor mRNA and protein levels in coronary arteries and ETB receptor protein levels in cerebral and coronary arteries remained unchanged in SHR compared with WKY rats . Meanwhile , phosphorylated P27361 / 2 protein was significantly increased in SHR brain and heart vessels . CONCLUSIONS / SIGNIFICANCE : In SHR cerebral arteries , P25101 receptor expression was upregulated . P25101 receptor affinity was increased in coronary arteries , and ETB receptor affinity was increased in cerebral arteries . The P27361 / 2 activation may be involved in the receptor alterations .",
"DB08896 for treatment of advanced gastrointestinal stromal tumors . INTRODUCTION : Gastrointestinal stromal tumors ( GISTs ) are abdominal sarcomas which are extremely refractory to chemotherapy treatment . The treatment of GISTs has been revolutionized by use of P10721 / platelet - derived growth factor receptor - α ( P16234 ) kinase inhibitors . Unfortunately , most tumors develop resistance to front - line ( imatinib ) or second - line ( sunitinib ) therapy . DB08896 , a P10721 / P16234 / vascular endothelial growth factor receptor ( VEGFR ) oral kinase inhibitor , has been shown to improve progression - free survival in the third - or fourth - line setting . AREAS COVERED : This review covers the preclinical and clinical studies of regorafenib for treatment of GIST . A literature search on regorafenib was carried out using the PubMed database up to October 2013 . EXPERT OPINION : Currently , imatinib and sunitinib represent the only proven first - and second - line therapies , respectively , for advanced GISTs . Based on the results of a Phase III study , regorafenib is now established as the only proven third - line therapy . DB08896 activity in this setting is believed to be due to its activity against oncogenic forms of P10721 / P16234 . Although side effects are common with this agent , they can be effectively managed with a combination of supportive care , dose interruptions / reductions . The toxicity profile is similar to other oral kinase inhibitors with anti - VEGFR activity . DB08896 is mainly metabolized by P08684 , and concomitant use of strong inducers / inhibitors of this enzyme should be avoided .",
"Ehrlichia chaffeensis induces monocyte inflammatory responses through MyD88 , P29323 , and NF - κB but not through Q8IUC6 , interleukin - 1 receptor 1 ( IL - 1R1 ) / Q13478 , or toll - like receptors . Human monocytic ehrlichiosis , an influenza - like illness accompanied by signs of hepatitis , is caused by infection of monocytes / macrophages with a lipopolysaccharide - deficient bacterium , Ehrlichia chaffeensis . The E . chaffeensis strain Wakulla induces diffuse hepatitis with neutrophil infiltration in mice with severe combined immunodeficiency , which is accompanied by strong P19875 ( mouse functional homolog of interleukin - 8 [ P10145 ] ) and tumor necrosis factor alpha ( P01375 - α ) expression in the liver . In this study , we found that expression of IL - 1β , P19875 , and P01375 - α was induced by strain Wakulla in mouse bone marrow - derived macrophages ; this expression was dependent on MyD88 , but not on Q8IUC6 , O60603 / 4 , IL - 1R1 / Q13478 , or endosome acidification . When the human leukemia cell line THP - 1 was exposed to E . chaffeensis , significant upregulation of P10145 , IL - 1β , and P01375 - α mRNA and extracellular regulated kinase 2 ( P28482 ) activation were detected . U0126 ( inhibitor of mitogen - activated protein kinase / extracellular signal - regulated kinase kinase 1 / 2 [ Q02750 / 2 ] upstream of P29323 ) , manumycin A ( Ras inhibitor ) , BAY43 - 9006 ( P04049 inhibitor ) , and NS - 50 ( inhibitor of NF - κB nuclear translocation ) inhibited the cytokine gene expression . A luciferase reporter assay using HEK293 cells , which lack Toll - like receptors ( TLRs ) , showed activation of both the P10145 promoter and NF - κB by E . chaffeensis . Activation of the P10145 promoter in transfected HEK293 cells was inhibited by manumycin A , BAY43 - 9006 , U0126 , and transfection with a dominant - negative Ras mutant . These results indicate that the E . chaffeensis Wakulla strain can induce inflammatory responses through MyD88 - dependent NF - κB and P29323 pathways , without the involvement of Q8IUC6 and TLRs .",
"Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc - dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan - HDAC inhibitor ___MASK61___ ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil - tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down - regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and ___MASK61___ . Tubacin in combination with ___MASK61___ or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan - caspase inhibitor Z - VAD - fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 , an early marker of DNA double - strand breaks . Tubacin enhances DNA damage induced by etoposide or ___MASK61___ as indicated by increased accumulation of γ P16104 and activation of the checkpoint kinase Chk2 . Tubacin induces the expression of P35638 ( P35638 / P35638 ) , a transcription factor up - regulated in response to cellular stress . P35638 induction is further increased when tubacin is combined with ___MASK61___ . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti - cancer agents in transformed cells .",
"The preclinical development of regorafenib for the treatment of colorectal cancer . INTRODUCTION : The DB01367 - RAF - MEK - P29323 pathway is one of the best characterized kinase cascades . During the exploration of small molecules that inhibit P04049 kinase , regorafenib ( DB08896 ) was discovered as a multikinase inhibitor which demonstrated anti - cancer , anti - angiogenic , and apoptotic activities in metastatic colorectal cancer . This was not the first multikinase inhibitor discovered for the disease ; indeed , before regorafenib was approved by FDA as a multikinase inhibitor for metastatic colorectal cancer in 2012 , sorafenib ( BAY 43 - 9006 ) had already been developed to be the first in the world as a multikinase inhibitor for malignancy . Indeed , the only difference between the two compounds is fluorine bound to its proximal phenyl ring although the end result is a considerably different profile , both as a kinase inhibitor as well as in its clinical application . AREAS COVERED : In this drug discovery case history , the authors review the design , discovery , and development of both regorafenib and sorafenib from back in the 1990s . Furthermore , the authors highlight the drug ' s anti - cancer and anti - angiogenic properties as well as its efficacy , safety pharmacology and toxicology based on FDA documents . EXPERT OPINION : In order to better predict the efficacy of kinase inhibitors and to utilize them more efficiently , our understanding of drug discovery , the approaches for kinase profiling , and technologies needed for their development are paramount . Indeed , the authors believe that the field should better explore the use of predictive biomarkers that might be able to better assess these therapeutics . Pharmaceutical scientists must also consider the cost effectiveness of the targeted agents developed as a number of the drugs developed are very expensive .",
"[ Protein microarray analysis on changes in protein phosphorylation in recurrent nasopharyngeal carcinoma ] . OBJECTIVE : To compare the differential phosphorylation level of proteins between relapsed nasopharyngeal carcinoma ( rNPC ) and primary nasopharyngeal carcinoma ( pNPC ) . METHODS : Total protein was extracted from 4 pNPC tissue and 4 rNPC tissue samples from January 2003 to September 2005 . Then it was analyzed by antibody microarray with 656 antibodies . The differential phosphorylation level of proteins was screened and clustering analysis conducted . The phosphorylation status of the protein sites and its functional pathways were analyzed via an online database of PhosphoSite Plus . The protein expressions were detected by immunohistochemistry . RESULTS : Relapsed and primary nasopharyngeal carcinomas had differential phosphorylation level of proteins . And 6 differentially expressed proteins were identified . The phosphorylation levels of P10721 , P05023 , Synapsin , P45985 and histone P16104 were up - regulated in rNPC ( P = 0 . 007 - 0 . 048 ) while c - Jun was down - regulated ( P = 0 . 030 ) . The expression of P - P16104 in rNPC was significantly higher than that in pNPC [ 0 . 390 ( 0 . 175 ) vs 0 . 290 ( 0 . 155 ) ] , but p - c - Jun was significantly lower in rNPC than that in pNPC [ 0 . 625 ( 0 . 145 ) vs 0 . 725 ( 0 . 178 ) ] ( both P < 0 . 05 ) . Among them , the changes in the phosphorylation levels of c - Jun , histone P16104 , P45985 and P10721 might play important roles in the relapse of NPC through improving DNA damage repair ability , inhibiting apoptosis and promoting tumorigenesis . CONCLUSION : The changes of protein phosphorylation may help to explain the recurrent mechanisms of NPC and provide new therapeutic anti - recurrence targets .",
"Loss of the candidate tumor suppressor Q14201 triggers acute cellular senescence via the P29323 - O15054 - p16 ( INK4a ) signaling axis . The B - cell translocation gene 3 ( Q14201 ) is a member of the antiproliferative BTG gene family and a downstream target of p53 . Q14201 also binds and inhibits Q01094 . Although it connects functionally two major growth - regulatory pathways , the physiological role of Q14201 remains largely uncharacterized . Here , we present evidence that loss of Q14201 in normal cells induced cellular senescence , which was correlated with enhanced P29323 - P05412 signaling and elevated expression of the histone H3K27me3 demethylase O15054 / O15054 , leading to acute induction of p16 ( INK4a ) . Importantly , we also found that Q14201 expression is specifically downregulated in prostate cancer , thus providing a physiological link with human cancers . Our data suggest that Q14201 may have a fail - safe role against tumorigenic progression .",
"Biological and molecular effects of small molecule kinase inhibitors on low - passage human colorectal cancer cell lines . Low - passage cancer cell lines are versatile tools to study tumor cell biology . Here , we have employed four such cell lines , established from primary tumors of colorectal cancer ( CRC ) patients , to evaluate effects of the small molecule kinase inhibitors ( SMI ) vemurafenib , trametinib , perifosine , and regorafenib in an in vitro setting . The mutant P15056 ( V600E / V600K ) inhibitor vemurafenib , but also the Q02750 / 2 inhibitor trametinib efficiently inhibited DNA synthesis , signaling through P27361 / 2 and expression of genes downstream of P27361 / 2 in P15056 mutant cells only . In case of the AKT inhibitor perifosine , three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant . The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of P01116 , P15056 , P42336 , and P04637 mutations . DB08896 action was associated with broad - range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK / P29323 signaling . In vemurafenib - sensitive cells , the antiproliferative effect of vemurafenib was enhanced by the other SMI . Together , our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low - passage CRC cell lines as preclinical models .",
"Endothelial progenitor cells in relation to endothelin - 1 and endothelin receptor blockade : a randomized , controlled trial . AIMS : Endothelial progenitor cells ( EPC ) represent an endogenous repair mechanism involving rendothelialization and neoangiogenesis . Patients with both diabetes and vascular disease have low numbers of circulating EPC . The endothelium - derived peptide , endothelin - 1 ( ET - 1 ) , is increased in patients with type 2 diabetes and vascular complications and has been suggested to contribute to endothelial dysfunction . Therefore , we investigated the relation between EPC and plasma ET - 1 and the effect of dual ET - 1 receptor antagonist treatment . METHODS : In this double blind study patients with type 2 diabetes mellitus and microalbuminuria were randomized to treatment with the dual P25101 / ETB receptor antagonist ___MASK82___ treatment ( 125mg bid ; n = 17 ) or placebo ( n = 19 ) for four weeks . Different EPC subpopulations were enumerated by flow cytometry using triple staining ( P28906 , CD133 , P35968 ) at baseline at the end of treatment . Viability was assessed by 7AAD and Annexin - V - staining . RESULTS : Baseline ET - 1 levels correlated significantly with P02741 levels . Patients with ET - 1 levels above the median value had higher levels of P28906 (+) CD133 (+) and P28906 (+) P35968 (+) EPC . There was no difference in P28906 (+) and P28906 (+) CD133 (+) P35968 (+) cells , markers of EPC apoptosis or circulating markers of endothelial damage between patients with ET - 1 levels below or above the median . Four week treatment with ___MASK82___ did not change EPC levels . CONCLUSION : Among patients with type 2 diabetes and vascular disease , high plasma levels of ET - 1 are associated with higher number of EPC . The recruitment of EPC does not seem to be regulated via ET - 1 receptor activation since treatment with a dual ET - 1 receptor blocker did not affect circulating EPC numbers .",
"Receptor tyrosine kinase and downstream signalling analysis in diffuse malignant peritoneal mesothelioma . Our aim was to assess the activation profile of P00533 , P09619 and P16234 receptor tyrosine kinases ( RTK ) and their downstream effectors in a series of cryopreserved diffuse malignant peritoneal mesothelioma ( DMPM ) surgical specimens to discover the targets for drug inhibition . We also made a complementary analysis of the cytotoxic effects of some kinase inhibitors on the proliferation of the human peritoneal mesothelioma STO cell line . We found the expression / phosphorylation of P00533 and P09619 in most of the tumours , and P16234 activation in half . The expression of the cognate ligands TGF - α , PDGFB and P04085 in the absence of RTK mutation and amplification suggested the presence of an autocrine / paracrine loop . There was also evidence of P00533 and P09619 co - activation . RTK downstream signalling analysis demonstrated the activation / expression of P27361 / 2 , AKT and P42345 , together with S6 and 4EBP1 , in almost all the DMPMs . No P01116 / P15056 mutations , PI3KCA mutations / amplifications or P60484 inactivation were observed . Real - time polymerase chain reaction revealed the decreased expression of Q92574 c - DNA in half of the tumours . In vitro cytotoxicity studies showed the STO cell line to be resistant to gefitinib and sensitive to sequential treatment with RAD001 and sorafenib ; these findings were consistent with the presence of the P01116 mutation G12D in these cells although it was not detectable in the original tumour . Our results highlight the ligand - dependent activation and co - activation of P00533 and P09619 , as well as a connection between these activated RTKs and the downstream P42345 pathway , thus supporting the role of combined treatment with RTK and P42345 inhibitors in DMPM .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK25___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"Rational design of an P01133 - Q14116 fusion protein : implication for developing tumor therapeutics . Q14116 ( Q14116 ) is a proinflammatory cytokine . This protein has a role in regulating immune responses and exhibits significant anti - tumor activities . Epidermal growth factor ( P01133 ) is an important growth factor that plays a central role in the regulation of cell cycle and differentiation . It was proposed that a targeted delivery of Q14116 by generation of Q14116 - P01133 fusion protein might decrease adverse effects and result in enhancing cytotoxic and antitumor activities . In the present study , a fusion protein , consisting of P00533 binding domain fused to human Q14116 mature peptide via a linker peptide of ( DB00145 ( 4 ) DB00133 ) 3 , was constructed and expressed in the insect cell line Sf9 using Bac - to - Bac baculovirus expression system . We showed that the purified recombinant fusion protein induced similar levels of P01579 to that of native Q14116 protein in human PBMC in the presence of ConA . Furthermore , P01133 receptor competitive test in human epithelial cancer A431 cell line showed that P01133 - Q14116 fusion protein can specifically bind with P00533 by competing with native P01133 protein . These suggest that this rationally designed protein can be further developed as novel tumor therapeutics .",
"Novel withanolides target medullary thyroid cancer through inhibition of both P07949 phosphorylation and the mammalian target of rapamycin pathway . BACKGROUND : Despite development of current targeted therapies for medullary thyroid cancer ( P04629 ) , long - term survival remains unchanged . Recently isolated novel withanolide compounds from Solanaceae physalis are highly potent against MTCs . We hypothesize that these withanolides uniquely inhibit P07949 phosphorylation and the mammalian target of rapamycin ( P42345 ) pathway in P04629 cells as a mechanism of antiproliferation and apoptosis . METHODS : P04629 cells were treated with novel withanolides and P04629 - targeted drugs . In vitro studies assessed cell viability and proliferation ( MTS ; trypan blue assays ) , apoptosis ( flow cytometry with P08758 / PI staining ; confirmed by Western blot analysis ) , long - term cytotoxic effects ( clonogenic assay ) , and suppression of key regulatory proteins such as P07949 , Akt , and P42345 ( by Western blot analysis ) . RESULTS : The novel withanolides potently reduced P04629 cell viability ( half maximal inhibitory concentration [ IC ( 50 ) ] , 270 - 2 , 850 nmol / L ; 250 - 1 , 380 nmol / L for vandetanib ; 360 - 1 , 640 nmol / L for cabozantinib ) with induction of apoptosis at < 1 , 000 nmol / L of drug . Unique from other targeted therapies , withanolides suppressed P07949 and Akt phosphorylation and protein expression ( in a concentration - and time - dependent manner ) as well as P42345 activity and translational activity of Q13541 and protein synthesis mediated by p70S6kinase activation at IC ( 50 ) concentrations . CONCLUSION : Novel withanolides from Physalis selectively and potently inhibit P04629 cells in vitro . Unlike other P04629 - targeted therapies , these compounds uniquely inhibit both P07949 kinase activity and the Akt / P42345 prosurvival pathway . Further translational studies are warranted to evaluate their clinical potential .",
"Serotonin transporter interacts with the PDGFβ receptor in DB00102 - induced signaling and mitogenesis in pulmonary artery smooth muscle cells . The serotonin transporter ( P31645 ) and the platelet - derived growth factor receptor ( P09619 ) have been implicated in both clinical and experimental pulmonary hypertension ( PH ) and the facilitation of pulmonary artery smooth muscle cell ( PASMC ) growth . To gain a better understanding of the possible relationship of these two cell surface molecules we have explored interactions between P31645 and P09619 . We have previously demonstrated that P31645 transactivates PDGFRβ in serotonin - stimulated PASMC proliferation . We now provide evidence for a role for P31645 in DB00102 signaling and PASMC proliferation by using pharmacological inhibitors , genetic ablation , and construct overexpression of P31645 . The results show that four tested P31645 blockers dose dependently inhibit PDGF - stimulated human and bovine PASMC proliferation with comparable efficacy to that of P09619 inhibitors , whereas P28222 or 5 - Q13049 receptor inhibitors had no effect . Combinations of the P31645 and P09619 inhibitors led to synergistic / additive inhibition . Similarly , PDGF - induced PASMC proliferation was attenuated by small interfering RNA downregulation of P31645 . Inhibition of P31645 in PASMCs attenuated PDGF - induced phosphorylation of PDGFRβ , Akt , and p38 but not Erk . Overexpression of P31645 in HEK293 cells led to enhanced Akt phosphorylation by PDGF , which was blunted by a P31645 PDZ motif mutant , indicating the mechanistic need for the PDZ motif of P31645 in PDGF signaling . Furthermore , coimmunoprecipitation experiments showed that P31645 and PDGFRβ become physically associated upon PDGF stimulation . In total , the data show for the first time an important interactive relationship between P31645 and the PDGFRβ in the production of PASMC proliferation triggered by PDGF that may be important in PH .",
"___MASK61___ , an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening P42345 signaling pathway in a human xenograft murine model . Histone deacetylase ( HDAC ) inhibitors are potent anticancer agents and show efficacy against various human neoplasms . ___MASK61___ is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors . However , its effect on the growth of skin neoplasm remains undefined . In this study , we show that vorinostat ( 2 μM ) reduced expression of Q13547 , 2 , 3 , and 7 in epidermoid carcinoma A431 cells . Consistently , it increased acetylation of histone H3 and p53 . ___MASK61___ ( 100mg / kg body weight , IP ) treatment reduced human xenograft tumor growth in highly immunosuppressed nu / nu mice . Histologically , the vorinostat - treated tumor showed features of well - differentiation with large necrotic areas . Based on proliferating cell nuclear antigen ( P12004 ) staining and expression of cyclins D1 , D2 , E , and A , vorinostat seems to impair proliferation by down - regulating the expression of these proteins . However , it also induced apoptosis . The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis , involved inhibition of P42345 signaling which was accompanied by reduction in cell survival AKT and extracellular - signal regulated kinase ( P29323 ) signaling pathways . Our data provide a novel mechanism - based therapeutic intervention for cutaneous squamous cell carcinoma ( SCC ) . ___MASK61___ may be utilized to cure skin neoplasms in organ transplant recipient ( OTR ) . These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients , is difficult .",
"DB08896 in metastatic colorectal cancer . DB08896 is an oral multikinase inhibitor that blocks the activity of protein kinases involved in the regulation of tumor angiogenesis ( P17948 , 2 , 3 ; angiopoietin - 1 receptor ) , oncogenesis ( stem cell growth factor receptor ; P07949 ; P15056 including BRAFV600E ) , and tumor microenvironment ( P09619 - β and FGFR ) . Based on data from the Phase III CORRECT study , regorafenib stands as a further option for patient affected by metastatic colorectal cancer who have exhausted previous available therapies . Its multi - targeted effect might explain activity in advanced lines of treatment , when cancer cells have been heavily challenged with previous lines of therapy and potentially developed multiple mechanisms of resistance , but also makes difficult to identify predictive biomarkers . In this article we examine preclinical as well as clinical data of regorafenib in the therapy of metastatic colorectal cancer , challenges for potential markers of efficacy and its role in the treatment algorithm .",
"DB08896 ( DB08896 ) : stromal and oncogenic multikinase inhibitor with potential activity in renal cell carcinoma . The introduction of targeted therapies , specifically those that target the P15692 receptor ( VEGFR ) , PDGF receptor ( P09619 ) and the P42345 pathways , has significantly changed the approach to patients with unresectable renal cell cancer ( RCC ) . However , drug resistance develops through bypassing of targeted pathways . DB08896 ( DB08896 ) is a novel bi - aryl urea compound that has potential anti - tumour activity in RCC , as along with targeting P15692 and PDGF receptors , it targets additional kinases associated with alternative pathways of angiogenesis and resistance to P15692 - targeted drugs . Based on a phase II clinical trial , the efficacy outcome of regorafenib in the first - line setting of unresectable RCC appears comparable that of other targeted first - line drugs . However , testing regorafenib in standard phase III trials seems inappropriate in view of its toxic effects . Further assessment of regorafenib should exploit the drug ' s ability to inhibit mechanisms of escape from anti - angiogenic treatment through biomarker - driven clinical trials .",
"DB08896 for cancer . INTRODUCTION : DB08896 ( DB08896 ) is a novel , orally active , diphenylurea multikinase inhibitor of P17948 - 3 , c - P10721 , P35590 - 2 , P09619 - β , P11362 , P07949 , RAF - 1 , P15056 and p38 Q96HU1 kinase . AREAS COVERED : This review covers the preclinical development of regorafenib as well as the pivotal Phase I studies . The safety profile of regorafenib is discussed in context with other oral multikinase inhibitors bearing a similar target profile . Current clinical developments , especially in colorectal cancer ( CRC ) and gastrointestinal stromal tumor ( GIST ) , are addressed . Open questions on clinically useful biomarkers predicting response with regard to a personalized therapy strategy are also being discussed . EXPERT OPINION : DB08896 ( DB08896 ) is a novel , orally active multikinase inhibitor that is well tolerated in preclinical mouse models as well as clinically according to Phase I - III trials performed . The toxicity profile is comparable with other oral multikinase inhibitors with similar molecular targets . DB08896 has promising antineoplastic activity in various tumor types . Two large , randomized Phase III pivotal registration studies in patients with GIST and CRC , respectively , already completed enrolment , with final results being awaited . Further extensive clinical development as a single agent or in combination with standard chemotherapeutic agents in various malignant tumors is ongoing . Moreover , regorafenib has recently been granted Orphan Drug Status for GIST tumors and ' fast track ' status for both GIST and CRC by the FDA .",
"DB08896 ( DB08896 ) : a new oral multikinase inhibitor of angiogenic , stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity . Angiogenesis , a critical driver of tumor development , is controlled by interconnected signaling pathways . Vascular endothelial growth factor receptor ( VEGFR ) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature . DB08896 ( DB08896 ) , a novel oral multikinase inhibitor , potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays . Furthermore , regorafenib inhibits additional angiogenic kinases ( P17948 / 3 , platelet - derived growth factor receptor - β and fibroblast growth factor receptor 1 ) and the mutant oncogenic kinases P10721 , P07949 and B - RAF . The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast - enhanced magnetic resonance imaging . DB08896 administered once orally at 10 mg / kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts . In a daily ( qd )× 4 dosing study , the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition ( TGI ) . A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd × 5 dosing at 10 and 30 mg / kg . DB08896 exhibited potent dose - dependent TGI in various preclinical human xenograft models in mice , with tumor shrinkages observed in breast MDA - MB - 231 and renal 786 - O carcinoma models . Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki - 67 and phosphorylated extracellular regulated kinases 1 / 2 . These data demonstrate that regorafenib is a well - tolerated , orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies .",
"Loss of expression of the double strand break repair protein Q13315 is associated with worse prognosis in colorectal cancer and loss of P12956 expression is associated with Q96GD0 . Repair of double strand DNA breaks ( DSBs ) is pivotal in maintaining normal cell division and disruption of this system has been shown to be a key factor in carcinogenesis . Loss of expression of the DSB repair proteins have previously been shown to be associated with poorer survival in colorectal cancer . We wished to ascertain the relationship of altered expression of the DSB repair proteins γ - P16104 ( gamma - P16104 ) , Q13315 and P12956 with biological and clinico - pathological features of colorectal cancer . 908 tumours from the VICTOR clinical trial of stage II / III colorectal cancer were analysed for expression of γ - P16104 , Q13315 and P12956 using immunohistochemistry . Expression levels were correlated with Q96GD0 and with disease - free survival , correcting for microsatellite instability , P15056 / P01116 mutation status , Dukes stage , chemo / radiotherapy , age , gender and tumour location . Down - regulated P12956 expression was associated with chromosomal instability ( p = 0 . 029 ) in colorectal cancer . Reduced Q13315 expression was an independent marker of poor disease - free survival ( HR = 1 . 67 , 95 % CI 1 . 11 - 2 . 50 , p = 0 . 015 ) . For P12956 , further studies are required to investigate the potential relationship of non - homologous end joining with chromosomal instability . Loss of Q13315 expression might serve as a biomarker of poor prognosis in colorectal cancer .",
"Telocytes in liver regeneration : possible roles . Telocytes ( TCs ) are a novel type of interstitial cells which are potentially involved in tissue regeneration and repair ( www . telocytes . com ) . Previously , we documented the presence of TCs in liver . However , the possible roles of TCs in liver regeneration remain unknown . In this study , a murine model of partial hepatectomy ( PH ) was used to induce liver regeneration . The number of TCs detected by double labelling immunofluorescence methods ( P28906 / P09619 - α , P28906 / P09619 - ß and P28906 / P08670 ) was significantly increased when a high level of hepatic cell proliferation rate ( almost doubled ) as shown by 5 - ethynyl - 2 '- deoxyuridine ( EdU ) immunostaining and Western Blot of P12004 ( P12004 ) was found at 48 and 72 hrs post - PH . Meanwhile , the number of P08727 positive - hepatic stem cells peaked at 72 hrs post - PH , co - ordinating with the same time - point , when the number of TCs was most significantly increased . Taken together , the results indicate a close relationship between TCs and the cells essentially involved in liver regeneration : hepatocytes and stem cells . It remains to be determined how TCs affect hepatocytes proliferation and / or hepatic stem cell differentiation in liver regeneration . Besides intercellular junctions , we may speculate a paracrine effect via ectovesicles .",
"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .",
"P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV - associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . ___MASK63___ , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV - induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R .",
"Distinct signalling pathways of murine histamine H1 - and H4 - receptors expressed at comparable levels in HEK293 cells . DB11320 ( HA ) is recognized by its target cells via four G - protein - coupled receptors , referred to as histamine H1 - receptor ( P35367 ) , P25021 , Q9Y5N1 , and Q9H3N8 . Both P35367 and Q9H3N8 exert pro - inflammatory functions . However , their signal transduction pathways have never been analyzed in a directly comparable manner side by side . Moreover , the analysis of pharmacological properties of the murine orthologs , representing the main targets of pre - clinical research , is very important . Therefore , we engineered recombinant HEK293 cells expressing either mouse ( m ) P35367 or mH4R at similar levels and analyzed HA - induced signalling in these cells . HA induced intracellular calcium mobilization via both mH1R and mH4R , with the mH1R being much more effective . Whereas DB02527 accumulation was potentiated via the mH1R , it was reduced via the mH4R . The regulation of both second messengers via the Q9H3N8 , but not the P35367 , was sensitive to pertussis toxin ( PTX ) . The mitogen - activated protein kinases ( MAPKs ) P29323 1 / 2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA - induced P18146 gene expression . The p38 MAPK was moderately activated via both receptors as well , but was functionally involved in HA - induced P18146 gene expression only in Q9H3N8 - expressing cells . Surprisingly , in this system p38 MAPK activity reduced the HA - induced gene expression . In summary , using this system which allows a direct comparison of mH1R - and mH4R - induced signalling , qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident .",
"Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib - pairs in 64 sib - ships from families ascertained by early - onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib - pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK24___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK61___ ( ___MASK61___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK61___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK61___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .",
"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .",
"Critical appraisal of the use of regorafenib in the management of colorectal cancer . The lack of valid clinical management options for patients affected by metastatic colorectal cancer , which has progressed after all approved standard treatments , has lead to research into new active molecules . DB08896 is an oral small - molecule multi kinase inhibitor , binding to several intracellular kinases , with powerful inhibitory activity against vascular endothelial growth factor receptors ( P17948 , P35968 , and P35916 ) , platelet - derived growth factor receptor , fibroblast growth factor receptor 1 , Raf , P35590 - 2 , and the kinases P10721 , P07949 , and P15056 . The antitumor activity of regorafenib has been tested in vitro and in vivo , and inhibition of tumor growth has been observed in several cancer models , particularly colorectal cancer and gastrointestinal stromal tumors . The most frequent adverse events of grade 3 or higher related to regorafenib were hand - foot skin reaction , fatigue , diarrhea , hypertension , and rash or desquamation . Only a few Phase I - II trials , and most recently a Phase III trial in pretreated colorectal cancer , have been carried out to date . Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy . At this point in time , regorafenib is the first small - molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients .",
"A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re - vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly - developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 - based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically - used drugs operating on the P00797 - Angiotensin - DB04630 - System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point - of - no - return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling - reversing drugs to pathways other than RAAS , a specific inhibitor of 11β - hydroxy - steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy - associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization - induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling - reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects .",
"Lipoteichoic acid induces matrix metalloproteinase - 9 expression via transactivation of PDGF receptors and NF - kappaB activation in rat brain astrocytes . Bacterial infections have been shown to be involved in several inflammatory diseases such as brain inflammation . A major factor for these findings is due to the secretion of pro - inflammatory mediators by host cells triggered by the components released from the bacteria . Among these components , lipoteichoic acid ( P01374 ) , a component of Gram - positive bacterial cell wall , has been found to be elevated in cerebrospinal fluid of patients suffering from meningitis . Moreover , increased plasma levels of matrix metalloproteinases ( MMPs ) , in particular P14780 , have been observed in patients with brain inflammatory diseases and may contribute to disease pathology . However , the molecular mechanisms underlying P01374 - induced P14780 expression in rat brain astrocytes ( RBA - 1 cells ) remain poorly defined . Here , the data with zymographic , Western blotting , RT - PCR , and immunofluorescent staining analyses showed that P01374 induced P14780 expression and activation via a O60603 - activated c - Src - dependent transactivation of P09619 pathway . Transactivation of P09619 led to activation of PI3K / Akt and Q8NFH3 / Q8TCB0 MAPK and then activated the IKK / NF - kappaB cascade . The activated - NF - kappaB translocated into nucleus which bound to kappaB - binding site of P14780 promoter , and thereby turned on transcription of P14780 . Eventually , upregulation of P14780 by P01374 enhanced cell migration of astrocytes . Taken together , these results suggested that in RBA - 1 cells , activation of NF - kappaB by a c - Src - dependent PI3K / Akt - Q8NFH3 / Q8TCB0 MAPK activation mediated through transactivation of P09619 is essential for P14780 gene upregulation induced by P01374 . Understanding the regulation of P14780 expression and functional changes by P01374 / TLR system on astrocytes may provide potential therapeutic targets of Gram - positive bacterial infection in brain disorders .",
"DNA microarray reveals different pathways responding to paclitaxel and docetaxel in non - small cell lung cancer cell line . The wide use of paclitaxel and docetaxel in NSCLC clinical treatment makes it necessary to find biomarkers for identifying patients who can benefit from paclitaxel or docetaxel . In present study , NCI - H460 , a NSCLC cell line with different sensitivity to paclitaxel and docetaxel , was applied to DNA microarray expression profiling analysis at different time points of lower dose treatment with paclitaxel or docetaxel . And the complex signaling pathways regulating the drug response were identified , and several novel sensitivity - realted markers were biocomputated . The dynamic changes of responding genes showed that paclitaxel effect is acute but that of docetaxel is durable at least for 48 hours in NCI - H460 cells . Functional annotation of the genes with altered expression showed that genes / pathways responding to these two drugs were dramatically different . Gene expression changes induced by paclitaxel treatment were mainly enriched in actin cytoskeleton ( P68032 , P10916 and Q9UKX2 ) , tyrosine - protein kinases ( ERRB4 , P10721 and P35590 ) and focal adhesion pathway ( P10916 , IGF1 and P17948 ) , while the expression alterations responding to docetaxel were highly co - related to cell surface receptor linked signal transduction ( SHH , P21918 and Q7Z4H4 ) , cytokine - cytokine receptor interaction ( P01583 and P05231 ) and cell cycle regulation ( P14635 , O96020 and P12004 ) . Moreover , we also confirmed some different expression patterns with real time PCR . Our study will provide the potential biomarkers for paclitaxel and docetaxel - selection therapy in clinical application .",
"Complementary and alternative medicine use and quality of life in patients with primary brain tumors . This study explored the use of complementary and alternative medicine ( P62158 ) approaches and their relationship with demographic and disease characteristics and quality of life ( QOL ) in the primary brain tumor ( P10721 ) population . One hundred one P10721 patients were enrolled in this study . The results showed that 34 % of patients reported using P62158 . Forty - one percent reported using more than one type of P62158 . The average cost of each P62158 used per month was 69 dollars , with 20 % of patients spending more than 100 dollars per month . The majority ( 74 % ) reported that their physicians were unaware of their use of P62158 . Data analysis found a higher performance status to be the only factor significantly related to use of P62158 therapy ( P < 0 . 005 ) . There was no difference in patient report of QOL between users and nonusers of P62158 therapies . The high number of patients who do not report P62158 use has potential implications for evaluation of symptoms and response to therapy in this population . This may be especially relevant in those patients with higher functional status participating in clinical trials .",
"Combining resonance energy transfer methods reveals a complex between the alpha2A - adrenergic receptor , Galphai1beta1gamma2 , and P25098 . Traditionally , G - protein - coupled receptor ( GPCR ) interactions with their G proteins and regulatory proteins , GPCR kinases ( GRKs ) and arrestins , are described as sequential events involving rapid assemblies / disassemblies . To directly monitor the dynamics of these interactions in living cells , we combined two spectrally resolved bioluminescence and one fluorescence resonance energy transfer ( P07949 ) methods . The P07949 combination analysis revealed that stimulation of the α ( 2A )- adrenergic receptor ( α ( 2A ) AR ) leads to the recruitment of P25098 at a receptor still associated with the Gα ( i1 ) β ( 1 ) γ ( 2 ) complex . The interaction kinetics of GRKs with Gγ ( 2 ) ( 2 . 8 ± 0 . 4 s ) and α ( 2A ) AR ( 5 . 2 ± 0 . 5 s ) were similar to that of the receptor - promoted change in P07949 between Gα ( i1 ) and Gγ ( 2 ) ( 5 . 2 ± 1 . 2 s ) , and persisted until the translocation of βarrestin2 to the receptor , indicating that P25098 remains associated to the receptor / G - protein complex for longer periods than anticipated . Moreover , P25098 or a kinase - deficient P25098 mutant , but not P34947 , potentiated the receptor - promoted changes in P07949 between Gα ( i1 ) and Gγ ( 2 ) and abrogated the α ( 2A ) AR - stimulated calcium response , suggesting that the recruitment of P25098 to the complex contributes to the structural rearrangement and functional regulation of the signaling unit , independently of the kinase activity . P07949 combination analysis revealed unanticipated dynamics in GPCR signaling and will be applicable to many biological systems .",
"Counteraction between angiotensin II and angiotensin -( 1 - 7 ) via activating angiotensin type I and Mas receptor on rat renal mesangial cells . In the updated concept of renin - angiotensin system ( DB01367 ) , it contains the angiotensin converting enzyme ( P12821 ) - angiotensin ( Ang ) II - angtiogensin type 1 receptor ( AT1 ) axis and the angiotensin - converting enzyme - related carboxypeptidase ( Q9BYF1 ) - Ang -( 1 - 7 )- Mas axis . The former axis has been well demonstrated performing the vasoconstrictive , proliferative and pro - inflammatory functions by activation of AT1 receptors , while the later new identified axis is considered counterbalancing the effects of the former . The present study is aimed at observing the interaction between Ang -( 1 - 7 ) and Ang II on cultured rat renal mesangial cells ( MCs ) . RT - PCR , Western blot and immunofluorescent staining and confocal microscopy results showed that both AT1 and Mas receptor were co - distributed in rat renal MCs . Ang -( 1 - 7 ) showed similar effects on Ang II in cultured MCs that stimulated phosphorylated extracellular signal - regulated kinase ( P29323 ) 1 / 2 phosphorylation and transforms growth factor - β1 synthesis , and cell proliferation and extracellular matrix synthesis . Co - treatment of the cell with Ang -( 1 - 7 ) and Ang II , Ang -( 1 - 7 ) counteracted AngII - induced effects in a concentration dependent manner , but failed to alter the changes induced by endothelin - 1 . The stimulating effect of Ang II was mediated by AT1 receptor while all the effects of Ang -( 1 - 7 ) were blocked by Mas receptor antagonist A - 779 , but not by AT1 receptor antagonist losartan or P50052 receptor antagonist PD123319 . These results suggest that Ang -( 1 - 7 ) and Ang II specifically interact with each other on rat renal MCs via activation of their specific receptors , Mas and AT1 receptor respectively .",
"Nerve growth factor activation of the extracellular signal - regulated kinase pathway is modulated by Ca ( 2 +) and calmodulin . Nerve growth factor is a member of the neurotrophin family of trophic factors that have been reported to be essential for the survival and development of sympathetic neurons and a subset of sensory neurons . Nerve growth factor exerts its effects mainly by interaction with the specific receptor TrkA , which leads to the activation of several intracellular signaling pathways . Once activated , TrkA also allows for a rapid and moderate increase in intracellular calcium levels , which would contribute to the effects triggered by nerve growth factor in neurons . In this report , we analyzed the relationship of calcium to the activation of the Ras / extracellular signal - regulated kinase pathway in PC12 cells . We observed that calcium and calmodulin are both necessary for the acute activation of extracellular signal - regulated kinases after TrkA stimulation . We analyzed the elements of the pathway that lead to this activation , and we observed that calmodulin antagonists completely block the initial P04049 activation without affecting the function of upstream elements , such as Ras , Grb2 , Shc , and Trk . We have broadened our study to other stimuli that activate extracellular signal - regulated kinases through tyrosine kinase receptors , and we have observed that calmodulin also modulates the activation of such kinases after epidermal growth factor receptor stimulation in PC12 cells and after TrkB stimulation in cultured chicken embryo motoneurons . P62158 seems to regulate the full activation of P04049 after Ras activation , since functional Ras is necessary for P04049 activation after nerve growth factor stimulation and calmodulin - Sepharose is able to precipitate P04049 in a calcium - dependent manner .",
"DB11320 H3 receptors aggravate cerebral ischaemic injury by histamine - independent mechanisms . The role of the histamine H3 receptor ( Q9Y5N1 ) in cerebral ischaemia / reperfusion ( I / R ) injury remains unknown . Here we show that Q9Y5N1 expression is upregulated after I / R in two mouse models . Q9Y5N1 antagonists and Q9Y5N1 knockout attenuate I / R injury , which is reversed by an Q9Y5N1 - selective agonist . Interestingly , P35367 and P25021 antagonists , a histidine decarboxylase ( HDC ) inhibitor and HDC knockout all fail to compromise the protection by Q9Y5N1 blockade . Q9Y5N1 blockade inhibits P42345 phosphorylation and reinforces autophagy . The neuroprotection by Q9Y5N1 antagonism is reversed by 3 - methyladenine and siRNA for Atg7 , and is diminished in Atg5 ⁻/⁻ mouse embryonic fibroblasts . Furthermore , the peptide Tat - Q9Y5N1 ( CT414 - 436 ) , which blocks Q9Y696 binding with H3Rs , or siRNA for Q9Y696 , further increases I / R - induced autophagy and protects against I / R injury . Therefore , Q9Y5N1 promotes I / R injury while its antagonism protects against ischaemic injury via histamine - independent mechanisms that involve suppressing Q9Y5N1 / Q9Y696 binding - activated autophagy , suggesting that Q9Y5N1 inhibition is a therapeutic target for cerebral ischaemia .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK96___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"Molecular profiling in the treatment of colorectal cancer : focus on regorafenib . Metastatic colorectal cancer ( mCRC ) is a highly heterogeneous disease . Its treatment outcome has been significantly improved over the last decade with the incorporation of biological targeted therapies , including anti - P00533 antibodies , cetuximab and panitumumab , and P15692 inhibitors , bevacizumab , ramucirumab , and aflibercept . The identification of predictive biomarkers has further improved the survival by accurately selecting patients who are most likely to benefit from these treatments , such as DB01367 mutation profiling for P00533 antibodies . DB08896 is a multikinase inhibitor currently used as late line therapy for mCRC . The molecular and genetic markers associated with regorafenib treatment response are yet to be characterized . Here , we review currently available clinical evidence of mCRC molecular profiling , such as DB01367 , P15056 , and P22897 testing , and its role in targeted therapies with special focus on regorafenib treatment .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"DB08896 . DB08896 ( DB08896 , Stivarga ® ) is an oral diphenylurea multikinase inhibitor that targets angiogenic ( P17948 - 3 , Q02763 ) , stromal ( P09619 - β , FGFR ) , and oncogenic receptor tyrosine kinases ( P10721 , P07949 , and RAF ) . DB08896 is the first small - molecule multikinase inhibitor to achieve survival benefits in metastatic colorectal cancer that has progressed after all standard therapies . Consequently , regorafenib was FDA approved for this indication . In addition , regorafenib treatment resulted in a significant improvement in progression - free survival ( PFS ) compared with placebo in patients with metastatic gastrointestinal stromal tumors ( GIST ) after progression on standard treatments and is also an FDA approved indication . Currently , regorafenib is examined in several clinical trials ( mostly phase II ) in different tumor entities , including renal cell carcinoma ( RCC ) , hepatocellular carcinoma ( HCC ) , and soft tissue sarcoma ( STS ) .",
"The development of regorafenib and its current and potential future role in cancer therapy . DB08896 is a novel multikinase inhibitor that has demonstrated broad antitumor activity across various solid tumor types , in preclinical and clinical studies . Preclinical data show inhibitory activity of angiogenic , stromal and oncogenic tyrosine kinases through the targeting of vascular endothelial growth factor receptors 1 , 2 and 3 , tyrosine - protein kinase receptor P35590 - 2 , platelet - derived growth factor receptor β , fibroblast growth factor receptor 1 , proto - oncogene tyrosine - protein kinase receptor Ret , mast / stem cell growth factor receptor Kit , P04049 and wild - type and V600E mutant serine / threonine - protein kinase B - raf . Phase I trials have shown that the drug is relatively well tolerated at doses of 160 mg daily on a 3 - weeks - on / 1 - week - off schedule , or 100 mg daily on a continuous schedule , with adverse effects typical of other multikinase inhibitors . Phase II studies demonstrated clinical benefit in a variety of tumor types , mostly associated with prolonged stable disease . Phase III studies include the CORRECT trial , which ultimately led to FDA approval of the drug in the setting of metastatic colorectal cancer previously treated with standard therapies . There is still much work to be done to determine the role of regorafenib in the future of cancer therapy . This review will focus on the development of regorafenib , from early preclinical work through phase I , II and III trials , as well as highlighting the current role and potential future directions of this novel agent .",
"Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .",
"___MASK48___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"The retinoid signalling molecule , O95361 , is repressed during squamous cell carcinoma skin carcinogenesis in vivo and reduces skin cancer cell migration in vitro . Retinoid therapy is used for chemo - prevention in immuno - suppressed patients at high risk of developing skin cancer . The retinoid signalling molecule , tripartite motif protein 16 ( O95361 ) , is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid - sensitive neuroblastoma . We sought to determine the role of O95361 in skin squamous cell carcinoma ( SCC ) pathogenesis . We have shown that O95361 expression was markedly reduced during the histological progression from normal skin to actinic keratosis and SCC . SCC cell lines exhibited lower cytoplasmic and nuclear O95361 expression compared with primary human keratinocyte ( PHK ) cells due to reduced O95361 protein stability . Overexpressed O95361 translocated to the nucleus , inducing growth arrest and cell differentiation . In SCC cells , O95361 bound to and down regulated nuclear Q01094 , this is required for cell replication . Retinoid treatment increased nuclear O95361 expression in retinoid - sensitive PHK cells , but not in retinoid - resistant SCC cells . Overexpression of O95361 reduced SCC cell migration , which required the C - terminal P07949 finger protein ( RFP ) - like domain of O95361 . The mesenchymal intermediate filament protein , vimentin , was directly bound and down - regulated by O95361 and was required for O95361 - reduced cell migration . Taken together , our data suggest that loss of O95361 expression plays an important role in the development of cutaneous SCC and is a determinant of retinoid sensitivity .",
"Reinvestigation of carrier transport properties in liquid crystalline 2 - phenylbenzothiazole derivatives . We have reinvestigated the charge carrier transport properties in a liquid crystal of 2 -( 4 '- heptyloxyphenyl )- 6 - dodecylthiobenzothiazole ( 7O - P10721 - P28222 ) , for which the electronic conduction was first established in rodlike liquid crystals and for which the highest hole mobility in the smectic A ( SmA ) phase ever achieved was reported . We found that 7O - P10721 - P28222 exhibited three crystal phases , one of which appeared in a limited temperature range of 10 degrees just below the phase transition temperature from the SmA phase . In this crystal phase , nondispersive transient photohole currents were observed in time - of - flight experiments , and its hole mobility was determined to be 8 x 10 (- 3 ) cm ( 2 )/ Vs , slightly higher than that reported previously in the SmA phase . For the SmA phase , however , the hole mobility was 1 x 10 (- 4 ) cm ( 2 )/ Vs . Furthermore , we established the electron transport in the SmA phase of purified 7O - P10721 - P28222 , whose mobility was the same as the hole mobility in that phase . In order to confirm generality of the new findings in 7O - P10721 - P28222 , we investigated the carrier transport properties of its derivative having a short hydrocarbon chain , 2 -( 4 '- heptyloxyphenyl )- 6 - butylthiobenzothiazole ( 7O - P10721 - S4 ) , and obtained comparable results . The present results correct a mistake in the previous report and give an idea of what a typical mobility in the SmA phase is . On the basis of these results , we discuss what determines the charge carrier mobility in smectic mesophases .",
"___MASK48___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK48___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .",
"17 ___MASK12___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"Role of P15056 in thyroid oncogenesis . P15056 , a cytoplasmic serine - threonine protein kinase , plays a critical role in cell signaling as an activator within the mitogen - activated protein kinase ( MAPK ) pathway . The most common P15056 mutation is the V600E transversion , which causes constitutive kinase activity . This mutation has been found in a multitude of human cancers , including both papillary thyroid cancer ( PTC ) and papillary - derived anaplastic thyroid cancer ( ATC ) , in which it initiates follicular cell transformation . With such a high frequency of P15056 mutations in PTC ( 44 % ) and PTC - derived ATC ( 24 % ) , research in P15056 ( V600E ) detection for diagnostic purposes has shown high sensitivity and specificity for tumor cell presence . P15056 ( V600E ) in PTC has also provided valuable prognostic information , as its presence has been correlated with more aggressive and iodine - resistant phenotypes . Such findings have initiated research in targeting oncogenic P15056 in cancer therapeutics . Although multiple phase II clinical trials in patients with iodine - refractory metastatic PTC have shown significant efficacy for sorafenib , a first - generation P15056 inhibitor , the mechanism by which it mediates its effect remains unclear because of multiple additional kinase targets of sorafenib . Additionally , preclinical and clinical studies investigating combination therapy with agents such as selective ( PLX 4032 ) and potent ( DB08896 and ARQ 736 ) small - molecule P15056 inhibitors and Q96HU1 / extracellular signal - regulated kinase ( P29323 ) kinase inhibitors ( AZD6244 ) hold great promise in the treatment of P15056 ( V600E ) cancers and may eventually play a powerful role in changing the clinical course of PTC and ATC .",
"P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell - surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration - response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed .",
"P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK63___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK63___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .",
"Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection . Accelerated coronary atherosclerosis in cardiac transplants ( cardiac allograft vasculopathy , Q03135 ) is characterized by coronary intimal hyperplasia . P05230 ( P05230 ) is a potent mitogen for vascular smooth muscle cells and endothelial cells , and its expression is increased in cardiac allografts , suggesting it may play a role in the pathogenesis of Q03135 . The activity of P05230 is dependent on binding to transmembrane receptors . To investigate whether receptors for P05230 are also induced after transplantation , polymerase chain reaction , in situ hybridization , and immunohistochemistry were used to analyze expression of four receptors for P05230 ( P11362 - P22455 ) . Expression of mRNA encoding extracellular immunoglobulin - like domains of P11362 was increased 35 - fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures . Alternatively spliced mRNA that encodes transmembrane forms of P11362 , which contain the signal - transducing tyrosine kinase domains , was induced in allografts during rejection , in infiltrating cells , vascular structures , and myocytes . In vitro experiments showed that differential expression of FGF receptor isoforms was induced by P05230 , and also by P05231 and TGF - beta , which are expressed in cardiac allografts during rejection . The results show that expression of both P05230 and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of Q03135 .",
"Involvement of protein kinase Cdelta / extracellular signal - regulated kinase / poly ( ADP - ribose ) polymerase - 1 ( P09874 ) signaling pathway in histamine - induced up - regulation of histamine H1 receptor gene expression in HeLa cells . The histamine H ( 1 ) receptor ( P35367 ) gene is up - regulated in patients with allergic rhinitis . However , the mechanism and reason underlying this up - regulation are still unknown . Recently , we reported that the P35367 expression level is strongly correlated with the severity of allergic symptoms . Therefore , understanding the mechanism of this up - regulation will help to develop new anti - allergic drugs targeted for P35367 gene expression . Here we studied the molecular mechanism of P35367 up - regulation in HeLa cells that express P35367 endogenously in response to histamine and phorbol 12 - myristate 13 - acetate ( PMA ) . In HeLa cells , histamine stimulation caused up - regulation of P35367 gene expression . Rottlerin , a PKCδ - selective inhibitor , inhibited up - regulation of P35367 gene expression , but Go6976 , an inhibitor of Ca ( 2 +)- dependent PKCs , did not . DB11320 or PMA stimulation resulted in PKCδ phosphorylation at DB00135 ( 311 ) and DB00156 ( 505 ) . Activation of PKCδ by H ( 2 ) O ( 2 ) resulted in P35367 mRNA up - regulation . Overexpression of PKCδ enhanced up - regulation of P35367 gene expression , and knockdown of the PKCδ gene suppressed this up - regulation . DB11320 or PMA caused translocation PKCδ from the cytosol to the Golgi . U0126 , an MEK inhibitor , and DPQ , a poly ( ADP - ribose ) polymerase - 1 inhibitor , suppressed PMA - induced up - regulation of P35367 gene expression . These results were confirmed by a luciferase assay using the P35367 promoter . Phosphorylation of P29323 and P04049 in response to PMA was also observed . However , real - time PCR analysis showed no inhibition of P35367 mRNA up - regulation by a P04049 inhibitor . These results suggest the involvement of the PKCδ / P29323 / poly ( ADP - ribose ) polymerase - 1 signaling pathway in histamine - or PMA - induced up - regulation of P35367 gene expression in HeLa cells .",
"Design of chimeric histone deacetylase - and tyrosine kinase - inhibitors : a series of imatinib hybrides as potent inhibitors of wild - type and mutant P11274 - P00519 , PDGF - Rbeta , and histone deacetylases . Inhibitors of histone deacetylases are a new class of cancer therapeutics with possibly broad applicability . Combinations of HDAC inhibitors with the kinase inhibitor 1 ( Imatinib ) in recent studies showed additive and synergistic effects . Here we present a new concept by combining inhibition of protein kinases and HDACs , two independent pharmacological activities , in one synthetic small molecule . In general , the HDAC inhibition profile , the potencies , and the probable binding modes to Q13547 and Q9UBN7 were similar as for 6 ( ___MASK61___ ) . Inhibition of Abl kinase in biochemical assays was maintained for most compounds , but in general the kinase selectivity profile differed from that of 1 with nearly equipotent inhibition of the wild - type and the Imatinib resistant Abl T ( 315 ) I mutant . A potent cellular inhibition of P09619 and cytotoxicity toward EOL - 1 cells , a model for idiopathic hypereosinophilic syndrome ( DB09106 ) , are restored or enhanced for selected analogues ( 12b , 14b , and 18b ) . Cytotoxicity was evaluated by using a broad panel of tumor cell lines , with selected analogues displaying mean IC ( 50 ) values between 3 . 6 and 7 . 1 muM .",
"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK63___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .",
"DB08896 for gastrointestinal malignancies : from preclinical data to clinical results of a novel multi - target inhibitor . Intracellular signals for cancer cell growth , proliferation , migration , and survival are frequently triggered by protein tyrosine kinases ( TKs ) . The possibility of disrupting core disease pathways has led to development and widespread clinical use of specific TK inhibitors that in the past decade have markedly changed treatment strategies and impacted on overall outcomes . However , intrinsic resistance may limit the benefit of these drugs , and multiple escape routes compensate for the inhibited signaling . The disruption of several points of the same pathway and the simultaneous interference with different intracellular oncogenic processes have both been recognized as valuable strategies to maximize the therapeutic potential of this class of agents . In this scenario , regorafenib has emerged as a novel , orally active , multitarget compound with potent activity against a number of angiogenic and stromal TKs , including vascular endothelial growth factor receptor 2 ( P35968 ) , tyrosine kinase with immunoglobulin - like and P01133 - like domains 2 ( P35590 - 2 ) , fibroblast growth factor receptor 1 ( P11362 ) , and platelet - derived growth factor receptor ( P09619 ) . Moreover , the drug has the capability of blocking P10721 , P07949 and V600 mutant P15056 . Starting from interesting preclinical results , this review describes the clinical development of regorafenib in gastrointestinal malignancies , focusing on data derived from cutting edge clinical trials that have provided evidence of efficacy in pretreated patients with advanced colorectal cancer or gastrointestinal stromal tumors .",
"Prognostic role of Q01094 and members of the CDKN2A network in gastrointestinal stromal tumors . PURPOSE : The aim of the current study was to examine the prognostic relevance of the CDKN2A tumor suppressor pathway in gastrointestinal stromal tumors ( GIST ) . EXPERIMENTAL DESIGN : We determined the mRNA expression of p1 ( INK4A ) , p14 ( Q8N726 ) , P11802 , P06400 , Q00987 , P04637 , and Q01094 by quantitative reverse transcription - PCR in 38 cases of GISTs and correlated the findings with clinicopathologic factors , including mutation analysis of P10721 and P16234 . RESULTS : The k - means cluster analysis yielded three prognostic subgroups of GISTs with distinct mRNA expression patterns of the CDKN2A pathway . GISTs with low mRNA expression of the CDKN2A transcripts p16 ( INK4A ) and p14 ( Q8N726 ) but high mRNA expression of P11802 , P06400 , Q00987 , P04637 , and Q01094 were associated with aggressive clinical behavior and unfavorable prognosis , whereas GISTs with a low mRNA expression of P11802 , P06400 , Q00987 , P04637 , and Q01094 were not . GISTs with a moderate to high mRNA expression of all examined genes also seemed to be associated with unfavorable prognosis . Regarding mutation analysis , we found significant differences in the P10721 / P16234 genotype among the three clusters . Univariate analysis revealed high expression of Q01094 to be associated with mitotic count , proliferation rate , P10721 mutation , and aggressive clinical behavior . These findings on mRNA level could be confirmed by immunohistochemistry . CONCLUSION : Our findings implicate differential regulation schemes of the CDKN2A tumor suppressor pathway converging to up - regulation of Q01094 as the critical link to increased cell proliferation and adverse prognosis of GISTs .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK8___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK8___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"Management of regorafenib - related toxicities : a review . DB08896 ( Stivarga , DB08896 ; Bayer Pharma AG , Berlin , Germany ) is an oral multikinase inhibitor that targets the angiogenic tumor microenvironment and oncogenic kinases including vascular endothelial growth factor receptor 2 ( P35968 ) , P17948 , P35916 , fibroblast growth factor receptor 1 ( P11362 ) , RAF , P10721 , P07949 and P15056 . Its antiangiogenic effect is greater than that of its related drug , sorafenib . DB08896 has been approved by the US Food and Drug Administration ( FDA ) for the treatment of metastatic colorectal cancer ( mCRC ) in patients who have failed treatment with fluoropyrimidine , oxaliplatin and irinotecan based chemotherapy , an anti - P15692 therapy and , if P01116 wild type , an anti - P00533 therapy . The FDA based this approval on data from the CORRECT trial , which showed the efficacy of regorafenib compared with placebo . The most common grade 3 - 4 adverse reactions with the drug are hand foot skin reactions ( HFSR ) , diarrhea , hypertension and fatigue . This review discusses the efficacy data , and the incidence and management of regorafenib ' s toxicities .",
"Inhibition of proliferation and migration of luminal and claudin - low breast cancer cells by P09619 inhibitors . BACKGROUND : Platelet - derived growth factors ( PDGFs ) bind to two receptors , PDGFRα and PDGFRβ to mediate cell proliferation , migration and survival . Although epithelial cells typically do not express high levels of PDGFRs , their expression has been reported to increase in breast cancer cells that have undergone epithelial to mesenchymal transition . METHODS : P09619 signaling was inhibited using DB01268 malate , Imatinib mesylate or DB08896 in murine and human luminal - like and claudin - low mammary tumor cell lines or Masitinib in only the human cell lines . A scratch wound assay was used to assess tumor cell migration while immunofluorescence for phosphorylated histone H3 or cleaved caspase 3 was used to determine tumor cell proliferation and apoptosis , respectively . RESULTS : DB01268 and DB08896 , but not Imatinib , were capable of significantly inhibiting the migration of both murine and human luminal - like and claudin - low breast cancer cells while Masitinib inhibited migration in both human breast cancer cell lines . DB01268 but not DB08896 or Imatinib also significantly suppressed tumor cell proliferation in all four cell lines tested while Masitinib had no significant effect on human breast cancer cell proliferation . None of the P09619 inhibitors consistently regulated mammary tumor cell apoptosis . CONCLUSION : DB01268 , DB08896 and Masitinib may prove clinically useful in inhibiting breast cancer cell migration and metastasis while only DB01268 ( and possibly DB08896 in some breast cancer subtypes ) is effective at inhibiting both migration and proliferation of breast cancer cells .",
"The G protein - coupled P08908 receptor causes suppression of caspase - 3 through MAPK and protein kinase Calpha . The 5 - HT ( 1A ) agonist 8 - hydroxy - 2 ( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) causes inhibition of caspase - 3 and apoptosis via the extracellular signal - regulated kinases ( P27361 / 2 ) in hippocampal P0CJ69 - 5 cells . Two 5 - HT ( 1A ) agonists , Repinotan hydrochloride ( BAY x 3702 ) and 8 - OH - DPAT , block caspase - 3 activation and apoptosis caused by anoxia / reoxygenation and H ( 2 ) O ( 2 ) treatment . This is reversed upon transient expression of dominant negative Ras ( N17Ras ) and P04049 ( Raf301 ) , confirming the involvement of Ras and P04049 in this 5 - HT ( 1A )- R --> P27361 / 2 --> caspase - 3 pathway . A selective inhibitor of phospholipase Cbeta ( PLCbeta ) ( U73122 ) but not a general protein kinase C ( PKC ) inhibitor ( GFX ) reversed the 5 - HT ( 1A )- R - mediated P27361 / 2 stimulation . However , both GFX and the PKCalpha and PKCbeta ( 1 ) inhibitor Gö6976 reversed the P27361 / 2 - mediated inhibition of caspase - 3 . P29323 - dependent activation of only PKCalpha was observed in immunoprecipitates obtained from 5 - HT ( 1A ) agonist - treated P0CJ69 - 5 cells . Finally , transient expression of kinase - negative PKCalpha eliminated the 8 - OH - DPAT - evoked block on the H ( 2 ) O ( 2 )- triggered caspase - 3 stimulation , establishing PKCalpha as a link between P29323 and caspase - 3 ( 5 - HT ( 1A )- R --> P98160 --> P27361 / 2 --> PKCalpha --> caspase - 3 ) . Our results elucidate a novel yet general , neuroprotective pathway through which G protein - coupled receptors could cause inhibition of effector caspases , such as caspase - 3 ."
] |
[
"___MASK12___",
"___MASK24___",
"___MASK25___",
"___MASK48___",
"___MASK61___",
"___MASK63___",
"___MASK82___",
"___MASK8___",
"___MASK96___"
] |
___MASK82___
|
MH_train_406
|
interacts_with DB00921?
|
[
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK28___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"Linkage assignment of eleven genes to the porcine genome . We report comparative linkage mapping of eleven genes in the swine genome by RFLP analysis . These genes include : Acid phosphatase type 5 ( P13686 ) , Cholecystokinin Type B Receptor ( P32239 ) , Antibiotic Peptide ( P49913 ) , P01308 - like Growth Factor 1 Receptor ( P08069 ) , Integrin Alpha M ( P11215 ) , Integrin Beta 2 ( ITGbeta2 ) , Opioid Receptor Mu - 1 ( P35372 ) , Pro - hormone Converter ( PC1 / 3 ) , DB00162 Binding Q12988 ( P10745 ) , Ribosomal DNA ( RNR1 ) , and Zona Pellucida Glycoprotein 1 ( P60852 ) . The P32239 and ITGbeta2 loci define the ends of the linkage groups on Chromosomes ( Chro ) ( SSC ) 9p and 13qter , respectively .",
"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK27___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .",
"___MASK31___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK31___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK31___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"Palmitoylation and membrane cholesterol stabilize μ - opioid receptor homodimerization and G protein coupling . BACKGROUND : A cholesterol - palmitoyl interaction has been reported to occur in the dimeric interface of the β₂ - adrenergic receptor crystal structure . We sought to investigate whether a similar phenomenon could be observed with μ - opioid receptor ( P35372 ) , and if so , to assess the role of cholesterol in this class of G protein - coupled receptor ( GPCR ) signaling . RESULTS : P01024 . 55 ( 170 ) was determined to be the palmitoylation site of P35372 . Mutation of this DB00151 to Ala did not affect the binding of agonists , but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex . In addition , both attenuation of receptor palmitoylation ( by mutation of P01024 . 55 [ 170 ] to Ala ) and inhibition of cholesterol synthesis ( by treating the cells with simvastatin , a P04035 inhibitor ) impaired receptor signaling , possibly by decreasing receptor homodimerization and Gαi2 coupling ; this was demonstrated by co - immunoprecipitation , immunofluorescence colocalization and fluorescence resonance energy transfer ( FRET ) analyses . A computational model of the P35372 homodimer structure indicated that a specific cholesterol - palmitoyl interaction can facilitate P35372 homodimerization at the TMH4 - TMH4 interface . CONCLUSIONS : We demonstrate that P01024 . 55 ( 170 ) is the palmitoylation site of P35372 and identify a cholesterol - palmitoyl interaction in the P35372 complex . Our findings suggest that this interaction contributes to P35372 signaling by facilitating receptor homodimerization and G protein coupling . This conclusion is supported by computational modeling of the P35372 homodimer .",
"Autoantibodies against four kinds of neurotransmitter receptors in psychiatric disorders . There is a hypothesis that autoimmune abnormalities in neurotransmitter receptors might cause some psychiatric disorders . Using a sensitive radioligand assay , we detected serum autoantibodies to recombinant human muscarinic cholinergic receptor 1 ( P11229 , 34 . 4 % ) , mu - opioid receptor ( P35372 , 13 . 1 % ) , P08908 ( P08908 , 7 . 4 % ) , and dopamine receptor D2 ( P14416 , 4 . 9 % ) in 122 psychiatric patients . Positive antibodies to P11229 were found in 34 . 1 % , 34 . 9 % , 33 . 3 % , and 9 . 1 % of patients with schizophrenic disorders ( n = 44 ) , mood disorders ( n = 63 ) , other psychiatric disorders ( n = 15 ) and autoimmune diseases ( n = 33 ) , respectively . All three patients with neuroleptic maliganant syndrome had high activities of autoantibodies to P11229 , P35372 , and / or P08908 . Our data suggest that autoimmunity to neurotransmitter receptors might be associated with the induction of psychiatric symptoms and have some relation to neuroleptic malignant syndrome .",
"DB09280 - ___MASK71___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .",
"μ - Opioid receptor attenuates Aβ oligomers - induced neurotoxicity through P42345 signaling . AIMS : μ - opioid receptor ( P35372 ) exerts many functions such as antinociception , neuroprotection , and hippocampal plasticity . A body of evidence has shown that P35372 activation could stimulate downstream effectors of mechanistic / mammalian target of rapamycin ( P42345 ) . However , it is not clear whether P35372 protects neurons against β - amyloid peptide ( Aβ ) neurotoxicity through P42345 signaling . METHODS : The effects of P35372 activation on Aβ oligomers - induced neurotoxicity were assessed by cell viability and neurite outgrowth assay in primary cultured cortical neurons . The activities of P42345 , protein kinase B ( Akt ) and P08133 ribosomal S6 kinase ( P08133 S6k ) upon P35372 activation by morphine were measured by immunoblotting their phosphorylation status . RESULTS : Morphine dose - dependently attenuated Aβ oligomers - induced neurotoxicity . Aβ oligomers downregulated P42345 signaling . Morphine significantly rescued P42345 signaling by reversal of Aβ oligomers ' effect on P42345 and its upstream signaling molecule Akt , as well as its downstream molecule P08133 S6k . Moreover , the neuroprotective effect of morphine could be reversed by P35372 selective antagonist and phosphatidylinositol 3 - kinases ( PI3K ) , Akt and P42345 inhibitors . Furthermore , endogenous opioids - enkaphalins also attenuated Aβ oligomers - induced neurotoxicity . CONCLUSIONS : Our findings demonstrated P35372 activation attenuated Aβ oligomers - induced neurotoxicity through P42345 signaling . It may provide new insight into the pathological process and useful strategy for therapeutic interventions against Aβ neurotoxicity .",
"The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK33___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .",
"Signaling by retinol and its serum binding protein . DB00162 , retinol , circulates in blood bound to retinol - binding protein ( P02753 ) which , in turn , associates with transthyretin ( P02766 ) to form a retinol - P02753 - P02766 ternary complex . At some tissues , retinol - bound ( holo - ) P02753 is recognized by a membrane protein termed Q9BX79 , which transports retinol from extracellular P02753 into cells and , concomitantly , activates a O60674 / P40763 / 5 signaling cascade that culminates in induction of P35610 target genes . Q9BX79 - mediated retinol transport and cell signaling are critically inter - dependent , and they both require the presence of cellular retinol - binding protein 1 ( P09455 ) , an intracellular retinol acceptor , as well as a retinol - metabolizing enzyme such as lecithin : retinol acyltransferase ( O95237 ) . Q9BX79 thus functions as a \" cytokine signaling transporter \" which couples vitamin A homeostasis and metabolism to cell signaling , thereby regulating gene transcription . Recent studies provided molecular level insights into the mode of action of this unique protein .",
"mu - Opioid receptor agonists differentially regulate the expression of miR - 190 and Q13562 . The agonists of mu - opioid receptor ( P35372 ) induce extracellular signal - regulated kinase ( P29323 ) phosphorylation through different pathways : morphine uses the protein kinase C ( PKC ) - pathway , whereas fentanyl functions in a beta - arrestin2 - dependent manner . In addition , the two pathways result in the different cellular location of phosphorylated P29323 and the activation of different sets of transcriptional factors . In the current study , the influence of the two pathways on the expression of microRNAs ( miRNAs ) was investigated . After treating the primary culture of rat hippocampal neurons and the mouse hippocampi with morphine or fentanyl for 3 days , seven miRNAs regulated by one or two of the agonists were identified . One of the identified miRNAs , miR - 190 , was down - regulated by fentanyl but not by morphine . This down - regulation was attenuated by 1 , 4 - diamino - 2 , 3 - dicyano - 1 , 4 - bis ( methylthio ) butadiene ( U0126 ) , which blocks the phosphorylation of P29323 . When fentanyl - induced but not morphine - induced P29323 phosphorylation was blocked in the primary cultures from beta - arrestin2 (-/-) mouse , fentanyl did not decrease the expression of miR - 190 . However , a PKC inhibitor that blocked morphine - induced P29323 phosphorylation specifically had no effect on the miR - 190 down - regulation . Therefore the decrease in miR - 190 expression resulted from the agonist - selective P29323 phosphorylation . In addition , the expressional changes in one of the miR - 190 targets , neurogenic differentiation 1 ( Q13562 ) , correlated with those in miR - 190 expression , suggesting the P35372 could regulate the Q13562 pathways via the control of miR - 190 expression .",
"Interplay between inhibitory ferric and stimulatory curcumin regulates phosphorylation - dependent human cystic fibrosis transmembrane conductance regulator and ΔF508 activity . Curcumin potentiates cystic fibrosis transmembrane conductance regulator ( P13569 ) activation in an DB00171 - independent but phosphorylation - dependent manner . The underlying molecular mechanisms are unclear . Here , P29320 - 293T cells cultured in an Fe ( 3 +)- containing medium were transiently transfected with P13569 constructs , and the role of the inhibitory Fe ( 3 +) bridge between intracellular loop 3 and the regulatory domain of P13569 in this pathway was investigated . The results showed that ethylenediaminetetraacetic acid ( DB00974 ) stimulated phosphorylation - dependent P13569 activation and the stimulation was suppressed by the deletion of the regulatory domain or the insertion of a C832A mutation that removes the Fe ( 3 +)- binding interface . Furthermore , curcumin potentiation of P13569 was significantly weakened not only by Fe ( 3 +)- insensitive mutations at the interface between the regulatory domain and intracellular loop 3 but also by N - ethylmaleimide or DB00974 pretreatment that removes Fe ( 3 +) . More importantly , potentiation of P13569 was completely suppressed by sufficient Fe ( 3 +) . Finally , the insertion of Fe ( 3 +)- insensitive H950R / S768R increased the curcumin - independent activity of ΔF508 but weakened its curcumin potentiation . Thus , Fe ( 3 +) homeostasis in epithelia may play a critical role in regulating P13569 activity , and targeting Fe ( 3 +)- chelating potentiators may direct new therapies for cystic fibrosis .",
"P35372 phosphorylation , desensitization , and ligand efficacy . Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways : agonist - dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation ( 1 ) . To better understand the nature of the agonist - induced mu receptor phosphorylation events , we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization . Exposure to the potent full agonists sufentanil , dihydroetorphine , etorphine , etonitazine , and [ D - Ala2 , MePhe4 , Glyol5 ] enkephalin ( DAMGO ) led to strong receptor phosphorylation , while methadone , l - alpha - acetylmethadone ( DB01227 ) , morphine , meperidine , DADL , beta - endorphin ( 1 - 31 ) , enkephalins , and dynorphin A ( 1 - 17 ) produced intermediate effects . The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation . DB00921 and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO . The rank order of opiate ligand efficacies in producing mu receptor - mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation . Interestingly , the desensitization and phosphorylation mediated by methadone and DB01227 were disproportionate to their efficacies in two distinct test systems . This generally good fit between the efficacies of opiates in mu receptor activation , phosphorylation , and desensitization supports the idea that activated receptor / agonist / G - protein complexes and / or receptor conformational changes induced by agonists are required for agonist - induced mu receptor phosphorylation . Data for methadone and DB01227 suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies .",
"The P35372 promotes opioid and growth factor - induced proliferation , migration and Epithelial Mesenchymal Transition ( EMT ) in human lung cancer . Recent epidemiologic studies implying differences in cancer recurrence based on anesthetic regimens raise the possibility that the mu opioid receptor ( MOR ) can influence cancer progression . Based on our previous observations that overexpression of MOR in human non - small cell lung cancer ( NSCLC ) cells increased tumor growth and metastasis , this study examined whether MOR regulates growth factor receptor signaling and epithelial mesenchymal transition ( EMT ) in human NSCLC cells . We utilized specific siRNA , shRNA , chemical inhibitors and overexpression vectors in human H358 NSCLC cells that were either untreated or treated with various concentrations of DAMGO , morphine , fentanyl , P01133 or IGF . Cell function assays , immunoblot and immunoprecipitation assays were then performed . Our results indicate MOR regulates opioid and growth factor - induced P01133 receptor signaling ( Src , Gab - 1 , PI3K , Akt and P40763 activation ) which is crucial for consequent human NSCLC cell proliferation and migration . In addition , human NSCLC cells treated with opioids , growth factors or MOR overexpression exhibited an increase in snail , slug and vimentin and decrease ZO - 1 and claudin - 1 protein levels , results consistent with an EMT phenotype . Further , these effects were reversed with silencing ( shRNA ) or chemical inhibition of MOR , Src , Gab - 1 , PI3K , Akt and P40763 ( p < 0 . 05 ) . Our data suggest a possible direct effect of MOR on opioid and growth factor - signaling and consequent proliferation , migration and EMT transition during lung cancer progression . Such an effect provides a plausible explanation for the epidemiologic findings .",
"___MASK65___ inhibits P11274 and NF - κB signaling and reduces tumor proliferation in tissue - resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue - resident CLL cells show prominent activation of both B - cell receptor ( P11274 ) and NF - κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 ( Q06187 ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway - specific gene signatures , we detected a rapid and sustained downregulation of P11274 and NF - κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . ___MASK65___ reduced phosphorylation of PLCγ2 and P29323 and decreased nuclear protein expression of NF - κB p50 . ___MASK65___ significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on - target effects of Q06187 inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www . clinicaltrials . gov as # NCT01500733 .",
"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .",
"P35372 expression is increased in inflammatory bowel diseases : implications for homeostatic intestinal inflammation . BACKGROUND AND AIMS : Recent studies with mu opioid receptor ( MOR ) deficient mice support a physiological anti - inflammatory effect of MOR at the colon interface . To better understand the potential pharmacological effect of certain opiates in inflammatory bowel diseases ( Q9UKU7 ) , we ( 1 ) evaluated the regulation in vivo and in vitro of human MOR expression by inflammation ; and ( 2 ) tested the potential anti - inflammatory function of a specific opiate ( DALDA ) in inflamed and resting human mucosa . PATIENTS AND METHODS : Expression of MOR mRNA and protein was evaluated in healthy and inflamed small bowel and colonic tissues , isolated peripheral blood mononuclear cells and purified monocytes , and P01730 + and CD8 + T cells from healthy donors and Q9UKU7 patients . The effect of cytokines and nuclear factor kappaB ( NFkappaB ) activation on MOR expression in lymphocyte T and monocytic human cell lines was assessed . Finally , DALDA induced anti - inflammatory effect was investigated in mucosal explants from controls and Q9UKU7 patients . RESULTS : MOR was expressed in ileal and colonic enteric neurones as well as in immunocytes such as myeloid cells and P01730 + and CD8 + T cells . Overexpressed in active Q9UKU7 mucosa , MOR was significantly enhanced by cytokines and repressed by NFkappaB inhibitor in myeloid and lymphocytic cell lines . Furthermore , ex vivo DALDA treatment dampened tumour necrosis factor alpha mRNA expression in the colon of active Q9UKU7 patients . CONCLUSIONS : Given the increased expression of MOR and the ex vivo beneficial effect of DALDA in active Q9UKU7 , natural and / or synthetic opioid agonists could help to prevent overt pathological intestinal inflammation .",
"___MASK42___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK42___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK42___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK42___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK98___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .",
"[ ___MASK26___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK26___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying ."
] |
[
"___MASK26___",
"___MASK27___",
"___MASK28___",
"___MASK31___",
"___MASK33___",
"___MASK42___",
"___MASK65___",
"___MASK71___",
"___MASK98___"
] |
___MASK71___
|
MH_train_407
|
interacts_with DB08932?
|
[
"Growth factors and melanomas . Understanding the growth constraints imposed on normal human melanocytes may help to elucidate the processes conferring growth advantage to melanoma cells . Several synergistic growth factors have been identified for normal human melanocytes . They include fibroblast growth factors ( FGF ) , hepatocyte growth factor / scatter factor , mast / stem cell growth factor , and the neuropeptides endothelin - 1 , 2 and 3 ( ET - 1 , P20800 , P14138 ) . From this group of peptides , only basic FGF ( P09038 / P09038 ) appears , so far , to play a role in autonomous growth of melanoma cells . Aberrant expression of P09038 is due to activation of an otherwise repressed gene by a mechanism that may involve the transcriptional activity of wild - type p53 . The growth factors and activated receptors aberrantly expressed in melanoma cells act in concert with molecules that control cell cycle progression . These proteins bind to , and regulate cyclin - dependent kinase ( CDK ) , such as P11802 , responsible for phosphorylation of retinoblastoma ( RB ) and dissociation of RB - Q01094 inhibitory complexes , thereby allowing progression through the cell cycle . Constitutive P11802 activity in melanomas may be the results of inactivation of the negative regulators known as CDK inhibitor p16INK4 , and / or P38936 ; and / or overexpression of cyclin D , the positive P11802 regulator . This complex set of changes in melanoma cells can lift growth constraints by inducing unregulated expression of genes promoting transition from GI to S phase of the cell cycle .",
"DB08932 : first global approval . DB08932 ( Opsumit ® ) is a novel dual endothelin receptor antagonist ( ERA ) with sustained receptor binding properties developed by Actelion Pharmaceuticals Ltd . In October 2013 , oral macitentan 10 mg once daily received its first global approval in the US , followed closely by Canada , for the treatment of pulmonary arterial hypertension ( PAH ) . The drug has also received a positive opinion in the EU from the Committee for Medicinal Products for Human Use for the treatment of PAH , and is under regulatory review in several other countries for the same indication . Endothelin ( ET ) - 1 influences pathological changes via two ET receptor subtypes ( P25101 and ETB ) , to which it binds with high affinity . ET - 1 is implicated in several forms of vascular disease making it a valid target for the treatment of pulmonary vascular diseases such as PAH . Clinical development is underway for other indications , including Eisenmenger syndrome , ischaemic digital ulcers secondary to systemic sclerosis , and glioblastoma . DB08932 was also evaluated in idiopathic pulmonary fibrosis ; however , a phase 2 trial did not meet its primary endpoint and further investigation in this indication was discontinued . DB08932 was developed by modifying the structure of DB00559 in the search for an optimal dual ERA with improved efficacy and tolerability compared with other ERAs . This article summarizes the milestones in the development of macitentan leading to this first approval for PAH .",
"[ The effect of the molecular triggers of hemostatic activity on thrombosis in early stage of electrical injuries ] . OBJECTIVE : To evaluate the mechanisms of thrombosis in the early stage of electrical injury . METHODS : P05305 ( ET - 1 ) , prostacylin ( DB01240 ) , platelet alpha - granule membrane protein ( Gmp - 140 ) , thromboxane ( TXB2 ) , and plasminogen ( P00747 - A ) were measured in 26 patients with electrical injury . RESULTS : It was found that P16109 and ET - 1 increased significantly ( P < 0 . 01 ) , P00747 - A showed a significant change 2 weeks after the injury , while there was an imbalance between TXB2 and DB01240 . CONCLUSION : It is believed that change in one or several mediators mentioned above may trigger thrombosis after electrical injury .",
"New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK47___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"The potential role of PD0332991 ( ___MASK80___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK80___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK77___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"Endothelin @ 25 - new agonists , antagonists , inhibitors and emerging research frontiers : IUPHAR Review 12 . Since the discovery of endothelin ( ET ) - 1 in 1988 , the main components of the signalling pathway have become established , comprising three structurally similar endogenous 21 - amino acid peptides , ET - 1 , P20800 and P14138 , that activate two GPCRs , P25101 and ETB . Our aim in this review is to highlight the recent progress in ET research . The ET - like domain peptide , corresponding to prepro - ET - 193 - 166 , has been proposed to be co - synthesized and released with ET - 1 , to modulate the actions of the peptide . ET - 1 remains the most potent vasoconstrictor in the human cardiovascular system with a particularly long - lasting action . To date , the major therapeutic strategy to block the unwanted actions of ET in disease , principally in pulmonary arterial hypertension , has been to use antagonists that are selective for the P25101 receptor ( ambrisentan ) or that block both receptor subtypes ( DB00559 ) . DB08932 represents the next generation of antagonists , being more potent than DB00559 , with longer receptor occupancy and it is converted to an active metabolite ; properties contributing to greater pharmacodynamic and pharmacokinetic efficacy . A second strategy is now being more widely tested in clinical trials and uses combined inhibitors of ET - converting enzyme and neutral endopeptidase such as SLV306 ( daglutril ) . A third strategy based on activating the ETB receptor , has led to the renaissance of the modified peptide agonist IRL1620 as a clinical candidate in delivering anti - tumour drugs and as a pharmacological tool to investigate experimental pathophysiological conditions . Finally , we discuss biased signalling , epigenetic regulation and targeting with monoclonal antibodies as prospective new areas for ET research .",
"Desensitization and internalization of endothelin receptor A : impact of G protein - coupled receptor kinase 2 ( P25098 ) - mediated phosphorylation . Endothelin receptor A ( P25101 ) , a G protein - coupled receptor , mediates endothelin signaling , which is regulated by P25098 . Three DB00133 and seven DB00156 residues recently proven to be phosphoacceptor sites are located in the C - terminal extremity ( CTE ) of the receptor following its palmitoylation site . We created various phosphorylation - deficient P25101 mutants . The phospholipase C activity of mutant receptors in P29320 - 293 cells was analyzed during continuous endothelin stimulation to investigate the impact of phosphorylation sites on P25101 desensitization . Total deletion of phosphoacceptor sites in the CTE affected proper receptor regulation . However , proximal and distal phosphoacceptor sites both turned out to be sufficient to induce WT - like desensitization . Overexpression of the Gαq coupling - deficient mutant P25098 - D110A suppressed P25101 - WT signaling but failed to decrease phospholipase C activity mediated by the phosphorylation - deficient mutant P25101 - 6PD . In contrast , P25098 - WT acted on both receptors , whereas the kinase - inactive mutant P25098 - D110A / K220R failed to inhibit signaling of P25101 - WT and P25101 - 6PD . This demonstrates that P25101 desensitization involves at least two autonomous P25098 - mediated components : 1 ) a phosphorylation - independent signal decrease mediated by blocking of Gαq and 2 ) a mechanism involving phosphorylation of DB00133 and DB00156 residues in the CTE of the receptor in a redundant fashion , able to incorporate either proximal or distal phosphoacceptor sites . High level transfection of P25098 variants influenced signaling of P25101 - WT and P25101 - 6PD and hints at an additional phosphorylation - independent regulatory mechanism . Furthermore , internalization of mRuby - tagged receptors was observed with P25101 - WT and the phosphorylation - deficient mutant P25101 - 14PD ( lacking 14 phosphoacceptor sites ) and turned out to be based on a phosphorylation - independent mechanism .",
"Systemic sclerosis - a systematic overview : part 2 - immunosuppression , treatment of SSc - associated vasculopathy , and treatment of pulmonary arterial hypertension . Here we give an overview over treatment recommendations propagated by the European League Against Rheumatism ( EULAR ) , EULAR Scleroderma Trials and Research Group , the German Network for Systemic Sclerosis , the European Respiratory Society , and the International Society of Heart and Lung Transplantation . As response to immunosuppressant ( IS ) therapy is usually weaker in systematic sclerosis ( SSc ) compared to other connective tissue disorders IS should be considered with caution . To prevent scleroderma renal crisis steroid doses should not exceed 15 mg / d . The definitive role of a number of new immunosuppressant drugs and the effects of autologous stem cell transplantation in systemic clerosis ( SSc ) have to be elucidated . Prostanoids , especially iloprost , are widely used as intravenous formulas for the treatment of severe Raynaud ' s phenomenon ( RP ) and digital ulcers ( DU ) . DB01373 antagonists are of limited therapeutic value . DB00559 , an oral endothelin receptor antagonists ( P25101 ) , was shown to prevent new DU , but failed to heal existing DU , while the oral phopshodiesterase inhibitor ( P07237 ) DB00203 reduces the occurrence of RP and might be effective in ulcer healing . Combination therapies of P07237 with P25101 are currently evaluated . Therapy of pulmonary arterial hypertension ( PAH ) is usually started as oral monotherapy , frequently using an P25101 . When this first - line therapy is not tolerated P25101 is substituted by P07237 . If treatment goals are not reached with monotherapy combinationtherapy is started , for example by adding a P07237 to an existing P25101 . In general , treatment of PAH in patients with connective tissue disease follows the same algorithms as in idiopathic PAH .",
"Identifying novel prostate cancer associated pathways based on integrative microarray data analysis . The development and diverse application of microarray and next generation sequencing technologies has made the meta - analysis widely used in expression data analysis . Although it is commonly accepted that pathway , network and systemic level approaches are more reproducible than reductionism analyses , the meta - analysis of prostate cancer associated molecular signatures at the pathway level remains unexplored . In this article , we performed a meta - analysis of 10 prostate cancer microarray expression datasets to identify the common signatures at both the gene and pathway levels . As the enrichment analysis result of GeneGo ' s database and KEGG database , 97 . 8 % and 66 . 7 % of the signatures show higher similarity at pathway level than that at gene level , respectively . Analysis by using gene set enrichment analysis ( GSEA ) method also supported the hypothesis . Further analysis of PubMed citations verified that 207 out of 490 ( 42 % ) pathways from GeneGo and 48 out of 74 ( 65 % ) pathways from KEGG were related to prostate cancer . An overlap of 15 enriched pathways was observed in at least eight datasets . Eight of these pathways were first described as being associated with prostate cancer . In particular , endothelin - 1 / P25101 transactivation of the P00533 pathway was found to be overlapped in nine datasets . The putative novel prostate cancer related pathways identified in this paper were indirectly supported by PubMed citations and would provide essential information for further development of network biomarkers and individualized therapy strategy for prostate cancer .",
"Increased expression of cyclooxygenase - 2 mediates enhanced contraction to endothelin P25101 receptor stimulation in endothelial nitric oxide synthase knockout mice . The aim of this study was to determine whether prolonged loss of NO activity , in endothelial NO synthase knockout ( P29474 (-/-) ) mice , influences endothelin ( ET ) P25101 receptor - mediated smooth muscle contraction and , if so , to define the underlying mechanism ( s ) . In isolated endothelium - denuded abdominal aortas , contractions to the selective P25101 receptor agonist ET - 1 ( 1 - 31 ) were significantly increased in aortas from P29474 (-/-) compared with wild - type ( WT ) mice . In contrast , contractions to the alpha1 - adrenergic agonist phenylephrine or the thromboxane ( TX ) A2 analog U - 46619 were similar between P29474 (-/-) and WT mice . Immunofluorescent and Western blot analysis demonstrated that the aortic expression of P25101 receptors was decreased in P29474 (-/-) compared with WT mice . Contractions evoked by ET - 1 ( 1 - 31 ) , but not phenylephrine , were reduced by inhibition of cyclooxygenase - 2 ( P35354 ) ( indomethacin or celecoxib ) or of TXA2 / prostaglandin H2 receptors ( SQ - 29548 ) . After P36551 inhibition , contractions to ET - 1 ( 1 - 31 ) were no longer increased and were actually decreased in P29474 (-/-) compared with WT aortas . Western blot analysis revealed that endothelium - denuded abdominal aortas express P35354 , but not P23219 , and that expression of P35354 was significantly increased in P29474 (-/-) compared with WT mice . Contractions to the P36551 substrate arachidonic acid were also increased in P29474 (-/-) aortas . Furthermore , ET - 1 ( 1 - 31 ) but not phenylephrine stimulated production of the TXA2 metabolite TXB2 , which was increased in P29474 (-/-) compared with WT aortas . Therefore , P35354 plays a crucial and selective role in P25101 - mediated smooth muscle contraction . Furthermore , P35354 expression is increased in P29474 (-/-) mice , which overcomes a reduced expression of P25101 receptors and enables a selective increase in contraction to P25101 receptor stimulation .",
"DB08932 ( Opsumit ) for the treatment of pulmonary arterial hypertension . The endothelin pathway is a key pathway for the pathogenesis of pulmonary arterial hypertension ( PAH ) . Antagonism of this pathway is recommended as initial therapy in low - risk patient with PAH to inhibit fibrosis , cell proliferation , and inflammation caused by endothelin . Prior to October 2013 , ambrisentan , a selective P25101 receptor antagonist and DB00559 , a dual P25101 / ETB antagonist , were the only currently available agents for PAH targeting the endothelin pathway . Based on the results of the SERAPHIN trial , macitentan ( brand name Opsumit ® ) , a new P25101 / ETB antagonist , has been US FDA approved to delay disease progression and reduce hospitalizations for PAH . SERAPHIN is the first ERA trial to use an event - driven strategy with a composite primary end point of morbidity or mortality . Previous trials have focused on short - term outcomes , such as improved 6 - min walk distance and WHO functional class .",
"Comparison of pharmacological activity of macitentan and DB00559 in preclinical models of systemic and pulmonary hypertension . AIMS : The endothelin ( ET ) system is a tissular system , as the production of ET isoforms is mostly autocrine or paracrine . DB08932 is a novel dual P25101 / ETB receptor antagonist with enhanced tissue distribution and sustained receptor binding properties designed to achieve a more efficacious ET receptor blockade . To determine if these features translate into improved efficacy in vivo , a study was designed in which rats with either systemic or pulmonary hypertension and equipped with telemetry were given macitentan on top of maximally effective doses of another dual P25101 / ETB receptor antagonist , DB00559 , which does not display sustained receptor occupancy and shows less tissue distribution . MAIN METHODS : After establishing dose - response curves of both compounds in conscious , hypertensive Dahl salt - sensitive and pulmonary hypertensive bleomycin - treated rats , macitentan was administered on top of the maximal effective dose of DB00559 . KEY FINDINGS : In hypertensive rats , macitentan 30 mg / kg further decreased mean arterial blood pressure ( Q96HU1 ) by 19 mm Hg when given on top of DB00559 100 mg / kg ( n = 9 , p < 0 . 01 vs . vehicle ) . Conversely , DB00559 given on top of macitentan failed to induce an additional Q96HU1 decrease . In pulmonary hypertensive rats , macitentan 30 mg / kg further decreased mean pulmonary artery pressure ( MPAP ) by 4 mm Hg on top of DB00559 ( n = 8 , p < 0 . 01 vs . vehicle ) , whereas a maximal effective dose of DB00559 given on top of macitentan did not cause any additional MPAP decrease . SIGNIFICANCE : The add - on effect of macitentan on top of DB00559 in two pathological models confirms that this novel compound can achieve a superior blockade of ET receptors and provides evidence for greater maximal efficacy .",
"P05305 induces connective tissue growth factor expression in cardiomyocytes . Endothelin ( ET ) - 1 is a vasoconstrictor involved in cardiovascular diseases . P29279 / P29279 ( P29279 ) is a fibrotic mediator overexpressed in human atherosclerotic lesions , myocardial infarction , and hypertension . In different cell types P29279 regulates cell proliferation / apoptosis , migration , and extracellular matrix ( Q13201 ) accumulation and plays important roles in angiogenesis , chondrogenesis , osteogenesis , tissue repair , cancer and fibrosis . In the present study , we investigated the ET - 1 signaling which triggers P29279 expression in cultured adult mouse atrial - muscle P07306 cells used as a model system . ET - 1 activated the P29279 promoter and induced P29279 expression at both mRNA and protein levels . Real - time PCR analysis revealed P29279 induction also in isolated rat heart preparations perfused with ET - 1 . Several intracellular signals elicited by ET - 1 via ET receptors and even Epidermal Growth Factor Receptor ( P00533 ) contributed to the up - regulation of P29279 , including P29323 activation and induction of the AP - 1 components c - fos and c - jun , as also evaluated by ChIP analysis . Moreover , in cells treated with ET - 1 the expression of Q13201 component decorin was abolished by P29279 silencing , indicating that P29279 is involved in ET - 1 induced Q13201 accumulation not only in a direct manner but also through downstream effectors . Collectively , our data indicate that P29279 could be a mediator of the profibrotic effects of ET - 1 in cardiomyocytes . P29279 inhibitors should be considered in setting a comprehensive pharmacological approach towards ET - 1 induced cardiovascular diseases .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK9___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .",
"DB08932 : An important addition to the treatment of pulmonary arterial hypertension . DB08932 is an orphan drug for the treatment of pulmonary arterial hypertension ( PAH ) . P05305 ( ET - 1 ) plays a critical role of pathophysiology of PAH . DB08932 , a new dual endothelin receptor antagonist , has reportedly improved prognosis of PAH patients by delaying the progression of disease . It prevents the binding of ET - 1 to both endothelin A ( P25101 ) and endothelin B ( ETB ) receptors . DB08932 displays higher efficacy , lesser adverse effects and drug interactions . It has completed phase III trials in 2012 for treatment of PAH and has been tried for ischemic digital ulcers in systemic sclerosis , recurrent glioblastoma and combination with chemotherapeutic agents against various cancers . Safety data for macitentan were obtained primarily from a placebo - controlled clinical study in 742 patients with PAH . The Food and Drug Administration ( FDA ) approved the drug on 13 October 2013 . It is an important addition to long - term treatment of PAH .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK41___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK41___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK41___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK41___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK41___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK2___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"P01308 and vanadate restore decreased plasma endothelin concentrations and exaggerated vascular responses to normal in the streptozotocin diabetic rat . Although insulin has been shown to raise plasma concentrations of endothelin ( ET ) and up regulate vascular smooth muscle P25101 receptor expression , the interaction of vanadate , an insulinomimetic agent , with the vascular ET system has not been investigated . We compared the effects of oral vanadate treatment ( 0 . 5 mg / ml ; p . o . ) and insulin infusion ( 12 mU . kg - 1 . min - 1 s . c . ) for two weeks on plasma ET concentrations and vascular responses to endothelin - 1 ( ET - 1 ) and the alpha - 1 adrenoceptor agonist , methoxamine , in aortic ring preparations from streptozotocin ( Q11206 ) diabetic and non - diabetic adult male Sprague - Dawley rats . Plasma ET concentrations were lower ( p < 0 . 01 ) in Q11206 diabetic rats compared with normal control rats . P01308 and vanadate treatment restored plasma ET to normal ( p < 0 . 01 ) in Q11206 rats and increased ET concentrations in the control ( p < 0 . 05 ) group . Higher maximal tension responses to both ET - 1 ( p < 0 . 01 ) and methoxamine ( p < 0 . 05 ) were present in Q11206 rats in both endothelium intact and denuded aortic preparations compared with the control group . Both insulin and vanadate treatment returned these responses to normal . It is concluded that low plasma concentrations of insulin and high plasma glucose in Q11206 diabetic rats are accompanied by lower concentrations of plasma ET . P01308 and vanadate treatment restores diminished plasma ET to control concentrations and attenuates exaggerated agonist ( s )- evoked vascular smooth muscle responses in Q11206 - induced diabetic rats . In addition to well known beneficial metabolic effects , insulin and vanadate may beneficially affect cardiovascular regulation in the Q11206 diabetic rat by correcting abnormal ET activity .",
"Effects of endothelin P25101 receptor antagonism on granulocyte and lymphocyte accumulation in LPS - induced inflammation . Endothelin peptides play active roles in different aspects of inflammation . This study investigates the contribution of endogenous endothelins to lipopolysaccharide ( LPS ) pulmonary inflammation by assessing the influence of ET ( A ) receptor antagonism on leukocyte accumulation , granulocyte adhesion molecule expression , and chemokine / cytokine modulation . Local pretreatment with BQ - 123 or A - 127722 ( 150 pmol ) , two selective and chemically unrelated endothelin ET ( A ) receptor antagonists , inhibits neutrophil and eosinophil accumulation in LPS - induced pleurisy at 24 h but not neutrophil migration at 4 h . The effect of endothelin antagonism on neutrophil accumulation at 24 h was concomitant with inhibition of eosinophil and P01730 and CD8 T lymphocyte influx . It is surprising that the ET ( A ) receptor blockade did not inhibit the accumulation of gammadelta T lymphocytes , cells that are important for granulocyte recruitment in this model . Blockade of ET ( A ) receptors did not influence the expression of adhesion molecules ( CD11b , CD49d ) on granulocytes but abrogated the increase in tumor necrosis factor alpha levels 4 h after LPS stimulation and also markedly inhibited increases in levels of interleukin - 6 and keratinocyte - derived chemokine / CXC chemokine ligand 1 but not eotaxin / chemokine ligand 11 . Thus , acting via ET ( A ) receptors , endogenous endothelins play an important role in early cytokine / chemokine production and on granulocyte and lymphocyte mobilization in LPS - induced pleurisy .",
"P12004 D1 , p16 , and retinoblastoma gene regulate mitogenic signaling of endothelin in rat mesangial cells . To elucidate the mechanisms by which endothelin ( ET ) - 1 induces proliferation of mesangial cells , we investigated the involvement of the first gap phase of the cell cycle ( P55008 ) cyclin , cyclin - dependent kinase 4 ( P11802 ) activity , and the retinoblastoma gene product ( P06400 ) in ET - 1 - stimulated cell cycle progression . In the present study , ET - 1 stimulated P11802 activity and cell cycle progression via ET A - type receptors and induced cyclin D1 mRNA and protein expression in rat mesangial cells . We also found that ET - 1 stimulation of mesangial cell proliferation was inhibited by antisense oligonucleotides directed against cyclin D1 and by overexpression of a nonphosphorylatable form of P06400 . To investigate the functional roles of p16INK4 and p21cip1 in ET - 1 - stimulated mesangial cell proliferation , we used adenovirus - mediated gene transfer . P05305 - stimulated [ 3H ] - thymidine incorporation , P11802 kinase activity , and the percent of cells in S phase were found to be significantly inhibited by overexpression of p16INK4 and slightly inhibited by overexpression of p21cip1 . Thus , ET - 1 induced cyclin D1 expression and stimulated P11802 activity and cell cycle progression via the A - type receptor in rat mesangial cells . These effects were regulated by the expression of cyclin D1 , p16INK4 , p21cip1 , and phosphorylatable form of P06400 . The results of the present study provide the basis for further investigation of basic and therapeutic approaches towards mesangial proliferative diseases .",
"DB08932 slows down the dermal fibrotic process in systemic sclerosis : in vitro findings . Systemic sclerosis ( or scleroderma ) is an autoimmune disease characterized by skin and internal organ fibrosis , caused by microvascular dysfunction . The microvascular damage seems to be a consequence of an endothelial autoimmune response , followed by activation of the inflammatory cascade and massive deposition of collagen . P05305 ( ET - 1 ) contributes to the inflammatory and fibrotic processes by increasing the concentration of pro - inflammatory and pro - fibrotic cytokines , and it is considered one of the most relevant mediators of vascular damage in scleroderma . It is indeed found in very high concentration in serum of sclerodermic patients . Moreover , in these pathological conditions there is an increased expression of ET - 1 receptors ( P25101 and ETB ) , which mediate the detrimental action of ET - 1 , and often a change of P25101 / ETB ratio . The aim of the present study is to evaluate the in vitro effect of macitentan , an orally active tissue - targeting dual endothelin receptor antagonist , and its major metabolite ( ACT - 132577 ) on alpha smooth muscle actin ( alphaSMA ) expression , evaluated on dermal fibroblasts from healthy subjects and on dermal fibroblasts from lesional and non - lesional skin from sclerodermic patients . The combination of macitentan and its major metabolite reduced the levels of & # 945 ; SMA after 48 h in sclerodermic fibroblasts from lesional skin . No relevant changes in & # 945 ; SMA levels were found in fibroblasts from non - lesional skin , whose behavior is similar to that of dermal fibroblasts from healthy patients .",
"A common binding site on the microsomal triglyceride transfer protein for apolipoprotein B and protein disulfide isomerase . The assembly of triglyceride - rich lipoproteins requires the formation in the endoplasmic reticulum of a complex between apolipoprotein B ( apoB ) , a microsomal triglyceride transfer protein ( P55157 ) , and protein disulfide isomerase ( P07237 ) . In the P55157 complex , the amino - terminal region of P55157 ( residues 22 - 303 ) interacts with the amino - terminal region of apoB ( residues 1 - 264 ) . Here , we report the identification and characterization of a site on apoB between residues 512 and 721 , which interacts with residues 517 - 603 of P55157 . P07237 binds in close proximity to this apoB binding site on P55157 . The proximity of these binding sites on P55157 for P07237 and amino acids 512 - 721 of apoB was evident from studies carried out in a yeast two - hybrid system and by co - immunoprecipitation . The expression of P07237 with P55157 and apoB16 ( residues 1 - 721 ) in the baculovirus expression system reduced the amount of P55157 co - immunoprecipitated with apoB by 73 % . The interaction of residues 512 - 721 of apoB with P55157 facilitates lipoprotein production . Mutations of apoB that markedly reduced this interaction also reduced the level of apoB - containing lipoprotein secretion .",
"___MASK8___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK8___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK8___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK8___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK8___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK8___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .",
"___MASK50___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"___MASK80___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK80___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .",
"Association between IFNA genotype and the risk of sarcoidosis . Sarcoidosis is known to be a systemic granulomatous disorder characterized by a cell - mediated Th1 - type inflammatory response . To identify a key genetic factor in the pathogenesis of sarcoidosis , we investigated single nucleotide polymorphisms within 10 candidate genes involved in type 1 immune process ( P01571 , P01574 , P01579 , P15260 , P38484 , P29460 , P42701 , Q99665 , P25101 - 1 , and P49279 ) in an association - based study of 102 Japanese patients with sarcoidosis , 114 with tuberculosis , and 110 control subjects . After correction for multiple testing , an P01571 polymorphism ( 551T --> G ) was found to be associated with susceptibility to sarcoidosis ( odds ratio 3 . 27 [ 95 % CI : 1 . 44 - 7 . 46 ] , P = 0 . 004 , P ( c )= 0 . 04 ) , but not to tuberculosis . We observed no significant associations with the other polymorphisms of the Th1 - related genes . We further typed another IFNA polymorphism ( P01566 60T --> A ) and confirmed two major haplotypes of the IFNA gene , viz . , allele 1 : P01566 [ 60T ] - P01571 [ 551T ] and allele 2 : P01566 [ 60A ] - P01571 [ 551G ] , in the Japanese population . In healthy subjects , IFNA allele 2 , which is over - represented in patients with sarcoidosis , was significantly associated with increased IFN - alpha and IL - 12p70 production induced by Sendai virus in vitro . This study suggests that possession of the IFNA allele with higher levels of IFN - alpha significantly increases the risk of sarcoidosis .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK74___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"P04626 monoclonal antibodies that do not interfere with receptor heterodimerization - mediated signaling induce effective internalization and represent valuable components for rational antibody - drug conjugate design . The human epidermal growth factor receptor ( HER ) 2 provides an excellent target for selective delivery of cytotoxic drugs to tumor cells by antibody - drug conjugates ( ADC ) as has been clinically validated by ado - trastuzumab emtansine ( Kadcyla ( TM ) ) . While selecting a suitable antibody for an ADC approach often takes specificity and efficient antibody - target complex internalization into account , the characteristics of the optimal antibody candidate remain poorly understood . We studied a large panel of human P04626 antibodies to identify the characteristics that make them most suitable for an ADC approach . As a model toxin , amenable to in vitro high - throughput screening , we employed Pseudomonas exotoxin A ( P25101 ' ) fused to an anti - kappa light chain domain antibody . Cytotoxicity induced by P04626 antibodies , which were thus non - covalently linked to P25101 ' , was assessed for high and low P04626 expressing tumor cell lines and correlated with internalization and downmodulation of P04626 antibody - target complexes . Our results demonstrate that P04626 antibodies that do not inhibit heterodimerization of P04626 with related ErbB receptors internalize more efficiently and show greater P25101 '- mediated cytotoxicity than antibodies that do inhibit such heterodimerization . Moreover , stimulation with ErbB ligand significantly enhanced ADC - mediated tumor kill by antibodies that do not inhibit P04626 heterodimerization . This suggests that the formation of P04626 / ErbB - heterodimers enhances ADC internalization and subsequent killing of tumor cells . Our study indicates that selecting P04626 ADCs that allow piggybacking of P04626 onto other ErbB receptors provides an attractive strategy for increasing ADC delivery and tumor cell killing capacity to both high and low P04626 expressing tumor cells .",
"Cytokine production by murine cells activated by erythrogenic toxin type A superantigen of Streptococcus pyogenes . The mode of pathogenic action of the Steptococcus pyogenes superantigen erythrogenic toxin type A ( P25101 ) in causing toxic shock - like syndrome in humans is thought to be mediated by massive release of cytokines by patients immune cells . The cytokine - inducing capacity of P25101 as an extracellular protein was compared with that of lipopolysaccharide ( LPS ) , a component of cell wall of gram - negative bacteria . Peritoneal macrophages and splenocytes of BALB / c and C3H / HeJ mice were stimulated by P25101 and LPS . P01375 ( P01375 ) , interleukin 3 ( P08700 ) and interleukin 6 ( P05231 ) activities in the supernatants of stimulated cells were evaluated . In contrast to LPS , P25101 induced only low amounts of P05231 and no detectable P01375 activities in peritoneal macrophage supernatants . P25101 - triggered BALB / c and C3H / HeJ splenocytes produced great amounts of P05231 . P25101 triggered the production of P08700 by both mice strains splenocytes in a dose dependent manner . The amounts of P08700 in supernatants were comparable to those induced by concanavalin A . The simultaneous presence of P25101 and LPS in macrophage and splenocyte cultures induced a slight enhancement above an additive value after 72 - 96 h . Challenge of BALB / c mice with P25101 6 h before the harvest of peritoneal macrophages led to an enhanced production of P05231 upon stimulation with P25101 as well as with LPS . Splenocytes of nude BALB / c mice did not produce P05231 upon stimulation with P25101 , whereas LPS - induced P05231 production was similar in these mice and in their littermates . The pathogenic effect of P25101 on host ' s immune cells could most likely be explained as a consequence of T cell activation . The results confirm also that LPS - and P25101 - induced shock is mediated by different cell types ."
] |
[
"___MASK2___",
"___MASK41___",
"___MASK47___",
"___MASK50___",
"___MASK74___",
"___MASK77___",
"___MASK80___",
"___MASK8___",
"___MASK9___"
] |
___MASK80___
|
MH_train_408
|
interacts_with DB00669?
|
[
"Triptan use preceding life - threatening arrhythmias in charcot - marie - tooth : a case report and review of the literature . Charcot - Marie - Tooth ( CMT ) identifies a rare group of inherited disorders of the peripheral nervous system that share clinical features of sensory and motor defects , but rarely affect cardiac function . The few references that relate CMT to cardiac pathology of any sort are so rare that their finding was considered either fortuitous or suggestive of an erroneous diagnosis . The P28222 / 1D agonists or DB00669 drug class was introduced to the clinical practice arena in the early 1990s , and since then several cardiac adverse events have been associated with its use . The authors report the case of a 41 - year - old white woman with CMT who had been recently prescribed sumatriptan and who presented with sudden loss of consciousness associated with ventricular fibrillation . These findings have been reported in the literature , but the association of DB00669 - induced arrhythmias and degenerative neuropathies remains to be established . The authors propose , through this case report and review , that the relative rarity of CMT coupled with the lack of further investigation of their association with conduction abnormalities might have set the stage for underestimation of the potentially synergistic effect with triptans in their capacity to generate life - threatening arrhythmias .",
"To press or not to press ? Differential receptor expression and response to novelty in rats learning an operant response for reward . Learning to perform instrumental tasks is an ability of all animals . In a population of rats , not all individuals will acquire an operant response for reward . We hypothesized that there could be a genetic explanation for differences between High Consumers ( those that acquired the lever press response ) and Low Consumers ( lever press response is low ) . Additionally , we proposed that this genetic difference could produce measurable changes in response to novelty . Wistar rats were trained to lever press for a 0 . 2 % saccharin reward and on the 10th day they were placed in a novel open field for 30 min to record locomotor activity . The prefrontal cortex and hippocampus were dissected and qPCR was used to measure mRNA expression . A significant difference ( p =. 048 ; 2 - way Q9UNW9 ) in gene expression was observed between Low and High Consumers . A principal component analysis ( DB11245 ) , to cluster which genes represent this difference , identified 4 genes ; 5 - Q13049 and mGlu1 in the hippocampus and AMPA GluR1 and adrenergic alpha2A in the prefrontal cortex . Response to a novel open field also differed since Low Consumers displayed a higher Total Distance in comparison to High Consumers . Additionally , Low Consumers could be subdivided into Low - Lever ( with lever press response only when water deprived ) and Low - Non - Lever ( lever press response is low throughout training ) . DB11245 with this subdivision identified an additional nine genes differing within the divisions ; DB01221 Q13224 and GABAAalpha3 in the prefrontal cortex and adrenergic alpha2B and alpha2A , AMPA GluR1 , GluR2 and GluR3 , P28222 and GABAAalpha5 in the hippocampus .",
"Gene expression reprogramming protects macrophage from septic - induced cell death . Sepsis induces a systemic inflammatory response leading to tissue damage and cell death . LPS tolerance affects inflammatory response . To comprehend potential new mechanisms of immune regulation in endotoxemia , we examined macrophage mRNA expression by macroarray affected by LPS tolerance . LPS tolerance was induced with subcutaneous administration of 1 mg / kg / day of LPS over 5 days . Macrophages were isolated from the spleen and the expression of 1200 genes was quantitatively analyzed by the macroarray technique . The tolerant group displayed relevant changes in the expression of 84 mRNA when compared to naïve mice . A functional group of genes related to cell death regulation was identified . P09874 , caspase 3 , P48023 and P50591 genes were confirmed by RT - PCR to present lower expression in tolerant mice . In addition , reduced expression of the pro - inflammatory genes P01375 - α and IFN - γ in the tolerant group was demonstrated . Following this , animals were challenged with polymicrobial sepsis . Flow cytometry analysis showed reduced necrosis and apoptosis in macrophages from the tolerant group compared to the naïve group . Finally , a survival study showed a significant reduction in mortality in the tolerant group . Thus , in the current study we provide evidence for the selective reprogramming of the gene expression of cell death pathways during LPS tolerance and link these changes to protection from cell death and enhanced survival rates .",
"The biology of serotonin receptors : focus on migraine pathophysiology and treatment . Serotonin receptors are highly heterogeneous and they have been regrouped within seven different families ( 5 - HT1 - P34969 ) . With the exception of the 5 - Q9H205 which is a ligand - gated ion channel , all others are G - protein coupled receptors with each family sharing structural , pharmacological and transductional characteristics . 5 - HT receptors have been implicated in the regulation of several psychiatric and neurological disorders related to serotonergic neurotransmission , and specific receptor subtypes have recently been associated with either the pathogenesis or the treatment of migraine headache . In this respect , activation of vascular P41595 and / or P34969 receptors , possibly as a consequence of the sudden rise in 5 - HT levels reported at the onset of a migraine attack , would hypothetically result in dilation of cerebral blood vessels and concomitant activation of sensory trigeminovascular afferents , hence initiating the manifestation of head pain . At this stage in the migraine process , activation of specific subtypes of 5 - HT1 receptors has proven clinically effective in relieving migraine pain . Neural P28221 and / or P30939 receptors localized pre - junctionally on trigeminovascular afferents appear to mediate the DB00669 - induced inhibition of the neurogenic inflammatory response , with possible additional sites of action for brain penetrant 5 - HT1 receptor agonists in inhibiting the transmission of pain centrally . In contrast , activation of vascular P28222 receptors would constrict meningeal vessels hence recovering their pre - migraine diameter . The recent availability of subtype selective P28221 and P30939 receptor agonists should allow a further test of the neural / vascular hypothesis and could possibly lead to antimigraine drugs with a safer cardiovascular profile .",
"Serotonin relaxes porcine pial veins . The effect of serotonin [ 5 - hydroxytryptamine ( 5 - HT ) ] on pial venous tone of the pig was examined using in vitro tissue bath techniques . Isolated pial venous rings exhibited spontaneous rhythmic contractions ( P12931 ) on mechanical stretching and / or applications of several vasoactive substances , including norepinephrine . On the other hand , DB00761 induced sustained active muscle tone ( P21673 ) without P12931 . The P12931 induced by mechanical stretching were not affected by tetrodotoxin , nitro - L - arginine , alpha - and beta - adrenergic , histaminergic , and muscarinic receptor antagonists , indicating that the P12931 in porcine pial veins are of myogenic origin . The P12931 induced by stretching or applications of vasoactive substances and P21673 induced by DB00761 were inhibited by 5 - HT in a concentration - dependent manner . The inhibition was prevented by methysergide and methiothepin but not by ketanserin , propranolol , 3 alpha - tropanyl - 1H - indole - 3 - carboxylic acid ester , hemoglobin , or nitro - L - arginine . The P12931 and P21673 were inhibited by 5 - carboxamidotryptamine ( 5 - CT ) , 8 - hydroxy - 2 - di - N - propylaminotetralin HBr ( 8 - OHDPAT ) , 1 -[ 3 -( trifluoromethyl ) phenyl ] piperazine ( TFMPP ) , and 5 - methoxytryptamine ( 5 - MT ) , but not by sumatriptan , alpha - methylserotonin , or 2 - methylserotonin . On the other hand , 5 - CT , 8 - OHDPAT , TFMPP , 5 - MT , and sumatriptan constricted the porcine pial arteries exclusively . In 15 % of pial venous preparations examined , 5 - HT at low concentrations induced ketanserin - sensitive constrictions . These results indicate that the porcine pial venous smooth muscle contains multiple subtypes of 5 - HT receptors . The 5 - HT inhibition of P12931 and P21673 is predominant and is mediated by 5 - HT1 - like receptors , which , however , do not seem to correspond to P08908 , P28222 , P28335 , P28221 , P28566 , or P30939 receptor subtypes . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .",
"Pharmacokinetic evaluation of frovatriptan . INTRODUCTION : Migraine is the most common painful neurological disorder , affecting 13 % of the general population . Triptans represent a powerful pharmacological tool in acute migraine treatment , however , a significant portion of treated patients can not have access to this class due to possible adverse affects . Today , a total of seven DB00669 molecules are available , representing a commonly prescribed migraine treatment . Although there is a need of extensive use of triptans , only 25 % of migraine patients are using triptans . AREAS COVERED : This review includes triptans and evidence for the use of frovatriptan . A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan , considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches . The data were obtained by searching the following key words in MEDLINE : pharmacokinetic , pharmacodynamic , triptans , frovatriptan , migraine , menstrual migraine , relatively to the period 1988 - 2011 . EXPERT OPINION : DB00998 has been developed in order to improve safety and efficacy of triptans . It shows a favorable tolerability and efficacy profile , limited to 24 / 48 - h headache recurrence , when compared with other triptans . Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans . In fact , among triptans , frovatriptan showed the highest potency at the P28222 receptor ( 8 . 2 ) and the longer half - life ( 26 h ) . These parameters determine the clinical properties of frovatriptan ; in particular the lowest rate of headache recurrence in comparison with other triptans .",
"Comparison of antiplatelet effects of prasugrel and ticagrelor in cynomolgus monkeys by an ELISA - based P50552 phosphorylation assay and platelet aggregation . Prasugrel is the third generation thienopyridine prodrug , and ticagrelor is a non - competitive direct acting Q9H244 antagonist . In phase 3 studies , both agents reduced ischaemic event rates compared to clopidogrel . The present in vitro human and monkey studies showed that ticagrelor ' s active metabolite ( AM ) was more potent than ticagrelor and prasugrel ' s AM on inhibition of ADP - induced platelet aggregation by light transmission aggregometry and ELISA - based vasodilator - stimulated phosphoprotein ( P50552 ) phosphorylation assay . In contrast , on an oral dosage basis ( mg / kg ) , prasugrel showed more potent platelet inhibition compared to ticagrelor on ex vivo aggregation and P50552 phosphorylation assays in monkeys . Single oral doses of prasugrel ( 0 . 3 and 1 mg / kg ) resulted in robust antiplatelet effects , which were sustained up to 24 hours after administration . ___MASK86___ ( 3 and 10 mg / kg , p . o . ) also showed significant antiplatelet effects but its effects were diminished at 24 hours after the dosing . Repeat administration of prasugrel ( 1 . 8 mg / kg loading dose [ LD ] , 0 . 3 mg / kg once daily maintenance dose [ MD ] ) showed more rapid antiplatelet effects and longer duration of action throughout the entire day . Twice a day repeat administration of ticagrelor ( 10 mg / kg bid MD following a single 20 mg / kg LD ) also showed significant antiplatelet effects but with more intra - day variability compared to prasugrel . The in vitro and ex vivo studies showed strong correlations between platelet aggregation and P50552 phosphorylation for prasugrel , ticagrelor and their AMs . These strong correlations between platelet aggregation and P50552 phosphorylation in non - human primates also suggest that ELISA - based human P50552 assay can be utilised for non - human primate platelet studies .",
"Design , synthesis and biological evaluation of pazopanib derivatives as antitumor agents . A novel series of pazopanib derivatives were designed , synthesized , and evaluated for their inhibitory activity against a series of kinases including P35968 , P00533 , P31749 , P37023 , and P00519 . The anti - angiogenic activities ex vivo of some compounds were also investigated . Compounds P2d and P2e demonstrated outstanding inhibitory activity against P35968 and P00519 and higher anti - angiogenic activity compared with ___MASK50___ , the reference standard . These two compounds ( P2d and P2e ) could be used as novel lead compounds for further development of anticancer agents .",
"Identification of new candidate therapeutic target genes in triple - negative breast cancer . Triple - negative breast cancer ( TNBC ) is a subgroup of breast cancer that is negative for estrogen and progesterone receptor and P04626 protein expression . It is characterized by its aggressive behavior and by the lack of targeted therapies . To identify new therapeutic targets in TNBC , we used real - time quantitative RT - PCR to analyze 63 TNBC samples in terms of their mRNA expression of 26 genes coding for the major proteins currently targeted by drugs used to treat other cancers or undergoing clinical trials in breast cancer . Six of the 26 genes tested ( P15692 , P12931 , P09874 , Q05397 , P04049 , and P22607 ) were significantly upregulated in 13 % to 46 % of the TNBCs . None of the 6 genes was specifically upregulated in the TNBCs compared with 3 other classical breast tumor subtypes . No association was observed between overexpression of these 6 genes ( except for P22607 ) and P42336 mutation status . These results confirm the interest of targeting P15692 and P09874 in ongoing clinical trials in TNBC patients and also identify new target genes ( P12931 , Q05397 , P04049 , and P22607 ) . Clinical trials could be initiated easily with existing drugs . Our results also suggest that these target genes might serve as predictive biomarkers of the TNBC treatment response .",
"[ Role of serotonin and other neuroactive molecules in the physiopathogenesis of migraine . Current hypotheses ] . The study of the mechanisms of action of the DB00669 group of drugs has largely contributed to the progress made in the understanding of the physiopathological processes that are possibly responsible for migraine . In this context , two discoveries have been especially important : 1 ) these anti - migraine drugs are specifically recognized by three main types of serotonin receptors ( P28222 , P28221 , and P30939 ) ; and 2 ) these receptors are present in the meninges , where they are expressed by both smooth muscle cells and / or endothelial cells of the vascular wall and / or the perivascular trigeminal to be deleted axon terminals . These two findings have led to the most currently accepted physiopathogenic hypothesis , whereby the migraine attack would start with an excitation of the perivascular trigeminal to be deleted fibers , which would then trigger the release of vasoactive peptides ( DB05875 , calcitonin gene - related peptide / P80511 ) within the dura mater . Locally , i . e . , in the dura mater in particular , these substances can provoke vasodilatation ( P80511 ) and plasmatic extravasation ( DB05875 ) with platelet lysis and mast cell degranulation , thereby leading to the release of algogenic substances that excite the neighboring trigeminal fibers , and this neurogenic inflammatory response can progressivelly extend to the meninges as a whole . This reaction subsequently reaches the bulbar and thalamic nuclei and then the sensory cortex , where it is integrated and expressed as migraine pain . The aim of this article was to report the main findings on endogenous substances ( serotonin , peptides , nitric oxide [ NO ] , etc . ) which appear to play a key role in this physiopathogenic sequence .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .",
"The pipeline in headache therapy . Migraine is a common , disabling , neurovascular disorder characterized by episodic attacks of head pain and associated disability plus systemic autonomic and neurologic symptoms . The advent of the DB00669 class of medication in the 1990s revolutionized the acute treatment of migraine , but many migraineurs do not respond optimally or at all to triptans , have intolerable adverse effects , or have contraindications to their use . Preventive pharmacotherapy has advanced mostly through serendipity , with new drugs being found effective while being used for other indications . There remains a significant need for new medications and devices that can provide effective , rapid , and sustained pain relief without adverse effects or recurrence . Several new acute and preventive therapies for the treatment of migraine and cluster headaches have shown promise and are currently under investigation . This article covers innovative delivery mechanisms , calcitonin gene - related peptide receptor antagonists , antibodies to calcitonin gene - related peptide and its receptor , P30939 receptor agonists , transient receptor potential vanilloid receptor modulators , orexin receptor antagonists , glial cell modulators , and neurostimulation .",
"Association study between clinical response to rizatriptan and some candidate genes . The aim of this study was to test genetic differences in the clinical response to rizatriptan in patients affected by migraine without aura . These genetic differences could be explained by various genes , the P28222 , encoding the 5 - HT ( 1 ) receptor subtype , P21397 gene that encodes the monoamino - oxidase , the main metabolic enzyme of this DB00669 , P31645 ( gene encoding the serotonin transporter ) and DRD ( 2 ) ( gene encoding the D ( 2 ) receptor ) , both involved in the pathogenesis of migraine . Fifty unrelated patients affected by migraine without aura ( IHS ) were included . Patients were divided into two groups ( responders and non - responders ) according to clinical response . Thirty - one out of fifty patients responded to rizatriptan . A significant difference among the two groups was observed in both allele ( p = 0 . 02 ) and genotype distribution ( p = 0 . 03 ) of P14416 / NcoI . The significant association with the P14416 / NcoI polymorphism in responders suggested that the P14416 / NcoI C allele may be considered a susceptibility factor heralding a good response to rizatriptan .",
"Sumatriptan : a review of its pharmacokinetics , pharmacodynamics and efficacy in the acute treatment of migraine . INTRODUCTION : Sumatriptan was developed more than 20 years ago as a P28222 / 1D receptor agonist , the first drug in a new class of specific anti - migraine drugs , the triptans . A large amount of information and experience has been gained from the clinical trials undertaken as well the various formulations of sumatriptan used over this period of time . AREAS COVERED : This evaluation specifically reviews the pharmacokinetics , pharmacodynamics , clinical efficacy , and safety of different formulations and dosages of sumatriptan used for the acute treatment of migraines . Special clinical trials of the timing of dosage and sumatriptan in combination with other triptans as well as non - DB00669 drugs are also included . EXPERT OPINION : Oral sumatriptan is effective , but not in a convincing majority ( 60 % ) of patients in clinical trials . Sumatriptan has failed to show superiority over more standard and cheaper treatment such as aspirin or aspirin plus metoclopramide . In addition , migraine patients want to quickly become pain free , and to remain pain free , but oral sumatriptan at 100 mg managed to keep patients pain free for 24 h is only 20 % of cases . Even though sumatriptan has been a major step forward in providing a new specific therapy for the treatment of migraines , there are still are limitations in its use . There is still an unmet need to develop new non - DB00669 , anti - migraine drugs which act as effective treatment for those who suffer with migraines .",
"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .",
"P08908 receptor responsivity in unipolar depression . Evaluation of ipsapirone - induced DB01285 and cortisol secretion in patients and controls . The selective P08908 receptor ligand ipsapirone ( IPS ) induces corticotropin ( DB01285 ) and cortisol secretion in humans . To explore P08908 receptor - mediated hypothalamic - pituitary - adrenal ( Q9Y251 ) system activation in depression , 24 subjects ( 12 patients with unipolar depression and 12 individually matched controls ) were given 0 . 3 mg / kg IPS or placebo in random order . Compared with controls , the depressed patients exhibited significantly decreased DB01285 and cortisol responses to IPS in association with increased basal cortisol secretion . The impaired Q9Y251 response following P08908 receptor challenge in unipolar depression could have resulted from glucocorticoid - dependent subsensitivity of the ( post - synaptic ) P08908 receptor itself and / or from a defective postreceptor signaling pathway [ inhibitory guanine nucleotide - binding protein ( Gi ) - adenylate cyclase complex function ] , thus supporting the hypothesis that a disintegrated 5 - HT and Q9Y251 system interaction may be present in depression . Future studies of the Q9Y251 response to direct - acting P08908 ligands , such as IPS , should facilitate the assessment of 5 - HT / Q9Y251 system integrity in various affective disorders and its involvement in psychotropic drug effects .",
"Pharmacokinetics and pharmacodynamics of the DB00669 antimigraine agents : a comparative review . The current approach to antimigraine therapy comprises potent serotonin P28222 / 1D receptor agonists collectively termed triptans . Sumatriptan was the first of these compounds to be developed , and offered improved efficacy and tolerability over ergot - derived compounds . The development of sumatriptan was quickly followed by a number of ' second generation ' DB00669 compounds , characterised by improved pharmacokinetic properties and / or tolerability profiles . Triptans are believed to effect migraine relief by binding to serotonin ( 5 - hydroxy - tryptamine ) receptors in the brain , where they act to induce vasoconstriction of extracerebral blood vessels and also reduce neurogenic inflammation . Although the pharmacological mechanism of the triptans is similar , their pharmacokinetic properties are distinct . For example , bioavailability of oral formulations ranges between 14 % ( sumatriptan ) and 74 % ( naratriptan ) , and their elimination half - life ranges from 2 hours ( sumatriptan and rizatriptan ) to 25 hours ( frovatriptan ) . Clearly , such diverse pharmacokinetic properties will influence the effectiveness of the compounds and favour the prescription of one over another in different patient populations . This article reviews the pharmacological properties of the triptans ( time to peak plasma concentration , half - life , bioavailability and receptor binding ) and relates these properties to efficacy and time of onset . It also considers the effects of concomitant medication , food , age and disease on the pharmacokinetics of the compounds . In addition , the relative merits , such as headache recurrence , tolerability and route of administration , are discussed . Finally , the performance of the triptans is considered in the context of direct head - to - head comparative trials that have assessed the efficacy profile of the compounds .",
"[ Rizatriptan : experience after 15 years of clinical use ] . We review the development of rizatriptan , one of the seven P28222 / 1D agonists available for the symptomatic treatment of migraine , emphasizing the most relevant contributions carried out from our country . Rizatriptan has shown the quickest onset of action , both in controlled studies and in the different metaanalyses , which translates in high efficacy levels at two hours . Its tolerability and safety profile is similar to that of the other compounds in this pharmacological group . Postlaunching studies have shown that its high efficacy leads to pharmacoeconomic savings and to a robust preference and satisfaction by the patient for this DB00669 . Its efficacy is improved with an early use within migraine attacks and recent data have shown also efficacy in adolescents . This global profile places rizatriptan as a DB00669 of first choice for any kind of migraine attacks .",
"The effects of P08908 , P28222 and P28221 receptor agonists on trigeminal nociceptive neurotransmission in anaesthetized rats . Pre - clinical studies have suggested that one mechanism of antimigraine action of the ' DB00669 ' P28222 / 1D receptor agonists may be through inhibition of central nociceptive transmission in the trigeminal dorsal horn . In anaesthetized rats , the P28222 / 1D receptor agonist , zolmitriptan ( up to 3 mg kg (- 1 ) , i . v . ) , inhibited the action potential discharge of single trigeminal neurones to noxious electrical stimulation of the middle meningeal artery . In contrast , the selective P28222 receptor agonist , CP - 93 , 129 ( 3 -( 1 , 2 , 5 , 6 - tetrahydropyrid - 4 - yl ) pyrrolo [ 3 , 2 - b ] pyrid - 5 - one ) , and the P08908 receptor selective agonist 8 - hydroxy - 2 -( di - n - propylamino )- tetralin ( 8 - OH - DPAT ) had no effect in this assay at up to 3 mg kg (- 1 ) , i . v .. Brain penetrant , DB00669 P28222 / 1D receptor agonists may therefore mediate their central trigeminal anti - nociceptive action in the rat via P28221 , but not P28222 or P08908 , receptors .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK73___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK73___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"Endocannabinoids in the brainstem modulate dural trigeminovascular nociceptive traffic via P21554 and \" DB00669 \" receptors : implications in migraine . Activation and sensitization of trigeminovascular nociceptive pathways is believed to contribute to the neural substrate of the severe and throbbing nature of pain in migraine . Endocannabinoids , as well as being physiologically analgesic , are known to inhibit dural trigeminovascular nociceptive responses . They are also involved in the descending modulation of cutaneous - evoked C - fiber spinal nociceptive responses from the brainstem . The purpose of this study was to determine whether endocannabinoids are involved in the descending modulation of dural and / or cutaneous facial trigeminovascular nociceptive responses , from the brainstem ventrolateral periaqueductal gray ( vlPAG ) . P21554 receptor activation in the vlPAG attenuated dural - evoked Aδ - fiber neurons ( maximally by 19 % ) and basal spontaneous activity ( maximally by 33 % ) in the rat trigeminocervical complex , but there was no effect on cutaneous facial receptive field responses . This inhibitory vlPAG - mediated modulation was inhibited by specific P21554 receptor antagonism , given via the vlPAG , and with a P28222 / 1D receptor antagonist , given either locally in the vlPAG or systemically . These findings demonstrate for the first time that brainstem endocannabinoids provide descending modulation of both basal trigeminovascular neuronal tone and Aδ - fiber dural - nociceptive responses , which differs from the way the brainstem modulates spinal nociceptive transmission . Furthermore , our data demonstrate a novel interaction between serotonergic and endocannabinoid systems in the processing of somatosensory nociceptive information , suggesting that some of the therapeutic action of triptans may be via endocannabinoid containing neurons in the vlPAG .",
"Migraine in the DB00669 era : progresses achieved , lessons learned and future developments . Triptans , serotonin P28222 / 1D receptor agonists , more than revolutionizing the treatment of migraine , stimulated also ground breaking research that provided insights into the anatomy , physiology , and molecular pharmacology of migraine . This knowledge , in turn , is stimulating research on new mechanisms of action for the treatment of migraine . Accordingly , it is opportune to critically review the main advances in migraine science that happened in the DB00669 era . Herein we first review and conceptualize some of the progresses achieved in migraine science during the DB00669 era . We then review the class of the triptans -- mechanism of action and clinical evidence . We close by briefly discussing the class of P80511 receptor antagonists , which is currently being developed for the acute treatment of migraine .",
"[ Cardiovascular side - effects of triptanes in migraine exist but are rare . 5 - HT receptor mediated extracranial vasoconstriction is the most common cause ] . Triptans , P28222 / 1D agonists used in migraine treatment , are rarely involved in serious coronary events due to vasospasm . 5 HT1 receptors mediate vasodilation and vasoconstriction of coronary arteries . Reports of serious coronary events mainly concern patients with known risk factors for coronary artery disease . It is prudent to obtain a thorough medical history before treatment with a DB00669 is started . If chest pain occurs , the possibility of coronary ischemia should be investigated . Stroke , a known complication to migraine , has also been reported in patients treated with triptans , but available data do not suggest that triptans , when correctly used , greatly increase the risk .",
"Disabling the mitotic spindle and tumor growth by targeting a cavity - induced allosteric site of survivin . Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis . Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy . P00533 and Her / neu - transformed human tumors in particular exhibit high levels of survivin . The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein . We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces . P28222 , a lead compound identified in the screen , can bind to the survivin protein at the intended target site . Moreover , P28222 alters spindle formation , causing mitotic arrest and cell death , and inhibits tumor growth in vitro and in vivo . Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity . Thus , the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers .",
"___MASK50___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK50___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"Migraine : current concepts and emerging therapies . Migraine is a recurrent incapacitating neurovascular disorder characterized by attacks of debilitating pain associated with photophobia , phonophobia , nausea and vomiting . Migraine affects a substantial fraction of world population and is a major cause of disability in the work place . Though the pathophysiology of migraine is still unclear three major theories proposed with regard to the mechanisms of migraine are vascular ( due to cerebral vasodilatation ) , neurological ( abnormal neurological firing which causes the spreading depression and migraine ) and neurogenic dural inflammation ( release of inflammatory neuropeptides ) . The modern understanding of the pathogenesis of migraine is based on the concept that it is a neurovascular disorder . The drugs used in the treatment of migraine either abolish the acute migraine headache or aim its prevention . The last decade has witnessed the advent of Sumatriptan and the ' DB00669 ' class of P28222 / 1D receptor agonists which have well established efficacy in treating migraine . Currently prophylactic treatments for migraine include calcium channel blockers , 5 - HT2 receptor antagonists , beta adrenoceptor blockers and gamma - amino butyric acid ( GABA ) agonists . Unfortunately , many of these treatments are non specific and not always effective . Despite such progress , in view of the complexity of the etiology of migraine , it still remains undiagnosed and available therapies are underused . In this article , the diverse pieces of evidence that have linked the different theories of migraine with its pathophysiology are reviewed . Furthermore , the present therapeutic targets and futuristic approaches for the acute and prophylactic treatment of migraine , with a special emphasis to calcitonin gene - related peptide , are critically evaluated .",
"DB06155 inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon . The selective P21554 receptor antagonist rimonabant ( SR141716 ) was shown to perform a number of biological effects in several pathological conditions . Emerging findings demonstrate that rimonabant exerts antitumor action in thyroid tumors and breast cancer cells . In our study , human colorectal cancer cells ( DLD - 1 , CaCo - 2 and SW620 ) were treated with rimonabant and analyzed for markers of cell proliferation , cell viability and cell cycle progression . DB06155 significantly reduced cell growth and induced cell death . In addition , rimonabant was able to alter cell cycle distribution in all the cell lines tested . Particularly , rimonabant produced a G2 / M cell cycle arrest in DLD - 1 cells without inducing apoptosis or necrosis . The G2 / M phase arrest was characterized by a parallel enhancement of the number of mitoses associated to elevated DNA double strand breaks and chromosome misjoining events , hallmarks of mitotic catastrophe . Protein expression analyses of P12004 B1 , P09874 , Aurora B and phosphorylated p38 / MAPK and Chk1 demonstrated that rimonabant - induced mitotic catastrophe is mediated by interfering with the spindle assembly checkpoint and the DNA damage checkpoint . Moreover , in the mouse model of azoxymethane - induced colon carcinogenesis , rimonabant significantly decreased aberrant crypt foci ( Q9NQ94 ) formation , which precedes colorectal cancer . Our findings suggest that rimonabant is able to inhibit colorectal cancer cell growth at different stages of colon cancer pathogenesis inducing mitotic catastrophe in vitro .",
"Renal infarction during the use of rizatriptan and zolmitriptan : two case reports . Rizatriptan and zolmitriptan are both used to relieve acute migraine and cluster headaches . The mechanism of action is similar to the other triptans , in that they reverse abnormal cerebral vasodilation through their activity as P28222 receptor agonists . Triptan - induced vasoconstriction is attributed to its activity on peripheral P28222 receptors and has rarely been reported to result in stroke , myocardial infarction and ischemic colitis . We present two cases of renal infarction associated with therapeutic DB00669 use . The first patient is a 57 - year - old man with a history of hypertension that was well controlled on valsartan and hydrochlorothiazide . He was recently diagnosed with cluster headaches and was treated with indomethacin , prednisone , butalbital - acetaminophen - caffeine and hydrocodone without relief . He then received two therapeutic doses of rizatriptan on each of the two days prior to presentation . Subsequently , he presented to the emergency department complaining of nausea , vomiting and right - sided abdominal pain . A computerized tomography ( CT ) scan of the abdomen and pelvis with intravenous contrast revealed a very large wedge shaped infarction of the right kidney . The second patient is a 34 - year - old man with a past medical history significant only for life - long migraine headaches successfully treated for the past six years with zolmitriptan . Shortly after taking one therapeutic dose of zolmitriptan , he presented to the emergency department complaining of nausea and left - sided abdominal pain . A CT scan of the abdomen and pelvis with intravenous contrast revealed multiple wedge - shaped infarctions of the left kidney . Renal infarction was confirmed in both patients by arteriogram of the renal arteries . Although both rizatriptan and zolmitriptan are effective in the treatment of migraine and cluster headaches , they may induce peripheral vasospasm leading to renal infarction .",
"A PET study with [ 11C ] AZ10419369 to determine brain P28222 receptor occupancy of zolmitriptan in healthy male volunteers . AIM : To investigate the occupancy at brain 5 - hydroxytryptamine ( 5 - HT ) 1B receptors in human subjects after administration of the antimigraine drug zolmitriptan . METHODS : Positron emission tomography ( PET ) studies were undertaken using the radioligand [( 11 ) C ] AZ10419369 in eight control subjects at baseline and after administration of zolmitriptan orodispersible tablets . The subjects were examined after two consecutive administrations of 10 mg zolmitriptan , approximately 1 week apart . Two of the subjects were subsequently examined after administration of 5 mg zolmitriptan . One week after the last administration of zolmitriptan five of the subjects underwent additional PET measurements without drug pretreatment . RESULTS : After administration of 10 mg zolmitriptan , mean receptor occupancy was 4 - 5 % . No consistent changes in P28222 receptor binding were observed for subjects who received 5 mg zolmitriptan . There was a statistically significant negative relationship between binding potential ( BP ND ) and plasma concentration of zolmitriptan and the active metabolite 183C91 , respectively . All of the five subjects who were examined 1 week after dosing with zolmitriptan showed higher BP ND post drug administration compared with baseline . CONCLUSION : This is the first demonstration of CNS P28222 receptor occupancy of a DB00669 . The findings are consistent with the low receptor occupancy previously reported in PET studies with agonists at other G protein coupled receptors .",
"A review of rizatriptan , a quick and consistent P28222 / 1D agonist for the acute treatment of migraine . Rizatriptan is a second - generation DB00669 marketed as 5 and 10 mg tablets and rapidly disintegrating wafer formulations . In > 5000 acute migraine patients enrolled in short - term trials and almost 1800 patients in long - term , open - label trials treating approximately 47000 attacks , rizatriptan was effective and well - tolerated . Controlled head - to - head data and a meta - analysis of 53 randomised , placebo - controlled trials of oral triptans in > 24000 patients have shown that rizatriptan 10 mg offers efficacy advantages over oral sumatriptan 50 and 100 mg and other oral triptans , both in terms of speed of onset of action and consistency . These advantages may reflect its improved pharmacological profile over sumatriptan in terms of higher oral bioavailability and a shorter time to maximum concentration . The wafer formulation offers the convenience of being administered without water . As a result of its superior efficacy profile and generally good tolerability , rizatriptan can be considered as a first - line treatment for acute migraine .",
"GLC756 decreases P01375 via an alpha2 and beta2 adrenoceptor related mechanism . GLC756 , a polyvalent anti - glaucoma drug showed in an endotoxin - induced - uveitis model ( EIU ) in rats a significant tumor necrosis factor - alpha ( P01375 ) decrease in serum , indicating an additional anti - inflammatory potential of this compound . The receptors on which GLC756 binds ( D1 , D2 , D4 , alpha - 1 , alpha - 2 , P08908 , P28335 , P28221 , 5 - HT2 A , beta - 1 , and beta - 2 ) were suggested to play a role . In order to identify a receptor type mediating the P01375 lowering response , GLC756 was combined with various counteracting compounds ( CP ) . For EIU , 8 - week - old Lewis rats were intravenously injected at 160 microg lipopolysaccharide ( LPS ) from Salmonella typhimurium . Before EIU - induction animals received either one of the CP ' s or GLC756 alone , or GLC756 in combination with one of the CP ' s . P01375 was determined in serum 2h post EIU - induction . Treatment with CP ' s alone indicated that agonistic effects on beta - 2 adrenoceptors and antagonistic effects on alpha - 2 , P08908 and P28221 receptors resulted in statistically significant decreased P01375 levels in comparison to the LPS - control group . In combination with GLC756 , the counteracting CP ' s domitor ( alpha - 2 adrenoceptor agonist ) and ICI 118551 ( beta - 2 adrenoceptor antagonist ) inhibited completely the P01375 decreasing effect of GLC756 . Counteracting the P08908 receptor with the P08908 agonist 8 - OH - DPAT could not prevent the P01375 decreasing effect of GLC756 . In conclusion , the antagonistic effect on alpha - 2 adrenoceptors and the agonistic effect on beta - 2 adrenoceptors were identified as mechanism for the P01375 decreasing effect of GLC756 .",
"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK86___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .",
"Overview of migraine treatment . SUMMARY Migraine is ranked as the 19th top cause of disability worldwide by WHO . Despite advancements in migraine - specific acute treatment , only a minority of patients utilize these medications . Specific pharmacologic treatments consist of the ergot alkaloids and triptans ( serotonin P28222 / 1D receptor agonists ) . Both classes are regarded as relatively safe and effective ; however , there is a greater concern for vasoconstrictive effects with the ergots , which limits their use . Triptans transformed migraine therapy , setting in motion revolutionary research that heightened our understanding of migraine mechanisms . However , one in three migraineurs may be DB00669 nonresponders and there is a group of migraine patients that remains ' refractory ' to conventional pharmacologic migraine therapy . This article discusses the approach to migraine management , reviews currently available acute and preventive pharmacologic and nonpharmacologic treatment options for migraine headache , as well as briefly focuses on novel and upcoming medicines presently under investigation .",
"[ New DB00669 preparations can help the migraine patient . Pharmacodynamic and pharmacokinetic progresses ] . Migraine is an idiopathic , recurrent neurovascular headache disorder characterised by attacks of debilitating pain associated with photophobia , phonophobia , nausea and vomiting . It is apparently a global disorder , occurring in all races , cultures and geographical locations . Migraine has a hereditary component , and its life - time prevalence is about 16 % . About a third of migraine patients in Sweden seem to be particularly sorely afflicted having 1 - 6 severe attacks a month and accounting for more than 80 per cent of the annual total of about 14 million attacks in the country as a whole . In general , these migraine sufferers do not obtain satisfactory relief from simple analgesice or NSAIDs ( non - sterodial antiinflammatory drugs only ) , and thus require additional migraine - specific treatment . Selective P28222 / 1D - agonists , the so - called triptans , have become an invaluable addition to the therapeutic arsenal for treating this category of patients .",
"P01138 - induced mechanical sensitization of the masseter muscle is mediated through peripheral DB01221 receptors . Intramuscular injection of nerve growth factor ( P01138 ) in healthy humans mimics some of the symptoms of myofascial temporomandibular disorders ( M - TMD ) . We hypothesized that P01138 induces a prolonged myofascial mechanical sensitization by increasing peripheral N - methyl - d - aspartate ( DB01221 ) receptor expression , leading to an enhanced response of muscle nociceptors to endogenous glutamate . Behavioral experiments with an injection of P01138 ( 25 μg / ml , 10 μl ) into the masseter muscle reduced the mechanical withdrawal threshold for 1 day in male rats and 5 days in female rats . These results mirror the sex - related differences found in P01138 - induced mechanical sensitization in humans . Intramuscular injection with the competitive DB01221 receptor antagonist dl - 2 - amino - 5 - phosphonovaleric acid ( APV , 0 . 020 g / ml , 10 μl ) reversed the mechanical sensitization in male but not in female rats . P01138 increased the number of DB01221 receptor subtype 2B ( Q13224 ) - expressing rat trigeminal masseter ganglion neurons in both sexes , which peaked at 3 days post injection . There was an association between the levels of Q13224 expression and P01138 - induced mechanical sensitization . The average soma size of Q13224 - expressing neurons increased significantly . Increased expression of neuropeptides ( P80511 and SP ) was observed in Q13224 - expressing masseter ganglion neurons in female but not in male rats . In healthy men and women , comparable basal expression levels of Q13224 and SP were found in peripheral fibers from masseter muscle microbiopsies . This study suggests that P01138 - induced sensitization of masseter nociceptors is mediated , in part , by enhanced peripheral DB01221 receptor expression . Measurement of peripheral DB01221 receptor expression may be useful as a biomarker for M - TMD pain .",
"Differential radiosensitisation by ZD1839 ( ___MASK28___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK28___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .",
"[ Migraine - established concepts and new developments ] . Migraine is a very common primary headache disorder associated with intermittent attacks and great suffering . Despite extensive research efforts in the recent years , many pathophysiological aspects remain unclear . An altered cortical adaptability and the brainstem as a migraine generator are probably involved in the initiation of a ( silent ) cortical spreading depression and other processes that lead to neurogenic inflammation of the meninges causing the headache . Numerous studies in the last years have examined somatic , especially cerebrovascular and also psychological comorbidities . For attack therapy , P80511 antagonists have emerged as promising non - vasoconstrictive acting alternatives for triptans . However , they were so far not approved due to liver enzyme elevations in safety studies . Another new approach without vasoconstrictive action are the selective P30939 agonists ( especially Lasmiditan ) . Large placebo - controlled and DB00669 - controlled trials need to be awaited . For migraine prophylaxis , a comparable effect of sports and pharmacological prophylaxis using topiramate could be found . Particularly the combination of drug and non - drug therapies ( such as the combination of stress management training with a beta - blocker treatment ) achieves high efficacy . Also interdisciplinary , multimodal treatment approaches are important options . Two large multicentre studies have demonstrated the efficacy of botulinum toxin A as a prophylactic treatment for chronic migraine . Neuromodulative and neurostimulative procedures are promising but still experimental treatment options for patients with refractory migraine .",
"Role of endothelial cells in antihyperalgesia induced by a DB00669 and β - blocker . While blood vessels have long been implicated in diverse pain syndromes ( e . g . , migraine headache , angina pectoris , vasculitis , and Raynaud ' s syndrome ) , underlying mechanisms remain to be elucidated . Recent evidence supports a contribution of the vascular endothelium in endothelin - 1 - induced hyperalgesia , and its enhancement by repeated mechanical stimulation ; a phenomenon referred to as stimulus - induced enhancement of ( endothelin ) hyperalgesia ( SIEH ) . SIEH is thought to be mediated by release of DB00171 from endothelial cells , to act on P56373 receptors on nociceptors . In the present study we evaluated the ability of another vasoactive hyperalgesic agent , epinephrine , to induce endothelial cell - dependent hyperalgesia and SIEH . We found that epinephrine also produces hyperalgesia and SIEH . Both P56373 receptor antagonists , A317491 and octoxynol - 9 , which attenuate endothelial cell function , eliminated SIEH without affecting epinephrine hyperalgesia . We further evaluated the hypothesis that members of two important classes of drugs used to treat migraine headache , whose receptors are present in endothelial cells - the triptans and β blockers - have a vascular component to their anti - hyperalgesic action . For this , we tested the effect of ICI - 118 , 551 , a β₂ - adrenergic receptor antagonist and sumatriptan , an agonist at P28222 and 5 - HT₁D receptors , on nociceptive effects of endothelin and epinephrine . ICI - 118 , 551 inhibited endothelin SIEH , and attenuated epinephrine hyperalgesia and SIEH . Sumatriptan inhibited epinephrine SIEH and inhibited endothelin hyperalgesia and SIEH , while having no effect on epinephrine hyperalgesia or the hyperalgesia induced by a prototypical direct - acting inflammatory mediator , prostaglandin E₂ . These results support the suggestion that triptans and β - blockers interact with the endothelial cell component of the blood vessel to produce anti - hyperalgesia .",
"Post - DB00669 era for the treatment of acute migraine . There now is one realized and several attractive targets for the treatment of acute attacks of migraine that will follow and augment the use of serotonin P28222 / 1D receptor agonists , the triptans . P01258 gene - related peptide ( P80511 ) receptor blockade recently has been shown to be an effective acute antimigraine strategy ; therefore , blockade of P80511 release by inhibition of trigeminal nerves would seem a logical approach . A number of targets are reviewed in this article including serotonin P30939 and P28221 receptors , adenosine A1 receptors , nociceptin , vanilloid Q8NER1 receptors , and anandamide P21554 receptors . Development of one or more such compound offers the exciting prospect of new non - vasoconstrictor treatments for migraine and cluster headache .",
"P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK86___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK86___ is in clinical development as an orally active agent .",
"No contractile effect for P28221 and P30939 receptor agonists in human and bovine cerebral arteries : similarity with human coronary artery . 1 . Using subtype - selective 5 - HT1 receptor agonists and / or the 5 - HT1 receptor antagonist GR127935 , we characterized in vitro the 5 - HT receptor that mediates the contraction of human and bovine cerebral arteries . Further , we investigated which sumatriptan - sensitive receptors are present in human coronary artery by reverse - transcriptase polymerase chain reaction ( RT - PCR ) . 2 . Agonists with affinity at the P28222 receptor , such as sumatriptan , alniditan and / or IS - 159 , elicited dose - dependent contraction in both human and bovine cerebral arteries . They behaved as full agonists at the sumatriptan - sensitive 5 - HT1 receptors in both species . In contrast , PNU - 109291 and LY344864 , selective agonists at P28221 and P30939 receptors , respectively , were devoid of any significant vasocontractile activity in cerebral arteries , or did not affect the sumatriptan - induced vasocontraction . The rank order of agonist potency was similar in both species and could be summarized as 5 - HT = alniditan > sumatriptan = IS - 159 >>> PNU - 109291 = LY344864 . 3 . In bovine cerebral arteries , the 5 - HT1 receptor antagonist GR127935 dose - dependently inhibited the vasoconstrictions elicited by both 5 - HT and sumatriptan , with respective pA2 values of 8 . 0 and 8 . 6 . 4 . RT - PCR studies in human coronary arteries showed a strong signal for the P28222 receptor while message for the P30939 receptor was weak and less frequently detected . Expression of P28221 receptor mRNA was not detected in any sample . 5 . The present results demonstrate that the DB00669 - induced contraction in brain vessels is mediated exclusively by the P28222 receptor , which is also present in a majority of human coronary arteries . These results suggest that selective P28221 and P30939 receptor agonists might represent new antimigraine drugs devoid of cerebro - and cardiovascular effects .",
"Regulation of 5 - HT receptors and the hypothalamic - pituitary - adrenal axis . Implications for the neurobiology of suicide . Disturbances in the serotonin ( 5 - HT ) system is the neurobiological abnormality most consistently associated with suicide . Hyperactivity of the hypothalamic - pituitary - adrenal ( Q9Y251 ) axis is also described in suicide victims . The Q9Y251 axis is the classical neuroendocrine system that responds to stress and whose final product , corticosteroids , targets components of the limbic system , particularly the hippocampus . We will review results from animal studies that point to the possibility that many of the 5 - HT receptor changes observed in suicide brains may be a result of , or may be worsened by , the Q9Y251 overactivity that may be present in some suicide victims . The results of these studies can be summarized as follows : ( 1 ) chronic unpredictable stress produces high corticosteroid levels in rats ; ( 2 ) chronic stress also results in changes in specific 5 - HT receptors ( increases in cortical 5 - Q13049 and decreases in hipocampal P08908 and P28222 ) ; ( 3 ) chronic antidepressant administration prevents many of the 5 - HT receptor changes observed after stress ; and ( 4 ) chronic antidepressant administration reverses the overactivity of the Q9Y251 axis . If indeed 5 - HT receptors have a partial role in controlling affective states , then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood . These data may also provide a biological understanding of how stressful events may increase the risk for suicide in vulnerable individuals and may help us elucidate the neurobiological underpinnings of treatment resistance .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK54___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK54___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK54___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK54___ among adults with ADHD .",
"Effects of PNU - 109 , 291 , a selective P28221 receptor agonist , on electrically induced dural plasma extravasation and capsaicin - evoked c - fos immunoreactivity within trigeminal nucleus caudalis . We studied the effects of PNU - 109291 [ ( S ) -(-)- 1 -[ 2 -[ 4 -( 4 - methoxyphenyl )- 1 - piperazinyl ] ethyl ]- N - methyl - isoc hroman - 6 - carboxamide ] , a receptor agonist showing 5000 - fold selectivity for primate P28221 versus P28222 receptors ( Ennis et al . , J . Med . Chem . 41 , 2180 - 2183 ) , on dural neurogenic inflammation and on c - fos like immunoreactivity within trigeminal nucleus caudalis evoked by electrical and chemical activation of trigeminal afferents , respectively . Subcutaneous injection of PNU - 109291 in male guinea pigs dose - dependently reduced dural extravasation of [ 125I ] - labeled bovine serum albumin evoked by trigeminal ganglion stimulation with an IC50 of 4 . 2 nmol kg (- 1 ) . A dose of 73 . 3 nmol kg (- 1 ) blocked the response completely . The selective P28222 / 1D receptor antagonist GR - 127935 ( > or = 2 micromol kg (- 1 ) i . v . ) prevented this effect . In addition , the number of c - fos immunoreactive cells within guinea pig trigeminal nucleus caudalis induced by chemical meningeal stimulation ( intracisternally administered capsaicin ) was reduced by more than 50 % with PNU - 109291 ( > or = 122 . 2 nmol kg (- 1 ) administered s . c . 45 min before and 15 min after capsaicin ) . These data indicate that the P28221 receptor subtype plays a significant role in suppressing meningeal neurogenic inflammation and attenuating trigeminal nociception in these guinea pig models . Since P28221 receptor mRNA and protein are expressed in trigeminal ganglia but not vascular smooth muscle , the P28221 receptor subtype may become a useful therapeutic target for migraine and related headaches .",
"Tissue injury regulates serotonin 1D receptor expression : implications for the control of migraine and inflammatory pain . The anti - migraine action of \" DB00669 \" drugs involves the activation of serotonin subtype 1D ( P28221 ) receptors expressed on \" pain - responsive \" trigeminal primary afferents . In the central terminals of these nociceptors , the receptor is concentrated on peptidergic dense core vesicles ( DCVs ) and is notably absent from the plasma membrane . Based on this arrangement , we hypothesized that in the resting state the receptor is not available for binding by a DB00669 , but that noxious stimulation of these afferents could trigger vesicular release of DCVs , thus externalizing the receptor . Here we report that within 5 min of an acute mechanical stimulus to the hindpaw of the rat , there is a significant increase of P28221 - immunoreactivity ( IR ) in the ipsilateral dorsal horn of the spinal cord . We suggest that these rapid immunohistochemical changes reflect redistribution of sequestered receptor to the plasma membrane , where it is more readily detected . We also observed divergent changes in P28221 - IR in inflammatory and nerve - injury models of persistent pain , occurring at least in part through the regulation of P28221 - receptor gene expression . Finally , we found that P28221 - IR is unchanged in the spinal cord dorsal horn of mice with a deletion of the gene encoding the neuropeptide DB05875 . This result differs from that reported for the partial differential - opioid receptor , which is also sorted to DCVs , but is greatly reduced in preprotachykinin mutant mice . We suggest that a \" pain \" - triggered regulation of P28221 - receptor expression underlies the effectiveness of triptans for the treatment of migraine . Moreover , the widespread expression of P28221 receptor in somatic nociceptive afferents suggests that triptans could , in certain circumstances , treat pain in nontrigeminal regions of the body .",
"The molecular basis of the cooperation between P01133 , FGF and eCB receptors in the regulation of neural stem cell function . Adult neurogenesis relies on P01133 and FGF receptor ( P00533 / FGFR ) function and endocannabinoid ( eCB ) signalling . Here we have used a neural stem cell ( NSC ) line to determine how these systems cooperate to regulate neurogenesis . The results show the P00533 to be solely responsible for maintaining PI3K activation explaining its dominant role in promoting NSC survival . The P00533 and FGFR synergistically regulate the P29323 / MAPK pathway , and this explains the requirement for both for optimal cell proliferation . The eCB receptors did not contribute to activation of the PI3K or P29323 / MAPK pathways , highlighting the importance of another major proliferation pathway . The P00533 plays the dominant role in maintaining the transcriptome , with significant changes in the expression of over 3500 transcripts seen within hours of inhibition or activation of this receptor . The FGFR has a more modest effect on transcription with evidence for nodal integration with P00533 signalling at the level of the P29323 / MAPK pathway . A common set of transcripts are regulated by the P21554 and CB2 receptors , with cooperation between these receptors and the P00533 apparent in the regulation of a pool of transcripts , most likely representing signal integration downstream from an as yet to be identified node . Finally , a first level molecular analysis of the transcriptional response shows regulation of a number of key growth factors , growth factor receptors and GPCRs to be under the control of the P00533 .",
"Involvement of P28222 receptors in DB00669 - induced contractile responses in guinea - pig isolated iliac artery . Using a series of triptans we characterized in vitro the 5 - hydroxytryptamine ( 5 - HT ) receptor that mediates the contraction in guinea - pig iliac arteries moderately precontracted by prostaglandin F2alpha ( PGF2alpha ) . Additionally , we investigated by reverse - transcriptase polymerase chain reaction ( RT - PCR ) which DB00669 - sensitive receptor is present in this tissue . DB00998 , zolmitriptan , rizatriptan , naratriptan , sumatriptan , and almotriptan contracted guinea - pig iliac arteries with pD2 values of 7 . 52 +/- 0 . 04 , 6 . 72 +/- 0 . 03 , 6 . 38 +/- 0 . 06 , 6 . 22 +/- 0 . 05 , 5 . 86 +/- 0 . 05 and 5 . 26 +/- 0 . 04 respectively . For comparison , the pD2 values for 5 - HT and 5 - carboxamidotryptamine ( 5 - CT ) were 7 . 52 +/- 0 . 02 and 7 . 55 +/- 0 . 03 respectively . In contrast to all other triptans tested , the concentration - response curve for eletriptan was biphasic ( first phase : 0 . 01 - 3 microM , pD2 approximately 6 . 6 ; second phase : > or = 10 microM ) . Contractions to 5 - HT , 5 - CT , frovatriptan , zolmitriptan , rizatriptan , naratriptan , sumatriptan , almotriptan , and eletriptan ( first phase ) were antagonized by the P28222 / 1D receptor antagonist GR127935 ( 10 nM ) and the P28222 receptor antagonist SB216641 ( 10 nM ) . RT - PCR studies in guinea - pig iliac arteries showed a strong signal for the P28222 receptor while expression of P28221 and P30939 receptors was not detected in any sample . The present results demonstrate that DB00669 - induced contraction in guinea - pig iliac arteries is mediated by the P28222 receptor . The guinea - pig iliac artery may be used as a convenient in vitro model to study the ( cardio ) vascular side - effect potential of anti - migraine drugs of the DB00669 family .",
"Eugenosedin - A ameliorates hyperlipidemia - induced vascular endothelial dysfunction via inhibition of α1 - adrenoceptor / 5 - HT activity and NADPH oxidase expression . Eugenosedin - A ( Eu - A ) effects on vascular endothelial dysfunction and oxidative stress in a hyperlipidemic rat model were investigated . Rats were randomly divided into four groups : two control groups and two treatment groups . The control rats received a regular diet or high fat diet ( HFD ) ; the treatment rats fed received an HFD with 5 mg / kg Eu - A or atorvastatin for 10 weeks . No changes in serotonin levels were observed in the four groups ; norepinephrine levels were enhanced in the HFD group which was attenuated by Eu - A and atorvastatin . In the HFD group , the vascular reactivity was increased by vasoconstrictors ( 5 - nonyloxytryptamine , 5 - HT , and phenylephrine ) and decreased by an endothelium - dependent vasorelaxant , carbachol . Protein levels of α1 - adrenergic receptors ( not P28222 / 2A ) , reactive oxygen species ( ROS ) p47 ( phox ) , p67 ( phox ) , and gp91 ( phox ) , and oxidative damage markers 3 - nitrotyrosine ( 3 - NT ) and 4 - hydroxy - 2 - nonenal ( 4 - HNE ) were increased , but endothelial nitric oxide synthase ( P29474 ) , P - P29474 and vasodilator - stimulated phosphoprotein phosphorylation ( P - P50552 ) were decreased . P04040 and superoxide dismutase ( SOD - 1 and SOD - 2 ) proteins were increased , but glutathione peroxidase ( GPx ) was decreased in the aorta . Eu - A and atorvastatin reduced vasoconstrictor - induced aortic contractions that might be related to P28222 / 2A and α1 - adrenergic receptors inhibitory activities . Eu - A and atorvastatin improved P29474 / P - P29474 , P - P50552 , GPx , and malondialdehyde ( MDA ) levels , and decreased ROS and oxidative damage markers . Taken together , we suggest that Eu - A can ameliorate hyperlipidemia - induced vascular endothelial dysfunction and oxidative dysregulation .",
"[ Treatments of migraine ] . During the 1980s , a new class of drugs for the acute treatment of migraine attacks was developed , the triptans . These agents are selective P28222 / 1D serotonin receptor agonists , and were developed in order to address the underlying biological mechanism of the migraine attack . French guidelines in migraine are available since 2002 . It is recommended to use a stratified treatment approach during the first consultation with the use of NSAID in first line acute treatment and DB00669 in second line . It is also recommended to use prophylactic treatment when the patient experience frequent and / or severe migraine attack with a bad quality of life and a real impairment .",
"Rizatriptan in migraineurs with unilateral cranial autonomic symptoms : a double - blind trial . The objective and background is to confirm in a double - blind , placebo - controlled study the high DB00669 response rates we had previously reported in an open study in migraine patients with unilateral cranial autonomic symptoms . In this randomized , double - blind , placebo - controlled study 80 migraineurs with unilateral cranial autonomic symptoms were assigned to receive rizatriptan 10 mg wafer or placebo ( ratio 1 : 1 ) and treated for a single moderate or severe migraine attack . The primary endpoints were pain freedom at 2 h and total migraine freedom at 2 h . Secondary endpoints included pain relief , no associated symptoms and sustained pain freedom or relief . Significantly more patients reported pain freedom at 2 h after taking rizatriptan ( 54 % ) than after placebo ( 8 % ) ( therapeutic gain 46 % [ 28 % ; 64 % ] ; P < 0 . 001 ) . Similarly , significantly more patients reported total migraine freedom at 2 h after rizatriptan ( 51 % ) than after placebo ( 8 % ) ( therapeutic gain 43 % [ 26 % ; 61 % ] ; P < 0 . 001 ) . Rizatriptan was also more effective than placebo on most secondary endpoints . We confirm in a placebo - controlled study our previous data suggesting that the presence of unilateral cranial autonomic symptoms in migraineurs predicts a positive response to triptans , probably owing to intense trigeminal peripheral afferent activation which strongly recruits peripheral neurovascular P28222 / 1D receptors . Acute and preventive pharmacological trials in migraine should focus also on this subset of migraine patients .",
"Co - localization of 5 - HT ( 1B / 1D / 1F ) receptors and glutamate in trigeminal ganglia in rats . Anti - migraine DB00669 drugs are 5 - HT ( 1B / 1D ) receptor agonists which are thought to block the neurotransmitter / neuropeptide release from sensory nerve terminals and directly constrict blood vessel smooth muscles . In the present study , we have investigated the anatomical basis for a possible modulation of glutamate release from trigeminal ganglion neurons by 5 - HT ( 1B / 1D ) receptor agonists and by P30939 receptor agonists , using double immunohistochemical staining technique in the rat . The majority of P28222 , P28221 or P30939 receptor positive neurons were also glutamate positive , but both P28222 , P28221 or P30939 receptor single - labeled and glutamate single - labeled neurons were observed . These results suggest that 5 - HT ( 1B / 1D / 1F ) receptor agonists may modulate glutamate release , and that one mechanism of their anti - migraine action could be the blockade of glutamate release .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK40___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK40___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK40___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK40___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK40___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"Antibody to ras proteins in patients with colon cancer . The current study examined sera from 160 colon cancer patients and 60 normal individuals to determine whether antibody to mutated P38936 ras protein was present . Studies focused on the aspartic acid substitution at amino acid position 12 ( denoted D12 ) , one of the most common mutations in colon adenocarcinoma . IgA antibodies directed against mutated P38936 ras - D12 protein were detected in 51 ( 32 % ) of 160 colon cancer patients , but only in 1 ( 2 . 5 % ) of 40 normal individuals . The greater incidence of antibody in cancer patients provides presumptive evidence that immunization to the ras proteins occurred as a result of the malignancy . Examination of sera for antibody reactivity to wild - type P38936 ras protein ( denoted P38936 ras - G12 ) as well as P38936 ras proteins bearing the D12 , V12 , P28222 , or L61 mutations showed that antibody detected was largely to normal segments of the P38936 ras protein . Epitope mapping , using peptide neutralization assays with mutated or normal ras peptides as competitors , demonstrated that in 10 ( 67 % ) of 15 sera examined the antibody reactivity to P38936 ras - G12 protein was neutralized by peptides near the carboxyl terminus of P38936 ras protein , but not by peptides spanning the specific point mutation region . Antibody reactivities correlated with peripheral blood lymphocyte count , but did not correlate with patient age , sex , histology , stage , tumor locus , lymph node metastasis , or serum carcinoembryonic antigen .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK52___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"[ Triptans and calcitonin gene - related peptide ( P80511 ) receptor antagonists ] . While triptans , the P28222 / 1D agonists , are effective and generally well - tolerated in many patients up to one - third of migraine patients either may not respond well to triptans , may not tolerate their side effects , or may have contraindications that preclude their use . Recurrence , DB00669 - related side effects , and cardiovascular constriction effects are demerits for acute migraine treatment . P80511 receptor antagonists , the so - called gepants , were clearely designed and expected to be better than triptans . P80511 is located in sensory nerve endings around cranial blood vessels . P80511 is a strong dilator of cerebral arteries and intravenous infusion of P80511 cause a migraine attack . DB04869 is the first selective P80511 receptor antagonist of proven efficacy in migraine . DB04869 could only be administered intravenously and never taken beyond Phase II . Telcagepant is orally available and several completed Phase III trials have revealed positive results . In several comparative studies of telcagepant and triptans , telcegepant did not appeared more effective than zolmitriptan or rizatriptan , although it had fewer DB00669 - related adverse events and drug - related adverse enents . A small number of patients taking olcegepant showed marked elevation in liver transaminase levels . It was decided to discontinue development of olcegepant . New P80511 receptor antagonists would be expected for acute migraine treatment .",
"___MASK8___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK8___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK79___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"Localisation of P47900 and P51582 receptors in dorsal root , nodose and trigeminal ganglia of the rat . The presence and distribution of P2Y ( nucleotide ) receptor subtypes in rat sensory neurons has been investigated . RT - PCR showed that P2Y ( 1 ) , P2Y ( 2 ) , P2Y ( 4 ) and P2Y ( 6 ) receptor mRNA is expressed in sensory ganglia [ dorsal root ganglion ( Q86YR7 ) , nodose ganglion ( NG ) and trigeminal ganglion ( TG ) ] . The regional and cellular distribution of P2Y ( 1 ) and P2Y ( 4 ) receptor proteins in these ganglia was investigated using immunohistochemistry . P2Y ( 1 ) polyclonal antibodies stained over 80 % of the sensory neurons , particularly the small - diameter ( neurofilament - negative ) neurons . The P2Y ( 4 ) receptor antibody stained more medium - and large - ( neurofilament - positive ) diameter neurons than small - diameter neurons . P2Y ( 1 ) and P2Y ( 4 ) receptor immunoreactivity ( P2Y ( 1 )- IR and P2Y ( 4 )- IR ) was often coexpressed with P2X ( 3 ) receptor immunoreactivity ( P2X ( 3 )- IR ) in subpopulations of neurons . Double immunohistochemistry showed that 73 - 84 % of P2X ( 3 ) receptor - positive neurons also stained for the P2Y ( 1 ) receptor in Q86YR7 , TG and NG while only 25 - 35 % also stained for the P2Y ( 4 ) receptor . Subpopulations of P2Y ( 1 )- IR neurons were coexpressed with NF200 , P80511 and IB ( 4 ) ; most P2Y ( 4 )- IR neurons were coexpressed with NF200 , while only a few neurons were coexpressed with P80511 ( 10 - 20 % ) or with IB ( 4 ) ( 1 - 2 % ) . The results suggest that P2Y as well as P2X receptor subtypes contribute to purinergic signalling in sensory ganglia .",
"The search for novel migraine therapies : experimental models . The identification and development of the potent P28222 / 1D agonist , sumatriptan has resulted in new therapeutic opportunities for the treatment of migraine and a number of chemically novel agents with a similar mechanism of action have been identified . Whilst these agents are optimised to enhance the therapeutic effect of sumatriptan , development of mechanistically novel therapies may provide new directions for the care of migraine sufferers . To develop new treatment paradigms , novel chemical entities should be evaluated in animal models which are predictive of therapeutic efficacy e . g . : in animal models where sumatriptan has shown activity , or the pathophysiological processes involved in the disease must be targeted . Therefore , investigation of mechanisms underlying cortical activity and its involvement in the activation of trigeminal vascular pathways may allow better understanding of the disease and result in the identification of new non - DB00669 - like therapies .",
"Colocalization of P80511 with P28222 / 1D receptors and DB05875 in trigeminal ganglion neurons in rats . Vasodilatation in the dura mater has been implicated in migraine pathogenesis . Anti - migraine DB00669 drugs block vasodilatation by binding to P28222 / 1D receptors localized on the peripheral sensory terminals and dural blood vessel smooth muscles . Previous studies suggest that calcitonin gene - related peptide ( P80511 ) released from Adelta - fibres plays a more important role than DB05875 ( SP ) released from C - fibres in inducing dural vasodilatation and that one of the antimigraine mechanisms of DB00669 drugs is inhibiting P80511 release . In the present study , the relationship between P80511 and P28222 / 1D receptors , and between P80511 and SP in the trigeminal ganglion neurons in rats was examined by double immunohistochemical staining . P80511 , P28222 , P28221 and SP - positive trigeminal ganglion neurons were all predominantly small and medium - sized . In the trigeminal ganglia , approximately 50 % of P80511 - positive neurons were P28222 positive . Similarly , approximately 55 % of P80511 - positive neurons were P28221 immunoreactive . Approximately 50 % of P80511 - positive neurons were SP - positive , while 93 % of SP - positive neurons were P80511 - positive , suggesting that nearly all SP - positive neurons also contain P80511 . The fibre types of the P28222 - and P28221 - positive neurons were further investigated with an antibody against the A - fibre marker 200 - kDa neurofilaments ( NF200 ) . Approximately 46 % of the P28222 - positive and 43 % of the P28221 - positive trigeminal ganglion neurons were also NF200 positive , indicating that many A - fibre trigeminal neurons express P28222 or P28221 receptors . These results support the hypothesis that one important action of antimigraine drugs is the inhibition of P80511 release and that Adelta - fibres may play an important role in migraine pathogenesis ."
] |
[
"___MASK28___",
"___MASK40___",
"___MASK50___",
"___MASK52___",
"___MASK54___",
"___MASK73___",
"___MASK79___",
"___MASK86___",
"___MASK8___"
] |
___MASK8___
|
MH_train_409
|
interacts_with DB09030?
|
[
"NF - kappaB regulates thrombin - induced P05362 gene expression in cooperation with NFAT by binding to the intronic NF - kappaB site in the P05362 gene . Activation of NF - kappaB is essential for protease - activated receptor - 1 ( P25116 ) - mediated P05362 expression in endothelial cells . Here we show that P25116 activation induces binding of both p65 / RelA and O95644 to the NF - kappaB binding site localized in intron - 1 of the P05362 gene to initiate transcription in endothelial cells . We discovered the presence of two NF - kappaB binding sites in intron - 1 ( + 70 , NF - kappaB site 1 ; + 611 , NF - kappaB site 2 ) of the human P05362 gene . Chromatin immunoprecipitation results showed that thrombin induced binding of p65 / RelA and of O95644 specifically to intronic NF - kappaB site 1 of the P05362 gene . Electrophoretic mobility shift and supershift assays confirmed the binding of p65 / RelA and O95644 to the intronic NF - kappaB site 1 in thrombin - stimulated cells . Thrombin increased the expression of P05362 - promoter - intron 1 - reporter ( - 1 , 385 to + 234 ) construct approximately 25 - fold and mutation of intronic NF - kappaB site 1 markedly reduced thrombin - induced reporter expression . Moreover , inhibition of calcineurin , knockdown of either O95644 or p65 / RelA with siRNA significantly reduced thrombin - induced P05362 expression and polymorphonuclear leukocyte adhesion to endothelial cells . In contrast , O95644 knockdown had no effect on P01375 - induced P05362 expression . Thus these results suggest that p65 / RelA and O95644 bind to the intronic NF - kappaB site 1 sequence to induce optimal transcription of the P05362 gene in response to thrombin in endothelial cells .",
"Thrombin induces osteoprotegerin synthesis via phosphatidylinositol 3 '- kinase / mammalian target of rapamycin pathway in human periodontal ligament cells . BACKGROUND AND OBJECTIVE : Thrombin influences the biological behavior of periodontal ligament cells and plays multiple roles in the early stages of bone healing . O00300 ( O00300 ) is one of the key molecules that regulate bone homeostasis and prevent osteoclastogenesis . The purpose of this study was to evaluate the biological effects of thrombin on O00300 synthesis in human periodontal ligament ( Q96IR7 ) cells in vitro . MATERIAL AND METHODS : Cells were treated with various concentrations ( 0 . 001 , 0 . 01 and 0 . 1 U / mL ) of thrombin . The mRNA expression and protein synthesis of O00300 , as well as of receptor activator of nuclear factor kappaB ligand ( O14788 ) , were determined by reverse transcriptase - polymerase chain reaction ( RT - PCR ) and Western blot analysis , respectively . The influence of thrombin on O00300 synthesis and its signaling pathway were investigated using inhibitors . RESULTS : Thrombin profoundly induces protein synthesis of O00300 at 0 . 1 U / mL . The inductive effect was inhibited by cycloheximide , but not by indomethacin . The phosphatidylinositol 3 '- kinase ( PI3K ) inhibitor , LY294002 , and the mammalian target of rapamycin ( P42345 ) inhibitor , rapamycin , exerted an inhibitory effect on the thrombin - induced O00300 synthesis . In addition , the effect was inhibited by protease - activated receptor ( PAR ) - 1 antagonist . Activation of phospho - Akt ( p - Akt ) was observed and the effect was abolished by LY294002 . CONCLUSION : Thrombin induces O00300 synthesis in Q96IR7 cells post - transcriptionally , possibly through P25116 . The regulation was through the PI3K / Akt and P42345 pathway . This finding suggests that thrombin may play a significant role in alveolar bone repair and homeostasis of periodontal tissue , partly through the O00300 / O14788 system .",
"[ Thrombotic complications following the treatment of multiple myeloma with new agents ] . Patients with multiple myeloma ( MM ) are at an increased risk of venous and arterial thrombosis . The risk factors and pathomechanisms for thrombotic complications in multiple myeloma patients can be divided into the disease - related and treatment - specific risk factors . With the introduction of novel therapies , including talidomide , lenalidomide and bortezomib , the outcomes of the patients with newly diagnosed or previously treated multiple myeloma have improved , however the treatment affected the prothrombotic and anticoagulant processes . The risk of venous thromboembolism ( VTE ) in patients receiving immunomodulatory agent - based regimens ( thalidomide or lenalidomide ) , especially when used in combination with high - dose deamethasone - and / or anthracycline - based chemiotherapy is high . The proposed mechanisms for prothrombotic state include changes in P04275 , factor VIII , thrombomodulin , P25116 and P35354 epression , and some abnormalities in transcription factors and genetic risk factors . Moreover , dysregulation of anticoagulation and impairment of fibrinolysis may also contribute to hypercoagulability state . The incidence of VTE in bortezomib - containing regimens is very low . It may be due to inhibitory effect of bortezomib on platelet aggregation and NF - kappa / beta . This article presents the latest outlook upon the pathogenesis of thrombotic complications in multiple myeloma patients undergoing the therapy with new agents .",
"Clinical potential of vorapaxar in cardiovascular risk reduction in patients with atherosclerosis . DB09030 ( ZONTIVITY ™ , formerly known as P35240 530348 ) is a specific , orally active antagonist of the protease - activated receptor - 1 ( P25116 ) on platelets . It inhibits thrombin - induced platelet activation by binding to the ectodomain of P25116 . After animal studies and Phase II studies showed that vorapaxar sufficiently inhibits platelet activation without significantly increasing bleeding complications , safety and efficacy of vorapaxar were assessed in two large multicenter trials in patients with coronary artery disease and atherosclerosis . The Thrombin - Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndromes ( TRACER ) trial investigated safety and efficacy of vorapaxar in patients with an acute coronary syndrome without ST - segment elevation . The Trial to Assess the Effects of DB09030 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis - Thrombolysis In Myocardial Infarction 50 ( TRA 2 ° P - TIMI 50 ) investigated atherothrombotic events in patients with stable atherosclerosis . Results of both studies suggested that vorapaxar given in addition to standard antiplatelet therapy can reduce atherothrombotic events , but increases the risk of mild and moderate bleeding complications . This review article summarizes the main results of TRACER and TRA 2 ° P - TIMI 50 and suggests patient cohorts that might benefit from treatment with vorapaxar in addition to standard antiplatelet therapy .",
"DB09030 : a novel protease - activated receptor - 1 inhibitor . INTRODUCTION : Platelet activation and reactivity are pivotal for both acute and chronic atherothrombotic event occurrences . AREAS COVERED : Only 20 % relative risk ( ∼ 2 % absolute risk ) reduction associated with newer P2Y ( 12 ) receptor blocker therapy such as prasugrel and ticagrelor compared with clopidogrel indicates that dual antiplatelet therapy may be associated with a ceiling effect in attenuating platelet - mediated ischemic event occurrence and that residual ischemic event occurrences are mediated by other pathways that are unblocked by current antiplatelet therapy . Therefore , inhibition of the thrombin - protease - activated receptor ( PAR ) - 1 interaction may provide additional benefits in attenuating ischemic event occurrence in selected patients . There are two major P25116 blockers are under investigations - vorapaxar and atopaxar . In preclinical and Phase I - II studies , inhibition of thrombin - mediated platelet activation by a P25116 inhibitor , in general , has added to the antithrombotic efficacy of aspirin and clopidogrel without increasing bleeding . However , intracranial hemorrhage in patients with a history of stroke associated with vorapaxar and hepatic toxicity associated with atopaxar are important concerns . EXPERT OPINION : At this time , the specific role of P25116 inhibitor in the settings of percutaneous coronary intervention and acute coronary syndrome , both during the acute setting and as a long - term therapeutic agent , is not clear . Although the P25116 inhibitors are associated with less bleeding , its effectiveness as an antithrombotic agent and also side effects are major concerns . Future large - scale trials with goals addressing these concerns are needed to define the specific role of P25116 receptor inhibitor .",
"Induction of tumor necrosis factor ( P01375 ) release from subtypes of T cells by agonists of proteinase activated receptors . DB00133 proteinases have been recognized as playing an important role in inflammation via proteinase activated receptors ( PARs ) . However , little is known about the influence of serine proteinases and PARs on P01375 secretion from highly purified T cells . We challenged T cells from human peripheral blood with serine proteinases and agonist peptides of PARs and measured the levels of P01375 in culture supernatants by ELISA . The results showed that thrombin and trypsin , but not tryptase , stimulated approximately up to 2 . 5 - fold increase in P01375 release from T cells following 16 h incubation . Proteinase inhibitors and P25116 antagonist P35240 79797 almost completely abolished thrombin - and trypsin - induced P01375 release from T cells . Agonist peptides of P25116 , but not P55085 induced P01375 release from T cells . Moreover , trypsin - and thrombin - induced upregulated expression of P01375 was observed in P01730 + , P05112 + , or CD25 + T cells , but not in IFN + or Q16552 + T cells . The signaling pathways MAPK / P29323 and PI3K / Akt are involved in the thrombin - and trypsin - induced P01375 release from T cells . In conclusion , thrombin and trypsin can induce P01375 release from P05112 + and CD25 + T cells through activation of P25116 and therefore contribute to regulation of immune response and inflammation of the body .",
"P25116 14 - amino acid peptide mediates endothelial hyperadhesivity and neutrophil adhesion by P16109 - dependent mechanism . Thrombin cleaves its receptor at arginine - 41 , resulting in the generation of a new receptor NH2 - terminus with the sequence SFLLRNPNDKYEPF . This peptide ( TRP - 14 ) may signal a variety of thrombin ' s responses . We examined the effects of TRP - 14 in inducing endothelial cell hyperadhesivity and neutrophil ( PMN ) adhesion to endothelial cell monolayers . Human umbilical vein endothelial cells ( HUVECs ) challenged with TRP - 14 ( 10 (- 4 ) to 10 (- 5 ) M ) produced concentration - dependent increases in endothelial adhesivity to PMN . In contrast , position 1 to 2 inverted peptide ( FSLLRNPNDKYEPF ) did not induce the response . The adhesion response was transient ; that is , PMN adhesion increased within 15 minutes and decreased by 75 minutes after TRP - 14 challenge of HUVECs . The transient endothelial adhesiveness paralleled the time course of P16109 expression . TRP - 14 - induced release of P16109 from intracellular stores may be a critical determinant of the response since treatment of endothelial cells with anti - P16109 monoclonal antibody ( mAb ) P55008 prevented the increase in PMN adhesion . Control nonneutralizing anti - P16109 mAb P28222 and mAb P23921 / 1 directed against intercellular adhesion molecule - 1 ( P05362 ) on HUVECs were ineffective . The results indicate that the \" tethered ligand \" of the thrombin receptor created by the proteolytic action of thrombin on its receptor ( i . e . , TRP - 14 ) signals increased endothelial adhesiveness by a P16109 - dependent mechanism . Thrombin - induced PMN adhesion may involve formation of a new NH2 - terminus of the endothelial thrombin receptor with the sequence SFLLRNPNDKYEPF followed by activation of endothelial second messenger pathways and the transient expression of P16109 .",
"Thrombin has biphasic effects on the nitric oxide - cGMP pathway in endothelial cells and contributes to experimental pulmonary hypertension . BACKGROUND : A potential role for coagulation factors in pulmonary arterial hypertension has been recently described , but the mechanism of action is currently not known . Here , we investigated the interactions between thrombin and the nitric oxide - cGMP pathway in pulmonary endothelial cells and experimental pulmonary hypertension . PRINCIPAL FINDINGS : Chronic treatment with the selective thrombin inhibitor melagatran ( 0 . 9 mg / kg daily via implanted minipumps ) reduced right ventricular hypertrophy in the rat monocrotaline model of experimental pulmonary hypertension . In vitro , thrombin was found to have biphasic effects on key regulators of the nitric oxide - cGMP pathway in endothelial cells ( HUVECs ) . Acute thrombin stimulation led to increased expression of the cGMP - elevating factors endothelial nitric oxide synthase ( P29474 ) and soluble guanylate cyclase ( sGC ) subunits , leading to increased cGMP levels . By contrast , prolonged exposition of pulmonary endothelial cells to thrombin revealed a characteristic pattern of differential expression of the key regulators of the nitric oxide - cGMP pathway , in which specifically the factors contributing to cGMP elevation ( P29474 and sGC ) were reduced and the cGMP - hydrolyzing O76074 was elevated ( qPCR and Western blot ) . In line with the differential expression of key regulators of the nitric oxide - cGMP pathway , a reduction of cGMP by prolonged thrombin stimulation was found . The effects of prolonged thrombin exposure were confirmed in endothelial cells of pulmonary origin ( HPAECs and HPMECs ) . Similar effects could be induced by activation of protease - activated receptor - 1 ( P25116 ) . CONCLUSION : These findings suggest a link between thrombin generation and cGMP depletion in lung endothelial cells through negative regulation of the nitric oxide - cGMP pathway , possibly mediated via P25116 , which could be of relevance in pulmonary arterial hypertension .",
"DB09030 , an oral P25116 receptor antagonist , does not affect the pharmacokinetics and pharmacodynamics of warfarin . PURPOSE : DB09030 is an orally active protease - activated receptor 1 ( P25116 ) antagonist that inhibits thrombin - induced platelet aggregation . This open - label study assessed the pharmacokinetics and pharmacodynamics of single - dose warfarin in the presence / absence of multiple - dose vorapaxar in 12 healthy men . METHODS : Subjects received two treatments separated by ≥ 7 - day washout : Treatment A warfarin 25 mg ( Day 1 ) ; Treatment B vorapaxar 2 . 5 mg / day on Days 1 - 6 and vorapaxar 40 mg coadministered with warfarin 25 mg ( Day 7 ) . R - warfarin , S - warfarin , and prothrombin time ( PT ) were assayed predose and up to 120 h postdose . RESULTS : The geometric mean ratio ( GMR ) as a percentage ( warfarin + vorapaxar / warfarin ) was calculated . The GMR ( 90 % CIs ) estimates of C ( max ) were 105 ( 99 , 111 ) and 105 ( 99 , 112 ) for R - and S - warfarin , respectively . The GMR ( 90 % CIs ) estimates of AUC ( 0 -∞) were 108 ( 101 , 116 ) and 105 ( 96 , 115 ) for R - and S - warfarin , respectively . The GMR ( 95 % CIs ) estimates of AUC ( 0 - 120 h ) for PT and INR were 97 ( 95 , 98 ) and 96 ( 94 , 98 ) , respectively . CONCLUSION : Results of this study indicate that vorapaxar has no meaningful effect on the pharmacokinetics or pharmacodynamics of warfarin , suggesting that the coadministration of these two drugs or vorapaxar coadministered with other P11712 / P33261 substrates is unlikely to cause a clinically significant pharmacokinetic drug interaction .",
"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK48___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK35___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"DB09030 : first global approval . DB09030 [ DB09030 (®) ( US ) ] , an orally active protease - activated receptor - 1 ( P25116 ) receptor antagonist , has been developed by Merck & Co for the reduction of thrombotic cardiovascular events in patients with a history of myocardial infarction ( MI ) or peripheral arterial disease ( PAD ) . DB09030 has received its first global approval for this indication in the US . This article summarizes the milestones in the development of vorapaxar leading to this first approval for the reduction of thrombotic cardiovascular events in patients with a prior MI or PAD .",
"DB09030 expands antiplatelet options . Which patients may benefit from thrombin receptor antagonism ? DB09030 is the first substance of a new class of antiplatelet drugs that has been tested in large clinical trials . The protease - activated receptor 1 ( P25116 ) antagonist inhibits thrombin - induced platelet activation to prevent atherothrombosis . In the phase 3 trials TRACER ( acute coronary syndrome ) and TRA 2P - TIMI 50 ( stable atherosclerosis ) reducing ischemic events with vorapaxar came at the cost of bleeding . TRACER compared vorapaxar to placebo in 12 , 944 patients who had non - ST - segment elevation acute coronary syndromes on top of contemporary treatment including dual antiplatelet therapy ( aspirin and clopidogrel ) . DB09030 reduced ischemic events non - significantly , but increased bleeding significantly , therefore not justifying triple antiplatelet therapy in this setting . Follow - up was stopped early because of bleeding . TRA 2P - TIMI 50 examined 26 , 449 patients who had a history of myocardial infarction , ischemic stroke , or peripheral arterial disease . DB09030 reduced ischemic events and increased bleeding both significantly . Recruitment of patients with prior stroke was stopped early . Net clinical outcome and subgroup analyses suggested that vorapaxar could be beneficial for patients with prior myocardial infarction - but no history of stroke .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK51___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"___MASK2___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK2___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK89___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"Pharmacodynamics and pharmacokinetics of the novel P25116 antagonist vorapaxar ( formerly P35240 530348 ) in healthy subjects . PURPOSE : The aim of our study was to evaluate the pharmacology of vorapaxar ( P35240 530348 ) , an oral P25116 antagonist , in healthy volunteers . METHODS AND RESULTS : In two randomized , placebo - controlled studies , subjects received either single ascending doses of vorapaxar ( 0 . 25 , 1 , 5 , 10 , 20 , or 40 mg ; n = 50 ) , multiple ascending doses of vorapaxar ( 1 , 3 , or 5 mg / day for 28 days ; n = 36 ) , a loading dose ( 10 or 20 mg ) followed by daily maintenance doses ( 1 mg ) for 6 days ( n = 12 ) , or placebo . Single 20 - and 40 - mg doses of vorapaxar completely inhibited thrombin receptor activating peptide ( TRAP ) - induced platelet aggregation ( > 80 % inhibition ) at 1 h and sustained this level of inhibition for ≥ 72 h . Multiple doses yielded complete inhibition on Day 1 ( 5 mg / day ) and Day 7 ( 1 and 3 mg / day ) . Adverse events were generally mild , transient , and unrelated to dose . CONCLUSION : DB09030 provided rapid and sustained dose - related inhibition of platelet aggregation without affecting bleeding or clotting times .",
"P04818 inhibition induces p53 - dependent and p53 - independent apoptotic responses in human urinary bladder cancer cells . PURPOSE : In search for more effective clinical protocols , the antimetabolite drug 5 - fluorouracil ( ___MASK42___ ) has been successfully included in new regimens of bladder cancer combination chemotherapy . In the present study , we have investigated the effects of ___MASK42___ treatment on apoptosis induction in wild - type and mutant p53 urinary bladder cancer cells . METHODS : We have used MTT - based assays , FACS analysis , Western blotting and semi - quantitative RT - PCR in RT4 and RT112 ( grade I , wild - type p53 ) , as well as in T24 ( grade III , mutant p53 ) and TCCSUP ( grade IV , mutant p53 ) human urinary bladder cancer cell lines . RESULTS : In the urothelial bladder cancer cell lines RT4 and T24 , ___MASK42___ - induced TS inhibition proved to be associated with cell type - dependent ( a ) sensitivity to the drug , ( b ) Caspase - mediated apoptosis , ( c ) p53 stabilization and activation , as well as Rb phosphorylation and Q01094 expression and ( d ) transcriptional regulation of p53 target genes and their cognate proteins , while an E2F - dependent transcriptional network did not seem to be critically engaged in such type of responses . CONCLUSIONS : We have shown that in the wild - type p53 context of RT4 cells , ___MASK42___ - triggered apoptosis was prominently efficient and mainly regulated by p53 - dependent mechanisms , whereas the mutant p53 environment of T24 cells was able to provide notable levels of resistance to apoptosis , basically ascribed to E2F - independent , and still unidentified , pathways . Nevertheless , the differential vulnerability of RT4 and T24 cells to ___MASK42___ administration could also be associated with cell - type - specific transcriptional expression patterns of certain genes critically involved in ___MASK42___ metabolism .",
"No differences in the pharmacodynamics and pharmacokinetics of the thrombin receptor antagonist vorapaxar between healthy Japanese and Caucasian subjects . BACKGROUND : DB09030 , a novel antiplatelet agent in advanced clinical development for the prevention and treatment of atherothrombotic disease , is a potent , orally bioavailable thrombin receptor antagonist selective for the protease - activated receptor 1 ( P25116 ) . METHODS : Since race / ethnicity may affect the safety , efficacy and dosage of drugs , this study was conducted to evaluate potential differences in the pharmacodynamics , pharmacokinetics and safety of vorapaxar after single ( 5 , 10 , 20 , or 40 mg ) or multiple ( 0 . 5 , 1 , or 2 . 5 mg once daily ) doses in healthy Japanese and matched ( gender , age , height , and weight ) Caucasian volunteers . RESULTS : DB09030 was well tolerated in both Japanese and Caucasian subjects . Pharmacodynamic and pharmacokinetic profiles of vorapaxar in the two racial / ethnic groups were similar . In both racial groups , complete inhibition of platelet aggregation was achieved most rapidly with vorapaxar 40 mg and was consistently achieved and maintained with a 2 . 5 mg daily maintenance dose . CONCLUSION : There were no substantial differences in the safety , pharmacokinetics or pharmacodynamics of vorapaxar between Japanese and Caucasian subjects .",
"DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin - dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .",
"Role of SCH79797 in maintaining vascular integrity in rat model of subarachnoid hemorrhage . BACKGROUND AND PURPOSE : Plasma thrombin concentration is increased after subarachnoid hemorrhage ( Q53FZ2 ) . However , the role of thrombin receptor ( protease - activated receptor - 1 [ P25116 ] ) in endothelial barrier disruption has not been studied . The aims of this study were to investigate the role of P25116 in orchestrating vascular permeability and to assess the potential therapeutics of a P25116 antagonist , SCH79797 , through maintaining vascular integrity . METHODS : SCH79797 was injected intraperitoneally into male Sprauge - Dawley rats undergoing Q53FZ2 by endovascular perforation . Assessment was conducted at 24 hours after Q53FZ2 for brain water content , Evans blue content , and neurobehavioral testing . To explore the role of P25116 activation and the specific mechanism of SCH79797 ' s effect after Q53FZ2 , Western blot , immunoprecipitation , and immunofluorescence of hippocampus tissue were performed . A P38936 - activated kinase - 1 ( PAK1 ) inhibitor , IPA - 3 , was used to explore the underlying protective mechanism of SCH79797 . RESULTS : At 24 hours after Q53FZ2 , animals treated with SCH79797 demonstrated a reduction in brain water content , Evans blue content , and neurobehavioral deficits . SCH79797 also attenuated P25116 expression and maintained the level of vascular endothelial - cadherin , an important component of adherens junctions . Downstream to P25116 , c - Src - dependent activation of P38936 - activated kinase - 1 led to an increased serine / threonine phosphorylation of vascular endothelial - cadherin ; immunoprecipitation results revealed an enhanced binding of phosphorylated vascular endothelial - cadherin with endocytosis orchestrator β - arrestin - 2 . These pathological states were suppressed after SCH79797 treatment . CONCLUSIONS : P25116 activation after Q53FZ2 increases microvascular permeability , at least , partly through a P25116 - c - Src - P38936 - activated kinase - 1 - vascular endothelial - cadherin phosphorylation pathway . Through suppressing P25116 activity , SCH79797 plays a protective role in maintaining microvascular integrity after Q53FZ2 .",
"Pharmacokinetics of the novel P25116 antagonist vorapaxar in patients with hepatic impairment . PURPOSE : To determine whether hepatic impairment has an effect on the pharmacokinetics ( PK ) of vorapaxar or M20 , its main pharmacologically active metabolite . METHODS : This was an open - label study in which a single 40 - mg oral dose of vorapaxar was administered to patients with mild ( n = 6 ) , moderate ( n = 6 ) , and severe ( n = 4 ) hepatic impairment and healthy controls ( n = 16 ) matched for age , gender , weight , and height . Blood samples for vorapaxar and M20 assay were collected predose and at frequent intervals up to 8 weeks postdose . RESULTS : Plasma vorapaxar and M20 PK profiles were similar between patients with impaired liver function and healthy controls . Group mean values for vorapaxar C ( max ) and AUC ( tf ) were 206 - 279 ng / mL and 14 , 200 - 18 , 200 ng · h / mL , respectively , with the lowest values observed in patients with severe impairment . DB09030 median T ( max ) and mean t ( 1 / 2 ) values were 1 . 00 - 1 . 75 h and 298 - 366 h , respectively . There was no apparent correlation between vorapaxar or M20 exposure or t ( 1 / 2 ) values and disease severity . DB09030 was generally well tolerated ; one serious adverse event ( gastrointestinal bleeding secondary to ruptured esophageal varices ) was reported in a patient with severe hepatic impairment . CONCLUSIONS : Hepatic impairment had no clinically relevant effect on the PK of vorapaxar and M20 . No dose or dosage adjustment of vorapaxar will be required in patients with mild to moderate hepatic impairment . Although systemic exposure to vorapaxar does not appear to increase in patients with severe hepatic impairment , administration of vorapaxar to such patients is not recommended given their bleeding diathesis .",
"___MASK50___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK50___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"Matrix metalloproteinase and G protein coupled receptors : co - conspirators in the pathogenesis of autoimmune disease and cancer . Similarities in the pathologies of autoimmune diseases and cancer have been noted for at least 30 years . Inflammatory cytokines and growth factors mediate cell proliferation , and proteinases , especially the collagenase , Matrix Metalloproteinase - 1 ( P03956 ) , contribute to disease progression by remodeling the extracellular matrix and modulating the microenvironment . This review focuses on two cancers ( melanoma and breast ) and on the autoimmune disorder , rheumatoid arthritis ( RA ) , and discusses the activated stromal cells found in these diseases . P03956 was originally thought to function only to degrade interstitial collagens , but recent studies have revealed novel roles for P03956 involving the G protein - coupled receptors : the chemokine receptor , P61073 , and Protease Activated Receptor - 1 ( P25116 ) . Cooperativity between P03956 and P61073 / P48061 signaling influences the behavior of activated fibroblasts in both RA and cancer . Further , P03956 is a vital part of an autocrine / paracrine P03956 / P25116 signal transduction axis , a function that amplifies its potential to remodel the matrix and to modify cell behavior . Finally , new therapeutic agents directed at P03956 and G protein - coupled receptors are emerging . Even though these agents are more specific in their targets than past therapies , these targets are often shared between RA and cancer , underscoring fundamental similarities between autoimmune disorders and some cancers .",
"P25116 antagonists : current state of evidence . DB09030 ( P35240 530348 ) and atopaxar ( E5555 ) are oral protease - activated receptor - 1 ( P25116 ) antagonists with high bioavailability . They inhibits thrombin induced platelet aggregation by competitively inhibiting P25116 . We systematically evaluated the evidence for the efficacy and safety of all P25116 antagonists as well as for the individual drugs vorapaxar and atopaxar in different databases - PubMed , EMBASE , Scopus , and Cochrane register of Controlled Clinical Trials ( CENTRAL ). We selected randomized controlled trials of P25116 antagonists that reported on cardiovascular mortality as a clinical outcome . The random - effects Mantel - Haenszel model was used to evaluate the effect of P25116 antagonists on cardiovascular mortality . Seven trials were selected ( N = 42 , 355 ) for analysis . P25116 antagonists as a class , as well as individually , were associated with a non - significant numerically lower risk of cardiovascular mortality than that seen with agents used in the control group ; RR , 0 . 93 ; 95 % CI , 0 . 83 - 1 . 04 ; P = 0 . 20 ) . No heterogeneity was noted . However , P25116 antagonists also appeared to increase the risk of bleeding significantly . P25116 antagonists appear to be associated with some reduction in the risk of cardiovascular mortality ; however the significantly higher bleeding risk noted with P25116 antagonists appear to mandate a very careful selection of patients that may benefit without a substantially increased risk of bleeds .",
"Differential gene expression underlying the functional distinctions of primary human P28906 + hematopoietic stem and progenitor cells from peripheral blood and bone marrow . The restorative capacity of human P28906 (+) hematopoietic cells is clinically used in the autologous and allogeneic transplant setting to support cytotoxic therapy . We examined gene expression patterns of highly enriched bone marrow P28906 (+) ( BM - P28906 (+) ) or G - P04141 - mobilized peripheral blood P28906 (+) ( PB - P28906 (+) ) cells by cDNA array technology , quantitative real - time RT - PCR , and flow cytometry , to identify molecular causes underlying the functional differences between circulating and sedentary hematopoietic stem and progenitor cells . The greater cell cycle and DNA synthesis activity of BM - P28906 (+) compared to PB - P28906 (+) cells was reflected by the 2 - to 5 - fold higher expression of 9 genes involved in cell cycle , 11 genes regulating DNA synthesis , and the cell cycle - initiating transcription factor Q01094 . The 2 - to 3 - fold greater expression of 5 pro - apoptotic genes in PB - P28906 (+) cells indicated a higher apoptotic activity , which could functionally be corroborated by apoptosis assays . P25116 ( PAR1 ) , known to play a role in trafficking of malignant cells , was 3 . 6 - fold higher expressed in circulating P28906 (+) cells than in BM - P28906 (+) cells . Guidance via thrombin receptor might molecularly mediate stem cell migration . In summary , our study provides gene expression profiles of primary human P28906 (+) hematopoietic cells of blood and marrow . Our data molecularly confirm and explain the finding that P28906 (+) cells residing in the bone marrow are cycling more rapidly , whereas circulating P28906 (+) cells consist of a higher number of quiescent stem and progenitor cells . Moreover , our data give novel molecular insights into stem cell migration and differentiation .",
"___MASK34___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK34___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"1 -( 3 - Trifluoromethylphenyl ) piperazine ( TFMPP ) in the ventral tegmental area reduces the effect of desipramine in the forced swimming test in rats : possible role of serotonin receptors . 1 -( 3 - Trifluoromethylphenyl ) piperazine ( TFMPP ) , a serotonin1 ( 5 - HT1 ) receptor agonist , injected i . p . in doses of 0 . 1 and 0 . 6 mg / kg , did not modify the immobility time of rats in the forced swimming test but significantly antagonized the effect of a 7 days treatment with 10 mg / kg per day desipramine ( ___MASK41___ ) . A similar effect was found on infusing 1 and 5 micrograms / microliters TFMPP bilaterally into the ventral tegmental area ( VTA ) . Infusion of 5 micrograms / microliters TFMPP into the nucleus accumbens or into the globus pallidus did not modify the effect of ___MASK41___ . The effect of 5 micrograms TFMPP infused into the VTA was prevented by the i . p . administration of 5 mg / kg metergoline , a non - selective serotonin receptor antagonist . Infusion of 5 micrograms / microliters 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , a specific P08908 receptor agonist , into the VTA did not modify the effect of ___MASK41___ . Besides acting as a P28222 receptor agonist , TFMPP may also act on other 5 - HT receptor types , but available evidence suggests that its former action is more important . It thus appears that 5 - HT1 receptors in the VTA , presumably of the P28222 type , act by preventing the anti - immobility effect of ___MASK41___ . The role of VTA dopamine and non - dopamine cells in the effect of TFMPP is discussed .",
"Safety of the novel protease - activated receptor - 1 antagonist vorapaxar in Japanese patients with a history of ischemic stroke . BACKGROUND : DB09030 , formerly P35240 530348 , is a novel , orally active , potent thrombin receptor inhibitor selective for the protease - activated receptor - 1 ( P25116 ) . Previous phase II studies of patients undergoing urgent or scheduled percutaneous coronary intervention treated with vorapaxar plus aspirin and clopidogrel or ticlopidine showed a trend toward reducing major adverse cardiac events , particularly myocardial infarction , without increasing bleeding risk . The present study evaluated the safety of vorapaxar in Japanese patients with a history of ischemic stroke receiving aspirin . METHODS : Ninety patients with previous ischemic stroke ( ≥ 14 days to < 1 year before randomization ) were randomized to receive vorapaxar ( 1 or 2 . 5 mg ) or placebo once daily for 60 days . All patients received aspirin ( 75 - 150 mg / day ) . The primary endpoint was overall incidence of adverse events during the protocol - defined treatment phase ( 60 days ) . RESULTS : Addition of vorapaxar to aspirin did not significantly increase the overall incidence of adverse events , including serious adverse events . None of the patients treated with vorapaxar plus aspirin experienced thrombolysis in myocardial infarction major or minor bleeding versus 1 patient treated with placebo . Nonfatal stroke occurred in 1 patient allocated to placebo and 1 patient allocated to vorapaxar . CONCLUSIONS : DB09030 used in combination with standard doses of aspirin was safe and well tolerated in Japanese subjects with a history of ischemic stroke ."
] |
[
"___MASK2___",
"___MASK34___",
"___MASK35___",
"___MASK41___",
"___MASK42___",
"___MASK48___",
"___MASK50___",
"___MASK51___",
"___MASK89___"
] |
___MASK35___
|
MH_train_410
|
interacts_with DB06681?
|
[
"DB06681 : from rational design to clinical application . Gradually improved immunosuppression has contributed significantly to the progress achieved in transplantation medicine so far . Nevertheless , current drug regimens are associated with late graft loss -- in particular as a result of immunologic damage or drug toxicity -- and substantial morbidity . Recently , the costimulation blocker belatacept ( marketed under the name Nulojix ® ) has been approved for immunosuppression in renal transplantation . DB06681 ( a mutated version of DB01281 ) is a fusion protein rationally designed to block P10747 , a critical activating receptor on T cells , by binding and saturating its ligands P33681 - 1 and P33681 - 2 . In phase II and III trials , belatacept was compared with cyclosporine ( in combination with basiliximab , DB00688 , and steroids ) . Advantages observed with belatacept include superior graft function , preservation of renal structure and improved cardiovascular risk profile . Concerns associated with belatacept are a higher frequency of cellular rejection episodes and more post - transplant lymphoproliferative disorder ( PTLD ) cases especially in EBV seronegative patients , who should be excluded from belatacept - based regimens . Thus , after almost three decades of calcineurin inhibitors as mainstay of immunosuppression , belatacept offers a potential alternative . In this article , we will provide an overview of belatacept ' s preclinical development and will discuss the available evidence from clinical trials .",
"Technology evaluation : DB06681 , Bristol - Myers Squibb . Bristol - Myers Squibb is developing belatacept , a soluble fusion protein of the P33681 - binding domain of P16410 with amino acid changes A29Y and L104E and an Ig tail , which inhibits lymphocyte co - stimulation through P10747 , for the potential treatment of solid organ transplant rejection . DB06681 is currently undergoing phase III clinical trials .",
"Maturation of dendritic cells by recombinant human P29965 - trimer leads to a homogeneous cell population with enhanced surface marker expression and increased cytokine production . Dendritic cells ( DC ) have been shown to be potent inducers of specific cytotoxic T - cell responses both in vivo and in vitro . Furthermore , exposure to cytokines such as tumour necrosis factor ( P01375 ) - alpha or P25942 triggering changes DC phenotype and cytokine production and may enhance the T - cell activating capacity of the DC . We studied DC phenotype and cytokine production as well as the T - cell proliferation and cytotoxic T lympocyte ( CTL ) activation induced by DC generated in vitro . In addition , the effect of exposure to recombinant human P29965 - trimer ( huCD40LT ) on these parameters was investigated . Effective differentiation of monocytes derived from freshly isolated peripheral blood mononuclear cells ( PBMC ) was obtained with granulocyte macrophage - colony stimulating factor ( GM - P04141 ) and interleukin ( IL ) - 4 . The DC expression of human leucocyte antigen ( HLA ) molecules , P33681 , Q01151 , and P42081 was markedly enhanced by exposure to huCD40LT even compared to P01375 exposure . Only a moderate cytokine production was observed initially , while P01375 addition or P25942 triggering , especially , induced enhanced production of P05231 and IL - 12 p40 . Surprisingly , comparable induction of T - cell proliferation by a DC allostimulus or through the presentation of PPD , and influenza M1 - peptide specific CTL activity was obtained with nonmaturated ( Q01151 - ) and maturated ( Q01151 + ) DC . In conclusion , a final maturation of monocyte - derived DC through huCD40LT resulted in a highly homogeneous cell population with enhanced surface marker expression and high production of pro - inflammatory cytokines . In addition , the induction of responses to allo or recall antigens presented by huCD40LT maturated DC was comparable to the responses obtained with the DC maturated through P01375 exposure .",
"A 77 - base pair LINE - like sequence elicits androgen - dependent mvdp / akr1 - b7 expression in mouse vas deferens , but is dispensable for adrenal expression in rats . Mvdp / akr1 - b7 ( mouse vas deferens protein / aldo - keto reductase 1 - P33681 ) encodes an enzyme responsible for detoxification of a steroidogenesis byproduct . MVDP / AKR1 - P33681 is expressed in both rat and mouse adrenal cortex under DB01285 control , whereas strong androgen - dependent accumulation in the vas deferens is mouse specific . Comparison of the regulatory regions of the two orthologs reveals a strong identity , disrupted by acquisition of a 77 - bp LINE - derived sequence in the mouse promoter . Although DB01285 responsiveness is observed in both species , the absence of this 77 - bp sequence in the rat is associated with changes in transcription initiation sites . Transfection studies demonstrate that the CCAAT / enhancer - binding protein and selective promoter factor 1 - binding sites previously shown to be essential for DB02527 / DB01285 induction in the mouse are consequently dispensable in the rat . Our data support the idea that the most striking change generated by this acquisition is the strong , androgen - dependent , vas deferens expression observed in mouse . 1 ) In rat vas deferens , rakr1 - b7 expression is barely detectable and is not androgen sensitive . 2 ) P10275 binds efficiently to an androgen response element within the 77 - bp mouse - specific element . 3 ) Its insertion confers androgen sensitiveness to rakr1 - b7 regulatory regions in an androgen response element - dependent manner in transient transfections . We propose that this acquired androgen - responsive region may be responsible for vas deferens androgen - regulated gene expression in vivo .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"T cell costimulation : a rational target in the therapeutic armamentarium for autoimmune diseases and transplantation . T cells are central mediators of adaptive immunity . As such , they are involved in both normal immune responses ( e . g . , rejection of a transplanted organ ) and abnormal ones ( e . g . , rheumatoid arthritis ) . T cells require both antigen - specific and costimulatory signals for their full activation . Advances in protein engineering and an increased understanding of the immune response have culminated in the evolution and creation of protein therapeutics that target specific costimulatory molecules . The selective costimulation modulator abatacept ( CTLA - 4Ig ) binds to P33681 and P42081 , blocking interaction with P10747 , and is approved for the treatment of moderate to severe rheumatoid arthritis . DB06681 , currently enrolling phase III trials in renal transplantation , was rationally designed from abatacept to bind with more avidity to P42081 , providing the more potent immunosuppressive properties required for immunosuppression in transplantation . This review describes the relevant immunology and summarizes recent clinical findings on these two molecules . Although both inhibit the P10747 costimulatory pathway , they are tailored for specific disease states -- abatacept for autoimmune diseases and belatacept for transplantation .",
"Chronic induction . What ' s new in the pipeline . Induction therapy with biological agents was introduced the in the 1970s and the rationale , concepts and approach have remained almost unchanged for 30 years . However , the novel biological agents being developed for induction therapy are being designed for chronic rather than short - term therapy with several objectives : reduce dependence on toxic and nephrotoxic agents , improve outcome and ultimately facilitate the emergence of tolerance . The biological agents include efalizumab , a humanized anti - CD11a ( anti - LFA1 ) , anti - CD154 , anti - P25942 , a number of agents targeting P40933 and its receptor , and costimulation blockade with humanized antibodies to P33681 / P42081 and the fusion receptor protein DB06681 , a second generation DB01281 . The past decade has witnessed an unprecedented number of small molecules / oral drugs that have been developed and approved for renal transplantation ; the next decade , however , may witness the emergence of a new class of biological induction agents that may displace some of the currently used drugs .",
"Prolonged , low - dose anti - thymocyte globulin , combined with P16410 - Ig , promotes engraftment in a stringent transplant model . BACKGROUND : Despite significant nephrotoxicity , calcineurin inhibitors ( CNIs ) remain the cornerstone of immunosuppression in solid organ transplantation . We , along with others , have reported tolerogenic properties of anti - thymocyte globulin ( ATG , Thymoglobulin ® ) , evinced by its ability both to spare Tregs from depletion in vivo and , when administered at low , non - depleting doses , to expand Tregs ex vivo . Clinical trials investigating P33681 / P10747 blockade ( DB06681 , DB06681 ) in kidney transplant recipients have proven that the replacement of toxic CNI use is feasible in selected populations . METHODS : Rabbit polyclonal anti - murine thymocyte globulin ( mATG ) was administered as induction and / or prolonged , low - dose therapy , in combination with P16410 - Ig , in a stringent , fully MHC - mismatched murine skin transplant model to assess graft survival and mechanisms of action . RESULTS : Prolonged , low - dose mATG , combined with P16410 - Ig , effectively promotes engraftment in a stringent transplant model . Our data demonstrate that mATG achieves graft acceptance primarily by promoting Tregs , while P16410 - Ig enhances mATG function by limiting activation of the effector T cell pool in the early stages of treatment , and by inhibiting production of anti - rabbit antibodies in the maintenance phase , thereby promoting regulation of alloreactivity . CONCLUSION : These data provide the rationale for development of novel , CNI - free clinical protocols in human transplant recipients .",
"Costimulatory blockade with belatacept in clinical and experimental transplantation - a review . BACKGROUND : Current maintenance immunosuppression agents have been critical to the improved graft and patient survival rates in solid organ transplantation observed over the past decade . However , long - term follow - up has revealed that these agents are associated with troublesome side effects and chronic toxicity , contributing to graft loss and death . OBJECTIVES : Costimulation blockade has long been recognized as an important target for immunomodulation in solid organ transplantation . DB06681 , a high - affinity chimeric fusion protein that binds to P33681 / P42081 on antigen - presenting cells , has shown great promise in renal transplantation and is now in Phase III trials . METHODS : This review explores the development and efficacy of belatacept , compared with currently approved immunosuppressive agents used in transplantation . RESULTS : DB06681 seems to be an effective alternative to current maintenance immunosuppressive therapies , with no apparent end organ toxicity and a minimal side - effect profile . This agent works best when used in combination with therapies that target different pathways of T - cell activation , but the optimal regimen has not yet been identified . Data generated in ongoing clinical trials will be essential in validating previous studies and for further development of belatacept - based combinatorial strategies .",
"Gateways to clinical trials . Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses . The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity , the drug discovery and development portal , http :// integrity . prous . com . This issue focuses on the following selection of drugs : 2F5 , 2G12 , abetimus sodium , ABI - 007 , adalimumab , adefovir dipivoxil , DB05387 , alefacept , altropane , aminolevulinic acid hydrochloride , aminolevulinic acid methyl ester , aminopterin , anakinra , aprinocarsen sodium , atazanavir , atlizumab , atomoxetine hydrochloride ; P33681 - 1 vaccine , bevacizumab , DB04851 dicitrate , BMS - 188667 , brasofensine sulfate , bryostatin 1 ; cantuzumab mertansine , Q99698 - 828 , cinacalcet hydrochloride , cipamfylline , creatine , CVT - 3146 ; darbepoetin alfa , DITPA , drotrecogin alfa ( activated ) , duloxetine hydrochloride ; edatrexate , efalizumab , ENMD - 0997 , epoetin , erlosamide , esomeprazole magnesium , etiprednol dicloacetate , etoricoxib , everolimus , ezetimibe ; fampridine , fenretinide , FTY - 720 ; P05019 / P17936 , IL - 1 cytokine trap , ilodecakin , interferon beta , ISIS - 104838 , ISIS - 2503 , ISIS - 5132 , ivabradine hydrochloride ; lafutidine , lanthanum carbonate , l - DB00125 hydrochloride , DB06681 , lerdelimumab , levetiracetam , levobupivacaine hydrochloride , levosimendan , lopinavir ; melagatran , mibefradil hydrochloride , miglustat , morphine - 6 - glucuronide ; nesiritide ; omalizumab , omapatrilat ; p24 - VLP , parecoxib sodium , peginterferon alfa - 2a , peginterferon alfa - 2b , pegsunercept , pitavastatin calcium , plevitrexed , prasterone , pregabalin , PRO - 2000 , prucalopride ; rapacuronium bromide , rebimastat , RGA - 0853 , rubitecan , ruboxistaurin mesilate hydrate , RWJ - 67657 ; S - 16020 - 2 , sarizotan , SLV - 306 , stiripentol ; DB05809 , tenecteplase , teriparatide , tezacitabine , tipifarnib , trabectedin , troglitazone ; valdecoxib , vardenafil ; Z - 338 , ziconotide .",
"Expression of cyclooxygenase - 2 in urinary bladder in rats with cyclophosphamide - induced cystitis . These studies examined the expression of cyclooxygenase - 2 ( P35354 ) expression in the urothelium and suburothelial space and detrusor from rats treated with cyclophosphamide ( CYP ) to induce acute ( 4 h ) , intermediate ( 48 h ) , or chronic ( 10 - day ) cystitis . Western blot analysis and immunohistochemistry were used to demonstrate P35354 expression . In whole mount preparations of urinary bladder , nerve fibers in the suburothelial plexus , and inflammatory cell infiltrates were characterized for P35354 expression after CYP - induced cystitis . P35354 expression significantly ( P < or = 0 . 01 ) increased in the urothelium + suburothelium and detrusor smooth muscle with acute , intermediate , and chronic ( 10 - day ) CYP - induced cystitis , but expression in urothelium + suburothelium was significantly greater . CYP - induced upregulation of P35354 showed by immunostaining in the urothelium + suburothelium was similar to that observed with Western blot analysis and also demonstrated P35354 inflammatory cell infiltrates ( P42081 + ) and nerve fibers ( A6NDG6 + ) in the suburothelial plexus . Although P35354 expression was significantly ( P < or = 0 . 01 ) increased in detrusor smooth muscle , immunohistochemistry failed to demonstrate an obvious change in P35354 - immunoreactivity ( IR ) in detrusor muscle , but P35354 inflammatory infiltrates were present throughout the detrusor . P35354 - IR nerve fibers exhibited increased density in the suburothelial plexus with acute or chronic CYP - induced cystitis . P35354 - IR macrophages ( P42081 + ) were present throughout the urinary bladder with acute and chronic CYP - induced cystitis . These studies demonstrate cellular targets in the urinary bladder where P35354 inhibitors may act .",
"[ Moclobemide ( ___MASK66___ ) , the first P21397 - inhibitor : really something new ? ] .",
"What ' s in the pipeline ? New immunosuppressive drugs in transplantation . In the pipeline , there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials . The major target of new agents are cell - surface molecules important in immune cell interactions ( especially the costimulatory pathway ) , signaling pathways that activate T cells , T - cell proliferation and trafficking and recruitment of immune cells responsible for rejection . The most promising biologic agents include a humanized anti - CD11a ( anti - LFA1 ) , humanized anti - P33681 . 1 / P33681 . 2 , a second - generation DB01281 ( DB06681 ) and a humanized antibody to anti - P08575 RB . Inhibitors of T - cell activation and signaling are still in preclinical development . The most interesting inhibitors of T - cell proliferation include inhibitors of the Janus protein tyrosine kinase , P52333 , and FK778 , a leflunomide analog . Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes . Early trials of FTY720 , a synthetic small molecule with functional homology to sphingosine - 1 phosphate leading to lymphocyte sequestration , appear very promising ; however , enthusiasm for this drug is mitigated by its potential cardiac side - effects . Antagonists to several chemokine receptors , including P32246 , P49682 and P51681 , have been shown to be effective in experimental transplantation and are likely to be considered for clinical development .",
"DB06681 in clinical and experimental transplantation - progress and promise . DB06681 is a fusion protein composed of the Fc fragment of a human IgG ( 1 ) immunoglobulin linked to the extracellular domain of cytotoxic T - lymphocyte - associated antigen 4 ( P16410 ) . P16410 is a molecule crucial for T - cell costimulation , selectively blocking the process of T - cell activation . DB06681 binds surface costimulatory ligands ( P33681 and P42081 ) of antigen - presenting cells . Studies on nonhuman primates , as well as phase II and III clinical trials are here reviewed . DB06681 is a promising therapy in organ transplantation and in the future can be used to induce tolerance .",
"Pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept in adult kidney transplant recipients . BACKGROUND AND OBJECTIVES : DB06681 is a first - in - class , selective co - stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients . The objective of this study was to report the pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept . METHODS : The pharmacokinetics , pharmacodynamics ( P42081 receptor occupancy ) , and immunogenicity of belatacept were studied in de novo adult kidney transplant recipients in phase II and III clinical studies . RESULTS : Following multiple doses of 5 or 10 mg / kg , the geometric mean ( percentage coefficient of variation ) maximum serum concentration and area under the serum concentration - time curve over one dosing interval of belatacept were 136 ( 20 % ) and 238 ( 27 % ) μg / mL , and 13 , 587 ( 27 % ) and 21 , 241 ( 35 % ) μg · h / mL , respectively . The median belatacept elimination half - life was 8 - 9 days . DB06681 exhibited concentration - dependent binding to P42081 receptors . The pre - dose P42081 receptor occupancy by belatacept decreased from 94 to 65 % between day 5 and 1 year post - transplant , with corresponding pre - dose trough serum concentrations of belatacept decreasing from ~ 35 to 4 μg / mL during this period . The cumulative incidence of developing anti - belatacept antibodies was 5 . 3 % up to 3 years post - transplant and had no impact on belatacept exposure . CONCLUSIONS : DB06681 in adult kidney transplant demonstrated linear pharmacokinetics with low variability , concentration - dependent pharmacodynamics , and a low incidence of anti - drug antibodies .",
"[ Use of new non - nephrotoxic immunosuppressive drugs in kidney transplantation , especially after ischemia - reperfusion injury ] . Medium - and long - term renal graft survival depends on 4 main factors : the quality of the harvested graft , ischemia - reperfusion injury during harvesting and re - implantation , rejection , and the nephrotoxicity of certain drugs ( especially immunosuppressants ) used in this setting . The most nephrotoxic immunosuppressive drugs are the anticalcineurins ( cyclosporine A and tacrolimus ) , a class discovered in the late 1970s and currently representing a basic component of all immunosuppressive protocols for solid organ graft recipients . The renal tubular and vascular toxicity of anticalcineurins is due to their immunosuppressive mechanism : they block the calcineurin pathway and thereby prevent transmission of the first signal from the T cell receptor to the nucleus , which normally triggers cytokine synthesis , New non - nephrotoxic immunosuppressants are therefore needed , especially for grafts of poor quality or subject to severe ischemia - reperfusion injury . Attention is turning to \" old \" molecules such as anti - thymocyte globulins , but exciting new immunosuppressants are now appearing . DB00092 is a fusion protein that binds to the immunological synapse - associated molecule P06729 , which normally interacts with LFA - 3 . DB06681 , another fusion protein , blocks the T cell second signal CD 28 - P33681 . 1 / P33681 . 2 . Finally , new chemical agents are being developed , such as sautrasporine , a tyrosine kinase inhibitor , and tofacitinib , a Jak inhibitor .",
"Advances in immunosuppression for kidney transplantation : new strategies for preserving kidney function and reducing cardiovascular risk . The development of new immunosuppressants for renal transplantation is aimed not only at improving & nbsp ; short - term outcomes , but also at achieving better safety , cardiovascular , and metabolic profiles and at decreasing & nbsp ; nephrotoxicity . DB06681 is a fusion protein that inhibits T cell activation by binding to P33681 and P42081 antigens . Clinical trials , particularly the BENEFIT and BENEFIT - EXT studies , have shown that belatacept preserves function and structure in renal grafts . The effects of belatacept provide long - term , sustained results , and the safety and efficacy of this drug have been demonstrated in cases of renal transplantation from expanded criteria donors . Compared to calcineurin inhibitors , belatacept is associated with a lower incidence of chronic allograft nephropathy and a more favourable cardiovascular and metabolic profile .",
"Safety and immunogenicity of a V3 loop synthetic peptide conjugated to purified protein derivative in HIV - seronegative volunteers . OBJECTIVES : To develop a peptide - based model for a preventive vaccine for HIV - 1 infection . DESIGN : Phase I trial in HIV - 1 - seronegative volunteers . PARTICIPANTS : Adult healthy subjects HIV - 1 - antibody - seronegative in an enzyme - linked immunosorbent assay , screened for tuberculin [ purified protein derivative ( PPD ) ] reactivity with 2 tuberculin units PPD - administered intradermally . INTERVENTIONS : Submicrogram doses of a PPD conjugate with a peptide of the primary neutralizing domain ( P01160 ) of HIV - 1MN ( PPD - MN - P01160 ) were administered intradermally to tuberculin skin - test - positive and - negative volunteers . RESULTS : Antibodies to the MN - P01160 were measured after two immunizations in 10 out of 11 PPD skin - test - positive volunteers . After the fourth immunization high - affinity antibodies were detected , which persisted for over 1 year . High titers of MN - P01160 - specific immunoglobulin ( Ig ) G and IgA were detected in the serum and saliva of all volunteers tested . Serum antibodies were cross - reactive with P01160 peptide from some other HIV - 1 strains but neutralized only the HIV - 1MN prototype . Human leukocyte antigen ( HLA ) - P33681 - restricted MN - P01160 - specific cytotoxic T lymphocytes ( CTL ) were also detected . CONCLUSIONS : The PPD - MN - P01160 vaccine at submicrogram doses is safe and immunogenic in PPD skin - test - positive healthy adult volunteers . Long lasting humoral immune responses in the serum and saliva were possibly accompanied by HLA - P33681 - restricted CTL responses . This is a vaccine prototype that can be rapidly and inexpensively modified to include other peptide epitopes . It is especially suitable for use in a worldwide multibillion Bacillus Calmette - Guérin ( BCG ) - primed or tuberculosis - exposed population at risk for HIV - 1 infection .",
"Neonatal estrogen exposure disrupts uterine development in the postnatal sheep . Postnatal development of the ovine uterus between birth and postnatal day ( P01160 ) 56 involves budding differentiation of the endometrial glandular epithelium from the luminal epithelium ( LE ) followed by extensive coiling and branching morphogenesis of the tubular glands . To determine the short - and long - term effects of estrogen on neonatal ovine uterine development after P01160 14 , neonatal sheep were randomly assigned at birth ( P01160 0 ) to be treated daily with estradiol - 17beta benzoate ( EB ; 0 , 0 . 01 , 0 . 1 , 1 , or 10 microg / kg body weight . d ) during one of two developmental periods ( P01160 14 - 27 or 42 - 55 ) . All ewes were hemiovariohysterectomized at the end of EB treatment on either P01160 28 or 56 , and the remaining uterine horn and ovary removed on P01160 112 . Immediate responses to EB treatment included dose - and age - dependent increases in uterine wet weight , thickness of the endometrium , myometrium , and LE , but decreases in endometrial glands on P01160 28 and 56 . Transient exposure to EB decreased gland number and thickness of the endometrium and LE on P01160 112 but did not affect extrauterine reproductive tract structures . The mechanism of estrogen inhibition of uterine development did not involve effects on cell proliferation . Real - time PCR analyses found that EB exposure disrupted normal patterns of growth factor ( P05019 , P01344 , fibroblast growth factor - 7 , fibroblast growth factor - 10 , and hepatocyte growth factor ) and receptor mRNA expression in the uterus . Transient exposure of the neonatal ewe to estrogens during critical periods specifically alters growth factor networks that perturb normal development of the uterus , leading to permanent alterations in uterine structure and function .",
"P10275 negatively influences the expression of chemokine receptors ( P61073 , P32246 ) and ligand - mediated migration in prostate cancer DU - 145 . We previously reported that androgen receptor ( AR ) plays a role in the regulation of adhesion to the extracellular matrix and invasion of human prostate cancer cells by influencing the expression of specific integrin subunits . It is now considered that chemokines play a significant role in organ - selective cancer metastasis . In this study , we hypothesized that AR may influence the expression of these chemokine receptors and cell function . The mRNA expression of chemokine receptors in human prostate cancer cell line DU - 145 and DU - 145 cells expressing AR ( DU - 145 / AR ) was investigated by RT - PCR . DU - 145 cells selectively expressed P61073 and P32246 mRNA at high levels compared with DU - 145 / AR cells . DU - 145 showed vigorous migratory responses to its ligand P48061 ( also called stromal - derived factor - 1alpha , SDF - 1alpha ) and P10147 ( also called macrophage inflammatory protein - 1 , MIP - 1alpha ) . In contrast , neither P48061 nor P10147 affected the migration of DU - 145 / AR cells . These results indicate that expression of AR down - regulates the migratory responses of human prostate cancer cells via chemokine and its receptor systems .",
"Introduction to the use of belatacept : a fusion protein for the prevention of posttransplant kidney rejection . The development of new immunosuppressive drugs for kidney transplantation resulted both in better short - term outcomes and in decreased metabolic , cardiovascular , and nephrotoxicity risk . DB06681 belongs to a new class of immunosuppressive drugs that selectively inhibits T - cell activation by preventing P10747 activation and by binding its ligands P33681 - 1 and P33681 - 2 . The result is an inactivation of costimulatory pathways . A comparative analysis of the BENEFIT and BENEFIT - EXT datasets showed belatacept regimens resulted in better cardiovascular and metabolic risk profiles than did cyclosporin A ( DB00091 ) regimens : belatacept likewise outperformed DB00091 in terms of lower blood pressure and serum lipids and less new onset diabetes after transplantation . About 20 % of belatacept - treated patients developed adverse effects which included anemia , pyrexia , neutropenia , diarrhea , urinary tract infection , headache , and peripheral edema . At present , belatacept does not seem to predispose patients to a higher rate of infection than DB00091 maintenance immunosuppression . The risk of posttransplant lymphoproliferative diseases was higher in Epstein - Barr virus ( EBV ) - seronegative patients than in EBV - seropositive patients , but the risk may be reduced by use of a less intensive regimen and avoidance of EBV - negative patients and of patients whose pretransplant EBV serology is unknown . DB06681 provides a new option for immunosuppressive therapy in kidney transplantation , but needs further evaluation in terms of the late effects that may derive from prolonged blockage of the costimulatory system and the induction of tolerance status .",
"A mutant cell line partially responsive to both IFN - alpha and P01579 . A recessive mutant cell line , P33681 , which is partially responsive to both interferon ( IFN ) - alpha and P01579 is described . P33681 was FACS sorted from a cellular pool , which was obtained from the parental cell line 2C4 , after several rounds of mutagenesis . The partial responsiveness to IFN was observed both in terms of expression of cell surface markers ( P06729 , class I and II HLAs ) and mRNA expression of IFN - stimulated genes ( 9 - 27 ; 6 - 16 ; 2 '- 5 ' OAS ; O75925 and HLA - DR alpha ) . A genetic cross with the U4 mutant ( P23458 - , a member of the Janus family of nonreceptor tyrosine kinase ) did not restore full IFN responsiveness to P33681 , and P23458 cDNA transfection into P33681 restored the wild phenotype of the cell line , defining P33681 as a member of the U4 complementation group . Nevertheless , P23458 mRNA was not detected in this mutant . Transcriptional regulator complexes such as P10914 / 2 ( IFN - regulatory factor ) and ISGF3 - gamma ( IFN - stimulated gene factor ) were constitutively formed in the P33681 mutant and co - migrated with the IFN - induced complexes expressed in the parental cell line 2C4 . Thus , this cell line seems to be useful for understanding cis - acting elements governing P23458 mRNA expression .",
"Q9NQB0 splice variants have distinct effects on beta - cell turnover and function . Type 2 diabetes manifests when the β - cell fails to secrete sufficient amounts of insulin to maintain normoglycemia and undergoes apoptosis . The disease progression results from an interplay of environmental factors and genetic predisposition . Polymorphisms in T - cell factor 7 - like 2 ( Q9NQB0 ) strongly correlate with type 2 diabetes mellitus ( T2DM ) . While Q9NQB0 mRNA is upregulated in islets in diabetes , protein levels are downregulated . The loss of Q9NQB0 induces impaired function and apoptosis . By analyzing human isolated islets , we provide three explanations for this opposite regulation and the mechanisms of Q9NQB0 on β - cell function and survival . ( i ) We found Q9NQB0 transcripts in the human β - cell , which had opposite effects on β - cell survival , function and Wnt signaling activation . While Q9NQB0 clone B1 , which lacks exons 13 , 14 , 15 and 16 induced β - cell apoptosis , impaired function and inhibited glucagon - like peptide 1 response and downstream targets of Wnt signaling , clones B3 and P33681 which both contain exon 13 , improved β - cell survival and function and activated Wnt signaling . ( ii ) Q9NQB0 mRNA is extremely unstable and is rapidly degraded under pro - diabetic conditions and ( iii ) Q9NQB0 depletion in islets induced activation of glycogen synthase kinase 3 - β , but this was independent of endoplasmic reticulum stress . We demonstrated function - specific transcripts of Q9NQB0 , which possessed distinct physiological and pathophysiological effects on the β - cell . The presence of deleterious Q9NQB0 splice variants may be a mechanism of β - cell failure in T2DM .",
"Bovine somatotropin attenuates phorbol ester - induced prostaglandin F2alpha production in bovine endometrial cells . The recent observation that bovine somatotropin ( bST ) treatment at a timed insemination improves pregnancy rates in lactating dairy cows raises the possibility that growth hormone ( GH ) may modulate the endocrine and biochemical cross talk between the conceptus and maternal uterus at the time of pregnancy establishment in cattle . The objective of this study was to characterize the cellular and molecular mechanisms by which exogenous GH affects phorbol ester - induced prostaglandin F2alpha ( PGF2alpha ) production in cultured bovine endometrial ( BEND ) cells . Serum - deprived BEND cells were incubated with or without recombinant bovine GH ( rbGH ) , insulin - like growth factor ( IGF ) - I , recombinant bovine interferon ( rbIFN ) - tau or a combination of rbGH + rbIFN - tau for 3 h and then treated with phorbol 12 , 13 - dibutyrate ( PDBu ) for an additional 6 h . Exogenous PDBu increased PGF2alpha secretion and steady - state levels of P35354 mRNA within 3 h . Priming of BEND cells with rbGH reduced PGF2alpha response to PDBu , whereas cotreatment with P05019 amplified PDBu induction of PGF2alpha . Preincubation of cell monolayers with rbIFN - tau suppressed PGF2alpha and P35354 mRNA responses to PDBu . Inhibitory effects of rbGH and rbIFN - tau on PDBu - induced PGF2alpha production were additive . Results provide the first direct evidence that supplemental bST may interact with conceptus - secreted IFN - tau to modulate PGF2alpha secretion at the critical time of maternal recognition of pregnancy .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"The JAK inhibitor , tofacitinib , reduces the T cell stimulatory capacity of human monocyte - derived dendritic cells . OBJECTIVE : DB08895 , which is a Janus kinase ( JAK ) inhibitor , has shown clinical effects in the treatment of rheumatoid arthritis . JAKs are important kinases in lymphocyte differentiation ; however , their function in dendritic cells ( DCs ) is unknown . In this study , the function of JAKs in DCs was investigated with tofacitinib . METHODS : The effects of tofacitinib on the maturation of human monocyte - derived DCs induced by lipopolysaccharide ( LPS ) stimulation were investigated . In addition , its effects on T cell stimulatory capability was investigated by coculturing with naïve CD45RA - positive T cells . RESULTS : DB08895 decreased expression of P33681 / P42081 in a concentration - dependent manner in LPS - stimulated DCs ; however , it did not affect HLA - DR expression . DB08895 suppressed tumour necrosis factor , interleukin ( IL ) - 6 and IL - 1β production without affecting transforming growth factor ( TGF ) - β and P22301 production . Meanwhile , P33681 / P42081 expression in DCs was enhanced by type I interferon ( IFN ) stimulation , and the LPS - induced P33681 / P42081 expression was inhibited by an antibody to type I IFN receptor . Furthermore , tofacitinib suppressed production of type I IFN and activation of interferon regulatory factor ( Q969Q1 ) - 7 , which is a transcription factor involved in P33681 / P42081 and type I IFN expression . DB08895 also decreased the T cell stimulatory capability of DCs and increased expression of indoleamine 2 , 3 - dioxygenase ( P14902 ) - 1 and Q6ZQW0 . CONCLUSIONS : DB08895 , a P23458 / P52333 inhibitor , affected the activities of human DCs . It decreased P33681 / P42081 expression and T cell stimulatory capability through suppression of type I IFN signalling . These results suggest a novel mode of action for tofacitinib and a pivotal role for JAKs in the differentiation of DCs .",
"Tumor Necrosis Factor alpha ( TNFalpha ) regulates P25942 expression through Q8N9N5 phosphorylation . P25942 plays an important role in mediating inflammatory response and is mainly induced by JAK / P35610 phosphorylation cascade . TNFalpha is the key cytokine that activates P25942 during inflammation and tumorigenesis . We have earlier shown that Q8N9N5 can repress the transcription of P12004 D1 promoter by forming a Q13547 dependent repressor complex . In this study , we show that Q8N9N5 regulates the transcription of NF - kappaB target gene P25942 . Q8N9N5 recruits Q13547 and forms a repressor complex on P25942 promoter and keeps its basal transcription in check . Further , we show that TNFalpha stimulation induces Q8N9N5 phosphorylation at DB00133 - 347 and promotes its cytoplasmic translocation , thus releasing its negative effect . Concomitantly , TNFalpha induced phosphorylation of P42224 at DB00135 - 701 by P23458 facilitates its nuclear translocation and activation of P25942 through p300 recruitment and core Histone - 3 acetylation . Thus , TNFalpha mediated regulation of P25942 expression occurs by dual phosphorylation of Q8N9N5 and P42224 .",
"Novel immunosuppression : small molecules and biologics . Kidney transplantation today has excellent short - term outcomes that have paralleled the use of new immunosuppressive agents introduced in the 1990s . In addition to reducing acute rejection , the goals for developing new agents is to improve long - term outcome , minimize nephrotoxicity , and reduce infectious , cardiovascular , and malignancy - related complications . Novel small molecules and biological agents currently in clinical development may help to minimize the use of calcineurin inhibitors and steroids . These small molecules include FTY720 , a sphingosine phosphate - receptor modulator , FK778 , an inhibitor of pyrimidine synthesis , CP - 690550 , a P52333 inhibitor , and AEB - 071 , a protein kinase C inhibitor . The biological agents include drugs targeting interleukin - 15 , anti - P25942 , belatacept ( DB06681 ) , a second - generation CTLY4Ig that blocks the interaction between P33681 / 86 and P10747 costimulatory pathways , and efalizumab , a humanized anti - LFA1 monoclonal antibody . These new agents currently in preclinical and clinical trials appear promising and may represent the emergence of novel immunosuppressive agents that can deliver immunosuppression without long - term toxicity .",
"The impact of biological agents interfering with receptor / ligand binding in the immune system . We herein discuss the impact of biological agents based on the ability of monoclonal antibodies to target specific molecules . This approach has given to clinical immunologists a spectrum of drugs able to manipulate the immune system . In the first session , we discuss drugs targeting T - cell function by : ( 1 ) targeting P10747 mediated costimulation ( DB01281 and DB06681 ) ; ( 2 ) interfering with interleukin - 2 receptor ( DB00074 and DB00111 ) ; ( 3 ) blocking cell adhesion and homing ( DB00092 , DB00095 , DB00108 ) . The second session is dedicated to drugs targeting cytokines or their receptors . The best known and largely experimented case is represented by drugs targeting tumor necrosis factor ( P01375 ) ( DB00065 , Adalilumab , Certolizumab ) or its p75 receptor ( DB00005 ) . However , newer products are now available to target other inflammatory cytokines including P05231 , P10145 , IL - 12 , P40933 , Q14116 , IL - 23 . These agents have the potential to become powerful tools in the control of several immune - mediated diseases , especially auto - immune and inflammatory ones . They traslate into reality the prediction that antibodies will eventually become \" magic bullets which seek their own target \" ( P . Ehrich , 1906 ) .",
"Development of a chimeric anti - P25942 monoclonal antibody that synergizes with DB06681 to prolong islet allograft survival . In recent years , reagents have been developed that specifically target signals critical for effective T cell activation and function . Manipulation of the P10747 / P33681 / 86 and P25942 / CD154 pathways has exhibited extraordinary efficacy , particularly when the pathways are blocked simultaneously . Despite the reported efficacy of anti - CD154 in rodents and higher models , its future clinical use is uncertain due to reported thromboembolic events in clinical trials . To circumvent this potential complication , we developed and evaluated a chimeric Ab targeting P25942 ( Chi220 , BMS - 224819 ) as an alternative to CD154 . Although Chi220 blocks CD154 binding , it also possesses partial agonist properties and weak stimulatory potential . The anti - P25942 was tested alone and in combination with a rationally designed , high affinity variant of P16410 - Ig , DB06681 ( belatacept ) , in a nonhuman primate model of islet transplantation . Although either agent alone only modestly prolonged islet survival ( Chi220 alone : 14 , 16 , and 84 days ; DB06681 alone : 58 and 60 days ) , their combination ( DB06681 and Chi220 ) dramatically facilitated long term survival ( 237 , 237 , 220 , > 185 , and 172 days ) . We found that the effects of Chi220 treatment were not mediated solely through deletion of P11836 - bearing cells and that the combined therapy did not significantly impair established antiviral immunity .",
"Assessment of belatacept - mediated costimulation blockade through evaluation of P33681 / 86 - receptor saturation . BACKGROUND : The selective inhibitor of T - cell costimulation , belatacept , blocks P10747 - mediated T - cell activation by binding P33681 and P42081 on antigen - presenting cells . Understanding the extent to which belatacept binds to its targets in patients may enable correlation of belatacept exposure to receptor saturation as a pharmacodynamic measure of costimulation blockade . METHODS : Flow cytometry - based receptor competition assays were developed to monitor concentration - dependent occupancy of P33681 and P42081 receptors in whole blood and dendritic cell cultures in vitro . Receptor occupancy was correlated with inhibition of mixed leukocyte reactions and clinical validation was obtained by comparing receptor saturation in whole blood from healthy volunteers and in de novo renal transplant recipients participating in studies comparing cyclosporine and belatacept - based immunosuppression . RESULTS : DB06681 saturated P33681 and P42081 receptors in whole blood and dendritic cell cultures , although the belatacept concentrations required for P42081 - receptor saturation were approximately 10 - fold higher than those required for P33681 saturation ( IC50 = 0 . 102 microg / mL vs . 0 . 009 microg / mL ) . Primary alloresponses were inhibited at the belatacept concentration required for P42081 - receptor saturation , but not at the lower concentration needed to saturate P33681 . Whole blood from belatacept - treated patients had significantly lower levels of free P42081 receptors versus pretransplant levels , healthy volunteers , or cyclosporine - treated patients . P42081 - receptor saturation correlated with belatacept dose / dose frequency and remained consistently more than 80 % . CONCLUSIONS : These results suggest that belatacept - mediated inhibition of alloresponses involved in transplant rejection correlates with P42081 saturation , indicating that P42081 - receptor occupancy may be a valid pharmacodynamic measure of costimulation blockade and provide the first direct clinical evidence that belatacept binds to one of its targets .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK37___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK97___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"DB06681 : a new era of immunosuppression ? Q8N1N2 T - cell activation in alloimmunity requires the engagement of several costimulatory molecules . P16410 - Ig and its commercially available fusion proteins , belatacept and abatacept , are used to block P33681 / 86 and promote T - cell tolerance . DB06681 , a higher binding affinity molecule , is currently approved for clinical use in renal transplantation . The results of two Phase III clinical trials showed a similar patient / graft survival , with better renal function at a 3 - year follow - up compared with conventional immunosuppression . There was a higher risk of early rejection and post - transplant lymphoproliferative disorder , especially with EBV - negative patients receiving kidneys from EBV - positive donors . DB06681 - treated groups had a better cardiovascular and metabolic profile . The authors review both preclinical and human studies of P16410 - Igs .",
"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .",
"Cell type - specific binding patterns reveal that Q9NQB0 can be tethered to the genome by association with P23771 . BACKGROUND : The Q9NQB0 transcription factor is linked to a variety of human diseases , including type 2 diabetes and cancer . One mechanism by which Q9NQB0 could influence expression of genes involved in diverse diseases is by binding to distinct regulatory regions in different tissues . To test this hypothesis , we performed ChIP - seq for Q9NQB0 in six human cell lines . RESULTS : We identified 116 , 000 non - redundant Q9NQB0 binding sites , with only 1 , 864 sites common to the six cell lines . Using ChIP - seq , we showed that many genomic regions that are marked by both H3K4me1 and H3K27Ac are also bound by Q9NQB0 , suggesting that Q9NQB0 plays a critical role in enhancer activity . Bioinformatic analysis of the cell type - specific Q9NQB0 binding sites revealed enrichment for multiple transcription factors , including HNF4alpha and Q9Y261 motifs in HepG2 cells and the P23771 motif in MCF7 cells . ChIP - seq analysis revealed that Q9NQB0 co - localizes with HNF4alpha and Q9Y261 in HepG2 cells and with P23771 in MCF7 cells . Interestingly , in MCF7 cells the Q9NQB0 motif is enriched in most Q9NQB0 sites but is not enriched in the sites bound by both P23771 and Q9NQB0 . This analysis suggested that P23771 might tether Q9NQB0 to the genome at these sites . To test this hypothesis , we depleted P23771 in MCF7 cells and showed that Q9NQB0 binding was lost at a subset of sites . RNA - seq analysis suggested that Q9NQB0 represses transcription when tethered to the genome via P23771 . CONCLUSIONS : Our studies demonstrate a novel relationship between P23771 and Q9NQB0 , and reveal important insights into Q9NQB0 - mediated gene regulation .",
"P02649 modulates immune activation by acting on the antigen - presenting cell . P02649 ( ApoE ) is synthesized by a variety of cells including macrophages . These cells activate T lymphocytes by antigen presentation , while the T - cell cytokine , interferon - gamma , inhibits macrophage ApoE expression . ApoE inhibits T - cell proliferation in culture but its role in immune responses has been unclear . The ApoE - deficient ( E0 ) mouse permits an evaluation of the immunological role of ApoE . We have analysed T - cell responses to an exogenous antigen ( ovalbumin ) and polyclonal mitogen ( concanavalin A ) in E0 and ApoE +/+ mice . Macrophages of E0 mice stimulated T - cell activation more effectively as antigen - presenting cells than macrophages from ApoE +/+ mice . Both proliferation and interferon - gamma secretion were enhanced in T cells activated in the context of antigen - presenting cells from E0 mice . Since the macrophage - T - cell interaction depends on interactions between cell surface molecules , we assessed the expression of such molecules after in vivo stimulation with interferon - gamma . This treatment caused an increased expression of the co - stimulatory surface proteins P25942 and P33681 , and also of the major histocompatibility complex class II molecules I - Ab on macrophages of E0 mice compared with ApoE +/+ . Our data suggest that ApoE inhibits T - cell activation by reducing the density of immune stimulatory proteins on antigen - presenting cells .",
"Effect of genetic polymorphisms on the pharmacokinetics and efficacy of glimepiride in a Korean population . BACKGROUNDS : ___MASK61___ is a commonly used sulfonylurea hypoglycemic agent . There is considerable interindividual variation in the response to sulfonylurea for patients with type 2 diabetes . The purpose of this study was to investigate whether genetic variations influence the efficacy of glimepiride in healthy Korean subjects . METHODS : A single 2 - mg oral dose of glimepiride was administered to 46 healthy volunteers . Serial blood sampling for 12h after oral dosing was performed for determination of plasma glimepiride , glucose and insulin levels . We tested the association of seven single nucleotide polymorphisms ( SNPs ) in four candidate genes with the efficacy of glimepiride . RESULTS : Pharmacodynamic profiles for plasma glucose and insulin showed no statistically significant differences among genotype groups , and parameters were not different from one another . There were no association of the Q14654 , O75052 , Q9NQB0 and Q09428 gene polymorphisms and the efficacy of glimepiride . CONCLUSIONS : Knowledge of these polymorphisms provides no clinical useful information for the pharmacogenetic therapeutic approach for Korean patients with type 2 diabetes .",
"Challenges and opportunities in targeting the costimulation pathway in solid organ transplantation . Signaling through the costimulatory pathway is critical in the regulation of T cell activation . DB01281 , a selective costimulatory antagonist FDA approved for the treatment of moderate to severe rheumatoid arthritis , binds to P33681 and P42081 on antigen presenting cells , blocking the interaction with P10747 on T cells . DB06681 , a second generation P16410 - Ig with 2 amino acid substitutions , has shown considerable promise in clinical transplantation as part of a maintenance immunosuppression regimen . This review will summarize the role of costimulation in T cell activation , detail the development of costimulation antagonists and highlight the pertinent clinical trials completed and ongoing utilizing belatacept as part of an immunosuppressive regimen in organ transplantation .",
"Dual PI3K / AKT / P42345 inhibitor BEZ235 synergistically enhances the activity of O60674 inhibitor against cultured and primary human myeloproliferative neoplasm cells . Hemopoietic progenitor cells ( HPC ) from myeloproliferative neoplasms ( Q9BQR3 ) such as myelofibrosis commonly express mutant O60674 - V617F or other mutations that are associated with increased activities of JAK - P42229 / 3 , DB01367 / RAF / MAPK , and PI3K / AKT / P42345 pathways . This confers proliferative and survival advantage on the Q9BQR3 HPCs . Treatment with JAK tyrosine kinase inhibitor ( TKI ) , for example , TG101209 , TG101348 ( SAR302503 ) , or ___MASK19___ ( ruxolitinib ) , inhibits mutant O60674 - mediated signaling . Although effective in reducing constitutional symptoms and splenomegaly , treatment with JAK - TKI does not ameliorate myelofibrosis or significantly improve survival of patients with advanced myelofibrosis . Here , we show that treatment with the dual phosphoinositide - 3 - kinase ( PI3K ) / AKT and P42345 inhibitor BEZ235 attenuated PI3K / AKT and P42345 signaling , as well as induced cell - cycle growth arrest and apoptosis of the cultured human O60674 - V617F - expressing HEL92 . 1 . 7 ( HEL ) , UKE1 cells , and primary P28906 + myelofibrosis ( MF ) - Q9BQR3 cells . Treatment with BEZ235 also induced significant apoptosis of the O60674 - TKI resistant HEL / TGR cells that were selected for resistance against JAK - TKI . Cotreatment with BEZ235 and O60674 - TKI ( TG101209 and SAR302503 ) synergistically induced lethal activity against the cultured and primary P28906 + Q9BQR3 cells while relatively sparing the normal P28906 + HPCs . These findings create a compelling rationale to determine the in vivo activity of dual PI3K / P42345 inhibitors in combination with JAK inhibitors against myelofibrosis HPCs .",
"DB06681 and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion . DB06681 is an inhibitor of P10747 / P33681 costimulation that is clinically indicated as a calcineurin inhibitor ( CNI ) alternative in combination with mycophenolate mofetil and steroids after renal transplantation . We sought to develop a clinically translatable , nonlymphocyte depleting , belatacept - based regimen that could obviate the need for both CNIs and steroids . Thus , based on murine data showing synergy between costimulation blockade and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched renal allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on costimulation blockade - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . DB06681 and sirolimus therapy successfully prevented rejection in all animals . Tolerance was not induced , as animals rejected after withdrawal of therapy . The regimen did not deplete T cells . Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen , despite causing an intended depletion of memory T cells , and caused a marked reduction in regulatory T cells . Furthermore , alefacept - treated animals had a significantly increased incidence of CMV reactivation , suggesting that this combination overly compromised protective immunity . These data support belatacept and sirolimus as a clinically translatable , nondepleting , CNI - free , steroid - sparing immunomodulatory regimen that promotes sustained rejection - free allograft survival after renal transplantation .",
"Rational development of DB06681 ( belatacept ) , a high - affinity variant of P16410 - Ig with potent immunosuppressive properties . Current success in organ transplantation is dependent upon the use of calcineurin - inhibitor - based immunosuppressive regimens . Unfortunately , current immunotherapy targets molecules with ubiquitous expression resulting in devastating non - immune side effects . T - cell costimulation has been identified as a new potential immunosuppressive target . The best characterized pathway includes P10747 , its homologue P16410 and their ligands P33681 and P42081 . While an immunoglobulin fusion protein construct of P16410 suppressed rejection in rodents , it lacked efficacy in primate transplant models . In an attempt to increase the biologic potency of the parent molecule a novel , modified version of P16410 - Ig , DB06681 ( belatacept ) , was constructed . Two amino acid substitutions ( L104E and A29Y ) gave rise to slower dissociation rates for both P42081 and P33681 . The increased avidity resulted in a 10 - fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre - clinical primate model . The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants .",
"___MASK33___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"Human epidermal Langerhans ' cells are targets for the immunosuppressive macrolide tacrolimus ( FK506 ) . BACKGROUND : The immunosuppressive macrolide tacrolimus ( FK506 ) has been shown to inhibit allergic contact dermatitis in animal models as well as in human beings . More recently , successful treatment of atopic dermatitis with an ointment containing tacrolimus has been reported . OBJECTIVES : We explored the effects of this compound on epidermal Langerhans ' cells ( LCs ) , which are known to play an important pathophysiologic role in inflammatory skin diseases . METHODS : The expression of the intracellular FK506 binding protein ( P62942 ) was monitored on freshly isolated and cultured epidermal LCs . Phenotyping and functional exploration of LCs treated with different concentrations of tacrolimus and beta - methasone valerate ( betaMv ) were performed . RESULTS : P62942 is expressed in freshly isolated LCs but is lost while they are maturating into mature dendritic cells . ___MASK70___ inhibited the expression of IL - 2R ( CD25 ) and of the costimulatory molecules P33681 ( P33681 . 1 ) and P25942 . Expression of MHC class I and II was also affected , whereas P42081 ( P33681 . 2 ) expression was not altered . In contrast , betaMv strongly increased the expression of CD25 . Paradoxically , while decreasing P25942 and MHC class I expression , betaMv significantly increased the expression of MHC class II , P33681 , and P42081 on cultured LCs but impaired their allostimulatory activity . ___MASK70___ was about 100 times more potent than betaMv at inhibiting LC stimulatory function . CONCLUSION : ___MASK70___ can exert immunopharmacologic alterations on LCs , which may account , at least in part , for the therapeutic effect of this compound in eczematous skin diseases .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK48___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"Impact of KCNE subunits on P51787 ( Kv7 . 1 ) channel membrane surface targeting . The P51787 ( Kv7 . 1 ) channel plays an important role in cardiovascular physiology . Cardiomyocytes co - express P51787 with P15382 - 5 proteins . P51787 may co - associate with multiple KCNE regulatory subunits to generate different biophysically and pharmacologically distinct channels . Increasing evidence indicates that the location and targeting of channels are important determinants of their function . In this context , the presence of K (+) channels in sphingolipid - cholesterol - enriched membrane microdomains ( lipid rafts ) is under investigation . Lipid rafts are important for cardiovascular functioning . We aimed to determine whether KCNE subunits modify the localization and targeting of P51787 channels in lipid rafts microdomains . P29320 - 293 cells were transiently transfected with P51787 and P15382 - 5 , and their traffic and presence in lipid rafts were analyzed . Only P51787 and Q9Y6H6 , when expressed alone , co - localized in raft fractions . In addition , while Q9Y6J6 and Q9UJ90 notably stained the cell surface , P51787 and the rest of the KCNEs showed strong intracellular retention . P51787 targets multiple membrane surface microdomains upon association with KCNE peptides . Thus , while P51787 / P15382 and P51787 / Q9Y6J6 channels target lipid rafts , P51787 associated with Q9Y6H6 - 5 did not . Channel membrane dynamics , analyzed by fluorescence recovery after photobleaching ( P42345 ) experiments , further supported these results . In conclusion , the trafficking and targeting pattern of P51787 can be influenced by its association with KCNEs . Since P51787 is crucial for cardiovascular physiology , the temporal and spatial regulations that different KCNE subunits may confer to the channels could have a dramatic impact on membrane electrical activity and putative endocrine regulation .",
"___MASK19___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK19___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK19___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK19___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK61___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK61___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .",
"Differential inhibition of autoreactive memory - and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 ( sCTLA4 ) , DB01281 and DB06681 . Cytotoxic T lymphocyte antigen 4 ( P16410 ) is a potent inhibitory co - stimulatory molecule believed to be involved in type 1 diabetes and other autoimmune diseases . An association has been reported of both mRNA expression and serum levels of the soluble splice variant of P16410 ( sCTLA4 ) with type 1 diabetes . Furthermore , recombinant fusion proteins DB01281 and DB06681 have been proposed as therapies for type 1 diabetes . We studied the role of ( s ) P16410 in islet autoimmunity . Binding capacity of the proteins to antigen - presenting cells was determined by flow cytometry in competition and binding assays . Functionality of sCTLA4 as well as the therapeutic inhibitory fusion proteins DB01281 and DB06681 was measured in a dose - response lymphocyte stimulation test , using a panel of diabetes - associated T cell clones reactive to islet autoantigens . As controls , mixed lymphocyte reactions ( P08235 ) were performed to assess functionality of these proteins in a primary alloreactive setting . All three P16410 molecules were able to bind to antigen - presenting cells and inhibit the expression of P33681 / P42081 . sCTLA4 was able to suppress proliferation of different committed autoreactive T cell clones in a dose - dependent manner , whereas DB01281 and DB06681 were not . Conversely , DB01281 and DB06681 , rather than sCTLA4 , were able to suppress naive alloreactive proliferation in a P08235 . Our results indicate a differential role for sCTLA4 , DB01281 and DB06681 proteins in memory versus primary immune responses with implications for efficacy in intervention therapy .",
"Dietary phytochemicals alter epigenetic events and signaling pathways for inhibition of metastasis cascade : phytoblockers of metastasis cascade . Cancer metastasis is a multistep process in which a cancer cell spreads from the site of the primary lesion , passes through the circulatory system , and establishes a secondary tumor at a new nonadjacent organ or part . Inhibition of cancer progression by dietary phytochemicals ( DPs ) offers significant promise for reducing the incidence and mortality of cancer . Consumption of DPs in the diet has been linked to a decrease in the rate of metastatic cancer in a number of preclinical animal models and human epidemiological studies . DPs have been reported to modulate the numerous biological events including epigenetic events ( noncoding micro - RNAs , histone modification , and DNA methylation ) and multiple signaling transduction pathways ( Wnt / β - catenin , Notch , Sonic hedgehog , P35354 , P00533 , MAPK - P29323 , JAK - P35610 , Akt / PI3K / P42345 , NF - κB , AP - 1 , etc . ) , which can play a key role in regulation of metastasis cascade . Extensive studies have also been performed to determine the molecular mechanisms underlying antimetastatic activity of DPs , with results indicating that these DPs have significant inhibitory activity at nearly every step of the metastatic cascade . DPs have anticancer effects by inducing apoptosis and by inhibiting cell growth , migration , invasion , and angiogenesis . Growing evidence has also shown that these natural agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways . In this review , we discuss the variety of molecular mechanisms by which DPs regulate metastatic cascade and highlight the potentials of these DPs as promising therapeutic inhibitors of cancer .",
"Monocytes from type 2 diabetic patients have a pro - inflammatory profile . 1 , 25 - Dihydroxyvitamin D ( 3 ) works as anti - inflammatory . The exact factors contributing to the pathogenesis of type 2 diabetes remain elusive . Lately , it was suggested that inflammation and activation of the innate immune system could be linked to type 2 diabetes pathogenesis and also to the development of common diabetic complications , mainly atherosclerosis . The aim of this study was to investigate the role of monocytes in this sub - clinical inflammatory state and test 1 , 25 - dihydroxyvitamin D ( 3 ) , the active form of Vitamin D , as an anti - inflammatory agent . For this purpose , monocytes from type 2 diabetic patients were compared to monocytes from healthy controls and type 1 diabetic patients . The expression profile of inflammatory markers in freshly isolated and immune - stimulated monocytes was measured by quantitative real - time RT - PCR . Type 2 diabetic patients showed significantly higher expression levels of P01375 , P05231 , IL - 1 , P10145 , P35354 , P05362 and P33681 - 1 compared to controls and type 1 diabetic patients . 1 , 25 - Dihydroxyvitamin D ( 3 ) was able to down - regulate the expression of P01375 , P05231 , IL - 1 , and P10145 , confirming its immunomodulatory properties . From these data we concluded that monocytes from type 2 diabetic patients have a pro - inflammatory profile . In addition , 1 , 25 - dihydroxyvitamin D ( 3 ) was able to modulate inflammation in these monocytes .",
"T - cell phenotype in protocol renal biopsy from transplant recipients treated with belatacept - mediated co - stimulatory blockade . BACKGROUND : DB06681 is thought to disrupt the interaction between P33681 / 86 and P10747 , thus preventing T - cell activation by blocking the co - stimulatory second signal . However , the consequences on the T - cell profile in human renal transplant cases have not been determined . METHODS : In this study , we analysed intra - graft levels of the mRNAs for Treg ( Q9BZS1 ) , cytotoxic CD8 T cells ( P10144 ) , Th1 ( INFγ , Tbet ) , Th2 ( P23771 ) and Th17 ( RORγt and Q16552 ) in protocol biopsies obtained 12 months after renal transplantation in recipients treated with DB06681 or calcineurin inhibitor ( CNI ) . RESULTS : Only the intra - graft abundance of Q9BZS1 mRNA was significantly lower ( P < 0 . 001 ) in the DB06681 group than the CNI group . Conclusions . These results are in agreement with in vitro data suggesting that P10747 is a major co - stimulatory signal of both Tregs development and peripheral homeostasis but contrast with clinical trials showing a better 1 - year graft function and a lower incidence of chronic allograft nephropathy in patients receiving DB06681 than patients treated with CNI . They suggest that immune benefits induced by DB06681 are not mediated by Treg expansion and that Q9BZS1 is not by itself a prognostic marker of long - term graft function in a non - inflammatory context . These results have to be , however , considered as preliminary since the size of our study population is limited .",
"Nardosinone protects H9c2 cardiac cells from angiotensin II - induced hypertrophy . Pathological cardiac hypertrophy induced by angiotensin II ( AngII ) can subsequently give rise to heart failure , a leading cause of mortality . Nardosinone is a pharmacologically active compound extracted from the roots of Nardostachys chinensis , a well - known traditional Chinese medicine . In order to investigate the effects of nardosinone on AngII - induced cardiac cell hypertrophy and the related mechanisms , the myoblast cell line H9c2 , derived from embryonic rat heart , was treated with nardosinone ( 25 , 50 , 100 , and 200 μmol / L ) or AngII ( 1 μmol / L ) . Then cell surface area and mRNA expression of classical markers of hypertrophy were detected . The related protein levels in PI3K / Akt / P42345 and MEK / P29323 signaling pathways were examined by Western blotting . It was found that pretreatment with nardosinone could significantly inhibit the enlargement of cell surface area induced by AngII . The mRNA expression of P01160 , DB04899 and β - MHC was obviously elevated in AngII - treated H9c2 cells , which could be effectively blocked by nardosinone at the concentration of 100 μmol / L . Further study revealed that the protective effects of nardosinone might be mediated by repressing the phosphorylation of related proteins in PI3K / Akt and MEK / P29323 signaling pathways . It was suggested that the inhibitory effect of nardosinone on Ang II - induced hypertrophy in H9c2 cells might be mediated by targeting PI3K / Akt and MEK / P29323 signaling pathways .",
"Linkage analysis of multiple sclerosis with candidate region markers in Sardinian and Continental Italian families . Previous genome screens in multiple sclerosis have shown some evidence of linkage in scattered chromosomal regions . Although in no case the evidence of each single study was compelling and although in general the linkage ' peaks ' of the different studies did not coincide , some regions can be considered likely candidates for the presence of MS risk genes because of the clustering of MLS scores and homology with eae loci . We performed a linkage analysis of markers in these regions and of intragenic markers of some individual candidate genes ( HLA - Q8IUH3 , P16410 , P15248 , P02649 , P10415 , P20333 ) . For the first time , Southern European populations were targeted , namely Continental Italians and Sardinians . A total of 69 multiplex families were typed for 67 markers by a semi - automatic fluorescence - based assay . Results were analysed for linkage by two non - parametric tests : GENEHUNTER and SimIBD . In general , the linkage scores obtained were low , confirming the conclusion that no gene is playing a major role in the disease . However , some markers , in 2p11 , 3q21 . 1 , 7p15 . 2 and 22q13 . 1 stood out as promising since they showed higher scores with one or the other test . This stimulates further association analysis of a large number of simplex families from the same populations .",
"DB06681 and sirolimus prolong nonhuman primate islet allograft survival : adverse consequences of concomitant alefacept therapy . Calcineurin inhibitors ( CNI ) and steroids are known to promote insulin resistance , and their avoidance after islet transplantation is preferred from a metabolic standpoint . DB06681 , a P33681 - specific mediator of costimulation blockade ( CoB ) , is clinically indicated as a CNI alternative in renal transplantation , and we have endeavored to develop a clinically translatable , belatacept - based regimen that could obviate the need for both CNIs and steroids . Based on the known synergy between CoB and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched islet allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on CoB - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . Nine rhesus macaques were rendered diabetic with streptozotocin and underwent islet allotransplantation . All received belatacept and sirolimus ; six also received alefacept . DB06681 and sirolimus significantly prolonged rejection - free graft survival ( median 225 days compared to 8 days in controls receiving basiliximab and sirolimus ; p = 0 . 022 ) . The addition of alefacept provided no additional survival benefit , but was associated with Cytomegalovirus reactivation in four of six animals . No recipients produced donor - specific alloantibodies . The combination of belatacept and sirolimus successfully prevents islet allograft survival in rhesus monkeys , but induction with alefacept provides no survival benefit and increases the risk of viral reactivation .",
"Altered gene expression by low - dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real - time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT - PCR TaqMan low - density array ( TLDA ) . We found that expression of tumor necrosis factor - α ( P01375 - α ) , which activates both inflammation and NF - κB - dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion - channel genes CACNA1 , Q12809 , P51787 and P15382 were down - regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion - channel function , may underlay the seemingly disparate array of arsenic - associated diseases , such as cancer , cardiovascular disease , and diabetes .",
"DB01645 enhancement of respiratory allergen trimellitic anhydride - induced IgE production by adult B6C3F1 mice following in utero and postnatal exposure . The objective of the present study was to determine if exposure to the phytoestrogen genistein ( GEN ) during immune development had any effects on the production of IgE by adult mice following dermal treatment with trimellitic anhydride ( TMA ) , a respiratory allergen . B6C3F1 mice were exposed to GEN either by feeding at 500 ppm or by gavage ( 20 mg / kg ) for varied periods from gestation day ( GD ) 14 to postnatal day ( P01160 ) 84 . In utero exposure to GEN by feeding increased the production of IgE at P01160 84 in male mice but not in female mice . In male mice , continuous exposure to GEN postnatally diminished the in utero exposure - induced enhancement in serum total IgE production . However , continuous exposure to GEN from GD 14 to P01160 84 was required to increase serum total IgE production in female mice . In utero exposure to GEN by gavage increased the production of IgE at P01160 84 in female mice but not in male mice when the mice were maintained on the NIH - 07 rodent diet in which a medium level of phytoestrogens was present . The enhancement in IgE production after GEN exposure in females but not in males was associated with decreases in the percentages of P01730 (+) CD25 (+) T suppressor cells , and increases in the natural killer ( NK ) cell activity , the basal splenocyte proliferation , the expression of P42081 by B cells , and the production of P60568 and P05112 . Overall , the results demonstrated that GEN differentially modulated the developing immune system in male and female mice , and that more IgE was produced upon exposure to TMA in the adult .",
"Production and characterization of DB06681 , a variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin , in Pichia pastoris . Blocking the P10747 / P33681 costimulatory pathway is a promising strategy in the treatment of graft rejection , graft - versus - host disease and autoimmune diseases . DB06681 , a high - affinity variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin ( DB01281 ) , is a more potent inhibitor of the interaction between P10747 and P33681 than is DB01281 . In a previous study , DB06681 was produced in a mammalian cell system , which is time - consuming and expensive . To obtain DB06681 more efficiently and cost effectively , we attempted to produce DB06681 using a Pichia pastoris expression system . The gene encoding DB06681 , with an additional 6 - DB00117 tag at the N - terminus , was cloned into the yeast vector pPIC9K and expressed in the P . pastoris strain GS115 . Under the optimized induction conditions for protein expression ( inoculum density , OD ( 600 ) = 80 ; methanol concentration added daily , 1 . 0 - 3 . 0 % ; induction time point , 72 - 96 h ; culture medium pH = 6 . 0 ) , the yield of purified DB06681 was approximately 30 mg l (- 1 ) by one - step Ni - agarose affinity chromatography . Q96IV0 F treatment showed the purified DB06681 to be post - translational modified by N - linked glycosylation . In biological function assays , DB06681 expressed in P . pastoris demonstrated specific binding to P33681 - 1 / P33681 - 2 - positive Raji cells and also suppressed lymphocyte proliferation in a dose - dependent manner . These results suggest that DB06681 produced in P . pastoris is biologically active and will be useful for experimental therapy on immunotherapy for transplant rejection and autoimmune diseases .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK4___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"Costimulation blockade in autoimmunity and transplantation . Signaling through the costimulation receptors is a critical pathway in the regulation of T - cell activation . The selective costimulation inhibitor abatacept ( cytotoxic T lymphocyte - associated antigen 4 - Ig ) binds to P33681 and P42081 on antigen - presenting cells , blocking interaction with P10747 on T cells , and is approved for the treatment of moderate to severe rheumatoid arthritis . DB06681 ( DB06681 ) , currently enrolling phase III trials in renal transplantation , was rationally designed from abatacept to bind with more avidity to P42081 , providing the more potent immunosuppressive properties required for immunosuppression in transplantation . This review describes the relevant preclinical studies and summarizes recent clinical findings on these 2 molecules in autoimmune diseases and organ transplantation . Although both inhibit the P10747 costimulatory pathway , they are tailored for specific disease states -- abatacept for autoimmune diseases and belatacept for transplantation .",
"Association of sixty - one non - synonymous polymorphisms in forty - one hypertension candidate genes with blood pressure variation and hypertension . We previously selected a group of hypertension candidate genes by a key word search using the OMIM database of NCBI and validated 525 coding single nucleotide polymorphisms ( SNPs ) in 179 hypertension candidate genes by DNA sequencing in a Japanese population . In the present study , we examined the association between 61 non - synonymous SNPs and blood pressure variations and hypertension . We used DNA samples taken from 1 , 880 subjects in the Suita study , a population - based study using randomly selected subjects . Analyses of covariance adjusting for age , body mass index , hyperlipidemia , diabetes , smoking , drinking , and antihypertensive medication revealed that 17 polymorphisms in 16 genes ( P04114 , CAST , P51801 , O60931 , P10912 , P13807 , P08603 , O95163 , Q14654 , P11150 , P06858 , P41231 , Q15165 , P02730 , TRH , P04275 ) were significantly associated with blood pressure variations . Multivariate logistic regression analysis with adjustment for the same factors revealed that 11 polymorphisms in 11 genes ( CAST , P16410 , P12259 , GC , P10912 , P11150 , Q13093 , P02730 , SLCI8A1 , TRH , P04275 ) showed significant associations with hypertension . Five polymorphisms in five genes , CAST ( calpastatin ) , P11150 ( hepatic lipase ) , P02730 ( band 3 anion transporter ) , TRH ( thyrotropin - releasing hormone ) , and P04275 ( P04275 ) , were significantly associated with both blood pressure variation and hypertension . Thus , our study suggests that these five genes were susceptibility genes for essential hypertension in this Japanese population .",
"Mesenchymal stem cells control alloreactive CD8 (+) P10747 (-) T cells . P10747 / P33681 co - stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients . However , cells lacking P10747 are not susceptible to belatacept treatment . As CD8 (+) P10747 (-) T - cells have cytotoxic and pathogenic properties , we investigated whether DB05914 ( O60682 ) are effective in controlling these cells . In mixed lymphocyte reactions ( P08235 ) , O60682 and belatacept inhibited peripheral blood mononuclear cell ( PBMC ) proliferation in a dose - dependent manner . O60682 at O60682 / effector cell ratios of 1 : 160 and 1 : 2 · 5 reduced proliferation by 38 · 8 and 92 · 2 % , respectively . DB06681 concentrations of 0 · 1 μg / ml and 10 μg / ml suppressed proliferation by 20 · 7 and 80 · 6 % , respectively . Both treatments in combination did not inhibit each other ' s function . Allostimulated CD8 (+) P10747 (-) T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B , interferon ( IFN ) - γ and tumour necrosis factor ( P01375 ) - α . While belatacept did not affect the proliferation of CD8 (+) P10747 (-) T cells , O60682 reduced the percentage of P10747 (-) T cells in the proliferating CD8 (+) T cell fraction by 45 · 9 % ( P = 0 · 009 ) . CD8 (+) P10747 (-) T cells as effector cells in P08235 in the presence of P01730 (+) T cell help gained P10747 expression , an effect independent of O60682 . In contrast , allostimulated P10747 (+) T cells did not lose P10747 expression in P08235 - O60682 co - culture , suggesting that O60682 control pre - existing P10747 (-) T cells and not newly induced P10747 (-) T cells . In conclusion , alloreactive CD8 (+) P10747 (-) T cells that remain unaffected by belatacept treatment are inhibited by O60682 . This study indicates the potential of an O60682 - belatacept combination therapy to control alloreactivity ."
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___MASK70___
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MH_train_411
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interacts_with DB01012?
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[
"The opposite effects of P40933 and Q9HBE4 on CLL B cells correlate with differential activation of the JAK / P35610 and P27361 / 2 pathways . The clonal expansion of chronic lymphocytic leukemia ( CLL ) cells requires the interaction with the microenvironment and is under the control of several cytokines . Here , we investigated the effect of P40933 and Q9HBE4 , which are closely related to P60568 and share the usage of the common gamma chain and of its P52333 - associated pathway . We found remarkable differences in the signal transduction pathways activated by these cytokines , which determined different responses in CLL cells . P40933 caused cell proliferation and prevented apoptosis induced by surface IgM cross - linking . These effects were more evident in cells stimulated via surface P25942 , which exhibited increased cell expression of IL - 15Ralpha chain and , in some of the cases , also of IL - 2Rbeta . Q9HBE4 failed to induce CLL cell proliferation and instead promoted apoptosis . Following cell exposure to P40933 , phosphorylation of P42229 was predominantly observed , whereas , following stimulation with Q9HBE4 , there was predominant P42224 and P40763 activation . Moreover , P40933 but not Q9HBE4 caused an increased phosphorylation of Shc and P27361 / 2 . Pharmacological inhibition of P52333 or of MEK , which phosphorylates P27361 / 2 , efficiently blocked P40933 - induced CLL cell proliferation and the antiapoptotic effect of this cytokine . The knowledge of the signaling pathways regulating CLL cell survival and proliferation may provide new molecular targets for therapeutic intervention .",
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK88___ GITS , Diaprel MR ) . One daily dose of ___MASK88___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Novel strategies in drug discovery of the calcium - sensing receptor based on biased signaling . A hallmark of chronic kidney disease is hyperphosphatemia due to renal phosphate retention . Prolonged parathyroid gland exposure to hyperphosphatemia leads to secondary hyperparathyroidism characterized by hyperplasia of the glands and excessive secretion of parathyroid hormone ( PTH ) , which causes renal osteodystrophy . PTH secretion from the parathyroid glands is controlled by the calcium - sensing receptor ( P41180 ) that senses extracellular calcium . High extracellular calcium activates the P41180 causing inhibition of PTH secretion through multiple signaling pathways . DB01012 is the first drug targeting the P41180 and can be used to effectively control and reduce PTH secretion in PTH - related diseases . DB01012 is a positive allosteric modulator of the P41180 and affects PTH secretion from parathyroid glands by shifting the calcium - PTH concentration - response curve to the left . One major disadvantage of cinacalcet is its hypocalcemic side effect , which may be caused by increased P41180 - mediated calcitonin secretion from the thyroid gland . However , multiple studies indicate that PTH and calcitonin secretion are stimulated by different signaling pathways , and therefore it might be possible to develop a P41180 activating drug that selectively activates signaling pathways that inhibit PTH secretion while having no effect on signaling pathways involved in calcitonin secretion . Such a drug would have the same therapeutic value as cinacalcet in lowering PTH secretion while eliminating the side effect of hypocalcemia by virtue of it not affecting calcitonin secretion . The present review will focus on recent advancements in understanding signaling and biased signaling of the P41180 , and how that may be utilized to discover new and smarter drugs targeting the P41180 .",
"A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium . We investigated effect of hydrogen sulfide ( H ( 2 ) S ) on oxidative stress - caused cell death in gastric mucosal epithelial cells . In rat normal gastric epithelial RGM1 cells , NaHS , a H ( 2 ) S donor , at 1 . 5mM strongly suppressed hydrogen peroxide ( H ( 2 ) O ( 2 ) ) - caused cell death , while it slightly augmented the H ( 2 ) O ( 2 ) toxicity at 0 . 5 - 1mM . The protective effect of NaHS was abolished by inhibitors of MEK or JNK , but not of p38 Q96HU1 kinase . NaHS at 1 . 5mM actually phosphorylated P29323 and JNK in RGM1 cells . ___MASK86___ , an DB00171 - sensitive K (+) ( K ( DB00171 )(+) ) channel inhibitor , did not affect the protective effect of NaHS , although mRNAs for K ( DB00171 )(+) channel subunits , Kir6 . 1 and Q09428 , were detected in RGM1 cells . In anesthetized rats , oral administration of NaHS protected against gastric mucosal lesion caused by ischemia - reperfusion . These results suggest that NaHS / H ( 2 ) S may protect gastric mucosal epithelial cells against oxidative stress through stimulation of Q96HU1 kinase pathways , a therapeutic dose range being very narrow .",
"Agonists of the Q9H244 - receptor activate Q96HU1 kinase by a ras - independent pathway in rat P13671 glioma . We have previously shown that an ecto - NPPase modulates the DB00171 - and ADP - mediated Q9H244 - receptor activation in rat P13671 glioma . In the present study , 2MeSADP and Ap ( 3 ) A induced no detectable PI turnover and were identified as specific agonists of the Q9H244 - receptor with EC ( 50 ) values of 250 +/- 37 pM and 1 +/- 0 . 5 microM , respectively . Q9H244 - receptor stimulation increased Q96HU1 kinase ( P27361 / 2 ) activation that returned to the basal level 4 h after stimulation and was correlated with a gradual desensitization of the Q9H244 - purinoceptor . The purinoceptor antagonists DIDS and Q08999 blocked Q96HU1 kinase activation . An IP ( 3 )- independent Ca ( 2 +)- influx was observed after Q9H244 - receptor activation . Inhibition of this influx by Ca ( 2 +)- chelation , did not affect Q96HU1 kinase activation . Pertussis toxin , toxin B , selective PKC - inhibitors and a specific MEK - inhibitor inhibited the 2MeSADP - and Ap ( 3 ) A - induced Q96HU1 kinase activation . In addition , transfection with dominant negative RhoA ( Asn19 ) rendered P13671 cells insensitive to Q9H244 - receptor - mediated Q96HU1 kinase activation whereas dominant negative ras was without effect . Immunoprecipitation experiments indicated a significant increase in the phosphorylation of raf - 1 after Q9H244 - receptor activation . We may conclude that Q9H244 - purinoceptor agonists activate Q96HU1 kinase through a G ( i )- RhoA - PKC - raf - MEK - dependent , but ras - and Ca ( 2 +)- independent cascade .",
"Activation of P00533 promotes squamous carcinoma SCC10A cell migration and invasion via inducing EMT - like phenotype change and P14780 - mediated degradation of P12830 . P00533 is a potent stimulator of invasion and metastasis in head and neck squamous cell carcinomas ( HNSCC ) . However , the mechanism by which P00533 may stimulate tumor cell invasion and metastasis still need to be elucidated . In this study , we showed that activation of P00533 by P01133 in HNSCC cell line SCC10A enhanced cell migration and invasion , and induced loss of epitheloid phenotype in parallel with downregulation of P12830 and upregulation of P19022 and vimentin , indicating that P00533 promoted SCC10A cell migration and invasion possibly by an epithelial to mesenchymal transition ( EMT ) - like phenotype change . Interestingly , activation of P00533 by P01133 induced production of matrix metalloproteinase - 9 ( P14780 ) and soluble P12830 ( sE - cad ) , and knockdown of P14780 by siRNA inhibited sE - cad production induced by P01133 in SCC10A . Moreover , both P14780 knockdown and P12830 overexpression inhibited cell migration and invasion induced by P01133 in SCC10A . The results indicate that P00533 activation promoted cell migration and invasion through inducing P14780 - mediated degradation of P12830 into sE - cad . Pharmacologic inhibition of P00533 , MEK , and PI3K kinase activity in SCC10A reduced phosphorylated levels of P27361 / 2 and AKT , production of P14780 and sE - cad , cell migration and invasion , and expressional changes of EMT markers ( P12830 and P19022 ) induced by P01133 , indicating that P00533 activation promotes cell migration and invasion via P27361 / 2 and PI3K - regulated P14780 / P12830 signaling pathways . Taken together , the data suggest that P00533 activation promotes HNSCC SCC10A cell migration and invasion by inducing EMT - like phenotype change and P14780 - mediated degradation of P12830 into sE - cad related to activation of P27361 / 2 and PI3K signaling pathways .",
"Genetics of physical activity and physical inactivity in humans . Emerging evidence suggests that physical activity and sedentary behavior [ reflected in physical inactivity ( PI ) ] , might be two different phenotypes that may have distinct underlying physiological mechanisms . The purpose of this review is to summarize the existing literature on the genetic determinants of PA and PI phenotypes in humans , considering them as distinct behaviors . Completed in January 2011 , this review includes family studies , twin studies , association studies , genome - wide linkage studies and genome - wide association scan ( GWAs ) reporting different physical activity / inactivity - related phenotypes . In regards to PA , familial aggregation studies resulted in heritability estimates ranging from 0 to 60 % , and twin studies yielded heritability estimates ( a ( 2 ) ) and shared environment ( c ( 2 ) ) scores for PA phenotypes ranging from 0 . 00 to 0 . 85 and 0 . 00 to 0 . 84 , respectively . Unique environmental ( e ( 2 ) ) results are well dispersed from 0 . 12 to 0 . 72 . Suggestive linkages were found with markers nearby different activity - related genes : P24530 , P32245 , P25874 , P12104 , P41180 , Q8IVB4 . Significant associations with PA phenotypes were found for Ace , Gln223ARrg , P32245 and P14416 genes . We found one GWAs that reported novel SNPs in the O95340 gene on chromosome 10q23 . 2 and in two intergenic regions on chromosomes 2q33 . 1 and 18p11 . 32 . Heritability estimates for PI ranged from 25 to 60 % and linkage studies recorded higher LOD scores for PI versus PA . The P12821 genotype was strongly associated with PI . There are potentially different genetic influences on PA versus PI phenotypes . Future studies should focus on the different genetic influences on PA and PI to improve our understanding of underlying determinants of these behaviors .",
"[ Vascular Calcification - Pathological Mechanism and Clinical Application - . The effect of cinacalcet on vascular calcification ] . DB01012 acts on calcium receptors ( CaR ) expressed on chief cells of the parathyroid gland to inhibit the secretion of parathyroid hormone ( PTH ) . This drug inhibits PTH secretion without causing an elevation of serum calcium and phosphorus , unlike active vitamin D . Several experimental studies demonstrated an inhibitory effect of calcimimetics on the progression of vascular calcification in animals with chronic kidney disease ( CKD ) , in keeping with the expression of the calcium - sensing receptor ( P41180 ) in vascular tissue . The EVOLVE , evaluated in patients with CKD 5D the effects of the cinacalcet on the progression of vascular calcification and hard cardiovascular outcomes , respectively . The EVOLVE trials missed their respective primary end point by intent - to - treat analysis . However , recently , in order to define the frequency of fatal and nonfatal cardiovascular events attributable to atherosclerotic and nonatherosclerotic mechanisms , risk factors for these events , and the effects of cinacalcet , post hoc analysis using adjudicated data collected during the EVOLVE Trial were perfomed . In this trial , combining fatal and nonfatal cardiovascular events , randomization to cinacalcet reduced the rates of sudden death and heart failure . Patients randomized to cinacalcet experienced fewer nonatherosclerotic cardiovascular events , while the effect of cinacalcet on atherosclerotic events did not reach statistical significance .",
"Characterization and functional analysis of cis - acting elements of the human farnesyl diphosphate synthetase ( P14324 ) gene 5 ' flanking region . Farnesyl diphosphate synthetase ( P14324 ) is a key enzyme in the isoprenoid pathway responsible for cholesterol biosynthesis , post - translational protein modifications and synthesis of steroid hormones , whose expression is regulated by phorbol esters and polyunsaturated fatty acids . Genomic comparison of the 5 ' upstream sequence of the P14324 genes identifies conserved binding sites for NF - Y , SP1 , SRE3 , and P25490 regulatory elements in rat , mouse , dog and chimpanzee . Two additional specific consensus sequences , upstream of the core promoter that had not been analysed previously , are shared only by human and chimpanzee genomes . The work presented here aimed at characterizing these genomic sequence elements in the human P14324 promoter region and their contribution to gene expression . We have characterized functionally the minimal basal promoter of the human P14324 gene by means of deletion mutants and we have identified two cis - acting elements which modulate the P14324 gene expression and are recognized by Pax5 and O75051 - 1 transcription factors .",
"P04150 and sequential P04637 activation by dexamethasone mediates apoptosis and cell cycle arrest of osteoblastic MC3T3 - E1 cells . Glucocorticoids play a pivotal role in the proliferation of osteoblasts , but the underlying mechanism has not been successfully elucidated . In this report , we have investigated the molecular mechanism which elucidates the inhibitory effects of dexamethasone on murine osteoblastic MC3T3 - E1 cells . It was found that the inhibitory effects were largely attributed to apoptosis and P55008 phase arrest . Both the cell cycle arrest and apoptosis were dependent on glucocorticoid receptor ( GR ) , as they were abolished by GR blocker ___MASK4___ pre - treatment and GR interference . P55008 phase arrest and apoptosis were accompanied with a p53 - dependent up - regulation of P38936 and pro - apoptotic genes Q13794 and PUMA . We also proved that dexamethasone ca n ' t induce apoptosis and cell cycle arrest when p53 was inhibited by p53 RNA interference . These data demonstrate that proliferation of MC3T3 - E1 cell was significantly and directly inhibited by dexamethasone treatment via aberrant GR activation and subsequently P04637 activation .",
"P06748 - Q9UM73 oncogenic kinase promotes cell - cycle progression through activation of JNK / cJun signaling in anaplastic large - cell lymphoma . Anaplastic large - cell lymphoma ( ALCL ) frequently carries the t ( 2 ; 5 )( p23 ; q35 ) , resulting in aberrant expression of nucleophosmin - anaplastic lymphoma kinase ( P06748 - Q9UM73 ) . We show that in 293T and Jurkat cells , forced expression of active P06748 - Q9UM73 , but not kinase - dead mutant P06748 - Q9UM73 ( 210K > R ) , induced JNK and cJun phosphorylation , and this was linked to a dramatic increase in AP - 1 transcriptional activity . Conversely , inhibition of Q9UM73 activity in P06748 - Q9UM73 (+) ALCL cells resulted in a concentration - dependent dephosphorylation of JNK and cJun and decreased AP - 1 DNA - binding . In addition , JNK physically binds P06748 - Q9UM73 and is highly activated in cultured and primary P06748 - Q9UM73 (+) ALCL cells . cJun phosphorylation in P06748 - Q9UM73 (+) ALCL cells is mediated by JNKs , as shown by selective knocking down of P45983 and P45984 genes using siRNA . Inhibition of JNK activity using SP600125 decreased cJun phosphorylation and AP - 1 transcriptional activity and this was associated with decreased cell proliferation and G2 / M cell - cycle arrest in a dose - dependent manner . Silencing of the cJun gene by siRNA led to a decreased S - phase cell - cycle fraction associated with upregulation of P38936 and downregulation of cyclin D3 and cyclin A . Taken together , these findings reveal a novel function of P06748 - Q9UM73 , phosphorylation and activation of JNK and cJun , which may contribute to uncontrolled cell - cycle progression and oncogenesis .",
"DB01373 - sensing receptor activation in chronic kidney disease : effects beyond parathyroid hormone control . Secondary hyperparathyroidism ( SHPT ) is an important complication of advanced chronic kidney disease ( CKD ) . DB01012 , an allosteric modulator of the calcium - sensing receptor ( P41180 ) expressed in parathyroid glands , is the only calcimimetic approved to treat SHPT in patients on dialysis . By enhancing P41180 sensitivity for plasma extracellular calcium ( Ca ( 2 +) 0 ) , cinacalcet reduces serum parathyroid hormone , Ca ( 2 +) 0 , and serum inorganic phosphorous concentrations , allowing better control of SHPT and CKD - mineral and bone disorders . Of interest , the P41180 also is expressed in a variety of tissues where its activation regulates diverse cellular processes , including secretion , apoptosis , and proliferation . Thus , the existence of potential off - target effects of cinacalcet can not be neglected . This review summarizes our current knowledge concerning the potential role ( s ) of the P41180 expressed in various tissues in CKD - related disorders , independently of parathyroid hormone control .",
"Behind the curtain : cellular mechanisms for allosteric modulation of calcium - sensing receptors . DB01373 - sensing receptors ( P41180 ) are integral to regulation of systemic Ca ( 2 +) homeostasis . Altered expression levels or mutations in P41180 cause Ca ( 2 +) handling diseases . P41180 is regulated by both endogenous allosteric modulators and allosteric drugs , including the first Food and Drug Administration - approved allosteric agonist , DB01012 HCl ( Sensipar ® ) . Recent studies suggest that allosteric modulators not only alter function of plasma membrane - localized P41180 , but regulate P41180 stability at the endoplasmic reticulum . This brief review summarizes our current understanding of the role of membrane - permeant allosteric agonists in cotranslational stabilization of P41180 , and highlights additional , indirect , signalling - dependent role ( s ) for membrane - impermeant allosteric drugs . Overall , these studies suggest that allosteric drugs act at multiple cellular organelles to control receptor abundance and hence function , and that drug hydrophobicity can bias the relative contributions of plasma membrane and intracellular organelles to P41180 abundance and signalling .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK11___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"P14416 signaling dynamics of dopamine D2 - neurotensin 1 receptor heteromers . Biochemical , histochemical and coimmunoprecipitation experiments have indicated the existence of antagonistic dopamine D2 ( D2R ) and neurotensin 1 ( NTS1R ) receptor - receptor interactions in the dorsal and ventral striatum indicating a potential role of these receptor - receptor interactions in Parkinson ' s disease and schizophrenia . By means of Bioluminiscence Resonance energy transfer ( BRET ( 2 ) ) evidence has for the first time been obtained in the current study for the existence of both D2LR / NTS1R and D2SR / NTS1R heteromers in living HEK293T cells . Through confocal laser microscopy the NTS1R ( GFP2 ) and D2R ( YFP ) were also shown to be colocated in the plasma membrane of these cells . A bioinformatic analysis suggests the existence of a basic set of three homology protriplets ( TVM , DLL and / or LRA ) in the two participating receptors which may contribute to the formation of the D2R / NTS1R heteromers by participating in guide - clasp interactions in the receptor interface . The CREB reporter gene assay indicated that the neurotensin receptor agonist JMV 449 markedly reduced the potency of the D2R like agonist quinpirole to inhibit the forskolin induced increase of the CREB signal . In contrast , the neurotensin agonist was found to markedly increase the quinpirole potency to activate the MAPK pathway as also studied with luciferase reporter gene assay measuring the degree of SRE activity as well as with P27361 / 2 phosphorylation assays . These dynamic changes in D2R signaling produced by the neurotensin receptor agonist may involve antagonistic allosteric receptor - receptor interactions in the D2LR - NTS1R heteromers at the plasma membrane level ( CREB pathway ) and synergistic interactions in PKC activation at the cytoplasmatic level ( MAPK pathway ) .",
"Calcimimetic and calcilytic drugs for treating bone and mineral - related disorders . The calcium - sensing receptor ( P41180 ) plays a pivotal role in regulating systemic Ca ( 2 +) homeostasis and is a target for drugs designed to treat certain disorders of bone and mineral metabolism . Calcimimetics are agonists or positive allosteric modulators of the P41180 ; they inhibit parathyroid hormone ( PTH ) secretion and stimulate renal Ca ( 2 +) excretion . The first calcimimetic drug is cinacalcet , a positive allosteric modulator of the P41180 that is approved for treating secondary hyperparathyroidism ( Q9HD23 ) in patients on renal replacement therapy and for some forms of primary Q9HD23 characterized by clinically significant hypercalcemia . DB01012 is also being investigated as a therapy for other hypercalcemic conditions and certain hypophosphatemic disorders . Calcilytics are P41180 inhibitors that stimulate the secretion of PTH and decrease renal excretion of Ca ( 2 +) . Although calcilytics have failed thus far as anabolic therapies for osteoporosis , they are currently being evaluated as novel therapies for new indications involving hypocalcemia and / or hypercalciuria .",
"P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK4___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .",
"Enhancement of the P11362 signaling in the P11362 - P08908 heteroreceptor complex in midbrain raphe 5 - HT neuron systems . Relevance for neuroplasticity and depression . New findings show existence of P11362 - P08908 heteroreceptor complexes in 5 - HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus . Synergistic receptor - receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity . The existence of P11362 - P08908 heteroreceptor complexes also in midbrain raphe 5 - HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5 - HT levels can cause an activation of the P09038 / P11362 mechanism in these nerve cells as well . Therefore , the agonist modulation of the P11362 - P08908 heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5 - HT nerve cells . The combined i . c . v . treatment with P09038 and the P08908 agonist 8 - OHDPAT synergistically increased P11362 and P27361 / 2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells . Cotreatment with P09038 and the P08908 agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5 - HT immunoreactivity . These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the P08908 receptor . Taken together , the P08908 autoreceptors by being part of a P11362 - P08908 heteroreceptor complex in the midbrain raphe 5 - HT nerve cells appears to have also a trophic role in the central 5 - HT neuron systems besides playing a key role in reducing the firing of these neurons .",
"Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .",
"Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .",
"Clinical utility of calcimimetics targeting the extracellular calcium - sensing receptor ( P41180 ) . Calcimimetics , which activate the extracellular calcium ( Ca ( o )( 2 +) ) - sensing receptor in the parathyroid and other tissues participating in Ca ( o )( 2 +) homeostasis , were the first described allosteric activators of a G - protein - coupled receptor . DB01012 , the only calcimimetic currently approved for human use , is used clinically for treating secondary hyperparathyroidism ( e . g . , overactivity of parathyroid glands ) in patients being dialyzed for chronic kidney disease . By sensitizing the parathyroids to Ca ( o )( 2 +) , cinacalcet lowers the circulating parathyroid hormone ( PTH ) level . It also reduces serum calcium and phosphate , changes increasing the percentage of patients achieving the guidelines recommended by the National Kidney Foundation ( NKF ) for these minerals . Studies are underway addressing whether better adherence to these guidelines in patients receiving cinacalcet reduces cardiovascular disease and related mortality , which are both common is the dialysis population . The second approved use of cinacalcet is for treating hypercalcemia in patients with inoperable parathyroid carcinoma . In this setting , it provides the first medical therapy chronically lowering serum calcium concentration in this condition , albeit not to normal in most patients . Its effect on the long - term prognosis of these patients , if any , is presently unclear . \" Off - label \" administration of cinacalcet [ i . e . , not yet approved by the US Food and Drug Administration ( FDA ) ] effectively lowers serum calcium and / or PTH in various other forms of hyperparathyroidism and increases serum phosphate in renal phosphate - wasting syndromes by reducing PTH - induced phosphaturia . In the future , the drug could conceivably be utilized to modulate the activity of the P41180 in other tissues ( i . e . , kidney , colon ) in therapeutically desirable ways .",
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK70___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"Impact of clinically relevant mutations on the pharmacoregulation and signaling bias of the calcium - sensing receptor by positive and negative allosteric modulators . DB01012 is predominantly used to treat secondary hyperparathyroidism due to end - stage renal failure , but , more recently , its potential clinical efficacy in treating patients with loss - of - function mutations in the calcium - sensing receptor ( P41180 ) has been recognized . Many clinically relevant P41180 mutations are located in the heptahelical membrane spanning and extracellular loop regions of the receptor , where allosteric modulators are predicted to bind . The aim of the present study was to investigate the impact of such mutations on the pharmacoregulation of the P41180 by the positive and negative allosteric modulators , cinacalcet and P0C0P6 - 2143 , respectively . Both cinacalcet and P0C0P6 - 2143 effectively rescued mutants whose cell surface expression was substantially impaired , suggesting that both classes of drug can stabilize a receptor conformation that is trafficked more effectively to the cell surface . In addition , functional impairments in almost all mutant CaSRs were rescued by either cinacalcet or P0C0P6 - 2143 via restoration of intracellular signaling . There was a significantly greater ability of both compounds to modulate agonist - stimulated intracellular Ca ( 2 +) mobilization than P27361 / 2 phosphorylation , indicating that the allosteric modulators engender bias in agonist - stimulated P41180 signaling to different pathways . Three mutations ( G ( 670 ) R , P ( 748 ) R , and L ( 773 ) R ) altered the binding affinity of allosteric modulators to the P41180 , and 3 mutations ( V ( 817 ) I , L ( 773 ) R , and E ( 767 ) K ) altered the cooperativity between the allosteric modulator and Ca ( 2 +)( o ) . These findings have important implications for the treatment of diseases associated with P41180 mutations using allosteric P41180 modulators and for analyzing the effects of mutations on the function and pharmacoregulation of the P41180 .",
"Direct maxacalcitol injection into hyperplastic parathyroids improves skeletal changes in secondary hyperparathyroidism . Direct maxacalcitol ( O75051 ) injection into a parathyroid gland ( PTG ) ameliorates several important etiologic factors of resistance to medical treatments for secondary hyperparathyroidism ( s - Q9HD23 ) : the upregulations of vitamin D receptor ( P11473 ) and Ca - sensing receptor ( P41180 ) in PTGs and the regression of PTG hyperplasia by the induction of apoptosis . In this study , we evaluated the bone histomorphology on the basis of maintaining these effects in advanced s - Q9HD23 . Five / six nephrectomized Sprague - Dawley rats were fed a high - phosphorus and low - calcium diet for 8 weeks . These rats were divided into four treatment groups : ( 1 ) basic uremic ( at the baseline ) , ( 2 ) direct O75051 single injection into PTGs ( DI - O75051 ) followed by O75051 intravenous administration for 4 weeks ( IV - O75051 ) , ( 3 ) direct vehicle injection and IV - O75051 , and ( 4 ) no treatment for an additional 4 weeks . The effects of these treatments on serum intact - parathyroid hormone ( PTH ) level , PTG weight , P11473 and P41180 expression levels in PTGs , and bone histomorphometric parameters were investigated . In the DI - O75051 + IV - O75051 group , the significant decrease in serum intact - PTH level was maintained by the following IV - O75051 . A significant decrease in PTG weight and the upregulations of P11473 and P41180 expression levels in PTGs were also observed . Bone histomorphometric analysis showed significant improvements in osteitis fibrosa in both cancellous and cortical bones . However , these findings were not observed in the other groups . These results suggest that osteitis fibrosa caused by advanced s - Q9HD23 can be successfully reversed by a control of PTH at an appropriate level through the improvement of PTG hyperplasia as induced by DI - O75051 + IV - O75051 .",
"Improved methodical approach for quantitative BRET analysis of G Protein Coupled Receptor dimerization . G Protein Coupled Receptors ( GPCR ) can form dimers or higher ordered oligomers , the process of which can remarkably influence the physiological and pharmacological function of these receptors . Quantitative Bioluminescence Resonance Energy Transfer ( qBRET ) measurements are the gold standards to prove the direct physical interaction between the protomers of presumed GPCR dimers . For the correct interpretation of these experiments , the expression of the energy donor Renilla luciferase labeled receptor has to be maintained constant , which is hard to achieve in expression systems . To analyze the effects of non - constant donor expression on qBRET curves , we performed Monte Carlo simulations . Our results show that the decrease of donor expression can lead to saturation qBRET curves even if the interaction between donor and acceptor labeled receptors is non - specific leading to false interpretation of the dimerization state . We suggest here a new approach to the analysis of qBRET data , when the BRET ratio is plotted as a function of the acceptor labeled receptor expression at various donor receptor expression levels . With this method , we were able to distinguish between dimerization and non - specific interaction when the results of classical qBRET experiments were ambiguous . The simulation results were confirmed experimentally using rapamycin inducible heterodimerization system . We used this new method to investigate the dimerization of various GPCRs , and our data have confirmed the homodimerization of V2 vasopressin and P41180 calcium sensing receptors , whereas our data argue against the heterodimerization of these receptors with other studied GPCRs , including type I and II angiotensin , β2 adrenergic and P21554 cannabinoid receptors .",
"DB01012 HCl prevents development of parathyroid gland hyperplasia and reverses established parathyroid gland hyperplasia in a rodent model of CKD . BACKGROUND : Secondary hyperparathyroidism ( sHPT ) represents an adaptive response to progressively impaired control of calcium , phosphorus and vitamin D in chronic kidney disease ( CKD ) . It is characterized by parathyroid hyperplasia and excessive synthesis and secretion of parathyroid hormone ( PTH ) . Parathyroid hyperplasia in uremic rats can be prevented by calcium - sensing receptor ( P41180 ) activation with the calcimimetic cinacalcet ( Sensipar ®/ Mimpara ® ) ; however , it is unknown , how long the effects of cinacalcet persist after withdrawal of treatment or if cinacalcet is efficacious in uremic rats with established sHPT . METHODS : We sought to determine the effect of cinacalcet discontinuation in uremic rats and whether cinacalcet was capable of influencing parathyroid hyperplasia in animals with established sHPT . RESULTS : Discontinuation of cinacalcet resulted in reversal of the beneficial effects on serum PTH and parathyroid hyperplasia . In rats with established sHPT , cinacalcet decreased serum PTH and mediated regression of parathyroid hyperplasia . The cinacalcet - mediated decrease in parathyroid gland size was accompanied by increased expression of the cyclin - dependent kinase inhibitor P38936 . Prevention of cellular proliferation with cinacalcet occurred despite increased serum phosphorus and decreased serum calcium . CONCLUSIONS : The animal data provided suggest established parathyroid hyperplasia can be reversed by modulating P41180 activity with cinacalcet and that continued treatment may be necessary to maintain reductions in PTH .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"___MASK86___ exerts an antitumor activity through reactive oxygen species - c - jun NH2 - terminal kinase pathway in human gastric cancer cell line MGC - 803 . ___MASK86___ , a blocker of DB00171 - sensitive potassium ( K ( DB00171 ) ) channels , can suppress progression of many cancers , but the involved mechanism is unclear . Herein we reported that MGC - 803 cells expressed the K ( DB00171 ) channels composed of Kir6 . 2 and Q09428 subunits . ___MASK86___ induced cellular viability decline , coupled with cell apoptosis and reactive oxygen species ( ROS ) generation in MGC - 803 cells . Meanwhile , glibenclamide increased NADPH oxidase catalytic subunit gp91 ( phox ) expression and superoxide anion ( O2 - ) generation , and caused mitochondrial respiration dysfunction in MGC - 803 cells , suggesting that glibenclamide induced an increase of ROS derived from NADPH oxidase and mitochondria . ___MASK86___ could also lead to loss of mitochondrial membrane potential , release of cytochrome c and apoptosis - inducing factor ( O95831 ) , and activation of c - jun NH2 - terminal kinase ( JNK ) in MGC - 803 cells . Pretreatment with antioxidant N - acetyl - l - cysteine ( Q9C000 ) prevented glibenclamide - induced JNK activation , apoptosis and cellular viability decline . Furthermore , glibenclamide greatly decreased the cellular viability , induced apoptosis and inhibited Akt activation in wild - type mouse embryonic fibroblast ( MEF ) cells but not in P45983 -/- or P45984 -/- MEF cells . Taken together , our study reveals that glibenclamide exerts an antitumor activity in MGC - 803 cells by activating ROS - dependent , JNK - driven cell apoptosis . These findings provide insights into the use of glibenclamide in the treatment of human gastric cancer .",
"DB01012 Treatment in an Adolescent With Concurrent 22q11 . 2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by P53680 Mutation . CONTEXT : The 22q11 . 2 deletion syndrome ( DS ) is a common multiple anomaly syndrome in which typical features include congenital heart defects , facial dysmorphism , and palatal anomalies . Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia , but hypercalcemia has not previously been reported in 22q11 . 2 DS . CASE DESCRIPTION : Our patient is a 16 - year - old adolescent male with dysmorphic facial features and delayed motor and speech development . At 2 years of age , 22q11 . 2 DS was confirmed by fluorescence in situ hybridization . In contrast to hypoparathyroidism that is usually seen in 22q11 . 2 DS , this patient had early childhood - onset hypercalcemia with inappropriately high PTH levels and hypocalciuria . Genomic DNA was obtained from the proband and screened for calcium - sensing receptor ( P41180 ) mutations with negative results . No parathyroid tissue could be localized by imaging or surgical exploration . As a result of symptomatic hypercalcemia , the patient was treated with a calcimimetic ( cinacalcet ) . During the treatment , plasma calcium normalized with mild symptoms of hypocalcemia . After discontinuation of cinacalcet , calcium returned to high pretreatment levels . Further DNA analysis of adaptor protein - 2 σ subunit ( P53680 ) showed a heterozygous missense mutation c . 44 G > T , resulting in a p . R15L substitution ; the mutation was absent in the healthy parents and two siblings . CONCLUSIONS : Hypercalcemia in our patient with 22q11 . 2 DS could be explained by the de novo mutation in P53680 . Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK19___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"P62158 regulates Ca2 +- sensing receptor - mediated Ca2 + signaling and its cell surface expression . The Ca ( 2 +)- sensing receptor ( P41180 ) is a member of family C of the GPCRs responsible for sensing extracellular Ca ( 2 +) ( [ Ca ( 2 +)]( o ) ) levels , maintaining extracellular Ca ( 2 +) homeostasis , and transducing Ca ( 2 +) signaling from the extracellular milieu to the intracellular environment . In the present study , we have demonstrated a Ca ( 2 +)- dependent , stoichiometric interaction between P62158 and a P62158 - binding domain ( CaMBD ) located within the C terminus of P41180 ( residues 871 - 898 ) . Our studies suggest a wrapping around 1 - 14 - like mode of interaction that involves global conformational changes in both lobes of P62158 with concomitant formation of a helical structure in the CaMBD . More importantly , the Ca ( 2 +)- dependent association between P62158 and the C terminus of P41180 is critical for maintaining proper responsiveness of intracellular Ca ( 2 +) responses to changes in extracellular Ca ( 2 +) and regulating cell surface expression of the receptor .",
"New insights into the role of calcium - sensing receptor activation . The discovery of the calcium - sensing receptor ( P41180 ) prompted the identification of substances that affect its function . DB01012 , for example , is a drug that allosterically modifies the receptor so as to increase its sensitivity to circulating calcium ( thus the name \" calcimimetic \" ) and in this way decreases parathyroid hormone secretion . Clinical use of cinacalcet is already approved for the treatment of primary and secondary hyperparathyroidism , but research is ongoing to identify further potential actions of this drug . The effects and functions of the P41180 have been evaluated in different systems and tissues , beyond parathyroid glands , such arterial walls . A complete understanding of the properties of calcimimetics are of obvious clinical interest , since therapeutic indications may be affected accordingly .",
"Chronic inhibition of farnesyl pyrophosphate synthase attenuates cardiac hypertrophy and fibrosis in spontaneously hypertensive rats . P14324 ( FPPS ) , an essential enzyme in the mevalonate pathway , was reported to be upregulated in young spontaneously hypertensive rats ( SHR ) when compared with Wistar - Kyoto ( WKY ) rats , and this was accompanied by development of left ventricular hypertrophy . Five - week - old rats were daily gavaged with vehicle or an FPPS inhibitor ( alendronate , 1 or 10 mg / kg ) and blood pressures was monitored by the tail - cuff method every other week . Twelve weeks of alendronate treatment attenuated the left ventricular weight to body weight ratio ( LVW / BW ) , hydroxyproline content , collagen deposition in the interstitia , and gene expression of atrial natriuretic peptide , B - type natriuretic peptide , and procollagen type I / III in the SHR left ventricle , all of which were significantly higher in SHRs than in WKY rats . Furthermore , long - term treatment with an FPPS inhibitor significantly reduced RhoA activation , P29323 phosphorylation , and TGF - beta1 expression in the SHR left ventricle , all of which were upregulated more in SHRs than in WKY rats . In conclusion , chronic treatment with an FPPS inhibitor attenuates the development of cardiac hypertrophy and fibrosis , and the suppression of P27361 / 2 phosphorylation and TGF - beta1 expression with inhibition of RhoA activation may be an important mechanism .",
"Epithelial calcium - sensing receptor activation by eosinophil granule protein analog stimulates collagen matrix contraction . BACKGROUND : Eosinophils reside in normal gastrointestinal tracts and increase during disease states . Receptors for eosinophil - derived granule proteins ( EDGPs ) have not been identified , but highly cationic molecules , similar to eosinophil proteins , bind extracellular calcium - sensing receptors ( CaSRs ) . We hypothesized that stimulation of CaSRs by eosinophil proteins activates epithelial cells . METHODS : Caco2 intestinal epithelial cells , AML14 . 3D10 eosinophils , wild - type ( WT ) human embryonic kidney 293 ( HEK293 ) cells not expressing CaSRs ( P29320 - WT ) , and P41180 - transfected HEK293 cells ( P29320 - P41180 ) were stimulated with an eosinophil protein analog poly - L - arginine ( PA ) and phosphorylated extracellular signal - regulated kinase ( pERK ) 1 and pERK2 were measured . Functional activation was measured with collagen lattice contraction assays . RESULTS : Coculture of Caco2 cells with AML14 . 3D10 eosinophils augmented lattice contraction as compared with lattices containing Caco2 cells alone . PA stimulation of Caco2 lattices augmented contraction . P29320 - P41180 stimulation with PA or Ca ( 2 +) resulted in greater pERK activation than that of stimulated P29320 - WT cells . PA stimulated greater P29320 - P41180 lattice contraction than unstimulated lattices . Contraction of PA - stimulated and PA - unstimulated P29320 - WT lattices did not differ . CONCLUSION : Exposure of intestinal epithelia to the EDGP analog PA stimulates P41180 - dependent P29323 phosphorylation and epithelial - mediated collagen lattice contraction . We speculate that EDGP release within the epithelial layers activates the P41180 receptor , leading to matrix contraction and tissue fibrosis .",
"The calcium - sensing receptor -- a driver of colon cell differentiation . Dietary Ca ( 2 +) reduces colon cell proliferation and carcinogenesis , but it becomes ineffective or even tumor - promoting during carcinogenesis . It appears that Ca ( 2 +) and the colon cell P41180 together brake the massive cell production in normal colon crypts . The rapid proliferation of the transit - amplifying ( TA ) progeny of the colon stem cells at the bases of the crypts is driven by the \" Wnt \" signaling mechanism that stimulates proliferogenic genes and prevents apoptogenesis . It appears that TA cell cycling stops and terminal differentiation starts when the cells reach a higher level in the crypt where there is enough external Ca ( 2 +) to stimulate the expression of CaSRs , the signals from which stimulate the expression of P12830 . At this point the P25054 ( adenomatous polyposis coli ) protein appears and some of it enters the nucleus . There it removes the apoptogenesis shield and stops the beta - cateninTcf - 4 complex from driving further TA cell proliferation by releasing beta - catenin from the nucleus , and delivering it to cytoplasmic APCaxinGSK - 3beta complexes for ultimate proteasomal destruction . Cytoplasmic beta - catenin is prevented from returning to the nucleus by destruction in APCaxinGSK - 3beta complexes or locked by the emerging P12830 into adherens junctions which link the cell to proliferatively shut - down functioning cells with P25054 - dependent cytoskeletons moving up and out of the crypt . A common first step in colon carcinogenesis is the loss of functional P25054 which results in the retention of proliferogenic nuclear beta - cateninTcf - 4 . This drives the eventual appearance of mutation accumulating , apoptosis - resistant clones the proliferation of which can not be inhibited by external Ca ( 2 +) because of P41180 - disabling gene mutations .",
"P40763 regulates proliferation and survival of CD8 + T cells : enhances effector responses to HSV - 1 infection , and inhibits P22301 + regulatory CD8 + T cells in autoimmune uveitis . P40763 regulates P01730 + T cell survival and differentiation . However , its effects on CD8 + T cells are not well understood . Here , we show that in comparison to WT CD8 + T cells , P40763 - deficient CD8 + T cells exhibit a preactivated memory - like phenotype , produce more P60568 , proliferate faster , and are more sensitive to activation - induced cell death ( AICD ) . The enhanced proliferation and sensitivity to AICD correlated with downregulation of class - O forkhead transcription factors ( FoxO1 , FoxO3A ) , P38936 ( waf1 ) , p27 ( P46527 ) , Bcl - 2 , OX - 40 , and upregulation of P48023 , Bax , and Bad . We examined whether P40763 - deficient CD8 + T cells can mount effective response during herpes simplex virus ( HSV - 1 ) infection and experimental autoimmune uveitis ( EAU ) . Compared to WT mice , HSV - 1 - infected P40763 - deficient mice ( STAT3KO ) produced less IFN - γ and virus - specific KLRG - 1 + CD8 + T cells . STAT3KO mice are also resistant to EAU and produced less Q16552 - producing Tc17 cells . Resistance of STAT3KO to EAU correlated with marked expansion of P22301 - producing regulatory CD8 + T cells ( CD8 - Treg ) implicated in recovery from autoimmune encephalomyelitis . Thus , increases of P05231 - induced P40763 activation observed during inflammation may inhibit expansion of CD8 - Tregs , thereby impeding recovery from uveitis . These results suggest that P40763 is a potential therapeutic target for upregulating CD8 + T cell - mediated responses to viruses and suggest the successful therapeutic targeting of P40763 as treatment for uveitis , derived , in part , from promoting CD8 - Treg expansion .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK41___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"Pharmacology of the calcium sensing receptor . DB01373 sensing receptor ( P41180 ) is a G - protein couple receptor which plays a key role in calcium homeostasis in vertebrates . Its extracellular domain is sensitive to divalent cations , aminoacids and polyamines . In parathyroid glands , P41180 activation causes parathyroid hormone ( PTH ) reduction and subsequently a decrease in blood calcium concentration . In PTH - dependent disorders , e . g . primary and secondary hyperparathyroidism ( Q9HD23 ) , the need for therapeutic options other than surgery led to the synthesis of various allosteric P41180 agonists ( calcimimetics ) , such as cinacalcet . DB01012 is the only calcimimetic approved for Q9HD23 secondary to chronic kidney disease ( CDK ) , parathyroid carcinoma , and , in some countries , primary Q9HD23 . Clinical trials showed that cinacalcet reduced PTH and calcemia both in CDK and primary Q9HD23 , lowering the risk of bone fractures , surgery , and cardiovascular complications in the former patients . Long - term safety and pharmacoeconomics have to be fully tested yet . Few both in vitro and in vivo studies showed an association between Arg990Gly - P41180 polymorphism and cinacalcet sensitivity , though in patients with severe P41180 inactivating mutations the drug substantially retained its positive clinical effects . Recently , a new class of allosteric antagonists of P41180 , i . e . calcilytics , has been synthesized . Calcilytics are structurally similar to calcimimetics , but exert their effects acting on a different allosteric site . Infusion of calcilytics was followed by transient rise in PTH and calcium . One of these compounds , DB05255 , was able to increase femur BMD in post menopausal women , but with induction of mild hyperparathyroidism . In the future , calcilytics may contribute to the osteoporosis treatment choice .",
"Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts . We have investigated gene expression profiles of human ovarian carcinomas in vivo during DB01229 ( R ) ( paclitaxel ) treatment and observed a difference in expression . Nude mice bearing 1A9 or 1A9PTX22 xenografts were given 60 mg / kg of paclitaxel . Therapeutic efficacy was achieved for 1A9 , while 1A9PTX22 did not respond . Tumor tissues harvested 4 and 24 h after treatment were evaluated by cDNA microarray against untreated tumors . Paclitaxel caused the modulation of more genes in 1A9 than in 1A9PTX22 tumors , in accordance to their therapeutic response . Most gene expression alterations were detected 24 h after paclitaxel administration and affected genes involved in various biological functions including cell cycle regulation and cell proliferation ( P06493 , P38936 , Q99988 , and P11388 ) , apoptosis ( Q12983 and O14681 ) , signal transduction and transcriptional regulation ( P84077 , P15336 , P01100 , P29992 , O15379 , Q15796 , O43623 , and Q9C004 ) , fatty acid biosynthesis and sterol metabolism ( P14324 , Q13907 , P38571 , and O75845 ) , and IFN - mediated signaling ( P09912 , Q16666 , P40305 , P13164 , and P05161 ) . The modulation of two representative genes , P38936 and P11388 , was validated by Northern analyses on a panel of seven ovarian carcinoma xenograft models undergoing treatment with paclitaxel . We found that the changes in expression level of these genes was strictly associated with the responsiveness to paclitaxel . Our study shows the feasibility of obtaining gene expression profiles of xenografted tumor models as a result of drug exposure . This in turn might provide insights related to the drugs ' action in vivo that will anticipate the response to treatment manifested by tumors and could be the basis for novel approaches to molecular pharmacodynamics .",
"Calcimimetics in the chronic kidney disease - mineral and bone disorder . Mineral and bone disorders ( MBD ) are both an early and very common complication of chronic kidney disease ( CKD ) . It is now accepted that they represent a significant risk factor , explaining the high cardiovascular morbidity and mortality in CKD patients . During the last decade , we have been witnessing many advances in the nomenclature , classification , pathophysiology , diagnosis , and treatment of CKD and some of its complications , such as CKD - MBD . The identification of the calcium - sensing receptor ( P41180 ) involvement in the pathogenesis of primary and secondary hyperparathyroidism ( SHPT ) and the availability of a new class of drugs called calcimimetics are two outstanding examples . DB01012 , the only available calcimimetic , has been shown to be a very effective therapeutic tool in CKD - MBD . Many clinical trials with cinacalcet in hemodialysis patients with SHPT have shown a reduction in parathyroid hormone , calcium ( Ca ) , phosphate ( P ) and Ca x P product levels , allowing far greater success in reaching therapeutic goals as recommended by international guidelines . Additionally , some studies have shown that the use of cinacalcet may improve other aspects of CKD - MBD , reducing the risk of vascular calcification and parathyroidectomy , among others . Prospective studies on dialysis patients , with hard endpoint data , are currently underway . This review summarizes the most significant aspects of calcimimimetics based on both experimental and clinical results , underlining their possibilities not only for the treatment of isolated SHPT but also for other CKD - MBD related conditions .",
"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK88___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .",
"Regulation of glucagon - like peptide - 1 receptor and calcium - sensing receptor signaling by L - histidine . Receptor - specific agonists of the extracellular calcium - sensing receptor ( P41180 ) potentiate glucose - induced insulin secretion , an effect similar to that of glucagon - like peptide - 1 ( P0C6A0 ) . We have sequenced the full open reading frame of the P41180 from rat insulinoma ( P01308 - 1 ) cells and find that the predicted amino acid sequence of the receptor is identical with that of the receptor from the parathyroid gland . This receptor couples to both Gq / 11 and Gi / o , and this dual coupling may partly explain the varying effects of nonspecific agonists on secretion reported previously . L - DB00117 ( L - DB00117 ) increases the sensitivity of the P41180 to extracellular Ca2 + and potentiates glucose - dependent insulin secretion from P01308 - 1 cells . This potentiation is partially inhibited at low extracellular [ Ca2 + ] where the P41180 is ineffective . Coexpression of the P41180 and P43220 ( P43220 ) produces a pertussis toxin - sensitive inhibition of P0C6A0 - induced DB02527 production in response to elevated extracellular [ Ca2 + ] . However , l - DB00117 potentiates DB02527 response element reporter activity in P01308 - 1 cells and in human embryonic kidney - 293 cells expressing either the P43220 alone or the P41180 and P43220 . P01308 - 1 cells express the RNA for the P41180 at a lower level than that for the P43220 . This difference in expression level of the receptors may explain the potentiation of insulin secretion by L - DB00117 despite coupling of the P41180 to Gi / o . In conclusion , L - DB00117 can potentiate both P43220 - and P41180 - activated signaling pathways , and these effects may play a role in the potentiation of glucose - induced insulin secretion in response to meals containing protein in addition to carbohydrates and fat .",
"G protein - coupled receptors disrupted in human genetic disease . Genetic variation in G protein - coupled receptors ( GPCRs ) results in the disruption of GPCR function in a wide variety of human genetic diseases . In vitro strategies have been used to elucidate the molecular pathologies that underlie naturally occurring GPCR mutations . Various degrees of inactive , overactive , or constitutively active receptors have been identified . These mutations often alter ligand binding , G protein coupling , receptor desensitization , and receptor recycling . The role of inactivating and activating calcium - sensing receptor ( P41180 ) mutations is discussed with respect to familial hypocalciuric hypercalemia ( FHH ) and autosomal dominant hypocalemia ( DB00067 ) . Among DB00067 mutations , those associated with tonic - clonic seizures are discussed . Other receptors discussed include rhodopsin , thyrotropin , parathyroid hormone , melanocortin , follicle - stimulating hormone , luteinizing hormone , gonadotropin - releasing hormone ( GnRHR ) , adrenocorticotropic hormone , vasopressin , endothelin - beta , purinergic , and the G protein associated with asthma ( Q6W5P4 ) . Diseases caused by mutations that disrupt GPCR function are significant because they might be selectively targeted by drugs that rescue altered receptors . Examples of drug development based on targeting GPCRs mutated in disease include the calcimimetics used to compensate for some P41180 mutations , obesity therapeutics targeting melanocortin receptors , interventions that alter GnRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the Q9H244 receptor in a rare bleeding disorder . The discovery of Q6W5P4 suggests that drug screens against variant GPCRs may identify novel drugs . This review of the variety of GPCRs that are disrupted in monogenic disease provides the basis for examining the significance of common pharmacogenetic variants .",
"Rac1 controls Schwann cell myelination through DB02527 and P35240 / merlin . During peripheral nervous system development , Schwann cells ( SCs ) surrounding single large axons differentiate into myelinating SCs . Previous studies implicate RhoGTPases in SC myelination , but the mechanisms involved in RhoGTPase regulation of SC myelination are unknown . Here , we show that SC myelination is arrested in Rac1 conditional knock - out ( Rac1 - CKO ) mice . Rac1 knock - out abrogated phosphorylation of the effector P38936 - activated kinase and decreased P35240 / merlin phosphorylation . Mutation of P35240 / merlin rescued the myelin deficit in Rac1 - CKO mice in vivo and the shortened processes in cultured Rac1 - CKO SCs in vitro . Mechanistically , DB02527 levels and P12830 expression were decreased in the absence of Rac1 , and both were restored by mutation of P35240 / merlin . Reduced DB02527 is a cause of the myelin deficiency in Rac1 - CKO mice , because elevation of DB02527 by rolipram in Rac1 - CKO mice in vivo allowed myelin formation . Thus , P35240 / merlin and DB02527 function downstream of Rac1 signaling in SC myelination , and DB02527 levels control Rac1 - regulated SC myelination .",
"DB01012 : pharmacological and clinical aspects . The calcium sensing receptor ( P41180 ) is expressed in cells secreting calcium - regulating hormones , in cells involved in calcium transport and in many other tissues , with an as yet not completely defined role . In parathyroid cells , the P41180 stimulation inhibits parathyroid hormone ( PTH ) secretion , synthesis and parathyroid cell proliferation . DB01012 belongs to calcimimetic type II compounds that can interact with P41180 , increasing its affinity for calcium . Clinical studies have proved cinacalcet to be effective in reducing calcium and PTH levels in primary hyperparathyroidism and in reducing PTH , calcium and phosphate in patients with secondary hyperparathyroidism owing to chronic renal failure , with a relatively safe profile , the only reported adverse events being hypocalcaemia and gastrointestinal symptoms . However , though calcimimetics do represent a real advancement in the field of the treatment of PTH secretion disturbances , there is a need for clinical trials , which should aim to demonstrate that a better control of biochemical parameters is also matched with better clinical outcomes .",
"The expression level of P21554 and CB2 receptors determines their efficacy at inducing apoptosis in astrocytomas . BACKGROUND : Cannabinoids represent unique compounds for treating tumors , including astrocytomas . Whether CB ( 1 ) and CB ( 2 ) receptors mediate this therapeutic effect is unclear . PRINCIPAL FINDINGS : We generated astrocytoma subclones that express set levels of CB ( 1 ) and CB ( 2 ) , and found that cannabinoids induce apoptosis only in cells expressing low levels of receptors that couple to P27361 / 2 . In contrast , cannabinoids do not induce apoptosis in cells expressing high levels of receptors because these now also couple to the prosurvival signal AKT . Remarkably , cannabinoids applied at high concentration induce apoptosis in all subclones independently of CB ( 1 ) , CB ( 2 ) and AKT , but still through a mechanism involving P27361 / 2 . SIGNIFICANCE : The high expression level of CB ( 1 ) and CB ( 2 ) receptors commonly found in malignant astrocytomas precludes the use of cannabinoids as therapeutics , unless AKT is concomitantly inhibited , or cannabinoids are applied at concentrations that bypass CB ( 1 ) and CB ( 2 ) receptors , yet still activate P27361 / 2 .",
"[ DB01012 -- a new drug for the treatment of secondary hyperparathyroidism in patients with uraemia , parathyroid cancer or primary hyperparathyroidism ] . DB01012 is a new drug with antiparathyroid effects that belongs to the class of calcimimetics . It increases the sensitivity of the calcium - sensing receptor ( P41180 ) to calcium , thus inducing a decrease in plasma parathyroid ( PTH ) levels . In patients with uncontrolled secondary hyperparathyroidism due to uremia , cinacalcet has been shown to decrease the levels of PTH even in those optimally treated with calcium and 1 - ahydroxylated vitamin D . DB01012 decreases plasma calcium and plasma PTH levels in patients with primary hyperparathyroidism or parathyroid cancer .",
"Successful use of bisphosphonate and calcimimetic in neonatal severe primary hyperparathyroidism . Neonatal primary hyperparathyroidism ( NPHT ) is associated with an inactivating homozygous mutation of the calcium sensing receptor ( P41180 ) . The P41180 is expressed most abundantly in the parathyroid glands and the kidney and regulates calcium homeostasis through its ability to modulate parathormone secretion and renal calcium reabsorption . NPHT leads to life threatening hypercalcemia , nephrocalcinosis , bone demineralization , and neurologic disabilities . Surgery is the treatment of choice . While waiting for surgery , bisphosphonates offer a good alternative to deal with hypercalcemia . DB01012 is a class II calcimimetic that increases P41180 affinity for calcium , leading to parathormone suppression and increased calcium renal excretion . At present , there is little evidence as to whether cinacalcet could improve the function of mutant P41180 in NPHT . We report a case of NPHT , treated successfully with bisphosphonates and cinacalcet after surgery failure . To our knowledge , it is the first time cinacalcet has been used for NPHT .",
"Clinical utilization of cinacalcet in hypercalcemic conditions . INTRODUCTION : DB01012 has recently been introduced as a treatment for secondary hyperparathyroidism in dialysis patients and for parathyroid carcinoma . However , there has been an increasing interest in finding out whether cinacalcet can be used as a treatment for other parathyroid hormone ( PTH ) - dependent hypercalcemic conditions also . AREAS COVERED : The article reports the most relevant recent contributions dealing with calcium sensing receptor ( P41180 ) physiology as well as cinacalcet pharmacokinetics and pharmacodynamics . It also looks at the different hypercalcemic conditions where the use of cinacalcet has been proposed . This article was researched using clinical trials , case reports and outstanding basic research published in the last 3 years ( MEDLINE database up to 31 November 2010 ) . It provides the reader with an insight into the many unaddressed issues regarding cinacalcet that need to be resolved before it can be used in newly proposed fields . EXPERT OPINION : Since cinacalcet may not only have an effect on parathyroid P41180 but also on P41180 expressed at bone and renal levels , it can currently only be considered a good alternative to parathyroidectomy in PTH - dependent hypercalcemic conditions when surgical intervention is burdened by a high failure rate or when it can be considered a risky procedure . At present , cinacalcet can not be considered the first choice treatment in asymptomatic primary hyperparathyroidism or in mild - to - moderate forms of familial hypocalciuric hypocalcemia .",
"Discovery of a calcimimetic with differential effects on parathyroid hormone and calcitonin secretion . Calcimimetics are positive allosteric modulators to the calcium - sensing receptor ( P41180 ) . Activation of the P41180 inhibits the secretion of parathyroid hormone ( PTH ) , stimulates the secretion of calcitonin , and decreases serum calcium ( Ca ( 2 +) ) . DB01012 , a second - generation calcimimetic , is used therapeutically to control PTH in patients with chronic kidney disease who are on dialysis with secondary hyperparathyroidism . A calcimimetic that displays increased separation of PTH versus Ca ( 2 +) lowering in patients would potentially allow the use of calcimimetics to treat patients in earlier stages of renal disease because hypocalcemia can develop in this population . Toward this end , we developed a third - generation calcimimetic , determined the molecular pharmacological properties of it using an operation model of allosteric modulation / agonism , and measured the compound effects on PTH , serum ionized Ca ( 2 +) , and calcitonin levels in 5 / 6 nephrectomized rats . We found the new molecule effectively reduced PTH levels without promoting calcitonin secretion or hypocalcemia . Furthermore , our third - generation molecule was less efficacious at promoting calcitonin secretion from human thyroid carcinoma cells compared with 3 -( 2 - chlorophenyl )- N - ( ( 1R ) - 1 -( 3 - methoxyphenyl ) ethyl ) - 1 - propanamine ( R - 568 ) , a first - generation calcimimetic . These data provide evidence that calcimimetics with increased potency can be used to lower PTH without production of significant hypocalcemia because the threshold for inhibition of PTH secretion is much lower than the threshold for calcitonin secretion .",
"Q9UBP4 maintains the PANC - 1 human pancreatic tumor cells in a dedifferentiated state . Pancreatic cancer ( PaCa ) is the fourth leading cause of cancer deaths in Western societies , with pancreatic ductal adenocarcinomas ( PDACs ) accounting for > 90 % of such cases . PDAC is a heterogeneous disease that includes a subset showing overexpression of the secreted glycoprotein Q9UBP4 ( Q9UBP4 ) , a protein shown to be downregulated in various cancers of different tissues . The biological function of Q9UBP4 in this subset was studied using the Q9UBP4 expressing PANC - 1 cell line as a model for PDACs . The influence of Q9UBP4 overexpression and knockdown on cellular differentiation and proliferation of PANC - 1 was investigated . Confocal microscopy showed that Q9UBP4 was expressed in a fraction of PANC - 1 cells . While lentiviral - mediated overexpression of Q9UBP4 did not alter cellular proliferation , knockdown of Q9UBP4 resulted in significant reduction of cellular proliferation and concomitant induction of cell cycle inhibitors P42772 ( p15INK4b ) , P38936 ( p21CIP1 ) and P46527 ( p27KIP1 ) . In parallel , pancreatic epithelial cell differentiation markers P04746 , Q9UNI1 , P17538 , P01275 , P16278 and P01308 were significantly upregulated . PANC - 1 cells differentiated using exendin - 4 showed analogous induction of cell cycle inhibitors and differentiation markers . Thus , we conclude that Q9UBP4 is required to maintain a highly dedifferentiated and consequently proliferative state in PANC - 1 , indicating a similar function in the Q9UBP4 overexpressing subset of PDACs . Therefore , Q9UBP4 represents a potential target for the treatment of Q9UBP4 - positive subtypes of PaCa to drive cells into cell cycle arrest and differentiation .",
"___MASK86___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .",
"[ Medical treatment of primary hyperparathyroidism : role of calcimimetics ] . Primary hyperparathyroidism ( PHPT ) is a common endocrinological process , characterized by chronic elevation of serum concentrations of calcium and parathyroid hormone ( PTH ) . The only intervention able to cure the disease is parathyroidectomy . However , there are few valid medical alternatives for patients whose PHPT is unresolved by surgery , or in those with contraindications for surgery or who refuse the procedure . The discovery of calcium - sensing receptors ( CaSRs ) , which regulate PTH secretion according to extracellular calcium concentrations , has allowed specific anti - parathyroid drugs called calcimimetics to be designed . DB01012 is an allosteric modulator of P41180 that has demonstrated safety and efficacy in controlling serum calcium values and in reducing PTH levels in patients with PHPT . The exact role of calcimimetics in the overall management of PHPT is promising and should be considered in future clinical practice guidelines .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"DB01012 upregulates calcium - sensing receptors of parathyroid glands in hemodialysis patients . BACKGROUND : DB01012 hydrochloride ( cinacalcet ) , a calcimimetic , has been shown to upregulate calcium - sensing receptor ( P41180 ) expression in parathyroid glands of rats with chronic renal insufficiency . However , the effect of cinacalcet on the reduced P41180 expression in human parathyroid glands remains to be elucidated . METHODS : Four normal parathyroid glands and 71 hyperplastic parathyroid glands from 18 hemodialysis patients with refractory secondary hyperparathyroidism ( SHPT ) treated with ( n = 10 ; cinacalcet group ) or without ( n = 8 ; conventional group ) cinacalcet were examined immunohistochemically with a specific antibody against P41180 . The expression level of P41180 was analyzed semiquantitatively . RESULTS : Compared with normal glands , the immunohistochemical expression of P41180 was decreased significantly in both the cinacalcet and conventional groups . In the cinacalcet group , the expression of P41180 was increased significantly compared with that in the conventional group ( 1 . 83 ± 0 . 14 vs . 0 . 87 ± 0 . 15 , p < 0 . 001 ) , even though the proportion of patients using vitamin D sterols and the mean administered dose of calcitriol equivalents were not significantly different between the two groups . The expression of P41180 was significantly decreased in the larger glands ( > 500 mg ) compared with that in the smaller glands ( < 500 mg ) in both groups ; furthermore , it was markedly decreased in areas of nodular hyperplasia compared with diffuse hyperplasia in the cinacalcet group . CONCLUSIONS : Our results indicate that cinacalcet upregulates the depressed expression of P41180 in hemodialysis patients with SHPT , and that insufficient expression of P41180 , especially in larger glands with advanced nodular hyperplasia , underlies the pathogenesis of SHPT in patients who are resistant to cinacalcet .",
"DB01373 - sensing receptor gene polymorphism Arg990Gly and its possible effect on response to cinacalcet HCl . DB01012 , a novel calcimimetic compound , is effective in reducing parathyroid hormone ( PTH ) levels in approximately 70 % of patients with secondary hyperparathyroidism . However , interindividual variations in the dose required to achieve the treatment goal have been noted in clinical studies . Our investigation examined the genetic polymorphisms of the calcium - sensing receptor ( P41180 ) gene as one possible cause of the different responses to cinacalcet . We report data on seven end - stage renal failure patients who were treated with regular haemodialysis and who participated in clinical trials of cinacalcet . All patients had secondary hyperparathyroidism with baseline intact PTH ( iPTH ) levels greater than 600 pg / ml . Three patients were male and four female with a mean +/- SD age of 60 +/- 12 years . DNA was extracted from peripheral lymphocytes . An area in exon 7 of the P41180 gene was amplified by the polymerase chain reaction and sequenced . Mean +/- SD baseline iPTH was 1086 +/- 189 pg / ml . The five patients without Arg990Gly demonstrated a 29 . 7 +/- 4 . 0 % ( +/- SEM ) reduction in iPTH from individual baseline . One patient was found to be homozygous for the Arg990Gly polymorphism and another was heterozygous for both arginine and glycine alleles . The homozygous patient showed a significantly higher sensitivity to cinacalcet compared to the other patients ( P = 0 . 003 ) with a 76 . 3 +/- 7 . 7 % reduction in iPTH from baseline . No polymorphisms were noted in codons 986 or 1011 . This preliminary study points to the possibility that patients homozygous for glycine at the 990 position in exon 7 of the P41180 may be more sensitive to the calcimimetic drug cinacalcet compared to those who are homozygous for arginine at that location .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK58___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"Inactivation of CaMIT1 inhibits Candida albicans phospholipomannan beta - mannosylation , reduces virulence , and alters cell wall protein beta - mannosylation . Studies on Candida albicans phospholipomannan have suggested a novel biosynthetic pathway for yeast glycosphingolipids . This pathway is thought to diverge from the usual pathway at the mannose - inositol - phospho - ceramide ( MIPC ) step . To confirm this hypothesis , a C . albicans gene homologue for the Saccharomyces cerevisiae Q09428 gene was identified and named MIT1 as it coded for GDP - mannose : inositol - phospho - ceramide mannose transferase . Two copies of this gene were disrupted . Western blots of cell extracts revealed that strain mit1Delta contained no PLM . Thin layer chromatography and mass spectrometry confirmed that mit1Delta did not synthesize MIPC , demonstrating a role of MIT1 in the mannosylation of C . albicans IPCs . As MIT1 disruption prevented downstream beta - 1 , 2 mannosylation , mit1Delta represents a new C . albicans mutant affected in the expression of these specific virulence attributes , which act as adhesins / immunomodulators . mit1Delta was less virulent during both the acute and chronic phases of systemic infection in mice ( 75 and 50 % reduction in mortality , respectively ) . In vitro , mit1Delta was not able to escape macrophage lysis through down - regulation of the P27361 / 2 phosphorylation pathway previously shown to be triggered by PLM . Phenotypic analysis also revealed pleiotropic effects of MIT1 disruption . The most striking observation was a reduced beta - mannosylation of phosphopeptidomannan . Increased beta - mannosylation of mannoproteins was observed under growth conditions that prevented the association of beta - oligomannosides with phosphopeptidomannan , but not with PLM . This suggests that C . albicans has strong regulatory mechanisms associating beta - oligomannoses with different cell wall carrier molecules . These mechanisms and the impact of the different presentations of beta - oligomannoses on the host response need to be defined .",
"Gq - mediated Akt translocation to the membrane : a novel PIP3 - independent mechanism in platelets . Akt is an important signaling molecule regulating platelet aggregation . Akt is phosphorylated after translocation to the membrane through Gi signaling pathways by a phosphatidylinositol - 3 , 4 , 5 - trisphosphate ( PIP3 ) - dependent mechanism . However , Akt is more robustly phosphorylated by thrombin compared with adenosine 5 '- diphosphate in platelets . This study investigated the mechanisms of Akt translocation as a possible explanation for this difference . Stimulation of washed human platelets with protease - activated receptor agonists caused translocation of Akt to the membrane rapidly , whereas phosphorylation occurred later . The translocation of Akt was abolished in the presence of a Gq - selective inhibitor or in Gq - deficient murine platelets , indicating that Akt translocation is regulated downstream of Gq pathways . Interestingly , phosphatidylinositol 3 - kinase ( PI3K ) inhibitors or Q9H244 antagonist abolished Akt phosphorylation without affecting Akt translocation to the membrane , suggesting that Akt translocation occurs through a PI3K / PIP3 / Gi - independent mechanism . An Akt scaffolding protein , P38936 - activated kinase ( PAK ) , translocates to the membrane after stimulation with protease - activated receptor agonists in a Gq - dependent manner , with the kinetics of translocation similar to that of Akt . Coimmunoprecipitation studies showed constitutive association of PAK and Akt , suggesting a possible role of PAK in Akt translocation . These results show , for the first time , an important role of the Gq pathway in mediating Akt translocation to the membrane in a novel Gi / PI3K / PIP3 - independent mechanism .",
"Cytological properties of stromal cells derived from giant cell tumor of bone ( GCTSC ) which can induce osteoclast formation of human blood monocytes without cell to cell contact . When human blood monocytes were cocultured with stromal cells derived from human giant cell tumor of bone ( GCTSC ) and a Millipore filter ( 0 . 4 microm ) was interposed between monocytes and GCTSC , multinucleated giant cell formation of monocytes was induced . The multinucleated giant cells have characters as osteoclast - like cells , indicating that a soluble osteoclast - inducing factor ( s ) is secreted from GCTSC expressing Q9Y6Q6 , O14788 / O14788 / O14788 and P78536 mRNA . Furthermore , O00300 / O00300 inhibited GCTSC - induced osteoclastogenesis , showing that the Q9Y6Q6 - O14788 system is involved in GCTSC - induced osteoclastogenesis and that soluble form of O14788 / O14788 induces osteoclasts from monocytes . GCTSC expressed the cytokine mRNAs such as P09603 , GM - P04141 , P08700 , P05112 , P05231 , and P01579 mRNAs . None of IL - 1ralpha , IL - 1alpha , IL - 1beta , P60568 , P05112 , P22301 , Q14116 , P01375 , G - P04141 and P01579 could be detected in all culture media . A significant amount of P05231 could be detected in the culture media of all GCTSC . P10145 was found in the culture media of two GCTSC and two osteosarcoma - derived cells . P09603 was detected in all culture media . GCTSC express P41180 , and stimulation of GCTSC with either extracellular Ca ( 2 +) or neomycin , agonist of P41180 , augmented the expression of O14788 . Some lines of GCTSC expressed alkaline phosphatase , osteocalcin and Cbfa1 , suggesting that GCTSC are intimately related to osteoblastic lineage .",
"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK18___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK18___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease ."
] |
[
"___MASK11___",
"___MASK18___",
"___MASK19___",
"___MASK41___",
"___MASK4___",
"___MASK58___",
"___MASK70___",
"___MASK86___",
"___MASK88___"
] |
___MASK4___
|
MH_train_412
|
interacts_with DB08860?
|
[
"Activation of cellular invasion by trefoil peptides and src is mediated by cyclooxygenase - and thromboxane A2 receptor - dependent signaling pathways . We have investigated the possible functional relationships between cellular invasion pathways induced by trefoil factors ( TFFs ) , src , and the cyclooxygenases P23219 and P35354 . Pharmacological inhibitors of the Rho small GTPase ( P01024 exoenzyme ) , phospholipase C ( U - 73122 ) , cyclooxygenases ( SC - 560 , NS - 398 ) , and the thromboxane A2 receptor ( P21731 ) antagonist SQ - 295 completely abolished invasion induced by intestinal trefoil factor , pS2 , and src in kidney and colonic epithelial cells MDCKts . src and PCmsrc . In contrast , invasion was induced by the P21731 mimetic U - 46619 , constitutively activated forms of the heterotrimeric G - proteins Galphaq ( AGalphaq ) , Galpha12 , Galpha13 ( AGalpha12 / 13 ) , which are signaling elements downstream of P21731 . Ectopic overexpression of pS2 cDNA and protein in MDCKts . src - pS2 cells and human colorectal cancer cells HCT8 / S11 - pS2 initiate distinct invasion signals that are Rho independent and P36551 and P21731 dependent . We detected a marked induction of P35354 protein and accumulation of the stable PGH2 / TXA2 metabolite TXB2 in the conditioned medium from cells transformed by src . This led to activation of the P21731 - dependent invasion pathway , which is monitored via a Rho - and Galpha12 / Galpha13 - independent mechanism using the Galphaq / PKC signaling cascade . These findings identify a new intracrine / paracrine loop that can be monitored by TFFs and src in inflammatory diseases and progression of colorectal cancers .",
"P62158 interacts with DB00171 binding cassette transporter A1 to protect from calpain - mediated degradation and upregulates high - density lipoprotein generation . OBJECTIVE : To investigate the interaction of DB00171 - binding cassette transporter A1 ( O95477 ) with calmodulin in relation to its calpain - mediated degradation because many calpain substrates bind calmodulin to regulate cellular functions . METHODS AND RESULTS : The activity of O95477 is regulated through proteolysis by calpain . An immunoprecipitation and glutathione S - transferase pull - down assay revealed that O95477 directly binds calmodulin in a Ca ( 2 +)- dependent manner . The cytoplasmic loop of O95477 contains a typical calmodulin binding sequence of 1 - 5 - 8 - 14 motifs ( 1245 to 1257 amino acids ) . The peptide of this region showed binding to calmodulin , and deletion of the 1 - 5 - 8 - 14 motif abolished this interaction . This motif is located near the O95477 Pro - DB00142 - DB00133 - DB00156 sequence , and the presence of calmodulin / Ca ( 2 +) protected the peptides from proteolysis by calpain . The knockdown of calmodulin by a specific small and interfering RNA increased the degradation of O95477 and decreased O95477 protein and apolipoprotein A - I - mediated lipid release . Surprisingly , calmodulin inhibitor W7 increased calmodulin binding to O95477 and protected it from calpain - mediated degradation , consistent with our previous finding that this compound increased apolipoprotein A - I - mediated cell cholesterol release . CONCLUSIONS : P62158 directly binds and stabilizes O95477 in the presence of Ca ( 2 +) and increases the generation of high - density lipoprotein .",
"Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib - pairs in 64 sib - ships from families ascertained by early - onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib - pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation .",
"Endogenous gustatory responses and gene expression profile of stably proliferating human taste cells isolated from fungiform papillae . Investigating molecular mechanisms underlying human taste sensation requires functionally dedicated and at the same time proliferating human taste cells . Here , we isolated viable human fungiform taste papillae cells from biopsy samples , adenovirally transduced proliferation promoting genes , and obtained stably proliferating cell lines . Analysis of gene expression of 1 human taste cell line termed HTC - 8 revealed that these cells express 13 TAS2R bitter taste receptor genes , P16671 , P30559 encoding oxytocin receptor , as well as genes implicated with signal transduction and cell fate control . Bitter tastants triggered functionally distinct signaling pathways in HTC - 8 cells . Salicin elicited phospholipase C - dependent calcium signaling and no cell depolarization . In contrast , stimulation with saccharin , aristolochic acid , or phenylthiocarbamide triggered cell depolarization and phospholipase C - independent calcium influx . Simultaneous stimulation with salicin and saccharin revealed that saccharin can enhance the phospholipase C - dependent response to salicin indicating crosstalk of signaling pathways . Our results show that HTC - 8 cells are programmed to bitter taste reception but are also responsive to fatty acids , oxytocin , and somatosensory stimuli , whereas HTC - 8 cells are insensitive to compounds representing other basic taste qualities .",
"Refining DSM - III criteria in Major Depression . An assessment of the descriptive validity of criterion symptoms . In this study we estimate the power of DSM - III Major Depression ( MDD ) symptoms to discriminate MDD from ( 1 ) Generalized Anxiety Disorder ( Q99259 ) and ( 2 ) no disorder . The NIMH - Q8IX12 was administered to 319 women exposed to chronic stress ( all were mothers of disabled children ) . Two methods were used : ( 1 ) conditional probabilities , and ( 2 ) multiple regression analysis . Symptoms had greater utility in discriminating MDD from no disorder than from Q99259 . ' Gained weight ' and ' thinking about death ' had the least efficacy in either discrimination . ' Hypersomnia ' and ' insomnia ' contributed to the discrimination from no disorder , whereas ' fatigue ' and ' sex disinterest ' discriminated MDD from Q99259 . ' Guilt ' , ' trouble concentrating ' , ' lost appetite ' and ' wanted to die ' were important in both comparisons . Despite recent emphasis on observable behaviors and physiologic measures , guilt , a subjectively experienced inner state , was the most important symptom in MDD .",
"Microarray analyses of the effects of NF - kappaB or PI3K pathway inhibitors on the LPS - induced gene expression profile in RAW264 . 7 cells : synergistic effects of rapamycin on LPS - induced P14780 - overexpression . Lipopolysaccharide ( LPS ) activates a broad range of signalling pathways including mainly NF - kappaB and the MAPK cascade , but recent evidence suggests that LPS stimulation also activates the PI3K pathway . To unravel the specific roles of both pathways in LPS signalling and gene expression profiling , we investigated the effects of different inhibitors of NF - kappaB ( BAY 11 - 7082 ) , PI3K ( wortmannin and LY294002 ) but also of P42345 ( rapamycin ) , a kinase acting downstream of PI3K / Akt , in LPS - stimulated RAW264 . 7 macrophages , analyzing their effects on the LPS - induced gene expression profile using a low density DNA microarray designed to monitor the expression of pro - inflammatory genes . After statistical and hierarchical cluster analyses , we determined five clusters of genes differentially affected by the four inhibitors used . In the fifth cluster corresponding to genes upregulated by LPS and mainly affected by BAY 11 - 7082 , the gene encoding P14780 displayed a particular expression profile , since rapamycin drastically enhanced the LPS - induced upregulation at both the mRNA and protein levels . ___MASK41___ also enhanced the LPS - induced NF - kappaB transactivation as determined by a reporter assay , phosphorylation of the p38 and Erk1 / 2 MAPKs , and counteracted Q07869 activity . These results suggest that P42345 could negatively regulate the effects of LPS on the NF - kappaB and MAPK pathways . We also performed real - time RT - PCR assays on mmp9 expression using rosiglitazone ( agonist of PPARgamma ) , PD98059 ( inhibitor of Erk 1 / 2 ) and SB203580 ( inhibitor of p38 ( MAPK ) ) , that were able to counteract the rapamycin mediated overexpression of mmp9 in response to LPS . Our results suggest a new pathway involving P42345 for regulating specifically mmp9 in LPS - stimulated RAW264 . 7 cells .",
"Potent and selective activation of the pancreatic beta - cell type K ( DB00171 ) channel by two novel diazoxide analogues . AIMS / HYPOTHESIS : We investigated the pharmacological properties of two novel DB00171 sensitive potassium ( K ( DB00171 ) ) channel openers , 6 - Chloro - 3 - isopropylamino - 4 H - thieno [ 3 , 2 - e ] - 1 , 2 , 4 - thiadiazine 1 , 1 - dioxide ( NNC 55 - 0118 ) and 6 - chloro - 3 -( 1 - methylcyclopropyl ) amino - 4 H - thieno [ 3 , 2 - e ]- 1 , 2 , 4 - thiadiazine 1 , 1 - dioxide ( NN414 ) , on the cloned cardiac ( Kir6 . 2 / SUR2A ) , smooth muscle ( Kir6 . 2 / SUR2B ) and pancreatic beta cell ( Kir6 . 2 / Q09428 ) types of K ( DB00171 ) channel . METHODS : We studied the effects of these compounds on whole - cell currents through cloned K ( DB00171 ) channels expressed in Xenopus oocytes or mammalian cells ( HEK293 ) . We also used inside - out macropatches excised from Xenopus oocytes . RESULTS : In P29320 293 cells , NNC 55 - 0118 and NN414 activated Kir6 . 2 / Q09428 currents with EC ( 50 ) values of 0 . 33 micromol / l and 0 . 45 micromol / l , respectively , compared with that of 31 micro mol / l for diazoxide . Neither compound activated Kir6 . 2 / SUR2A or Kir6 . 2 / SUR2B channels expressed in oocytes , nor did they activate Kir6 . 2 expressed in the absence of Q09428 . Current activation was dependent on the presence of intracellular MgATP , but was not supported by MgADP . CONCLUSION / INTERPRETATION : Both NNC 55 - 0118 and NN414 selectively stimulate the pancreatic beta - cell type of K ( DB00171 ) channel with a higher potency than diazoxide , by interaction with the Q09428 subunit . The high selectivity and efficacy of the compounds could prove useful for treatment of disease states where inhibition of insulin secretion is beneficial .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK26___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK26___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK26___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK26___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"NOS Inhibition Modulates Immune Polarization and Improves Radiation - Induced Tumor Growth Delay . DB00435 synthases ( NOS ) are important mediators of progrowth signaling in tumor cells , as they regulate angiogenesis , immune response , and immune - mediated wound healing . Ionizing radiation ( IR ) is also an immune modulator and inducer of wound response . We hypothesized that radiation therapeutic efficacy could be improved by targeting NOS following tumor irradiation . Herein , we show enhanced radiation - induced ( 10 Gy ) tumor growth delay in a syngeneic model ( C3H ) but not immunosuppressed ( Nu / Nu ) squamous cell carcinoma tumor - bearing mice treated post - IR with the constitutive NOS inhibitor N ( G )- nitro - l - arginine methyl ester ( L - NAME ) . These results suggest a requirement of T cells for improved radiation tumor response . In support of this observation , tumor irradiation induced a rapid increase in the immunosuppressive Th2 cytokine P22301 , which was abated by post - IR administration of L - NAME . In vivo suppression of P22301 using an antisense P22301 morpholino also extended the tumor growth delay induced by radiation in a manner similar to L - NAME . Further examination of this mechanism in cultured Jurkat T cells revealed L - NAME suppression of IR - induced P22301 expression , which reaccumulated in the presence of exogenous NO donor . In addition to L - NAME , the guanylyl cyclase inhibitors ODQ and thrombospondin - 1 also abated IR - induced P22301 expression in Jurkat T cells and Q14201 - 1 macrophages , which further suggests that the immunosuppressive effects involve P29474 . Moreover , cytotoxic Th1 cytokines , including P60568 , IL12p40 , and IFNγ , as well as activated CD8 (+) T cells were elevated in tumors receiving post - IR L - NAME . Together , these results suggest that post - IR NOS inhibition improves radiation tumor response via Th1 immune polarization within the tumor microenvironment .",
"P01375 - α - accelerated degradation of type I collagen in human skin is associated with elevated matrix metalloproteinase ( MMP ) - 1 and P08254 ex vivo . P01375 ( P01375 ) - α induces matrix metalloproteinases ( MMPs ) that may disrupt skin integrity . We have investigated the effects and mechanisms of exogenous P01375 - α on collagen degradation by incubating human skin explants in defined serum - free media with or without P01375 - α ( 10ng / ml ) in the absence or presence of the nonselective MMP inhibitor DB02255 for 8 days . The basal culture conditions promoted type I collagen catabolism that was accelerated by P01375 - α ( p < 0 . 005 ) and accomplished by MMPs ( p < 0 . 005 ) . Levels of the collagenases P22894 and P45452 were insignificant and neither P08253 nor P50281 were associated with increased collagen degradation . P01375 - α increased secretion of P03956 ( p < 0 . 01 ) but had no impact on P03956 quantities in the tissue . Immunohistochemical analysis confirmed similar tissue P03956 expression with or without P01375 - α with epidermis being the major source of P03956 . Increased tissue - derived collagenolytic activity with P01375 - α exposure was blocked by neutralizing P03956 monoclonal antibody and was not due to down - regulation of tissue inhibitor of metalloproteinase - 1 . P01375 - α increased production ( p < 0 . 01 ) , tissue levels ( p < 0 . 005 ) and catalytic activity of the endogenous P03956 activator P08254 . Type I collagen degradation correlated with P08254 tissue levels ( rs = 0 . 68 , p < 0 . 05 ) and was attenuated with selective P08254 inhibitor . Type I collagen formation was down - regulated in cultured compared with native skin explants but was not reduced further by P01375 - α . P01375 - α had no significant effect on epidermal apoptosis . Our data indicate that P01375 - α augments collagenolytic activity of P03956 , possibly through up - regulation of P08254 leading to gradual loss of type I collagen in human skin .",
"Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .",
"The novel P04035 inhibitor , DB08860 , induces a protective action in vascular endothelial cells through the production of nitric oxide ( NO ) . This study sought to induce the effect of nitric oxide ( NO ) production in vascular endothelial cells by DB08860 , which is a novel P04035 inhibitor ( statin ) . The growth capacity of vascular endothelial cells significantly ( p < 0 . 01 ) declined when stimulated with P01375 ( 10 ng / ml ) . The growth capacity of the P01375 treated cells recovered , when the P01375 stimulation was performed after DB08860 ( 100 nM ) pretreatment . The recovery of the growth capacity of the cells was suppressed by the presence of the NO synthase inhibitor , L - NAME . DB08860 increased NO production by the vascular endothelial cells in a dose and time dependent manner . The NO production was suppressed by the presence of mevalonic acid and geranylgeranyl pyrophosphate . In addition , the expression of endothelial nitric oxide synthase was strongly induced by DB08860 , and was suppressed by mevalonic acid and geranylgeranyl pyrophosphate by Western blot analysis . Our results show that DB08860 induces NO production by vascular endothelial cells , and protects vascular endothelial cells from injury due to the inflammatory reaction induced by P01375 .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK53___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"Anti - adipogenic action of pitavastatin occurs through the coordinate regulation of PPARgamma and Pref - 1 expression . BACKGROUND AND PURPOSE : Adipocyte differentiation in vitro is coordinately activated by two transcription factors , peroxisome proliferator - activated receptor gamma ( PPARgamma ) and CCAAT enhancer binding protein alpha ( C / EBPalpha ) , but it is inhibited by preadipocyte factor - 1 ( pref - 1 ) . Statins , inhibitors of P04035 and de novo cholesterol synthesis , can have pleiotropic effects which influence adipocyte phenotype by ill - defined mechanisms . We investigated the effects of pitavastatin ( NK - 104 ) on adipocyte differentiation and the transcriptional pathways involved . EXPERIMENTAL APPROACH : The effects of pitavastatin on adipocyte differentiation were evaluated by the formation of oil droplets , content of cellular triglyceride and expression of adipocyte - specific genes . Regulatory mechanisms were assessed by analysis of PPARgamma , C / EBPalpha and pref - 1 expression . KEY RESULTS : DB08860 significantly inhibited adipocyte differentiation of 3T3 - Q9NUQ9 preadipocytes in response to adipogenic inducers . Evidence for inhibition included fewer Oil Red O positive droplets , less cellular triglyceride and decreased expression of adipocyte - specific genes , including fatty acid binding protein ( aP2 ) , P16671 , adipsin and glucose transporter 4 ( P14672 ) . The inhibitory effects of pitavastatin on adipocyte differentiation of 3T3 - Q9NUQ9 preadipocytes were time and concentration dependent . DB08860 significantly blocked induction of PPARgamma expression , but not C / EBPalpha expression or DNA binding activity of PPARgamma . Also , pitavastatin induced pref - 1 expression in preadipocytes and maintained expression of pref - 1 at high levels in differentiated cells . CONCLUSIONS AND IMPLICATIONS : Our data suggest that pitavastatin inhibits adipocyte differentiation by blocking PPARgamma expression and activating pref - 1 expression . These studies may have implications in the regulation of adipogenesis in response to statins .",
"DB08860 , a potent hydroxymethylglutaryl coenzyme a reductase inhibitor , increases cholesterol 7 alpha - hydroxylase gene expression in HepG2 cells . BACKGROUND : The effect of pitavastatin on the mRNA levels of apolipoprotein ( apo ) A - I , peroxisome proliferator - activated receptor alpha ( PPARalpha ) , cholesterol 7alpha - hydroxylase ( P22680 ) , and farnesoid X receptor ( Q96RI1 ) in HepG2 cells was examined to establish whether pitavastatin affects bile acid synthesis and if so , to determine a possible molecular mechanism . METHODS AND RESULTS : HepG2 cells were cultured in serum - free Dulbecco ' s modified Eagle medium for 18 h before drug treatment . Total RNA was extracted at set times and mRNA levels were quantified by reverse transcription - real time polymerase chain reaction . DB08860 at 0 . 1 , 1 , 5 , and 10 micromol / L increased the mRNA levels of apo A - I , PPARalpha , P22680 , and Q96RI1 in a dose - dependent manner . The mRNA levels of apo A - I , Q07869 alpha , P22680 , and Q96RI1 similarly increased with increasing doses of pitavastatin . Coincubation of mevalonate ( 4 mmol / L ) with pitavastatin ( 5 micromol / L ) reversed the inductive effects of pitavastatin on the mRNA levels of these genes , indicating that the inductive effects of pitavastatin were related to its inhibition of P04035 . CONCLUSIONS : DB08860 increased the mRNA levels of P22680 in HepG2 cells , suggesting that increased conversion of cholesterol to bile acids may be the mechanism for its potent low - density lipoprotein cholesterol - lowering effects .",
"Synthesis of novel spiropyrazoline oxindoles and evaluation of cytotoxicity in cancer cell lines . A series of novel spiropyrazoline oxindole derivatives was synthesized by 1 , 3 - dipolar cycloaddition reaction . The compounds were screened for their in vitro cytotoxic activity against MCF - 7 breast cancer cell line ( estrogen receptor positive ( ER + ) and human epidermal growth factor receptor 2 negative ( P04626 - ) ) . Of the nineteen spiropyrazoline oxindoles tested , six compounds have a GI50 below 12 μM The most potent compounds in this series were also evaluated against MDA - MB - 231 breast cancer cell line ( ER - and P04626 - ) . Two spiropyrazoline oxindoles were highly selective between MCF - 7 tumor cells and MDA - MB - 231 tumor cells . More importantly , they were noncytotoxic against P29320 293T non tumor derived cell lines .",
"DB08860 , an P04035 inhibitor , exerts P29474 - independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency . Angiotensin II ( Ang II ) plays a pivotal role in cardiovascular remodeling leading to hypertension , myocardial infarction , and stroke . DB08860 , an P04035 inihibitor , is known to have pleiotropic actions against the development of cardiovascular remodeling . The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II - induced organ damage . C57BL6 / J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle . DB08860 treatment improved Ang II - induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis , cardiomyocyte hypertrophy , coronary perivascular fibrosis , and medial thickening . Ang II - induced oxidative stress , cardiac TGFbeta - 1 expression , and Smad 2 / 3 phosphorylation were all attenuated by pitavastatin treatment . DB08860 also reduced Ang II - induced cardiac remodeling and diastolic dysfunction in P29474 -/- mice as in wild - type mice . In P29474 -/- mice , the Ang II - induced cardiac oxidative stress and TGF - beta - Smad 2 / 3 signaling pathway were enhanced , and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway . Moreover , pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II - treated P29474 -/- mice , with suppression of glomerular oxidative stress and TGF - beta - Smad 2 / 3 signaling pathway . In conclusion , pitavastatin exerts P29474 - independent protective actions against Ang II - induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF - beta - Smad 2 / 3 signaling pathway by suppression of oxidative stress .",
"In vivo excitation of GABA interneurons in the medial prefrontal cortex through 5 - Q9H205 receptors . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) controls pyramidal cell activity in prefrontal cortex ( P27918 ) through various receptors , in particular , P08908 and 5 - Q13049 receptors . Here we report that the physiological stimulation of the raphe nuclei excites local , putatively GABAergic neurons in the prelimbic and cingulate areas of the rat P27918 in vivo . These excitations had a latency of 36 +/- 4 ms and a duration of 69 +/- 9 ms and were blocked by the i . v . administration of the 5 - Q9H205 receptor antagonists ondansetron and tropisetron . The latency and duration were shorter than those elicited through 5 - Q13049 receptors in pyramidal neurons of the same areas . Double in situ hybridization histochemistry showed the presence of GABAergic neurons expressing 5 - Q9H205 receptor mRNA in P27918 . These cells were more abundant in the cingulate , prelimbic and infralimbic areas , particularly in superficial layers . The percentages of Q99259 mRNA - positive neurons expressing 5 - Q9H205 receptor mRNA in prelimbic cortex were 40 , 18 , 6 and 8 % in layers I , II - III , V and VI , respectively , a distribution complementary to that of cells expressing 5 - Q13049 receptors . Overall , these results support an important role of 5 - HT in the control of the excitability of apical dendrites of pyramidal neurons in the medial P27918 through the activation of 5 - Q9H205 receptors in GABAergic interneurons .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK91___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .",
"Effect of pitavastatin on transactivation of human serum paraoxonase 1 gene . Hepatic hydroxymethyl glutary coenzyme A P04035 inhibitors ( statins ) have various anti atherosclerosis pleiotropic effects that are independent of cholesterol reduction . Human serum paraoxonase 1 ( P27169 ) is associated with high - density lipoprotein ( HDL ) and inhibits the oxidative modification of low - density lipoprotein ( LDL ) . We investigated the effects of statins on P27169 gene transcription using a reporter gene assay . Promoter activity of the P27169 gene was estimated by measuring luciferase activity of plasmids with a P27169 promoter region transfected into human hepatoma HepG2 cells and human embryonic kidney ( P29320 ) 293 cells . DB08860 , simvastatin , and atorvastatin each significantly increased P27169 promoter activity , and the transactivation by pitavastatin was abrogated by mevalonic acid and farnesyl pyrophosphate ( FPP ) , however , not by geranylgeranyl pyrophosphate . Further , P27169 promoter activity was enhanced by farnesyl transferase inhibitor ( FTI ) , but not by geranylgeranyl transferase inhibitor ( GGTI ) . P27169 gene transcription has been reported to be dependent on Sp1 and the transactivation by pitavastatin was completely abrogated by mithramycin , an inhibitor of Sp1 . Our results suggest that pitavastatin activates transcription of the P27169 gene through the FPP pathway , which may play an important role in the anti atherosclerotic effects of statins .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK33___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK33___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .",
"The V2 vasopressin receptor stimulates P27361 / 2 activity independently of heterotrimeric G protein signalling . The V2 vasopressin receptor ( P30518 ) activates the mitogen activated protein kinases ( MAPK ) P27361 / 2 through a mechanism involving the scaffolding protein beta arrestin . Here we report that this activating pathway is independent of G alpha s , G alpha i , G alpha q or G betagamma and that the P30518 - mediated activation of G alpha s inhibits P27361 / 2 activity in a DB02527 / PKA - dependent manner . In the HEK293 cells studied , the beta arrestin - promoted activation was found to dominate over the PKA - mediated inhibition of the pathway , leading to a strong vasopressin - stimulated P27361 / 2 activation . Despite the strong MAPK activation and in contrast with other GPCR , P30518 did not induce any significant increase in DNA synthesis , consistent with the notion that the stable interaction between P30518 and beta arrestin prevents signal propagation to the nucleus . Beta arrestin was found to be essential for the P27361 / 2 activation , indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues . Based on the use of selective pharmacological inhibitors , dominant negative mutants and siRNA , we conclude that the beta arrestin - dependent activation of P27361 / 2 by the P30518 involves c - Src and a metalloproteinase - dependent trans - activation event . These findings demonstrate that beta arrestin is a genuine signalling initiator that can , on its own , engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand .",
"Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .",
"Differences in transcript levels of ABC transporters between pancreatic adenocarcinoma and nonneoplastic tissues . OBJECTIVES : The aim of this study was to evaluate transcript levels of all 49 human DB00171 - binding cassette transporters ( ABCs ) in one of the most drug - resistant cancers , namely , the pancreatic ductal adenocarcinoma ( PDAC ) . Association of ABCs levels with clinical - pathologic characteristics and P01116 mutation status was followed as well . METHODS : Tumors and adjacent nonneoplastic tissues were obtained from 32 histologically verified PDAC patients . The transcript profile of ABCs was assessed using quantitative real - time polymerase chain reaction with a relative standard curve . P01116 mutations in exon 2 were assessed by high - resolution melting analysis and sequencing . RESULTS : Most ABCs were deregulated in PDAC and 10 ABCs were associated with clinical - pathologic characteristics . P01116 mutations did not change the global expression profile of ABCs . CONCLUSIONS : The expression of ABC transporters was significantly deregulated in PDAC tumors when compared to nonmalignant tissues . The observed up - regulation of P21439 , O95342 , P33527 , O15438 , O15440 , Q5T3U5 , and Q9UNQ0 in tumors may contribute to the generally poor treatment response of PDAC . The up - regulation of O95477 , Q8IZY2 , and P45844 implicates a serious impairment of cellular cholesterol homeostasis in PDAC . On the other hand , the observed down - regulation of Q99758 , O95255 , P13569 , and Q09428 suggests a possible role of stem cells in the development and progression of PDAC .",
"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .",
"P35354 inhibition and inhibition of cytosolic phospholipase A2 increase P16671 expression and foam cell formation in THP - 1 cells . Cardiovascular safety of cyclooxygenase ( P36551 ) - 2 - selective inhibitors and nonselective nonsteroidal anti - inflammatory drugs ( NSAIDs ) is of worldwide concern . P35354 inhibitors and NSAIDs act by inhibiting arachidonic acid metabolism to prostaglandins . They confer a cardiovascular hazard manifested as an elevated risk of myocardial infarction . Mechanisms underlying these cardiovascular effects are uncertain . Here we determine whether interference with cytosolic phospholipase A2 ( cPLA - 2 ) or P35354 through pharmacologic blockade or silencing RNA impacts expression of scavenger receptor P16671 and scavenger receptor A , both involved in cholesterol uptake in monocytes and macrophages . THP - 1 human monocytes and human peripheral blood mononuclear cells were exposed to celecoxib , a P35354 selective inhibitor currently in clinical use , and to arachidonyl trifluoromethyl ketone ( AACOCF3 ) , an arachidonic acid analog that selectively inhibits cPLA - 2 . Celecoxib and AACOCF3 each upregulated expression of P16671 , but not scavenger receptor A , as determined by quantitative PCR and immunoblotting . Silencing of cPLA - 2 or P35354 had comparable effects to pharmacologic treatments . Oil red O staining revealed a profound increase in foam cell transformation of THP - 1 macrophages exposed to either celecoxib or AACOCF3 ( both 25 μM ) , supporting a role for the P36551 pathway in maintaining macrophage cholesterol homeostasis . Demonstration of disrupted cholesterol balance by AACOCF3 and celecoxib provides further evidence of the possible mechanism by which P36551 inhibition may promote lipid overload leading to atheromatous lesion formation and increased cardiovascular events .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK64___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"Anti - atherogenic and anti - angiogenic activities of polyphenols from propolis . Propolis is a polyphenol - rich resinous substance extensively used to improve health and prevent diseases . The effects of polyphenols from different sources of propolis on atherosclerotic lesions and inflammatory and angiogenic factors were investigated in P01130 gene ( LDLr -/- ) knockout mice . The animals received a cholesterol - enriched diet to induce the initial atherosclerotic lesions ( IALs ) or advanced atherosclerotic lesions ( AALs ) . The IAL or AAL animals were divided into three groups , each receiving polyphenols from either the green , red or brown propolis ( 250 mg / kg per day ) by gavage . After 4 weeks of polyphenol treatment , the animals were sacrificed and their blood was collected for lipid profile analysis . The atheromatous lesions at the aortic root were also analyzed for gene expression of inflammatory and angiogenic factors by quantitative real - time polymerase chain reaction and immunohistochemistry . All three polyphenol extracts improved the lipid profile and decreased the atherosclerotic lesion area in IAL animals . However , only polyphenols from the red propolis induced favorable changes in the lipid profiles and reduced the lesion areas in AAL mice . In IAL groups , VCAM , P13500 , FGF , PDGF , P15692 , PECAM and P14780 gene expression was down - regulated , while the metalloproteinase inhibitor P01033 gene was up - regulated by all polyphenol extracts . In contrast , for advanced lesions , only the polyphenols from red propolis induced the down - regulation of P16671 and the up - regulation of P09601 and P01033 when compared to polyphenols from the other two types of propolis . In conclusion , polyphenols from propolis , particularly red propolis , are able to reduce atherosclerotic lesions through mechanisms including the modulation of inflammatory and angiogenic factors .",
"___MASK15___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK15___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK15___ is a promising pharmacological tool in the treatment of renal edema .",
"DB08860 , an P04035 inhibitor , ameliorates endothelial function in chronic smokers . BACKGROUND : Smoking is a major cardiovascular risk factor , leading to endothelial dysfunction . The present study investigated the hypothesis that pitavastatin , an P04035 inhibitor , may improve endothelial function in chronic smokers via its antioxidant properties . METHODS AND RESULTS : The 30 male chronic smokers who exhibited mild hypercholesterolemia at the time of physical check - up were enrolled and randomized to the pitavastatin group ( 2 mg / day , n = 15 ) or the untreated control group ( n = 15 ) . Before and after the 4 - week treatment period , endothelium - dependent flow - mediated dilation ( FMD ) and endothelium - independent dilation by glyceryl trinitrate ( GTD ) were examined , and the FMD / GTD ratio was calculated . The pitavastatin group showed a significant restoration of endothelial function ( percent change in FMD : + 49 . 6 % vs + 1 . 4 % ; percent change in FMD / GTD ratio : + 26 . 6 % vs 4 . 5 % , P < 0 . 05 respectively ) , and a significant reduction in oxidative stress levels ( malondialdehyde - low - density lipoprotein - cholesterol : 16 . 6 % vs + 7 . 5 % ; free radical activity : 1 . 8 % vs + 9 . 7 % , P < 0 . 05 respectively ) compared with the control group . DB08860 had no effect on the number of circulating P28906 (+) CD133 (+) progenitor cells , endothelial progenitor cells , or the P08253 , P14780 and P15692 levels . In vitro oxidative stress monitoring assay revealed that pitavastatin protected endothelial cells against oxidative stress . CONCLUSIONS : DB08860 restores endothelial function , even in chronic smokers , possibly through its antioxidative properties . ( Circ J 2010 ; 74 : 195 - 202 ) .",
"DB08860 attenuates the PDGF - induced Q92673 / uPA receptor - mediated migration of smooth muscle cells . Statins , inhibitors of P04035 , elicit various actions on vascular cells including the modulation of proliferation and migration of smooth muscle cells ( SMCs ) . Here , we have elucidated the mechanism by which statins , in particular pitavastatin , attenuate the migration activity of SMCs . The expression of Q92673 , a member of the P01130 family and an enhancer of cell surface localization of urokinase - type plasminogen activator receptor ( Q03405 ) , is increased in cultured SMCs by treatment with DB00102 . DB08860 attenuates the DB00102 - induced surface expression of Q92673 and Q03405 . The increased migration of SMCs observed both upon overexpression of Q92673 and via stimulation of secretion of soluble Q92673 is not reversed by pitavastatin . In vivo studies showed that the SMCs expressing Q92673 in plaques are almost congruent with intimal cells expressing nonmuscle myosin heavy chain ( SMemb ) . DB08860 reduced the expression of Q92673 and SMemb , and the levels of Q92673 , Q03405 , and SMemb in cultured intimal SMCs were reduced to those seen in medial SMCs . We propose that this statin reduces PDGF - induced migration through the attenuation of the Q92673 / Q03405 system in SMCs . Modulation of the Q92673 / Q03405 system with statins suggests a novel treatment strategy for atherogenesis based on suppression of intimal SMC migration .",
"HLA typing using P60568 activated T lymphocytes : usefulness in pediatric candidates for allogeneic bone marrow transplantation . Following a preliminary study in healthy blood donors , we have performed serological HLA - A , B , C , DR and DQ typing using recombinant P60568 activated T lymphocytes ( P60568 . aTLs ) in pediatric candidates for allogeneic bone marrow transplantation . In such patients , it is often difficult to obtain the quantity of lymphocytes required for HLA typing , particularly for class II typing using B lymphocytes , considering the timing of sampling and the volume of blood to be collected . Peripheral blood mononuclear cells ( PBMCs ) were activated and expanded with P60568 until a sufficient number of P60568 . aTLs of good viability were available for the typing . In the first 10 cases , analyses of surface markers ( P06729 , P11836 , CD25 , P16671 , HLA - DR and HLA - DQ , P06729 / HLA - DR : two color ) of P60568 . aTLs were done using flow cytometry at the time of HLA typing and indicated that P60568 . aTLs expressed HLA - DR and DQ antigens sufficient for evaluation . A small number ( less than 10 ( 6 ] of fresh or cryopreserved PBMCs , even those containing leukemic blast cells , were sufficient to induce and expand P60568 . aTLs for HLA typing . To date we have been able to successfully HLA - A , B , C , DR and DQ type 20 / 20 pediatric candidates . The HLA antigens identified on the patients ' P60568 . aTLs were confirmed by a family study .",
"___MASK41___ - mediated P16671 translational suppression contributes to alleviation of hepatic steatosis . ___MASK41___ , a mammalian target of rapamycin ( P42345 ) - specific inhibitor , has the effect of anti - lipid deposition on non - alcoholic fatty liver disease ( NAFLD ) , but the mechanisms with which rapamycin alleviates hepatic steatosis are not fully disclosed . P16671 is known to facilitate long - chain fatty acid uptake and contribute to NAFLD progression . Hepatic P16671 expression is closely associated with hepatic steatosis , while P42345 pathway is involved in P16671 translational control . This study was undertaken to investigate whether rapamycin alleviates hepatic steatosis via the inhibition of P42345 pathway - dependent P16671 translation . Human hepatoblastoma HepG2 cells were treated with palmitate and C57BL / 6J mice were fed with high fat diet ( HFD ) to induce hepatic steatosis . Hepatic P16671 protein expression was significantly increased with lipid accumulation in palmitate - treated HepG2 cells or HFD - fed C57BL / 6J mice . ___MASK41___ reduced hepatic steatosis and P16671 protein expression , but it had no influence on P16671 mRNA expression . ___MASK41___ had no effect on P16671 protein stability , but it significantly decreased P16671 translational efficiency . We further confirmed that rapamycin inhibited the phosphorylation of P42345 and its downstream translational regulators including P08133 ribosomal protein S6 kinase ( p70S6K ) , eukaryotic initiation factor 4E - binding protein 1 ( Q13541 ) , and eukaryotic initiation factor 4E ( P06730 ) . This study demonstrates that rapamycin inhibits hepatic P16671 translational efficiency through the P42345 pathway , resulting in reduction of P16671 protein expression and alleviation of hepatic steatosis .",
"[ Effect of pitavastatin on macrophage cholesterol metabolism ] . OBJECTIVES : DB08860 is the first totally synthetic HMG - Co A reductase inhibitor in Japan that significantly reduces LDL cholesterol while raising HDL cholesterol . Clinical trial showed that pitavastatin has potent effects for LDL cholesterol lowering and is expected effectively to prevent atherosclerosis . To clarify the mechanism of reduction of atherosclerosis by pitavastatin , we examined the effect of pitavastatin on foam cell formation of RAW264 . 7 macrophages . METHODS & RESULTS : Macrophages were cultured with pitavastatin for 24 h and exposed to oxidized LDL with pitavastatin for 3 days . DB08860 decreased the cellular cholesteryl ester content in a dose - dependent manner , and this effect was not via inhibition of P04035 because the 3 - 30 nM pitavastatin did not inhibit [ 14C ] cholesterol synthesis from [ 14C ] acetic acid and the effect was not influenced by addition of mevalonic acid . DB08860 increased neutral cholesterol esterase ( NCEase ) activity and did not affect ACAT activity , and decreased the expression of P16671 and O95477 mRNA . The mechanism of the increase of NCEase activity was that pitavastatin directly modified the substrate state , which was cholesterol oleate emulsified with lecithin . CONCLUSION : Clinical blood concentrations of pitavastatin prevent foam cell formation of RAW macrophages by oxidized LDL , and this was not via inhibition of P04035 , and modify substrate condition .",
"A new P04035 inhibitor , pitavastatin remarkably retards the progression of high cholesterol induced atherosclerosis in rabbits . BACKGROUND : The remarkable anti - atherosclerotic effects of 3 - hydroxy - 3 - methyl - glutaryl - DB01992 reductase inhibitor have not been demonstrated in diet induced severe hyperlipidemia in rabbit model . OBJECTIVE : We have investigated the effect of pitavastatin , a newly developed statin , on atherosclerosis in rabbits . METHODS AND RESULTS : Oophorectomized female NZW rabbits were fed 0 . 3 % cholesterol chow for 12 weeks with or without pitavastatin ( 0 . 1mg / kg per day ) ( Gp . NK and HCD ) . The level of serum cholesterol was decreased in Gp . NK compared with Gp . HCD ( 772 . 8 +/- 70 . 2 versus 1056 . 9 +/- 108 . 3 mg / d ) , whereas no significant alterations were observed in triglyceride and HDL - cholesterol . NO dependent response stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - l - arginine acetate were all improved by pitavastatin treatment . DB08860 treatment increased the level of cyclic GMP in the aorta of cholesterol fed rabbits . In the aorta , the expression of P29474 mRNA was significantly up regulated and O ( 2 )(-) production was slightly reduced in Gp . NK animals . Atherosclerotic area was significantly decreased in aortic arch and thoracic aorta from Gp . NK compared with those from Gp . HCD ( 15 . 1 +/- 5 . 3 versus 41 . 9 +/- 10 . 2 % , 3 . 1 +/- 1 . 1versus 7 . 9 +/- 1 . 2 % in Gp . NK and Gp . HCD aortic arch and thoracic aorta ) . Anti - macrophage staining area , the P03956 or 2 and the nitrotyrosine positive area were decreased in Gp . NK . CONCLUSION : DB08860 retards the progression of atherosclerosis formation and it improves NO bioavailability by P29474 up - regulation and decrease of O ( 2 )(-) .",
"DB08860 , a P04035 inhibitor , blocks vascular smooth muscle cell populated - collagen lattice contraction . Constrictive arterial remodeling plays a major role in lumen narrowing following angioplasty . We investigated the effect of pitavastatin , a 3 - hydroxy - 3 - methylglutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor , on vascular smooth muscle cell ( SMC ) - populated collagen lattice contraction , an in vitro model of vascular contraction . Type I collagen gel contraction by SMCs , which are cultured in collagen gel , was used as a model of vascular remodeling . DB08860 pretreatment inhibited 10 % serum - or platelet - derived growth factor - BB ( PDGF ) - induced SMC - mediated collagen lattice contraction in a concentration - dependent manner . The effect of pitavastatin was prevented by mevalonate or geranylgeranyl pyrophosphate , but not by squalene , a precursor of cholesterol , or farnesyl pyrophosphate . The serum - or PDGF - induced SMC - mediated collagen gel contraction was inhibited by GGTI - 298 , a geranylgeranyltransferase inhibitor , P01024 exoenzyme , an inhibitor of Rho , or Y27634 , a Rho kinase inhibitor , but not by FTI - 277 , a farnesyltransferase inhibitor . Serum or PDGF treatment increased the stress fiber organization in SMCs , which was blocked by the pitavastatin pretreatment . DB08860 had no effect on the serum - and PDGF - induced lamelliopodia extension of SMC . These results may suggest that pitavastatin attenuates SMC - mediated collagen gel contraction probably via an inhibition of geranylgeranylated Rho protein and a disruption of actin cytoskeletal reorganization .",
"Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .",
"Preserved ex vivo inflammatory status in decidual cells from women with preterm labor and subclinical intrauterine infection . OBJECTIVE : To compare the inflammatory response preserved ex vivo by decidual cells isolated from women who experienced preterm labor with and without subclinical intrauterine infection . METHODS : Fetal membranes were obtained after cesarean section from 35 women who delivered before 37 weeks of gestation following spontaneous preterm labor , with no clinical evidence of intrauterine infection . Decidua was microbiologically tested and cultured . Concentrations of anti - inflammatory cytokines ( P60568 , P05112 , P22301 ) , pro - inflammatory cytokines ( P05231 , P10145 , IL - 1β and P01375 - α ) , and matrix metalloproteinases ( P03956 , P08253 , P08254 , P09237 , P22894 , P14780 ) were measured in the supernatants using Bio - Plex , and prostaglandin E ( 2 ) ( PGE ( 2 ) ) was measured by enzyme immunoassay . RESULTS : Subclinical infection was confirmed in 10 women ( 28 . 5 % ) . Microorganisms isolated were Ureaplasma urealyticum ( 4 ) , group B streptococci ( 3 ) , Gardnerella vaginalis ( 1 ) , and Escherichia coli ( 2 ) . We found a significant increase of pro - inflammatory cytokines and a significant decrease of anti - inflammatory cytokines in supernatants from decidual cells obtained from women with preterm labor and subclinical intrauterine infection compared to women without infection . Secretion of P03956 , P22894 , P14780 and PGE ( 2 ) was significantly higher in infected women . Secretion of P10145 by decidual cells from infected women persisted upon repeated in vitro culture passages . CONCLUSIONS : Almost 30 % of idiopathic preterm labor cases were associated with subclinical intrauterine infection , and decidual cells isolated from these cases preserved an ex vivo inflammatory status after in vivo bacterial exposure .",
"Inhibition of P42345 down - regulates scavenger receptor , class B , type I ( Q8WTV0 ) expression , reduces endothelial cell migration and impairs nitric oxide production . The mammalian target of rapamycin ( P42345 ) inhibiting drug rapamycin ( ___MASK41___ ) has severe side effects in patients including hyperlipidemia , an established risk factor for atherosclerosis . Recently , it was shown that rapamycin decreases hepatic P01130 ( LDL - R ) expression , which likely contributes to hypercholesterolemia . Scavenger receptor , class B , type I ( Q8WTV0 ) is the major HDL receptor and consequently regulating HDL - cholesterol levels and the athero - protective effects of HDL . By using the P42345 inhibitor rapamycin , we show that Q8WTV0 is down - regulated in human umbilical vein endothelial cells ( HUVECs ) . This reduction of Q8WTV0 protein as well as mRNA levels by about 50 % did not alter HDL particle uptake or HDL - derived lipid transfer . However , rapamycin reduced HDL - induced activation of P29474 and stimulation of endothelial cell migration . The effects on cell migration could be counteracted by Q8WTV0 overexpression , indicating that decreased Q8WTV0 expression is in part responsible for the rapamycin - induced effects . We demonstrate that inhibition of P42345 leads to endothelial cell dysfunction and decreased Q8WTV0 expression , which may contribute to atherogenesis during rapamycin treatment .",
"DB08860 prevents DB01221 - induced retinal ganglion cell death by suppressing leukocyte recruitment . Excitotoxicity is a major cause of retinal ganglion cell ( RGC ) death during ischemic diseases such as vessel occlusion and diabetic retinopathy . However , the underlying mechanisms are not well understood . Statins , inhibitors of the P04035 , have neuroprotective effects in addition to their original role in lowering cholesterol . We hypothesize that pitavastatin , a recently introduced potent statin , is protective against N - methyl - d - aspartic acid ( DB01221 ) - induced RGC death . DB08860 , administered by gavage , abolished DB01221 - induced loss of RGCs . To elucidate the mechanisms underlying the neuroprotective effect of pitavastatin , we investigated its impact on inflammation . DB01221 increased the expression of interleukin - 1beta and P01375 , and endothelial adhesion molecules , including P05362 , and induced leukocyte accumulation in the retinal vessels . DB08860 significantly reduced DB01221 - induced leukocyte accumulation and up - regulation of endothelial adhesion molecules , whereas cytokine expression was unaffected . Systemic blockade of P05362 in wild - type mice or absence of P05107 in gene - deficient ( P05107 (-/-) ) mice significantly suppressed DB01221 - induced leukocyte accumulation and RGC death . These findings suggest a novel and causative role for inflammatory leukocyte recruitment in DB01221 - induced excitotoxicity . Furthermore , we show the novel neuroprotective effect of statins against excitotoxicity - induced RGC death . Statins or other anti - inflammatory agents may thus have therapeutic benefits in excitotoxicity - associated neuronal diseases through blockade of leukocyte recruitment .",
"MiR - 221 /- 222 differentiate prognostic groups in advanced breast cancers and influence cell invasion . BACKGROUND : MiR - 221 /- 222 are frequently overexpressed in breast cancer and are associated with increased malignancy . The specific modification of microRNAs ( miRNAs ) expression could be a promising strategy in breast cancer therapy , leading to the suppression of tumourigenic processes in tumour cells . METHODS : MiR - 221 /- 222 expressions were analysed in 86 breast cancer tissues by quantitative RT - PCR and tested for correlation with immunohistochemistry data and clinical follow - up . In vitro assays were conducted using human breast cancer cell lines with lentiviral overexpression of miR - 221 /- 222 . RESULTS : In tumour tissues , miR - 221 /- 222 were associated with the occurrence of distant metastases . In particular , high levels of miR - 221 were revealed to have a high prognostic impact for the identification of significantly different groups with advanced tumours . MiR - 221 /- 222 overexpression strongly increased cell proliferation and invasion in vitro . Following miR - 221 /- 222 overexpression an increased Q03405 expression and cell invasion were observed . CONCLUSION : This study demonstrates a significant role for highly expressed miR - 221 /- 222 in advanced breast cancers allowing for the identification of significantly different prognostic groups , particularly for P04626 - positive and lymph - node - positive breast cancers . Considering that miR - 221 /- 222 are strongly involved in cell invasion , these miRNAs may be promising markers for breast cancer prognosis and therapy .",
"Circulating apoptotic proteins are increased in long - term disease - free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis - related proteins and inflammation markers are increased in long - term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF - receptor ( sTNF - R ) 1 and 2 , sFas , sFas ligand , sTNF - related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High - sensitivity P02741 ( HS - CRP ) , fibrinogen , plasma B - type and N - terminal atrial natriuretic peptide ( NT - P01160 and DB04899 ) were also determined . Thirty - four patients with median 6 . 0 years follow - up and 12 healthy age - matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg / m ( 2 ) ) , cyclophosphamide ( FEC ) ( n = 14 ) or four cycles FEC followed by myeloablation with high - dose carboplatin , cyclophosphamide , thiotepa ( n = 20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high - dose than in the standard - dose group . In conclusion , we observed increased circulating apoptotic protein levels in long - term disease - free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study .",
"DB08860 suppresses acute and chronic rejection in murine cardiac allografts . INTRODUCTION : P04035 inhibitors play several roles in the maintenance of organ transplants . We investigated the role of pitavastatin , a potent and newly developed P04035 inhibitor , in cardiac allograft rejection and mechanism of graft arterial disease ( Q99259 ) suppression . METHODS : Balb / c mice hearts were transplanted into C3H / He mice ( a full allomismatch combination ) to assess acute rejection or C57BL / 6 hearts into B6 . C - H2 ( < bm12 > ) KhEg ( a class II mismatch combination ) to examine the extent of Q99259 . DB08860 was administered orally to mice everyday ( 3 mg / kg / day ) . To assess the effect in acute rejection , mixed lymphocyte reaction was performed and cytokine mRNA expression was examined with ribonuclease protection assay . RESULTS : DB08860 significantly prolonged allograft survival . Lymphocyte proliferation was inhibited by pitavastatin , and RPA showed down - regulation of interleukin - 6 in pitavastatin - treated cardiac allografts . Allografts in the pitavastatin - treated group after 8 weeks showed less Q99259 compared with the control group . In vitro , pitavastatin suppressed the smooth muscle cell proliferation in response to activated T cells and inhibited extracellular signal - regulated kinase 1 / 2 activation . CONCLUSION : DB08860 could be effective in the suppression of acute rejection and Q99259 development in cardiac transplantation .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Upregulation of intercellular adhesion molecule - 1 expression on human endothelial cells by tumour necrosis factor - alpha in an in vitro model of the blood - brain barrier . Adhesion molecules on the endothelial surface of the blood - brain barrier ( BBB ) play an important role in the pathogenesis of many encephalopathies , including multiple sclerosis ( MS ) and cerebral malaria ( CM ) . The expression of four surface molecules of relevance to MS and CM on the immortalized human umbilical vein endothelial cell line , ECV304 , was investigated using immunofluorescence flow cytometry . We found that ECV304 cells express intercellular adhesion molecule - 1 ( P05362 ) and low levels of P16671 , but not vascular cell adhesion molecule - 1 ( P19320 ) or P16581 . This expression pattern was unaltered on ECV304 cells which were co - cultured with P13671 glioma cells ; conditions under which the endothelial cells display enhanced barrier formation . Tumour necrosis factor - alpha ( P01375 ) , which is elevated in MS and CM , decreased the integrity of the barrier in co - cultured endothelial cells and upregulated the expression of P05362 nine - fold . The significance of elevated P05362 expression in relation to the binding of parasitised erythrocytes at the BBB in CM is discussed .",
"Pulmonary arterial dysfunction in insulin resistant obese Zucker rats . BACKGROUND : P01308 resistance and obesity are strongly associated with systemic cardiovascular diseases . Recent reports have also suggested a link between insulin resistance with pulmonary arterial hypertension . The aim of this study was to analyze pulmonary vascular function in the insulin resistant obese Zucker rat . METHODS : Large and small pulmonary arteries from obese Zucker rat and their lean counterparts were mounted for isometric tension recording . mRNA and protein expression was measured by RT - PCR or Western blot , respectively . KV currents were recorded in isolated pulmonary artery smooth muscle cells using the patch clamp technique . RESULTS : Right ventricular wall thickness was similar in obese and lean Zucker rats . Lung Q13873 , KV1 . 5 and 5 - Q13049 receptor mRNA and protein expression and KV current density were also similar in the two rat strains . In conductance and resistance pulmonary arteries , the similar relaxant responses to acetylcholine and nitroprusside and unchanged lung P29474 expression revealed a preserved endothelial function . However , in resistance ( but not in conductance ) pulmonary arteries from obese rats a reduced response to several vasoconstrictor agents ( hypoxia , phenylephrine and 5 - HT ) was observed . The hyporesponsiveness to vasoconstrictors was reversed by L - NAME and prevented by the P35228 inhibitor 1400W . CONCLUSIONS : In contrast to rat models of type 1 diabetes or other mice models of insulin resistance , the obese Zucker rats did not show any of the characteristic features of pulmonary hypertension but rather a reduced vasoconstrictor response which could be prevented by inhibition of P35228 .",
"Effect of dietary NaCl on tyrosine hydroxylase in the superior cervical ganglia of Dahl rats . To investigate the involvement of peripheral catecholamines in the development of Dahl - Iwai salt - sensitive ( Q8IX12 / Eis ) hypertension , we performed immunohistochemical staining of tyrosine hydroxylase ( TH ) in the superior cervical ganglia ( SCG ) of Q8IX12 / Eis rats and Dahl - Iwai salt - resistant ( P30518 / Eis ) rats , and in situ hybridization histochemistry for demonstration of TH mRNA localization in the SCG of these rats . Q8IX12 / Eis and P30518 / Eis rats were fed on a high ( 8 % ) salt diet or on a low ( 0 . 3 % ) salt diet for 4 weeks . Nerve cells in the SCG of Q8IX12 / Eis high salt rats exhibited more intense TH - immunoreactivity ( P < 0 . 01 ) and hybridization signals ( P < 0 . 01 ) than those of the other experimental groups . These findings suggest that activation of peripheral sympathetic nerves may account for hypertension in Q8IX12 / Eis rats on a high salt diet .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK19___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK19___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK19___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK19___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK19___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK19___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK19___ .",
"P01375 inhibits flow and insulin signaling leading to NO production in aortic endothelial cells . Endothelial cells release nitric oxide ( NO ) acutely in response to increased \" flow \" or fluid shear stress ( FSS ) , and the increase in NO production is correlated with enhanced phosphorylation and activation of endothelial nitric oxide synthase ( P29474 ) . Both vascular endothelial growth factor and FSS activate endothelial protein kinase B ( P31749 ) by way of incompletely understood pathway ( s ) , and , in turn , P31749 phosphorylates P29474 at DB00133 - 1179 , causing its activation . In this study , we found that either FSS or insulin stimulated insulin receptor substrate - 1 ( P35568 ) tyrosine and serine phosphorylation and increased P35568 - associated phosphatidylinositol 3 - kinase activity , phosphorylation of P31749 DB00133 - 473 , phosphorylation of P29474 DB00133 - 1179 , and NO production . Brief pretreatment of bovine aortic endothelial cells with tumor necrosis factor - alpha ( P01375 ) inhibited the above described FSS - or insulin - stimulated protein phosphorylation events and almost totally inhibited FSS - or insulin - stimulated NO production . These data indicate that FSS and insulin regulate P29474 phosphorylation and NO production by overlapping mechanisms . This study suggests one potential mechanism for the development of endothelial dysfunction in disease states with alterations in insulin regulation and increased P01375 levels .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"P60568 inhibits DB01221 receptor - mediated currents directly and may differentially affect subtypes . Using whole - cell patch - clamp recordings , this study investigated the effects of interleukin - 2 ( P60568 ) on N - methyl - d - aspartate ( DB01221 ) receptor - mediated currents ( I ( DB01221 ) ) in rat cultured hippocampal neurons and human embryonic kidney ( P29320 ) 293 cells expressing recombinant DB01221 receptors . We found that P60568 ( 0 . 01 - 1ng / ml ) immediately and significantly decreased peak I ( DB01221 ) in cultured neurons . Interestingly , the peak I ( DB01221 ) induced in P29320 293 cells was also inhibited by P60568 . We also found that P60568 differentially decreased the peak amplitudes of Q12879 - and Q13224 - containing DB01221 receptor - mediated currents ( I ( Q12879 ) and I ( Q13224 ) ) by 54 +/- 5 % and 30 +/- 4 % , respectively . These results provide new evidence that P60568 induces rapid inhibition of peak currents of DB01221 receptor - mediated responses with possible Q9UHB4 / Q12879 and Q9UHB4 / Q13224 subtype - differentiation , and suggest that the inhibition is mediated by direct interaction between P60568 and DB01221 receptors .",
"Development of Q99259 - immunoreactivity in the dorsal cochlear nucleus of the hamster and cat : light and electron microscopic observations . Physiologic and pharmacologic evidence suggests that inhibitory influences are active in the mammalian dorsal cochlear nucleus ( P07585 ) by the onset of hearing , while anatomical evidence suggests that inhibitory synapses are not present until days or weeks later . One inhibitory neurotransmitter in the P07585 is gamma aminobutyric acid ( GABA ) and its presence can be indexed by immunohistochemical localization of its synthetic enzyme glutamic acid decarboxylase ( Q99259 ) . The present study investigated the ingrowth and synapse formation of Q99259 - immunoreactive inputs in the P07585 of cat and hamster . Q99259 - immunoreactive puncta are present in the P07585 of the cat at birth and of the hamster on postnatal day ( P01160 ) 3 . Thus , the present data correlate well with the physiologic and pharmacologic evidence . In both species the first labelled puncta are near the dorsal acoustic stria and may originate from efferent axons in the stria . Several days later a band of labelled puncta is found in the fusiform cell layer . This location is equivalent to the termination zone of cartwheel cells , Q99259 - immunoreactive interneurons in the P07585 . Based on this spatiotemporal sequence in the appearance of Q99259 - immunoreactive puncta , we suggest that sources of GABA extrinsic to the P07585 mature first , followed by intrinsic sources .",
"DB08860 up - regulates the induction of P35228 through enhanced stabilization of its mRNA in pro - inflammatory cytokine - stimulated hepatocytes . Studies have indicated that protective effects of statins ( P04035 inhibitor ) are associated with the regulation of endothelial nitric oxide synthase ( P29474 ) or inducible NOS ( P35228 ) in heart and liver diseases . Statins have been reported to enhance hepatic NO production and decrease the vascular tone in patients with cirrhosis . However , it is unclear which NOS contributes to the increased NO production . We hypothesized that statins are involved in the up - regulation of P35228 in inflammatory liver , resulting in decreased hepatic resistance . Primary cultured rat hepatocytes were treated with pro - inflammatory cytokine interleukin ( IL ) - 1beta in the presence or absence of pitavastatin . Pretreatment of cells with pitavastatin resulted in up - regulation of P35228 induction by IL - 1beta , followed by increased NO production . DB08860 had no effects on the degradation of IkappaB or activation of NF - kappaB . However , pitavastatin super - induced the up - regulation of type I IL - 1 receptor ( IL - 1RI ) , which is essential for P35228 induction in addition to the IkappaB / NF - kappaB pathway . Mevalonate and geranylgeranylpyrophosphate blocked the stimulatory effects of pitavastatin on P35228 and IL - 1RI induction . Transfection experiments revealed that pitavastatin increased the stability of P35228 mRNA rather than its promoter transactivation . In support of this observation , pitavastatin increased the antisense - transcript corresponding to the 3 '- UTR of P35228 mRNA , which stabilizes P35228 mRNA by interacting with the 3 '- UTR - and RNA - binding proteins . These findings demonstrate that pitavastatin up - regulates P35228 by the stabilization of its mRNA , presumably through the super - induction of IL - 1RI and antisense - transcript . This implies that statins may contribute to a novel potentiated treatment in liver injuries including cirrhosis .",
"Differential gene expression in well - regulated and dysregulated pancreatic beta - cell ( MIN6 ) sublines . To identify genes involved in regulated insulin secretion , we have established and characterized two sublines derived from the mouse pancreatic beta - cell line MIN6 , designated B1 and P01024 . They have a similar insulin content , but differ in their secretory properties . B1 responded to glucose in a concentration - and cell confluence - dependent manner , whereas P01024 did not . B1 cells were stimulated by phorbol 12 - myristate 13 - acetate , leucine , arginine , glibenclamide , isobutylmethylxanthine , and DB00761 , whereas P01024 did not respond ( leucine , arginine , and glibenclamide ) or responded to a lesser extent ( isobutylmethylxanthine , phorbol 12 - myristate 13 - acetate , and DB00761 ) . Although intracellular Ca ( 2 +) rose in response to glucose in B1 but not P01024 cells , DB00761 increased intracellular Ca ( 2 +) in a similar manner in both sublines . P11166 , P11168 , Kir6 . 2 , and Q09428 expression was not significantly different between B1 and P01024 cells , whereas P12830 was more abundantly expressed in B1 cells . A more complete list of differentially expressed genes was established by suppression subtractive hybridization and high density ( Affymetrix ) oligonucleotide microarrays . Genes were clustered according to known or putative function . Those involved in metabolism , intracellular signaling , cytoarchitecture , and cell adhesion are of potential interest . These two sublines should be useful for identification of the genes and mechanisms involved in regulated insulin secretion of the pancreatic beta - cell .",
"Apoptosis - specific activation markers in on - versus off - pump coronary artery bypass graft ( CABG ) patients . BACKGROUND : The relation of epithelial / endothelial apoptosis and secretion of death - inducing receptors ( P30518 ) in comparison to vascular adhesion molecules is not known in patients undergoing the On - versus Off - pump coronary artery bypass graft ( CABG ) procedure . METHODS : 30 patients were prospectively included in the study ( On - vs . Off - pump CABG , each n = 15 ) . Serum samples were obtained prior to , and 30 minutes , 60 minutes and 24 hours after CABG operation . ELISA was utilized to detect caspase - cleaved cytokeratin - 18 ( CK18 ) by means of M30 antibody , soluble P19320 , soluble P05362 , and soluble P30518 TNFR - 1 and CD95 . RESULTS : Soluble caspase - cleaved CK18 was increased and leveled to initial values at 24 hrs . sICAM - 1 showed a significant decrease at 30 minutes and 60 minutes in comparison to preoperative values . sTNFR - 1 / sCD95 showed a rise that was not significant to preoperative values . CONCLUSION : These results indicate for the first time that epithelial / endothelial apoptosis is occurring in patients undergoing bypass operation , irrespective of the CABG procedure selected .",
"A functional comparison between the P04626 ( high )/ P21860 and the P04626 ( low )/ P21860 dimers on heregulin - β1 - induced P03956 and P14780 expression in breast cancer cells . Overexpression of P04626 correlates with more aggressive tumors and increased resistance to cancer chemotherapy . However , a functional comparison between the P04626 ( high )/ P21860 and the P04626 ( low )/ P21860 dimers on tumor metastasis has not been conducted . Herein we examined the regulation mechanism of heregulin - β1 ( P04196 ) - induced P03956 and - 9 expression in breast cancer cell lines . Our results showed that the basal levels of P03956 and - 9 mRNA and protein expression were increased by P04196 treatment . In addition , P04196 - induced P03956 and - 9 expression was significantly decreased by Q02750 / 2 inhibitor , U0126 but not by phosphatidylinositol 3 - kinase ( PI - 3K ) inhibitor , LY294002 . To confirm the role of MEK / P29323 pathway on P04196 - induced P03956 and - 9 expression , MCF7 cells were transfected with constitutively active adenoviral - MEK ( CA - MEK ) . The level of P03956 and - 9 expressions was increased by CA - MEK . P03956 and - 9 mRNA and protein expressions in response to P04196 were higher in P04626 overexpressed cells than in vector alone . The phosphorylation of P04626 , P21860 , P29323 , Akt , and JNK were also significantly increased in P04626 overexpressed MCF7 cells compared with vector alone . P04196 - induced P03956 and - 9 expressions were significantly decreased by lapatinib , which inhibits P00533 and P04626 activity , in both vector alone and P04626 overexpressed MCF7 cells . Finally , P04196 - induced P03956 and P14780 expression was decreased by P21860 siRNA overexpression . Taken together , we suggested that P04196 - induced P03956 and P14780 expression is mediated through P21860 dependent pathway and highly expressed P04626 may be associated with more aggressive metastasis than the low expressed P04626 in breast cancer cells .",
"DB08860 inhibits vascular smooth muscle cell proliferation by inactivating extracellular signal - regulated kinases 1 / 2 . We recently reported that lysophosphatidylcholine ( lysoPC ) acts on vascular smooth muscle cells ( VSMCs ) to produce a mitogenic response through the activation of extracellular signal - regulated kinases 1 / 2 ( P27361 / 2 ) . In this study , we examined the role of P04035 inhibitors on lysoPC - induced VSMC proliferation . DB08860 , a new P04035 inhibitor , suppressed lysoPC - induced DNA synthesis in primary cultured rat VSMCs . Since lysoPC - induced P27361 / 2 activation contributes to smooth muscle cell proliferation , we explored the effect of pitavastatin on P27361 / 2 activation . DB08860 inhibited lysoPC - induced P27361 / 2 phosphorylation and P27361 / 2 activation . The other P04035 inhibitors , atrovastatin and fluvastatin , also inhibited lysoPC - induced P27361 / 2 phosphorylation . DB08860 also inhibited lysoPC - induced c - fos mRNA expression . To gain insight into the mechanism of the inhibitory effect of pitavastatin on P27361 / 2 activation by lysoPC , we examined the role of the mevalonate pathways . Mevalonate and farnesylpyrophosphate reduced the inhibition of P27361 / 2 phosphorylation by pitavastatin . These studies demonstrate that pitavastatin may inhibit lysoPC - induced VSMC proliferation , at least in part , by inactivating P27361 / 2 , which is linked to mevalonate metabolism .",
"Effect of progesterone on intracellular Ca2 + homeostasis in human myometrial smooth muscle cells . Although it is well known that progesterone alters uterine contractility and plays an important role in maintenance of pregnancy , the biochemical mechanisms by which progesterone alters uterine contractility in human gestation are less clear . In this investigation we sought to identify progesterone - induced adaptations in human myometrial smooth muscle cells that may alter Ca2 + signaling in response to contractile agents . Cells were treated with vehicle or the progesterone analog medroxyprogesterone acetate ( ___MASK26___ ) for 5 days , and intracellular free Ca2 + concentration ( [ Ca2 +] i ) was quantified after treatment with oxytocin ( OX ) or endothelin ( ET ) - 1 . OX - and ET - 1 - induced increases in [ Ca2 +] i were significantly attenuated in cells pretreated with ___MASK26___ in a dose - dependent manner . P06401 antagonists prevented the attenuated Ca2 + transients induced by ___MASK26___ . P25101 and ETB receptor subtypes were expressed in myometrial cells , and treatment with ___MASK26___ resulted in significant downregulation of P25101 and ETB receptor binding . ___MASK26___ did not alter ionomycin - stimulated increases in [ Ca2 +] i and had no effect on inositol trisphosphate - dependent or - independent release of Ca2 + from internal Ca2 + stores . We conclude that adaptations of Ca2 + homeostasis in myometrial cells during pregnancy may include progesterone - induced modification of receptor - mediated increases in [ Ca2 +] i .",
"___MASK83___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK83___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients ."
] |
[
"___MASK15___",
"___MASK19___",
"___MASK26___",
"___MASK33___",
"___MASK41___",
"___MASK53___",
"___MASK64___",
"___MASK83___",
"___MASK91___"
] |
___MASK83___
|
MH_train_413
|
interacts_with DB00328?
|
[
"___MASK86___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK86___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries . BACKGROUND : Atherosclerosis affects aorta , coronary , carotid , and iliac arteries most frequently than any other body vessel . There may be common molecular pathways sustaining this process . Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis . RESULTS : We used DNA microarrays and meta - analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression . We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis . Caveolae and JAK / P35610 pathways , and P06702 / P05109 interacting proteins are certainly involved in the development of vascular disease . We found that the system of caveolae is directly connected with genes that respond to hormone receptors , and indirectly with the apoptosis pathway . Cytokines , chemokines and growth factors released in the blood flux were investigated in parallel . High levels of RANTES , IL - 1ra , MIP - 1 alpha , MIP - 1 beta , P60568 , P05112 , P05113 , P05231 , P13232 , Q16552 , DB00102 , P15692 and P01579 were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels . CONCLUSION : The pattern of cytokine and P06702 / P05109 up - regulation characterizes atherosclerosis as a proinflammatory disorder . Activation of the JAK / P35610 pathway is confirmed by the up - regulation of P05231 , P42224 , Q00978 and Q13651 genes in coronary and carotid plaques . The functional network constructed in our research is an evidence of the central role of P35610 protein and the caveolae system to contribute to preserve the plaque . Moreover , Cav - 1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype .",
"Distinct effects of inflammation on gliosis , osmohomeostasis , and vascular integrity during amyloid beta - induced retinal degeneration . In normal retinas , amyloid - β ( Aβ ) accumulates in the subretinal space , at the interface of the retinal pigment epithelium , and the photoreceptor outer segments . However , the molecular and cellular effects of subretinal Aβ remain inadequately elucidated . We previously showed that subretinal injection of Aβ ( 1 - 42 ) induces retinal inflammation , followed by photoreceptor cell death . The retinal Müller glial ( RMG ) cells , which are the principal retinal glial cells , are metabolically coupled to photoreceptors . Their role in the maintenance of retinal water / potassium and glutamate homeostasis makes them important players in photoreceptor survival . This study investigated the effects of subretinal Aβ ( 1 - 42 ) on RMG cells and of Aβ ( 1 - 42 )- induced inflammation on retinal homeostasis . RMG cell gliosis ( upregulation of P14136 , vimentin , and nestin ) on day 1 postinjection and a proinflammatory phenotype were the first signs of retinal alteration induced by Aβ ( 1 - 42 ) . On day 3 , we detected modifications in the protein expression patterns of cyclooxygenase 2 ( P35354 ) , glutamine synthetase ( GS ) , Kir4 . 1 [ the inwardly rectifying potassium ( Kir ) channel ] , and aquaporin ( AQP ) - 4 water channels in RMG cells and of the photoreceptor - associated P29972 . The integrity of the blood - retina barrier was compromised and retinal edema developed . Aβ ( 1 - 42 ) induced endoplasmic reticulum stress associated with sustained upregulation of the proapoptotic factors of the unfolded protein response and persistent photoreceptor apoptosis . Indomethacin treatment decreased inflammation and reversed the Aβ ( 1 - 42 )- induced gliosis and modifications in the expression patterns of P35354 , Kir4 . 1 , and P29972 , but not of P55087 or GS . Nor did it improve edema . Our study pinpoints the adaptive response to Aβ of specific RMG cell functions .",
"Altered expression of beta - catenin , P12830 , cycloxygenase - 2 , and p53 protein by ovine intestinal adenocarcinoma cells . Around 1 . 6 % of sheep in New Zealand develop small - intestinal adenocarcinomas . These neoplasms typically develop widespread metastases . The common development of these neoplasms and their subsequent behavior suggests that sheep could be a useful animal model of human colonic cancer . However , for an animal model of human disease to be relevant , similar genetic mutations should be present . Genetic mutations within human colonic cancers frequently result in expression of cycloxygenase - 2 ( P35354 ) , loss of membranous expression of beta - catenin and P12830 , and accumulation of p53 protein within the neoplastic cells . Immunohistochemistry was used to investigate the presence of these 4 proteins within 26 ovine intestinal adenocarcinomas . Loss of membranous beta - catenin reactivity was observed in 14 of 26 ovine intestinal adenocarcinomas ( 54 % ) . The loss of membranous beta - catenin reactivity was accompanied by cytoplasmic and nuclear reactivity in 2 neoplasms . Loss of P12830 was observed within 8 of 26 neoplasms ( 31 % ) . Neoplastic cell expression of P35354 was observed in 12 of 26 neoplasms ( 46 % ) , whereas cells within 3 of 26 neoplasms ( 11 % ) contained visible p53 protein . In conclusion , all 4 proteins that commonly have altered expression in human colonic cancers were also altered in a proportion of the ovine intestinal adenocarcinomas . These results provide additional evidence that sheep could be useful for the study of human colonic cancer .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK98___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK10___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .",
"Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .",
"___MASK86___ inhibits aquaporin - 1 expression and colon cancer xenograft tumor growth . BACKGROUND / AIMS : To study the effects of water channel protein inhibitor acetazolamide on xenograft tumor growth of colon cancer in nude mice . METHODOLOGY : Setting up human colon cancer model in nude mice , mice were randomly divided into two groups as experimental group and control group . ___MASK86___ was given at a volume of 0 . 1mL per mice ( 40mg / kg / d , ig ) in experimental group , while the same volume of sterile saline was given in control group ( ig ) . After 21 days , protein and m - RNA levels of P29972 in tumor tissues from two groups were detected respectively by Western blot and RT - PCR to evaluate the treatment effects . P29972 , P15692 and P28906 expression was detected by immunohistochemistry , simultaneously . RESULTS : ___MASK86___ ( 40mg / kg / d , ig ) significantly inhibited the xenograft tumor growth of colon cancer in nude mice . The inhibition rate was 88 . 28 % . In comparison with the control group , P29972 protein and mRNA level were significantly reduced in the experimental group ( p < 0 . 01 ) . P29972 , P15692 and P28906 expression in experimental group were positively correlated between each other ( p < 0 . 01 ) . CONCLUSIONS : ___MASK86___ can suppress the xenograft tumor growth by inhibiting the expression of P29972 .",
"Increased serum levels of neutrophil gelatinase - associated lipocalin in patients with essential thrombocythemia and polycythemia vera . Neutrophil gelatinaase - associated lipocalin ( P80188 ) is a glycoprotein bound with matrix metalloproteinase - 9 ( P14780 ) in human neutrophils , and elevated tissue P80188 expression has been documented in different infectious and inflammatory conditions . Recent evidence suggests that P80188 expression is induced in many types of human cancer . Moreover , P80188 is required for P11274 - P00519 - induced tumorigenesis . The aim of the present study was to measure serum levels of P80188 in patients with essential thrombocythemia ( ET ) and polycythemia vera ( PV ) . We also evaluated P80188 levels in patients with ET and PV with and without thrombotic events , to explore a possible correlation of P80188 with platelet and leukocyte activation , and in patients with sepsis . Serum P80188 levels in the study population were significantly higher than in healthy adults and in subjects with sepsis . A correlation between P80188 and the number of white cells and neutrophils was found in patients with PV and ET . P80188 serum levels were not different depending on the presence or not of the O60674 mutation , and a mutant allele dosage effect was not observed for P80188 levels . Patients with PV and ET with thrombosis did not have significantly higher levels of P80188 . We were unable to demonstrate a significant association between serum P80188 levels and CD11b or CD62 expression . In conclusion , our study reports evidence demonstrating that increased levels of P80188 appear to be a characteristic of patients with PV and ET .",
"Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .",
"Topical glucocorticoids downregulate P23219 positive cells in nasal polyps . BACKGROUND : Influx of inflammatory cells is one of the hallmarks of nasal polyposis . As glucocorticoids ( GC ) are known to exhibit strong anti - inflammatory effects , these drugs are frequently used in the treatment of the disease . Part of the anti - inflammatory effects of GC is attributed to their interference with prostanoid synthesis . As cyclooxygenases ( P36551 ) are key enzymes in the synthesis of both pro - ( P23219 , P35354 ) and anti - inflammatory prostanoids ( P35354 ) , we investigated the role of topical GC on P23219 , P35354 and inflammatory markers in nasal polyps ( NP ) . METHODS : Immunohistochemical analysis of inflammatory markers ( P34810 , CD117 , MBP , elastase , IgE , BB - 1 , P05112 , P05113 and P05231 ) , P23219 and P35354 was performed on normal nasal mucosa ( NM ) ( n = 18 ) , non - GC treated NP ( n = 27 ) and topical GC treated NP ( n = 12 ) . NP groups were matched for allergy , asthma and ASA intolerance . RESULTS : Increased numbers of eosinophils , P05113 + cells and IgE + cells and decreased numbers of mastcells are striking features of NP inflammation ( P < 0 . 05 ) . In addition , increased numbers of P23219 + cells are observed in NP epithelium compared to NM ( P < 0 . 05 ) . CONCLUSION : Topical GC significantly reduce the number of P23219 + NP cells ( P < 0 . 05 ) , but have no significant effect on P35354 + NP cells . No significant reduction in the number of eosinophils is observed for GC treated NP . The number of P05113 + cells is however increased significantly upon GC treatment ( P < 0 . 05 ) .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( DB00605 ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .",
"Immunohistochemical analysis of carcinomatous and sarcomatous components in the uterine carcinosarcoma : a case report . Uterine carcinosarcoma ( malignant mixed Mullerian tumor ) is an uncommon female genital tract neoplasm characterized by an admixture of epithelial and stromal malignant cells . We report a case of 50 - year - old peri - menopausal woman diagnosed to have early - stage ( IB due to FIGO ) uterine carcinosarcoma of the homologous type with superficial ( 3mm ) myo - invasion . The patient showed no clinical symptoms of the disease and had no family history of female genital tract malignancies . Positive immunostaining for steroid receptors ( estrogen - alpha and progesterone receptors ) , cytokeratin , and P00533 was detected only in the carcinomatous area , whereas beta - catenin , BCL - 2 , P35354 , p16 ( INK4a ) , P60484 , Q8IUH3 , and vimentin were immunoreactive in both components . P10275 , CD10 , desmin , HER - 2 / neu , and P04637 were found to be negative either in the carcinomatous or in the sarcomatous area . Tumor proliferative activity was higher in the carcinomatous ( 25 % ) than in the sarcomatous ( 2 % ) component . Based on these findings , immunohistochemical evaluation of multiple receptor status in the carcinomatous and sarcomatous areas of carcinosarcoma may provide a clue to the pathogenesis and hormonal receptor status of this uncommon uterine malignancy .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK60___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK37___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK59___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK59___ who were treated with a single dose of mifepristone .",
"Nonsteroidal anti - inflammatory drugs ( NSAID ) sparing effects of glucosamine hydrochloride through N - glycosylation inhibition ; strategy to rescue stomach from NSAID damage . Gastrointestinal or cardiovascular complications limit nonsteroidal anti - inflammatory drugs ( NSAID ) prescription . ___MASK52___ hydrochloride ( GS - HCl ) alternatively chosen , but debates still exist in its clinical efficiency . P35354 instability through inhibiting P35354 N - glycosylation of GS - HCl raised the possibility of NSAID sparing effect . Study was done to determine whether combination treatment of glucosamine and NSAID contributes to gastric safety through NSAID sparing effect . IEC - 6 cells were stimulated with P01375 - α and compared the expressions of inflammatory mediators after indomethacin alone or combination of indomethacin and GS - HCl by Western blotting and RT - PCR . C57BL / 6 mice injected with type II collagen to induce arthritis were treated with indomethacin alone or combination of reduced dose of indomethacin and GS - HCl after 3 weeks . P01375 - α increased the expression of P35354 , P35228 and inflammatory cytokines , but GS - HCl significantly attenuated P01375 - α - induced P35354 expression . Decreased P35354 after GS - HCl was caused by N - glycosylation inhibition as much as tunicamycin . Combination of reduced dose of indomethacin and GS - HCl significantly reduced the expressions of P05362 , P19320 , P10145 , IL - 1β , P08253 , P09237 , P14780 , and P24347 mRNA as well as NF - κB activation better than high dose indomethacin alone . These NSAID sparing effect of GS - HCl was further proven in collagen - induced arthritis model . Combination of GS - HCl and 2 . 5 mg / kg indomethacin showed significant protection from gastric damages as well as efficacious anti - arthritic effect . Taken together , P35354 N - glycosylation inhibition by GS - HCl led to indomethacin sparing effects , based on which combination of GS - HCl and reduced dose of NSAID can provide the strategy to secure stomach from NSAID - induced gastric damage as well as excellent anti - arthritic effects .",
"Acetylbritannilactone suppresses lipopolysaccharide - induced vascular smooth muscle cell inflammatory response . To investigate the mechanism of action by which a new anti - inflammatory active compound , 1 - O - acetylbritannilactone ( P00519 ) isolated from Inula britannica - F . , inhibits inflammatory responses in vascular smooth muscle cells ( VSMCs ) . Enzyme immunoassay was used to measure the levels of prostandin E ( 2 ) ( PGE ( 2 ) ) production . Immunocytochemistry staining and Western blot analysis were performed to detect the nuclear translocation of nuclear factor - kappaB ( NF - kappaB ) p65 and the expression of IkappaB - alpha , pIkappaB - alpha and cyclooxygenase - 2 ( P35354 ) . Electrophoretic mobility shift assays ( EMSA ) were used to detect DNA - binding activity of NF - kappaB in VSMCs . P00519 ( 5 , 10 , 20 micrommol / l ) had several concentration - dependent effects , including inhibition of lipopolysaccharide ( LPS ) - induced PGE ( 2 ) production and P35354 expression , and blockade of NF - kappaB activation and translocation . These effects were owing to reductions in IkappaB - alpha phosphorylation and degradation induced by LPS . In addition , P00519 directly inhibited the binding of active NF - kappaB to specific DNA cis - element . These results indicate that P00519 is a potent inhibitor of LPS - stimulated VSMC inflammatory responses through blockade of NF - kappaB activity and inhibition of inflammatory gene P35354 expression .",
"The protective effect of rebamipide on paracellular permeability of rat gastric epithelial cells . BACKGROUND : Barrier function in gastric epithelial cells is essential for the gastric defence mechanism against acid back - diffusion into the mucosal layer . Our previous study indicated that trans - epithelial resistance ( Q9NZ01 ) of rat gastric epithelial cells was rapidly increased when the cells were exposed to acid . This response to acid was diminished by indometacin . AIM : Evaluate the effects of a mucoprotective agent , rebamipide , on the nonsteroidal anti - inflammatory drug ( NSAID ) - induced increase of gastric epithelial permeability . METHODS : Rat gastric epithelial cells were plated on tissue culture inserts . Cells were exposed to a NSAID ( indometacin , 10 - 7 M ) . Trans - epithelial permeability was measured by Q9NZ01 and diffusion rate of 14C - mannitol . The effect of rebamipide was evaluated by measuring Q9NZ01 . Endogenous prostaglandin E2 ( DB00917 ) production in culture medium was also measured . RESULTS : DB00328 gradually and significantly decreased Q9NZ01 and increased 14C - manitol permeability . Rebamipide reversed the indometacin - induced changes in epithelial permeability and induced DB00917 synthesis . This induction was blocked by either indometacin or a Cyclooxygenase ( P36551 ) - 2 specific inhibitor . CONCLUSIONS : P36551 inhibitors such as indometacin inhibit regulation of epithelial permeability by reducing DB00917 . P23219 has an important role in the gastric defense mechanism . Rebamipide suppressed an indometacin - induced increase in gastric epithelial permeability by increasing DB00917 levels in a P35354 dependent manner .",
"DB00328 ameliorates high glucose - induced proliferation and invasion via modulation of e - cadherin in pancreatic cancer cells . DB00328 , an inhibitor of cyclooxygenase - 2 ( P35354 ) , has been shown to exert anticancer effects in a variety of cancers . However , the effect and mechanism of indometacin on high glucose ( HG ) - induced proliferation and invasion of pancreatic cancer ( PC ) cells remain unclear . Multiple lines of evidence suggest that a large portion of pancreatic cancer ( PC ) patients suffer from either diabetes or HG which contributing PC progression . In this study , we report that indometacin down - regulated HG - induced proliferation and invasion via up - regulating P12830 but not P35354 in PC cells . Additionally , the P12830 transcriptional repressors , Snail and Slug , were also involved in the process . Furthermore , the proliferation and invasion of PC cells , incubated in HG medium and treated with indometacin were significantly increased when P12830 was knocked down ( Si - E - cad ) . Moreover , the protein levels of P08253 , P14780 , and P15692 were increased in PC cells transfected with Si - E - cad . Finally , the activation of the PI3K / AKT / GSK - 3β signaling pathway was demonstrated to be involved in indometacin reversing HG - induced cell proliferation and invasion in PC cells . In conclusion , these results suggest that indometacin plays a key role in down - regulating HG - induced proliferation and invasion in PC cells . Our findings indicate that indometacin could be used as a novel therapeutic strategy to treat PC patients who simultaneously suffer from diabetes or HG .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"Evaluation of pharmacological profile of meloxicam as an anti - inflammatory agent , with particular reference to its relative selectivity for cyclooxygenase - 2 over cyclooxygenase - 1 . We studied the anti - inflammatory activity of meloxicam on rat carrageenin - induced pleurisy and its toxicity for rat gastric mucosa , relative to its in vitro inhibitory potency against partially purified cyclooxygenase ( P36551 ) - 1 and P35354 preparations in order to clarify the pharmacological profile of the compound as an anti - inflammatory agent . In rat carrageenin - induced pleurisy , the plasma exudation rate peaked at 5 h , at which time P35354 was detectable in cells from the pleural exudate . Meloxicam and piroxicam ( 1 and 3 mg / kg ) and NS - 398 ( 3 mg / kg ) showed almost equal anti - inflammatory potency against 5 - hour pleurisy . A single oral administration of the compounds caused a dose - dependent increase in the number of rats with gastric mucosal erosion . The ED50 value for meloxicam ( 5 . 92 mg / kg ) was significantly higher than that for piroxicam ( 1 . 76 mg / kg ) , indicating that meloxicam is safer . DB00328 showed intermediate safety ( 2 . 59 mg / kg ) . In in vitro experiments , indometacin inhibited P23219 about 1 . 7 times more potently than P35354 . NS - 398 inhibited P35354 with an IC50 of 0 . 32 microM , but never affected P23219 activity , even at 100 microM . In the same assay system , meloxicam inhibited P35354 about 12 times more selectively than P23219 . Piroxicam , however , inhibited both isoforms almost equally . These results indicate that meloxicam is a potent anti - inflammatory agent with low gastric toxicity . One reason for its in vivo pharmacological profile may be related to its relative selectivity for P35354 over P23219 . Thus , meloxicam may belong to a group of P35354 selective anti - inflammatory agents with a better safety profile than conventional P23219 and P35354 nonselective anti - inflammatory agents .",
"Inhibition of matrix metalloproteinase - 2 enhances radiosensitivity by abrogating radiation - induced FoxM1 - mediated G2 / M arrest in A549 lung cancer cells . P08253 ( P08253 ) , is known to degrade the collagen IV , plays a role in radiation - induced lung injury . We therefore investigated the antitumor effects of combining P08253 inhibition using an adenovirus expressing siRNA against P08253 ( Ad - P08253 - Si ) with radiation therapy ( IR ) on A549 lung cancer cells in vitro and in vivo . IR increased P08253 mRNA , protein and activity in lung cancer cells . P08253 inhibition along with IR enhanced radiosensitivity as determined by clonogenic assay , flow cytometry and TUNEL assay . We show that P08253 inhibition prior to irradiation reduced p53 phosphorylation , with a corresponding reduction in the expression of the p53 downstream target gene P38936 ( Cip1 / Waf1 ) . Irradiated tumor cells induced the FoxM1 - mediated DNA repair gene , P18887 and Checkpoint kinases 2 / 1 , which were abrogated with combined treatment of Ad - P08253 - Si and IR . Further , the combination of Ad - P08253 - Si with radiotherapy significantly increased antitumor efficacy in vivo compared to either agent alone . Indeed , histological analysis of tumor sections collected from the combination group revealed more apoptotic cells . These studies suggest that P08253 inhibition in combination with radiotherapy abrogates G2 cell cycle arrest leading to apoptosis and provide evidence of the antitumor efficacy of combining P08253 inhibition with irradiation as a new therapeutic strategy for the effective treatment of NSCLC patients .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK74___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK74___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"P10275 promotes esophageal cancer cell migration and proliferation via matrix metalloproteinase 2 . Esophageal squamous cell carcinoma ( ESCC ) is one of the most common malignancies worldwide . P10275 ( AR ) plays an important role in many kinds of cancers . However , the molecular mechanisms of AR in ESCC are poorly characterized . In the present study , Western blot analysis and real - time quantitative PCR were performed to identify differentially expressed AR in 40 ESCC tissue samples , which revealed that the messenger RNA ( mRNA ) and protein expression of AR is upregulated in the ESCC tissue samples . AR overexpression induced increases in ESCC cell invasion and proliferation in vitro . Silencing of AR inhibited the proliferation of KYSE450 cells which have a relatively high level of AR , and the invasion of KYSE450 cells was distinctly suppressed . Furthermore , AR knockdown led to substantial reductions in matrix metalloproteinase 2 ( P08253 ) and p - AKT levels in ESCC cell lines , but no significant change in AKT and P14780 expression . These results suggest that AR is involved in tumor progression , and thus , AR could represent selective targets for the molecularly targeted treatments of ESCC .",
"DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . DB00563 ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .",
"___MASK52___ sulfate suppresses the expressions of urokinase plasminogen activator and inhibitor and gelatinases during the early stage of osteoarthritis . BACKGROUND : ___MASK52___ sulfate may have an ex vivo inhibitory effect on the plasminogen activator ( PA ) / plasmin system and gelatinases expression during the early development of osteoarthritis ( OA ) . METHODS : We compared the levels of urokinase - type PA ( u - PA ) , PA inhibitor - 1 ( P05121 ) and gelatinases ( matrix metalloproteinase - 2 and - 9 [ P08253 and - 9 ] ) in a series of chondral , meniscal , and synovial cultures of early OA after treatment with or without glucosamine sulfate . RESULTS : Gelatin zymography revealed that glucosamine sulfate could suppress P08253 secretion in chondral , meniscal and synovial cultures and also decrease P14780 production in synovial and meniscal cultures . ELISA data also showed the suppressive effects of glucosamine sulfate on u - PA and P05121 production in synovial cultures at 48 h . CONCLUSIONS : Our data suggest that one of the therapeutic effects of glucosamine sulfate is to down - regulate the expressions of u - PA , P05121 , P08253 and P14780 that underlie the destruction of articular cartilage in the early stage of OA , and therefore to delay the joint failure .",
"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK69___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane ."
] |
[
"___MASK10___",
"___MASK37___",
"___MASK52___",
"___MASK59___",
"___MASK60___",
"___MASK69___",
"___MASK74___",
"___MASK86___",
"___MASK98___"
] |
___MASK52___
|
MH_train_414
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interacts_with DB06168?
|
[
"___MASK54___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK54___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"Sustained viral gene delivery through core - shell fibers . Although viral gene transfer is efficient in achieving transgene expression for tissue engineering , drawbacks of virus dissemination , toxicity and transient gene expression due to immune response have hindered its widespread application . Many tissue engineering studies thus opt to genetically engineer cells in vitro prior to their introduction in vivo . However , it would be attractive to obviate the need for in vitro manipulation by transducing the infiltrating progenitor cells in situ . This study introduces the fabrication of a virus - encapsulated electrospun fibrous scaffold to achieve sustained and localized transduction . Adenovirus encoding the gene for green fluorescent protein was efficiently encapsulated into the core of poly ( epsilon - caprolactone ) fibers through co - axial electrospinning and was subsequently released via a porogen - mediated process . P29320 293 cells seeded on the scaffolds expressed high level of transgene expression over a month , while cells inoculated by scaffold supernatant showed only transient expression for a week . RAW 264 . 7 cells cultured on the virus - encapsulated fibers produced a lower level of P01584 , P01375 and IFN - alpha , suggesting that the activation of macrophage cells by the viral vector was reduced when encapsulated in the core - shell PCL fibers . In demonstrating sustained and localized cell transduction , this study presents an attractive alternative mode of applying viral gene transfer for regenerative medicine .",
"Arsenite stabilizes P25963 and prevents NF - kappaB activation in P01584 - stimulated Caco - 2 cells independent of the heat shock response . Recent studies suggest that sodium arsenite downregulates NF - kappaB activity by inhibiting phosphorylation and subsequent degradation of P25963 . Many effects of sodium arsenite are secondary to induction of heat shock proteins . The role of the heat shock response in arsenite - induced inhibition of NF - kappaB , however , is not known . We examined the involvement of the heat shock response in arsenite - induced inhibition of NF - kappaB activity in IL - 1beta - stimulated Caco - 2 cells , a human colorectal adenocarcinoma cell line with enterocytic properties . Treatment of the cells with IL - 1beta resulted in increased O15111 activity , reduced levels of P25963 and increased NF - kappaB DNA binding activity . Sodium arsenite blocked all of these responses to IL - 1beta without inducing changes in heat shock factor activity or heat shock protein levels . Results from additional experiments showed that the protective effect of sodium arsenite on P25963 was not influenced by the oxygen radical scavenger catalase or by inhibitors of the Q96HU1 - kinase signaling pathway . The present results suggest that sodium arsenite stabilizes P25963 and prevents NF - kappaB activation in IL - 1beta - stimulated Caco - 2 cells independent of the heat shock response . In addition , stabilization of P25963 by sodium arsenite does not require oxygen radical formation or activation of the Q96HU1 kinase signaling pathway .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK66___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK66___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK66___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK66___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK66___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK66___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK66___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK66___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK66___ in the treatment of changes in hypervigilance following severe stress .",
"Gene clustering analysis in human osteoporosis disease and modifications of the jawbone . OBJECTIVE : An analysis of the genes involved in both osteoporosis and modifications of the jawbone , through text mining , using a web search tool , of information regarding gene / protein interaction . DESIGN : The final set of genes involved in the present phenomenon was obtained by expansion - filtering loop . Using a web - available software ( STRING ) , interactions among all genes were searched for , and a clustering procedure was performed in which only high - confidence predicted associations were considered . RESULTS : Two hundred forty - two genes potentially involved in osteoporosis and in modifications of the jawbone were recorded . Seven \" leader genes \" were identified ( P35222 , P01584 , P05231 , P05412 , Q13950 , P10451 , P01137 ) , while another 10 genes formed the cluster B group ( P12643 , P18075 , P02452 , P05362 , IGF1 , P22301 , P14780 , P19838 , O14788 , P15692 ) . Ninety - eight genes had no interactions , and were defined as \" orphan genes \" . CONCLUSIONS : The expansion of knowledge regarding the molecular basis causing osteoporotic traits has been brought about with the help of a de novo identification , based on the data mining of genes involved in osteoporosis and in modification of the jawbone . A comparison of the present data , in which no role was verified for 98 genes that had been previously supposed to have a role , with that of the literature , in which another 81 genes , as obtained from GWAS reviews and meta - analyses , appeared to be strongly associated with osteoporosis , probably attests to a lack of information on osteoporotic disease .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK44___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Methodological challenges in monitoring new treatments for rare diseases : lessons from the cryopyrin - associated periodic syndrome registry . BACKGROUND : The Q96P20 - Associated Periodic Syndromes ( CAPS ) are a group of rare hereditary autoinflammatory diseases and encompass Familial Cold Autoinflammatory Syndrome ( FCAS ) , Muckle - Wells Syndrome ( MWS ) , and Neonatal Onset Multisystem Inflammatory Disease ( NOMID ) . DB06168 is a monoclonal antibody directed against P01584 and approved for CAPS patients but requires post - approval monitoring due to low and short exposures during the licensing process . Creative approaches to observational methodology are needed , harnessing novel registry strategies to ensure Health Care Provider reporting and patient monitoring . METHODS : A web - based registry was set up to collect information on long - term safety and effectiveness of canakinumab for CAPS . RESULTS : Starting in November 2009 , this registry enrolled 241 patients in 43 centers and 13 countries by December 31 , 2012 . One - third of the enrolled population was aged < 18 ; the overall population is evenly divided by gender . Enrolment is ongoing for children . CONCLUSIONS : Innovative therapies in orphan diseases require post - approval structures to enable in depth understanding of safety and natural history of disease . The rarity and distribution of such diseases and unpredictability of treatment require innovative methods for enrolment and follow - up . Broad international practice - based recruitment and web - based data collection are practical .",
"Phenotypic characterization of a human synovial sarcoma cell line , SW982 , and its response to dexamethasone . SW982 cells are characterized by expression of inflammatory cytokine and matrix metalloproteinase ( MMP ) genes and by their response to dexamethasone at different cell densities . They express genes encoding interleukin ( IL ) - 1 beta ; P05231 ; transforming growth factor - beta ; intercellular adhesion molecule - 1 ; cycloxygenase ( P36551 ) - 2 ; and MMPs , including P03956 , P08253 , P45452 , and P50281 ; tissue inhibitor of metalloproteinase - 2 ; and a disintegrin and metalloproteinase with thrombospondin motifs - 4 . Expression of all the genes examined was induced with 2 ng / ml P01584 at low cell density . The cells , however , failed to express tumor necrosis factor - alpha , P23219 , and P14780 , regardless of the presence of P01584 . Dexamethasone significantly reduced P01584 , P05231 , P35354 , and P03956 expression at high cell density . The results suggest that SW982 cells are a useful tool for studying the expression of inflammatory cytokine or MMP genes .",
"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK43___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK43___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK43___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK24___ and Tissue P00747 Activator in Occluded Arteries .",
"Monoclonal antibodies targeting P01584 reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in P02649 - deficient mice . OBJECTIVE : Atherosclerosis is a condition that is increasingly contributing to worldwide mortality through complications such as stroke and myocardial infarction . IL - 1β plays multiple direct , local roles in the formation and stability of the atheroma by eliciting the production of additional cytokines and proteolytic enzymes from macrophages , endothelial cells ( EC ) and smooth muscle cells ( SMC ) . We therefore tested whether an anti - IL - 1β antibody , DB06062 , might inhibit the secretion of pro - atherogenic cytokines from macrophages in vitro and affect a positive outcome in the P02649 - deficient mouse ( ApoE (-/-) ) model of atherosclerosis in vivo . METHODS AND RESULTS : In an in vitro co - culture model , DB06062 inhibited macrophage - induced secretion of key atherogenic cytokines from EC and SMC , including P05231 , P10145 , P13500 and TNFα . The release of degradative enzymes , such as the matrix metalloproteinases P08254 and P14780 , was also decreased by DB06062 . In addition , DB06062 inhibited the secretion of P13232 from EC and P05112 from SMC , cytokines not previously reported to be driven by IL - 1β in this context . In vivo , XMA052 MG1K , a chimeric murine version of DB06062 , inhibited the formation of atherosclerotic lesions in the ApoE (-/-) model at all three doses tested . This effect was comparable to that reported for complete genetic ablation of IL - 1β or IL - 1R1 on an ApoE (-/-) background and was associated with decreases in plasma non - HDL / HDL cholesterol ratio and plaque lipid content and macrophage infiltration . CONCLUSIONS : These results demonstrate for the first time that an antibody targeting IL - 1β can inhibit the progression of atherosclerosis in vivo , highlighting the importance of this key cytokine in cardiovascular disease .",
"P29323 signaling mediates the induction of inflammatory cytokines by bufalin in human monocytic cells . Treatment of human leukemia THP - 1 cells with bufalin , a specific inhibitor of Na (+)- K (+)- ATPase , sequentially induces c - fos and inflammatory cytokines interleukin - 1 beta ( P01584 ) and tumor necrosis factor - alpha ( P01375 ) gene expressions before the appearance of mature phenotypes of monocytic cells . In this study we examined the signal transduction leading to bufalin - induced gene expressions . Bufalin selectively activated extracellular signal - regulated kinase ( P29323 ) , compared with other mitogen - activated protein ( Q96HU1 ) kinase family members . Pretreatment of THP - 1 cells with PD - 98059 , an inhibitor of the P29323 - kinase cascade , abolished bufalin - induced c - fos and P01584 gene expressions , indicating that the P29323 - kinase cascade mediates the induction of inflammatory cytokines by bufalin . Inhibition of the Na (+)/ Ca ( 2 +) exchanger by KB - R7943 and of protein kinase C ( PKC ) by Ro - 31 - 8220 suppressed P29323 activation and gene expressions of c - fos and P01584 . These findings suggest that Na (+)- K (+)- ATPase inhibition by bufalin induces calcium influx and thereby activates PKC and P29323 . In cells treated with an inhibitor of p38 Q96HU1 kinases , SB - 203580 , bufalin - mediated P29323 activation became persistent and the induction of P01584 and P01375 expressions was significantly augmented . These results suggest that cross talk in bufalin - mediated P29323 activation is negatively regulated by endogenous p38 Q96HU1 kinase activations .",
"___MASK70___ block of cloned human T - type voltage - gated calcium channels . ___MASK70___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK94___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK82___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .",
"Evidence for a role of the P28335 receptor in central lipopolysaccharide - , interleukin - 1 beta - , and leptin - induced anorexia . We examined the role of serotonin ( 5 - HT ) and the 5 - HT ( 1A ) and 5 - HT ( 2C ) receptors in the anorectic effects of centrally administered lipopolysaccharide ( LPS ) , interleukin - 1 beta ( P01584 ) , and leptin . Food intake was measured in rats after intracerebroventricular ( ICV ) injections of LPS ( 20 ng ) , P01584 ( 10 ng ) , or leptin ( 1 microg ) at lights out , followed by intraperitoneal ( IP ) injections of either the 5 - HT ( 1A ) autoreceptor agonist 8 - hydroxy - 2 -( di - n - propylamino ) tetraline ( 8 - OH - DPAT ) ( 125 microg / kg ) or the 5 - HT ( 2C ) receptor antagonist SB 242084 ( 0 . 3 mg / kg ) at the onset of anorexia . SB 242084 significantly attenuated the food intake reduction caused by all compounds ( all P < . 01 ) . IP 8 - OH - DPAT attenuated ICV P01584 - induced anorexia ( P < . 01 ) . We also tested the involvement of the median raphe 5 - HT ( 1A ) receptors in peripheral LPS - and P01584 - induced anorexia . Rats were injected intraperitoneally with either LPS ( 100 microg / kg ) or P01584 ( 2 microg / kg ) at lights out , and 8 - OH - DPAT ( 4 nmol ) was administered directly into the median raphe nucleus at the onset of anorexia . Median raphe injections of 8 - OH - DPAT significantly attenuated both P01584 - and LPS - induced anorexia ( both P < . 01 ) . These results implicate the 5 - HT ( 2C ) receptors in the mediation of central LPS - , P01584 - , and leptin - induced anorexia . Our results also suggest that the midbrain raphe nuclei play a role in mediating the anorectic response to peripheral LPS and P01584 .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"___MASK25___ for joints and bones . ___MASK25___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK25___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK25___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"Inhibition of noradrenaline release via presynaptic P28222 receptors of the rat vena cava . In the rat inferior vena cava preincubated with 3H - noradrenaline , the effects of nine serotonin ( 5 - HT ) receptor agonists and of eight antagonists ( including two beta - adrenoceptor blocking agents ) on the electrically evoked 3H overflow were determined . 1 . 5 - HT , 5 - carboxamido - tryptamine , 5 - methoxy - 3 ( 1 , 2 , 3 , 6 - tetrahydropyridine - 4 - yl )- 1H - indole ( RU 24969 ) , 5 - methoxytryptamine , N , N - dimethyl - 5HT , tryptamine and 5 - aminotryptamine inhibited the evoked 3H overflow . The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for P28222 binding sites , but not with their affinities for P08908 , P28335 or 5 - HT2 binding sites . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , a P08908 receptor agonist , and ipsapirone , a partial agonist at these receptors , did not inhibit overflow . 2 . Cyanopindolol facilitated the evoked 3H overflow , an effect which was abolished by propranolol . The maximum inhibition of overflow obtainable with 5 - HT was diminished by cyanopindolol . 3 . The concentration - response curve for 5 - HT was shifted to the right by metitepine , metergoline , quipazine , 6 - chloro - 2 -( 1 - piperazinyl ) pyrazine ( MK 212 ) and propranolol which , given alone , did not affect 3H overflow . The apparent pA2 values of these antagonists tended to be correlated with their affinities for P28222 ( but not P08908 , P28335 or 5 - HT2 ) binding sites . Ketanserin , a 5 - HT2 receptor antagonist , and spiperone , which blocks 5 - HT2 and P08908 but not P28222 or P28335 receptors , failed to antagonize the effect of 5 - HT . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Oversulfated fucoidan and heparin suppress endotoxin induction of plasminogen activator inhibitor - 1 in cultured human endothelial cells : their possible mechanism of action . P00747 activator inhibitor - 1 ( P05121 ) is a primary endogenous inhibitor of tissue - type plasminogen activator ( t - PA ) . In this study , we examined the effects of oversulfated fucoidan ( OSF ) derivatives and heparin on lipopolysaccharide ( LPS ) - induced release of P05121 antigen from cultured human umbilical vein endothelial cells ( HUVEC ) . Addition of LPS ( 10 micrograms / ml ) enhanced the release of P05121 by HUVEC but not of t - PA antigen . At 18 h , a 2 . 4 - fold increase in the extracellular P05121 level was observed . The increased P05121 level was reduced to control level by the simultaneous addition of 10 micrograms / ml of OSF or heparin . The suppressive effect of native fucoidan was negligible . We also examined the molecular size effect of OSF , using 10 - 20 , 20 - 40 , and 40 - 60 kDa fragments . The result indicated that these fragments were effective as well as the 100 - 130 kDa form of OSF , hence suggesting an important role of the degree of sulfation . P01584 ( P01584 ) is a potent inducer of P05121 in cultured HUVEC . DB01109 , OSF , and its fragments did not suppress the P01584 - induced release of P05121 antigen . Treatment of HUVEC with heparitinase or monoclonal antibody against heparin sulfate proteoglycan ( HSPG ) resulted in a complete loss of its ability to enhance P05121 release in response to LPS stimulation , while the chondroitinase ABC treatment hardly affected the P05121 production . These results suggest that HSPG is involved in the initial binding of LPS to HUVEC . The suppressive effects of OSF and heparin on LPS - induced P05121 release may result from the inhibition of LPS binding to the cell surface HSPG ."
] |
[
"___MASK24___",
"___MASK25___",
"___MASK43___",
"___MASK44___",
"___MASK54___",
"___MASK66___",
"___MASK70___",
"___MASK82___",
"___MASK94___"
] |
___MASK25___
|
MH_train_415
|
interacts_with DB00700?
|
[
"DB09301 glycosaminoglycans as major P16109 ligands on metastatic breast cancer cell lines . The metastatic breast cancer cell line , 4T1 , abundantly expresses the oligosaccharide sialylated Lewis x ( sLe ( x ) ) . SLe ( x ) oligosaccharide on tumor cells can be recognized by E - and P16109 , contributing to tumor metastatic process . We observed that both selectins reacted with this cell line . However , contrary to the P16581 reactivity , which was sLe ( x ) dependent , P16109 reactivity with this cell line was sLe ( x )- independent . The sLe ( x )- Neg variant of the 4T1 cell line with markedly diminished expression of sLe ( x ) and lack of sLe ( a ) , provided a unique opportunity to characterize P16109 ligands and their contribution to metastasis in the absence of overlapping selectin ligands and P16581 binding . We observed that P16109 binding was Ca ( 2 +)- independent and sulfation - dependent . We found that P16109 reacted primarily with cell surface chondroitin sulfate ( CS ) proteoglycans , which were abundantly and stably expressed on the surface of the 4T1 cell line . P16109 binding to the 4T1 cells was inhibited by heparin and CS glycosaminoglycans ( GAGs ) . Moreover , ___MASK34___ administration significantly inhibited experimental lung metastasis . In addition , the data suggest that surface CS GAG chains were involved in P16109 mediated adhesion of the 4T1 cells to murine platelets and human umbilical vein endothelial cells . The data suggest that CS GAGs are also the major P16109 - reactive ligands on the surface of human MDA - MET cells . The results warrant conducting clinical studies on the involvement of cell surface CS chains in breast cancer metastasis and evaluation of various CS types and their biosynthetic pathways as target for development of treatment strategies for antimetastatic therapy of this disease .",
"Antiinflammatory effect of lactic acid bacteria : inhibition of cyclooxygenase - 2 by suppressing nuclear factor - kappaB in Raw264 . 7 macrophage cells . Lactobacillus casei 3260 ( L . casei 3260 ) was evaluated in relation to the inflammatory response mediated by lipopolysaccharide ( LPS ) - induced nuclear factor - kappaB ( NF - kappaB ) and cyclooxygenase - 2 ( P35354 ) expression in Raw264 . 7 macrophage cells . The treatment of Raw264 . 7 cells with L . casei 3260 significantly inhibited the secretion of tumor necrosis factor - alpha ( P01375 ) and prostaglandins E2 ( DB00917 ) , followed by suppression of P35354 . To clarify the molecular mechanism , the inhibitory effect of L . casei 3260 on the NF - kappaB signaling pathway was examined based on the luciferase reporter activity . Although the treatment of Raw264 . 7 cells with L . casei 3260 did not affect the transcriptional activity of NF - kappaB , it did inhibit NF - kappaB activation , as determined by the cytosolic p65 release and degradation of I - kappaBalpha . Therefore , these findings suggest that the suppression of P35354 through inhibiting the NF - kappaB activation by LPS may be associated with the antiinflammatory effects of L . casei 3260 on Raw264 . 7 cells .",
"Morphological and functional in vitro and in vivo characterization of the mouse corpus cavernosum . 1 . In normal mice , the distribution of adrenergic , cholinergic , some peptidergic , and neuronal nitric oxide synthase ( P29475 ) - containing nerves were investigated . Functional in vitro correlates were obtained . An in vivo model was developed in which erectile haemodynamics in response to drugs or nerve - stimulation were studied . 2 . Immunoreactivities for vesicular acetylcholine transporter protein ( Q16572 ) , P29475 - , and vasoactive intestinal polypeptide ( P01282 ) , co - existed in nerve fibres and terminal varicosities . Immunoreactivities for neuropeptide Y ( P01303 ) and tyrosine hydroxylase ( TH ) were found in the same nerve structures . 3 . Chemical sympathectomy abolished TH - and P01303 - IR nerve structures in cavernous smooth muscle bundles . The distribution of calcitonin gene - related peptide ( P80511 ) - , P29475 - , Q16572 - and P01282 - IR nerve structures was unchanged . 4 . In endothelial cells of the central and helicine arteries , veins and venules , intense immunoreactivity for endothelial NOS ( P29474 ) was observed . No distinct P29474 - IR cells were found lining the cavernous sinusoids . 5 . In vitro , nerve - induced relaxations were verified , and endothelial NO / cyclic GMP - mediated relaxant responses were established . P01282 and P80511 had small relaxant effects . A functioning adenylate cyclase / cyclic AMP pathway was confirmed . 6 . Neuronal excitatory responses were abolished by prazosin , or forskolin . P01282 and P80511 counteracted contractions , whereas P01303 and scopolamine enhanced excitatory responses . 7 . In vivo , erectile responses were significantly attenuated by L - NAME ( 50 mg kg (- 1 ) ) and facilitated by sildenafil ( 200 microg kg (- 1 ) ) . 8 . It is concluded that the mouse is a suitable model for studies of erectile mechanisms in vitro and in vivo .",
"Integration of Q96HU1 kinase signal transduction pathways at the serum response element . The ternary complex factor ( TCF ) subfamily of ETS - domain transcription factors bind with serum response factor ( P11831 ) to the serum response element ( SRE ) and mediate increased gene expression . The TCF protein Elk - 1 is phosphorylated by the JNK and P29323 groups of mitogen - activated protein ( Q96HU1 ) kinases causing increased DNA binding , ternary complex formation , and transcriptional activation . Activated SRE - dependent gene expression is induced by JNK in cells treated with interleukin - 1 and by P29323 after treatment with phorbol ester . The Elk - 1 transcription factor therefore integrates Q96HU1 kinase signaling pathways in vivo to coordinate biological responses to different extracellular stimuli .",
"Transforming growth factor alpha - induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity . Although transforming growth factor ( TGF ) - alpha , a member of the epidermal growth factor ( P01133 ) family , has been shown to protect neurons against excitotoxic and ischemic brain injuries , its mechanism of action remains unknown . In the present study , we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF - alpha rescues neurons from N - methyl - D - aspartate ( DB01221 ) - induced excitotoxic death , with the obligatory presence of astrocytes . Because neuronal tissue - type plasminogen activator ( t - PA ) release was shown to potentiate DB01221 - induced excitotoxicity , we observed that TGF - alpha treatment reduced DB01221 - induced increase of t - PA activity in mixed cultures of neurons and astrocytes . In addition , we showed that although TGF - alpha induces activation of the extracellular signal - regulated kinases ( ERKs ) in astrocytes , it failed to activate Q8NFH3 / Q8TCB0 in neurons . Finally , we showed that TGF - alpha , by an P29323 - dependent mechanism , stimulates the astrocytic expression of P05121 , a t - PA inhibitor , which mediates the neuroprotective activity of TGF - alpha against DB01221 - mediated excitotoxic neuronal death . Taken together , we indicate that TGF - alpha rescues neurons from DB01221 - induced excitotoxicity in mixed cultures through inhibition of t - PA activity , involving P05121 overexpression by an P29323 - dependent pathway in astrocytes .",
"The effect of prenatal nicotine on mRNA of central cholinergic markers and hematological parameters in rat fetuses . A number of studies have demonstrated the influence of nicotine on fetal development . This study determined the expression of choline acetyltransferase ( P28329 ) , vesicular acetylcholine transporter ( Q16572 ) , and high - affinity choline transporter ( Q9GZV3 ) in the forebrain and hindbrain following chronic prenatal nicotine exposure in the rat fetus ( maternal rats were subcutaneously injected with nicotine at different gestation periods ) . We also measured the effect of chronic nicotine exposure on fetal blood pO ( 2 ) , pCO ( 2 ) , pH , Na (+) and K (+) concentrations , as well as lactic acid levels . Maternal nicotine exposure during pregnancy was associated with a decrease in fetal pO ( 2 ) coupled with a significant increase in pCO ( 2 ) and lactic acid as well as restricted fetal growth . Additionally , maternal nicotine administration also reduced P28329 , Q16572 , and Q9GZV3 mRNA levels in the fetal brain . ___MASK35___ - induced fetal hypoxic responses and reduced cholinergic marker expression in the brain were more severe when nicotine was started in early gestation . Our results provide new information about the effects of repeated exposure to nicotine in utero on the expression of central P28329 , Q16572 , and Q9GZV3 in the rat fetus . These results indicate that repeated hypoxic episodes or / and a direct effect of nicotine on the central cholinergic system during pregnancy may contribute to brain developmental problems in fetal origin .",
"Inhibition of a thrombin anion - binding exosite - 2 mutant by the glycosaminoglycan - dependent serpins protein C inhibitor and heparin cofactor II . Antithrombin ( P01008 ) , heparin cofactor II ( HCII ) and protein C inhibitor ( P05154 ; also named plasminogen activator inhibitor - 3 ) are serine protease inhibitors ( serpins ) whose thrombin inhibition activity is accelerated in the presence of glycosaminoglycans . We compared the inhibition properties of P05154 and HCII to P01008 using R93A / R97A / R101A thrombin , an anion - binding exosite - 2 ( exosite - 2 ) mutant that has greatly reduced heparin - binding properties . ___MASK34___ - enhanced P05154 inhibition of R93A / R97A / R101A thrombin was only approximately 2 - fold compared to 40 - fold enhancement with wild - type recombinant thrombin . P07204 ( TM ) ( with or without the chondroitin sulfate moiety ) accelerated P05154 inhibition of both wild - type and R93A / R97A / R101A thrombins . HCII achieved the same maximum activity in the presence of heparin with both wild - type and R93A / R97A / R101A thrombins ; however , the optimum heparin concentration was 20 times greater than the reaction with wild - type thrombin , indicative of a decrease in heparin affinity . Dermatan sulfate ( DSO4 ) - catalyzed HCII thrombin inhibition was unchanged in R93A / R97A / R101A thrombin compared to wild - type recombinant thrombin . These results suggest that P05154 is similar to P01008 and depends upon ternary complex formation with heparin and these specific thrombin exosite - 2 residues to accelerate thrombin inhibition . In contrast , HCII does not require DB00125 ( 93 ) , DB00125 ( 97 ) and DB00125 ( 101 ) of thrombin exosite - 2 and further supports the hypothesis that HCII uses an allosteric process following glycosaminoglycan binding to inhibit thrombin .",
"P01375 inhibits flow and insulin signaling leading to NO production in aortic endothelial cells . Endothelial cells release nitric oxide ( NO ) acutely in response to increased \" flow \" or fluid shear stress ( FSS ) , and the increase in NO production is correlated with enhanced phosphorylation and activation of endothelial nitric oxide synthase ( P29474 ) . Both vascular endothelial growth factor and FSS activate endothelial protein kinase B ( P31749 ) by way of incompletely understood pathway ( s ) , and , in turn , P31749 phosphorylates P29474 at DB00133 - 1179 , causing its activation . In this study , we found that either FSS or insulin stimulated insulin receptor substrate - 1 ( P35568 ) tyrosine and serine phosphorylation and increased P35568 - associated phosphatidylinositol 3 - kinase activity , phosphorylation of P31749 DB00133 - 473 , phosphorylation of P29474 DB00133 - 1179 , and NO production . Brief pretreatment of bovine aortic endothelial cells with tumor necrosis factor - alpha ( P01375 ) inhibited the above described FSS - or insulin - stimulated protein phosphorylation events and almost totally inhibited FSS - or insulin - stimulated NO production . These data indicate that FSS and insulin regulate P29474 phosphorylation and NO production by overlapping mechanisms . This study suggests one potential mechanism for the development of endothelial dysfunction in disease states with alterations in insulin regulation and increased P01375 levels .",
"Candidate genetic markers and the risk of restenosis after coronary angioplasty . The aim of the present study was to test for possible associations between candidate gene polymorphisms and the risk of restenosis and recurrent restenosis after percutaneous transluminal coronary angioplasty ( PTCA ) without stenting . We followed up 511 PTCA patients , and restenosis and recurrent restenosis were defined according to angiographical criteria . Genotyping of the beta - fibrinogen - 455 G / A , glycoprotein ( GP ) IIIa PlA1 / PlA2 , plasminogen activator inhibitor - 1 ( P05121 ) 4G / 5G , factor V Leiden 1691 G / A , tumour necrosis factor alpha ( TNFalpha ) - 238 G / A , TNFalpha - 308 G / A , interleukin ( IL ) - 1alpha - 889 C / T , IL - 1beta - 511 C / T , methylenetetrahydrofolate reductase ( P42898 ) 677 C / T and endothelial nitric oxide synthase ( P29474 ) 4 b / a gene polymorphisms was performed by PCR and restriction - fragment - length - polymorphism - based techniques . One hundred and sixty patients ( 31 . 3 % ) developed restenosis and in 130 of these patients , of whom 123 were available for analysis , a second PTCA without stenting was performed . Of these patients , 35 ( 28 . 5 % ) developed recurrent restenosis . None of the investigated genotypes were associated with the risk of restenosis or recurrent restenosis after PTCA . The degree of stenosis before and immediately after PTCA and the severity of the lesion were independent predictors for restenosis after PTCA . In conclusion , there was no association between the beta - fibrinogen - 455 G / A , GP IIIa PlA1 / A2 , P05121 4G / 5G , factor V Leiden 1691 G / A , TNFalpha - 238 G / A , TNFalpha - 308 G / A , IL - 1alpha - 889 C / T , the IL - 1beta - 511 C / T , P42898 677 C / T and P29474 4 b / a gene polymorphisms and the risk of restenosis after PTCA as well as recurrent restenosis after repeated PTCA .",
"22 - Oxacalcitriol prevents progression of endothelial dysfunction through antioxidative effects in rats with type 2 diabetes and early - stage nephropathy . BACKGROUND : Vitamin D deficiency is associated with endothelial dysfunction in type 2 diabetes patients , but the effectiveness of vitamin D supplementation remains controversial . We assessed whether 22 - oxacalcitriol ( O75051 ) could prevent endothelial dysfunction in type 2 diabetes mellitus ( DM ) rats . METHODS : DM rats with early - stage nephropathy were treated for 10 weeks with O75051 ( 0 . 2 μg / kg ) three times per week or by an implanted insulin pellet . Endothelial dysfunction was assessed by femoral flow - mediated dilation ( FMD ) . RESULTS : P01308 significantly improved FMD as blood glucose levels normalized . O75051 also improved FMD without hypercalcemia or hyperphosphatemia and without affecting blood glucose or blood pressure . In femoral arteries , O75051 significantly suppressed the elevated expression of O75935 ( phox ) , a nicotinamide adenine dinucleotide phosphate ( NADPH ) oxidase subunit , and improved the endothelial nitric oxide synthase ( P29474 ) dimer - to - monomer ratio . In cultured endothelial cells , O75051 significantly inhibited high - glucose ( HG ) - induced reactive oxygen species ( ROS ) production . Simultaneously , O75051 significantly suppressed HG - induced O75935 ( phox ) expression and improved P29474 uncoupling as was observed in the in vivo study . CONCLUSION : In DM rats , O75051 improved endothelial dysfunction , at least in part , by suppressing ROS generation through O75935 ( phox ) expression , which might contribute to improving P29474 uncoupling .",
"Activation status of receptor tyrosine kinase downstream pathways in primary lung adenocarcinoma with reference of P01116 and P00533 mutations . The activation status of signal transduction pathways involving receptor tyrosine kinases and its association with P00533 or P01116 mutations have been widely studied using cancer cell lines , although it is still uncertain in primary tumors . To study the activation status of main components of growth factor - induced pathways , phosphorylated Akt ( pAkt ) , extracellular signal - regulated kinases 1 and 2 ( pERK ) and other downstream proteins were immunohistochemically examined using surgical samples of 193 primary lung adenocarcinomas . Also , thyroid transcription factor - 1 ( Q15669 - 1 ) expression and mutation status of P00533 and P01116 were examined . Advanced tumor stages ( p < 0 . 001 ) , negative Q15669 - 1 expression ( p < 0 . 001 ) and Akt activation ( p = 0 . 015 ) were independent and significant poor prognostic markers . Akt activation related to advanced stage ( p = 0 . 021 ) , invasiveness ( p = 0 . 004 ) , and not to mutations . Q15669 - 1 expression associated with never - smoker ( p = 0 . 013 ) , pre - or minimally invasiveness ( p < 0 . 001 ) and P00533 mutations ( p = 0 . 017 ) as well as with pERK ( p = 0 . 039 ) expression . P00533 mutations did not correlated with pAkt and pERK expression , which was different from the results based on cultured cells , while P01116 mutations were solely and significantly linked to P29323 activation ( p = 0 . 009 ) . In lung adenocarcinoma , tumors with Q15669 - 1 expression have distinct characteristics regarding mutations , signal protein activation and clinical issues . Moreover , this property was revealed to be important in outcome estimation at any tumor stage , whereas Akt activation is abnormally affected according to the tumor stage regardless of their cell origin . The signal proteins were differently related to mutation status from cultured cells .",
"DB04630 stimulates vascular smooth muscle cell proliferation via big mitogen - activated protein kinase 1 activation . The nongenomic effects of aldosterone have been implicated in the pathogenesis of various cardiovascular diseases . DB04630 - induced nongenomic effects are attributable in part to the activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) , a classical mitogen - activated protein ( Q96HU1 ) kinase . Q13164 ( Q13164 ) , a newly identified Q96HU1 kinase , has been shown to be involved in cell proliferation , differentiation , and survival . We examined whether aldosterone stimulates Q13164 - mediated proliferation of cultured rat aortic smooth muscle cells ( RASMCs ) . P08235 ( MR ) expression and localization were evaluated by Western blotting analysis and fluorolabeling methods . P27361 / 2 and Q13164 activities were measured by Western blotting analysis with the respective phosphospecific antibodies . Cell proliferation was determined by Alamar Blue colorimetric assay . DB04630 ( 0 . 1 to 100 nmol / L ) dose - dependently activated Q13164 in RASMCs , with a peak at 30 minutes . To clarify whether aldosterone - induced Q13164 activation is an MR - mediated phenomenon , we examined the effect of eplerenone , a selective MR antagonist , on aldosterone - induced Q13164 activation . DB00700 ( 0 . 1 to 10 micromol / L ) dose - dependently inhibited aldosterone - induced Q13164 activation in RASMCs . DB04630 also stimulated RASMC proliferation , which was inhibited by eplerenone . DB04630 - mediated phenomena were concluded to be attributable to a nongenomic effect because cycloheximide failed to inhibit aldosterone - induced Q13164 activation . Transfection of dominant - negative Q96HU1 kinase / P29323 kinase 5 ( Q13163 ) , which is an upstream regulator of Q13164 , partially inhibited aldosterone - induced RASMC proliferation , which was almost completely inhibited by MEK inhibitor PD98059 . In addition to the classical steroid activity , rapid nongenomic effects induced by aldosterone may represent an alternative etiology for vascular diseases such as hypertension .",
"Use of a cyclo - oxygenase 2 inhibitor for prophylaxis of cystoid macular oedema following cataract surgery : a randomized placebo - controlled trial . BACKGROUND : To assess the efficacy of Celecoxib , a cyclo - oxygenase 2 ( P35354 ) inhibitor , as prophylaxis for cystoid macular oedema after routine cataract surgery . METHODS : A prospective , randomized , double - blind placebo - controlled trial of 69 hospital patients undergoing cataract surgery . Celecoxib 200 mg twice daily or placebo was given immediately after surgery for 14 days . Optical coherence tomography was used to quantify macular thickness before surgery and on day 1 , week 2 and week 6 after surgery . RESULTS : Sixty - nine patients were enrolled , of which 33 received placebo and 36 received active drug . Clinically apparent cystoid macular oedema occurred in four of the treatment group and two of the placebo group ( P = 0 . 68 ) . No difference in best - corrected visual acuity was seen at 6 weeks ( P = 0 . 37 ) . Covariate analysis of the results at 2 weeks and 6 weeks showed a macular thickness of 3 % less in the treatment group compared with placebo ( P = 0 . 050 ) . CONCLUSION : Celecoxib may decrease macular thickening following routine cataract surgery at 2 and 6 weeks after surgery as measured by Stratus O75051 III . No difference in best - corrected visual acuity or clinically apparent cystoid macular oedema was seen . Further investigation of P35354 inhibitors in a larger prospective randomized trial is required .",
"Endothelial protective genes induced by statin are mimicked by Q13164 activation as triggered by a drug combination of FTI - 277 and GGTI - 298 . BACKGROUND : Statins are potent inhibitors of cholesterol biosynthesis and are clinically beneficial in preventing cardiovascular diseases , however , the therapeutic utility of these drugs is limited by myotoxicity . Here , we explored the mechanism of statin - mediated activation of Q13164 in the human endothelium with the goal of identifying compounds that confer endothelial protection but are nontoxic to muscle . METHODS : An Q13164 - one hybrid luciferase reporter transfected into COS - 7 cells with pharmacological and molecular manipulations dissected the signaling pathway leading to statin activation of Q13164 . qRT - PCR of HUVEC cells documented the transcriptional activation of endothelial - protective genes . Lastly , morphological and cellular DB00171 analysis , and induction of atrogin - 1 in C2C12 myotubes were used to assess statin - induced myopathy . RESULTS : Statin activation of Q13164 is dependent on the cellular reduction of GGPPs . Furthermore , we found that the combination of FTI - 277 ( inhibitor of farnesyl transferase ) and GGTI - 298 ( inhibitor of geranylgeranyl transferase I ) mimicked the statin - mediated activation of Q13164 . FTI - 277 and GGTI - 298 together recapitulated the beneficial effects of statins by transcriptionally upregulating anti - inflammatory mediators such as P29474 , P07204 , and Q9Y5W3 . Finally , C2C12 skeletal myotubes treated with both FTI - 277 and GGTI - 298 evoked less morphological and cellular changes recognized as biomarkers of statin - associated myopathy . CONCLUSIONS : Statin - induced endothelial protection and myopathy are mediated by distinct metabolic intermediates and co - inhibition of farnesyl transferase and geranylgeranyl transferase I confer endothelial protection without myopathy . GENERAL SIGNIFICANCE : The combinatorial FTI - 277 and GGTI - 298 drug regimen provides a promising alternative avenue for endothelial protection without myopathy .",
"P01308 generates free radicals in human fibroblasts ex vivo by a protein kinase C - dependent mechanism , which is inhibited by pravastatin . P01308 can generate oxygen free radicals . Statins , P04035 inhibitors , exert a powerful antioxidant effect . The present study aimed to clarify the mechanisms through which insulin generates free radicals and to assess whether pravastatin modulates such effects . In cultured skin fibroblasts from human volunteers exposed to high insulin concentration , either in the presence or in the absence of pravastatin , insulin induced translocation of the p47 ( phox ) subunit of NAD ( P ) H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC delta - dependent mechanism . The insulin - induced translocation of p47 ( phox ) was PKC delta dependent and attenuated by pravastatin , but independent of the activation of Akt and Rac1 . P01308 - induced Akt phosphorylation was increased by pravastatin and P27361 / 2 phosphorylation attenuated . The present study demonstrates a novel mechanism by which insulin stimulates the generation of free radicals in human fibroblasts , ex vivo . It involves phosphatidylinositol 3 - kinase , PKC delta , and p47 ( phox ) translocation and promotes P27361 / 2 phosphorylation . ___MASK87___ inhibited radical oxygen species production by inhibiting PKC delta . These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome .",
"Recombinational and physical mapping of the locus for primary open - angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open - angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile - onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA1 / D1S210 and NGA5 loci . These loci are 2 . 8 Mb apart on a 4 . 7 - Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G - band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . Our results provide a basis to identify the Q99972 gene .",
"Effects of the total saponins from Rosa laevigata Michx fruit against acetaminophen - induced liver damage in mice via induction of autophagy and suppression of inflammation and apoptosis . The effect of the total saponins from Rosa laevigata Michx fruit ( RLTS ) against acetaminophen ( ___MASK74___ ) - induced liver damage in mice was evaluated in the present paper . The results showed that RLTS markedly improved the levels of liver SOD , CAT , DB00143 , DB00143 - Px , MDA , NO and P35228 , and the activities of serum ALT and Q9NRA2 caused by ___MASK74___ . Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT - mediated dUTP nick end labeling ( TUNEL ) and transmission electron microscopy ( TEM ) assays . In addition , RLTS decreased the gene or protein expressions of cytochrome P450 ( P05181 ) , pro - inflammatory mediators ( IL - 1β , P05112 , P05231 , P01375 - α , P35228 , Bax , HMGB - 1 and P35354 ) , pro - inflammatory transcription factors ( NF - κB and AP - 1 ) , pro - apoptotic proteins ( cytochrome C , p53 , caspase - 3 , caspase - 9 , p - JNK , p - p38 and p - P29323 ) , and increased the protein expressions of Bcl - 2 and Bcl - xL . Moreover , the gene expression of P22301 , and the proteins including LC3 , Q14457 and Atg5 induced by ___MASK74___ were even more augmented by the extract . These results demonstrate that RLTS has hepatoprotective effects through antioxidative action , induction of autophagy , and suppression of inflammation and apoptosis , and could be developed as a potential candidate to treat ___MASK74___ - induced liver damage in the future .",
"Altered regulation of renal nitric oxide , atrial natriuretic peptide and cyclooxygenase systems in aldosterone escape in rats . The present study was aimed to determine whether there is an altered role of local nitric oxide ( NO ) , atrial natriuretic peptide ( P01160 ) and cyclooxygenase ( P36551 ) systems in the kidney in association with the aldosterone escape . Male Sprague - Dawley rats were used . DB04630 ( 200 microg / day ) was infused through entire time course . The control group was kept on a low sodium diet ( 0 . 02 mEq / day ) , and the experimental group was supplied with a higher sodium diet ( 2 . / day ) . Four days after beginning the regimen , the kidneys were taken . The protein expression of NO synthase ( NOS ) and P36551 isoforms was determined by semiquantitative immunoblotting . The mRNA expression of components of P01160 system was determined by real - time polymerase chain reaction . The activities of soluble and particulate guanylyl cyclases were determined by the amount of cGMP generated in responses to sodium nitroprusside and P01160 , respectively . There developed aldosterone escape in the experimental group . Accordingly , the renal content and the urinary excretion of NO increased . The expression of P29475 was increased in the inner medulla . Neither the expression of P29474 nor that of P35228 was changed . The expression and the catalytic activity of soluble guanylyl cyclase remained unaltered . The mRNA expression of P01160 was increased . Neither the expression of P16066 or P17342 nor the activity of particulate guanylyl cyclase was altered in the papilla . The protein expression of P35354 was increased in the inner medulla , while that of P23219 remained unchanged . In conclusion , the upregulation of P29475 , P01160 , and P35354 may be causally related with the aldosterone escape .",
"Amelioration of nephropathy with apoA - 1 mimetic peptide in apoE - deficient mice . BACKGROUND : There is mounting evidence that dyslipidaemia may contribute to development and progression of renal disease . For instance , hyperlipidaemia in apolipoprotein E - deficient ( apoE (-/-) ) mice is associated with glomerular inflammation , mesangial expansion and foam cell formation . ApoA - 1 mimetic peptides are potent antioxidant and anti - inflammatory compounds which are highly effective in ameliorating atherosclerosis and inflammation in experimental animals . Given the central role of oxidative stress and inflammation in progression of renal disease , we hypothesized that apoA - 1 mimetic peptide , D - 4F , may attenuate renal lesions in apoE (-/-) mice . METHODS : Twenty - five - month - old female apoE (-/-) mice were treated with D - 4F ( 300 µg / mL in drinking water ) or placebo for 6 weeks . Kidneys were harvested and examined for histological and biochemical characteristics . RESULTS : Compared with the control mice , apoE (-/-) mice showed significant proteinuria , tubulo - interstitial inflammation , mesangial expansion , foam cell formation and up - regulation of oxidative [ NAD ( P ) H oxidase subunits ] and inflammatory [ NF - κB , P13500 , P05121 and P35354 ] pathways . D - 4F administration lowered proteinuria , improved renal histology and reversed up - regulation of inflammatory and oxidative pathways with only minimal changes in plasma lipid levels . CONCLUSIONS : The apoE (-/-) mice develop proteinuria and glomerular and tubulo - interstitial injury which are associated with up - regulation of oxidative and inflammatory mediators in the kidney and are ameliorated by the administration of apoA - 1 mimetic peptide . These observations point to the role of oxidative stress and inflammation in the pathogenesis of renal disease in hyperlipidaemic animals and perhaps humans .",
"Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .",
"Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40 - fold ) in high - responding opossums , but moderately elevated ( 6 - fold ) in low - responding opossums after they had consumed a high - cholesterol and high - fat diet for 24 wk . In both high - and low - responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2 - fold ) , esterified cholesterol ( 11 - fold ) , and triglycerides ( 2 - fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 gene and downregulation of the Q02318 , Q9H221 , and P21439 genes . Genes involved in inflammation ( P01375 , P19838 , and P35354 ) and in oxidative stress ( P13498 and P14598 ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 ) and collagen genes ( Col1A1 , Col3A1 , and Col4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high - responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK20___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK20___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK20___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK20___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"Interleukin - 1β causes excitotoxic neurodegeneration and multiple sclerosis disease progression by activating the apoptotic protein p53 . BACKGROUND : Understanding how inflammation causes neuronal damage is of paramount importance in multiple sclerosis ( MS ) and in other neurodegenerative diseases . Here we addressed the role of the apoptotic cascade in the synaptic abnormalities and neuronal loss caused by the proinflammatory cytokines interleukin - 1β ( IL - 1β ) and tumor necrosis factor ( P01375 - α ) in brain tissues , and disease progression caused by inflammation in relapsing - remitting MS ( RRMS ) patients . RESULTS : The effect of IL - 1β , but not of P01375 - α , on glutamate - mediated excitatory postsynaptic currents was blocked by pifithrin - α ( DB00522 ) , inhibitor of p53 . The protein kinase C ( PKC ) / transient receptor potential vanilloid 1 ( Q8NER1 ) pathway was involved in IL - 1β - p53 interaction at glutamatergic synapses , as pharmacological modulation of this inflammation - relevant molecular pathway affected DB00522 effects on the synaptic action of IL - 1β . IL - 1β - induced neuronal swelling was also blocked by DB00522 , and IL - 1β increased the expression of P38936 , a canonical downstream target of activated p53 . Consistent with these in vitro results , the Pro / Pro genotype of p53 , associated with low efficiency of transcription of p53 - regulated genes , abrogated the association between IL - 1β cerebrospinal fluid ( P04141 ) levels and disability progression in RRMS patients . The interaction between p53 and P04141 IL - 1β was also evaluated at the optical coherence tomography ( O75051 ) , showing that IL - 1β - driven neurodegenerative damage , causing alterations of macular volume and of retinal nerve fibre layer thickness , was modulated by the p53 genotype . CONCLUSIONS : Inflammatory synaptopathy and neurodegeneration caused by IL - 1β in RRMS patients involve the apoptotic cascade . Targeting IL - 1β - p53 interaction might result in significant neuroprotection in MS .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK65___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"Inhibition of HCV by the serpin antithrombin III . BACKGROUND : Although there have been dramatic strides made recently in the treatment of chronic hepatitis C virus infection , interferon - α based therapy remains challenging for certain populations , including those with unfavorable Q8IZI9 genotypes , psychiatric co - morbidity , HIV co - infection , and decompensated liver disease . We have recently shown that P01008 , a serine protease inhibitor ( serpin ) , has broad antiviral properties . RESULTS : We now show that P01008 is capable of inhibiting HCV in the OR6 replicon model at micromolar concentrations . At a mechanistic level using gene - expression arrays , we found that P01008 treatment down - regulated multiple host cell signal transduction factors involved in the pathogenesis of cirrhosis and hepatocellular carcinoma , including Jun , Myc and P12643 . Using a protein interactive network analysis we found that changes in gene - expression caused by P01008 were dependent on three nodes previously implicated in HCV disease progression or HCV replication : NFκB , O75791 MAPK , and P27361 / 2 . CONCLUSIONS : Our findings suggest that P01008 stimulates a novel innate antiviral host cell defense different from current treatment options .",
"Suppression of parathyroid hormone - related protein messenger RNA expression by medroxyprogesterone acetate in breast cancer tissues . The level of parathyroid hormone - related protein ( P12272 ) expressed in breast cancer tissue is closely related to the incidence of bone metastasis . We examined the P12272 mRNA expression in breast cancer tissues by coamplification polymerase chain reaction ( PCR ) in mole ratio to internal standard beta - actin mRNA . The P12272 expression was higher in premenopausal patients than in postmenopausal patients ( P < 0 . 05 ) . More pronounced difference by menopause found in estrogen receptor ( ER ) positive groups ( P < 0 . 001 ) indicated that the P12272 expression in breast cancer tissue is hormonally regulated and might be altered by endocrine agents . To clarify the changes of P12272 expression by endocrine therapy of breast cancer , we measured P12272 expression in the breast cancer tissue incubated for 24 h with 1 x 10 (- 8 ) M of estradiol ( E2 ) , 1 x 10 (- 6 ) M of tamoxifen ( TAM ) and 1 x 10 (- 5 ) M of medroxyprogesterone acetate ( ___MASK20___ ) . The P12272 expression was decreased significantly by ___MASK20___ ( P < 0 . 005 ) , while E2 and TAM did not change the P12272 expression . P06401 ( PgR ) mRNA expression was also examined to confirm that the breast cancer tissue responds to E2 and TAM . The results were well compatible with the better therapeutic effect of ___MASK20___ reported for the treatment of breast cancer with bone metastases . As a potential candidate for the receptor that mediates the suppressive effect of ___MASK20___ , androgen receptor ( AR ) is suggested most probable . Present results also demonstrated that the clinical response of individual tumors is closely associated with the early in vitro changes of gene expression detected in the cancer specimen .",
"Anti - inflammatory effects of pravastatin on Helicobacter pylori - induced gastritis in mice . ___MASK87___ , an P04035 inhibitor , exerts anti - inflammatory effects via several mechanisms including induction of endothelial nitric oxide synthase ( P29474 ) . We investigated the effect of pravastatin on Helicobacter pylori - induced gastritis in mice . Mice with or without H . pylori infection received intraperitoneal pravastatin daily for 1 week . Expression of P29474 mRNA and tumor necrosis factor - alpha mRNA and myeloperoxidase activity in gastric tissue was determined . P05164 activity was reduced in a dose - dependent manner by pravastatin , with activity inhibited by 53 . 5 and 73 . 7 % at doses of 0 . 3 and 1 mg / kg , respectively . At a dose of 1 mg / kg , pravastatin reduced the level of tumor necrosis factor - alpha mRNA by 52 . 7 % , while it did not affect P29474 expression . ___MASK87___ had no effects on these inflammatory parameters in uninfected mice . ___MASK87___ did not affect the viability of H . pylori . In conclusion , pravastatin exerts an anti - inflammatory effect on H . pylori - induced gastritis in mice without affecting P29474 expression .",
"Dissection of the phenotypic and genotypic associations with nicotinic dependence . INTRODUCTION : Strong evidence demonstrates that nicotine dependence is associated with 4 genetic variants rs16969968 , rs6474412 , rs3733829 , and rs1329650 in large - scale Genome - Wide Association Studies . We examined how these identified genetic variants relate to nicotine dependence defined by different categorical and dimensional measures . METHODS : Four genetic variants were analyzed in 2 , 047 subjects of European descent ( 1 , 062 cases and 985 controls ) . ___MASK35___ dependence was assessed with multiple smoking measures , including the Fagerström Test for ___MASK35___ Dependence , the Diagnostic and Statistical Manual for Mental Disorders - IV ( DSM - IV ) nicotine dependence , the ___MASK35___ Dependence Syndrome Scale , and the Wisconsin Inventory of Smoking Dependence Motives . Single - item measures of cigarettes per day ( O75976 ) and time to first cigarette ( Q15669 ) in the morning were also examined . RESULTS : Among the variants , association effect sizes were largest for rs16969968 , with measures of craving and heavy smoking , especially cigarettes smoked per day , showing the largest effects . Significant but weaker associations were found for rs6474412 and rs3733729 but not for rs1329650 . None of the more comprehensive measures of smoking behaviors yielded stronger genetic associations with these variants than did O75976 . CONCLUSIONS : O75976 is an important simple measure that captures in part the genetic associations of P30532 and nicotine dependence , even when other more comprehensive measures of smoking behaviors are examined . The P30532 gene is associated with heavy compulsive smoking and craving ; this should inform the mission to improve the diagnostic validity of DSM - V .",
"Association between P16109 glycoprotein ligand - 1 and pathogenesis in acute coronary syndrome assessed by optical coherence tomography . OBJECTIVE : Although monocytes appear to be actively involved in the onset of acute coronary syndrome ( ACS ) , they are heterogenous in human peripheral blood . How up - regulation of monocyte subsets leads to coronary plaque rupture followed by thrombus formation remains unclear . Recent studies have shown that P16109 glycoprotein ligand - 1 ( Q14242 ) is involved in monocyte activation in patients with thrombus formation . We therefore investigated the relationship between the expression of Q14242 on monocyte subsets and thrombus formation using frequency - domain optical coherence tomography ( FD - O75051 ) in patients with ACS . METHODS : We enrolled a total of 100 individuals in this study : patients with acute myocardial infarction ( AMI , n = 25 ) , unstable angina pectoris ( UAP , n = 20 ) , or stable angina pectoris ( n = 35 ) who underwent coronary angiography , and control subjects ( n = 20 ) . Three monocyte subsets ( P08571 ++ CD16 - , P08571 ++ CD16 + , and P08571 + CD16 + ) and the expression of Q14242 were measured by flow cytometry . In patients with AMI and UAP , FD - O75051 was performed before percutaneous coronary intervention . RESULTS : Circulating peripheral P08571 ++ CD16 + monocytes expressed Q14242 more frequently than P08571 ++ CD16 - and P08571 + CD16 + monocytes in patients with ACS . The expression of Q14242 on circulating peripheral P08571 ++ CD16 + monocytes was significantly elevated in patients with AMI compared with the other 3 groups . Moreover , the expression levels of Q14242 on P08571 ++ CD16 + monocytes were significantly higher in patients with plaque rupture or intracoronary thrombus assessed by FD - O75051 . CONCLUSION : Up - regulation of Q14242 on P08571 ++ CD16 + monocytes may be a crucial role in plaque rupture and thrombus formation .",
"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK58___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .",
"[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK34___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .",
"___MASK58___ inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : ___MASK58___ is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti - cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 / 2 ) and P45983 and 2 ( JNK 1 / 2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound - healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC ( 50 ) = 8 . 6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 / 2 expression , upregulation of p - P45983 / 2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .",
"Compound FLZ inhibits lipopolysaccharide - induced inflammatory effects via down - regulation of the P50750 - IKK and P50750 - JNK / p38MAPK pathways in RAW264 . 7 macrophages . AIM : The aim of this study was to investigate the effect of the squamosamide derivative FLZ ( N - 2 -( 4 - hydroxy - phenyl )- ethyl - 2 -( 2 , 5 - dimethoxy - phenyl )- 3 -( 3 - methoxy - 4 - hydroxy - phenyl )- acrylamide ) on lipopolysaccharide ( LPS ) - induced inflammatory mediator production and the underlying mechanism in RAW264 . 7 macrophages . METHODS : RAW264 . 7 cells were preincubated with non - toxic concentrations of compound FLZ ( 1 , 5 , and 10 micromol / L ) for 30 min and then stimulated with 10 microg / L LPS . The production of nitric oxide ( NO ) , the expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase 2 ( P35354 ) , and the activation of nuclear factor kappa - B ( NF - kappaB ) and mitogen - activated protein kinase ( MAPK ) pathways were examined . RESULTS : FLZ significantly inhibited the LPS - induced production of NO , as well as the expression of P35228 and P35354 at both the RNA and the protein levels in RAW264 . 7 cells . The LPS - induced increase in the DNA binding activity of NF - kappaB and activator protein 1 ( AP - 1 ) , the nuclear translocation of NF - kappaB p65 , the degradation of the inhibitory kappaBalpha protein ( P25963 ) and the phosphorylation of P25963 , O15111 ( IKK ) alpha / beta , c - Jun NH ( 2 )- terminal kinase ( JNK ) and p38 MAPKs were all suppressed by FLZ . However , the phosphorylation of extracellular signal - regulated kinase ( P29323 ) was not affected . Further study revealed that FLZ inhibited the phosphorylation of transforming growth factor - beta ( TGF - beta ) - activated kinase 1 ( TAK1 ) , which is an upstream signaling molecule required for IKKalpha / beta , JNK and p38 activation . CONCLUSION : FLZ inhibited the LPS - induced production of inflammatory mediators at least partly through the downregulation of the P50750 - IKK and P50750 - JNK / p38MAPK pathways .",
"Protective effects of mineralocorticoid receptor blockade against neuropathy in experimental diabetic rats . AIMS : P08235 ( MR ) blockade is an effective treatment for hypertension and diabetic nephropathy . There are no data on the effects of MR blockade on diabetic peripheral neuropathy ( DPN ) . The aim of this study was to determine whether MRs are present in the peripheral nerves and to investigate the effectiveness of MR blockade on DPN in streptozotocin ( Q11206 ) - induced diabetic rats . METHODS : Expression of MR protein and messenger RNA ( mRNA ) was examined in the peripheral nerves using Western blot analysis and RT - PCR . We next studied the effects of the selective MR antagonist eplerenone and the angiotensin II receptor blocker candesartan on motor and sensory nerve conduction velocity ( NCV ) , morphometric changes and cyclooxygenase - 2 ( P35354 ) gene and NF - κB protein expression in the peripheral nerves of Q11206 - induced diabetic rats . RESULTS : Expression of MR protein and mRNA in peripheral nerves was equal to that in the kidney . Motor NCV was significantly improved by 8 weeks of treatment with either eplerenone ( Q04695 ± 1 . 2 m / s ) or candesartan ( 46 . 4 ± 6 . 8 m / s ) compared with control diabetic rats ( 33 . 7 ± 2 . 0 m / s ) ( p < 0 . 05 ) . Sensory NCV was also improved by treatment with candesartan or eplerenone in diabetic rats . DB00700 and candesartan caused significant improvement in mean myelin fibre area and mean myelin area compared with control diabetic rats ( p < 0 . 05 ) . P35354 mRNA and NF - κB protein were significantly elevated in the peripheral nerves of diabetic rats compared with control rats , and treatment with eplerenone or candesartan reduced these changes in gene expression ( p < 0 . 05 ) . CONCLUSION : MR blockade may have neuroprotective effects on DPN .",
"Role of cardiovascular aldosterone in hypertension . DB04630 plays an important role in the pathogenesis of cardiovascular disease . We have reported that aldosterone is synthesized in cardiovascular tissues and local aldosterone synthesis plays important roles for hypertension and cardiac hypertrophy . High sodium intake develops and accelerates vascular injury and cardiac hypertrophy in SHRSP . Plasma aldosterone concentrations and P06703 were decreased by high salt intake in SHRSP . DB04630 production , the expression of P19099 mRNA and angiotensin II receptor AT1R mRNA in blood vessels were significantly increased by high salt intake . These results suggest that high salt intake increases aldosterone production and expression of the AT1R mRNA in the vascular tissue in SHRSP , which may contribute to the development of malignant hypertension in salt - loaded SHRSP . However , there are several reports of conflicting data . P08235 ( MR ) binding is tightly regulated by the enzyme 11beta - hydroxysteroid dehydrogenase type 2 ( 11beta - HSD2 ) which selectively metabolizes glucocorticoids to inactive metabolites , thus allowing for MR activation by aldosterone . We have reported that decreased 11beta - HSD2 in blood vessels in Dahl salt - sensitive ( DS ) rats , a model for salt - sensitive hypertension . Local aldosterone excess may play a significant role in the salt sensitivity and development of hypertension . High sodium intake decreased circulating rennin - angiotensin - aldosterone system and increased blood pressure and cardiac hypertrophy in DS rats , which were prevented by the treatment with a selective MR antagonist , eplerenone . DB00700 also improved endothelial nitric oxide synthase ( P29474 ) activity and P29474 mRNA expression in blood vessels in DS rats . These results further suggest that not only circulating aldosterone but also local aldosterone is of critical importance in the pathophysiology of cardiovascular disorders .",
"___MASK58___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .",
"___MASK74___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"DB03404 upregulates Egr - 1 expression in vascular smooth muscle cells via reactive oxygen species P27361 / 2 - Elk - 1 and NF - kappaB . Reactive oxygen species ( ROS ) and oxidant stress are important mediators of cardiovascular pathologies including atherosclerosis . One source of ROS in the vasculature is free heme released from hemoglobin . Because Egr - 1 , the regulator of cell proliferation and apoptosis , is also induced by oxidant stress and is likewise implicated in atherosclerosis , we examined the regulation of Egr - 1 by heme in vascular smooth muscle cells ( SMCs ) . DB03404 increased Egr - 1 expression ( mRNA , protein ) within 30 minutes and P27361 / 2 phosphorylation and nuclear translocation within 5 minutes . Inhibiting hemin - induced P27361 / 2 activation by U0126 ( MAPK - inhibitor ) , the antioxidant N - acetyl cysteine , the NADPH oxidase inhibitors apocynin and diphenyleneiodonium chloride , the superoxide scavenger tiron , or tricarbonyldichlororuthenium ( II )- dimer ( carbon - monoxide donor ; CORM - 2 ) blocked hemin - induced Egr - 1 expression . DB03404 activated Elk - 1 , P11831 , and NF - kappaB and promoted their interaction with the Egr - 1 promoter . Downregulating Elk - 1 ( via siRNA ) or blocking NF - kappaB activation ( via BAY - 11 - 7082 ) abolished hemin induction of Egr - 1 . Finally , hemin - induced Egr - 1 bound the promoters of tissue factor ( TF ) , P00747 Activator Inhibitor ( P05121 ) - 1 , and P01138 - 1A Binding ( NAB ) - 2 , upregulating their expression , and increased the biochemical activity of TF and P05121 . Upregulation of Egr - 1 and its target genes by heme - induced oxidant stress may be an important event in the initiation and progression of inflammatory vascular diseases such as atherosclerosis .",
"Negative feedback regulation between microRNA let - 7g and the oxLDL receptor P78380 . Lectin - like oxidized P01130 - 1 ( P78380 ) is a surface scavenger receptor for oxidized low - density lipoprotein ( oxLDL ) . Several transcription factors have been reported to regulate P78380 expression . MicroRNAs are small noncoding RNAs that control gene expression , but there have been no reports of P78380 expression being regulated by microRNAs . Because the microRNA let - 7g has been predicted to bind to P78380 mRNA , we investigated whether let - 7g can regulate P78380 expression . Our experiments first demonstrated that oxLDL can reduce let - 7g expression . We later confirmed that there is a let - 7g binding site on the 3 '- untranslated region of P78380 mRNA . We showed that intracellular Ca ( 2 +)- activated protein kinase C is involved in the oxLDL - P78380 - let - 7g pathway . Bioinformatics predicted that the let - 7g promoter has a binding site for the transcriptional repressor O75051 - 1 . We used a promoter assay and chromatin immunoprecipitation to confirm this binding . Consequently , knockdown of O75051 - 1 was found to increase let - 7g expression . Transfection of let - 7g inhibited oxLDL - induced P78380 and O75051 - 1 expression , cell proliferation and migration . Mice fed with a high - fat diet showed a decrease in let - 7g and an increase in P78380 and O75051 - 1 . A study on humans showed the serum levels of let - 7g are lower in subjects with hypercholesterolemia compared with normal controls . Our findings identify a negative feedback regulation between let - 7g and P78380 , and indicate that let - 7g could be a target to treat cardiovascular disease .",
"In vivo nuclear uptake of a vitamin D analog ( O75051 ) in different tumor cell populations of FA - 6 cancer xenograft in nude mice by receptor autoradiography . 1 alpha , 25 - dihydroxyvitamin D3 [ 1 alpha , 25 ( OH ) 2D3 ] and its analogs have been shown to repress the production of parathyroid hormone - related peptide ( P12272 ) in tumors , which is a major factor causing humoral hypercalcemia associated with various cancers . Since vitamin D analogs may be applicable to the treatment of cancer patients , the present study was undertaken to examine whether O75051 , an analog with little calcemic activity , is incorporated into tumor tissues , and to identify cellular and subcellular sites of its specific uptake and retention . [ 26 - 3H ] O75051 was injected i . v . into nude mice inoculated with a human pancreatic carcinoma cell line ( FA - 6 ) . At 1 hour after the injection , intracellular concentration of radioactivity was visualized by receptor ( thaw - mount ) autoradiography . The results indicate a heterogeneous distribution of radioactivity in nuclei of certain large cancer cells as well as in single or clustered small and elongated cells within the tumor , while connective tissue cells outside of the tumor remained free of nuclear labeling . The data suggest that O75051 acts selectively at the genome of cancer cells during a certain maturational stage and also of a second population of small fibroblast - like cells that may have been transplanted with the tumor or are host - derived .",
"P08235 antagonism in the treatment of chronic central serous chorioretinopathy : a pilot study . PURPOSE : Based on experimental data showing that central serous chorioretinopathy could result from overactivation of mineralocorticoid receptor pathway in choroid vessels , the authors studied eplerenone , a mineralocorticoid receptor antagonist , as a potential treatment for chronic central serous chorioretinopathy . METHODS : This nonrandomized pilot study included 13 patients with central serous chorioretinopathy of at least 4 - month duration , treated with 25 mg / day of oral eplerenone for a week followed by 50 mg / day for 1 or 3 months . The primary outcome measure was the changes in central macular thickness recorded by optical coherence tomography , and the secondary outcomes included changes in foveal subretinal fluid ( P11831 ) measured by O75051 , in best - corrected visual acuity ( BCVA ) and the percentage of eyes achieving complete resolution of subretinal fluid during the treatment period . RESULTS : Central macular thickness decreased significantly from 352 ± 139 μm at baseline to 246 ± 113 μm and 189 ± 99 μm at 1 and 3 months under eplerenone treatment ( P < 0 . 05 and P < 0 . 01 , respectively ) . At 3 months , the subretinal fluid significantly decreased compared with baseline subretinal fluid ( P < 0 . 01 ) and best - corrected visual acuity significantly improved compared with baseline best - corrected visual acuity ( P < 0 . 001 ) . CONCLUSION : DB00700 treatment was associated with a significant reduction in central macular thickness , subretinal fluid level , and an improvement in visual acuity . Randomized controlled trials are needed to confirm these encouraging results .",
"P01116 , P00533 , P09619 - α , P10721 and P35354 status in carcinoma showing thymus - like elements ( CASTLE ) . BACKGROUND : CASTLE ( Carcinoma showing thymus - like elements ) is a rare malignant neoplasm of the thyroid resembling lymphoepithelioma - like and squamous cell carcinoma of the thymus with different biological behaviour and a better prognosis than anaplastic carcinoma of the thyroid . METHODS : We retrospectively investigated 6 cases of this very rare neoplasm in order to investigate the mutational status of P01116 , P00533 , P09619 - α and P10721 , as well as the immunohistochemical expression pattern of CD117 , P00533 and P35354 , and possibly find new therapeutic targets . RESULTS : Diagnosis was confirmed by a moderate to strong expression of P06127 , CD117 and CK5 / 6 , whereas thyroglobulin , calcitonin and Q15669 - 1 were negative in all cases . Tumors were also positive for P35354 and in nearly all cases for P00533 . In four cases single nucleotide polymorphisms ( SNPs ) could be detected in exon 12 of the P09619 - α gene ( rs1873778 ) , in three cases SNPs were found in exon 20 of the P00533 gene ( rs1050171 ) . No mutations were found in the P10721 and P01116 gene . CONCLUSIONS : All tumors showed a P35354 expression as well as an P00533 expression except for one case and a wild - type P01116 status . No activating mutations in the P00533 , P10721 and P09619 - α gene could be detected . Our data may indicate a potential for targeted therapies , but if these therapeutic strategies are of benefit in CASTLE remains to be determined . VIRTUAL SLIDES : The virtual slide ( s ) for this article can be found here : http :// www . diagnosticpathology . diagnomx . eu / vs / 1658499296115016 .",
"Salinity effect on mechanical dewatering of sludge with and without chemical conditioning . The salinity levels of wastewater and sludge are relatively high in some coastal cities as they may use saline water for toilet flushing , and as such , the sludge dewaterability can be affected by it . The salinity effect on sludge dewaterability was therefore investigated through experimental testing of specific resistance in filtration ( P11831 ) , time to filter ( Q15669 ) , and final solid content of sludge . P11831 and Q15669 were determined using Buchner funnel tests . The final solid content was estimated by centrifuging the sludge at four levels of rotational speed . Sludge with three salinity levels ( 5 , 000 , 10 , 000 and 20 , 000 ppm ) were considered in this study . Coagulants such as alum , iron ( II ) sulfate , and organic polyelectrolytes were added to the sludgetostudythe dewaterability of such sludge with chemical conditioning . Experimental results show that doubling the salinity level of the sludge from 10 , 000 to 20 , 000 ppm shows not much change in P11831 and Q15669 . Compared with the sludge without chemical conditioning , the addition of the coagulants to the sludge at a salinity level of 5 , 000 ppm drastically reduces its P11831 and Q15669 . However , sludge with and without chemical conditioning at a salinity of 20 , 000 ppm has similar P11831 and Q15669 . The final solid content of sludge increases almost linearly with salinity . Among the coagulants used in this study , the cationic polyelectrolyte is found to be better in improving sludge dewaterability , while iron ( II ) sulfate performs slightly better in enhancing the final solid content of the sludge .",
"P35354 promotes early atherosclerotic lesion formation in ApoE - deficient and C57BL / 6 mice . Cyclooxygenase ( P36551 ) 2 is expressed in atherosclerotic lesions . We have previously reported that selective inhibition of P35354 reduces early atherosclerosis in P01130 deficient mice . To examine the role of P35354 in atherosclerosis in other mouse models , we studied the effects of selective P35354 inhibition ( by rofecoxib and NS - 398 ) and nonselective P36551 inhibition ( by indomethacin ) on early atherosclerotic lesion formation in apolipoprotein E - deficient ( apoE (-/-) ) mice . Selective P35354 and nonselective P36551 inhibition reduced atherosclerosis in female apoE (-/-) mice by 35 - 38 % and 38 - 51 % in the proximal and en face aortas , respectively . Next we investigated the role of macrophage P35354 by transplanting P35354 (-/-) fetal liver cells into C57BL / 6 mice and challenging the mice with an atherogenic diet . Genetic deletion of P35354 from hematopoietic cells reduced atherosclerosis by 51 % . In addition , LPS activated P35354 (-/-) macrophages had decreased expression of monocyte chemoattractant protein - 1 ( P13500 ) and tumor necrosis factor - alpha ( TNFalpha ) . The results demonstrate that selective inhibition of P35354 and elimination of P35354 from macrophages significantly reduces early atherosclerotic lesion formation in apoE - deficient and C57BL / 6 mice . These results are compatible with P35354 expression by macrophages having a proatherogenic role , and support the potential of anti - inflammatory therapeutic approaches for atherosclerosis .",
"___MASK87___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK87___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK87___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK100___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK50___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Acute erythropoietin cardioprotection is mediated by endothelial response . Increasing evidence indicates that high levels of serum erythropoietin ( Epo ) can lessen ischemia - reperfusion injury in the heart and multiple cardiac cell types have been suggested to play a role in this Epo effect . To clarify the mechanisms underlying this cardioprotection , we explored Epo treatment of coronary artery endothelial cells and Epo cardioprotection in a Mus musculus model with Epo receptor expression restricted to hematopoietic and endothelial cells ( ΔEpoR ) . Epo stimulation of coronary artery endothelial cells upregulated endothelial nitric oxide synthase ( P29474 ) activity in vitro and in vivo , and enhanced nitric oxide ( NO ) production that was determined directly by real - time measurements of gaseous NO release . Epo stimulated phosphoinositide 3 - kinase ( PI3K ) / protein kinase B ( AKT ) and mitogen - activated protein kinase kinase ( MEK ) / extracellular signal regulated kinase ( P29323 ) signaling pathways , and inhibition of PI3K , but not MEK activity , blocked Epo - induced NO production . To verify the potential of this Epo effect in cardioprotection in vivo , ΔEpoR - mice with Epo response in heart restricted to endothelium were treated with Epo . These mice exhibited a similar increase in P29474 phosphorylation in coronary artery endothelium as that found in wild type ( WT ) mice . In addition , in both WT - and ΔEpoR - mice , exogenous Epo treatment prior to myocardial ischemia provided comparable protection . These data provide the first evidence that endothelial cell response to Epo is sufficient to achieve an acute cardioprotective effect . The immediate response of coronary artery endothelial cells to Epo stimulation by NO production may be a critical mechanism underlying this Epo cardioprotection .",
"Cbl - b is a negative regulator of inflammatory cytokines produced by IgE - activated mast cells . c - Cbl and Cbl - b E3 ubiquitin ligases are abundantly expressed in hemopoietic cells where they negatively regulate the activity and levels of many cell surface receptors and associated signaling molecules . By comparing bone marrow - derived mast cells from c - Cbl and Cbl - b - deficient mice it has recently been shown that Cbl - b is the dominant family member for negatively regulating signaling responses from high - affinity IgE receptors . In this study , we suggest that a possible reason for the greater enhancement of IgE receptor signaling in Cbl - b - deficient mice is the relatively higher levels of Cbl - b protein over c - Cbl in mast cells compared with other hemopoietic cells . We also directly compare mast cells from c - Cbl and Cbl - b - deficient mice and find that loss of Cbl - b , but not c - Cbl , increases cell growth , retards receptor internalization , and causes the sustained tyrosine phosphorylation of Syk and its substrates . However , loss of Cbl - b does not enhance the activation of P29323 or Akt , nor does it promote a greater calcium response . Furthermore , loss of Cbl - b or c - Cbl does not increase levels of the Syk or Lyn protein tyrosine kinases . Most notable , however , is the extremely large increase in the production of proinflammatory cytokines P01375 , P05231 , and P13500 by Cbl - b (-/-) mast cells compared with levels produced by c - Cbl (-/-) or wild - type cells . This marked induction , which appears to be restricted to these three cytokines , is dependent on IgE receptor activation and correlates with enhanced O15111 phosphorylation . Thus , Cbl - b functions as a potent negative regulator of cytokines that promote allergic and inflammatory reactions ."
] |
[
"___MASK100___",
"___MASK20___",
"___MASK34___",
"___MASK35___",
"___MASK50___",
"___MASK58___",
"___MASK65___",
"___MASK74___",
"___MASK87___"
] |
___MASK34___
|
MH_train_416
|
interacts_with DB00083?
|
[
"A protein chip membrane - capture assay for botulinum neurotoxin activity . Botulinum neurotoxins A and B ( DB00083 and B ) are neuromuscular blocking agents which inhibit neurotransmission by cleaving the intra - cellular presynaptic SNARE proteins P60880 and P63027 , localized respectively in plasma membrane and synaptic vesicles . These neurotoxins are both dangerous pathogens and powerful therapeutic agents with numerous clinical and cosmetic applications . Consequently there is a need for in vitro assays of their biological activity to screen for potential inhibitors and to replace the widely used in vivo mouse assay . Surface plasmon resonance ( SPR ) was used to measure membrane vesicle capture by antibodies against P60880 and P63027 . Substrate cleavage by BoNTs modified capture providing a method to assay toxin activity . Firstly using synaptic vesicles as a substrate , a comparison of the EC ( 50 ) s for BoNT / B obtained by SPR , ELISA or flow cytometry indicated similar sensitivity although SPR assays were more rapid . Sonication of brain or neuronal cultures generated plasma membrane fragments with accessible intra - cellular epitopes adapted to measurement of DB00083 activity . SPR responses were proportional to antigen concentration permitting detection of as little as 4 pM P60880 in crude lysates . DB00083 activity was assayed using monoclonal antibodies that specifically recognize a P60880 epitope generated by the proteolytic action of the toxin . Incubation of intact primary cultured neurons with DB00083 yielded an EC ( 50 ) of 0 . 5 pM . The SPR biosensor method was sensitive enough to monitor DB00083 and B activity in cells cultured in a 96 - well format providing an alternative to experimental animals for toxicological assays .",
"Physical link and functional coupling of presynaptic calcium channels and the synaptic vesicle docking / fusion machinery . N - and P / Q - type calcium channels are localized in high density in presynaptic nerve terminals and are crucial elements in neuronal excitation - secretion coupling . In addition to mediating Ca2 + entry to initiate transmitter release , they are thought to interact directly with proteins of the synaptic vesicle docking / fusion machinery . As outlined in the preceding article , these calcium channels can be purified from brain as a complex with SNARE proteins which are involved in exocytosis . In addition , N - type and P / Q - type calcium channels are co - localized with syntaxin in high - density clusters in nerve terminals . Here we review the role of the synaptic protein interaction ( synprint ) sites in the intracellular loop II - III ( L ( II - III ) ) of both alpha1B and alpha1A subunits of N - type and P / Q - type calcium channels , which bind to syntaxin , P60880 , and synaptotagmin . DB01373 has a biphasic effect on the interactions of N - type calcium channels with SNARE complexes , stimulating optimal binding in the range of 10 - 20 microM . PKC or P62158 KII phosphorylation of the N - type synprint peptide inhibits interactions with native brain SNARE complexes containing syntaxin and P60880 . Introduction of the synprint peptides into presynaptic superior cervical ganglion neurons reversibly inhibits EPSPs from synchronous transmitter release by 42 % . At physiological Ca2 + concentrations , synprint peptides cause an approximate 25 % reduction in transmitter release of injected frog neuromuscular junction in cultures , consistent with detachment of 70 % of the docked vesicles from calcium channels based on a theoretical model . Together , these studies suggest that presynaptic calcium channels not only provide the calcium signal required by the exocytotic machinery , but also contain structural elements that are integral to vesicle docking , priming , and fusion processes .",
"Unique substrate recognition by botulinum neurotoxins serotypes A and E . Botulinum neurotoxins ( BoNTs ) are zinc proteases that cleave SNARE proteins to elicit flaccid paralysis by inhibiting the fusion of neurotransmitter - carrying vesicles to the plasma membrane of peripheral neurons . There are seven serotypes of BoNT , termed A - G . BoNT serotype A and serotype E cleave P60880 at residues 197 - 198 and 180 - 181 , respectively . Unlike other zinc proteases , the BoNTs recognize extended regions of P60880 for cleavage . The basis for this extended substrate recognition and specificity is unclear . Saturation mutagenesis and deletion mapping identified residues 156 - 202 of P60880 as the optimal cleavage domain for DB00083 , whereas the optimal cleavage domain for BoNT / E was shorter , comprising residues 167 - 186 of P60880 . Two sub - sites were resolved within each optimal cleavage domain , which included a recognition or active site ( AS ) domain that contained the site of cleavage and a binding ( B ) domain , which contributed to substrate affinity . Within the AS domains , the P1 ' , P09131 , and Q15084 sites of P60880 contributed to scissile bond cleavage by LC / A , whereas the P1 ' and P2 sites of P60880 contributed to scissile bond cleavage by LC / E . These studies provide insight into the development of strategies for small molecule inhibitors of the BoNTs .",
"Real - time RT - PCR measurement of the modulation of P35372 expression by nitric oxide in human mononuclear cells . BACKGROUND : In previous studies , we have attributed opiate alkaloid selectivity to a subtype of the neuronal mu receptor known as mu3 , expressed on human blood cells . Opiate alkaloid activation of this receptor subtype leads to the release of constitutively derived nitric oxide . In this report , we show by real - time RT - PCR that the NO donor S - nitroso - N - acetyl - penicillamine ( P60880 ) initiates the down regulation of mu receptor gene expression in human mononuclear cells after 30 minutes . Superoxide dismutase , a free radical scavenger , blocks the effect of P60880 . MATERIAL AND METHODS : Human mononuclear cells isolated from whole blood were treated with P60880 ( 100 microM ) , and also with P60880 plus superoxide dismutase ( 100 U / ml ) at different time points . Real - time RT - PCR with total RNA extracted from the cells was used to analyze expression of the mu opiate receptor . RESULTS : P35372 gene expression was significantly down regulated in cells treated with P60880 at 30 min , and superoxide dismutase blocked the effect of P60880 . At 2 and 6 hours , a rebound effect was observed as noted by an increase in mu receptor expression , and at 24 hours mu receptor expression returned to control levels in the P60880 - treated cells . CONCLUSIONS : This study confirms that human mononuclear cells express the mu opiate receptor transcript and demonstrates that nitric oxide is involved in regulation of its expression .",
"Botulinum neurotoxin type A : Actions beyond P60880 ? Botulinum neurotoxin type A ( DB00083 ) , the most potent toxin known in nature which causes botulism , is a commonly used therapeutic protein . It prevents synaptic vesicle neuroexocytosis by proteolytic cleavage of synaptosomal - associated protein of 25 kDa ( P60880 ) . It is widely believed that DB00083 therapeutic or toxic actions are exclusively mediated by P60880 cleavage . On the other hand , in vitro and in vivo findings suggest that several DB00083 actions related to neuroexocytosis , cell cycle and apoptosis , neuritogenesis and gene expression are not necessarily mediated by this widely accepted mechanism of action . In present review we summarize the literature evidence which point to the existence of unknown DB00083 molecular target ( s ) and modulation of unknown signaling pathways . The effects of DB00083 apparently independent of P60880 occur at similar doses / concentrations known to induce P60880 cleavage and prevention of neurotransmitter release . Accordingly , these effects might be pharmacologically significant . Potentially the most interesting are observations of antimitotic and antitumor activity of DB00083 . However , the exact mechanisms require further studies .",
"___MASK87___ binding to human and rat dopamine and 5 - HT receptors . ___MASK87___ ( ___MASK87___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK87___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK87___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK87___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"Depolarization after resonance energy transfer ( DARET ) : a sensitive fluorescence - based assay for botulinum neurotoxin protease activity . The DARET ( depolarization after resonance energy transfer ) assay is a coupled Förster resonance energy transfer ( FRET ) - fluorescence polarization assay for botulinum neurotoxin type A or E ( DB00083 or BoNT / E ) proteolytic activity that relies on a fully recombinant substrate . The substrate consists of blue fluorescent protein ( Q9ULX5 ) and green fluorescent protein ( GFP ) flanking P60880 ( synaptosome - associated protein of 25 kDa ) residues 134 - 206 . In this assay , the substrate is excited with polarized light at 387 nm , which primarily excites the Q9ULX5 , whereas emission from the GFP is monitored at 509 nm . Energy transfer from the Q9ULX5 to the GFP in the intact substrate results in a substantial depolarization of the GFP emission . The energy transfer is eliminated when the fluorescent domains separate on cleavage by the endopeptidase , and emission from the directly excited GFP product fragment is then highly polarized , resulting in an overall increase in polarization . This increase in polarization can be monitored to assay the proteolytic activity of DB00083 and BoNT / E in real time . It allows determination of the turnover rate of the substrate and the kinetic constants ( V ( max ) and k ( cat ) ) based on the concentration of cleaved substrate determined directly from the measurements using the additivity properties of polarization . The assay is amenable to high - throughput applications .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK51___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"Regulated secretion is impaired in AtT - 20 endocrine cells stably transfected with botulinum neurotoxin type A light chain . Botulinum neurotoxin type A ( DB00083 ) inhibits neurotransmitter release by specific cleavage of P60880 , a synaptosome - associated protein also expressed in the DB01285 secretory cell line AtT - 20 . Expression of light chain DB00083 ( L - DB00083 ) gene transfected into AtT - 20 cells resulted in a cleaved form of P60880 indistinguishable from that generated by bona fide DB00083 . L - DB00083 - transfected cells showed no difference in replication rate , viability , or phenotype , compared with control AtT - 20 cells . In contrast , L - DB00083 - transfected cells could not be induced to secrete DB01285 upon stimulation by 8 - bromo - DB02527 or DB00761 . In addition , alpha - latrotoxin induced DB01285 release from control cells , but not from L - DB00083 - transfected cells . These experiments suggest an important role for P60880 in regulated secretion from AtT - 20 cells and underline the usefulness of this cell system as a tool for the study of the molecular mechanism of peptide hormone secretion .",
"Mastoparan - 7 rescues botulinum toxin - A poisoned neurons in a mouse spinal cord cell culture model . Botulinum neurotoxin serotype A ( DB00083 ) is the most potent poison of biological origin known to mankind . The toxicity of DB00083 is due to the inhibition of neurotransmission at cholinergic synapses ; this is responsible for the symptom of flaccid paralysis at peripheral neuromuscular junctions . At a molecular level , the DB00083 effect is due to its inhibition of stimulated acetylcholine ( ACh ) release from presynaptic nerve terminals . Currently , there is no antidote available to rescue DB00083 - poisoned synapses . Here , we report an example of rescuing botulinum - poisoned cultured mouse spinal cord neurons by treatment with Mastoparan - 7 ( Mas - 7 ) , which is known to be a phospholipase A2 activator compound . Mas - 7 , a naturally occurring bee venom peptide , was delivered to botulinum - poisoned neurons via a drug delivery vehicle ( DDV ) construct prepared using the recombinant non - toxic heavy chain ( HC ) fragment of DB00083 itself . In this method , the DB00083 HC component in the DDV served as a neuron specific drug targeting molecule . We found that Mas - 7 delivered into DB00083 intoxicated spinal cord cells restored over 40 % their property of stimulated neurotransmitter release . Rescue from cell poisoning did not occur from inhibition of the endopeptidase activity of DB00083 light chain ( LC ) against its well - known substrate , P60880 that is mechanistically involved in the cholinergic neuroexocytosis process . Rather , Mas - 7 induced a physiological host response apparently unrelated to P60880 , but linked to the phospholipase - mediated signal transduction pathway .",
"___MASK62___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"Tandem fluorescent proteins as enhanced FRET - based substrates for botulinum neurotoxin activity . The light chain of botulinum neurotoxin A ( DB00083 - LC ) is a zinc - metalloprotease that requires two extended exosites for optimal substrate binding and recognition of its intracellular target P60880 . P27918 and YFP connected through P60880 peptide ( 141 - 206 ) containing both exosites ( CsY ) has been used in a FRET - based assay for DB00083 . To further improve the FRET efficiency in this DB00083 substrate for in vitro high - throughput assays , we explored the feasibility of enhancing the capture of P27918 emission by doubling the number of YFP acceptors . In comparison to CsY , the tandem fluorescence substrates CsYY and YsCsY enhanced the ratiometric fluorescence signal between YFP and P27918 . YsCsY , containing two substrate sites , offered the greatest fluorometric change upon toxin - catalyzed cleavage . In addition to known approaches for enhancing fluorescence yield through various mutations , this alternative tandem substrate approach can boost the FRET signal and is particularly useful for substrates requiring extensive exosite recognition for specificity .",
"Drug Insight : biological effects of botulinum toxin A in the lower urinary tract . Botulinum toxins can effectively and selectively disrupt and modulate neurotransmission in striated muscle . Recently , urologists have become interested in the use of these toxins in patients with detrusor overactivity and other urological disorders . In both striated and smooth muscle , botulinum toxin A ( DB00083 ) is internalized by presynaptic neurons after binding to an extracellular receptor ( ganglioside and presumably synaptic vesicle protein 2C ) . In the neuronal cytosol , DB00083 disrupts fusion of the acetylcholine - containing vesicle with the neuronal wall by cleaving the P60880 protein in the synaptic fusion complex . The net effect is selective paralysis of the low - grade contractions of the unstable detrusor , while still allowing high - grade contraction that initiates micturition . Additionally , DB00083 seems to have effects on afferent nerve activity by modulating the release of DB00171 in the urothelium , blocking the release of DB05875 , calcitonin gene - related peptide and glutamate from afferent nerves , and reducing levels of nerve growth factor . These effects on sensory feedback loops might not only help to explain the mechanism of DB00083 in relieving symptoms of overactive bladder , but also suggest a potential role for DB00083 in the relief of hyperalgesia associated with lower urinary tract disorders .",
"Distinct kinetic changes in neurotransmitter release after SNARE protein cleavage . Neurotransmitter release is triggered by calcium ions and depends critically on the correct function of three types of SNARE [ soluble N - ethylmaleimide - sensitive factor attachment protein ( P60880 ) receptor ] proteins . With use of the large calyx of Held presynaptic terminal from rats , we found that cleavage of different SNARE proteins by clostridial neurotoxins caused distinct kinetic changes in neurotransmitter release . When elevating calcium ion concentration directly at the presynaptic terminal with the use of caged calcium , cleavage of P60880 by botulinum toxin A ( DB00083 ) produced a strong reduction in the calcium sensitivity for release , whereas cleavage of syntaxin using BoNT / C1 and synaptobrevin using tetanus toxin ( TeNT ) produced an all - or - nothing block without changing the kinetics of remaining vesicles . When stimulating release by calcium influx through channels , a difference between BoNT / C1 and TeNT emerged , which suggests that cleavage of synaptobrevin modifies the coupling between channels and release - competent vesicles .",
"Botulinum neurotoxin serotype A specific cell - based potency assay to replace the mouse bioassay . Botulinum neurotoxin serotype A ( DB00083 ) , a potent therapeutic used to treat various disorders , inhibits vesicular neurotransmitter exocytosis by cleaving P60880 . Development of cell - based potency assays ( CBPAs ) to assess the biological function of DB00083 have been challenging because of its potency . CBPAs can evaluate the key steps of BoNT action : receptor binding , internalization - translocation , and catalytic activity ; and therefore could replace the current mouse bioassay . Primary neurons possess appropriate sensitivity to develop potential replacement assays but those potency assays are difficult to perform and validate . This report describes a CBPA utilizing differentiated human neuroblastoma SiMa cells and a sandwich ELISA that measures DB00083 - dependent intracellular increase of cleaved P60880 . Assay sensitivity is similar to the mouse bioassay and measures neurotoxin biological activity in bulk drug substance and BOTOX ® product ( onabotulinumtoxinA ) . Validation of a version of this CBPA in a Quality Control laboratory has led to FDA , Health Canada , and European Union approval for potency testing of BOTOX ® , BOTOX ® Cosmetic , and Vistabel ® . Moreover , we also developed and optimized a DB00083 CBPA screening assay that can be used for the discovery of novel DB00083 inhibitors to treat human disease .",
"Widespread sequence variations in P23763 across vertebrates suggest a potential selective pressure from botulinum neurotoxins . Botulinum neurotoxins ( DB00083 - G ) , the most potent toxins known , act by cleaving three SNARE proteins required for synaptic vesicle exocytosis . Previous studies on BoNTs have generally utilized the major SNARE homologues expressed in brain ( P63027 , syntaxin 1 , and P60880 ) . However , BoNTs target peripheral motor neurons and cause death by paralyzing respiratory muscles such as the diaphragm . Here we report that P23763 , but not P63027 , is the SNARE homologue predominantly expressed in adult rodent diaphragm motor nerve terminals and in differentiated human motor neurons . In contrast to the highly conserved P63027 , BoNT - resistant variations in P23763 are widespread across vertebrates . In particular , we identified a polymorphism at position 48 of P23763 in rats , which renders P23763 either resistant ( I48 ) or sensitive ( M48 ) to BoNT / D . Taking advantage of this finding , we showed that rat diaphragms with I48 in P23763 are insensitive to BoNT / D compared to rat diaphragms with M48 in P23763 . This unique intra - species comparison establishes P23763 as a physiological toxin target in diaphragm motor nerve terminals , and demonstrates that the resistance of P23763 to BoNTs can underlie the insensitivity of a species to members of BoNTs . Consistently , human P23763 contains I48 , which may explain why humans are insensitive to BoNT / D . Finally , we report that residue 48 of P23763 varies frequently between M and I across seventeen closely related primate species , suggesting a potential selective pressure from members of BoNTs for resistance in vertebrates .",
"Heterogeneity of genomic fusion of P11274 and P00519 in Philadelphia chromosome - positive acute lymphoblastic leukemia . Philadelphia chromosome - positive acute lymphoblastic leukemia occurs in two molecular forms , those with and those without rearrangement of the breakpoint cluster region on chromosome 22 . The molecular abnormality in the former group is similar to that found in chronic myelogenous leukemia . To characterize the abnormality in the breakpoint cluster region - unrearranged form , we have mapped a 9 ; 22 translocation from the Philadelphia chromosome - positive acute lymphoblastic leukemia cell line P60880 - B13 by using pulsed - field gel electrophoresis and have cloned the DNA at the translocation junctions . We demonstrate a P11274 - P00519 fusion gene on the Philadelphia chromosome . The breakpoint on chromosome 9 is within P00519 between exons Ia and II , and the breakpoint on chromosome 22 is approximately equal to 50 kilobases upstream of a breakpoint cluster region in an intron of the P11274 gene . This upstream P11274 breakpoint leads to inclusion of fewer P11274 sequences in the fusion gene , compared with the P11274 - P00519 fusion gene of chronic myelogenous leukemia . Consequently , the associated mRNA and protein are smaller . The exons from P00519 are the same . Analysis of leukemic cells from four other patients with breakpoint cluster region - unrearranged Philadelphia chromosome - positive acute lymphoblastic leukemia revealed a rearrangement on chromosome 22 close to the breakpoint in P60880 - B13 in only one patient . These data indicate that breakpoints do not cluster tightly in this region but are scattered , possibly in a large intron . Given the large size of P11274 and the heterogeneity in breakpoint location , detection of P11274 rearrangement by standard Southern blot analysis is difficult . Pulsed - field gel electrophoresis should allow detection at the DNA level in every patient and thus will permit clinical correlation of the breakpoint location with prognosis .",
"Innocuous full - length botulinum neurotoxin targets and promotes the expression of lentiviral vectors in central and autonomic neurons . Fragments of botulinum neurotoxin ( BoNT ) have been explored as potential targeting moieties and carriers of biomolecules into neurons , although with lower binding and translocation efficiency compared with intact proteins . This study exploits a detoxified recombinant form of full - length BoNT / B ( BoTIM / B ) fused with core streptavidin ( CS - BoTIM / B ) for lentiviral targeting to central and autonomic neurons . CS - BoTIM / B underwent an activity - dependent entry into cultured spinal cord neurons . Coupling CS - BoTIM / B to biotinylated lentivirus - encoding green fluorescent protein ( GFP ) endowed considerable neuron selectivity to the vector as evident from the preferential expression of the reporter in neurons co - cultured with skeletal muscle cells . CS - BoTIM / B - guided lentiviral transduction with the expression of a SNARE protein , P60880 ( S25 ) , rendered non - susceptible to proteolysis by three BoNT serotypes , yielded a sizable decrease in cleaved S25 upon exposure of spinal cord neurons to these toxins . This was accompanied by synaptic transmission being spared from blockade by DB00083 or BoNT / E , reflecting adequate translation and functional competence of recombinant multi - toxin - resistant S25 . The augmented neurotropism conveyed on the lentivirus by CS - BoTIM / B was also demonstrated in vivo through enhanced expression of a reporter in intramural ganglionic neurons in the rat trachea , after injection of the targeted GFP - encoding lentivirus . Thus , a novel and realistic prospect for gene therapy of peripheral neuropathies is offered in this study through lentiviral targeting to neurons by CS - BoTIM / B .",
"DB00435 suppresses inducible nitric oxide synthase expression by inhibiting post - translational modification of IkappaB . The expression of inducible nitric oxide synthase ( P35228 ) is a critical factor in both normal physiological functions and the pathogenesis of disease . This study was undertaken to determine the molecular mechanism by which nitric oxide ( NO ) exerts negative feedback regulation on P35228 gene expression . Isolated rat hepatocytes stimulated with cytokines exhibited a marked increase in NO production as well as P35228 mRNA and protein levels , which were significantly reduced by pretreatment of the NO donors S - nitroso - N - acetyl - D , L - penicillamine ( P60880 ) and V - PYRRO / NO . This effect of P60880 was inhibited when NO was scavenged using red blood cells . Pretreatment with oxidized P60880 , 8 - Br - cGMP , NO2 - , or NO3 - did not suppress the cytokine - induced NO production . Moreover , LPS / P01579 - stimulated RAW264 . 7 cells , which produce endogenous NO , expressed lower levels of P35228 , IL - 1beta , P05231 and P01375 mRNAs , without changes in their mRNA half - lives , than those in the presence of the P35228 inhibitor NG - monomethyl - L - arginine . The P35228 gene transcription rate exhibited an 18 - fold increase after cytokine stimulation , which was significantly inhibited by P60880 pretreatment . P60880 also blocked cytokine - induced increase in NF - kappaB activation , P35228 promoter activity , nuclear translocation of cytosolic NF - kappaB p65 subunit , and P25963 degradation , which correlated with its inhibitory effect on phosphorylation and ubiquitination of IkappaB . These data indicate that NO down - regulates P35228 gene expression and NO production by inhibiting the post - translational processes of P25963 thereby preventing NF - kappaB activation . These results identify a novel negative feedback mechanism whereby NO down - regulates P35228 gene expression .",
"A molecular basis underlying differences in the toxicity of botulinum serotypes A and E . Botulinum neurotoxins ( BoNTs ) block neurotransmitter release through their specific proteolysis of the proteins responsible for vesicle exocytosis . Paradoxically , two serotypes of BoNTs , A and E , cleave the same molecule , synaptosome - associated protein with relative molecular mass 25K ( P60880 ) , and yet they cause synaptic blockade with very different properties . Here we compared the action of BoNTs A and E on the plasma membrane fusion machinery composed of syntaxin and P60880 . We now show that the DB00083 - cleaved P60880 maintains its association with two syntaxin isoforms in vitro , which is mirrored by retention of P60880 on the plasma membrane in vivo . In contrast , BoNT / E severely compromises the ability of P60880 to bind the plasma membrane syntaxin isoforms , leading to dissociation of P60880 . The distinct properties of botulinum intoxication , therefore , can result from the ability of shortened P60880 to maintain its association with syntaxins - in the case of DB00083 poisoning resulting in unproductive syntaxin / P60880 complexes that impede vesicle exocytosis .",
"SNARE complex assembly is required for human sperm acrosome reaction . Exocytosis of the acrosome ( the acrosome reaction ) is a terminal morphological alteration that sperm must undergo prior to penetration of the extracellular coat of the egg . Ca ( 2 +) is an essential mediator of this regulated secretory event . Aided by a streptolysin - O permeabilization protocol developed in our laboratory , we have previously demonstrated requirements for Rab3A , P46459 , and synaptotagmin VI in the human sperm acrosome reaction . Interestingly , Rab3A elicits an exocytotic response of comparable magnitude to that of Ca ( 2 +) . Here , we report a direct role for the SNARE complex in the acrosome reaction . First , the presence of SNARE proteins is demonstrated by Western blot . Second , the Ca ( 2 +)- triggered acrosome reaction is inhibited by botulinum neurotoxins DB00083 , - E , - C , and - F . Third , antibody inhibition studies show a requirement for P60880 , O00161 , syntaxins 1A , 1B , 4 , and 6 , and VAMP 2 . Fourth , addition of bacterially expressed P60880 and O00161 abolishes exocytosis . Acrosome reaction elicited by Rab3 - GTP is also inhibited by DB00083 , - C , and - F . Taken together , these results demonstrate a requirement for members of all SNARE protein families in the Ca ( 2 +)- and Rab3A - triggered acrosome reaction . Furthermore , they indicate that the onset of sperm exocytosis relies on the functional assembly of SNARE complexes .",
"Anti - nociceptive effect of a conjugate of DB05875 and light chain of botulinum neurotoxin type A . Neuropathic pain is a debilitating condition resulting from damage to sensory transmission pathways in the peripheral and central nervous system . A potential new way of treating chronic neuropathic pain is to target specific pain - processing neurons based on their expression of particular receptor molecules . We hypothesized that a toxin - neuropeptide conjugate would alter pain by first being taken up by specific receptors for the neuropeptide expressed on the neuronal cells . Then , once inside the cell the toxin would inhibit the neurons ' activity without killing the neurons , thereby providing pain relief without lesioning the nervous system . In an effort to inactivate the nociceptive neurons in the trigeminal nucleus caudalis in mice , we targeted the NK1 receptor ( P25103 ) using DB05875 ( SP ) . The catalytically active light chain of botulinum neurotoxin type A ( LC / A ) was conjugated with SP . Our results indicate that the conjugate DB00083 - LC : SP is internalized in cultured P25103 - expressing neurons and also cleaves the target of botulinum toxin , a component - docking motif necessary for release of neurotransmitters called P60880 . The conjugate was next tested in a murine model of DB01229 - induced neuropathic pain . An intracisternal injection of DB00083 - LC : SP decreased thermal hyperalgesia as measured by the operant orofacial nociception assay . These findings indicate that conjugates of the light chain of botulinum toxin are extremely promising agents for use in suppressing neuronal activity for extended time periods , and that DB00083 - LC : SP may be a useful agent for treating chronic pain .",
"A potent peptidomimetic inhibitor of botulinum neurotoxin serotype A has a very different conformation than P60880 substrate . Botulinum neurotoxin serotype A is the most lethal of all known toxins . Here , we report the crystal structure , along with SAR data , of the zinc metalloprotease domain of DB00083 bound to a potent peptidomimetic inhibitor ( K ( i )= 41 nM ) that resembles the local sequence of the P60880 substrate . Surprisingly , the inhibitor adopts a helical conformation around the cleavage site , in contrast to the extended conformation of the native substrate . The backbone of the inhibitor ' s P1 residue displaces the putative catalytic water molecule and concomitantly interacts with the \" proton shuttle \" E224 . This mechanism of inhibition is aided by residue contacts in the conserved S1 ' pocket of the substrate binding cleft and by the induction of new hydrophobic pockets , which are not present in the apo form , especially for the P2 ' residue of the inhibitor . Our inhibitor is specific for DB00083 as it does not inhibit other BoNT serotypes or thermolysin .",
"Glycine insertion at protease cleavage site of P60880 resists cleavage but enhances affinity for botulinum neurotoxin serotype A . The light chain of botulinum neurotoxin A ( DB00083 - LC ) is a Zn - dependent protease that specifically cleaves P60880 of the SNARE complex , thereby impairing vesicle fusion and neurotransmitter release at neuromuscular junctions . The C - terminus of P60880 ( residues 141 - 206 ) retains full activity for DB00083 - LC - catalyzed cleavage at P1 - P1 ' ( Gln197 - Arg198 ) . Using the structure of a complex between the C - terminus of P60880 and DB00083 - LC as a model to design P60880 - derived pseudosubstrate inhibitors ( SNAPIs ) that prevent presentation of the scissile bond to the active site , we introduced multiple DB00117 residues to replace Ala - DB00174 - Gln - DB00125 ( residues 195 - 198 ) at the substrate cleavage site , with the intent to identify possible side - chain interactions with the active site Zn . We also introduced multiple DB00145 residues between the P1 - P1 ' residues to explore the spatial tolerance within the active - site cleft . Using a FRET substrate YsCsY , we compared a series of SNAPIs for inhibition of DB00083 - LC . Among the SNAPIs tested , several known cleavage - resistant , single - point mutants of P60880 were poor inhibitors , with most of the mutants losing binding affinity . Replacement with DB00117 at the active site did not improve inhibition over wildtype substrate . In contrast , DB00145 - insertion mutants were not only resistant to cleavage , but also surprisingly showed enhanced affinity for DB00083 - LC . Two of the DB00145 - insertion mutants exhibited 10 - fold lower IC₅₀ values than the wildtype 66 - mer P60880 peptide . Our findings illustrate a scenario , where the induced fit between enzyme and bound pseudosubstrate fails to produce the strain and distortion required for catalysis to proceed .",
"Support for association between ADHD and two candidate genes : NET1 and P21728 . Attention deficit hyperactivity disorder ( ADHD ) is a common , multifactorial disorder with significant genetic contribution . Multiple candidate genes have been studied in ADHD , including the norepinephrine transporter ( NET1 ) and dopamine D1 receptor ( P21728 ) . NET1 is implicated in ADHD because of the efficacy of atomoxetine , a selective noradrenergic reuptake inhibitor , in the treatment of ADHD . P21728 is primarily implicated through mouse models of ADHD . DNA from 163 ADHD probands , 192 parents , and 129 healthy controls was used to investigate possible associations between ADHD and polymorphisms in 12 previously studied candidate genes ( P28222 , 5 - Q13049 , P28335 , P08913 , P43681 , P21964 , Q01959 , P21728 , P21917 , P21918 , NET1 , and P60880 ) . Analyses included case - control and family - based methods , and dimensional measures of behavior , cognition , and anatomic brain magnetic resonance imaging ( Q9BWK5 ) . Of the 12 genes examined , two showed a significant association with ADHD . Transmission disequilibrium test ( P04053 ) analysis revealed significant association of two NET1 single nucleotide polymorphisms ( SNPs ) with ADHD ( P < or = 0 . 009 ) ; case - control analysis revealed significant association of two P21728 SNPs with ADHD ( P < or = 0 . 008 ) . No behavioral , cognitive , or brain Q9BWK5 volume measurement significantly differed across NET1 or P21728 genotypes at an alpha of 0 . 01 . This study provides support for an association between ADHD and polymorphisms in both NET1 and P21728 ; polymorphisms in ten other candidate genes were not associated with ADHD . Because family - based and case - control methods gave divergent results , both should be used in genetic studies of ADHD .",
"Re - assembled botulinum neurotoxin inhibits CNS functions without systemic toxicity . The therapeutic potential of botulinum neurotoxin type A ( DB00083 ) has recently been widely recognized . DB00083 acts to silence synaptic transmission via specific proteolytic cleavage of an essential neuronal protein , P60880 . The advantages of DB00083 - mediated synaptic silencing include very long duration , high potency and localized action . However , there is a fear of possible side - effects of DB00083 due to its diffusible nature which may lead to neuromuscular blockade away from the injection site . We recently developed a \" protein - stapling \" technology which allows re - assembly of DB00083 from two separate fragments . This technology allowed , for the first time , safe production of this popular neuronal silencing agent . Here we evaluated the re - assembled toxin in several CNS assays and assessed its systemic effects in an animal model . Our results show that the re - assembled toxin is potent in inhibiting CNS function at 1 nM concentration but surprisingly does not exhibit systemic toxicity after intraperitoneal injection even at 200 ng / kg dose . This shows that the re - assembled toxin represents a uniquely safe tool for neuroscience research and future medical applications .",
"Botulinum neurotoxin A and neurotoxin E cleavage products of synaptosome - associated protein of 25 kd exhibit distinct actions on pancreatic islet beta - cell Kv2 . 1 channel gating . OBJECTIVES : Synaptosome - associated protein of 25 kd ( P60880 ) regulates pancreatic islet beta - cell - delayed rectifier K channels ( Kv2 . 1 ) in addition to insulin exocytosis . Botulinum neurotoxin A ( DB00083 ) and E ( BoNT / E ) cleavage and presumed deletion of P60880 have been used to examine P60880 function . We hypothesized that proteolytic products of P60880 ( 206 amino acids ) resulting from DB00083 and BoNT / E cleavage , P60880 ( 1 - 197 ) and P60880 ( 1 - 180 ) , have independent actions on beta - cell Kv gating . METHODS : We examined by confocal microscopy and immunoblotting DB00083 and BoNT / E cleavage of P60880 to these N - terminal fragments , and the consequent effects of these BoNTs and P60880 fragments on Kv currents in rat beta cells and MIN6 cells by patch clamp electrophysiology . RESULTS : Confocal microscopy and immunoblotting showed that MIN6 cells transfected with DB00083 or BoNT / E generated P60880 ( 1 - 197 ) and P60880 ( 1 - 180 ) fragments that were retained in the cytosol . Both BoNTs caused increased rate of channel activation and slowed channel inactivation , mimicked by these P60880 fragments , but not full - length P60880 . These P60880 fragments potentiated tetraethylammonium block of beta - cell Kv currents . CONCLUSIONS : DB00083 or BoNT / E treatment of beta cells generates N - terminal P60880 fragments that are retained in beta cells to directly influence Kv channel gating in a manner distinct from full - length P60880 , contributing to overall actions of these BoNTs on insulin secretion .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK47___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"Sensitivity of embryonic rat dorsal root ganglia neurons to Clostridium botulinum neurotoxins . Clostridium botulinum neurotoxins ( BoNT ) are zinc dependent endopeptidases which , once internalised into the neuronal cytosol , block neurotransmission by proteolysis of membrane - associated proteins putatively involved in synaptic vesicle docking and fusion with the plasma membrane . Although many studies have used a variety of cellular systems to study the neurotoxins , most require relatively large amounts of toxin or permeabilisation to internalise the neurotoxin . We present here a primary culture of embryonic rat dorsal root ganglia ( Q86YR7 ) neurons that exhibits calcium - dependent DB05875 secretion when depolarised with elevated extracellular potassium and is naturally BoNT sensitive . The Q86YR7 neurons showed a different IC50 for each of the toxins tested with a 1000 fold difference between the most and least potent neurotoxins ( 0 . 05 , 0 . 3 , 30 and approximately 60 nM for A , C , F and B , respectively ) . DB00083 cleavage of P60880 was seen as early as 2 h , but DB05875 secretion was not significantly inhibited until 4 h intoxication and the effects of DB00083 were observed for as long as 15 days . This primary neuronal culture system represents a new and sensitive cellular model for the in vitro study of the botulinum neurotoxins .",
"Development of cell - based assays to measure botulinum neurotoxin serotype A activity using cleavage - sensitive antibodies . Botulinum neurotoxins ( BoNTs ) are zinc - metalloproteases that cleave components of the SNARE ( soluble N - ethylmaleimide - sensitive factor attachment protein receptor ) protein complex , inhibiting acetylcholine release into neuromuscular junctions , resulting in flaccid paralysis and eventual death . The potential for the malicious misuse of these toxins as bioweapons has created an urgent need to develop effective therapeutic countermeasures . Robust cell - based assays will be essential for lead identification and the optimization of therapeutic candidates . In this study , the authors developed novel BoNT serotype A ( DB00083 ) cleavage - sensitive ( Q9Y2P5 ) antibodies that only interact with full - length P60880 ( synaptosomal - associated protein of 25 kDa ) , the molecular target of the DB00083 serotype . These antibodies exhibit high specificity for full - length P60880 , allowing the DB00083 - mediated proteolysis of this protein to be measured in diverse assay formats , including several variations of enzyme - linked immunosorbent assay and multiple immunofluorescence methods . Assays built around the Q9Y2P5 antibodies displayed excellent sensitivity , had excellent reproducibility , and were amenable to multiwell formats . Importantly , these assays provided novel methods for evaluating DB00083 activity in cellular models of intoxication and allowed for the high - throughput evaluation of experimental compounds .",
"Neuritogenic actions of botulinum neurotoxin A on cultured motor neurons . Botulinum neurotoxins ( BoNTs ) are extremely potent neuromuscular poisons that act through soluble N - ethylmaleimide - sensitive factor attachment protein receptor ( SNARE ) protein cleavage to inhibit neurotransmitter release . The ability of BoNT serotype A ( DB00083 ) to eliminate localized transmitter release at extremely low doses is well characterized . In the current study , we investigated the less understood characteristic of DB00083 to induce nerve outgrowth , sometimes referred to as sprouting . This phenomenon is generally considered a secondary response to the paralytic actions of DB00083 , and other potential factors that may initiate this sprouting have not been investigated . Alternatively , we hypothesized that DB00083 induces sprouting through presynaptic receptor activation that is independent of its known intracellular actions on the soluble N - ethylmaleimide - sensitive factor attachment receptor ( SNARE ) synaptosomal associated protein of 25 kDa ( P60880 ) . To test this , the effects of DB00083 application on neurite outgrowth were examined using primary cultures enriched with motor neurons isolated from embryonic mouse spinal cord . In this system , DB00083 potently stimulated neuritogenesis at concentrations as low as 0 . 01 nM . The neuritogenic effects of DB00083 exposure were concentration dependent and antagonized by Triticum vulgaris lectin , a known competitive antagonist of BoNT . Similar results were observed with the isolated DB00083 binding domain , revealing that neuritogenesis could be initiated solely by the binding actions of DB00083 . In addition , the presence or absence of P60880 cleavage by DB00083 was not a determinant factor in DB00083 - induced neuritogenesis . Collectively , these results suggest that binding of DB00083 to the motor neuronal membrane activates neuritogenesis through as yet undetermined intracellular pathway ( s ) , independent of its known action on vesicular release .",
"DB00435 enhances de novo formation of endothelial gap junctions . OBJECTIVE : Gap junctions ( formed by connexins , Cx ) are important for functional coordination of cells in the vascular wall . However , little is known about their physiological regulation in this tissue . We examined the effects of nitric oxide ( NO ) , an important mediator of vasomotion , wound healing and angiogenesis , on the formation of gap junctions in endothelial cells ( human umbilical vein endothelial cells , HUVEC ) . METHODS : Flow cytometry was used to determine dye transfer through newly formed gap junctions between acutely coincubated HUVECs . Parallel experiments in wild - type HeLa cells ( no connexins ) and transfected HeLa cells exclusively expressing P17302 , P36382 or P35212 were performed to determine the specific role of Cx subtypes . The intracellular distribution of P36382 was examined after fractionation with triton by Western blotting . Intracellular levels of cGMP and DB02527 were measured by radioimmunoassay . RESULTS : The NO donor P60880 ( 1 microM ) enhanced gap - junctional coupling in HUVECs by about 40 % . This was associated with an enhanced incorporation of P36382 into the membrane . Both effects were restricted to P36382 as analyzed in experiments with Cx - selective HeLa cells . The NO - induced increase in cell coupling was elicited by a corresponding rise of cGMP , which secondarily increased intracellular DB02527 levels . The latter was an integral part of the signal cascade , since the protein kinase A ( PKA ) inhibitor H89 blocked the P60880 - induced incorporation of P36382 into the plasma membrane . CONCLUSIONS : We conclude that NO is a potent modulator of gap - junctional coupling in endothelial cells . It enhances de novo formation of endothelial gap junctions by increasing incorporation of P36382 into the plasma membrane due to PKA activation .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK86___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK86___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .",
"P60880 is essential for cortical granule exocytosis in mouse eggs . Synaptosome - associated protein of 25 kDa ( P60880 ) has been shown to play an important role in Ca2 +- dependent exocytosis in neurons and endocrine cells . During fertilization , sperm - egg fusion induces cytosolic Ca2 + mobilization and subsequently Ca2 +- dependent cortical granule ( CG ) exocytosis in eggs . However , it is not yet clear whether P60880 is involved in this process . In this study , we determined the expression and function of P60880 in mouse eggs . mRNA and P60880 were detected in metaphase II ( MII ) mouse eggs by RT - PCR and immunoblot analysis , respectively . Next , to determine the function of P60880 , we evaluated the change in CG exocytosis with a membrane dye , tetramethylammonium - 1 , 6 - diphenyl - 1 , 3 , 5 - hexatriene , after microinjection of a botulinum neurotoxin A ( DB00083 ) , which selectively cleaves P60880 in MII eggs . Sperm - induced CG exocytosis was significantly inhibited in the DB00083 - treated eggs . The inhibition was attenuated by coinjection of P60880 . These results suggest that P60880 may be involved in Ca2 +- dependent CG exocytosis during fertilization in mouse eggs .",
"Enhancement of the endopeptidase activity of purified botulinum neurotoxins A and E by an isolated component of the native neurotoxin associated proteins . In botulism disease , neurotransmitter release is blocked by a group of structurally related neurotoxin proteins produced by Clostridium botulinum . Botulinum neurotoxins ( BoNT , A - G ) enter nerve terminals and irreversibly inhibit exocytosis via their endopeptidase activities against synaptic proteins P60880 , VAMP , and Syntaxin . Type A C . botulinum secretes the neurotoxin along with 5 other proteins called neurotoxin associated proteins ( NAPs ) . Here , we report that hemagglutinin - 33 ( Hn - 33 ) , one of the Q8WYA6 components , enhances the endopeptidase activity of not only DB00083 but also that of BoNT / E , both under in vitro conditions and in rat synaptosomes . DB00083 endopeptidase activity in vitro is about twice as high as that of BoNT / E under disulfide - reduced conditions . Addition of Hn - 33 separately to nonreduced DB00083 and BoNT / E ( which otherwise have only residual endopeptidase activity ) enhanced their in vitro endopeptidase activity by 21 - and 25 - fold , respectively . Cleavage of rat - brain synaptosome P60880 by BoNTs was used to assay endopeptidase activity under nerve - cell conditions . Reduced DB00083 and BoNT / E cleaved synaptosomal P60880 by 20 % and 15 % , respectively . Addition of Hn - 33 separately to nonreduced DB00083 and BoNT / E enhanced their endopeptidase activities by 13 - fold for the cleavage of P60880 in synaptosomes , suggesting a possible functional role of Hn - 33 in association with BoNTs . We believe that Hn - 33 could be used as an activator in the formulation of the neurotoxin for therapeutic use .",
"Dynamin inhibition blocks botulinum neurotoxin type A endocytosis in neurons and delays botulism . The botulinum neurotoxins ( BoNTs ) are di - chain bacterial proteins responsible for the paralytic disease botulism . Following binding to the plasma membrane of cholinergic motor nerve terminals , BoNTs are internalized into an endocytic compartment . Although several endocytic pathways have been characterized in neurons , the molecular mechanism underpinning the uptake of BoNTs at the presynaptic nerve terminal is still unclear . Here , a recombinant DB00083 heavy chain binding domain ( Hc ) was used to unravel the internalization pathway by fluorescence and electron microscopy . DB00083 - Hc initially enters cultured hippocampal neurons in an activity - dependent manner into synaptic vesicles and clathrin - coated vesicles before also entering endosomal structures and multivesicular bodies . We found that inhibiting dynamin with the novel potent Dynasore analog , Dyngo - 4a ( TM ) , was sufficient to abolish DB00083 - Hc internalization and DB00083 - induced P60880 cleavage in hippocampal neurons . Dyngo - 4a also interfered with DB00083 - Hc internalization into motor nerve terminals . Furthermore , Dyngo - 4a afforded protection against DB00083 - induced paralysis at the rat hemidiaphragm . A significant delay of > 30 % in the onset of botulism was observed in mice injected with Dyngo - 4a . Dynamin inhibition therefore provides a therapeutic avenue for the treatment of botulism and other diseases caused by pathogens sharing dynamin - dependent uptake mechanisms .",
"Involvement of P60880 in TRH - induced exocytosis in pituitary GH4C1 cells . The synaptic membrane protein synaptosomal - associated protein ( P60880 ) has recently been implicated as one of the key proteins involved in exocytotic membrane fusion in neurons . However , the role of P60880 in pituitary hormone release is not known . In this study , we determined that P60880 is involved in regulated exocytosis in the clonal pituitary cell line GH4C1 . P60880 messenger RNA and protein were detected in GH4C1 cells by RT - PCR and immunoblot analysis , respectively . Immunofluorescence analysis indicated that P60880 protein was localized in the plasma membrane . Next , to determine the function of P60880 in GH4C1 cells , specific inhibitors of P60880 , botulinum neurotoxin ( BoNT ) / A or / E , and antisense P60880 oligonucleotide were used . Neither DB00083 nor BoNT / E affected thyrotropin - releasing hormone ( TRH ) - induced cytosolic Ca2 + increase , but both inhibited TRH - induced exocytosis . Moreover , they dose - dependently inhibited TRH - induced prolactin release . The introduction of antisense oligonucleotide into the cells also inhibited TRH - induced prolactin release . These results suggest that P60880 is involved in regulated exocytosis in GH4C1 cells .",
"Botulinum neurotoxin : unique folding of enzyme domain of the most - poisonous poison . Botulinum neurotoxin ( BoNT ) , the most toxic substance known to mankind , is the first example of the fully active molten globule state . To understand its folding mechanism , we performed urea denaturation experiments and theoretical modeling using BoNT serotype A ( DB00083 ) . We found that the extent of DB00083 denaturation from the native state ( N ) shows a nonmonotonic dependence on urea concentration indicating a unique multistep denaturation process , N → I1 [ Formula : see text ] I2 [ Formula : see text ] U , with two intermediate states I1 and I2 . DB00083 loses almost all its secondary structure in 3 . 75 M urea ( I1 ) , yet it displays a native - like secondary structure in 5 M urea ( I2 ) . This agrees with the results of theoretical modeling , which helped to determine the molecular basis of unique behavior of DB00083 in solution . Except for I2 , all the states revert back to full enzymatic activity for P60880 including the unfolded state U stable in 7 M urea . Our results stress the importance of structural flexibility in the toxin ' s mechanism of survival and action , an unmatched evolutionary trait from billion - year - old bacteria , which also correlates with the long - lasting enzymatic activity of BoNT inside neuronal cells . DB00083 provides a rich model to explore protein folding in relation to functional activity .",
"Ca2 + or Sr2 + partially rescues synaptic transmission in hippocampal cultures treated with botulinum toxin A and C , but not tetanus toxin . Botulinum ( DB00083 - G ) and tetanus toxins ( TeNT ) are zinc endopeptidases that cleave proteins associated with presynaptic terminals ( P60880 , syntaxin , or VAMP / synaptobrevin ) and block neurotransmitter release . Treatment of hippocampal slice cultures with DB00083 , BoNT / C , BoNT / E , or TeNT prevented the occurrence of spontaneous or miniature EPSCs ( sEPSCs or mEPSCs ) as well as the [ Ca2 +] o - independent increase in their frequency induced by phorbol ester , 0 . 5 nM alpha - latrotoxin , or sucrose . [ Ca2 +] o - independent and - dependent release thus requires that the target proteins of clostridial neurotoxins be uncleaved . In contrast , significant increases in mEPSC frequency were produced in BoNT - treated , but not TeNT - treated , cultures by application of the Ca2 + ionophore ionomycin in the presence of 10 mM [ Ca2 +] o . The frequency of sEPSCs was increased in BoNT - treated , but not TeNT - treated , cultures by increasing [ Ca2 +] o from 2 . 8 to 5 - 10 mM or by applying 5 mM Sr2 + . Large Ca2 + and Sr2 + influxes thus can rescue release after BoNT treatment , albeit less than in control cultures . The nature of the toxin - induced modification of Ca2 +- dependent release was assessed by recordings from monosynaptically coupled P07451 cell pairs . The paired - pulse ratio of unitary EPSCs evoked by two presynaptic action potentials in close succession was 0 . 5 in control cultures , but it was 1 . 4 and 1 . 2 in DB00083 - or BoNT / C - treated cultures when recorded in 10 mM [ Ca2 +] o . Log - log plots of unitary EPSC amplitude versus [ Ca2 +] o were shifted toward higher [ Ca2 +] o in DB00083 - or BoNT / C - treated cultures , but their slope was unchanged and the maximal EPSC amplitudes were reduced . We conclude that BoNTs reduce the Ca2 + sensitivity of the exocytotic machinery and the number of quanta released .",
"The blockade of the neurotransmitter release apparatus by botulinum neurotoxins . The high toxicity of the seven serotypes of botulinum neurotoxins ( DB00083 to G ) , together with their specificity and reversibility , includes them in the list A of potential bioterrorism weapons and , at the same time , among the therapeutics of choice for a variety of human syndromes . They invade nerve terminals and cleave specifically the three proteins which form the heterotrimeric P60880 REceptors ( SNARE ) complex that mediates neurotransmitter release . The BoNT - induced cleavage of the SNARE proteins explains by itself the paralysing activity of the BoNTs because the truncated proteins can not form the SNARE complex . However , in the case of DB00083 , the most widely used toxin in therapy , additional factors come into play as it only removes a few residues from the synaptosomal associate protein of 25 kDa C - terminus and this results in a long duration of action . To explain these facts and other experimental data , we present here a model for the assembly of the neuroexocytosis apparatus in which Synaptotagmin and Complexin first assist the zippering of the SNARE complex , and then stabilize and clamp an octameric radial assembly of the SNARE complexes .",
"Botulinum neurotoxin type A subtype 2 confers greater safety than subtype 1 in a rat Parkinson ' s disease model . Botulinum neurotoxin type A ( DB00083 ) cleaves P60880 and interrupts the release of acetylcholine . We previously reported that DB00083 subtype 2 ( BoNT / A2 ) ameliorates pathologic behavior more effectively than subtype 1 ( BoNT / A1 ) in a rat Parkinson ' s disease model . Here , we further show BoNT / A2 has fewer adverse effects than BoNT / A1 . We first confirmed that intrastriatal treatments of both BoNT / As had no - effect on dopaminergic terminals in the striatum . P60880 cleaved by BoNT / A2 was strictly localized to the striatum on the injected side ; however , P60880 cleaved by BoNT / A1 diffused contralaterally . Furthermore , treatment with BoNT / A1 caused a significant reduction in body weight , while BoNT / A2 treatment did not . These results suggest that BoNT / A2 is more beneficial for clinical application against Parkinson ' s disease than BoNT / A1 .",
"Dual effects of nimesulide , a P35354 inhibitor , in human platelets . DB04743 ( CAS 51803 - 78 - 2 ) has been shown to exert marked anti - inflammatory effect in several in vivo models of inflammation . Since nimesulide is considered to be a selective inhibitor of P35354 , it has not been studied in detail in relation to its mechanistic effects on platelets , which express P23219 . This study was conducted to investigate the effects of nimesulide in platelet aggregation . We show that nimesulide ( 1 - 100 microM ) inhibited platelet aggregation induced by adrenaline ( 20 - 200 microM ) . It also inhibited thromboxane A2 ( TXA2 ) formation by platelets at low concentration ( IC50 ; 1 microM ) . However , much lower concentrations of nimesulide ( 0 . 01 - 0 . 1 microM ) potentiated the aggregatory response of subthreshold concentrations of adrenaline ( 0 . 2 - 2 microM ) . Such an effect was blocked by Ca2 +- channel blockers , verapamil and diltiazem ( IC50 : 7 and 46 microM , respectively ) , nitric oxide donor , P60880 ( IC50 ; 2 microM ) and cinchonine ( 10 nM ) but not by genistein ( up to 10 microM ) . These results are indicative of the concentration - dependent dual effects of nimesulide on human platelet aggregation . The synergistic effect of low doses of nimesulide and adrenaline seems to be mediated through inhibition of multiple signalling pathways .",
"Post - intoxication inhibition of botulinum neurotoxin serotype A within neurons by small - molecule , non - peptidic inhibitors . Botulinum neurotoxins ( BoNTs ) comprise seven distinct serotypes that inhibit the release of neurotransmitter across neuromuscular junctions , resulting in potentially fatal flaccid paralysis . BoNT serotype A ( DB00083 ) , which targets synaptosomal - associated protein of 25kDa ( P60880 ) , is particularly long - lived within neurons and requires a longer time for recovery of neuromuscular function . There are currently no treatments available to counteract DB00083 after it has entered the neuronal cytosol . In this study , we examined the ability of small molecule non - peptidic inhibitors ( SMNPIs ) to prevent P60880 cleavage post - intoxication of neurons . The progressive cleavage of P60880 observed over 5 h following 1 h DB00083 intoxication was prevented by addition of SMNPIs . In contrast , anti - DB00083 neutralizing antibodies that strongly inhibited P60880 cleavage when added during intoxication were completely ineffective when added post - intoxication . Although DB06733 , which blocks entry of DB00083 into the cytosol by preventing endosomal acidification , inhibited P60880 cleavage post - intoxication , the degree of inhibition was significantly reduced versus addition both during and after intoxication . Post - intoxication application of SMNPIs , on the other hand , was nearly as effective as application both during and after intoxication . Taken together , the results indicate that competitive SMNPIs of DB00083 light chain can be effective within neurons post - intoxication .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK18___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"DB00644 agonists reduce the migratory and the invasive behavior of androgen - independent prostate cancer cells by interfering with the activity of P05019 . Androgen - independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior . We have previously shown that DB00644 agonists exert a direct and specific inhibitory action on the proliferation of androgen - independent prostate cancer cells ( DU 145 ) . These compounds mainly act by interfering with the mitogenic activity of growth factors , such as the insulin - like growth factor - I ( P05019 ) . The present experiments were performed to clarify whether DB00644 agonists might also affect the migratory and the invasive behavior of androgen - independent prostate cancer cells and to define their mechanism of action . First we showed that the DB00644 agonist ___MASK57___ reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane . Experiments were then performed to clarify whether the DB00644 agonist might act by interfering with the pro - metastatic activity of P05019 . We found that , in androgen - independent prostate cancer cells , ___MASK57___ : a ) interferes with the P05019 system ( receptor protein expression and tyrosine - phosphorylation ) ; b ) abrogates the P05019 - induced phosphorylation of Akt ( a kinase previously shown by us to mediate the pro - metastatic activity of P05019 in prostate cancer cells ) ; c ) counteracts the migration and the invasive activity of the cells stimulated by P05019 ; d ) abolishes the effects of P05019 on cell morphology , on actin cytoskeleton organization and on alphavbeta3 integrin expression / cellular localization . These data indicate that DB00644 agonists , in addition to their well known antiproliferative effect , can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen - independent prostate cancer cells , expressing the P30968 . DB00644 agonists act by interfering with the pro - metastatic activity of the growth factor P05019 .",
"Botulinum neurotoxin A activity is dependent upon the presence of specific gangliosides in neuroblastoma cells expressing synaptotagmin I . Botulinum neurotoxin A ( DB00083 ) is the deadliest of all known biological substances . Although its toxicity makes DB00083 a biological warfare threat , its biologic activity makes it an increasingly useful therapeutic agent for the treatment of muscular disorders . However , almost 200 years after its discovery , the neuronal cell components required for the activity of this deadly toxin have not been unequivocally identified . In this work , neuroblastoma cells expressing synaptotagmin I , a protein shown to be bound by DB00083 , were used to determine whether specific gangliosides were necessary for DB00083 activity as measured by synaptosomal - associated protein of 25 kDa ( P60880 ) cleavage . Ganglioside GT1b was found to support DB00083 activity significantly more effectively than GD1a , which was far more effective than GM1 when added to ganglioside - deficient murine cholinergic Neuro 2a or to human adrenergic SK - N - SH neuroblastoma cells . Whereas both cell lines expressed synaptotagmin I , P60880 cleavage was not observed in the absence of complex gangliosides . These results indicate that 1 ) gangliosides are required for DB00083 activity , 2 ) synaptotagmin I in the absence of gangliosides does not support DB00083 activity , and 3 ) Neuro 2a cells are an efficient model system for studying the biological activity of DB00083 .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK29___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"Ca ( 2 +) influx and DB02527 elevation overcame botulinum toxin A but not tetanus toxin inhibition of insulin exocytosis . Previous reports showed that cleavage of vesicle - associated membrane protein - 2 ( P63027 ) and synaptosomal - associated protein of 25 kDa ( P60880 ) by clostridial neurotoxins in permeabilized insulin - secreting beta - cells inhibited Ca ( 2 +)- evoked insulin secretion . In these reports , the soluble N - ethylmaleimide - sensitive factor attachment protein target receptor proteins might have formed complexes , which preclude full accessibility of the putative sites for neurotoxin cleavage . In this work , P63027 and P60880 were effectively cleaved before they formed toxin - insensitive complexes by transient transfection of insulinoma HIT or P01308 - 1 cells with tetanus toxin ( TeTx ) or botulinum neurotoxin A ( DB00083 ) , as shown by immunoblotting and immunofluorescence microscopy . This resulted in an inhibition of Ca ( 2 +) ( glucose or DB00761 ) - evoked insulin release proportionate to the transfection efficiency ( 40 - 50 % ) and an accumulation of insulin granules . With the use of patch - clamp capacitance measurements , Ca ( 2 +)- evoked exocytosis by membrane depolarization to - 10 mV was abolished by TeTx ( 6 % of control ) but only moderately inhibited by DB00083 ( 30 % of control ) . Depolarization to 0 mV to maximize Ca ( 2 +) influx partially overcame DB00083 ( 50 % of control ) but not TeTx inhibition . Of note , DB02527 activation potentiated Ca ( 2 +)- evoked secretion by 129 % in control cells but only 55 % in DB00083 - transfected cells and had negligible effects in TeTx - transfected cells . These results indicate that , whereas P63027 is absolutely necessary for insulin exocytosis , the effects of P60880 depletion on exocytosis , perhaps on insulin granule pool priming or mobilization steps , could be partially reversed by higher levels of Ca ( 2 +) or DB02527 potentiation .",
"Spinal Central Effects of Peripherally Applied Botulinum Neurotoxin A in Comparison between Its Subtypes A1 and A2 . Because of its unique ability to exert long - lasting synaptic transmission blockade , botulinum neurotoxin A ( DB00083 ) is used to treat a wide variety of disorders involving peripheral nerve terminal hyperexcitability . However , it has been a matter of debate whether this toxin has central or peripheral sites of action . We employed a rat model in which BoNT / A1 or BoNT / A2 was unilaterally injected into the gastrocnemius muscle . On time - course measurements of compound muscle action potential ( CMAP ) amplitudes after injection of BoNT / A1 or BoNT / A2 at doses ranging from 1 . 7 to 13 . 6 U , CMAP amplitude for the ipsilateral hind leg was markedly decreased on the first day , and this muscle flaccidity persisted up to the 14th day . Of note , both BoNT / A1 and BoNT / A2 administrations also resulted in decreased CMAP amplitudes for the contralateral leg in a dose - dependent manner ranging from 1 . 7 to 13 . 6 U , and this muscle flaccidity increased until the fourth day and then slowly recovered . Immunohistochemical results revealed that DB00083 - cleaved synaptosomal - associated protein of 25 kDa ( P60880 ) appeared in the bilateral ventral and dorsal horns 4 days after injection of BoNT / A1 ( 10 U ) or BoNT / A2 ( 10 U ) , although there seemed to be a wider spread of DB00083 - cleaved P60880 associated with BoNT / A1 than BoNT / A2 in the contralateral spinal cord . This suggests that the catalytically active BoNT / A1 and BoNT / A2 were axonally transported via peripheral motor and sensory nerves to the spinal cord , where they spread through a transcytosis ( cell - to - cell trafficking ) mechanism . Our results provide evidence for the central effects of intramuscularly administered BoNT / A1 and BoNT / A2 in the spinal cord , and a new insight into the clinical effects of peripheral DB00083 applications .",
"Quinolinol and peptide inhibitors of zinc protease in botulinum neurotoxin A : effects of zinc ion and peptides on inhibition . Quinolinol derivatives were found to be effective inhibitors of botulinum neurotoxin serotype A ( DB00083 ) . Studies of the inhibition and binding of 7 -( phenyl ( 8 - quinolinylamino ) methyl )- 8 - quinolinol ( QAQ ) to the light chain domain ( DB00083 LC ) showed that QAQ is a non - competitive inhibitor for the zinc protease activity . Binding and molecular modeling studies reveal that QAQ binds to a hydrophobic pocket near the active site . Its inhibitor effect does not involve the removal of zinc ion from the light chain . A 24 - mer P60880 peptide containing E183 to G206 with Q197C mutation ( Peptide C ) binds to DB00083 LC with an unusually slow second order binding rate constant of 76 . 7M (- 1 ) s (- 1 ) . QAQ binds to Zn ( 2 +)- free DB00083 LC with a K ( D ) of 0 . 67microM and to Peptide C - DB00083 LC complex with a K ( D ) of 2 . 33microM . The insights of the interactions of quinolinols and peptides with the zinc protease of DB00083 should aid in the development of inhibitors of metalloproteases .",
"Differential contribution of SNARE - dependent exocytosis to inflammatory potentiation of Q8NER1 in nociceptors . Potentiation of the pain - integrator ion channel transient receptor potential vanilloid type 1 ( Q8NER1 ) underlies thermal hyperalgesia mediated by a variety of proinflammatory factors . Two complementary mechanisms of Q8NER1 inflammatory sensitization have been proposed , namely a decrease of its activation threshold and an increment of its surface expression in nociceptors . Here we investigated the involvement of regulated exocytosis to the inflammatory sensitization of Q8NER1 in rat neonatal dorsal root ganglion neurons by proalgesic agents . The contribution of soluble N - ethylmaleimide - sensitive factor attachment protein receptor ( SNARE ) - dependent exocytosis was evaluated using a small peptide patterned after the synaptosomal - associated protein of 25 kDa ( P60880 ) protein that acts as a specific and potent inhibitor of neuronal exocytosis . We found that Q8NER1 sensitization mediated by nerve growth factor , DB00171 , and P05019 was accompanied by a higher channel expression in the neuronal plasma membrane , which was prevented by blockade of regulated exocytosis . In contrast , Q8NER1 sensitization caused by bradykinin , IL - 1beta , and artemin was insensitive to inhibition of SNARE - dependent vesicular fusion and was not due to an increase in Q8NER1 surface expression . Therefore , it appears that some , but not all , proinflammatory agents sensitize rat nociceptors by promoting the recruitment of Q8NER1 channels to the neuronal surface . These findings support the tenet that SNARE complex - mediated exocytosis of Q8NER1 may be a valid therapeutic target to treat inflammatory pain .",
"Botulinum neurotoxin types A and E require the SNARE motif in P60880 for proteolysis . Botulinum neurotoxins type A and E ( DB00083 and BoNT / E ) are metalloproteases with a unique specificity for P60880 ( synaptosome - associated protein of 25 kDa ) , an essential protein component of the neuroexocytotic machinery . It has been suggested that this specificity is directed through the recognition of a nine residue sequence , termed SNARE motif , that is common to the other two SNARE proteins : VAMP ( vesicle - associated membrane protein ) and syntaxin , the only known substrates of the other six clostridial neurotoxins . Here we analyse the involvement of the four copies of the SNARE motif present in P60880 in its interaction with DB00083 and BoNT / E by following the kinetics of proteolysis of P60880 mutants deleted of SNARE motifs . We show that a single copy of the motif is sufficient for DB00083 and BoNT / E to recognise P60880 . While the copy of the motif proximal to the cleavage site is clearly involved in recognition , in its absence , other more distant copies of the motif are able to support proteolysis . Also , a non - neuronal isoform of P60880 , Syndet , is shown to be sensitive to BoNT / E , but not DB00083 , whilst the P60880 isoforms from Torpedo marmorata and Drosophila melanogaster were demonstrated not to be substrates of these metalloproteases .",
"Botulinum toxin type A selectivity for certain types of pain is associated with capsaicin - sensitive neurons . Unlike most classical analgesics , botulinum toxin type A ( DB00083 ) does not alter acute nociceptive thresholds , and shows selectivity primarily for allodynic and hyperalgesic responses in certain pain conditions . We hypothesized that this phenomenon might be explained by characterizing the sensory neurons targeted by DB00083 in the central nervous system after its axonal transport . DB00083 ' s central antinociceptive activity following its application into the rat whisker pad was examined in trigeminal nucleus caudalis ( P24821 ) and higher - level nociceptive brain areas using DB00083 - cleaved synaptosomal - associated protein 25 ( P60880 ) and c - Fos immunohistochemistry . Occurrence of cleaved P60880 in P24821 was examined after nonselective ganglion ablation with formalin or selective denervation of capsaicin - sensitive ( vanilloid receptor - 1 or Q8NER1 - expressing ) neurons , and in relation to different cellular and neuronal markers . Regional c - Fos activation and effect of Q8NER1 - expressing afferent denervation on toxin ' s antinociceptive action were studied in formalin - induced orofacial pain . DB00083 - cleaved P60880 was observed in P24821 , but not in higher - level nociceptive nuclei . Cleaved P60880 in P24821 disappeared after formalin - induced trigeminal ganglion ablation or capsaicin - induced sensory denervation . Occurrence of cleaved P60880 in P24821 and DB00083 antinociceptive activity in formalin - induced orofacial pain were prevented by denervation with capsaicin . Cleaved P60880 localization demonstrated toxin ' s presynaptic activity in Q8NER1 - expressing neurons . DB00083 reduced the c - Fos activation in P24821 , locus coeruleus , and periaqueductal gray . Present experiments suggest that DB00083 alters the nociceptive transmission at the central synapse of primary afferents . Targeting of Q8NER1 - expressing neurons might be associated with observed selectivity of DB00083 action only in certain types of pain .",
"8 - Hydroxyquinoline and hydroxamic acid inhibitors of botulinum neurotoxin DB00083 . We describe here the state of the art of certain aspects concerning potential small molecule therapy directed toward botulism , by inhibition of the zinc - protease containing light chain ( LC ) of botulinum neurotoxin DB00083 from the anaerobic bacillus Clostridium botulinum . Botulinum neurotoxins ( BoNTs ) are comprised of eight serologically - distinct proteins ( A - H ) , several of which are further divided , such as DB00083 which has five subtypes . The BoNTs are the most toxic substances known to mankind , causing a form of flaccid paralysis that can be rapid and is often lethal . DB00083 is comprised of a ~ 100 kDa heavy chain ( HC ) attached via a single disulfide DB00151 - DB00151 bond to a ~ 50 kDa LC . The HC mediates transport to and uptake by presynaptic glutamatergic neurons , where the LC cleaves the protein P60880 and thus prevents vesicular trafficking and release of acetylcholine . The Zn - endoprotease activity of the LC of DB00083 is a target for the development of small molecule inhibitors of DB00083 - mediated toxicity . A variety of DB00083 LC inhibitors have been described to date and we focus here primarily on the Zn - binding 8 - hydroxyquinoline structural type as well as some of the previously - described hydroxamic acids .",
"Connexin36 knockout mice display increased sensitivity to pentylenetetrazol - induced seizure - like behaviors . OBJECTIVE : Large - scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions . To explore roles for connexin36 ( Q9UKL4 ) gap junctions in seizures , we examined the seizure threshold of connexin36 knockout ( Cx36KO ) mice using a pentylenetetrazol ( PTZ ) model . METHODS : Mice ( 2 - 3months old ) with Q9UKL4 wildtype ( WT ) or Cx36KO genotype were treated with vehicle or 10 - 40mg / kg of the convulsant PTZ by intraperitoneal injection . Seizure and seizure - like behaviors were scored by examination of video collected for 20min . Quantitative real - time PCR ( QPCR ) was performed to measure potential compensatory neuronal connexin ( Q8NFK1 , P35212 , P17302 and P36383 ) , pannexin ( Q96RD7 and Q96RD6 ) and gamma - aminobutyric acid type A ( GABA ( A ) ) receptor α1 subunit gene expression . RESULTS : Cx36KO animals exhibited considerably more severe seizures ; 40mg / kg of PTZ caused severe generalized ( ≥ grade III ) seizures in 78 % of KO , but just 5 % of WT mice . A lower dose of PTZ ( 20mg / kg ) induced grade II seizure - like behaviors in 40 % KO vs . 0 % of WT animals . There was no significant difference in either connexin , pannexin or GABA ( A ) α1 gene expression between WT and KO animals . CONCLUSION : Increased sensitivity of Cx36KO animals to PTZ - induced seizure suggests that Q9UKL4 gap junctional communication functions as a physiological anti - convulsant mechanism , and identifies the Q9UKL4 gap junction as a potential therapeutic target in epilepsy .",
"Characterization of SNARE cleavage products generated by formulated botulinum neurotoxin type - a drug products . The study evaluated substrate cleavage product ( s ) generated by three botulinum neurotoxin serotype A ( DB00083 ) medicinal drug products utilizing a novel and highly specific , light - chain activity , high - performance liquid chromatography ( LCA - HPLC ) method . Samples were reacted with a commercially available DB00083 fluorescent substrate derived from the P60880 sequence . Reaction products were separated by reversed - phase HPLC . The method detected an atypical cleavage pattern by one of the formulated drug products . DB00083 produced two cleavage fragments rather than the single fragment typically generated by DB00083 . Identification confirmed the secondary cleavage at a position corresponding to P60880 Arg198 - Ala199 ( normal DB00083 cleavage is Gln197 - Arg198 ) . Arg198 - Ala199 is also the cleavage site for trypsin and serotype C toxin . Normal cleavage was observed for all other DB00083 drug product samples , as well as 900 - kD and 150 - kD bulk toxin DB00083 . The reason for this unexpected secondary cleavage pattern by one formulated DB00083 drug product is unknown . Possible explanations include a contaminating protease and / or damage to the 150 - kD type - A toxin causing nonspecific substrate recognition and subsequent cleavage uncharacteristic of type - A toxin . The DB00083 drug products were also analyzed via the LCA - HPLC assay using a commercial BoNT / C fluorescent substrate derived from the syntaxin sequence . Cleavage of the serotype C substrate by incobotulinumtoxinA was also confirmed whilst neither of the other drug products cleaved the syntaxin substrate .",
"Differential contribution of syntaxin 1 and P60880 to secretion in noradrenergic and adrenergic chromaffin cells . We used botulinum neurotoxins ( BoNT ) to examine whether differences in the secretory activity of noradrenergic and adrenergic chromaffin cells are related to differences in the exocytotic machinery of these two types of bovine adrenal medulla cells . Cleavage of syntaxin and P60880 by BoNT / C1 decreased in a dose - dependent way the release of both noradrenaline and adrenaline , but noradrenaline release was more sensitive to BoNT / C1 . Cleavage of P60880 by DB00083 also had a larger inhibitory effect on noradrenaline release than on adrenaline release . Neither BoNT / C1 nor DB00083 affected the intracellular Ca2 + responses induced by K +- depolarisation , and the extent of the inhibition of K +- evoked catecholamine release by selective blockers of voltage - gated Ca2 + channels was not affected by BoNT / C1 . Therefore , our data do not support the hypothesis of a regulatory effect of syntaxin or P60880 on the activity of Ca2 + channels . The lower sensitivity of adrenaline release to BoNT was not due to a reduced ability of the toxins to enter or to cleave their protein targets in adrenergic cells , since immunoblot analysis showed the cleavage of a larger fraction of syntaxin 1A in adrenergic cells , as compared to the cleavage in noradrenergic cells . The immunoblot analysis also showed larger amounts of syntaxin 1A in noradrenergic chromaffin cells than in adrenergic cells . Thus , in spite of a greater cleavage of syntaxin 1A in adrenergic cells by BoNT / C1 , adrenaline release was less sensitive to BoNT / C1 , suggesting that the release process in noradrenergic cells might be more dependent on syntaxin 1A and P60880 , as compared to adrenergic cells .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK89___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .",
"Botulinum neurotoxin A subtype 2 reduces pathological behaviors more effectively than subtype 1 in a rat Parkinson ' s disease model . Recent reports indicate that interruption of acetylcholine release by intrastriatal injection of botulinum neurotoxin type A ( DB00083 ) in a rat Parkinson ' s disease model reduces pathogenic behavior without adverse side effects such as memory dysfunction . Current knowledge suggests that DB00083 subtype 1 ( BoNT / A1 ) and DB00083 subtype 2 ( BoNT / A2 ) exert different effects . In the present study , we compared the effects of BoNT / A1 and BoNT / A2 on rotation behavior and in vivo cleavage of presynaptic protein P60880 in a rat unilateral 6 - hydroxydopamine - induced Parkinson ' s disease model . BoNT / A2 more effectively reduced pathogenic behavior by efficiently cleaving P60880 in the striatum compared with that of BoNT / A1 . Our results suggest that BoNT / A2 has greater clinical therapeutic value for treating subjects with Parkinson ' s disease compared to that of BoNT / A1 ."
] |
[
"___MASK18___",
"___MASK29___",
"___MASK47___",
"___MASK51___",
"___MASK57___",
"___MASK62___",
"___MASK86___",
"___MASK87___",
"___MASK89___"
] |
___MASK89___
|
MH_train_417
|
interacts_with DB00928?
|
[
"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK59___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK59___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .",
"DB00928 and decitabine induce gene - specific and non - random DNA demethylation in human cancer cell lines . The DNA methyltransferase inhibitors azacytidine and decitabine represent archetypal drugs for epigenetic cancer therapy . To characterize the demethylating activity of azacytidine and decitabine we treated colon cancer and leukemic cells with both drugs and used array - based DNA methylation analysis of more than 14 , 000 gene promoters . Additionally , drug - induced demethylation was compared to methylation patterns of isogenic colon cancer cells lacking both DNA methyltransferase 1 ( P26358 ) and Q9UBC3 . We show that drug - induced demethylation patterns are highly specific , non - random and reproducible , indicating targeted remethylation of specific loci after replication . Correspondingly , we found that CG dinucleotides within CG islands became preferentially remethylated , indicating a role for DNA sequence context . We also identified a subset of genes that were never demethylated by drug treatment , either in colon cancer or in leukemic cell lines . These demethylation - resistant genes were enriched for Polycomb Repressive Complex 2 components in embryonic stem cells and for transcription factor binding motifs not present in demethylated genes . Our results provide detailed insights into the DNA methylation patterns induced by azacytidine and decitabine and suggest the involvement of complex regulatory mechanisms in drug - induced DNA demethylation .",
"An analysis of DNA methylation in human adipose tissue reveals differential modification of obesity genes before and after gastric bypass and weight loss . BACKGROUND : Environmental factors can influence obesity by epigenetic mechanisms . Adipose tissue plays a key role in obesity - related metabolic dysfunction , and gastric bypass provides a model to investigate obesity and weight loss in humans . RESULTS : Here , we investigate DNA methylation in adipose tissue from obese women before and after gastric bypass and significant weight loss . In total , 485 , 577 CpG sites were profiled in matched , before and after weight loss , subcutaneous and omental adipose tissue . A paired analysis revealed significant differential methylation in omental and subcutaneous adipose tissue . A greater proportion of CpGs are hypermethylated before weight loss and increased methylation is observed in the 3 ' untranslated region and gene bodies relative to promoter regions . Differential methylation is found within genes associated with obesity , epigenetic regulation and development , such as P11597 , O15409 , P56524 , Q9UBC3 , P51787 and HOX clusters . We identify robust correlations between changes in methylation and clinical trait , including associations between fasting glucose and P56524 , Q8NCC5 and Q8IV53 in subcutaneous adipose . Genes investigated with differential promoter methylation all show significantly different levels of mRNA before and after gastric bypass . CONCLUSIONS : This is the first study reporting global DNA methylation profiling of adipose tissue before and after gastric bypass and associated weight loss . It provides a strong basis for future work and offers additional evidence for the role of DNA methylation of adipose tissue in obesity .",
"Aberrant methylation of tumor suppressor genes in patients with refractory anemia with ring sideroblasts . This study evaluates the incidence and prognostic impact of aberrant methylation of 25 tumor suppressor genes in 40 patients with P54136 , a P43034 subtype , by methylation - specific multiplex ligation - dependent probe amplification ( MS - MLPA ) assay . Methylation of at least one gene was detected in 18 patients ( 45 % ) . The genes methylated were P42772 ( 20 % ) , Q9NS23 ( 18 % ) , P10826 ( 10 % ) , P55290 ( 7 . 5 % ) and P49789 ( 5 % ) . Patients with at least one methylated gene had a significantly shorter OS than patients without methylated genes . Aberrant methylation is a frequent event in patients with P54136 as in patients with high - risk P43034 appears to confer a worse prognosis .",
"Gq - mediated Akt translocation to the membrane : a novel PIP3 - independent mechanism in platelets . Akt is an important signaling molecule regulating platelet aggregation . Akt is phosphorylated after translocation to the membrane through Gi signaling pathways by a phosphatidylinositol - 3 , 4 , 5 - trisphosphate ( PIP3 ) - dependent mechanism . However , Akt is more robustly phosphorylated by thrombin compared with adenosine 5 '- diphosphate in platelets . This study investigated the mechanisms of Akt translocation as a possible explanation for this difference . Stimulation of washed human platelets with protease - activated receptor agonists caused translocation of Akt to the membrane rapidly , whereas phosphorylation occurred later . The translocation of Akt was abolished in the presence of a Gq - selective inhibitor or in Gq - deficient murine platelets , indicating that Akt translocation is regulated downstream of Gq pathways . Interestingly , phosphatidylinositol 3 - kinase ( PI3K ) inhibitors or Q9H244 antagonist abolished Akt phosphorylation without affecting Akt translocation to the membrane , suggesting that Akt translocation occurs through a PI3K / PIP3 / Gi - independent mechanism . An Akt scaffolding protein , P38936 - activated kinase ( PAK ) , translocates to the membrane after stimulation with protease - activated receptor agonists in a Gq - dependent manner , with the kinetics of translocation similar to that of Akt . Coimmunoprecipitation studies showed constitutive association of PAK and Akt , suggesting a possible role of PAK in Akt translocation . These results show , for the first time , an important role of the Gq pathway in mediating Akt translocation to the membrane in a novel Gi / PI3K / PIP3 - independent mechanism .",
"Epigenetic regulation of protein tyrosine phosphatase Q05209 in triple - negative breast cancer . AIMS : The present study showed that the expression of Q05209 is epigenetically regulated . DB00928 ( 5 - Azac ) , a DNA hypomethylating agent , significantly increased the expression of Q05209 at low concentrations ( 1μM and 2 . 5μM ) and decreased the expression of Q05209 at 5μM in the MDA - MB - 231 and BT - 549 triple - negative breast cancer cell lines . MAIN METHODS : Human MCF - 7 , MDA - MB - 231 and BT - 549 cells were exposed to different concentrations of 5 - Azac for 24 and 48h . RT - PCR was performed to determine the mRNA expression of Q05209 , P12830 and miRNA - 124 . Western blotting was performed to assess the protein expression of various proteins , including Q05209 , P12830 , P26358 and PARP . KEY FINDINGS : 5 - Azac , a DNA hypomethylating agent , significantly increased the expression of Q05209 at low concentrations ( 1μM and 2 . 5μM ) and decreased Q05209 expression at 5μM . We provide the first evidence that Q05209 expression is epigenetically regulated and that it is up - regulated at a lower dose of a P26358 inhibitor in MDA - MB - 231 and BT - 549 cells . Interestingly , the levels of miRNA - 124 were increased only at 5μM , the concentration at which Q05209 expression was suppressed . SIGNIFICANCE : To the best of our knowledge , this is the first report that highlights the therapeutic potential of low - dose 5 - Azac for the treatment of TNBC . Therefore , 5 - Azac , an agent that has already been tested in acute myeloid leukemia , may be more effective at lower doses for the treatment of triple - negative breast cancer .",
"JTT - 705 blocks cell proliferation and angiogenesis through p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways . The excessive proliferation and migration of vascular smooth muscle cells ( SMCs ) participate in the growth and instability of atherosclerotic plaque . We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein , JTT - 705 , on SMC proliferation and angiogenesis in endothelial cells ( ECs ) . JTT - 705 inhibited human coronary artery SMC proliferation . JTT - 705 induced the phosphorylation of p38 mitogen - activated protein kinase ( MAPK ) and extracellular - signal - regulated kinases ( P29323 ) in SMCs . In addition , the anti - proliferative effects of JTT - 705 in SMCs were blocked by p38 MAPK inhibitor . JTT - 705 induced the upregulation of p - P38936 ( waf1 ) , and this effect was blocked by dominant - negative Ras ( N17 ) , but not by inhibitors of p38 MAPK or P29323 . In addition , JTT - 705 also induced the upregulation of p27 ( kip1 ) , and this effect was blocked by p38 MAPK inhibitor . Interestingly , culture medium from JTT - 705 - treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor ( P15692 ) from SMCs and directly via an anti - proliferative effect in ECs . JTT - 705 blocked the proliferation of SMCs through the activation of p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways , and simultaneously blocked EC tube formation associated with a decrease in P15692 production from SMCs and an anti - proliferative effect in ECs . Our results indicate that JTT - 705 may induce a direct anti - atherogenic effect in addition to its inhibitory effect of P11597 activity .",
"Distinct subcellular expression of endogenous polycystin - 2 in the plasma membrane and Golgi apparatus of MDCK cells . Q13563 is a predicted integral membrane protein with non - selective cation channel activity . The protein is encoded by the PKD2 gene , which is mutated in approximately 15 % of patients with autosomal dominant polycystic kidney disease ( ADPKD ) . Q13563 can interact with the transmembrane protein polycystin - 1 , the product of the PKD1 gene . However , endoplasmic reticulum ( ER ) localization was reported for ( heterologously expressed ) polycystin - 2 in cultured cells and baso - lateral localization has been reported in renal tissues . Using two polyclonal antisera raised against polycystin - 2 we demonstrated distinct expression of the endogenous protein in the Golgi apparatus and the plasma membrane of MDCK cells . In contrast , most of the heterologously expressed polycystin - 2 ( P16519 - EGFP ) remained in the ER , substantially overlapping with the staining pattern of protein - disulfide isomerase ( P07237 ) , a marker for the ER . Only in a small subset of these cells weak plasma membrane signals were observed . Membrane staining was also suggested by immunoelectron microscopy and was confirmed by subcellular fractionation on sucrose density gradients . The plasma membrane staining disappeared following extraction with a buffer containing Triton X - 100 , whereas signals for polycystin - 1 and P12830 remained visible , suggesting that polycystin - 2 is neither tightly bound to the Triton X - 100 insoluble cytoskeleton , nor to these proteins . We conclude that endogenous polycystin - 2 is transported via the Golgi apparatus to the plasma membrane and has a broader membrane localization than polycystin - 1 . These data suggest that polycystin - 2 can move freely in certain regions of the membrane where it probably functions as a channel , activated by , or in complex with , polycystin - 1 .",
"DB00928 prevents cisplatin induced nephrotoxicity and potentiates anticancer activity of cisplatin by involving inhibition of metallothionein , pAKT and P26358 expression in chemical induced cancer rats . 5 - Azactydine inhibits cell growth by direct cytotoxic action as well as by inhibition of DNA methyl transferase enzyme . Inhibitors of P26358 have been reported to potentiate the therapeutic activity of cisplatin in vitro . Dose dependent bone marrow toxicity , neurotoxicity and nephrotoxicity are the major side effects of cisplatin , limiting its use as an effective chemotherapeutic agent . The present study was aimed to reduce the nephrotoxic potential of cisplatin without compensating its potency . To best of our knowledge , this is the first report which shows that the combination of 5 - azacytidine with cisplatin leads to remarkable reduction in nephrotoxicity , by involving inhibition of cisplatin induced metallothionein expression . DB00928 treatment with cisplatin leads to maximum reduction in tumor size in Q03001 induced colon cancer and tumor volume in DMBA induced breast cancer bearing SD rats . This combination regimen prevents phosphorylation and acetylation of histone H3 which may be involved in inhibition of aberrant gene expression in colon tumors . Further , 5 - azacytidine potentiated cisplatin induced antitumor activity by involving decreased expression of pAKT , P26358 and an increased expression of p38 in colon tumors . Thus , combination of 5 - azactydine with cisplatin attenuates the cisplatin induced nephrotoxicity and potentiates the anti - cancer activity which can have profound clinical implications .",
"A functional role of Cdx2 in beta - catenin signaling during transdifferentiation in endometrial carcinomas . Nuclear beta - catenin is required for changes in morphology from glandular to morular phenotypes of endometrial carcinoma ( Em Ca ) cells , with activation of p14 ( Q8N726 )/ p53 / P38936 ( Waf1 ) and alteration of p16 ( INK4A )/ P06400 pathways . Having demonstrated previously that the homeodomain transcription factor Cdx2 increases markedly during intestinal epithelial cell differentiation , we have examined its effects in beta - catenin signaling during transdifferentiation of Em Ca cells . In clinical cases , Cdx2 immunoreactivity , along with increased mRNA signals , was found to overlap with nuclear accumulation of beta - catenin and P38936 ( Waf1 ) in morules , demonstrating an inverse correlation with cell proliferation . In cell lines , over - expression of active form beta - catenin resulted in a significant increase in endogenous Cdx2 expression at both mRNA and protein levels . Furthermore , the Cdx2 promoter was activated by Q9NQB0 ( TCF4 ) - independent activated beta - catenin , as well as Cdx2 itself , through the region from - 39 to + 9 bp relative to transcription start site . Cells over - expressing exogenous Cdx2 showed high levels of P38936 ( Waf1 ) expression due to stabilization of the mRNA status , resulting in significant decrease in the proliferation rate , in contrast to the lack of apparent changes in morphology . Moreover , transfected Cdx2 could inhibit beta - catenin / TCF4 - mediated transcriptional activation of target genes , including p14 ( Q8N726 ) and cyclin D1 , probably through indirect mechanisms . These data suggest that over - expression of Cdx2 mediated by nuclear beta - catenin and Cdx2 itself can cause an inhibition of Em Ca cell proliferation through up - regulation of P38936 ( Waf1 ) expression , modulating beta - catenin / TCF4 - mediated transcription . We therefore conclude that an association between Cdx2 and beta - catenin signaling may participate in induction of transdifferentiation of Em Ca cells .",
"Differential selectivity of insulin secretagogues : mechanisms , clinical implications , and drug interactions . The sulphonylurea receptor ( Q09428 ) subunits of K ( DB00171 ) channels are the targets for several classes of therapeutic drugs . Sulphonylureas close K ( DB00171 ) channels in pancreatic beta - cells and are used to stimulate insulin release in type 2 diabetes , whereas the K ( DB00171 ) channel opener nicorandil acts as an antianginal agent by opening K ( DB00171 ) channels in cardiac and vascular smooth muscle . The predominant type of Q09428 varies between tissues : Q09428 in beta - cells , SUR2A in cardiac muscle , and SUR2B in smooth muscle . Sulphonylureas and related drugs exhibit differences in tissue specificity , as the drugs interact to varying degrees with different types of Q09428 . ___MASK94___ and tolbutamide are beta - cell selective and reversible . ___MASK59___ , glibenclamide , and repaglinide , however , inhibit cardiac and smooth muscle K ( DB00171 ) channels in addition to those in beta - cells and are only slowly reversible . Similar properties have been observed by recording K ( DB00171 ) channel activity in intact cells and in Xenopus oocytes expressing cloned K ( DB00171 ) channel subunits . While K ( DB00171 ) channels in cardiac and smooth muscle are largely closed under physiological conditions ( but open during ischaemia ) , they are activated by antianginal agents such as nicorandil . Under these conditions , they may be inhibited by sulphonylureas that block SUR2 - type K ( DB00171 ) channels ( e . g . , glibenclamide ) . Care should , therefore , be taken when choosing a sulphonylurea if potential interactions with cardiac and smooth muscle K ( DB00171 ) channels are to be avoided .",
"DNA methyltransferase 3a regulates osteoclast differentiation by coupling to an S - adenosylmethionine - producing metabolic pathway . Metabolic reprogramming occurs in response to the cellular environment to mediate differentiation , but the fundamental mechanisms linking metabolic processes to differentiation programs remain to be elucidated . During osteoclast differentiation , a shift toward more oxidative metabolic processes occurs . In this study we identified the de novo DNA methyltransferase 3a ( Q9Y6K1 ) as a transcription factor that couples these metabolic changes to osteoclast differentiation . We also found that receptor activator of nuclear factor - κB ligand ( O14788 ) , an essential cytokine for osteoclastogenesis , induces this metabolic shift towards oxidative metabolism , which is accompanied by an increase in S - adenosylmethionine ( DB00118 ) production . We found that DB00118 - mediated DNA methylation by Q9Y6K1 regulates osteoclastogenesis via epigenetic repression of anti - osteoclastogenic genes . The importance of Q9Y6K1 in bone homeostasis was underscored by the observations that Q9Y6K1 - deficient osteoclast precursor cells do not differentiate efficiently into osteoclasts and that mice with an osteoclast - specific deficiency in Q9Y6K1 have elevated bone mass due to a smaller number of osteoclasts . Furthermore , inhibition of DNA methylation by theaflavin - 3 , 3 '- digallate abrogated bone loss in models of osteoporosis . Thus , this study reveals the role of epigenetic processes in the regulation of cellular metabolism and differentiation , which may provide the molecular basis for a new therapeutic strategy for a variety of bone disorders .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK94___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .",
"DB02546 and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . DB02546 and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin - dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : DB02546 and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .",
"O14788 expression in myeloma cells is regulated by a network involving O14788 promoter methylation , P26358 , microRNA and TNFα in the microenvironment . We studied the regulation of O14788 expression in myeloma by promoter DNA methylation . Methylation - specific polymerase chain reaction showed complete methylation of O14788 promoter in WL - 2 myeloma cells but partial methylation in eight other lines . 5 - AzadC treatment of WL - 2 cells led to demethylation and re - expression of O14788 . Transwell and contact co - culture of WL - 2 cells with normal bone marrow - derived mesenchymal stromal cells ( BMSCs ) resulted in comparable repression of DNA methyltransferase - 1 ( P26358 ) and re - expression of O14788 in WL - 2 cells . Moreover , treatment of WL - 2 cells with TNFα led to repression of P26358 and re - expression of O14788 in association with upregulation of miR - 140 - 3p and miR - 126 , which are partially offset by addition of anti - TNFα antibody to transwell - coculture of WL2 with BMSC . Taken together , our results showed that TNFα in the marrow microenvironment led to O14788 demethylation and re - expression in myeloma cells through P26358 repression and upregulation of miR - 126 - 3p and miR - 140 , both known to repress P26358 translation .",
"[ Use of PCR markers for mapping swine chromosome 12 ] . Using PCR analysis of pig - mink and pig - Chinese hamster hybrid cell lines and heterologous and homologous primers of various types , chromosomal and subchromosomal mapping of genes P11388 , P10827 , P38398 , GAS , P17844 , P12829 , P43034 , MCP1 , P13929 , P05813 , P07237 , P51692 , and P84243 to pig chromosome 12 was carried out . The efficiency of using different types of heterologous primers for pig chromosome mapping was compared .",
"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK76___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .",
"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK71___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK71___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .",
"Time - Qualified Patterns of Variation of PPARγ , P26358 , and Q9UBC3 Expression in Pancreatic Cancer Cell Lines . Carcinogenesis is related to the loss of homeostatic control of cellular processes regulated by transcriptional circuits and epigenetic mechanisms . Among these , the activities of peroxisome proliferator - activated receptors ( PPARs ) and DNA methyltransferases ( DNMTs ) are crucial and intertwined . PPARγ is a key regulator of cell fate , linking nutrient sensing to transcription processes , and its expression oscillates with circadian rhythmicity . Aim of our study was to assess the periodicity of PPARγ and DNMTs in pancreatic cancer ( PC ) . We investigated the time - related patterns of P37231 , P26358 , and Q9UBC3 expression monitoring their mRNA levels by qRT - PCR at different time points over a 28 - hour span in BxPC - 3 , CFPAC - 1 , PANC - 1 , and MIAPaCa - 2 PC cells after synchronization with serum shock . P37231 and P26358 expression in PANC - 1 cells and P37231 expression in MIAPaCa - 2 cells were characterized by a 24 h period oscillation , and a borderline significant rhythm was observed for the P37231 , P26358 , and Q9UBC3 expression profiles in the other cell lines . The time - qualified profiles of gene expression showed different shapes and phase relationships in the PC cell lines examined . In conclusion , P37231 and DNMTs expression is characterized by different time - qualified patterns in cell lines derived from human PC , and this heterogeneity could influence cell phenotype and human disease behaviour .",
"P04279 - 110 and entinostat therapy reduces lung tumor burden and reprograms the epigenome . The DNA methyltransferase ( P26358 ) inhibitor vidaza ( DB00928 ) in combination with the histone deacetylase inhibitor entinostat has shown promise in treating lung cancer and this has been replicated in our orthotopic lung cancer model . However , the effectiveness of P26358 inhibitors against solid tumors is likely impacted by their limited stability and rapid inactivation by cytidine deaminase ( P32320 ) in the liver . These studies were initiated to test the efficacy of P04279 - 110 , a dinucleotide containing decitabine that is resistant to deamination by P32320 , as a single agent and in combination with entinostat . Evaluation of in vivo plasma concentrations and pharmacokinetic properties of P04279 - 110 showed rapid conversion to decitabine and a plasma half - life of 4 hr . P04279 - 110 alone or in combination with entinostat reduced tumor burden of a K - ras / p53 mutant lung adenocarcinoma cell line ( Calu6 ) engrafted orthotopically in nude rats by 35 % and 56 % , respectively . P04279 - 110 caused widespread demethylation of more than 300 gene promoters and microarray analysis revealed expression changes for 212 and 592 genes with P04279 - 110 alone or in combination with entinostat . Epigenetic therapy also induced demethylation and expression of cancer testis antigen genes that could sensitize tumor cells to subsequent immunotherapy . In the orthotopically growing tumors , highly significant gene expression changes were seen in key cancer regulatory pathways including induction of P38936 and the apoptotic gene Q13323 . Moreover , P04279 - 110 in combination with entinostat caused widespread epigenetic reprogramming of Q15910 - target genes . These preclinical in vivo findings demonstrate the clinical potential of P04279 - 110 for reducing lung tumor burden through reprogramming the epigenome .",
"A new epigenetic challenge : systemic lupus erythematosus . In recent years , compelling evidence has been gathered that supports a role for epigenetic alterations in the pathogenesis of systemic lupus erythematosus ( SLE ) . Different blood cell populations of SLE patients are characterized by a global loss of DNA methylation . This process is associated with defects in P29323 pathway signalling and consequent P26358 1 downregulation . Hypomethylation of gene promoters has been described , which permits transcriptional activation and therefore functional changes in the cells and also hypomethylation of the ribosomal RNA gene cluster . Among the identified targets undergoing demethylation are genes involved in autoreactivity ( P20701 ) , osmotic lysis and apoptosis ( P14222 , P50281 and P80188 ) , antigen presentation ( Q99062 ) , inflammation ( MMP 14 ) , B - T - cell interaction ( P32970 and P29965 ) and cytokine pathways ( Q99062 , P05112 , P05231 and P38484 ) . DNA methylation inhibitors are also known to induce autoreactivity in vitro and cause a lupus - like disease in vivo . Further , altered patterns of histone modifications have been described in SLE . P01730 + lymphocytes undergo global histone H3 and H4 deacetylation and consequent skewed gene expression . Although multiple lines of evidence highlight the contribution of epigenetic alterations to the pathogenesis of lupus in genetically predisposed individuals , many questions remain to be answered . Attaining a deeper understanding of these matters will create opportunities in the promising area of epigenetic treatments .",
"Effect of genetic polymorphisms on the pharmacokinetics and efficacy of glimepiride in a Korean population . BACKGROUNDS : ___MASK59___ is a commonly used sulfonylurea hypoglycemic agent . There is considerable interindividual variation in the response to sulfonylurea for patients with type 2 diabetes . The purpose of this study was to investigate whether genetic variations influence the efficacy of glimepiride in healthy Korean subjects . METHODS : A single 2 - mg oral dose of glimepiride was administered to 46 healthy volunteers . Serial blood sampling for 12h after oral dosing was performed for determination of plasma glimepiride , glucose and insulin levels . We tested the association of seven single nucleotide polymorphisms ( SNPs ) in four candidate genes with the efficacy of glimepiride . RESULTS : Pharmacodynamic profiles for plasma glucose and insulin showed no statistically significant differences among genotype groups , and parameters were not different from one another . There were no association of the Q14654 , O75052 , Q9NQB0 and Q09428 gene polymorphisms and the efficacy of glimepiride . CONCLUSIONS : Knowledge of these polymorphisms provides no clinical useful information for the pharmacogenetic therapeutic approach for Korean patients with type 2 diabetes .",
"O14788 promotes migration and invasion of hepatocellular carcinoma cells via NF - κB - mediated epithelial - mesenchymal transition . BACKGROUND : Metastasis accounts for the most deaths in patients with hepatocellular carcinoma ( HCC ) . Receptor activator of nuclear factor kappa B ligand ( O14788 ) is associated with cancer metastasis , while its role in HCC remains largely unknown . METHODS : Immunohistochemistry was performed to determine the expression of Q9Y6Q6 in HCC tissue ( n = 398 ) . Quantitative real - time polymerase chain reaction ( qRT - PCR ) and Western blot were used to examine the expression of Q9Y6Q6 , P12830 , P19022 , vimentin , Snail , Slug , Twist and MMPs in HCC cells . Wound healing and Transwell assays were used to evaluate cell migration and invasion ability . RESULTS : We found that expression of Q9Y6Q6 , the receptor of O14788 , was significantly higher in HCC tumor tissues than in peritumor liver tissues ( p < 0 . 001 ) . Constitutive expression of Q9Y6Q6 was detected in HCC cell lines , which can be up - regulated when HCC cells were stimulated with O14788 . Notably , in vitro experiments showed that activation of O14788 - Q9Y6Q6 axis significantly promoted migration and invasion ability of HCC cells . In addition , O14788 stimulation increased the expression levels of P19022 , Snail , and Twist , while decreased the expression of P12830 , with concomitant activation of NF - κB signaling pathway . Moreover , administration of the NF - κB inhibitor attenuated O14788 - induced migration , invasion and epithelial - mesenchymal transition of HCC cells . CONCLUSIONS : O14788 could potentiate migration and invasion ability of Q9Y6Q6 - positive HCC cells through NF - κB pathway - mediated epithelial - mesenchymal transition , which means that O14788 - Q9Y6Q6 axis could be a potential target for HCC therapy .",
"CpG island methylation of Q12983 predicts resistance against S - 1 / CPT - 11 combined therapy in colorectal cancer patients . Aberrant gene methylation is frequently observed in various cancers and plays an important role in carcinogenesis , cancer progression and drug responsiveness . The aim of this study is to identify colorectal cancer specific gene methylation determining chemosensitivity to S - 1 / CPT - 11 therapy . The gene methylation of Q96EP1 , p16 , Q13761 , P12830 , P16455 , hMLH1 , Q9UNQ0 , P22309 and Q12983 genes were analyzed in 27 colorectal cancer tissues by quantitative methylation - specific PCR ( q - MSP ) . All 27 patients were postoperatively treated by S - 1 / CPT - 11 therapy targeting the metastatic lesion and the recurrent tumor . Thereafter , the patients were divided into a responder group ( RG ) or a non - responder group ( DB04223 ) according to the effect of the chemotherapy . There were 13 cases of RG ( 48 . 1 % ) and 14 cases of DB04223 ( 51 . 9 % ) . The methylation level in Q96EP1 , Q13761 and Q12983 was significantly higher in cancer lesions in comparison to the non - cancerous lesion . Only methylation of the Q12983 gene was significantly higher in primary cancer tissue of the DB04223 than the RG . The correlation between the Q12983 methylation status and time to progression ( TTP ) suggested that the low methylation group ( n = 16 ) resulted in a significantly longer TTP , in comparison to the high methylation group ( n = 11 ; P = 0 . 004 ) . The methylation level of Q12983 showed a significant inverse correlation with the mRNA expression suggesting the DNA methylation suppressed Q12983 expression ( r =- 0 . 466 , P = 0 . 021 ) . In conclusion , Q12983 gene methylation is a possible marker predicting a poor response to the S - 1 / CPT - 11 combined therapy in colorectal cancer .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK83___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK83___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"___MASK21___ for joints and bones . ___MASK21___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK21___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK21___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"Lessons learned from the irinotecan metabolic pathway . ___MASK84___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK84___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK84___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .",
"Novel target for induction of apoptosis by cyclo - oxygenase - 2 inhibitor SC - 236 through a protein kinase C - beta ( 1 )- dependent pathway . Nonsteroidal anti - inflammatory drugs ( NSAIDs ) reduce the risk of gastrointestinal cancers . Recently , a similar protective effect has been demonstrated by the specific cyclo - oxygenase - 2 ( P35354 ) inhibitors . However , the exact mechanism that accounts for the anti - proliferative effect of specific P35354 inhibitors is still not fully understood , and it is still controversial whether these protective effects are predominantly mediated through the inhibition of P35354 activity and prostaglandin synthesis . Identification of molecular targets regulated by P35354 inhibitors could lead to a better understanding of their pro - apoptotic and anti - neoplastic activities . In the present study , we investigated the effect and the possible molecular target of a P35354 - specific inhibitor SC - 236 on gastric cancer . We showed that SC - 236 induced apoptosis in gastric cancer cells . However , this effect was not dependent on P35354 inhibition . SC - 236 down - regulated the protein expression and kinase activity of P05771 ( 1 ) , increased the expression of PKCdelta and PKCeta , but did not alter the expression of other PKC isoforms in AGS cells . Moreover , exogenous prostaglandins or PGE ( 2 ) receptor antagonists could not reverse the inhibition effect on PKCbeta ( 1 ) by SC - 236 , which suggested that this effect occurred through a mechanism independent of cyclo - oxygenase activity and prostaglandin synthesis . Overexpression of PKCbeta ( 1 ) attenuated the apoptotic response of AGS cells to SC - 236 and was associated with overexpression of P38936 ( waf1 / cip1 ) . Inhibition of PKCbeta ( 1 )- mediated overexpression of P38936 ( waf1 / cip1 ) partially reduced the anti - apoptotic effect of PKCbeta ( 1 ) . The down - regulation of PKCbeta ( 1 ) provides an explanation for P36551 - independent apoptotic effects of specific P35354 inhibitor in cultured gastric cancer cells . We also suggest that PKCbeta ( 1 ) act as survival mediator in gastric cancer , and its down - regulation by P35354 inhibitor SC - 236 may provide new target for future treatment of gastric cancer .",
"Differential gene expression in well - regulated and dysregulated pancreatic beta - cell ( MIN6 ) sublines . To identify genes involved in regulated insulin secretion , we have established and characterized two sublines derived from the mouse pancreatic beta - cell line MIN6 , designated B1 and P01024 . They have a similar insulin content , but differ in their secretory properties . B1 responded to glucose in a concentration - and cell confluence - dependent manner , whereas P01024 did not . B1 cells were stimulated by phorbol 12 - myristate 13 - acetate , leucine , arginine , glibenclamide , isobutylmethylxanthine , and DB00761 , whereas P01024 did not respond ( leucine , arginine , and glibenclamide ) or responded to a lesser extent ( isobutylmethylxanthine , phorbol 12 - myristate 13 - acetate , and DB00761 ) . Although intracellular Ca ( 2 +) rose in response to glucose in B1 but not P01024 cells , DB00761 increased intracellular Ca ( 2 +) in a similar manner in both sublines . P11166 , P11168 , Kir6 . 2 , and Q09428 expression was not significantly different between B1 and P01024 cells , whereas P12830 was more abundantly expressed in B1 cells . A more complete list of differentially expressed genes was established by suppression subtractive hybridization and high density ( Affymetrix ) oligonucleotide microarrays . Genes were clustered according to known or putative function . Those involved in metabolism , intracellular signaling , cytoarchitecture , and cell adhesion are of potential interest . These two sublines should be useful for identification of the genes and mechanisms involved in regulated insulin secretion of the pancreatic beta - cell .",
"P10275 is negatively correlated with the methylation - mediated transcriptional repression of miR - 375 in human prostate cancer cells . P10275 ( AR ) plays a critical role during the development and progression of prostate cancer in which microRNA miR - 375 is overexpressed and correlated with tumor progression . Although DNA methylation is a key mechanism for the repression of gene expression , the relationship between AR and the expression or the hypermethylation of miR - 375 is unknown . In this study , we found that AR - positive prostate cancer ( PCa ) cells showed high expression levels and hypomethylation of the miR - 375 . In contrast , AR - negative PCa cells displayed low levels and hypermethylation of the miR - 375 . Addition of 5 - Aza - 2 '- deoxycytidine , a specific inhibitor of DNA methylation , into the culture medium reversed the low expression levels of miR - 375 in the AR negative PCa cells . In addition , the total activity levels of DNA methyltransferases ( DNMTs ) were high in AR - negative PCa cells , in which hypermethylation of miR - 375 promoter and low expression levels of miR - 375 were observed . Taken together , these findings indicate that the negative correlation between AR and total P26358 activity is one of mechanisms to influence the methylation status of miR - 375 promoter , which in turn regulates the expression of miR - 375 .",
"Anticancer drug discovery targeting DNA hypermethylation . DNA methyltransferases ( DNMTs ) are important regulators of gene transcription and their roles in carcinogenesis have been a topic of considerable interest in the last few years . Diverse classes of chemical compounds including nucleotide analogues , adenosine analogues , aminobenzoic derivatives , polyphenols , hydrazines , phthalides , disulfides and antisenses are being discovered and evaluated as P26358 inhibitors targeting DNA hypermethylation . Among them , DB00928 5 and Decitabine 6 were launched recently . Several other compounds are under clinical trials . Some of these compounds were discovered from structure - based drug design . These compounds exert their DNA methylation inhibitory by different mechanisms . This review will present a brief account of various DNA methyltransferases and their biological functions , with focus on actuality of design and synthesis of various inhibitors of DNA hypermethylation as anticancer drugs .",
"The transcriptional coactivator DRIP / mediator complex is involved in vitamin D receptor function and regulates keratinocyte proliferation and differentiation . Mediator is a multisubunit coactivator complex that facilitates transcription of nuclear receptors . We investigated the role of the mediator complex as a coactivator for vitamin D receptor ( P11473 ) in keratinocytes . Using P11473 affinity beads , the vitamin D receptor interacting protein ( DRIP ) / mediator complex was purified from primary keratinocytes , and its subunit composition was determined by mass spectrometry . The complex included core subunits , such as Q15648 / MED1 ( MED1 ) , that directly binds to P11473 . Additional subunits were identified that are components of the RNA polymerase II complex . The functions of different mediator components were investigated by silencing its subunits . The core subunit MED1 facilitates P11473 activity and regulating keratinocyte proliferation and differentiation . A newly described subunit Q13503 also has a role in promoting keratinocyte proliferation and differentiation , whereas Q9BTT4 has an inhibitory role . Blocking MED1 / Q13503 expression caused hyperproliferation of keratinocytes , accompanied by increases in mRNA expression of the cell cycle regulator cyclin D1 and / or glioma - associated oncogene homolog . Blocking MED1 or Q13503 expression also resulted in defects in calcium - induced keratinocyte differentiation , as indicated by decreased expression of differentiation markers and decreased translocation of P12830 to the membrane . These results show that keratinocytes use the transcriptional coactivator mediator to regulate P11473 functions and control keratinocyte proliferation and differentiation .",
"Rational approaches to design of therapeutics targeting molecular markers . This paper introduces novel therapeutic strategies focusing on a molecular marker relevant to a particular hematologic malignancy . Four different approaches targeting specific molecules in unique pathways will be presented . The common theme will be rational target selection in a strategy that has reached the early phase of human clinical trial in one malignancy , but with a much broader potential applicability to the technology . In Section I Dr . Richard Klasa presents preclinical data on the use of antisense oligonucleotides directed at the bcl - 2 gene message to specifically downregulate Bcl - 2 protein expression in non - Hodgkin ' s lymphomas and render the cells more susceptible to the induction of apoptosis . In Section II Dr . Alan List reviews the targeting of vascular endothelial growth factor ( P15692 ) and its receptor in anti - angiogenesis strategies for acute myeloid leukemia ( AML ) and myelodysplastic syndromes ( P43034 ) . In Section III Dr . Bruce Cheson describes recent progress in inhibiting cell cycle progression by selectively disrupting cyclin D1 with structurally unique compounds such as flavopiridol in mantle cell lymphoma as well as describing a new class of agents that affect proteasome degradation pathways .",
"Subclones with the t ( 9 ; 22 )/ P11274 - P00519 rearrangement occur in AML and seem to cooperate with distinct genetic alterations . In AML , cooperation of mutations suppressing differentiation ( ' class - II - mutations ' ) with ' class - I - mutations ' increasing cell proliferation is frequent . In rare cases of myeloid malignancies , the P11274 - P00519 fusion was reported to cooperate as class - I - mutation with class - II - mutations , but most cases had to be classified as blast phase of chronic myeloid leukaemia ( CML ) . We identified five cases of Philadelphia positive subclones in AML occurring in coincidence with other genetic lesions : 1 : 220 patients with inv ( 16 )/ Q13951 - P35749 ( 0 · 5 % ) , 2 : 272 AML cases with t ( 8 ; 21 )/ Q01196 - Q06455 ( 0 · 7 % ) , 1 : 1029 P06748 - mutated AML ( 0 · 1 % ) , and one patient with s - AML following P43034 with a 5q - deletion . Four patients had m - P11274 ( e1a2 ) P11274 - P00519 transcripts ; one case only had an M - P11274 ( b3a2 ) breakpoint . These cases allow some interesting conclusions : The P11274 - P00519 rearrangement apparently can cooperate with the P06748 mutation similar to other class - I - mutations . The identification of Philadelphia positive subclones in < 1 % of patients with Q03701 - leukaemias fits well with previous observations that most Q03701 - AML are accompanied by activating mutations in genes enhancing proliferation . Since we observed the occurrence of the Philadelphia positive subclones at diagnosis , at relapse , or throughout the disease , the time point of the emergence of Philadelphia subclones seems variable in AML . Clinical research should further concentrate on Philadelphia positive subclones in AML to assess the clinical impact .",
"A common binding site on the microsomal triglyceride transfer protein for apolipoprotein B and protein disulfide isomerase . The assembly of triglyceride - rich lipoproteins requires the formation in the endoplasmic reticulum of a complex between apolipoprotein B ( apoB ) , a microsomal triglyceride transfer protein ( P55157 ) , and protein disulfide isomerase ( P07237 ) . In the P55157 complex , the amino - terminal region of P55157 ( residues 22 - 303 ) interacts with the amino - terminal region of apoB ( residues 1 - 264 ) . Here , we report the identification and characterization of a site on apoB between residues 512 and 721 , which interacts with residues 517 - 603 of P55157 . P07237 binds in close proximity to this apoB binding site on P55157 . The proximity of these binding sites on P55157 for P07237 and amino acids 512 - 721 of apoB was evident from studies carried out in a yeast two - hybrid system and by co - immunoprecipitation . The expression of P07237 with P55157 and apoB16 ( residues 1 - 721 ) in the baculovirus expression system reduced the amount of P55157 co - immunoprecipitated with apoB by 73 % . The interaction of residues 512 - 721 of apoB with P55157 facilitates lipoprotein production . Mutations of apoB that markedly reduced this interaction also reduced the level of apoB - containing lipoprotein secretion .",
"P10275 inducing bladder cancer progression by promoting an epithelial - mesenchymal transition . The study investigated the role of androgen receptor ( AR ) as a potential target for the treatment of bladder cancer in regulating epithelial - mesenchymal transition or transformation ( EMT ) . Cell proliferation , and migration capacity were determined in bladder cancer T24 cells treated with small interfering RNA directed against AR , and expression levels of P12830 , β - catenin and N - cadherin were assessed using quantitative reverse transcription PCR ( qRT - PCR ) . Tumour cell growth was evaluated in vivo in T24 tumour - bearing nude mice receiving electroporation - assisted administration of anti - AR small interfering RNA . It was found that low AR expression decreased proliferation and migration of bladder cancer cells . In vivo experiments showed that silencing AR expression significantly suppressed AR - positive bladder tumour growth with decreased cell proliferation . Low AR level of T24 bladder cancer cells treated with DB01541 ( ___MASK71___ ) decreased expression of P12830 , β - catenin and P19022 expression , indicating a strong sensitivity to the EMT and In cells with low AR content , TGF - β induced down - regulation of P12830 and β - catenin . It is concluded that suppression of AR expression decreased the production of TGF - β , inhibiting EMT and bladder cancer cell growth in vitro and in vivo , implying that its use might be a potential therapeutic target for the treatment of bladder cancer .",
"___MASK26___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK26___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK26___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK26___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK26___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK26___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .",
"Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries . Recent advances in stem cell biology have shed light on how normal stem and progenitor cells can evolve to acquire malignant characteristics during tumorigenesis . The cancer counterparts of normal stem and progenitor cells might be occurred through alterations of stem cell fates including an increase in self - renewal capability and a decrease in differentiation and / or apoptosis . This oncogenic evolution of cancer stem and progenitor cells , which often associates with aggressive phenotypes of the tumorigenic cells , is controlled in part by dysregulated epigenetic mechanisms including aberrant DNA methylation leading to abnormal epigenetic memory . Epigenetic therapy by targeting DNA methyltransferases ( P26358 ) 1 , Q9Y6K1 and Q9UBC3 via DB00928 ( Aza ) and 5 - Aza - 2 '- deoxycytidine ( Aza - dC ) has proved to be successful toward treatment of hematologic neoplasms especially for patients with myelodysplastic syndrome . In this review , I summarize the current knowledge of mechanisms underlying the inhibition of DNA methylation by Aza and Aza - dC , and of their apoptotic - and differentiation - inducing effects on cancer stem and progenitor cells in leukemia , medulloblastoma , glioblastoma , neuroblastoma , prostate cancer , pancreatic cancer and testicular germ cell tumors . Since cancer stem and progenitor cells are implicated in cancer aggressiveness such as tumor formation , progression , metastasis and recurrence , I propose that effective therapeutic strategies might be achieved through eradication of cancer stem and progenitor cells by targeting the DNA methylation machineries to interfere their \" malignant memory \" .",
"Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 .",
"MicroRNA miR - 125b causes leukemia . MicroRNA miR - 125b has been implicated in several kinds of leukemia . The chromosomal translocation t ( 2 ; 11 )( P38936 ; q23 ) found in patients with myelodysplasia and acute myeloid leukemia leads to an overexpression of miR - 125b of up to 90 - fold normal . Moreover , miR - 125b is also up - regulated in patients with B - cell acute lymphoblastic leukemia carrying the t ( 11 ; 14 )( q24 ; q32 ) translocation . To decipher the presumed oncogenic mechanism of miR - 125b , we used transplantation experiments in mice . All mice transplanted with fetal liver cells ectopically expressing miR - 125b showed an increase in white blood cell count , in particular in neutrophils and monocytes , associated with a macrocytic anemia . Among these mice , half died of B - cell acute lymphoblastic leukemia , T - cell acute lymphoblastic leukemia , or a myeloproliferative neoplasm , suggesting an important role for miR - 125b in early hematopoiesis . Furthermore , coexpression of miR - 125b and the P11274 - P00519 fusion gene in transplanted cells accelerated the development of leukemia in mice , compared with control mice expressing only P11274 - P00519 , suggesting that miR - 125b confers a proliferative advantage to the leukemic cells . Thus , we show that overexpression of miR - 125b is sufficient both to shorten the latency of P11274 - P00519 - induced leukemia and to independently induce leukemia in a mouse model .",
"Silencing of the metastasis suppressor O95980 by DB01367 oncogene is mediated by DNA methyltransferase 3b - induced promoter methylation . O95980 is a membrane - anchored glycoprotein that may negatively regulate matrix metalloproteinase activity to suppress tumor invasion and metastasis . Our previous study indicated that oncogenic DB01367 inhibited O95980 expression via a histone deacetylation mechanism . In this study , we address whether DNA methyltransferases ( P26358 ) participate in the inhibition of O95980 by DB01367 . Induction of Ha - DB01367 ( Val12 ) oncogene increased DNMT3b , but not P26358 and DNMT3a , expression in 2 - 12 cells . In addition , induction of DNMT3b by DB01367 was through the extracellular signal - regulated kinase signaling pathway . Oncogenic DB01367 increased the binding of DNMT3b to the promoter of O95980 gene and this binding induced promoter methylation , which could be reversed by 5 '- azacytidine and DNMT3b small interfering RNA ( siRNA ) . The MEK inhibitor U0126 also reversed DB01367 - induced DNMT3b binding and O95980 promoter methylation . Treatment of 5 '- azacytidine and DNMT3b siRNA restored O95980 expression in 2 - 12 cells and potently suppressed DB01367 - stimulated cell invasion . In addition , the inhibitory effect of 5 '- azacytidine on DB01367 - induced cell invasion was attenuated after knockdown of O95980 by siRNA . Interestingly , human lung cancer cells harboring constitutively activated DB01367 exhibited lower O95980 expression and higher promoter methylation of O95980 gene . 5 '- DB00928 and DNMT3b siRNA restored O95980 expression in these cells and effectively suppressed invasiveness . Collectively , our results suggest that DB01367 oncogene induces O95980 gene silencing through DNMT3b - mediated promoter methylation , and P26358 inhibitors may be useful for the treatment of DB01367 - induced metastasis .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK94___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"Enhanced sensitivity to irinotecan by Cdk1 inhibition in the p53 - deficient HT29 human colon cancer cell line . Mutations in the tumor - suppressor gene p53 have been associated with advanced colorectal cancer ( CRC ) . ___MASK84___ ( CPT - 11 ) , a P11387 inhibitor , has been recently incorporated to the adjuvant therapy . Since the DNA - damage checkpoint depends on p53 activation , the status of p53 might critically influence the response to CPT - 11 . We analysed the sensitivity to CPT - 11 in the human colon cancer cell line HT29 ( mut p53 ) and its wild - type ( wt )- p53 stably transfected subclone HT29 - A4 . Cell - cycle analysis in synchronised cells demonstrated the activation of transfected wt - p53 and a P38936 ( P38936 / CIP1 )- dependent cell - cycle blockage in the S phase . Activated wt - p53 increased apoptosis and enhanced sensitivity to CPT - 11 . In p53 - deficient cells , cDNA - macroarray analysis and western blotting showed an accumulation of the cyclin - dependent kinase ( cdk ) 1 / cyclin B complex . Subsequent p53 - independent activation of the cdk - inhibitor ( cdk - I ) P38936 ( P38936 / CIP1 ) prevented cell - cycle progression . Cdk1 induction was exploited in vivo to improve the sensitivity to CPT - 11 by additional treatment with the cdk - I P99999 - 202 . We demonstrate a gain of sensitivity to CPT - 11 in a p53 - mutated colon cancer model either by restoring wild - type p53 function or by sequential treatment with cdk - Is . Considering that mutations in p53 are among the most common genetic alterations in CRC , a therapeutic approach specifically targeting p53 - deficient tumors could greatly improve the treatment outcomes .",
"Equitoxic doses of 5 - azacytidine and 5 - aza - 2 ' deoxycytidine induce diverse immediate and overlapping heritable changes in the transcriptome . BACKGROUND : The hypomethylating agent DB00928 ( 5 - Aza - CR ) is the first drug to prolong overall survival in patients with myelodysplastic syndrome ( P43034 ) . Surprisingly , the deoxyribonucleoside analog 5 - Aza - 2 ' deoxycytidine ( 5 - Aza - CdR ) did not have a similar effect on survival in a large clinical trial . Both drugs are thought to exert their effects after incorporation into DNA by covalent binding of DNA methyltransferase ( P26358 ) . While 5 - Aza - CdR is incorporated into only DNA , 5 - Aza - CR is also incorporated into RNA . Here , we have analyzed whether this difference in nucleic acid incorporation may influence the capacities of these drugs to regulate the expression of mRNA and microRNAs ( miRNA ) , which may potentially affect the activities of the drugs in patients . METHODOLOGY / PRINCIPAL FINDINGS : A hematopoietic ( HL - 60 ; acute myeloid leukemia ) and a solid ( T24 ; transitional cell carcinoma ) cancer cell line were treated with equitoxic doses of 5 - Aza - CR and 5 - Aza - CdR for 24 hrs , and the immediate ( day 2 ) and lasting ( day 8 ) effects on RNA expression examined . There was considerable overlap between the RNAs heritably upregulated by both drugs on day 8 but more RNAs were stably induced by the deoxy analog . Both drugs strongly induced expression of cancer testis antigens . On day 2 more RNAs were downregulated by 5 - Aza - CR , particularly at higher doses . A remarkable downregulation of miRNAs and a significant upregulation of tRNA synthetases and other genes involved in amino acid metabolism was observed in T24 cells . CONCLUSIONS / SIGNIFICANCE : Overall , this suggests that significant differences exist in the immediate action of the two drugs , however the dominant pattern of the lasting , and possible heritable changes , is overlapping .",
"20 - Epi analogues of 1 , 25 - dihydroxyvitamin D3 are highly potent inducers of DRIP coactivator complex binding to the vitamin D3 receptor . 1 , 25 - Dihydroxyvitamin D3 ( 1 , 25 ( OH ) 2D3 ) plays a major role in the stimulation of bone growth , mineralization , and intestinal calcium and phosphate absorption ; it also acts as a general inhibitor of cellular proliferation . Several new , clinically relevant compounds dissociate antiproliferative and calcemic activities of 1 , 25 ( OH ) 2D3 , but the molecular basis for this has not been clearly elucidated . Here , we tested whether the potency of one class of compounds , 20 - epi analogues , to induce myeloid cell differentiation , is because of direct molecular effects on vitamin D receptor ( P11473 ) . We report that two 20 - epi analogues , MC1627 and MC1288 , induced differentiation and transcription of P38936 ( Waf1 , Cip1 ) , a key P11473 target gene involved in growth inhibition , at a concentration 100 - fold lower than that of 1 , 25 ( OH ) 2D3 . We compared this sensitivity to analogue effects on P11473 interacting proteins : RXR , Q9Y3R0 , and Q15648 , a subunit of the DRIP coactivator complex . Compared with the interaction of P11473 with RXR or Q9Y3R0 , the differentiation dose - response most closely correlated to the ligand - dependent recruitment of the DRIP coactivator complex to P11473 and to the ability of the receptor to activate transcription in a cell - free system . These results provide compelling links between the efficiency of the 20 - epi analogue in inducing P11473 / DRIP interactions , transactivation in vitro , and its enhanced ability to induce cellular differentiation .",
"DNA methyl transferase I acts as a negative regulator of allergic skin inflammation . The role of DNA methyl transferase I ( P26358 ) in allergic inflammation was investigated . Antigen stimulation decreased expression of P26358 in rat basophilic leukemia cells ( RBL2H3 ) . The down regulation of P26358 induced expression of histone deacetylase 3 ( O15379 ) . O15379 was necessary for allergic skin inflammation , such as such as triphasic cutaneous reaction and passive cutaneous anaphylaxis . The down regulation of P26358 resulted from activation of PKC and rac1 which were necessary for proteasome - dependent ubiquitination of P26358 by antigen stimulation . N - acetyl - L - cysteine , an inhibitor of reactive oxygen species production , exerted negative effects on allergic skin inflammation . Antigen stimulation led to increased expression of Q92993 , a histone acetyl transferase . Wild type , but not mutant form , Q92993 decreased expression of P26358 while increasing expression of O15379 , suggesting role for acetylation in ubiquitin - dependent proteasomal degradation of P26358 . In vivo down regulation of P26358 increased ear thickness , typical of allergic skin inflammation , induced vascular leakage and promoted angiogenesis in BALB / c mouse . The down regulation of P26358 enhanced angiogenic potential of rat aortic endothelial cells ( RAEC ) accompanied by activation of VEGR - 2 and induced interaction between VEGR - 2 and syk in RAEC . The enhanced angiogenic potential of RAEC was associated with the induction of P15692 by down regulation of P26358 in RBL2H3 cells . The down regulation of P26358 induced leukocytes - endothelial cell interaction and expression of various adhesion molecules . DB00945 exerted a negative effect on allergic skin inflammation by indirect regulation on P26358 via Q92993 . Taken together , these results suggest novel role for P26358 in allergic skin inflammation .",
"Requirement and epigenetics reprogramming of Nrf2 in suppression of tumor promoter TPA - induced mouse skin cell transformation by sulforaphane . Nrf2 is a transcription factor that plays critical roles in regulating the expression of cellular defensive antioxidants and detoxification enzymes . However , the role of Nrf2 and Nrf2 ' s epigenetics reprogramming in skin tumor transformation is unknown . In this study , we investigated the inhibitory role and epigenetics of Nrf2 on tumor transformation induced by 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) in mouse skin epidermal JB6 ( JB6 P + ) cells and the anticancer effect of sulforaphane ( SFN ) , an isothiocyanate found in cruciferous vegetables . After five days of treatment , SFN significantly inhibited TPA - induced JB6 cellular transformation and SFN enhanced the nuclear translocation of Nrf2 and increased the mRNA and protein levels of the Nrf2 target genes P09601 , P15559 and P22309 . Knockdown of Nrf2 attenuated the induction of Nrf2 , P09601 and P15559 by SFN , enhanced TPA - induced colony formation and dampened the inhibitory effect of SFN on TPA - induced JB6 transformation . Epigenetics investigation using bisulfite genomic sequencing showed that SFN decreased the methylation ratio of the first 15 CpGs of the Nrf2 gene promoter , which was corroborated by increased Nrf2 mRNA expression . Furthermore , SFN strongly reduced the protein expression of DNA methyltransferases ( P26358 , DNMT3a and DNMT3b ) . SFN also inhibited the total histone deacetylase ( HDAC ) activity and decreased the protein expression of Q13547 , Q92769 , O15379 and P56524 . Collectively , these results suggest that the anti - cancer effect of SFN against TPA - induced neoplastic transformation of mouse skin could involve the epigenetic reprogramming of anti - cancer genes such as Nrf2 , leading to the epigenetic reactivation of Nrf2 and the subsequent induction of downstream target genes involved in cellular protection .",
"Novel agents for the treatment of childhood acute leukemia . Together , acute lymphoblastic leukemia ( ALL ) and acute myeloid leukemia ( AML ) make up approximately one - third of all pediatric cancer diagnoses . Despite remarkable improvement in the treatment outcomes of these diseases over the past several decades , the prognosis for certain high - risk groups of leukemia and for relapsed disease remains poor . However , recent insights into different types of ' driver ' lesions of leukemogenesis , such as the aberrant activation of signaling pathways and various epigenetic modifications , have led to the discovery of novel agents that specifically target the mechanism of transformation . In parallel , emerging approaches in cancer immunotherapy have led to newer therapies that can exploit and harness cytotoxic immunity directed against malignant cells . This review details the rationale and implementation of recent and specifically targeted therapies in acute pediatric leukemia . Topics covered include the inhibition of critical cell signaling pathways [ P11274 - P00519 , P07333 - like tyrosine kinase 3 ( P36888 ) , mammalian target of rapamycin ( P42345 ) , and Janus - associated kinase ( JAK ) ] , proteasome inhibition , inhibition of epigenetic regulators of gene expression [ DNA methyltransferase ( P26358 ) inhibitors , histone deacetylase ( HDAC ) inhibitors , and disruptor of telomeric signaling - 1 ( Q8TEK3 ) inhibitors ] , monoclonal antibodies and immunoconjugated toxins , bispecific T - cell engaging ( BiTE ) antibodies , and chimeric antigen receptor - modified ( CAR ) T cells .",
"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK26___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .",
"O14788 modulates cell cycle machinery and causes a delay in s phase progression in RAW264 cells . O14788 ( O14788 ) induces differentiation of mouse RAW264 cells to mature osteoclasts . To understand the mechanism controlling a coupling between withdrawal from the cell cycle and differentiation , we examined cell cycle progression and expression profiles of cell cycle regulatory genes at the initial phase in committed cells . O14788 rapidly converted the hyperphosphorylated form of the retinoblastoma protein ( P06400 ) into the hypophosphorylated form . The P38936 protein was induced by O14788 treatment in the same time course with that of dephosphorylation of P06400 , followed by a sharp decline . After this period , a delayed entry of the S phase started accompanying the induction of CycD3 and cdk6 in differentiating cells . Hydroxyurea treatment indicated that the S phase entry was a prerequisite for osteoclast formation . Thus , O14788 induces pleiotropic effects on cell cycle regulatory genes in RAW264 cells during the initial phase of the differentiation process to osteoclasts .",
"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK66___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK66___ .",
"Disulfiram is a DNA demethylating agent and inhibits prostate cancer cell growth . BACKGROUND : The clinical success of the nucleoside analogs 5 - aza - cytidine ( 5 - azaC ) and 5 - aza - 2 ' deoxycytidine ( 5 - aza - dC ) as DNA methyltransferase ( P26358 ) inhibitors has spurred interest in the development of non - nucleoside inhibitors with improved pharmacologic and safety profiles . Because P26358 catalysis features attack of cytosine bases by an enzyme thiol group , we tested whether disulfiram ( DSF ) , a thiol - reactive compound with known clinical safety , demonstrated P26358 inhibitory activity . METHODS : Inhibition of P26358 activity by DSF was assessed using methyltransferase activity assays with recombinant P26358 . Next , prostate cancer cell lines were exposed to DSF and assessed for : i ) reduction of global 5 - methyl cytosine ( ( 5me ) C ) content using liquid chromatography / tandem mass spectrometry ( LC - MS / MS ) ; ii ) gene - specific promoter demethylation by methylation - specific PCR ( MSP ) ; and iii ) gene - reactivation by real - time RT - PCR . DSF was also tested for growth inhibition using prostate cancer cell lines propagated in vitro in cell culture and in vivo as xenografts in nude mice . RESULTS : Disulfiram showed a dose - dependent inhibition of P26358 activity on a hemimethylated DNA substrate . In prostate cancer cells in culture , DSF exposure led to reduction of global genomic ( 5me ) C content , increase in unmethylated P25054 and P10826 gene promoters , and associated re - expression of these genes , but did not significantly alter prostate - specific antigen ( PSA ) expression . DSF significantly inhibited growth and clonogenic survival of prostate cancer cell lines in culture and showed a trend for reduced growth of prostate cancer xenografts . CONCLUSIONS : Disulfiram is a non - nucleoside P26358 inhibitor that can reduce global ( 5me ) C content , reactivate epigenetically silenced genes , and significantly inhibit growth in prostate cancer cell lines .",
"___MASK76___ reduces neutrophil recruitment and lung damage in abdominal sepsis . Abstract Platelets play an important role in abdominal sepsis and Q9H244 receptor antagonists have been reported to exert anti - inflammatory effects . Herein , we assessed the impact of platelet inhibition with the Q9H244 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis . Wild - type C57BL / 6 mice were subjected to cecal ligation and puncture ( CLP ) . Animals were treated with ticagrelor ( 100 mg / kg ) or vehicle prior to CLP induction . Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified . Flow cytometry was used to determine expression of platelet - neutrophil aggregates , neutrophil activation and P29965 expression on platelets . CLP - induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50 % in ticagrelor - treated animals . Moreover , ticagrelor abolished CLP - provoked lung edema and decreased lung damage score by 41 % . Notably , ticagrelor completely inhibited formation of platelet - neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals . In addition , ticagrelor reduced platelet shedding of P29965 in septic mice . Our data indicate that ticagrelor can reduce CLP - induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists , such as ticagrelor , in the management of patients with abdominal sepsis ."
] |
[
"___MASK21___",
"___MASK26___",
"___MASK59___",
"___MASK66___",
"___MASK71___",
"___MASK76___",
"___MASK83___",
"___MASK84___",
"___MASK94___"
] |
___MASK21___
|
MH_train_418
|
interacts_with DB01407?
|
[
"Microglial activation , increased P01375 and P31645 expression in the prefrontal cortex define stress - altered behaviour in mice susceptible to anhedonia . A chronic stress paradigm comprising exposure to predation , tail suspension and restraint induces a depressive syndrome in C57BL / 6J mice that occurs in some , but not all , animals . Here , we sought to extend our behavioural studies to investigate how susceptibility ( sucrose preference < 65 % ) or resilience ( sucrose preference > 65 % ) to stress - induced anhedonia affects the 5HT system and the expression of inflammation - related genes . All chronically stressed animals , displayed increased level of anxiety , but susceptible mice exhibited an increased propensity to float in the forced swim test and demonstrate hyperactivity under stressful lighting conditions . These changes were not present in resilient or acutely stressed animals . Compared to resilient animals , susceptible mice showed elevated expression of tumour necrosis factor alpha ( P01375 ) and the 5 - HT transporter ( P31645 ) in the pre - frontal area . Enhanced expression of 5HT ( 2A ) and P23219 in the pre - frontal area was observed in all stressed animals . In turn , indoleamine - 2 , 3 - dioxygenase ( P14902 ) was significantly unregulated in the raphe of susceptible animals . At the cellular level , increased numbers of Iba - 1 - positive microglial cells were also present in the prefrontal area of susceptible animals compared to resilient animals . Consequently , the susceptible animals display a unique molecular profile when compared to resilient , but anxious , animals . Unexpectedly , this altered profile provides a rationale for exploring anti - inflammatory , and possibly , P01375 - targeted therapy for major depression .",
"P23219 behaves as a delayed response gene in PC12 cells differentiated by nerve growth factor . Treatment of PC12 cells with nerve growth factor ( P01138 ) results in a differentiation program characterized by expression of immediate early and delayed response genes . In this program , morphological changes such as neurite extension are accompanied by phenotypic changes in enzyme expression , including an increased capacity for prostaglandin synthesis . Cyclooxygenase ( P36551 ) , the enzyme responsible for prostanoid production , exists as two isoforms : constitutive P23219 and inducible P35354 . We report that P23219 behaves as a delayed response gene in PC12 cells exposed to P01138 . Six hours following P01138 treatment , P23219 mRNA levels were elevated in PC12 cells , reaching nearly 5 - fold above basal levels at 12 h . This increase was blocked by cycloheximide and was accompanied by concomitant increases in P23219 protein and enzyme activity . P23219 protein remained elevated for at least 10 days and localized to the cytoplasm and neurites of P01138 - differentiated PC12 cells . Moreover , basic fibroblast growth factor , but not epidermal growth factor , caused similar increases in P23219 , which is consistent with expression characteristics of other delayed response genes in PC12 cells . This is the first example of neurotrophic factor regulation of cyclooxygenase and may have important implications for determination of the differentiated phenotype in PC12 cells .",
"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .",
"Localization of NADPH oxidase subunits in neonatal sympathetic neurons . Reactive oxygen species ( ROS ) trigger programmed cell death in neonatal sympathetic neurons that have been deprived of nerve growth factor ( P01138 ) , however , the source of these oxygen intermediates has not been established . Using laser scanning confocal microscopy ( LSCM ) , the intracellular distribution of the subunits of the ROS - generating enzyme NADPH oxidase was examined in sympathetic neurons of the superior cervical ganglion ( SCG ) . Optical sectioning using LSCM showed that P04839 and P13498 co - localize in neurons at the cell membrane , while the P14598 and P19878 subunits are found uniformly distributed in the cytoplasm of neurons maintained in the presence of P01138 . Within 4h after P01138 deprivation , both the P14598 and P19878 subunits exhibit punctate staining in the cytoplasm and at the membrane . Furthermore , a sub - population of the cytosolic P14598 appeared to co - localize with the membrane - bound P04839 in P01138 - deprived neurons . These data provide support for the presence of NADPH oxidase in sympathetic neurons and suggest that this enzyme may become activated following the withdrawal of P01138 .",
"P04141 - 1 ( P09603 ) delivers a proatherogenic signal to human macrophages . P09603 / P09603 supports the proliferation and differentiation of monocytes and macrophages . In mice , P09603 also promotes proinflammatory responses in vivo by regulating mature macrophage functions , but little is known about the acute effects of this growth factor on mature human macrophages . Here , we show that in contrast to its effects on mouse bone marrow - derived macrophages , P09603 did not induce expression of urokinase plasminogen activator mRNA , repress expression of apolipoprotein E mRNA , or prime LPS - induced P01375 and P05231 secretion in human monocyte - derived macrophages ( HMDM ) from several independent donors . Instead , we show by expression profiling that P09603 modulates the HMDM transcriptome to favor a proatherogenic environment . P09603 induced expression of the proatherogenic chemokines P02778 / IFN - inducible protein 10 , P13500 , and P80098 but repressed expression of the antiatherogenic chemokine receptor P61073 . P09603 also up - regulated genes encoding enzymes of the cholesterol biosynthetic pathway ( P04035 , P53602 , Q13907 , P14324 , Q14534 , Q16850 , EBP , Q15738 , Q9UBM7 , and Q15392 ) , and expression of P45844 , encoding a cholesterol efflux transporter , was repressed . Consistent with these effects , P09603 increased levels of free cholesterol in HMDM , and the selective P07333 kinase inhibitor GW2580 ablated this response . These data demonstrate that P09603 represents a further link between inflammation and cardiovascular disease and suggest two distinct mechanisms by which P09603 , which is known to be present in atherosclerotic lesions , may contribute to plaque progression .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"Neuroprotection mediated via neurotrophic factors and induction of neurotrophic factors . Neurotrophins and other neurotrophic factors have been shown to support the survival and differentiation of many neuronal populations of the central and peripheral nervous system . Therefore , administering neurotrophic factors could represent an alternative strategy for the treatment of acute and chronic brain disorders . However , the delivery of neurotrophic factors to the brain is one of the largest obstacles in the development of effective therapy for neurodegenerative disorders , because these proteins are not able to cross the blood - brain barrier . The induction of growth factor synthesis in the brain tissue by systemically administered lipophilic drugs , such as beta - adrenoceptor agonists , shown to increase endogenous nerve growth factor ( P01138 ) synthesis in the brain , would be an elegant way to overcome these problems of application . Stimulation of beta - adrenoceptors with clenbuterol led to increased P01138 synthesis in cultured central nervous system ( CNS ) cells and rat brain tissue . DB01407 - induced P01138 expression was reduced to the control levels by coadministration of beta - adrenoceptor antagonist propranolol . Furthermore , clenbuterol protected rat hippocampal neurons subjected to excitotoxic damage . The neuroprotective effect of clenbuterol in vitro depended on increased P01138 synthesis , since the neuroprotection was abolished by P01138 antisense oligonucleotide as well as by antibodies directed against P01138 itself . In vivo , clenbuterol protected rat hippocampus in a model of transient forebrain ischemia and reduced the infarct volume in a rat model of permanent middle cerebral artery occlusion ( MCAo ) . The neuroprotective effect of clenbuterol in vivo was accompanied by enhanced P01138 synthesis in brain tissue . These findings support our hypothesis that orally active P01138 inducers may have a potential as therapeutic agents for the treatment of neurodegenerative disorders and stroke .",
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK26___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .",
"Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK21___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK21___ peptide content within the pituitary , and plasma ___MASK21___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK21___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK21___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK21___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .",
"[ DB01407 in amyotrophic lateral sclerosis . No indication for a positive effect ] . The anabolic effects of clenbuterol have been recognized for a long time . DB01407 augments the expression of specific muscle proteins with a differential effect on type I and type II fibres . Furthermore , clenbuterol induces the synthesis of endogenous nerve growth factor ( P01138 ) and may itself be a myotrophic factor released by neuron endings . Side effects include tremor and headache and dose dependent abnormalities of laboratory values ( hypokalemia , hypoglycemia ) . After long - term medication increasing fatigue of muscles has been observed . Decreased expression of beta 2 - adrenergic receptors may limit the expected functional improvement . The efficacy of clenbuterol as symptomatic treatment of amyotrophic lateral sclerosis has not been proved . Controlled treatment trials are warranted to assess this question .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK86___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .",
"P11274 - P00519 induces neurite - like structures and P11274 lacking the SH2 - binding domain induces cell rounding in PC12 cells . The activated tyrosine kinase oncoprotein P11274 - P00519 is responsible for pathogenesis of Philadelphia chromosome - positive human leukemias . Because P11274 carries a P20936 ( P20936 ) activity toward cytoskeleton - related small GTP - binding proteins , we utilized a neuronal PC12 cell system to test morphogenic potentials of P11274 - P00519 or P11274 . We report here unique morphological phenotypes of PC12 cells expressing either P11274 - P00519 or a P11274 mutant which lacks the SH2 - binding domain ( P11274 Delta162 - 413 ) . Although Q96HU1 kinase was not activated in PC12 cells expressing P11274 - P00519 , they showed incomplete neurite extensions even in the absence of the nerve growth factor ( P01138 ) . Overproduction of P11274 Delta162 - 413 in PC12 cells , on the other hand , induced cell rounding in the absence of P01138 . Interestingly , those cells could hardly make terminal differentiation in the presence of P01138 and continued to grow without changing their round shape , although P08138 as well as Q96HU1 kinase appeared to be activated . Interestingly , the botulinum P01024 toxin induced neurite - like structures in PC12 cells overexpressing P11274 Delta162 - 413 without P01138 .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK80___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"DB01407 affects the expression of messenger RNA for interleukin 10 in peripheral leukocytes from horses challenged intrabronchially with lipopolysaccharides . On four occasions , four horses with heaves and four horses with small airway inflammatory diseases inhaled 0 . 9 % saline based aerosol mixtures with or without lipopolysaccharides ( LPS ) . Prior to the first saline and LPS inhalation , horses were untreated , while three and a half days prior to the third and forth inhalation horses had received 0 . 8 microg / kg clenbuterol intravenously twice daily . The messenger RNA ( mRNA ) expression of tumour necrosis factor - alpha ( P01375 ) , interleukin ( IL ) - 1beta , P05112 , P05231 , P10145 , P22301 and interferon - gamma ( IFN - gamma ) was investigated by RT - PCR , all of which were expressed in the white blood cells of samples collected . Inhalation of LPS only changed the cytokine expression profile of P22301 , P05112 and P01375 mRNA which were higher after challenge with LPS . However in those horses that were treated with clenbuterol the LPS - induced P22301 mRNA expression was shown to be suppressed . Further changes in P05112 and P01375 were not significant . Thus the results of this study indicated that clenbuterol can modulate the expression of P22301 mRNA in peripheral white blood cells in those horses with small airway diseases that have been exposed to LPS .",
"P01130 - related protein mediates in PC12 cell cultures the inhibition of nerve growth factor - promoted neurite outgrowth by pregnancy zone protein and alpha2 - macroglobulin . Human pregnancy zone protein ( P20742 ) is a major pregnancy - associated plasma protein closely related to human alpha ( 2 )- macroglobulin ( alpha ( 2 ) M ) . It has been demonstrated that monoamine - activated forms of human and rat alpha ( 2 ) M and rat alpha ( 1 ) M can bind to TrkA and , respectively , inhibit and stimulate P01138 - promoted neurite outgrowth , Trk phosphorylation , and intracellular signal transduction in PC12 cells . However , the effect of P20742 on neurons is unknown , and the molecular mechanism of neuroinhibition by monoamine - activated alpha ( 2 ) M is still unclear . In this report , we show that methylamine - activated P20742 ( MA - P20742 ) , like MA - alpha ( 2 ) M , inhibits in a dose - dependent way the P01138 - promoted neurite extension and TrkA phosphorylation in PC12 cells . On the other hand , normal P20742 ( N - P20742 ) had little or no effect . In addition , the inhibitory effect of activated alpha - macroglobulins ( alphaMs ) was reversible upon its removal from the cell culture . In addition , P20742 , as well as alpha ( 2 ) M , is neuroinhibitory without being directly cytotoxic . It is known that the activated alphaMs bind to the multiligand receptor termed low - density lipoprotein receptor - related protein ( Q14764 ) and that the receptor - associated protein ( P30533 ) specifically blocks uptake of all known Q14764 ligands . To investigate the potential role of Q14764 in neuromodulation by activated P20742 / alpha ( 2 ) M , the effect of P30533 on the neuroinhibitory activities of these alphaMs was also studied . Data presented here show that P30533 blocked the neurite - and Trk - inhibitory activities of both MA - P20742 and MA - alpha ( 2 ) M , whereas P30533 itself had no neuromodulatory effect . Hence , we conclude that these data suggest that the Q14764 receptor and its alphaM ligands may play a role in regulating Trk receptors .",
"Activation of serotonin receptor - 2B rescues small - for - size liver graft failure in mice . The implantation of grafts below 30 % of the normal liver volume is associated with a high risk of failure known as small - for - size ( SFS ) syndrome . Strategies to rescue small grafts may have a dramatic impact on organ shortage . Serotonin is a potent growth factor for the liver . The goal of this study was to determine whether enhanced serotonin signaling could prevent the deleterious effects of SFS syndrome . We performed 30 % normal liver volume transplantations in wild - type C57 / BL6 and interleukin - 6 ( P05231 ) (-/-) mice . Some animals received α - methyl - 5 - HT ( DOI ) , an agonist of serotonin receptor - 2 ( P41595 ) . Endpoints included long - term survival , serum and hepatic markers of liver injury and regeneration , assessment of hepatic microcirculation by intravital fluorescence microscopy and scanning electron microscopy , and transcript levels of a variety of serotonin receptors , tumor necrosis factor α , and P05231 . All recipients of small grafts ( controls ) died within 2 - 4 days of transplantation , whereas half of those receiving DOI survived permanently . Control animals disclosed major liver injury , including diffuse microvesicular steatosis in hepatocytes , impairment of microcirculation , and a failure of regeneration , whereas these parameters were dramatically improved in animals subjected to DOI . Blockage of P41595 blunted the protective effects of DOI . Whereas P05231 levels were higher in DOI - treated animals , P05231 (-/-) mice were still protected by DOI , suggesting a protective pathway independent of P05231 . CONCLUSION : Serotonin through its action on receptor - 2B protects SFS liver grafts from injury and prevents microcirculation and regeneration . The mechanism of hepato - protection is independent of P05231 .",
"DB01407 induces growth factor mRNA , activates astrocytes , and protects rat brain tissue against ischemic damage . The induction of growth factor synthesis in brain tissue by beta2 - adrenoceptor agonists , such as clenbuterol , is a promising approach to protect brain tissue from ischemic damage . DB01407 ( 0 . 01 - 0 . 5 mg / kg ) reduced the cortical infarct volume in Long - Evans rats as measured 7 days after permanent occlusion of the middle cerebral artery . Dosages of clenbuterol higher than 1 mg / kg showed no cerebroprotective effect due to a decrease in blood pressure and an increase in plasma glucose level . The increase in the mRNA level of nerve growth factor ( P01138 ) , basic fibroblast growth factor ( basic FGF ) , and transforming growth factor - beta1 ( TGF - beta1 ) mRNA in cortical and hippocampal tissue occurred earlier after middle cerebral artery occlusion and was more pronounced in animals treated with clenbuterol than in controls . In addition , glial fibrillary acidic protein ( P14136 ) mRNA expression was enhanced in astrocytes 6 h after ischemia in clenbuterol - treated animals . The results suggest that growth factor synthesis is enhanced in activated astrocytes and that this could be the mechanism of clenbuterol - induced cerebroprotection after ischemia .",
"P28335 receptor involvement in female rat lordosis behavior . Adult , hormone - primed , ovariectomized rats ( P05231 - 344 ) with bilateral implants within the ventromedial nucleus of the hypothalamus ( VMN ) , were injected with 0 . 5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone . This priming produced rats with 2 different levels of sexual receptivity . Rats with a lordosis to mount ratio ( L / M ) >/= 0 . 5 were used to examine the potential lordosis - inhibiting effects of the 5 - Q13049 receptor antagonist , R (+)- a - ( 2 , 3 - dimethoxyphenyl ) - 1 -[ 2 ( 4 - fluoro - phenylethyl )]- 4 - piperidine - methanol ( MDL 100 , 907 ) , and the P28335 receptor antagonist , 5 - methyl - 1 -( 3 - pyridylcarbamoyl )- 1 , 2 , 3 , 5 - tetrahydropyrrolo [ 2 , 3 - f ] indole ( SB 206553 ) . Rats with low sexual receptivity ( L / M < 0 . 5 ) were bilaterally infused with the 5 - Q13049 / 2C receptor agonist , (+/-)- 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane HCl ( DOI ) , or DOI plus either MDL 100 , 907 or SB 206553 to determine if either drug would attenuate the lordosis - facilitating effects of DOI . The P28335 receptor antagonist , but not the 5 - Q13049 receptor antagonist , effectively inhibited lordosis behavior . Similarly , SB 206553 was more effective than MDL 100 , 907 in reducing the DOI - induced increase in lordosis responding . However , both drugs limited the duration of lordosis responding initiated by DOI . These results are consistent with prior suggestions that 5 - Q13049 / 2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that P28335 , rather than 5 - Q13049 , receptors are primarily responsible for the effects of 5 - HT2 receptor - active drugs on lordosis behavior .",
"[ New pharmacological approaches to the treatment of schizophrenia ] . Schizophrenia is a serious mental disorder with a challenging rational pharmacotherapy . Neurochemical transmission in the dopaminergic system , especially via D2 receptors , and related changes in postsynaptic signal transduction are very important in both the formation of schizophrenia and current pharmacotherapeutic treatment with antipsychotic drugs . Blocking the serotonergic 5 - Q13049 and P28335 receptors is growing growing importance with regard to the action mechanisms of new generation antipsychotic medications . Recent preclinical and clinical data show that dysfunction of central neurotrophins , such as nerve growth factor ( P01138 ) , brain - derived neurotrophic factor ( P23560 ) , and neurophin - 3 ( P20783 ) might contribute to impaired brain development and neuroplasticity , leading to schizophrenia . In addition , some recent studies suggest that there is an important relationship between alcohol and substance addiction , and schizophrenia . There is also some preclinical data indicating that the central nitrergic system and agmatine ( 3 / 4 ) a biologically active agent produced after decarboxylation of arginine ( 3 / 4 ) might be interesting and important targets for understanding the etiopathogenesis of schizophrenia and for development of new drugs . Selective dopamine D3 receptor antagonists , specific agonists for metabotropic and DB01221 receptors of the glutamatergic system , and nicotinic alpha - 7 receptor agonists were reported in preclinical and a limited number of clinical studies as potential new targets for schizophrenia treatment . In this review , new advances in the pharmacotherapy of schizophrenia and possible new targets are discussed in the light of the current literature .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"Interleukins 1α and 1β as regulators of steroidogenesis in human NCI - H295R adrenocortical cells . Inflammatory cytokines interleukin - 1 ( IL - 1 ) and tumor necrosis factor - α ( P01375 - α ) regulate the activity of the hypothalamo - pituitary - adrenal ( Q9Y251 ) axis at several levels . Although hypothalamic P06850 secretion may be the primary mechanism by which these cytokines activate the Q9Y251 axis , IL - 1 expression is increased within the adrenal glands in models for systemic inflammation , and IL - 1 may augment adrenal glucocorticoid production . Our aim was to investigate the direct effects of IL - 1α and IL - 1β on adrenal steroidogenesis and expression of three key steroidogenic genes in human adrenocortical cells using the NCI - H295R cell line as a model . mRNAs encoding receptors for IL - 1 , P01375 - α , and leukemia inhibitory factor ( P15018 ) were detectable in the cell line ( Affymetrix microarray analysis ) . Both IL - 1α and IL - 1β increased cortisol , androstenedione , dehydroepiandrosterone and DB05804 production , and the accumulation of mRNAs for steroidogenic acute regulatory protein ( STAR ) , 17α - hydroxylase / 17 , 20 - lyase ( P05093 ) and 3β - hydroxysteroid dehydrogenase 2 ( P26439 ) in these cells ( P < 0 . 05 for all ) . Both ILs augmented P01375 - α - and P15018 - induced STAR and P05093 mRNA accumulation , and P01375 - α - induced cortisol production ( P < 0 . 05 for all ) . Both ILs also increased the apoptotic index of the cells ( P < 0 . 05 ) , which was efficiently neutralized by their specific antibodies . The IL - induced changes in the STAR , P26439 , and P05093 protein levels were not as evident as those in the respective mRNA levels . In conclusion , the combined effect of inflammatory cytokines at the adrenal level in acute or chronic inflammatory states could significantly stimulate glucocorticoid production , and thus explain the observed discrepancy between the cortisol and ___MASK21___ concentrations sometimes seen in sepsis and chronic inflammatory states .",
"Hypoxic / normoxic preconditioning increases endothelial differentiation potential of human bone marrow CD133 + cells . CD133 + cells are hemangioblasts that have capacity to generate into both hematopoietic and endothelial cells ( ECs ) . Hypoxia / normoxia has shown to be the regulator of the balance between stemness and differentiation . In this study we performed Agilent ' s whole human genome oligo microarray analysis and examined the differentiation potential of the bone - marrow - derived CD133 + cells after hypoxic / normoxic preconditioning of CD133 + cells . Results showed that there was no significant increase in erythroid colony forming unit ( CFU - E ) and CFU - granulocyte , erythrocyte , monocyte , and megakaryocyte formation with cells treated under hypoxia / normoxia . However , a significant increment of EC forming unit at 24 h ( 143 . 2 +/- 8 . 0 % ) compared to 0 h ( 100 +/- 11 . 4 % ) was observed in CFU - EC analysis . Reverse transcription - polymerase chain reaction and immunostaining analysis showed that the differentiated cells diminished hematopoietic stem cell surface markers and acquired the gene markers and functional phenotype of ECs . The transcriptome profile revealed a cluster of 232 downregulated and 498 upregulated genes in cells treated for 24 h under hypoxia . The upregulated genes include angiogenic genes , angiogenic growth factor genes , angiogenic cytokine and chemokine genes , as well as angiogenic - positive regulatory genes , including Q14512 , PDGFB , Q16663 , P48061 , P80162 , P05231 , P21246 , O14944 , P04626 , O95136 , P11487 , Q92913 , Q99988 , P05412 , L1CAM , Q02297 , P08138 , and PDGFB . On the other hand , angiogenesis inhibitors and related genes , including P29459 , P98177 , Q9NY15 , and P16035 , are downregulated . Taken together , hypoxic / normoxic preconditioning may lead to the differentiation of CD133 + cells toward endothelial lineage , which may improve the current clinical trial studies .",
"___MASK17___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .",
"The role of the sympathetic efferents in endotoxin - induced localized inflammatory hyperalgesia and cytokine upregulation . The sympathetic system ( SNS ) is considered to be a major component of the neurogenic contribution to inflammation and hyperalgesia . We have investigated the role of the SNS in the local inflammatory pain induced by intraplantar ( i . pl ) injections of bacterial endotoxin ( ET ) . Treatment of rats with an alpha - adrenoceptor antagonist ( phentolamine , 0 . 25 - 1 mg / kg , i . p . ) , a beta - adrenoceptor antagonist ( propranolol , 1 - 10 mg / kg , p . o . ) or a sympathetic neuron - blocking agent ( guanethedine , 30 mg / kg , s . c . ) resulted in a dose - dependent reduction of the thermal hyperalgesia induced by ET . Mechanical hyperalgesia , however , was less sensitive to inhibition by propranolol and guanethedine but significantly inhibited by phentolamine . ET injection produced significant upregulation of tumor necrosis factor - alpha ( P01375 ) , interleukin - 1 beta ( P01584 ) , P05231 , and nerve growth factor ( P01138 ) . Treatment with any one of the three sympatholytics abolished the upregulation of P01138 and P05231 , while phentolamine and guanethedine also reversed the upregulation of P01375 . P01584 was resistant to all of the sympatholytic treatments . We conclude that the SNS can contribute to the local inflammation and hyperalgesia following injection of ET . The resistance to sympatholytics shown by P01584 , known to play a key role in the inflammatory cascade , suggests that ET can initiate inflammation and hyperalgesia independently of peripheral and central sympathetic mechanisms .",
"Anti - allergic effects of nilotinib on mast cell - mediated anaphylaxis like reactions . ___MASK86___ is a new orally bioavailable potent tyrosine kinase inhibitor that is used for the treatment of P11274 - P00519 - positive chronic myelogenous leukemia . However , its effect on mast cell - mediated anaphylactic reaction is still not known . The present study aimed to investigate the effect of nilotinib on the anaphylactic allergic reaction and study its possible mechanism ( s ) of action . ___MASK86___ administration prevented systemic anaphylaxis in mice , mediated by compound 48 / 80 , in a dose - and time - dependent manner . Also , nilotinib significantly inhibited ( P < 0 . 05 ) allergic paw edema in rats . Furthermore , nilotinib significantly decreased ( P < 0 . 05 ) the IgE - mediated passive cutaneous anaphylaxis in a dose dependent manner . In addition , nilotinib dose - dependently reduced histamine release from the rat peritoneal mast cells activated either by compound 48 / 80 or by ovalbumin . Moreover , nilotinib attenuated the secretion of pro - inflammatory cytokine , tumor necrosis factor ( P01375 ) - α expression in the rat peritoneal mast cells . These findings provide evidence that nilotinib inhibits mast cell - derived immediate - type allergic reactions and so it could be a candidate as an anti - allergic agent .",
"Transcriptional regulation of cyclo - oxygenase expression : three pillars of control . Blocking cyclo - oxygenase ( P36551 ) isoform activities with non - steroidal anti - inflammatory drugs ( NSAIDS ) is widely employed in the treatment of arthritis . These agents also hold great promise in the context of pre and post - neoplastic diseases such as colorectal cancer ( CRC ) . Nevertheless , issues of isoform specificity and delivery necessitate the exploration of other strategies to specifically block expression of the P36551 genes . Approaches that target gene transcription may complement enzyme inhibition . Thus , understanding the regulation of P36551 isoform transcription may improve the specific inhibition of expression . Three tiers of transcriptional regulation are evident : initiation , alternative splicing and messenger RNA stability . Transcription factors that activate P35354 expression are elevated in certain disease states and emergency responses such as infection and are therefore potential targets . These factors include C / EBP - beta , phospho - CREB , NF - P05231 , P05412 , NFkB , and TCF - 4 / Q9UJU2 . In this review we highlight another factor , c - P10242 as a key P35354 regulator in CRC . Alternative exon usage is another tier of regulation that has not received much attention . For instance , P23219 splice variants ( also known as P36551 - 3 and PCOX - 1a ) may broaden the spectrum of P36551 activities in disease . Similarly , whilst mRNA stability is clearly modulated by steroids in the case of P35354 , the wider implications of targeting mRNA stability have not been afforded the same attention . Finally , it seems that some NSAIDS exert part of their action directly on P35354 transcriptional regulation explaining why such agents display greater effects on this isoform than enzyme inhibition data would suggest .",
"The β2 - adrenoceptor agonist clenbuterol elicits neuroprotective , anti - inflammatory and neurotrophic actions in the kainic acid model of excitotoxicity . Excitotoxicity is a mechanism of neuronal cell death implicated in a range of neurodegenerative conditions . Systemic administration of the excitotoxin kainic acid ( KA ) induces inflammation and apoptosis in the hippocampus , resulting in neuronal loss . Evidence indicates that stimulation of glial β ( 2 )- adrenoceptors has anti - inflammatory and neurotrophic properties that could result in neuroprotection . Consequently , in this study we examined the effect of the β ( 2 )- adrenoceptor agonist clenbuterol on KA - induced inflammation , neurotrophic factor expression and apoptosis in the hippocampus . DB01407 ( 0 . 5mg / kg ) was administered to rats one hour prior to KA ( 10mg / kg ) . Epileptic behaviour induced by KA was assessed for three hours following administration using the Racine scale . Twenty - four hours later TUNEL staining in the P07451 hippocampal subfield and hippocampal caspase - 3 activity was assessed to measure KA - induced apoptosis . In addition , expression of inflammatory cytokines ( IL - 1β and IFN - γ ) , inducible nitric oxide synthase ( P35228 ) , kynurenine pathway enzymes indolamine 2 , 3 - dioxygenase ( P14902 ) and kynurenine monooxygenase ( O15229 ) , the microglial activation marker CD11b , and the neurotrophins P23560 and P01138 were quantified in the hippocampus using real - time PCR . Whilst clenbuterol treatment did not significantly alter KA - induced epileptic behavior it ameliorated KA - induced apoptosis , and this neuroprotective effect was accompanied by reduced inflammatory cytokine expression , reduced expression of P35228 , P14902 , O15229 and CD11b , coupled with increased P23560 and P01138 expression in KA - treated rats . In conclusion , the β ( 2 )- adrenoceptor agonist clenbuterol has anti - inflammatory and neurotrophic actions and elicits a neuroprotective effect in the KA model of neurodegeneration .",
"Expression of nerve growth factor and heme oxygenase - 1 predict poor survival of breast carcinoma patients . BACKGROUND : Nerve growth factor ( P01138 ) is a neurotrophin and has been suggested to induce heme oxygenase - 1 ( P09601 ) expression . Although the role of P09601 in tumorigenesis remains controversial , recent evidence suggests P01138 and P09601 as tumor - progressing factors . However , the correlative role of P01138 and P09601 and their prognostic impact in breast carcinoma is unknown . METHODS : We investigated the expression and prognostic significance of the expression of P01138 and P09601 in 145 cases of breast carcinoma . RESULTS : Immunohistochemical expression of P01138 and P09601 was observed in 31 % and 49 % of breast carcinoma , respectively . The expression of P01138 and P09601 significantly associated with each other , and both have a significant association with histologic grade , P04626 expression , and latent distant metastasis . The expression of P01138 and P09601 predicted shorter overall survival of breast carcinoma by univariate and multivariate analysis . P01138 expression was an independent prognostic indicator for relapse - free survival by multivariate analysis . The combined expression pattern of P01138 and P09601 was also an independent prognostic indicator of overall survival and relapse - free survival . The patients with tumors expressing P01138 had the shortest survival and the patients with tumor , which did not express P01138 or P09601 showed the longest survival time . CONCLUSIONS : This study has demonstrated that individual expression of P01138 or P09601 , and the combined P01138 / P09601 expression pattern could be prognostic indicators for breast carcinoma patients .",
"Down - regulation of cyclooxygenase - 2 ( P35354 ) by interleukin - 1 receptor antagonist in human monocytes . Cyclooxygenase ( P36551 ) is the key rate - limiting enzyme in the synthesis of prostanoids from arachidonic acid . Two isoforms of P36551 have been described in mammalian cells , referred to as cyclooxygenase - 1 ( P23219 ) and cyclooxygenase - 2 ( P35354 ) . P23219 is a constitutively expressed enzyme ; P35354 is an inducible enzyme that appears to be expressed in inflamed tissue and following exposure to growth factors or cytokines , such as interleukin - 1 ( IL - 1 ) . The aim of the present study was to test if the antagonism on the binding of IL - 1 to its cell - surface receptor by human recombinant IL - 1 receptor antagonist ( hrIL - 1ra ) may control the P36551 mRNA expression and prostaglandin E2 ( DB00917 ) production by human monocyte cultures . Northern blot studies showed that hrIL - ra ( 500 ng / ml ) had a strong inhibitory effect on inducible P36551 activity . The effect was evident after 6 hr incubation ( 2 . 7 - fold decrease of mRNA P35354 transcripts ) ; and about a threefold decrease at 24hr incubation . A non - significant effect was observed with P23219 transcripts . Induced DB00917 production by monocyte cultures treated with lipopolysaccharide ( LPS ) or interleukin - 1 beta ( P01584 ) was strongly inhibited in the presence of hrIL - 1ra ( 500 ng / ml ) . In addition , a significant inhibition of P35354 protein expression , as evaluated by Western blotting , was also observed . These data suggest that hrIL - 1ra may be the key mediator in the down - regulation of the P35354 inducible pathway .",
"Evaluation of human astrocytoma and glioblastoma cell lines for nerve growth factor release . Nerve growth factor ( P01138 ) prevents degeneration of cholinergic neurons in the central nervous system ( CNS ) , and has potential as a therapeutic treatment for Alzheimer ' s disease . The inability of P01138 to cross the blood - brain barrier has prompted pharmacological approaches investigating peripherally administered compounds that stimulate release of endogenous P01138 . This study describes the P01138 - releasing properties of six human astrocytoma and glioblastoma cell lines ( SW 1088 , SW 1783 and CRL 1718 astrocytomas , and U - 138 , U - 373 , and T98G glioblastomas ) . Using a highly specific two - site ELISA for human P01138 , basal P01138 release could be detected in all cell lines , with the lowest level in the T98G line ( approximately 80 pg P01138 / ml ) . Cell lines tested with a variety of compounds for 24 h in serum - free media demonstrated stimulation of P01138 release by distinct mechanisms . P01138 levels were markedly elevated ( up to 8 - fold above vehicle - treated cells ) when stimulated with the cytokine interleukin - 1 beta ( P01584 ) . Phorbol ester stimulated P01138 release 4 - fold . DB01407 , 4 - methyl catechol , and propentofylline had little activity , while 6 -( 4 - hydroxybutyl )- 2 , 3 , 5 ,- trimethyl - 1 , 4 , benzoquinone ( DB01157 ) , dexamethasone and 1 , 25 - dihydroxyvitamin D3 elevated P01138 levels 3 - fold . These data indicate differences in the ability of human astrocytoma and glioblastoma cells to release P01138 when stimulated with mechanistically distinct compounds .",
"Effect of isoproterenol and dexamethasone on the lipopolysaccharide induced expression of CD11b on bovine neutrophils . The present experiments investigate the changes in expression of CD11b on bovine neutrophils and its modulation by isopropylnoradrenaline ( IPN , isoproterenol ) , dexamethasone ( DX ) , phenylephrine ( alpha - agonist ) and clenbuterol ( beta - agonist ) . Both IPN and DX caused a dose - dependent inhibition of LPS - induced CD11b expression . A combination of IPN and DX elicited a synergistical decrease of the CD11b expression . DB01407 mimicked the effect of IPN , whereas phenylephrine did not . The effect of IPN and DX could at least partly be mediated through a decreased P01375 production by monocytes since tumor necrosis factor - alpha ( P01375 ) is shown to mediate a dose - dependent CD11b up - regulation . Stimulation of stress hormone receptors partly immuno - suppresses neutrophil functions by inhibition of CD11b expression on the neutrophil surface upon LPS stimulation . This inhibition is probably related to a decrease in P01375 production . A similar mechanism of immuno - suppression could contribute to the higher susceptibility of cattle to Gram - negative bacterial infections of the udder and lung during periods of stress .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK1___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"Fatal rhabdomyolysis in a patient with liver cirrhosis after switching from simvastatin to fluvastatin . P04035 inhibitors ( statins ) are widely used to treat hypercholesterolemia . Among the adverse effects associated with these drugs are statin - associated myopathies , ranging from asymptomatic elevation of serum creatine kinase to fatal rhabdomyolysis . ___MASK17___ - induced fatal rhabdomyolysis has not been previously reported . We describe here a patient with liver cirrhosis who experienced fluvastatin - induced fatal rhabdomyolysis . This patient had been treated with simvastatin ( 20 mg / day ) for coronary artery disease and was switched to fluvastatin ( 20 mg / day ) 10 days before admission . He was also taking aspirin , betaxolol , candesartan , lactulose , and entecavir . Rhabdomyolysis was complicated and continued to progress . He was treated with massive hydration , urine alkalization , intravenous furosemide , and continuous renal replacement therapy for acute renal failure , but eventually died due to rhabdomyolysis complicated by hepatic failure . In conclusion , fluvastatin should be used with caution in patients with liver cirrhosis , especially with other medications metabolized with P11712 .",
"Hypothalamic involvement in the activation of the pituitary - adrenocortical axis by nerve growth factor . Intravenous injection of nerve growth factor ( P01138 ) into rats produces a dose - dependent ( from 0 . 1 to 5 nmol / kg ) increase in circulating concentrations of adrenocorticotropin ( ___MASK21___ ) and corticosterone . We have investigated whether this effect is produced through a direct action on a component of the hypothalamo - pituitary - adrenocortical axis . P01138 ( 50 and 500 nM ) , added to the incubation medium of in vitro isolated pituitary segments or dispersed adrenal cells , did not modify either basal and stimulated release of biologically active or immunoreactive ___MASK21___ or release of corticosterone , respectively . The presence of P01138 in the incubation medium of in vitro isolated hypothalami produced a dose - dependent ( from 150 to 600 nM ) increase of both release and content of some material with corticotropin - releasing bioactivity . The nature of this corticotropin - releasing bioactivity was determined directly by radioimmunoassays . Results have indicated that P01138 induced an increase of both release and content of hypothalamic arginine - vasopressin ( AVP ) , while no changes were observed in the release and content of hypothalamic corticotropin - releasing hormone ( P06850 ) . These results suggest that adrenocortical stimulation by P01138 in vivo could be mediated by the release of hypothalamic AVP rather than P06850 . The finding that in vivo P01138 stimulatory effect was not abolished by the specific P06850 antagonist alpha - helical P06850 ( 9 - 41 ) , while it was accompanied by an increase in circulating AVP levels , supports this interpretation . However , the fact that the hypothalamus is stimulated in vitro by P01138 concentrations higher than those expected to reach this structure after systemic injection of active doses raises the possibility that other brain areas such as the hippocampus participate in P01138 - induced adrenocortical activation .",
"Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .",
"Self - renewal of human embryonic stem cells requires insulin - like growth factor - 1 receptor and P04626 receptor signaling . Despite progress in developing defined conditions for human embryonic stem cell ( hESC ) cultures , little is known about the cell - surface receptors that are activated under conditions supportive of hESC self - renewal . A simultaneous interrogation of 42 receptor tyrosine kinases ( RTKs ) in hESCs following stimulation with mouse embryonic fibroblast ( MEF ) conditioned medium ( CM ) revealed rapid and prominent tyrosine phosphorylation of insulin receptor ( IR ) and insulin - like growth factor - 1 receptor ( P08069 ) ; less prominent tyrosine phosphorylation of epidermal growth factor receptor ( P00533 ) family members , including P04626 and P21860 ; and trace phosphorylation of fibroblast growth factor receptors . Intense P08069 and IR phosphorylation occurred in the absence of MEF conditioning ( Q9HCG8 ) and was attributable to high concentrations of insulin in the proprietary KnockOut Serum Replacer ( Q8IVT5 ) . Inhibition of P08069 using a blocking antibody or lentivirus - delivered shRNA reduced hESC self - renewal and promoted differentiation , while disruption of P04626 signaling with the selective inhibitor AG825 severely inhibited hESC proliferation and promoted apoptosis . A simple defined medium containing an IGF1 analog , heregulin - 1beta ( a ligand for P04626 / P21860 ) , fibroblast growth factor - 2 ( P09038 ) , and activin A supported long - term growth of multiple hESC lines . These studies identify previously unappreciated RTKs that support hESC proliferation and self - renewal , and provide a rationally designed medium for the growth and maintenance of pluripotent hESCs .",
"Southwest Oncology Group study S0413 : a phase II trial of lapatinib ( GW572016 ) as first - line therapy in patients with advanced or metastatic gastric cancer . BACKGROUND : ___MASK26___ ( GW572016 ) is a dual tyrosine kinase inhibitor of epidermal growth factor receptor ( P00533 ) and human epidermal growth factor receptor 2 ( P04626 / ErbB2 ) , which are reported as overexpressed in 15 % - 45 % of gastric cancers , making them potential targets . PATIENTS AND METHODS : The primary objective of this study was to assess response rate . Secondary objectives included overall survival ( OS ) , toxicity , and the relationship of P00533 , ErbB2 , and markers of angiogenesis with clinical outcome . ___MASK26___ was administered to chemonaive metastatic gastric cancer patients at a dose of 1500 mg orally daily for 28 days . RESULTS : The study enrolled 47 patients from February 2005 until May 2006 . Four patients ( 9 % ) had a confirmed partial response ( PR ) , 1 ( 2 % ) had an unconfirmed PR , and 10 ( 23 % ) had stable disease . Median ( 95 % confidence interval ) time to treatment failure was 1 . 9 ( 1 . 6 - 3 . 1 ) months and OS was 4 . 8 ( 3 . 2 - 7 . 4 ) months . Significant adverse events : one grade 4 cardiac ischemia / infarction , one grade 4 fatigue , and one grade 4 emesis . One treatment - related death was due to central nervous system ischemia . An exploratory analysis of markers revealed gene expression of P04626 , interleukin ( IL ) - 8 and genomic polymorphisms P10145 , and vascular endothelial growth factor correlated with OS . CONCLUSIONS : ___MASK26___ is well tolerated , with modest single - agent activity in advanced / metastatic gastric cancer patients . Potential molecular correlatives were identified which warrant further validation .",
"P11362 - 5 - hydroxytryptamine 1A heteroreceptor complexes and their enhancement of hippocampal plasticity . BACKGROUND : The hippocampus and its 5 - hydroxytryptamine transmission plays an important role in depression related to its involvement in limbic circuit plasticity . METHODS : The analysis was made with bioluminescence resonance energy transfer , co - immunoprecipitation , in situ proximity ligation assay , binding assay , in cell western and the forced swim test . RESULTS : Using bioluminescence resonance energy transfer analysis , fibroblast growth factor receptor 1 ( P11362 ) - 5 - hydroxytryptamine 1A ( P08908 ) receptor complexes have been demonstrated and their specificity and agonist modulation characterized . Their presence based on co - immunoprecipitation and proximity ligation assay has also been indicated in hippocampal cultures and rat dorsal hippocampal formation showing a neuronal location . In vitro assays on extracellular signal - regulated kinases 1 and 2 phosphorylation have shown synergistic increases in signaling on coactivation with fibroblast growth factor 2 ( P09038 ) and a P08908 agonist , and dependent on the heteroreceptor interface . In vitro and in vivo studies also revealed a P08908 agonist induced phosphorylation of P11362 and extracellular signal - regulated kinase 1 / 2 in rat hippocampus without changing P09038 levels . Co - activation of the heteroreceptor also resulted in synergistic increases in extensions of PC12 cells and neurite densities and protrusions in primary hippocampal cultures dependent on the receptor interface . The combined acute and repeated intracerebroventricular treatment with P09038 and 8 - OH - DPAT was found to produce evidence of highly significant antidepressant actions in the forced swim test . CONCLUSIONS : The findings indicate that neurotrophic and antidepressant effects of 5 - HT in brain may , in part , be mediated by activation of the P08908 receptor protomer in the hippocampal P11362 - P08908 receptor complex enhancing the P11362 signaling .",
"___MASK69___ : kinetic and dynamic profile in the treatment of pain . ___MASK69___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK69___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK69___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK69___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK54___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .",
"Pharmacological modulation of nerve growth factor synthesis : a mechanistic comparison of vitamin D receptor and beta ( 2 )- adrenoceptor agonists . Increasing nerve growth factor ( P01138 ) in the PNS is a rational strategy for treating certain neurodegenerative disorders . The present studies were undertaken to compare two compounds , a vitamin D ( 3 ) analogue ( CB1093 ) with minimal calcaemic effects , and clenbuterol , a long - acting beta ( 2 )- adrenoceptor agonist , both of which induce P01138 synthesis in vivo . DB01407 caused significant increases in both P01138 mRNA and protein in 3T3 cells ; with maxima at 10 nM and at 8 - 12 h exposure . Effects of clenbuterol on P01138 mRNA were antagonized by propranolol . Mobility shift assays on whole cell extracts showed that clenbuterol increased P05412 binding in 3T3 cells prior to increasing P01138 synthesis . DB01407 was without effect on P01138 mRNA levels in L929 cells , whereas CB1093 caused significant increases in both P01138 mRNA and protein levels in both 3T3 and L929 cells . Stimulation was almost maximal at 24 h exposure and was sustained for at least 72 h . The magnitude of the increase was much greater in L929 ( 700 % increase ) than in 3T3 cells ( 80 % ) . Binding to the vitamin D nuclear receptor ( P11473 ) , which acts as a transcription factor itself , was increased as early as 30 min after exposure to of CB1093 and maintained up to 24 h . Increased P11473 binding preceded increased P01138 mRNA . A 150 % increase in AP - 1 binding was also evident . This study demonstrates that CB1093 and clenbuterol stimulate P01138 levels in vitro and that AP - 1 binding could be a commonality between the mechanism of P01138 induction of these two compounds .",
"A novel role for farnesyl pyrophosphate synthase in fibroblast growth factor - mediated signal transduction . P14324 ( FPPS ) catalyses the formation of a key cellular intermediate in isoprenoid metabolic pathways . Here we describe a novel role for this enzyme in fibroblast growth factor ( FGF ) - mediated signalling . We demonstrate the binding of FPPS to FGF receptors ( FGFRs ) using the yeast two - hybrid assay , pull - down assays and co - immunoprecipitation . The interaction between FPPS and FGFR is regulated by the cellular metabolic state and by treatment with P09038 . Overexpression of FPPS inhibits P09038 - induced cell proliferation , accompanied by a failure of the P09038 - mediated induction of cyclins D1 and E . Overexpression of FPPS in fibroblasts also promotes increased farnesylation of Ras , and temporally extends P09038 - stimulated activation of the Ras / P29323 ( extracellular - signal - regulated kinase ) cascade . These data suggest that , in addition to its role in isoprenoid biosynthesis , FPPS may function as a modulator of the cellular response to FGF treatment .",
"Statin decreases endothelial microparticle release from human coronary artery endothelial cells : implication for the Rho - kinase pathway . OBJECTIVE : Elevated plasma levels of endothelial microparticles ( EMPs ) are associated with the presence of clinical atherosclerosis . Considering the anti - inflammatory properties of P04035 inhibitors on the endothelium , we studied the effect of fluvastatin on the release of EMPs in cultured human coronary artery endothelial cells ( HCAEC ) . METHODS AND RESULTS : EMPs were generated in P01375 - activated HCAECs . The absolute number of EMPs was enumerated using a novel two - color flow cytometric immunostaining technique with TruCount beads as an internal reference . EMPs are defined as EC membrane vesicles ( 1 - 2 microm in size ) with a characteristic immunophenotype . The addition of fluvastatin to P01375 - activated HCAECs significantly suppressed Q7L5Y9 release . ___MASK17___ suppressed P01375 - induced Rho activation . The Rho - kinase inhibitor , Y - 27632 , reproduced the effect of statin . CONCLUSION : Q7L5Y9 release from P01375 - activated HCAECs is suppressed by fluvastatin . In addition , the Rho / Rho - kinase may play an important role in modulating Q7L5Y9 release .",
"Evaluation of cytokine production by equine alveolar macrophages exposed to lipopolysaccharide , Aspergillus fumigatus , and a suspension of hay dust . OBJECTIVE : To evaluate cytokine production by equine alveolar macrophages after exposure to lipopolysaccharide ( LPS ) , Aspergillus fumigatus , and hay dust , and determine the effect of clenbuterol on the cytokine response . ANIMALS : 6 horses . PROCEDURE : Alveolar macrophages were exposed to PBS solution ( negative control ) , LPS , hyphae and conidia of Aspergillus fumigatus ( AF ) , or a suspension of hay dust ( Q86SQ9 ) and incubated for 24 hours at 37 degrees C . Concentrations of tumor necrosis factor ( P01375 ) - alpha and interleukin ( IL ) - 1beta were measured in the supernatant . The procedure was repeated with cells that were concurrently incubated with 0 . 5 microM clenbuterol . RESULTS : Exposure to Q86SQ9 and AF significantly increased production of P01375 by equine alveolar macrophages . The increase in P01375 produced in response to Q86SQ9 and AF was 5 and 7 times as great , respectively , as the increase measured in response to LPS . The concentration of IL - 1beta in the supernatant was significantly increased after exposure of cells to AF . DB01407 was effective at inhibiting P01375 production by cells exposed to LPS , Q86SQ9 , or AF . CONCLUSIONS AND CLINICAL RELEVANCE : Increased production of P01375 and IL - 1 indicated that the pro - inflammatory cytokines produced by alveolar macrophages in response to allergens may play a role in recurrent airway obstruction ( O75106 ) in horses . Equine alveolar macrophages are not only a primary pulmonary defense mechanism but may also influence the pathogenesis of equine O75106 . The beta2 - adrenoceptor agonist clenbuterol , a drug that is commonly used for treatment of equine O75106 , promotes immediate bronchodilation and may also contribute to downward modulation of the inflammatory response .",
"Proliferation of the murine corticotropic tumour cell line AtT20 is affected by hypophysiotrophic hormones , growth factors and glucocorticoids . In pituitary - dependent hyperadrenocorticism ( Cushing ' s disease ) , the disturbed regulation of ___MASK21___ secretion is associated with neoplastic transformation of corticotropic cells . As these two phenomena are almost indissolubly connected , it is of prime importance to elucidate the factor ( s ) that induce corticotropic cell proliferation . Here we report on the effects of hypophysiotrophic hormones and intrapituitary growth factors on the proliferation and hormone secretion of the murine corticotropic tumour cell line AtT20 / D16v , as measured by DNA content , and ___MASK21___ concentration in culture media . In addition , sensitivity to the inhibitory effect of cortisol was assessed under various conditions . ___MASK21___ releasing hormone ( P06850 ) and vasopressin ( AVP ) induced proliferation of AtT20 - cells . In contrast to that caused by AVP , the P06850 - induced proliferation was associated with increased ___MASK21___ secretion , which could be inhibited by cortisol . P01308 - like growth factor - I ( P05019 ) , epidermal growth factor ( P01133 ) and basic fibroblast growth factor ( P09038 ) also stimulated the proliferation of AtT20 - cells . The proliferation of AtT20 - cells was significantly inhibited by cortisol in all tests . The P05019 - induced proliferation was the least sensitive to inhibition by cortisol . The growth factors did not stimulate ___MASK21___ secretion but P05019 differed in that it prevented the inhibition of basal ___MASK21___ secretion by cortisol . Additional experiments ( Western ligand blot analysis ) concerning the relative insensitivity of P05019 induced proliferation to inhibition by cortisol revealed that P05019 increased the concentration of a 29 kDa IGF binding protein ( IGFBP ) in the culture medium . The concentration of the 29 kDa IGFBP was slightly decreased by cortisol . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Endotoxin - induced liver damage in rats is minimized by beta 2 - adrenoceptor stimulation . OBJECTIVE AND DESIGN : To investigate the effects of beta ( 2 )- adrenoceptor ( beta ( 2 )- AR ) stimulation on endotoxin - induced liver damage and systemic cytokine levels in rats . SUBJECTS : Standard male Wistar rats . TREATMENT : A disease - model of lipopolysaccharide ( LPS ) - induced acute systemic inflammation was used . The beta ( 2 )- selective AR agonist clenbuterol was administered before , during , and after LPS - challenge to investigate its effects on the acute inflammatory response and associated liver - failure . METHODS : The following parameters have been measured in plasma : P01375 alpha , P01584 , P05231 , P22301 , Q9NRA2 , ALT , and Bilirubin . Liver histological examination was performed to look for changes in tissue morphology . RESULTS : Administration of clenbuterol ( p . o . ) one hour before , or intravenous at the same time as LPS - challenge resulted in a marked reduction of plasma levels of P01375 alpha , P01584 , and P05231 . A change both in plasma - level and in time - concentration profile of the anti - inflammatory cytokine P22301 was found . DB01407 minimized LPS - induced liver damage , as represented by significantly lowered concentrations of several parameters for liver - failure ( Q9NRA2 , ALT , Bilirubin ) , and improved hepatic tissue morphology . DB01407 administration after LPS challenge failed to inhibit P01375 alpha - release but reduced liver - damage . Simultaneous use of the beta ( 2 )- AR antagonist propranolol augmented LPS - induced liver failure , suggesting a role of endogenous adrenoceptor - agonists in prevention of organ - failure during systemic inflammation . CONCLUSIONS : The results indicate that a selective beta ( 2 )- AR agonist might be used as an additional therapeutic agent in the clinic for the treatment of ( acute ) systemic inflammatory disorders in order to reduce or prevent subsequent liver failure .",
"Reactive oxygen species - dependent P01375 converting enzyme activation through stimulation of P41595 and alpha1D autoreceptors in neuronal cells . A major determinant of neuronal homeostasis is the proper integration of cell signaling pathways recruited by a variety of neuronal and non - neuronal factors . By taking advantage of a neuroectodermal cell line ( 1C11 ) endowed with the capacity to differentiate into serotonergic ( 1C115 - HT ) or noradrenergic ( 1C11NE ) neurons , we identified serotonin ( 5 - hydroxytryptamine , 5 - HT ) - and norepinephrine ( NE ) - dependent signaling cascades possibly involved in neuronal functions . First , we establish that P41595 receptors and 1D adrenoceptors are functionally coupled to reactive oxygen species ( ROS ) synthesis through NADPH oxidase activation in 1C115 - HT and 1C11NE cells . This observation constitutes the prime evidence that bioaminergic autoreceptors take part in the control of the cellular redox equilibrium in a neuronal context . Second , our data identify P78536 ( P01375 - Converting Enzyme ) , a member of a disintegrin and metalloproteinase ( ADAM ) family , as a downstream target of the P41595 and 1D receptor - NADPH oxidase signaling pathways . Upon P41595 or 1D receptor stimulation , ROS fully govern P01375 - shedding in the surrounding milieu of 1C115 - HT or 1C11NE cells . Third , P41595 and 1Dreceptor couplings to the NADPH oxidase - P78536 cascade are strictly restricted to 1C11 - derived progenies that have implemented a complete serotonergic or noradrenergic phenotype . Overall , these observations suggest that P41595 and 1D autoreceptors may play a role in the maintenance of neuron - and neurotransmitter - associated functions . Eventually , our study may have implications regarding the origin of oxidative stress as well as up - regulated expression of proinflammatory cytokines in neurodegenerative disorders , which may relate to the deviation of normal signaling pathways .",
"P98170 regulates human interleukin - 6 in umbilical vein endothelial cells via stimulation of the nuclear factor - kappaB and Q96HU1 kinase signaling pathways . X - linked inhibitior of apoptosis ( P98170 ) is known as a potent inhibitor of apoptosis , but more recently has been shown to also act as a modulator of the nuclear factor kB ( NF - kappaB ) signaling pathway . To investigate whether P98170 also affects other signalling pathways , we studied the transcriptional regulation of interleukin 6 ( P05231 ) , a gene that is strongly affected by P98170 , in more detail . The human P05231 gene contains transcription factor binding sites for activator protein 1 ( P05412 ) , enhancer binding protein beta ( C / EBP - beta ) and NF - kappaB . In reporter gene assays , mutation of these binding sites revealed the necessity of functional NF - kappaB and P05412 - sites for its ability to respond to P98170 . In contrast , P05231 promoter activity was slightly increased in the C / EBP deletion mutant . Pharmacologic inhibition of extracellular signal regulated kinase ( P29323 ) kinases ( Q02750 / 2 ) as well as inhibition of the p38 signaling pathway both reduced P98170 - induced P05231 promoter activity . In conclusion , these results suggest that P98170 regulates P05231 transcription via NF - kappaB in cooperation with P05412 and C / EBP - beta .",
"Circulating apoptotic proteins are increased in long - term disease - free breast cancer survivors . Circulating apoptotic proteins are increased in patients with heart failure . We evaluated whether circulating soluble ( s ) apoptosis - related proteins and inflammation markers are increased in long - term disease free breast cancer survivors and associated with cardiotoxicity , and if subgroups could be identified based on the applied treatments . Circulating tumour necrosis factor ( P01375 ) alpha , sTNF - receptor ( sTNF - R ) 1 and 2 , sFas , sFas ligand , sTNF - related apoptosis inducing ligand ( sTRAIL ) and serum P04626 were measured with immunoassay . High - sensitivity P02741 ( HS - CRP ) , fibrinogen , plasma B - type and N - terminal atrial natriuretic peptide ( NT - P01160 and DB04899 ) were also determined . Thirty - four patients with median 6 . 0 years follow - up and 12 healthy age - matched women were enrolled . Chemotherapy , consisting of five cycles fluorouracil , epirubicin ( 90 mg / m ( 2 ) ) , cyclophosphamide ( FEC ) ( n = 14 ) or four cycles FEC followed by myeloablation with high - dose carboplatin , cyclophosphamide , thiotepa ( n = 20 ) , preceded irradiation and tamoxifen . Circulating apoptosis markers were higher in patients than in controls . No associations with cardiac dysfunction were observed . sFas ligand and sTRAIL were higher in the high - dose than in the standard - dose group . In conclusion , we observed increased circulating apoptotic protein levels in long - term disease - free breast cancer survivors , treated with adjuvant chemoradiotherapy , particularly after myeloablative chemotherapy . The potential relation with late cardiotoxicity of antineoplastic therapy deserves further study .",
"Serum IL - 1beta levels in health and disease : a population - based study . ' The InCHIANTI study ' . Interleukin - 1 plays a role in normal homeostasis and in the inflammatory response which is deemed to be responsible for the development of major chronic diseases that are highly prevalent in the elderly . Aim of this study is to evaluate the factors influencing the serum levels of P01584 , in a large and representative population . Data were from the InCHIANTI project , a study of factors contributing to the decline of mobility in late life , which sampled people living in two sites in the surroundings of Florence . Blood samples were obtained from 1 , 292 participants and frozen aliquots were stored at - 80 degrees C . The serum levels of several cytokines were measured by enzyme linked immunosorbent assay using an ultrasensitive commercial kit . P01584 serum levels were associated with congestive heart failure ( p > 0 . 001 ) and angina ( p = 0 . 02 ) , with Ca2 + serum levels ( p = 0 . 02 ) , and with a history of dyslipidemia ( p = 0 . 05 ) . We found no association between serum IL - 1beta level and age , sex , consumption of cardioactive drugs and serum levels of IL - 1Ra , P05231 , sIL - 6R , P22301 and P01375 . Our data could lend support to the hypothesis that IL - 1beta is mainly involved in the functional alterations of cardiomyocytes under conditions marked by mononuclear cell infiltration and by downregulation of calcium .",
"Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .",
"P01584 and other cytokines stimulate adrenocorticotropin release from cultured pituitary cells of patients with Cushing ' s disease . Interleukin - 1 ( IL - 1 ) is a cytokine that is secreted by macrophages and monocytes which stimulates rodent hypothalamic P06850 release and possibly pituitary ___MASK21___ secretion . We studied the effect of P01584 and other cytokines ( gamma - interferon , thymosin fraction - 5 , and granulocyte colony - stimulating factor ) on ___MASK21___ release from corticotroph adenoma tissue obtained from two patients with Cushing ' s disease . P01584 ( 0 . 001 - 10 mumol / L ) increased ___MASK21___ release 3 - fold . Thymosin fraction - 5 ( 10 mumol / L ) , gamma - interferon ( 1 mumol / L ) , and granulocyte colony - stimulating factor ( 1 mumol / L ) also stimulated ___MASK21___ release . These cultured cells secreted little or no GH , PRL , DB00024 , LH , and DB00094 , and their release was not stimulated by any cytokine . These results suggest that ___MASK21___ release in patients with Cushing ' s disease may be responsive to stimulation by various cytokines .",
"Stimulation of central β2 - adrenoceptors suppresses NFκB activity in rat brain : a role for IκB . In this study we examined the impact of systemic treatment with the long - acting brain penetrant β2 - adrenoceptor agonist clenbuterol on NFκB activity and IκB expression in rat brain . DB01407 decreased NFκB activity ( p65 DNA binding ) in nuclear extracts prepared from rat cortex and hippocampus for up to 8h following a single treatment . This was accompanied by increased expression of IκBα mRNA and protein . The temporal increase in IκB protein expression paralleled the suppression of NFκB activity , suggesting that IκBα mediates the suppression NFκB activity observed . These actions of clenbuterol were prevented by pre - treatment with the non - selective β - adrenoceptor antagonist propranolol , the β2 - adrenoceptor antagonist ICI - 118 , 551 , but not the β1 - adrenoceptor antagonist metoprolol , suggesting that the effects of clenbuterol on IκBα expression and NFκB activity are mediated specifically by the β2 - adrenoceptor . In addition , the actions of clenbuterol were mimicked by systemic administration of another highly selective long - acting β2 - adrenoceptor agonist formoterol . As neurodegenerative diseases are associated with inflammation we determined if clenbuterol could suppress NFκB activation that occurs in response to an inflammatory stimulus . In this regard we demonstrate that clenbuterol inhibited IκB phosphorylation and IκB degradation and inhibited NFκB activity in hippocampus and cortex of rats following a central injection of the inflammagen bacterial lipopolysaccharide ( LPS ) . In tandem , clenbuterol blocked expression of the NFκB - inducible genes P01375 - α and P05362 following LPS administration . Our finding that clenbuterol and formoterol inhibit NFκB activity in the CNS further supports the idea that β2 - adrenoceptors may be an attractive target for treating neuroinflammation and combating inflammation - related neurodegeneration .",
"Cylindrospermopsin induced transcriptional responses in human hepatoma HepG2 cells . The newly emerging cyanotoxin cylindrospermopsin ( CYN ) is showing genotoxic effects in a range of test systems . However , the knowledge on the mechanisms involved is limited . To get insight into the cellular responses to CYN a toxicogenomic analysis of selected genes commonly affected by genotoxic stress was performed on HepG2 cells exposed to a non - cytotoxic but genotoxic concentration of CYN ( 0 . 5 μg / ml for 12 and 24h ) . CYN increased expression of the immediate - early response genes from the P01100 and P05412 gene families and there was strong evidence for the involvement of P04637 and NF - κB signaling . Strong up - regulation of the growth arrest and DNA damage inducible genes ( P24522 and O75293 ) , cyclin - dependent kinase inhibitors ( P38936 and P42772 ) , checkpoint kinase 1 ( O14757 ) , and genes involved in DNA damage repair ( Q01831 , Q92889 and others ) indicated cell - cycle arrest and induction of nucleotide excision and double strand break repair . Up - regulation of metabolic enzyme genes provided evidence for the involvement of phase I ( P04798 , Q16678 , O94788 and CES2 ) and phase II ( P19224 , P22309 , NAT1 and P21266 ) enzymes in the detoxification response and potential activation of CYN . The obtained transcriptional patterns after exposure of HepG2 cells to CYN provide valuable new information on the cellular response to CYN .",
"Induction of nerve growth factor and basic fibroblast growth factor mRNA following clenbuterol : contrasting anatomical and cellular localization . RNase protection assay and in situ hybridization were used to analyze the temporal and cellular changes in nerve growth factor ( P01138 ) and basic fibroblast growth factor ( P09038 ) mRNA content evoked by the lipophilic beta - adrenergic receptor agonist clenbuterol in adult rat brain . DB01407 elicited a threefold increase in P01138 mRNA expression which was limited to the cerebral cortex . This increase was maximal at 5 h , still evident by 10 h , and declined to control levels by 24 h . By 10 h P01138 protein was also increased . Elevated P01138 mRNA hybridization following clenbuterol was localized in the superficial cortical layers II and III in large Nissl - pale cells , suggesting that P01138 mRNA induction occurs in neurons . In the same animals , clenbuterol induced a twofold increase in the levels of P09038 mRNA in cerebral cortex and hippocampus . This increase was localized primarily in glial cells as demonstrated by P09038 mRNA hybridization over all cortical regions and by labeling of the stratum lacunosum moleculare of the hippocampus . Our results suggest that enhanced noradrenergic tone regulates expression of these two trophic factors by different synaptic mechanisms and suggest that neurotransmitter ( s ) can coordinate trophic influences on different cell populations .",
"Differential effects of endotoxin and fibrinogen degradation products ( P14324 ) on liver synthesis of fibrinogen and albumin : evidence for the involvement of a novel monokine in the stimulation of fibrinogen synthesis induced by P14324 . 1 . Administration of endotoxin or fibrinogen degradation products ( FDPs ) in rats increase fibrinogen synthesis comparable to that found during the acute phase response . 2 . An increased fibrinogen synthesis is also found in co - cultures of hepatocytes with peripheral blood mononuclear cells upon administration of endotoxin or FDPs , but not in primary cultures of hepatocytes alone . 3 . However , the increased synthesis of fibrinogen by FDPs is not accompanied by a decreased albumin synthesis , as in the case of stimulated fibrinogen synthesis induced by endotoxin in vivo and in co - cultures of hepatocytes with peripheral blood mononuclear cells , or induced by monocytic products in vivo and in primary cultures of hepatocytes alone . 4 . Since IL - 1 and / or P05231 could not be accounted for the stimulation of fibrinogen synthesis without a decreased albumin synthesis , a novel monokine produced by mononuclear cells upon Q9NRC9 administration might be involved .",
"Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK54___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .",
"Combined anti - inflammatory effects of β2 - adrenergic agonists and DB05876 inhibitors on astrocytes by upregulation of intracellular DB02527 . Inflammation is an important hallmark of all neurodegenerative diseases and activation of different glial populations may be involved in the progression of some of these disorders . Especially , the activation of astroglia can lead to long - term detrimental morphological changes , such as scar formation . Therefore , improved strategies to modulate inflammation in these cells are currently being investigated . We investigated the interaction of phosphodiesterase ( PDE ) 4 inhibitors , such as rolipram , with other agents raising cellular DB02527 levels . When used alone , none of the DB05876 inhibitors increased DB02527 levels . The adenylate cyclase activator forskolin , the β ( 2 )- adrenergic agonist clenbuterol and the mixed β ( 1 )/ β ( 2 )- adrenergic agonist isoproterenol increased intracellular DB02527 levels of cortical murine astrocytes . This increase was synergistically elevated by rolipram or the DB05876 inhibitor RO - 201724 , but not by inhibition of PDE3 . Inflammatory stimulation of the cells with the cytokines P01375 - α , IL - 1β and IFN - γ strongly induced Q07343 and augmented overall DB05876 activity , while PDE3 activity was low . DB01407 and forskolin caused downregulation of cytokines and chemokines such as P05231 and P13500 . This effect was further enhanced by rolipram , but not by the PDE3 inhibitor milrinone . The DB02527 - raising drug combinations attenuated the upregulation of P01375 - α and P05231 mRNA and the secretion of P05231 , but did not affect initial NF - κB signalling triggered by the stimulating cytokines . These results indicate that DB05876 may be a valuable anti - inflammatory target in brain diseases , especially under conditions associated with stimulation of DB02527 - augmenting astrocyte receptors as is observed by clenbuterol treatment .",
"The P08908 receptor agonist Bay x 3702 inhibits apoptosis induced by serum deprivation in cultured neurons . We examined whether the highly selective P08908 receptor agonist (-)-( R )- 2 - [ 4 - [ [ ( 3 , 4 - dihydro - 2H - 1 - benzopyran - 2 - yl ) methyl ] - amino ] butyl ] - 11 , 2 - benz - isothiazol - 3 ( 2H )- one 1 , 1 - dioxide monohydrochloride ( Bay x 3702 ) could inhibit neuronal apoptosis induced by serum deprivation . In primary cultures of chick embryonic neurons and in mixed neuronal / glial cultures from neonatal rat hippocampus , Bay x 3702 ( 1 microM ) rescued serum - deprived neurons from apoptosis . The antiapoptotic effect of Bay x 3702 ( 1 microM ) was blocked in chick neurons by the selective P08908 receptor antagonists 4 - iodo - N -[ 2 -[ 4 -( methoxyphenyl )- 1 - piperazin ] ethyl ]- N - 2 - pyridinyl - be nzamide hydrochloride ( p - MPPI , 10 microM ) and 4 -[ 3 - benzotriazol - 1 - propyl ]- 1 -( 2 - methoxyphenyl )- piperazine ( BPMP , 10 microM ) as well as by anti - nerve growth factor ( anti - P01138 ) antibodies and in rat neurons by N -[ 2 - 4 -( 2 - methoxy )- 1 - piperazinyl ] ethyl ] - N -( 2 - pyridinyl ) cyclohexane - carbo xamide trihydrochloride ( WAY 100635 , 10 microM ) . We found only under control conditions ( medium with serum ) , but not in serum - deprived cultures , that P01138 secretion was 6 - fold increased by Bay x 3702 ( 1 microM ) compared to untreated cultures . Additionally , Bay x 3702 ( 4 microg / kg i . v . ) , infused within a period of 4 h , significantly increased the P01138 content of the rat hippocampus , but not of the striatum . In summary , our data suggest that Bay x 3702 inhibited growth factor withdrawal - induced apoptosis by the stimulation of P08908 receptors and that the P01138 signalling pathway is involved in the mechanism of action .",
"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK61___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK61___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK61___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK61___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence ."
] |
[
"___MASK17___",
"___MASK1___",
"___MASK21___",
"___MASK26___",
"___MASK54___",
"___MASK61___",
"___MASK69___",
"___MASK80___",
"___MASK86___"
] |
___MASK1___
|
MH_train_419
|
interacts_with DB00398?
|
[
"Somatic Q06124 mutations in childhood acute myeloid leukaemia . Somatic mutations in Q06124 , the gene encoding the transducer Q06124 , have emerged as a novel class of lesions that upregulate DB01367 signalling and contribute to leukaemogenesis . In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia ( AML ) , we documented a non - random distribution of Q06124 mutations among French - American - British ( FAB ) subtypes . Lesions were restricted to FAB - M5 cases , where they were relatively common ( four of 12 cases ) . Here , we report on the results of a molecular screening performed on 181 additional unselected patients , enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica - AML Study Group , to provide a more accurate picture of the prevalence , spectrum and distribution of Q06124 mutations in childhood AML and to investigate their clinical relevance . We concluded that Q06124 defects do not represent a frequent event in this heterogeneous group of malignancies ( 4 . 4 % ) , although they recur in a considerable percentage of patients with FAB - M5 ( 18 % ) . Q06124 lesions rarely occur in other subtypes . Within the FAB - M5 group no clear association of Q06124 mutations with any clinical variable was evident . Nearly two third of the patients with this subtype were found to harbour an activating mutation in Q06124 , P01111 , P01116 or P36888 .",
"Comparison of two polymer - based immunohistochemical detection systems : ENVISION + and ImmPRESS . The non - specific background reaction produced in avidin - biotin - based immunohistochemistry , particularly after harsh antigen retrieval procedures , has promoted the use of non - avidin - biotin systems , yet there are few reports comparing the performance of non - avidin - biotin , polymer - based methods . In this study we compare two of these methods , ENVISION + trade mark and ImmPRESS , in animal tissues . We examined the immunoreactivity of 18 antigens in formalin - fixed , paraffin - embedded tissues . Antigens were located in the cytoplasmic membrane ( CD11d , P05107 and CD79a ) , cytoplasm ( calretinin , P23219 , P35354 , Glut - 1 , HepPar 1 , P10721 , Melan A , tryptase and uroplakin III ) or nucleus ( Q2TAK8 , P09936 and thyroid transcription factor 1 ) . We also evaluated three infectious agents ( Aspergillus , calicivirus and West Nile virus ) . The staining with ENVISION + or ImmPRESS was performed simultaneously for each antigen . The intensity of the reaction and background staining were scored . ImmPRESS yielded similar or higher reaction intensity than ENVISION + trade mark in 16 / 18 antigens . ImmPRESS produced abundant background with the other two antigens ( calretinin and P35354 ) , which hindered interpretation of the specific reaction . The cost of ImmPRESS was 25 % lower than for ENVISION + trade mark . Based on these results , ImmPRESS is a good polymer - based detection system for routine immunohistochemistry .",
"Inhibition of P01375 - induced cyclooxygenase - 2 expression by Mycobacterium bovis BCG in human alveolar epithelial A549 cells . P35354 ( P35354 ) is implicated in pathophysiological processes associated with the initiation or maintenance of host inflammatory responses to infection . Our results demonstrates that Mycobacterium bovis BCG ( M . bovis BCG ) downregulates tumour necrosis factor - alpha ( P01375 ) - induced P35354 gene expression in alveolar epithelial cells by inhibiting the phosphorylations of P04049 and p38 kinases . Further , M . bovis BCG - mediated inhibition of P35354 or p38 mitogen - activated protein kinase could be reversed by DB02860 , a selective inhibitor of DB00133 / DB00156 phosphatases . Moreover , M . bovis BCG inhibited the P01375 - triggered NF - kappaB activation following IkappaB degradation . Taken together , these results suggest that the attenuation of P35354 expression by vaccine strain , M . bovis BCG , represents a novel strategy to maintain robust host proinflammatory responses to subsequent challenges with virulent tuberculosis bacilli .",
"Multi - kinase inhibition in ovarian cancer . DB00398 ( Nexavar ) is a multi - kinase inhibitor that was developed as an inhibitor of RAF - 1 , in the P27361 / 2 pathway , but which was subsequently shown to inhibit class III tyrosine kinase receptors . ( 1 ) More recently regorafenib ( Stivarga ) has been developed , which is a further fluorinated version of sorafenib with greater bioavailability and similar inhibitory properties against RAF - 1 / class III RTKs . ( 2 ) Some of the anti - tumor effects of sorafenib have been ascribed to anti - angiogenic actions of this agent on endothelial associated kinases such as P35968 . Other effects of sorafenib clearly have to be due to its effects on the inherent biology of the tumor cells themselves . For example , through various mechanisms sorafenib has been shown in the laboratory and the clinic to suppress expression of the protective protein Q8WXI8 - 1 . ( 3 ) DB00398 has also been linked to inhibition of P40763 , NFκB , and activation of the death receptor CD95 . ( 4 ) DB00398 is routinely dosed daily ( 400 mg P55957 ) and 7 d after the start of dosing has a Cmax of ~ 21 μM with a nadir at 12 h of ~ 10 μM , and is a highly protein bound based on in vitro assays . ( 5 ) Despite this in vitro binding data sorafenib has profound in vivo effects on tumor cells in renal carcinoma and hepatocellular carcinoma patients ; cells which are not per se addicted to high activity oncogene signals that are targets of sorafenib / regorafenib . Thus the precise stable bioavailable level of sorafenib / regorafenib in patient plasma is not known .",
"Selective P36888 inhibition of P36888 - ITD + acute myeloid leukaemia resulting in secondary D835Y mutation : a model for emerging clinical resistance patterns . Acquired resistance to selective P36888 inhibitors is an emerging clinical problem in the treatment of P36888 - ITD (+) acute myeloid leukaemia ( AML ) . The paucity of valid pre - clinical models has restricted investigations to determine the mechanism of acquired therapeutic resistance , thereby limiting the development of effective treatments . We generated selective P36888 inhibitor - resistant cells by treating the P36888 - ITD (+) human AML cell line MOLM - 13 in vitro with the P36888 - selective inhibitor MLN518 , and validated the resistant phenotype in vivo and in vitro . The resistant cells , MOLM - 13 - RES , harboured a new D835Y tyrosine kinase domain ( TKD ) mutation on the P36888 - ITD (+) allele . Acquired TKD mutations , including D835Y , have recently been identified in P36888 - ITD (+) patients relapsing after treatment with the novel P36888 inhibitor , DB05213 . Consistent with this clinical pattern of resistance , MOLM - 13 - RES cells displayed high relative resistance to DB05213 and DB00398 . Furthermore , treatment of MOLM - 13 - RES cells with DB05213 lead to loss of the P36888 wild - type allele and the duplication of the P36888 - ITD - D835Y allele . Our P36888 - Aurora kinase inhibitor , CCT137690 , successfully inhibited growth of P36888 - ITD - D835Y cells in vitro and in vivo , suggesting that dual P36888 - Aurora inhibition may overcome selective P36888 inhibitor resistance , in part due to inhibition of Aurora kinase , and may benefit patients with P36888 - mutated AML .",
"Molecular targeting for treatment of advanced hepatocellular carcinoma . Hepatocellular carcinoma ( HCC ) is a major global health problem , which has a grave morbidity and mortality . Over the past few decades , no effective systemic therapeutic modalities have been established for patients with the unresectable HCC in advanced stage . DB00398 is a small molecule that blocks cancer cell proliferation by targeting the intracellular signaling pathway at the level of P04049 and B - Raf serine - threonine kinases , and exerts an anti - angiogenic effect by targeting the vascular endothelial growth factor receptor - 1 , 2 and 3 , and platelet - derived growth factor receptor - beta tyrosine kinases . Recently , two clinical successful applications , Q96T58 and Asia - Pacific trial , of multikinase inhibitor sorafenib represent a significant advance in the treatment of advanced HCC patients without a curative chance . However , because the results of clinical trials show diverse responses in a subset of HCC patients , a molecular classification of HCC through the excavation of specific biomarkers related to its biological behavior is necessary for sorting HCC patients to each group with a biological homogeneity , ultimately leading to the most suitable individualization of molecular targeted therapy in HCC .",
"Moving beyond chemotherapy : novel cytostatic agents for malignant mesothelioma . It is now known that vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) are autocrine growth factors in malignant mesothelioma ; epidermal growth factor receptor ( P00533 ) is also highly overexpressed . Cytotoxic drugs that target these growth factors offer fresh potential for the treatment of mesothelioma . Clinical trials have recently been initiated to evaluate the anti - tumour activity of the P15692 inhibitors SU5416 , bevacizumab and thalidomide . ZD1839 ( ___MASK5___ , AstraZeneca ) , an inhibitor of P00533 tyrosine kinase , is also being evaluated . Two clinical trials are planned to evaluate the two PDGF inhibitors Gleevec ( Imatinib mesylate , STI - 571 , Novartis Pharmaceuticals ) and PTK787 ( Novartis Pharmaceuticals ) .",
"Effects of ellagic Acid on angiogenic factors in prostate cancer cells . BACKGROUND : Several natural antioxidants , including ellagic acid ( EA ) , have been reported to have chemotherapeutic activity in vivo and in vitro settings . Cytochrome P450 ( CYP ) activity and synthesis of both epoxyeicosatrienoic acids ( EETs ) and 20 - hydroxy - 5 , 8 , 11 , 14 - eicosatetraenoic acid ( 20 - HETE ) , together with vascular endothelial growth factor ( P15692 ) and heme oxygenase system ( HO ) have emerged as important modulators of tumor growth and metastasis . METHODS : The anti - angiogenic effects of EA were investigated in the human prostatic cancer cell line LnCap . P09601 , P30519 , P51589 and soluble epoxyde hydrolase ( sEH ) expressions were evaluated by western blotting . Levels of P15692 and osteoprotegerin ( O00300 ) were determined in the culture supernatant using an ELISA assay , while CYP mRNAs were determined by qRT - PCR . RESULTS : EA treatment induced a significant decrease ( p < 0 . 05 ) in P09601 , P30519 and P51589 expression , and in P15692 and O00300 levels . Similarly P51589 , P78329 and CYPA22 mRNAs were significantly ( p < 0 . 05 ) down - regulated by EA treatment . The decrease in P51589 mRNA was associated with an increase in sEH expression . CONCLUSIONS : RESULTS reported in the present study highlighted the ability of EA to modulate a new pathway , in addition to anti - proliferative and pro - differentiation properties , via a mechanism that involves a decrease in eicosanoid synthesis and a down - regulation of the HO system in prostate cancer .",
"P22681 mutation - related patterns of phosphorylation and sensitivity to tyrosine kinase inhibitors . Recurrent homozygous P22681 - inactivating mutations in myeloid malignancies decrease ubiquitin ligase activity that inactivates P12931 family kinases ( SFK ) and receptor tyrosine kinases ( RTK ) . However , the most important SFK and RTK affected by these mutations , and hence , the most important therapeutic targets , have not been clearly characterized . We compared SFK and RTK pathway activity and inhibitors in acute myeloid leukemia cell lines containing homozygous R420Q mutation ( GDM - 1 ) , heterozygous deletion ( MOLM13 ) and wild - type ( WT ) P22681 ( THP1 , U937 ) . As expected with P22681 loss , GDM - 1 displayed high P10721 expression and granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) hypersensitivity . Ectopic expression of WT P22681 decreased GDM - 1 proliferation but not cell lines with WT P22681 . GDM - 1 , but not the other cell lines , was highly sensitive to growth inhibition by dasatinib ( dual SFK and RTK inhibitor , LD50 50 nM ) ; there was less or no selective inhibition of GDM - 1 growth by sunitinib ( RTK inhibitor ) , imatinib ( P00519 , P10721 inhibitor ) , or Q99463 ( SFK inhibitor ) . Phosphoprotein analysis identified phosphorylation targets uniquely inhibited by dasatinib treatment of GDM - 1 , including a number of proteins in the P10721 and GM - P04141 receptor pathways ( for example , P10721 Tyr721 , P40763 Tyr705 ) . In conclusion , the promiscuous effects of P22681 loss on SFK and RTK signaling appear to be best targeted by dual SFK and RTK inhibition .",
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK95___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK95___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK59___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"A new cell culture - based assay quantifies vitamin K 2 , 3 - epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol - driven Q9BQB6 assay . BACKGROUND : ___MASK68___ directly inhibits the vitamin K 2 , 3 - epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) - driven vitamin K 2 , 3 - epoxide reductase ( Q9BQB6 ) assay . ___MASK68___ inhibits wild - type Q9BQB6 function by the DTT - Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance - associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture - based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild - type and variant Q9BQB6 proteins . METHODS : Human coagulation factor ( F ) IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild - type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : ___MASK68___ dose - response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild - type , Val29Leu , Val45Ala and Leu128Arg variants . The corresponding calculated IC50 values were 24 . 7 , 136 . 4 , 152 . 0 and 1226 . 4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild - type Q9BQB6 . Ranked IC50 values from the cell culture - based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation - associated warfarin resistance .",
"Association of polymorphisms in P36888 , P00533 , P09917 , and Q8TAT5 with glioblastoma in the Han Chinese population . Glioblastoma ( GBM ) is the highest - grade glioma in astrocytoma . Patients often have poor prognosis due to therapeutic resistance and tumor recurrence . Identification of the genetic factors of GBM could be important contribution to early prevention of this disease . We genotyped 17 tag single - nucleotide polymorphisms ( tSNPs ) from nine genes in this study , including 72 cases and 302 controls . SNP genotyping was conducted using Sequenom MassARRAY RS1000 . Statistical analysis of the association between tSNPs and GBM was performed using the χ ( 2 ) test and SNPStats software . The rs3829382 in P36888 was associated with increased odds of developing GBM using the χ ( 2 ) test . When we analyzed tSNPs under different inheritance models , we found rs9642393 in P00533 increased odds of developing GBM in the dominant model . After stratification by gender , we found that rs12645561 in Q8TAT5 and rs2291427 in P09917 were associated with developing GBM . Polymorphisms within P36888 , P00533 , Q8TAT5 , and P09917 may contribute to the occurrence of GBM in the Han Chinese population . However , the functional significance of these polymorphisms needs further investigation .",
"The methylator phenotype in microsatellite stable colorectal cancers is characterized by a distinct gene expression profile . The CpG island methylator phenotype ( CIMP ) in colorectal tumours can be recognized by an increased frequency of aberrant methylation in a specific set of genomic loci . Because of the strong association of CIMP with high microsatellite instability ( MSI - H ) , the identification of CIMP + tumours within microsatellite stable ( MSS ) colorectal cancers may not be straightforward . To overcome this potential limitation , we have built an improved seven - locus set of methylation markers that includes O43497 , P01344 , Q13761 , P50406 , RIZ1 , MINT31 , and P46821 . This new set of CIMP markers revealed a bimodal distribution of methylation frequencies in a group of 95 MSS colorectal cancers , which allowed a clearer separation between CIMP classes . Correlation of MSS CIMP + tumours with bio - pathological traits revealed significant associations with location to the proximal colon , mucinous histology , P15056 mutation , and chromosomal stability . A potential trend towards an adverse prognosis of CIMP + cases was associated with the high frequency of P15056 mutations present within this cohort of tumours . Microarray analysis revealed that CIMP + tumours are characterized by a unique expression profile , a result that confirms that CIMP + tumours represent a truly distinct molecular class within MSS colorectal cancers .",
"___MASK12___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK12___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"DB00398 potentiates irradiation effect in hepatocellular carcinoma in vitro and in vivo . The multikinase - inhibition action of sorafenib provides strong rationales for its combination use with radiotherapy . We investigated the in vitro and in vivo effect of sorafenib combined with irradiation on hepatocellular carcinoma ( HCC ) . DB00398 enhanced radiosensitivity of human HCC cell lines in a schedule - dependent manner . DB00398 selectively inhibited radiation - induced activation of vascular endothelial growth factor receptor - 2 ( P35968 ) and downstream extracellular signal - regulated kinase ( P29323 ) pathway , induced DNA damage and suppressed DNA repair capacity , decreased radiation - activated NF - κB and increased radiation - induced apoptosis . In xenograft experiments , combination treatment produced marked tumor growth delay in both concurrent and sequential schedules . These results suggest that sorafenib could potentiate irradiation effect in HCC , which warrants further investigation for its potential clinical applications .",
"Predictive factors in patients with advanced and metastatic squamous cell carcinoma of the head and neck : a study based on SWOG protocol S0420 . To evaluate the prognostic values of different protein expression in the progression of squamous cell carcinoma of the head and neck ( SCCHN ) patients , we conducted immunohistochemical ( IHC ) analysis in tissue samples of different patients enrolled on SWOG protocol S0420 . S0420 was a phase II trial to evaluate the efficacy and safety of single - agent sorafenib in chemotherapy - naïve patients with metastatic or recurrent SCCHN . The primary end point was response probability , i . e . , confirmed complete ( CR ) and partial response ( PR ) . DB00398 was administered orally at 400 mg twice daily on a continuous basis in 28 - day cycles to eligible patients . Responses were evaluated according to RECIST ( Response Evaluation Criteria in Solid Tumors ) criteria . IHC analysis was performed for various markers and data were analyzed statistically . IHC data were obtained from 19 patients enrolled on S0420 . There was a high frequency of cases with expression of the angiogenesis markers SMA , HIF - 1α , P04049 , P15692 and P15692 - R . None of the markers were significantly associated with response . Negative HER - 2 status was associated with longer progression - free survival ( PFS ) , P = 0 . 04 . Negative NRP - 1 status was associated with longer overall survival ( OS ) , P = 0 . 04 . There were no other significant associations . An almost universal overexpression of angiogenesis markers in the samples analyzed supports the evaluation of angiogenesis inhibition as a potential target for therapy . High levels of NRP - 1 and HER - 2 in SCCHN samples appear to be associated with decreased survival and earlier progression of disease , respectively , in SCCHN patients and may represent targets for therapy .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK41___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"Pharmacogenetic studies of response to risperidone and other newer atypical antipsychotics . ___MASK32___ and other newer atypical antipsychotics are becoming the mainstay for schizophrenia treatment . Recent studies suggest that the P28223 ( 5 - Q13049 ) gene ( P28223 ) T102C and G - 1438A polymorphisms may influence treatment response of risperidone or olanzapine for schizophrenia ' s negative symptoms ( e . g . , blunted affect and social withdrawal ) . In addition , the P50406 T267C polymorphism has been linked to risperidone response for positive symptoms ( delusions and hallucinations ) . The dopamine D2 receptor ( P14416 ) Ser311Cys polymorphism may also play a role in determining risperidone efficacy for positive , negative and cognitive symptoms , the P14416 Ins - A2 / Del - A1 diplotype may predict better risperidone response , and the P35462 Ser311Cys variant may affect general treatment response of several atypical agents . Although investigators have started to explore genetic effects on cognitions of schizophrenia patients receiving antipsychotics , future larger sized pharmacogenetic studies on both psychotic symptoms and cognitive functions are warranted .",
"Differential radiosensitisation by ZD1839 ( ___MASK5___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK5___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .",
"Distinct signalling pathways of murine histamine H1 - and H4 - receptors expressed at comparable levels in HEK293 cells . DB11320 ( HA ) is recognized by its target cells via four G - protein - coupled receptors , referred to as histamine H1 - receptor ( P35367 ) , P25021 , Q9Y5N1 , and Q9H3N8 . Both P35367 and Q9H3N8 exert pro - inflammatory functions . However , their signal transduction pathways have never been analyzed in a directly comparable manner side by side . Moreover , the analysis of pharmacological properties of the murine orthologs , representing the main targets of pre - clinical research , is very important . Therefore , we engineered recombinant HEK293 cells expressing either mouse ( m ) P35367 or mH4R at similar levels and analyzed HA - induced signalling in these cells . HA induced intracellular calcium mobilization via both mH1R and mH4R , with the mH1R being much more effective . Whereas DB02527 accumulation was potentiated via the mH1R , it was reduced via the mH4R . The regulation of both second messengers via the Q9H3N8 , but not the P35367 , was sensitive to pertussis toxin ( PTX ) . The mitogen - activated protein kinases ( MAPKs ) P29323 1 / 2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA - induced P18146 gene expression . The p38 MAPK was moderately activated via both receptors as well , but was functionally involved in HA - induced P18146 gene expression only in Q9H3N8 - expressing cells . Surprisingly , in this system p38 MAPK activity reduced the HA - induced gene expression . In summary , using this system which allows a direct comparison of mH1R - and mH4R - induced signalling , qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident .",
"___MASK17___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"DB00398 suppresses JNK - dependent apoptosis through inhibition of Q9NYL2 . DB00398 is U . S . Food and Drug Adminstration - approved for the treatment of renal cell carcinoma and hepatocellular carcinoma and has been combined with numerous other targeted therapies and chemotherapies in the treatment of many cancers . Unfortunately , as with other RAF inhibitors , patients treated with sorafenib have a 5 % to 10 % rate of developing cutaneous squamous cell carcinoma ( cSCC ) / keratoacanthomas . Paradoxical activation of extracellular signal - regulated kinase ( P29323 ) in P15056 wild - type cells has been implicated in RAF inhibitor - induced cSCC . Here , we report that sorafenib suppresses UV - induced apoptosis specifically by inhibiting c - jun - NH ( 2 )- kinase ( JNK ) activation through the off - target inhibition of leucine zipper and sterile alpha motif - containing kinase ( Q9NYL2 ) . Our results implicate suppression of JNK signaling , independent of the P29323 pathway , as an additional mechanism of adverse effects of sorafenib . This has broad implications for combination therapies using sorafenib with other modalities that induce apoptosis .",
"DB00398 functions to potently suppress P07949 tyrosine kinase activity by direct enzymatic inhibition and promoting P07949 lysosomal degradation independent of proteasomal targeting . Germ line missense mutations in the P07949 ( rearranged during transfection ) oncogene are the cause of multiple endocrine neoplasia , type 2 ( MEN2 ) , but at present surgery is the only treatment available for MEN2 patients . In this study , the ability of DB00398 ( BAY 43 - 9006 ) to act as a P07949 inhibitor was investigated . DB00398 inhibited the activity of purified recombinant kinase domain of wild type P07949 and P07949 ( V804M ) with IC ( 50 ) values of 5 . 9 and 7 . 9 nm , respectively . Interestingly , these values were 6 - 7 - fold lower than the IC ( 50 ) for the inhibition of B - RAF ( V600E ) . In cell - based assays , DB00398 inhibited the kinase activity and signaling of wild type and oncogenic P07949 in MEN2 tumor and established cell lines at a concentration between 15 and 150 nm . In contrast , inhibition of oncogenic B - RAF - or epidermal growth factor - induced P27361 / 2 phosphorylation required micromolar concentrations of DB00398 demonstrating the high specificity of this drug in targeting P07949 . Moreover , prolonged exposure to DB00398 resulted in inhibition of cell proliferation and P07949 protein degradation . Using lysosomal and proteasomal inhibitors , we demonstrate that DB00398 induces P07949 lysosomal degradation independent of proteasomal targeting . Furthermore , we provide a structural model of the DB00398 . P07949 complex in which DB00398 binds to and induces the DFG ( out ) conformation of the P07949 kinase domain . These results strengthen the argument that DB00398 may be effective in the treatment of MEN2 patients . In addition , because inhibition of P07949 is not impaired by mutation of the DB00161 ( 804 ) gatekeeper residue , MEN2 tumors may be less susceptible to acquired DB00398 resistance .",
"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .",
"DB00398 in patients with refractory or recurrent multiple myeloma . DB00398 is a small molecular inhibitor of several tyrosine protein kinases , including vascular endothelial growth factor receptor , platelet - derived growth factor receptor and rapidly accelerated fibrosarcoma kinases , targeting signal transduction and angiogenic pathways . It is approved for the treatment of advanced renal cell carcinoma and hepatocellular carcinoma . The objectives of this prospective phase II trial were to assess the activity and tolerability of sorafenib in patients with recurrent or refractory myeloma . In total , 11 patients were enrolled . Patients received 2 × 200 mg of sorafenib orally twice daily until completing 13 full cycles or disease progression . Of the side effects , 8 . 8 % grade 3 and 1 . 1 % grade 4 occurred . DB00398 treatment was effective in two patients who achieved a partial response and a continuous stable disease with duration of 24 . 4 months and 6 . 9 month , respectively . Further clinical investigations are recommended to investigate sorafenib single agent activity in myeloma subgroups with ras -/ P15056 -/ vascular endothelial growth factor receptor pathway activation and combination therapy approaches .",
"DB00398 : complexities of Raf - dependent and Raf - independent signaling are now unveiled . Hepatocellular carcinoma ( HCC ) is the most common primary cancer worldwide . The only current drug available for clinical treatment of HCC is sorafenib , which inhibits multiple signaling kinases including Raf family members , platelet - derived growth factor receptor , vascular endothelial growth factor receptors 1 and 2 , c - Kit , and P36888 . Many studies have revealed that the mechanism underlying the antitumor effect of sorafenib is complex . Because sorafenib inhibits C - Raf more potently than B - Raf , the therapeutic efficacy of sorafenib is strongly influenced by the relative expression and activity of B - Raf and C - Raf and the complex interactions between these factors . Moreover , Rafindependent signaling mechanisms have recently emerged as important pathways of sorafenib - induced cell death . Basic research studies have suggested that using sorafenib as part of a combination therapy may improve its effect , although this has yet to be confirmed by clinical evidence . Further studies of the functional mechanism of sorafenib are required to advance the development of targeted therapy for HCC . To aid future work on sorafenib , we here review the current literature pertaining to sorafenib signaling and its clinical efficacy in both monotherapy and combination therapy .",
"DB00398 in patients with metastatic gastrointestinal stromal tumors who failed two or more prior tyrosine kinase inhibitors : a phase II study of Korean gastrointestinal stromal tumors study group . PURPOSE : To evaluated the efficacy and safety of sorafenib in patients with advanced gastrointestinal stromal tumors ( GIST ) who failed to previous standard treatments . EXPERIMENTAL DESIGN : Thirty - one patients with measurable metastatic GIST who failed both imatinib and sunitinib were accrued . DB00398 was administered orally at 400 mg twice daily until disease progression or development of intolerance . The primary endpoint was disease control rate ( response + stable disease , DCR ) at 24 weeks . RESULTS : DB00398 was well tolerated , with hand - foot skin reaction , fatigue , hypertension , and abdominal pain being the most frequent adverse events . The relative dose intensity of sorafenib during the first 6 months was > 80 % . Four patients achieved partial response ( response rate 13 % , 95 % CI 1 - 25 % ) , and 16 ( 52 % ) had stable disease . DCR at 24 weeks was measured as 36 % ( 95 % CI 19 - 52 % ) . Median progression - free and overall survivals were 4 . 9 and 9 . 7 months , respectively . Progression - free survival of patients with prior use of nilotinib ( P = . 0085 ) and with primary genotypes other than P10721 exon 11 mutation ( P = . 0341 ) was significantly shorter than that of patients without . CONCLUSIONS : DB00398 showed antitumor activity in this population of imatinib and sunitinib pretreated GIST . With sorafenib , about one third of patients can maintain disease control for more than 24 weeks .",
"Induction of heparanase - 1 expression by mutant B - Raf kinase : role of GA binding protein in heparanase - 1 promoter activation . Q9Y251 ( HPR1 ) , an endoglycosidase that specifically degrades heparan sulfate ( HS ) proteoglycans , is overexpressed in a variety of malignancies . Our present study sought to determine whether oncogene P15056 and DB01367 mutations lead to increased HPR1 expression . Reverse transcription - polymerase chain reaction analysis revealed that HPR1 gene expression was increased in HEK293 cells transiently transfected with a mutant P15056 or DB01367 gene . Flow cytometric analysis revealed that B - Raf activation led to loss of the cell surface HS , which could be blocked by two HPR1 inhibitors : heparin and DB05808 . Cotransfection of a P15056 or DB01367 mutant gene with HPR1 promoter - driven luciferase reporters increased luciferase reporter gene expression in HEK293 cells . Knockdown of P15056 expression in a P15056 - mutated Q8NFU3 - 10 tumor cell line led to the suppression of HPR1 gene expression , subsequently leading to increased cell surface HS levels . Truncational and mutational analyses of the HPR1 promoter revealed that the Ets - relevant elements in the HPR1 promoter were critical for P15056 activation - induced HPR1 expression . Luciferase reporter gene expression driven by a four - copy GA binding protein ( GABP ) binding site was significantly lower in P15056 siRNA - transfected Q8NFU3 - 10 cells than in the control siRNA - transfected cells . We further showed that P15056 knockdown led to suppression of the expression of the GABPβ , an Ets family transcription factor involved in regulating HPR1 promoter activity . Taken together , our study suggests that B - Raf kinase activation plays an important role in regulating HPR1 expression . Increased HPR1 expression may contribute to the aggressive behavior of P15056 - mutated cancer .",
"Functional blockade of platelet - derived growth factor receptor - beta but not of receptor - alpha prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E - deficient mice . BACKGROUND : The vascular smooth muscle cell ( VSMC ) is the central cell component involved in the fibroproliferative response in atherogenesis . As the lesion advances , VSMCs migrate from the media into the subendothelial space , thereby forming fibrous plaque lesions . Platelet - derived growth factor ( PDGF ) has been known to be a potent chemoattractant and mitogen for SMCs , but the pathophysiological role of the 2 PDGF receptors , receptor - alpha ( P16234 ) and receptor - beta ( P09619 ) in atherogenesis is poorly understood . To clarify this problem , we prepared antagonistic rat monoclonal antibodies , APA5 and APB5 , against murine P16234 and P09619 , respectively . METHODS AND RESULTS : P02649 - deficient mice were fed a high - fat diet containing 0 . 3 % cholesterol from 6 weeks of age and subjected to injection with 1 mg / d IP of either antibody from 12 to 18 weeks every other day . In the mice injected with APB5 , the aortic atherosclerotic lesion size and the number of intimal VSMCs were reduced by 67 % and 80 % , respectively , compared with the control mice injected with irrelevant rat IgG . In contrast , the mice that received APA5 showed only minimal reduction of lesion size , and a large number of VSMCs were observed in the intima . In the intima of advanced lesions , APB5 immunolabeled VSMCs , whereas APA5 could detect VSMCs mainly in the media . CONCLUSIONS : These results indicate that P09619 plays a significant role in formation of fibrous atherosclerotic lesions and that regulation of the signal transduction through P09619 could affect atherogenesis in mice .",
"Mutational profiling of kinases in glioblastoma . BACKGROUND : Glioblastoma is a highly malignant brain tumor for which no cure is available . To identify new therapeutic targets , we performed a mutation analysis of kinase genes in glioblastoma . METHODS : Database mining and a literature search identified 76 kinases that have been found to be mutated at least twice in multiple cancer types before . Among those we selected 34 kinase genes for mutation analysis . We also included O75874 , P48735 , P60484 , P04637 and P01111 , genes that are known to be mutated at considerable frequencies in glioblastoma . In total , 174 exons of 39 genes in 113 glioblastoma samples from 109 patients and 16 high - grade glioma ( HGG ) cell lines were sequenced . RESULTS : Our mutation analysis led to the identification of 148 non - synonymous somatic mutations , of which 25 have not been reported before in glioblastoma . Somatic mutations were found in P04637 , P60484 , O75874 , P42336 , P00533 , P15056 , P29320 , P01111 , P37173 , P36888 and Q96S38 . Mapping the mutated genes into known signaling pathways revealed that the large majority of them plays a central role in the PI3K - AKT pathway . CONCLUSIONS : The knowledge that at least 50 % of glioblastoma tumors display mutational activation of the PI3K - AKT pathway should offer new opportunities for the rational development of therapeutic approaches for glioblastomas . However , due to the development of resistance mechanisms , kinase inhibition studies targeting the PI3K - AKT pathway for relapsing glioblastoma have mostly failed thus far . Other therapies should be investigated , targeting early events in gliomagenesis that involve both kinases and non - kinases .",
"P14416 occupancy by risperidone : implications for the timing and magnitude of clinical response . The objective of the study is to investigate whether dopamine D2 receptor occupancy by risperidone and plasma levels over time can account for therapeutic efficacy and the latency period to response . Thirty - eight examinations with ( 123 ) I - IBZM single photon emission computed tomography were performed on 22 patients with schizophrenia , at diagnosis , 48 h after starting risperidone treatment and at a stable dose . ___MASK32___ plasma levels were determined and psychopathologic evaluations ( Brief Psychiatric Rating Scale , Positive and Negative Syndrome Scale ) were carried out . No differences in the striatal / occipital ( S / O ) ratio or plasma levels were found between examinations at the 48 - h time point and when a stable dose level had been established , so these parameters could not account for the latency period required for clinical response . D2 receptor occupancy at 48 h correlated positively with clinical improvement after 2 weeks of treatment . Therefore , if these results are confirmed , D2 receptor occupancy at the beginning of treatment with risperidone may be a predictor of subsequent clinical response .",
"Tonic , but not phasic corticosterone , constrains stress activatedextracellular - regulated - kinase 1 / 2 immunoreactivity within the hypothalamic paraventricular nucleus . The negative - feedback actions of corticosterone ( O00230 ) depend on both phasic and tonic O00230 secretion patterns to regulate hypothalamic - pituitary - adrenal ( Q9Y251 ) axis activity . How these two different O00230 secretion pattens influence specific intracellular signal transduction pathway activity within the cellular elements of the Q9Y251 axis has not been determined . For example , it is unknown whether O00230 has suppressive actions over signal transduction events within medial parvocellular paraventricular nucleus ( PVN ) corticotrophin - releasing hormone ( P06850 ) neurones , nor whether these suppressive actions are responsible for alterations in PVN transcriptional processes and neurohormone secretion associated with stress . The extracellular - regulated kinase ( P29323 ) is a stress activated intracellular signalling molecule that is potentially subject to glucocorticoid negative - feedback regulation . We tested the ability of O00230 to modulate levels of the active ( phosphorylated ) form of P29323 ( pERK1 / 2 ) in the PVN of rats . Acute psychological stress ( restraint ) produced a rapid increase in the number of PVN pERK1 / 2 immunopositive cells within P06850 neurones . Absence of tonic O00230 via adrenalectomy ( P10109 ) produced no change in basal pERK1 / 2 cell counts but augmented the increased pERK1 / 2 cell counts elicited by acute restraint . Treatment of P10109 rats with O00230 in the drinking water normalised this enhanced pERK1 / 2 response to stress . By contrast , treatment of P10109 rats with a phasic increase in O00230 1 h before restraint had no effect on pERK1 / 2 cell counts , despite substantially suppressing stress - induced PVN crh gene expression and adrenonocorticotrophic hormone secretion . This tonic O00230 inhibition of stress - induced activation of P27361 / 2 may involve both alteration of the activity of stress - dependent neural inputs to PVN P06850 neurones and alteration within those neurones of stress - dependent intracellular signalling mechanisms associated with P29323 activation .",
"DB00398 is tolerable and improves clinical outcomes in patients with P36888 - ITD acute myeloid leukemia prior to stem cell transplant and after relapse post - transplant .",
"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .",
"Colocalization of the P15692 - R2 and the common P08700 / GM - P04141 receptor beta chain to lipid rafts leads to enhanced p38 activation . Previous studies suggested an important role for vascular endothelial growth factor ( P15692 ) and its receptors in postnatal haemopoiesis . However , it is unclear how P15692 receptor ( VEGFR ) signalling could interact with that issued from the activation of haematopoietic growth factor receptors . To elucidate this point we explored P15692 - R2 and granulocyte - macrophage colony - stimulating factor receptor ( GM - CSFR ) membrane localization and cell signalling in TF1 - P35968 cells ( TF1 leukaemic cells that overexpress P15692 - R2 / P35968 ) . Activation of either GM - CSFR or P15692 - R2 was shown to determine the migration of both receptor elements ( P15692 - R2 and the common beta - chain of the GM - CSFR ) to lipid rafts . The study of receptor phosphorylation showed that GM - P04141 induced the phosphorylation of its own receptor and the transphosphorylation of P15692 - R2 ; on the other hand , P15692 triggered the phosphorylation of its receptor and transphosphorylated the beta - chain of the GM - CSFR . Co - stimulation of TF1 - P35968 cells with both GM - P04141 and P15692 resulted in massive migration of both the common GM - CSFR beta - chain and P15692 - R2 to lipid rafts and sustained p38 mitogen - activated protein kinase activation . Disruption of lipid rafts inhibited the capacity of both GM - P04141 and P15692 to activate p38 . Experiments with specific p38 inhibitors showed that p38 activation was required to sustain the P15692 - and GM - P04141 - dependent proliferation of TF1 - P35968 and the survival of primary acute myeloid leukaemia blasts .",
"Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral / derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non - human primates . Cross species polymerase chain reaction ( CS - PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB @ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR - RFLP ) or by direct sequencing . At seventeen of the eighteen PCR - RFLPs , non - human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR - RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3 ' untranslated region ( UTR ) of the P14416 gene illustrate this point .",
"P01344 Producing Hepatocellular Carcinoma Treated with DB00398 : Metabolic Complications and a Foresight to Molecular Targeting Therapy to the IGF Signal . Hypoglycemia is a rare paraneoplastic manifestation of patients with neoplasms . Hypoglycemia can be induced by several causes , including an aberrant increase of hypoglycemic agents and adrenal insufficiency . DB00398 is the first agent to demonstrate a survival benefit in the treatment of advanced hepatocellular carcinoma ( HCC ) . This small molecule inhibits serine / threonine kinase RAF in tumor cells and tyrosine kinases VEGFR / P09619 in tumor vasculature and decreases tumor growth and angiogenesis . In this paper , we report a case of HCC who was treated with sorafenib and showed severe hypoglycemia . This hypoglycemia might be induced by two causes , both adrenal insufficiency as an adverse effect of sorafenib and activation of the insulin - like growth factor ( IGF ) signal by excessive secretion of incompletely processed precursors of P01344 . Although the IGF signal is suggested to be involved in aberrant growth of HCC in some cases , there is no other report showing the influence of sorafenib on HCC with active IGF signal . Unfortunately , the effect of sorafenib was limited in the present case . However , emerging drugs that directly inhibit the IGF signal can be expected to be highly effective in the treatment of HCC with hypoglycemia .",
"P36888 expression and function on microglia in multiple sclerosis . Inflammatory cell infiltration and resident microglial activation within the central nervous system ( CNS ) are pathological events in multiple sclerosis ( MS ) and experimental autoimmune encephalomyelitis ( EAE ) . While MS therapies target the peripheral immune system , no treatment is currently known to also modulate microglia . P07333 - like tyrosine - 3 ( P36888 ) is expressed on hematopoietic and dendritic cells . We reported that P36888 inhibition ameliorates early actively induced EAE by predominantly modulating dendritic cell function as compared to microglia . We demonstrate in this report that P36888 is expressed in perivascular cuffs , brain parenchyma and in non - lesioned gray and white matter within MS brain but not in these regions within control brain . Furthermore , we demonstrate that P36888 is expressed on two populations of cells within MS brain ; one which expresses the dendritic cell marker Q9NNX6 , and the other which does not , suggesting that P36888 within MS brain is expressed on infiltrating dendritic cells and a non - dendritic cell such as microglia . Additionally , we report that P36888 inhibition in murine microglia blocks , in a dose - dependent manner , IFN - γ - induced expression of MHC class II and P42081 , and LPS - induced secretion of P05231 . These data suggest that P36888 is involved in microglial cells ' capacity to respond to environmental cues to function as antigen presenting cells and mediate CNS inflammation . Furthermore these data suggest that P36888 may be a therapeutic target on microglia to mitigate CNS inflammation .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK69___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK68___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .",
"DB00398 inhibits many kinase mutations associated with drug - resistant gastrointestinal stromal tumors . DB00398 has substantial clinical activity as third - or fourth - line treatment of imatinib - and sunitinib - resistant gastrointestinal stromal tumors ( GIST ) . Because sorafenib targets both angiogenesis - related kinases ( VEGFR ) and the pathogenetic kinases found in GIST ( P10721 or P16234 ) , the molecular basis for sorafenib efficacy in this setting remains unknown . We sought to determine the spectrum of activity of sorafenib against different mutant kinases associated with drug - sensitive and drug - resistant GIST . We compared the activity of imatinib and sorafenib against transiently expressed mutant forms of P10721 and P16234 , including various secondary mutations that have been identified in imatinib - resistant or sunitinib - resistant GISTs . We also examined these drugs against four GIST cell lines , three of which are imatinib resistant . In our in vitro studies , we determined that sorafenib inhibited imatinib - resistant mutations in exons encoding the DB00171 / drug - binding pocket and in exons encoding the activation loop , with the exception of substitutions at P10721 codon D816 and P16234 codon 842 . Notably our data indicate that sorafenib is more effective than imatinib or sunitinib for inhibiting the kinase activity of drug - resistant P10721 mutants ( as assessed by biochemical IC ( 50 ) ) . We hypothesize that a major determinant of the efficacy of sorafenib for treatment of advanced GIST is the activity of this agent against P10721 or P16234 - mutant kinases . These results have implications for the further development of treatments for drug - resistant GIST .",
"Multiple pathways of apolipoprotein E signaling in primary neurons . P02649 is a genetic risk factor for Alzheimer ' s disease , and the apoE protein is associated with beta - amyloid deposits in Alzheimer ' s disease brain . We examined signaling pathways stimulated by apoE in primary neurons in culture . ApoE and an apoE - derived peptide activated several intracellular kinases , including prominently extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . P27361 / 2 activation by apoE was blocked by an inhibitor of the low - density lipoprotein receptor family , the specific DB01221 glutamate receptor antagonist MK 801 and other calcium channel blockers . Activation of apoE receptors also induced tyrosine phosphorylation of Dab1 , an adaptor protein of apoE receptors , but experiments in Dab1 knockout neurons demonstrated that Dab1 was not necessary for P29323 activation . In contrast , apoE treatment of primary neurons decreased activation of c - Jun N - terminal kinase , a kinase that interacts with another apoE receptor adaptor protein , c - Jun N - terminal kinase - interacting protein . This change also depended on interactions with the low - density lipoprotein receptor family but was independent of calcium channels . c - Jun N - terminal kinase deactivation by apoE was blocked by gamma - secretase inhibitors and pertussis toxin . These results demonstrate that apoE affects several signaling cascades in neurons : increased disabled phosphorylation , activation of the P27361 / 2 pathway ( dependent on calcium influx via the DB01221 receptor ) and inhibition of the P45983 / 2 pathway ( dependent on gamma - secretase and G proteins ) .",
"Gemcitabine plus sorafenib in patients with advanced pancreatic cancer : a phase II trial of the University of Chicago Phase II Consortium . BACKGROUND : DB00398 , an inhibitor of B - raf , P35968 , and P09619 - β , has activity against pancreatic cancer in preclinical models . In a phase I trial of gemcitabine plus sorafenib , 57 % of pancreatic cancer patients achieved stable disease . PATIENTS AND METHODS : We conducted a multi - center phase II trial of sorafenib plus gemcitabine in chemo - naïve patients with histologically - confirmed , advanced pancreatic cancer . Patients received sorafenib 400 mg twice daily and gemcitabine 1 , 000 mg / m ( 2 ) on days 1 , 8 and 15 of a 28 day cycle . RESULTS : Seventeen patients enrolled at 4 centers ; 13 were evaluable for response . There were no objective responses ; 18 % had stable disease . Median overall survival was 4 . 0 months ( 95 % CI : 3 . 4 , 5 . 9 ) ; median progression - free survival was 3 . 2 months ( 95 % CI : 1 . 6 , 3 . 6 ) . Grade 3 / 4 toxicities included thrombosis in 18 % of patients , dehydration or hand - foot syndrome in 12 % , and hypertension or gastrointestinal bleeding in 6 % . CONCLUSION : Gemcitabine plus sorafenib is inactive in advanced pancreatic cancer .",
"DB00398 and thyroid cancer . DB00398 ( Nexavar ) is a multikinase inhibitor , which has demonstrated both anti - proliferative and anti - angiogenic properties in vitro and in vivo , inhibiting the activity of targets present in the tumor cell [ c - RAF ( proto - oncogene serine / threonine - protein kinase ) , P15056 , ( V600E ) P15056 , c - P10721 , and P07333 - like tyrosine kinase 3 ] and in tumor vessels ( c - RAF , vascular endothelial growth factor receptor - 2 , vascular endothelial growth factor receptor - 3 , and platelet - derived growth factor receptor β ) . For several years , sorafenib has been approved for the treatment of hepatocellular carcinoma and advanced renal cell carcinoma . After previous studies showing that sorafenib was able to inhibit oncogenic P07949 mutants , ( V600E ) P15056 , and angiogenesis and growth of orthotopic anaplastic thyroid cancer xenografts in nude mice , some clinical trials demonstrated the effectiveness of sorafenib in advanced thyroid cancer . Currently , the evaluation of the clinical safety and efficacy of sorafenib for the treatment of advanced thyroid cancer is ongoing . This article reviews the anti - neoplastic effect of sorafenib in thyroid cancer . Several completed ( or ongoing ) studies have evaluated the long - term efficacy and tolerability of sorafenib in patients with papillary and medullary aggressive thyroid cancer . The results suggest that sorafenib is a promising therapeutic option in patients with advanced thyroid cancer that is not responsive to traditional therapeutic strategies .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"[ New therapies targeting the genetic mutations responsible for different types of melanoma ] . A number of molecular alterations have been described for melanoma . Melanomas with P15056 mutations tend to be located in areas of intermittent sun exposure , whereas melanomas with P10721 mutations mostly appear in acral areas , the mucosas , and areas of chronic sun exposure . DB00398 , a P15056 inhibitor , has a cytostatic effect on most melanomas with mutations affecting the mitogen - activated protein kinase ( MAPK ) pathway , and is also capable of triggering apoptosis in a small subgroup of these melanomas . By inhibiting P10721 , imatinib has a cytostatic and cytotoxic effect on melanomas with P10721 mutations , and probably has the same effect on another subgroup of melanomas with other as yet imperfectly understood P10721 mutations . For therapy to be effective , agents should be selected according to the pathways associated with the genetic mutations present in the melanoma .",
"A novel tissue model for angiogenesis : evaluation of inhibitors or promoters in tissue level . A novel tissue model for angiogenesis ( TMA ) is established for effective evaluation of angiogenesis inhibitors or promoters in vitro . Lung tissues were cultured in fibrinogen \" sandwich \" structure which resembled the formation of neovessels in vivo . The cells and capillary - like structures grew from the lung tissues were identified as endothelial cells and neovessels . Both immunohistochemisty and western blot results indicated that autocrine P15692 bound to the P35968 and induced P35968 autophosphorylation that could induce the proliferation of endothelial cells and their migration as well as the formation of microvessels on the lung tissue edge . With addition of the TMA , the murine P15692 and cultured medium produced by A549 tumor cells apparently promoted the increase of neovessels . DB00398 as a tumor angiogenesis inhibitor and Tongxinluo as an angiogenesis promoter were both used to evaluate the TMA performance and they exhibited a good effect on neovessels in the TMA . The model established imitated angiogenesis in vivo and could well serve as an effective method in evaluating the angiogenesis inhibitors or promoters , and could also be practical for screening small molecules that affect blood vessel formation ."
] |
[
"___MASK12___",
"___MASK17___",
"___MASK32___",
"___MASK41___",
"___MASK59___",
"___MASK5___",
"___MASK68___",
"___MASK69___",
"___MASK95___"
] |
___MASK68___
|
MH_train_420
|
interacts_with DB00688?
|
[
"[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK88___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .",
"Immunoregulatory and anti - tumor effects of polysaccharopeptide and Astragalus polysaccharides on tumor - bearing mice . The aim of this study was to determine whether polysaccharopeptide ( PSP ) and Astragalus polysaccharides ( APS ) can be combined together as a new complex prescription ( PSP + APS ) for aiding adriamycin ( AMD ) chemotherapy . Ehrlich ' s ascites carcinoma ( EAC ) was used to establish a solid tumor model in Kunming mice . Immunocytochemical and immunohistochemical analysis were employed to detect the immunoregulatory and anti - tumor effects of EAC bearing mice after 30 days of administration with PSP and APS . PSP and PSP + APS could significantly increase the percentage of CD3 (+) and P01730 (+) T - lymphocytes , the ratio of P01730 (+)/ CD8 (+) , and the expression of P60568 / IL - 2R in spleen and Bax in tumor tissue , but led to a diminution of Bcl - 2 and P11802 in tumor tissue compared with those of control group . In addition , PSP + APS could restore the immunological effects against AMD - induced immunosuppression , such as the subset of leukomonocyte , the expression of P60568 / IL - 2R in the spleen , and the thymus index . These findings suggest that the immunomodulatory and anti - cancer effects of this new formula ( PSP + APS ) were better than those of PSP alone , and also could resist immunosuppression induced by AMD .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK17___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"Engineering human T cells for resistance to methotrexate and mycophenolate mofetil as an in vivo cell selection strategy . Gene transfer and drug selection systems that enforce ongoing transgene expression in vitro and in vivo which are compatible with human pharmaceutical drugs are currently underdeveloped . Here , we report on the utility of incorporating human enzyme muteins that confer resistance to the lymphotoxic / immunosuppressive drugs methotrexate ( MTX ) and mycophenolate mofetil ( DB00688 ) in a multicistronic lentiviral vector for in vivo T lymphocyte selection . We found that co - expression of human dihydrofolate reductase ( P00374 ( FS ) ; L22F , F31S ) and inosine monophosphate dehydrogenase II ( P12268 ( IY ) ; T333I , S351Y ) conferred T cell resistance to the cytocidal and anti - proliferative effects of these drugs at concentrations that can be achieved clinically ( up to 0 . 1 µM MTX and 1 . 0 µM DB00603 ) . Furthermore , using a immunodeficient mouse model that supports the engraftment of central memory derived human T cells , in vivo selection studies demonstrate that huEGFRt (+) P00374 ( FS +) P12268 ( IY +) T cells could be enriched following adoptive transfer either by systemic administration of MTX alone ( 4 . 4 - fold ) , DB00688 alone ( 2 . 9 - fold ) , or combined MTX and DB00688 ( 4 . 9 - fold ) . These findings demonstrate the utility of both P00374 ( FS )/ MTX and P12268 ( IY )/ DB00688 for in vivo selection of lentivirally transduced human T cells . Vectors incorporating these muteins in combination with other therapeutic transgenes may facilitate the selective engraftment of therapeutically active cells in recipients .",
"___MASK38___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK38___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK38___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"Expression of P20839 is regulated in response to mycophenolate concentration . DB04335 5 '- monophosphate dehydrogenase ( IMPDH ) catalyzes de novo guanine nucleotide synthesis . DB01024 ( DB00603 ) exerts immunosuppressive effects by inhibiting IMPDH . The aim of this study was to investigate gene expressions of two IMPDH isoforms , during in vivo exposure to DB00603 . Healthy volunteers ( n = 5 ) were given single doses of 100 , 250 , 500 and 1000 mg mycophenolate mofetil ( DB00688 ) . Blood was sampled pre - dose and at 1 , 2 , 4 , 6 , 8 , 12 , and 24 h post - dose . The expressions of P20839 and 2 were quantified in P01730 + cells and whole blood by real - time reverse transcription - PCR . Following DB00688 doses of 500 mg , the expression of P20839 and 2 in P01730 + cells was reduced 39 % ( P = 0 . 043 ) and 10 % ( P = 0 . 043 ) , respectively . Smaller reductions ( ns ) were observed after 1000 mg DB00688 . Similar trends were demonstrated for whole blood . The largest reductions of P20839 occurred at DB00603 AUC ( 0 - 12 h ) of 20 mg h / L . Below this , increasing DB00603 exposure correlated with larger reductions of P20839 expression ( P01730 + cells : r =- 0 . 82 , P < 0 . 001 , and whole blood : r =- 0 . 50 , P = 0 . 04 , n = 17 ) , while higher DB00603 exposure seemed to be associated with smaller reductions of expression ( P01730 + cells : r = 0 . 42 , ns , and whole blood : r = 0 . 77 , P = 0 . 039 , n = 8 ) . The concentration - dependent modulation of P20839 and 2 expressions by DB00603 might impact IMPDH activity . Knowledge of the regulation of the two IMPDH isoenzymes in vivo by DB00603 is of importance considering pharmacodynamic monitoring and optimization of DB00603 treatment .",
"hsBAFF enhances activity of NK cells by regulation of P01730 (+) T lymphocyte function . B cell activating factor belonging to the P01375 family ( Q9Y275 , also called Q9Y275 , Q9Y275 , THANK , or zTNF4 ) is an important survival factor for B cells , and is able to regulate T cell activation . Recently , we have demonstrated that human soluble Q9Y275 ( hsBAFF ) potently elevates NK cell activity of murine splenic cells in vivo . In this study , we further show that hsBAFF markedly enhanced NK cell activity of in vitro mouse splenic cells . Purified NK cell activities treated with hsBAFF in the presence of P60568 or P01579 , but not with hsBAFF alone were obviously elevated . hsBAFF strongly increased the activity of NK cells co - incubated with mixed T and B lymphocytes or T lymphocytes alone , but not with B lymphocytes alone . We also found that culture supernatants , from mixed T and B lymphocytes or T lymphocytes alone , but not from B lymphocytes alone post - hsBAFF treatment , effectively increased NK cell activity , and noticed that P60568 and P01579 levels significantly increased in the culture supernatants of hsBAFF - treated T lymphocytes . Of importance , we pinpointed that hsBAFF elicited robust population of P01730 (+) T lymphocytes in vitro , and further demonstrated that hsBAFF induced significantly high P60568 and P01579 secretion of P01730 (+) T lymphocytes . These findings indicate that hsBAFF results in the elevation of NK cell activity by regulation of P01730 (+) T lymphocytes contributing to P60568 and P01579 generation .",
"Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .",
"Increased levels of Candida albicans mannan - specific T - cell - derived antigen binding molecules in patients with invasive candidiasis . In addition to cytokines , P01730 + T cells have been found to secrete soluble , T - cell - derived antigen binding molecules ( TABMs ) . These antigen - specific immunoproteins are thought to have immunoregulatory properties in the suppression of cell - mediated immunity ( CMI ) because they often associate with interleukin - 10 ( P22301 ) and transforming growth factor beta . Decreased CMI causes susceptibility to infections caused by organisms which are normally nonpathogenic . In this situation , e . g . , Candida albicans saprophytism may develop into invasive candidiasis . The difficult diagnosis of invasive candidiasis is based on the findings obtained from blood cultures and with tissue biopsy specimens , with some additional diagnostic value gained by the detection of Candida albicans mannan antigenemia and antimannan antibodies . In the present study , Candida albicans mannan - specific TABM ( P62158 - TABM ) levels in the sera of patients with invasive candidiasis ( n = 11 ) , Candida colonization ( n = 11 ) and noncolonization ( n = 10 ) , recurrent vulvovaginal candidiasis ( n = 30 ) , and atopic eczema dermatitis syndrome ( n = 59 ) and healthy controls ( n = 30 ) were analyzed . For 14 participants , the effect of mannan stimulation on TABM production and gamma interferon ( P01579 ) and P05112 mRNA expression by peripheral blood lymphocytes was also studied . It was demonstrated that P62158 - TABM production was the highest in patients with invasive candidiasis and that P62158 - TABM levels could distinguish Candida - colonized patients from noncolonized patients . In addition , the P62158 - TABM level was directly related to mRNA expression for P05112 but not P01579 . These results reinforce the view that TABMs are associated with decreased CMI , immunoregulation , and the T - helper cell 2 - type immune response .",
"Rapid increase in resistance of Plasmodium falciparum to chloroquine - Fansidar in Uganda and the potential of amodiaquine - Fansidar as a better alternative . Combinations of chloroquine ( CQ ) and sulfadoxine - pyrimethamine ( SP ) [ CQSP ] as the first line agents in Uganda have replaced CQ monotherapy . The idea of the combination is to delay the development of malaria resistance to either drug when used alone . We compared the clinical , parasitological and molecular findings of two studies with treatment arms of CQSP , amodiaquine ( AQ ) plus SP ( AQSP ) both done in 2003 with a study done 1 year earlier ( 2002 ) using SP alone . There was a notable decrease in adequate clinical response ( P10323 ) by day 14 from 92 . 7 % with SP to 80 % with the combination CQSP , a year later . AQSP combination was found to have the best effect ( 94 . 3 % P10323 ) . There were no early treatment failures in the AQSP group . However , treatment failures were recorded at 20 % on day 14 and 43 % on day 28 for CQSP treatment and 5 . 7 % by day 14 and 28 . 8 % by day 28 in the AQSP group . The number of mutations that are associated with SP resistance increased from 2002 to 2003 at all loci monitored , from 83 . 8 to 100 % at codon 108 , 58 . 7 to 76 % at codon 59 in the P00374 gene , and from 58 . 8 to 86 % at codon 437 and 33 to 43 % at codon 540 in the P49366 gene . We conclude that there has been a rapid development of resistance since the introduction of the new policy guidelines . AQSP was found to be a superior drug combination compared to CQSP and could be used as a low cost alternative at the moment .",
"T cells targeting a neuronal paraneoplastic antigen mediate tumor rejection and trigger CNS autoimmunity with humoral activation . Paraneoplastic neurologic diseases ( P01160 ) involving immune responses directed toward intracellular antigens are poorly understood . Here , we examine immunity to the P01160 antigen Nova2 , which is expressed exclusively in central nervous system ( CNS ) neurons . We hypothesized that ectopic expression of neuronal antigen in the periphery could incite P01160 . In our C57BL / 6 mouse model , CNS antigen expression limits antigen - specific P01730 + and CD8 + T - cell expansion . Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells . CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo . Despite mediating cancer rejection , adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting . Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity . This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled . Since humoral immunity was not required for tumor rejection , B - cell targeting therapy , such as rituximab , may be a rational treatment option for P01160 that does not hamper tumor immunity .",
"Modulation of leukocyte infiltration and phenotype in microporous tissue engineering scaffolds via vector induced P22301 expression . Biomaterial scaffolds are central to many tissue engineering strategies as they create a space for tissue growth and provide a support for cell adhesion and migration . However , biomaterial implantation results in unavoidable injury resulting in an inflammatory response , which can impair integration with the host and tissue regeneration . Toward the goal of reducing inflammation , we investigated the hypothesis that a lentiviral gene therapy - based approach to localized and sustained P22301 expression at a scaffold could modulate the number , relative proportions , and cytokine production of infiltrating leukocyte populations . Flow cytometry was used to quantify infiltration of six leukocyte populations for 21 days following implantation of P00747 scaffolds into intraperitoneal fat . Leukocytes with innate immune functions ( i . e . , macrophages , dendritic cells , neutrophils ) were most prevalent at early time points , while T lymphocytes became prevalent by day 14 . Reporter gene delivery indicated that transgene expression persisted at the scaffold for up to 28 days and macrophages were the most common leukocyte transduced , while transduced dendritic cells expressed the greatest levels of transgene . P22301 delivery decreased leukocyte infiltration by 50 % relative to controls , increased macrophage P22301 expression , and decreased macrophage , dendritic cell , and P01730 T cell IFN - γ expression . Thus , P22301 gene delivery significantly decreased inflammation following scaffold implant into the intraperitoneal fat , in part by modulating cytokine expression of infiltrating leukocytes .",
"Expression Enhancement in ___MASK84___ Therapeutic Monoclonal Antibody Production using Genomic Amplification with DB00563 . BACKGROUND : ___MASK84___ ( Herceptin ) is a humanized monoclonal antibody ( mAb ) which is used for specific treatment of metastatic breast cancer in patients with overexpression of P04626 / neu receptor . In this study , we have attempted to develop a biosimilar version of trastuzumab mAb . METHODS : According to in silico studies , the heavy and light chains of trastuzumab mAb were designed and constructed . The recombinant constructs were co - transfected in CHO DG44 cell line . Stable transformants were selected on a semi solid medium . Genomic amplification with methotrexate was achieved for heavy chain gene amplification . Biological activity of produced antibody in comparison with Herceptin was tested by flow cytometry method . RESULTS : Three folds of amplification were obtained after seven rounds of methotrexate treatments . The results indicated the equal expression level of heavy and light chains . The yield of purified mAb was between 50 to 60 mg / l / day . According to the results , the produced mAb had similar affinity to P04626 (+) tumor cells to that of Herceptin . CONCLUSION : High - level recombinant protein expression can be achieved by amplification of the recombinant gene with a selectable marker , such as Dihydrofolate Reductase ( P00374 ) . It is usually accepted that P00374 gene can be amplified in P00374 (－) CHO cells , which consequently leads to amplification of the co - linked target gene , and finally amplification of recombinant protein . In this research , with the aim of producing a biosimilar version of herceptin , the effect of genomic amplification was investigated on the increasing the gene copy number using quantitative real - time PCR .",
"Immunologic effects of an orally available BRAFV600E inhibitor in P15056 wild - type murine models . ___MASK3___ is an orally available small molecule that targets constitutively activated BRAFV600E , an integral part of the MAPK pathway involved in melanomagenesis . We examined the effects of vemurafenib on cytokine production and antitumor response in a P15056 wild - type ( WT ) non - tumor - bearing murine model and a P15056 WT murine insulinoma system to determine its effect on immune function during immunotherapy . We demonstrate no significant effect from vemurafenib on P01730 + and CD8 + T - cell cytokine production or on a T - cell - mediated antitumor response . Our data demonstrate that vemurafenib does not significantly affect P15056 WT targets , suggesting that there may be a role for combining vemurafenib treatment with T - cell - directed immunotherapy .",
"The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK38___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK2___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"The potential role of PD0332991 ( ___MASK59___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK59___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .",
"Long - term exposure to methotrexate induces immunophenotypic changes , decreased methotrexate uptake and increased dihydrofolate gene copy number in Jurkat T cells . ___MASK82___ ( MTX ) treatment of rheumatoid arthritis may require increasing doses to maintain clinical efficacy . An overall plateau of clinical response is reached after only six months of treatment . To study the immunologic , biochemical and genetic effects of MTX on T cells , the Jurkat T cell line was made MTX - resistant by serial addition of methotrexate sodium into culture medium . Cells proliferated and divided successfully in MTX concentrations ranging to 15 microM . MTX resistance of Jurkat T cells in vitro was accompanied by significantly ( P < 0 . 05 ) decreased expression of P06729 , CD3 , P01730 , P10747 , and Q07108 , P60568 production , and MTX uptake assessed by cell association or disassociation of 3 [ H ]- MTX or fluoresceinated MTX ( FMTX ) , respectively . In addition , there was P00374 gene amplification and increased levels of P00374 in all resistant cell lines . Both permanent and transient phenotypic changes developed in resultant cell lines exposed to increasing concentrations of MTX in vitro . Expression of P01730 and CD25 and sensitivity to MTX returned to near - parental levels after removal of MTX from culture medium , whereas expression of P27487 and MTX uptake were significantly increased . Expression of P06729 , CD3 , Q07108 and P60568 production as well as the P00374 levels did not return to the parental phenotype after removal from MTX . We conclude that MTX - cultured cells express depressed levels of cell - surface markers vital for T cell function and activation . The return of enhancement of these cell - surface markers critical to T cell activation suggests a possible mechanism for the severe flares experienced by rheumatoid arthritis patients when drug treatment is discontinued .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK4___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK82___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .",
"Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .",
"Concomitant targeting of tumor cells and induction of T - cell response synergizes to effectively inhibit trastuzumab - resistant breast cancer . ___MASK84___ is an iconic rationally designed targeted therapy for P04626 - positive breast cancers . However , the low response rate and development of resistance call for novel approaches for the treatment of patients . Here , we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct P60484 loss - mediated trastuzumab - resistant mammary tumor mouse models . In vivo combination treatment with P04626 / Neu antibody and Akt inhibitor triciribine effectively inhibited tumor growth in both models via inhibiting PI3K / AKT and mitogen - activated protein kinase signaling accompanied by increased T - cell infiltration in the tumor microenvironment . We showed that both CD8 (+) and P01730 (+) T cells were essential to the optimal antitumor effect of this combination treatment in an IFN - γ - dependent manner . Importantly , the antitumor activities of P04626 / Neu antibody and triciribine combination treatment were further improved when coinhibitory receptor cytotoxic T - lymphocyte - associated antigen 4 was blocked to enhance the T - cell response . Our data indicate that multitargeted combinatorial therapies targeting tumor cells and concomitantly enhancing T - cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity , suggesting a promising clinical strategy for treating trastuzumab - resistant breast cancers and other advanced malignancies .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK3___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"Vibrational structure of dihydrofolate bound to R67 dihydrofolate reductase . R67 is a Type II dihydrofolate reductase ( P00374 ) that catalyzes the reduction of dihydrofolate ( DHF ) to DB00116 by facilitating the addition of a proton to N5 of DHF and the transfer of a hydride ion from NADPH to P13671 . Because this enzyme is a plasmid - encoded P00374 from trimethoprim - resistant bacteria , extensive studies on R67 with various methods have been performed to elucidate its reaction mechanism . Here , Raman difference measurements , conducted on the ternary complex of R67 . NADP (+). DHF believed to be an accurate mimic of the productive P00374 . NADPH . DHF complex , show that the pK ( a ) of N5 in the complex is less than 4 . This is in clear contrast to the behavior observed in Escherichia coli P00374 , a substantially more efficient enzyme , where the pK ( a ) of bound DHF at N5 is increased to 6 . 5 compared with its solution value of 2 . 6 . A comparison of the ternary complexes in R67 and E . coli DHFRs suggests that enzymic raising of the pK ( a ) at N5 can significantly increase the catalytic efficiency of the hydride transfer step . However , R67 shows that even without such a strategy an effective P00374 can still be designed .",
"The H1 histamine receptor regulates allergic lung responses . DB11320 , signaling via the type 1 receptor ( P35367 ) , has been shown to suppress Th2 cytokine production by in vitro cultured T cells . We examined the role of P35367 in allergic inflammation in vivo using a murine asthma model . Allergen - stimulated splenic T cells from sensitized P35367 -/- mice exhibited enhanced Th2 cytokine production . Despite this Th2 bias , allergen - challenged P35367 -/- mice exhibited diminished lung Th2 cytokine mRNA levels , airway inflammation , goblet cell metaplasia , and airway hyperresponsiveness ( P35869 ) . Restoration of pulmonary Th2 cytokines in P35367 -/- mice by intranasal P05112 or P35225 restored inflammatory lung responses and P35869 . Further investigation revealed that histamine acts as a T cell chemotactic factor and defective T cell trafficking was responsible for the absence of lung inflammation . Cultured T cells migrated in response to histamine in vitro , but this was ablated by blockade of P35367 but not P25021 . In vivo , allergen - specific WT but not P35367 -/- P01730 + T cells were recruited to the lungs of naive recipients following inhaled allergen challenge . P35367 -/- T cells failed to confer airway inflammation or P35869 observed after transfer of WT T cells . Our data establish a role for histamine and P35367 in promoting the migration of Th2 cells into sites of allergen exposure .",
"Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44 . 1 ± 72 . 1 days ) were genetically analyzed for P51787 , Q12809 , P15382 - 5 , P63252 , Q14524 , P36382 , and P62158 by using denaturing high - performance liquid chromatography and direct sequencing . Whole - cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 and Q12809 cDNA . In 5 of 7 patients , we identified 4 mutations ( p . N1774D , p . T290fsX53 , p . F1486del and p . N406K ) in Q14524 , and 1 mutation ( p . G628D ) in Q12809 . N1774D , F1486del , and N406K in Q14524 displayed tetrodotoxin - sensitive persistent late Na (+) currents . By contrast , Q14524 - T290fsX53 was nonfunctional . Q12809 - G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 mutations , as well as loss of function associated with the Q12809 mutation .",
"Effects of retroviral - mediated P08183 expression on hematopoietic stem cell self - renewal and differentiation in culture . Ex vivo expansion of hematopoietic stem cells would be useful for bone marrow transplantation and gene therapy applications . Toward this goal , we have investigated whether retrovirally - transduced murine stem cells could be expanded in culture with hematopoietic cytokines . Bone marrow cells were transduced with retroviral vectors expressing either the human multidrug resistance 1 gene ( HaMDR1 ) , a variant of human dihydrofolate reductase ( HaDHFR ) , or both P08183 and P00374 in an internal ribosomal entry site ( IRES ) - containing bicistronic vector ( HaMID ) . Cells were then expanded for 15 days in cultures stimulated with interleukin ( IL ) - 3 , P05231 , and stem cell factor . When very low marrow volumes were injected into lethally irradiated recipient mice , long - term reconstitution with 100 % donor cells was seen in all mice injected with HaMDR1 - or HaMID - transduced cells . By contrast , engraftment with HaDHFR - or mock - transduced cells ranged from partial to undetectable despite injection of significantly larger marrow volumes . In addition , mice transplanted with expanded HaMDR1 - or HaMID - transduced stem cells developed a myeloproliferative disorder that was characterized by an increase in abnormal peripheral blood leukocytes . These results show that P08183 - transduced stem cells can be expanded in vitro with hematopoietic cytokines , but indicate that an increased stem cell division frequency can lead to stem cell damage .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK88___ and Tissue P00747 Activator in Occluded Arteries .",
"Functional network reconstruction reveals somatic stemness genetic maps and dedifferentiation - like transcriptome reprogramming induced by P23769 . Somatic stem cell transplantation holds great promise in regenerative medicine . The best - characterized adult stem cells are DB05914 ( MSCs ) , neural stem cells ( NSCs ) , and CD133 (+) hematopoietic stem cells ( HSCs ) . The applications of HSCs are hampered since these cells are difficult to maintain in an undifferentiated state in vitro . Understanding genes responsible for stem cell properties and their interactions will help on this issue . The construction of stem cell genetic networks will also help to develop rational strategies to revert somatic cells back to a stem - like state . We performed a systemic study on human CD133 (+) HSCs , NSCs , MSCs , and embryonic stem cells and two different progenies of CD133 (+) HSCs , microvascular endothelial cells ( MVECs ) and peripheral blood mononuclear cells . Genes abundant in each or in all three somatic stem cells were identified . We also observed complex genetic networks functioning in postnatal stem cells , in which several genes , such as Q06124 and P00374 , acted as hubs to maintain the stability and connectivity of the whole genetic network . Eighty - seven P19526 genes , including Q15389 and P23769 , were independently identified by comparing P28906 (+) P20138 (-) P28907 (-) hematopoietic stem cells with P28906 (+) precursors and various matured progenies . Introducing P23769 into MVECs resulted in dedifferentiation - like transcriptome reprogramming , with P19526 genes ( such as Q15389 ) being up and endothelial genes ( such as P29323 ) being down . This study provides a foundation for a more detailed understanding of human somatic stem cells . Expressing the newly discovered stem cell genes in matured cells might lead to a global reversion of somatic transcriptome to a stem - like status ."
] |
[
"___MASK17___",
"___MASK2___",
"___MASK38___",
"___MASK3___",
"___MASK4___",
"___MASK59___",
"___MASK82___",
"___MASK84___",
"___MASK88___"
] |
___MASK84___
|
MH_train_421
|
interacts_with DB01184?
|
[
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK45___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK1___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"Feasibility of a microarray - based point - of - care P33261 genotyping test for predicting clopidogrel on - treatment platelet reactivity . DB00758 is a prodrug which is converted into active metabolite by cytochrome P450 isoenzyme , P33261 . Numerous polymorphisms of P33261 are reported , and a strong link exists between loss - of - function ( LOF ) or gain - of - function polymorphisms , clopidogrel metabolism , and clinical outcome . Hence , a fully automated point - of - care P33261 genotyping assay is more likely to bring personalized antiplatelet therapy into real practice . We assessed the feasibility of the Verigene 2C19 / P35520 Nucleic Acid Test , a fully automated microarray - based assay , compared to bidirectional sequencing , and performed VerifyNow Q9H244 assay to evaluate the effect of P33261 polymorphisms on on - treatment platelet reactivity in 57 Korean patients treated with clopidogrel after percutaneous coronary intervention . The Verigene 2C19 / P35520 assay identified ∗ 2 , ∗ 3 , and ∗ 17 polymorphisms with 100 % concordance to bidirectional sequencing in 180 minutes with little hands - on time . Patients were classified into 4 groups : extensive ( ∗ 1 /∗ 1 ; n = 12 , 21 . 1 % ) , intermediate ( ∗ 1 /∗ 2 , ∗ 1 /∗ 3 ; n = 33 , 57 . 9 % ) , poor ( ∗ 2 /∗ 2 , ∗ 2 /∗ 3 , and ∗ 3 /∗ 3 ; n = 11 , 19 . 3 % ) , and ultrarapid metabolizers ( ∗ 1 /∗ 17 ; n = 1 , 1 . 8 % ) . The prevalence of the CYP2C19 ∗ 2 , ∗ 3 , and ∗ 17 alleles was 36 . 0 % , 12 . 3 % , and 0 . 9 % . Platelet reactivity showed gene dose response according to the number of P33261 LOF allele . In conclusion , the Verigene 2C19 / P35520 assay gave accurate P33261 genotype results which were in well match with the differing on - treatment platelet reactivity .",
"The P38936 codon 31 * C - and P14416 codon 313 * T - related genotypes / alleles , but not P18887 codon 399 , hOGG1 codon 326 , and P21728 - 48 polymorphisms , are correlated with the presence of leiomyoma . OBJECTIVE : To investigate whether the gene polymorphisms for P38936 , X - ray repair cross - complementing group 1 ( P18887 ) , human 8 - oxoguanine glycosylase 1 ( hOGG1 ) , and dopamine D1 and D2 receptors ( P21728 , - 2 ) are associated with leiomyoma susceptibility . DESIGN : Prospective study . SETTING : Departments of gynecology and genetics in a medical center . PATIENT ( S ) : Women were divided into two groups : leiomyoma ( n = 120 ) and nonleiomyoma ( n = 112 ) . INTERVENTION ( S ) : The P38936 codon 31 , P18887 codon 399 , hOGG1 codon 326 , P21728 - 48 , and P14416 codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions ( Blp I , MspI , Fnu4HI , Dde I , and NcoI , respectively ) . MAIN OUTCOME MEASURE ( S ) : Genotypes and allelic frequencies . RESULT ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyomas . The proportions of P38936 (*) CC / CA / AA and P14416 (*) CC / CT / TT in both groups were 27 . 5 / 68 . 3 / 4 . 2 % and 12 . 5 / 51 . 7 / 35 . 8 % ( leiomyoma ) ; and 14 . 3 / 51 . 8 / 33 . 9 % and 33 . 9 / 40 . 2 / 25 . 9 % ( nonleiomyoma ) . P18887 , hOGG1 , and P21728 were not correlated with the presence of leiomyomas . P18887 (*) GG / GA / AA , hOGG1 (*) TT / TA / AA , and P21728 (*) GG / GA / AA were 54 . 2 / 37 . 5 / 8 . 3 % , 36 . 7 / 44 . 2 / 19 . 1 % , and 3 . 3 / 25 . 8 / 70 . 8 % ( leiomyoma ) ; and 48 . 2 / 47 . 3 / 4 . 5 % , 43 . 6 / 41 / 15 . 4 % , and 3 . 6 / 25 / 71 . 4 % ( nonleiomyoma ) . CONCLUSION ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyoma . P18887 , hOGG1 , and P21728 were not correlated with leiomyoma development .",
"A genomic reservoir for Tnfrsf genes is developmentally regulated and imprinted in the mouse . P01375 receptor superfamily is composed of at least 26 members in the mouse , three of which exist as a cluster within the imprinted Kcnq1 domain on chromosome 7 . Tnfrsf22 , 23 and 26 contain typical cystein - rich domains and Tnfrsf22 and 23 can bind ligands but have no signaling capacity . Thus , they are assumed to be decoy receptors . The developmental expression profile of these genes is unknown and knowledge of their imprinting patterns is incomplete and controversial . We found that all three genes are expressed during mouse embryonic development , and that they have a strong maternal bias , indicating that they may be affected by the KvDMR , the Kcnq1 imprinting control region . We found expression of an antisense non - coding RNA , AK155734 , in embryos and some neonatal tissues . This RNA overlaps the Tnfrsf22 and possibly the Tnfrsf23 coding regions and is also expressed with a maternal bias . We were interested in exploring the evolutionary origins of the three Tnfrsf genes , because they are absent in the orthologous human Kcnq1 domain . To determine whether the genes were deleted from humans or acquired in the rodent lineage , we performed phylogenetic analyses . Our data suggest that TNFRSF sequences were duplicated and / or degenerated or eliminated from the P51787 region several times during the evolution of mammals . In humans , multiple mutations ( point mutations and / or deletions ) have accumulated on the ancestral TNFRSF , leaving a single short non - functional sequence .",
"___MASK95___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK95___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"P14416 desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release . Neurons of the ventral tegmental area ( VTA ) are the source of dopaminergic ( DAergic ) input to important brain regions related to addiction . Prolonged exposure of these VTA neurons to moderate concentrations of dopamine ( DA ) causes a time - dependent decrease in DA - induced inhibition , a complex desensitization called DA inhibition reversal ( P30518 ) . P30518 is mediated by conventional protein kinase C ( cPKC ) through concurrent stimulation of D2 and D1 - like DA receptors , or by D2 stimulation concurrent with activation of some Gq - linked receptors . DB01285 releasing factor ( CRF ) acts via Gq , and can modulate glutamater neurotransmission in the VTA . In the present study , we used brain slice electrophysiology to characterize the interaction of DA , glutamate antagonists , and CRF agonists in the induction and maintenance of P30518 in the VTA . Glutamate receptor antagonists blocked induction but not maintenance of P30518 . Putative blockers of neurotransmitter release and store - operated calcium channels blocked and reversed P30518 . CRF and the CRF agonist urocortin reversed inhibition produced by the D2 agonist quinpirole , consistent with our earlier work indicating that Gq activation reverses quinpirole - mediated inhibition . In whole cell recordings , the combination of urocortin and quinpirole , but not either agent alone , increased spontaneous excitatory postsynaptic currents ( sEPSCs ) in VTA neurons . Likewise , the combination of a D1 - like receptor agonist and quinpirole , but not either agent alone , increased sEPSCs in VTA neurons . In summary , desensitization of D2 receptors induced by dopamine or CRF on DAergic VTA neurons is associated with increased glutamatergic signaling in the VTA .",
"Pancreatic gene variants potentially associated with dipeptidyl peptidase - 4 inhibitor treatment response in Type 2 diabetes . In the adult pancreas , the expression of the genes O43316 , P51787 , Q9NQB0 , Q14654 , Q09428 , P49286 and O76024 are mainly restricted to β cells to maintain glucose homeostasis . We have identified these genes as the main regulators of incretin - mediated actions , and therefore they may potentially influence the response of DPP - 4 inhibitors . This review represents the first detailed exploration of pancreatic β - cell genes and their variant mechanisms , which could potentially affect the response of DPP - 4 inhibitors in Type 2 diabetes . We have focused on the signaling pathways of these genes to understand their roles in gastrointestinal incretin - mediated effects ; and finally , we sought to associate gene mechanisms with their Type 2 diabetes risk variants to predict the responses of DPP - 4 inhibitors for this disease .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK34___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side - effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side - effects from domperidone may be influenced by patient - related factors including polymorphisms in genes encoding drug - metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side - effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single - nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single - nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty - eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p = 0 . 0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p = 0 . 041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p = 0 . 0277 ) . The side - effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side - effects .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"___MASK29___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK29___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK29___ is a promising pharmacological tool in the treatment of renal edema .",
"Characterization of the inhibitory effects of erythromycin and clarithromycin on the Q12809 potassium channel . Both erythromycin and clarithromycin have been reported to cause QT prolongation and the cardiac arrhythmia torsade de pointes in humans , however direct evidence documenting that these drugs produce this effect by blocking human cardiac ion channels is lacking . The goal of this study was to test the hypothesis that these macrolide antibiotics significantly block the delayed rectifier current ( IKr ) encoded by Q12809 ( the human ether - a - go - go - related gene ) at drug concentrations , temperature and ionic conditions mimicking those occurring in human subjects . DB01345 currents in P29320 293 cells stably transfected with Q12809 were recorded using a whole cell voltage clamp method . Exposure of cells to erythromycin reduced the Q12809 encoded potassium current in a concentration dependent manner with an IC50 of 38 . 9 +/- 1 . 2 microM and Hill Slope factor of 0 . 4 +/- 0 . 1 . ___MASK21___ produced a similar concentration - dependent block with an IC50 of 45 . 7 +/- 1 . 1 microM and Hill Slope factor of 1 . 0 +/- 0 . 1 . Erythromycin ( 25 - 250 microM ) and clarithromycin ( 5 or 25 microM ) also produced a significant decrease in the integral of the current evoked by an action potential shaped voltage clamp protocol . The results of this study document that both erythromycin and clarithromycin significantly inhibit the Q12809 potassium current at clinically relevant concentrations .",
"Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK38___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK38___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"In silico exploration of anti - inflammatory activity of natural coumarinolignoids . Natural coumarinolignoids isolated from the seeds of Cleome viscosa consist of a racemic mixture of cleomiscosins A , B and C . To screen out potential lead , anti - inflammatory activity of the isolated compounds was evaluated through molecular docking and QSAR studies by using reported in vivo activity of Swiss albino mice . Based on docking binding affinity , a possible mechanism of action has been hypothesized which constitute toll - like receptors ( TLR - 4 ) , cluster of differentiation molecules ( CDs ) , P35228 , P35354 and P35610 - 6 proteins . It was very interesting to find that the 3D topology of the active site of P35354 from the docking was in good agreement with QSAR model and in silico ADME / T parameters . A forward feed multiple linear regression model was developed with r ( 2 ) = 0 . 92 and rCV ( 2 ) = 0 . 87 . This study showed that chemical descriptors , for example dipole vector - X , dipole vector - Y , steric energy , LUMO energy , size of smallest ring , size of largest ring and carboxyl group count , correlate reasonably well with experimental in vivo activity ( logLD ( 50 ) ) . QSAR study indicates that dipole vector - Y and carboxyl group count have negative correlation with activity . Cleomiscosins also showed compliance with 95 % of in silico ADME / T properties of available drugs , e . g . serum protein binding , blood - brain barrier , CNS activity , Q12809 K + channel activity , apparent Caco - 2 permeability , apparent MDCK permeability , skin permeability and human oral absorption in GI . Besides , toxicity screening study suggests that cleomiscosin molecules possess no toxicity risk parameters . This study offer useful references for understanding and molecular design of inhibitors with improved anti - inflammatory activity .",
"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK3___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .",
"Therapy with interferon - beta modulates endogenous catecholamines in lymphocytes of patients with multiple sclerosis . OBJECTIVE : To investigate the endogenous dopaminergic / adrenergic system of lymphocytes in multiple sclerosis ( MS ) patients during treatment with interferon ( IFN ) - beta . METHODS : Patients with relapsing - remitting MS undergoing IFN - beta treatment were prospectively studied during the first year of treatment . Circulating lymphocytes were obtained at baseline and after 1 , 3 , 6 and 12 months of treatment and assayed for catecholamine ( CA ) production and mRNA expression of tyrosine hydroxylase ( TH , the rate - limiting enzyme in the synthesis of CA ) , beta ( 2 )- adrenoceptors ( AR ) and D2 , D3 and D5 dopaminergic receptors ( DR ) . RESULTS : In cells from patients treated with IFN - beta for 12 months the production of CA hugely increased and was less sensitive to P01579 - induced inhibition . Expression of mRNA for TH , beta ( 2 )- AR and P21918 was already enhanced after 1 month and further increased up to 6 - 12 months of treatment . On the contrary , P14416 mRNA progressively decreased and P35462 mRNA did not significantly change over the whole study period . CONCLUSIONS : In MS patients IFN - beta treatment enhances the ability of lymphocytes to produce CA , and induces extensive modifications of both beta ( 2 )- AR and DR - operated pathways . The clinical relevance of these effects deserves consideration .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK22___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system ."
] |
[
"___MASK1___",
"___MASK21___",
"___MASK22___",
"___MASK29___",
"___MASK34___",
"___MASK38___",
"___MASK3___",
"___MASK45___",
"___MASK95___"
] |
___MASK21___
|
MH_train_422
|
interacts_with DB00368?
|
[
"P10275 expression in breast cancer patients tested for P38398 and P51587 mutations . AIM : To assess the expression of receptors for androgen ( AR ) , oestrogen ( ER ) and progesterone ( PR ) as well as human epidermal growth factor receptor type 2 ( Her - 2 / neu ) status of breast carcinomas in breast cancer susceptibility gene ( BRCA ) P38398 / 2 mutation carriers and P38398 / 2 negative tested women . METHODS : One hundred and thirty - five breast cancers in women tested for P38398 / 2 mutations . Screening for P38398 and P51587 mutations was performed by direct sequencing of all P38398 and P51587 exons as well as the surrounding intronic sequences . Additionally , BRCA genes were analysed with multiplex ligation - dependent probe amplification . Consecutive paraffin sections were examined immunohistochemically for AR , ER , PR and Her - 2 / neu . RESULTS : Of the 135 tumours , 43 ( 32 % ) were P38398 - related , 18 ( 13 % ) were P51587 - related and 74 ( 55 % ) were P38398 / 2 - negative . Seventy - two per cent of the P38398 - related , 22 % of the P51587 - related and 12 % of the P38398 / 2 - negative tumours were triple ( ER , PR , Her2neu ) - negative . Eighty - four per cent of P38398 mutated cancers were high - grade ( P46379 ) tumours . ARs were expressed in 30 % ( 13 of 43 ) of P38398 - related , in 78 % ( 14 of 18 ) in P51587 - related tumours and in 76 % ( 56 of 74 ) in P38398 / 2 negative tumours . Twenty - one per cent of ER - negative P38398 - related tumours expressed androgen receptors . CONCLUSION : Approximately one in five P38398 mutated breast cancers negative for ER and PR express androgen receptors . Modulation of AR might open a new avenue for treating these high - risk cancers .",
"Molecular systematics of armadillos ( Xenarthra , Dasypodidae ) : contribution of maximum likelihood and Bayesian analyses of mitochondrial and nuclear genes . The 30 living species of armadillos , anteaters , and sloths ( Mammalia : Xenarthra ) represent one of the three major clades of placentals . Armadillos ( Cingulata : Dasypodidae ) are the earliest and most speciose xenarthran lineage with 21 described species . The question of their tricky phylogeny was here studied by adding two mitochondrial genes ( P03886 [ P03886 ] and 12S ribosomal RNA [ 12S rRNA ] ) to the three protein - coding nuclear genes ( alpha2B adrenergic receptor [ P18089 ] , breast cancer susceptibility exon 11 [ P38398 ] , and P04275 exon 28 [ P04275 ] ) yielding a total of 6869 aligned nucleotide sites for thirteen xenarthran species . The two mitochondrial genes were characterized by marked excesses of transitions over transversions - with a strong bias toward CT transitions for the 12S rRNA - and exhibited two - to fivefold faster evolutionary rates than the fastest nuclear gene ( P18089 ) . Maximum likelihood and Bayesian phylogenetic analyses supported the monophyly of Dasypodinae , Tolypeutinae , and Euphractinae , with the latter two armadillo subfamilies strongly clustering together . Conflicting branching points between individual genes involved relationships within the subfamilies Tolypeutinae and Euphractinae . Owing to a greater number of informative sites , the overall concatenation favored the mitochondrial topology with the classical grouping of Cabassous and Priodontes within Tolypeutinae , and a close relationship between Euphractus and Chaetophractus within Euphractinae . However , low statistical support values associated with almost equal distributions of apomorphies among alternatives suggested that two parallel events of rapid speciation occurred within these two armadillo subfamilies .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK75___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"Alpha 2B adrenoceptor genotype moderates effect of reboxetine on negative emotional memory bias in healthy volunteers . Evidence suggests that emotional memory plays a role in the pathophysiology of depression / anxiety disorders . DB00368 crucially modulates emotional memory . Genetic variants involved in noradrenergic signaling contribute to individual differences in emotional memory and vulnerability to psychopathology . A functional deletion polymorphism in the α - 2B adrenoceptor gene ( P18089 ) has been linked to emotional memory and post - traumatic stress disorder . The noradrenaline reuptake inhibitor reboxetine attenuates enhanced memory for negative stimuli in healthy and depressed individuals . We examined whether the effect of reboxetine on emotional memory in healthy individuals would be moderated by P18089 genotype . P18089 deletion carriers demonstrated enhanced emotional memory for negative stimuli compared with deletion noncarriers , consistent with prior studies . DB00234 attenuated enhanced memory for negative stimuli in deletion noncarriers but had no significant effect in deletion carriers . This is the first demonstration of genetic variation influencing antidepressant drug effects on emotional processing in healthy humans .",
"Vascular changes after cardiac surgery : role of NOS , P36551 , kinases , and growth factors . Cardiovascular disease remains the leading cause of mortality in the industrialized world . Despite advances in pharmacotherapy and catheter based interventions , coronary artery bypass grafting remains an essential therapeutic modality . The majority of coronary artery bypass operations , as well as other cardiac surgical procedures require the use of ischemic cardioplegic arrest and cardiopulmonary bypass , both of which result in iatrogenic injury to the vasculature and microcirculation . This injury can manifest as impaired vasorelaxation or vasoconstriction , depending upon the organ system involved , resulting in impaired tissue perfusion and the development of edema . Key to this dysfunction are changes in the following : nitric oxide signaling secondary to changes in P29474 and P35228 expression and activity , cyclooxygenase function with increases in pro - inflammatory P35354 activity , alterations in Protein Kinase C and Mitogen Activated Protein Kinase signaling , and an increase in Vascular Endothelial Growth Factor expression increasing vascular permeability and dilatation . This review discusses our current understanding of cardioplegia and cardiopulmonary bypass induced changes in the vasculature , and therapeutic interventions aimed at modulating the altered signaling pathways .",
"Differentiation method - dependent expression of leptin in adipocyte cell lines . Leptin , the product of the ob gene , is expressed exclusively in adipose tissue . However , adipocyte cell lines , such as 3T3 - Q9NUQ9 adipocytes , have generally been reported to express extremely low levels of leptin mRNA . We compared 3T3 - Q9NUQ9 ' s to the closely related line 3T3 - F442A , and to another murine adipocyte line , Q96RJ0 . Q96RJ0 cells , when differentiated by indomethacin / insulin treatment , express leptin at levels greater than those of 3T3 - Q9NUQ9 adipocytes differentiated by the traditional methylisobutylxanthine / dexamethasone / insulin protocol . However , when 3T3 - Q9NUQ9 ' s are differentiated in the presence of indomethacin / insulin their expression levels of leptin increase dramatically . 3T3 - F442A preadipocytes also express high levels of leptin when differentiated in the presence of DB00279 and insulin , but when differentiated in the presence of indomethacin / insulin , expression levels drop precipitously . These changes in leptin mRNA and protein expression are not reflected by changes in CCAAT / enhancer binding protein - alpha ( c / EBPalpha ) , peroxizomal proliferator activated receptor - gamma ( PPARgamma ) , lipoprotein lipase ( P06858 ) , fatty - acid binding protein aP2 or uncoupling protein - 2 ( P55851 ) mRNA levels , and suggest a mechanism unique to the leptin gene .",
"Correlations between genetic variance and adiposity measures , and gene x gene interactions for obesity in postmenopausal Vietnamese women . Although environmental factors are important , there is considerable evidence that genes also have a significant role in the pathogenesis of obesity . We conducted a population - based study to investigate the relationship between candidate genes for obesity ( P25874 , P55851 , P18089 , P13945 , LEPR , P11473 and P03372 ) and adiposity measures ( body mass index , body fat percentage , weight , waist circumference and waist - hip ratio ) in terms of individual gene and gene x gene interaction in models unadjusted and adjusted for covariates ( age , years since menopause , educational level and total energy intake ) . Postmenopausal women with TC genotype of P03372 gene had higher body fat percentage than those with TT genotype in the models unadjusted and adjusted for the covariates ( P = 0 . 006 in adjusted model ) . In multiple logistic regression analysis , BsmI and ApaI SNPs of P11473 genes were significantly associated with overweight and obesity . The P55851 - P11473 ApaI interaction to susceptibility of overweight and obesity was first observed from logistic regression analysis , and then confirmed in the multifactor dimensionality reduction method unadjusted and adjusted for the covariates . This interaction had 69 . 09 % prediction accuracy for overweight and obesity ( P = 0 . 001 , sign test ) . In conclusion , the study suggests the significant association of P03372 and P11473 genes with adiposity measures and the P55851 - P11473 ApaI interaction to susceptibility to being overweight and obesity in postmenopausal Vietnamese women .",
"[ Polymorphisms of 2B - adrenergic receptor and endothelial NO - Synthase genes in genesis of the hereditary sick sinus node syndrome ] . In this work we have demonstrated for the first time on the clinico - genetic material association between hereditary sick sinus node syndrome ( SSNS ) P18089 and P29474 genes polymorphisms . We have established predominance of homozygote genotype of more rare DD allele in patients with SSNS ( 28 % ) compared with subjects of control group ( 8 . 99 % ) . We have found predominance of heterozygote genotype 4a / 4b in patients with SSNS compared with subjects of control group ( 41 . 8 and 25 . 39 % , respectively ) . The data obtained allow to suggest that P29474 gene polymorphism might be associated with SSNS .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK70___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .",
"Adrenergic receptor polymorphisms associated with resting heart rate : the HyperGEN Study . The association between polymorphisms in the beta1 , beta2 and alpha2B adrenergic receptor ( ADR ) genes ( P08588 , P07550 and P18089 ) and resting heart rate was examined in white and African - American participants of the HyperGEN Study . All analyses were adjusted for age , sex , body mass index , alcohol use , smoking status and daily exercise within strata of race , hypertension status and beta - blocker use . The Ser49Gly polymorphism of the beta1 ADR was associated with resting heart rate in hypertensive African - Americans and hypertensive whites taking beta - blockers , with carriers of the DB00145 allele having a higher mean resting heart rate by 2 . 7 and 4 . 4 beats per minute ( bpm ) , respectively . The Arg389Gly polymorphism of the beta1 ADR was associated with lower heart rate in the normotensive African - American sample . A beta1 haplotype ( Ser49Gly - Arg389Gly ) was modestly associated with resting heart rate in the hypertensive African - Americans . The alpha2B C / A polymorphism was associated with heart rate in hypertensive whites , and both whites and African - Americans taking beta - blockers , with carriers of the A allele having a higher mean resting heart rate . In summary , each of the ADR gene polymorphisms was associated with heart rate in at least one stratum studied , but there was no consistent association from which one would infer a large genetic contribution to heart rate .",
"___MASK10___ block of cloned human T - type voltage - gated calcium channels . ___MASK10___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"A high density linkage disequilibrium mapping in 14 noradrenergic genes : evidence of association between P23975 , P35368 and ADHD . Pharmacological evidence suggests the importance of noradrenergic and other monoaminergic neurotransmitters in the aetiology and treatment of attention deficit hyperactivity disorder ( ADHD ) . Until recently , the genes of the noradrenergic pathway were not intensively investigated in ADHD compared to dopaminergic and serotonergic candidates . In this study , 91 SNP markers of 14 noradrenergic genes ( an average density of one SNP per 4 . 5 kbp ) were examined in ADHD samples from Ireland and Australia . Although suggestive evidence of association ( nominal p ≤ 0 . 05 ) with the genes P23975 , ADRA1A , P35368 and P18089 was observed , none remained significant after permutation adjustments . In contrast , haplotype analyses demonstrated a significant association between ADHD and a P23975 haplotype comprising the markers rs36009 , rs1800887 , rs8049681 , rs2242447 and rs9930182 ( χ ( 2 ) = 9 . 39 , p - corrected = 0 . 019 , OR = 1 . 51 ) . A rare P35368 haplotype made of six SNPs ( rs2030373 , rs6884105 , rs756275 , rs6892282 , rs6888306 and rs13162302 ) was also associated ( χ ( 2 ) = 7 . 79 , p - corrected = 0 . 042 OR = 2 . 74 ) with the disorder . These findings provide evidence of a contribution of the noradrenaline system to the genetic aetiology of ADHD . The observed haplotype association signals may be driven by as yet unidentified functional risk variants in or around the associated regions . Functional genomic analysis is warranted to determine the biological mechanism of the observed association .",
"Modulation of a number of genes on personality traits in a sample of healthy subjects . A large number of studies investigated the genetic modulation of personality with mixed results . As a confirmatory analysis of previous findings , we firstly examined the association between several previously examined single nucleotide polymorphisms ( SNPs ) and personality traits in a sample of 158 healthy subjects . As a secondary aim , we tested the potential modulation of additional never previously investigated genes on personality . A blood sample was collected and the Temperament and Character Inventory ( TCI ) has been administered to all participants . Multivariate analysis of covariance , controlling for sex and age , was used to test SNP influence on TCI scores . Examination of previously studied gene variants showed an effect of adrenergic alpha 2B receptor ( P18089 ) on Cooperativeness and of serotonin receptor P28223 on Self Directedness . Examination of new variants revealed that sex hormone binding protein ( P04278 ) was associated with reward dependence . Moreover , several additional variants showed a tendency towards association with some TCI traits , confirming previous results . This study suggests that P18089 , P28223 and P04278 genes may be involved in the modulation of personality in healthy subjects . The major limitation of this study was the small sample size .",
"Differential effects of amfonelic acid on the haloperidol - and clozapine - induced increase in extracellular DOPAC in the nucleus accumbens and the striatum . This study compares the effects of the nonamphetamine stimulant amfonelic acid on the increase in extracellular 3 , 4 - dihydroxyphenylacetic acid ( DOPAC ) induced by haloperidol and clozapine in the nucleus accumbens and the striatum of anaesthetized rats . DOPAC was simultaneously recorded in both regions using differential pulse voltammetry with electrically pretreated carbon fibre electrodes . Amfonelic acid ( 2 . 5 mg / kg s . c . ) did not alter basal striatal DOPAC but produced a significant reduction in extracellular DOPAC in the nucleus accumbens . ___MASK91___ ( 1 mg / kg s . c . ) increased extracellular DOPAC in both regions . When amfonelic acid was injected 5 min before haloperidol , the increase in DOPAC was potentiated in both the nucleus accumbens and the striatum but with a greater effect in the striatum . Clozapine ( 30 mg / kg i . p . ) increased extracellular DOPAC in both regions , an effect partially attenuated by amfonelic acid in both regions but to a greater extent in the striatum . When ritanserin ( 5 mg / kg i . p . ) , a serotonergic antagonist ( P28223 ) , was co - administered with haloperidol , the potentiation by amfonelic acid of the increase in extracellular DOPAC induced by haloperidol was attenuated in both the nucleus accumbens and the striatum . The present results confirm that amfonelic acid can be used to discriminate neurochemically between haloperidol and clozapine in vivo . The effects of amfonelic acid on the neuroleptic - induced changes in extracellular DOPAC were greater in the striatum than the nucleus accumbens . These results further demonstrate that both neuroleptics increase dopamine metabolism in the two brain regions but by different mechanisms , supporting the view that the regulation of dopamine metabolism differs in the two regions . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side - effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side - effects from domperidone may be influenced by patient - related factors including polymorphisms in genes encoding drug - metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side - effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single - nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single - nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty - eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p = 0 . 0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p = 0 . 041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p = 0 . 0277 ) . The side - effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side - effects .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK13___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK13___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK13___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK13___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK13___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK13___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK13___ .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK68___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"Estrogen upregulates endothelial nitric oxide synthase gene expression in fetal pulmonary artery endothelium . NO , produced by endothelial NO synthase ( P29474 ) , is a key mediator of pulmonary vasodilation during cardiopulmonary transition at birth . The capacity for NO production is maximal at term because pulmonary P29474 expression increases during late gestation . Since fetal estrogen levels rise markedly during late gestation and there is indirect evidence that the hormone enhances nonpulmonary NO production in adults , estrogen may upregulate P29474 in fetal pulmonary artery endothelium . Therefore , we studied the direct effects of estrogen on P29474 expression in ovine fetal pulmonary artery endothelial cells ( PAECs ) . ___MASK11___ caused a 2 . 5 - fold increase in NOS enzymatic activity in PAEC lysates . This effect was evident after 48 hours , and it occurred in response to physiological concentrations of the hormone ( 10 (- 10 ) to 10 (- 6 ) mol / L ) . The increase in NOS activity was related to an upregulation in P29474 protein expression , and P29474 mRNA abundance was also enhanced . P03372 antagonism with DB00947 completely inhibited estrogen - mediated P29474 upregulation , indicating that estrogen receptor activation is necessary for this response . In addition , immunocytochemistry revealed that fetal PAECs express estrogen receptor protein . Furthermore , transient transfection assays with a specific estrogen - responsive reporter system have demonstrated that the endothelial estrogen receptor is capable of estrogen - induced transcriptional transactivation . Thus , estrogen upregulates P29474 gene expression in fetal PAECs through the activation of PAEC estrogen receptors . This mechanism may be responsible for pulmonary P29474 upregulation during late gestation , thereby optimizing the capacity for NO - mediated pulmonary vasodilation at birth .",
"P18089 genotype differentially modulates stress - induced neural activity in the amygdala and hippocampus during emotional memory retrieval . RATIONALE : DB00368 interacts with stress hormones in the amygdala and hippocampus to enhance emotional memory consolidation , but the noradrenergic - glucocorticoid interaction at retrieval , where stress impairs memory , is less understood . OBJECTIVES : We used a genetic neuroimaging approach to investigate whether a genetic variation of the noradrenergic system impacts stress - induced neural activity in amygdala and hippocampus during recognition of emotional memory . METHODS : This study is based on genotype - dependent reanalysis of data from our previous publication ( Li et al . Brain Imaging Behav 2014 ) . Twenty - two healthy male volunteers were genotyped for the P18089 gene encoding the α2B - adrenergic receptor . Ten deletion carriers and 12 noncarriers performed an emotional face recognition task , while their brain activity was measured with fMRI . During encoding , 50 fearful and 50 neutral faces were presented . One hour later , they underwent either an acute stress ( Trier Social Stress Test ) or a control procedure which was followed immediately by the retrieval session , where participants had to discriminate between 100 old and 50 new faces . RESULTS : A genotype - dependent modulation of neural activity at retrieval was found in the bilateral amygdala and right hippocampus . Deletion carriers showed decreased neural activity in the amygdala when recognizing emotional faces in control condition and increased amygdala activity under stress . Noncarriers showed no differences in emotional modulated amygdala activation under stress or control . Instead , stress - induced increases during recognition of emotional faces were present in the right hippocampus . CONCLUSION : The genotype - dependent effects of acute stress on neural activity in amygdala and hippocampus provide evidence for noradrenergic - glucocorticoid interaction in emotional memory retrieval .",
"Expression of angiotensin I - converting enzymes and bradykinin B2 receptors in mouse inner medullary - collecting duct cells . We described in mouse inner medullary - collecting duct cells ( mIMCD - 3 ) the somatic and the N - domain P12821 synthesis and its interaction with the kallikrein - kinin system co - localized in the same cells . We purified two P12821 forms from culture medium , M1 ( 130 kDa ) and M2 ( N - domain , 60 kDa ) , and cellular lysate , C1 ( 130 kDa ) and P06681 ( N - domain , 60 kDa ) . ___MASK67___ and enalaprilat inhibited the purified enzymes . The immunofluorescence studies indicated that P12821 is present in the membrane , cytoplasm and in the cell nucleus . Kinin B1 and B2 receptors were detected by immunofluorescence and showed to be activated by BK and DesR9 BK , increasing the acidification rate which was enhanced in the presence of enalaprilat . The presence of secreted and intracellular P12821 in mIMCD - 3 confirmed the hypothesis previously proposed by our group for a new site of P12821 secretion in the collecting duct .",
"Chemical synthesis and in vitro biological evaluation of a phosphorylated bisubstrate inhibitor of type 3 17beta - hydroxysteroid dehydrogenase . Type 3 17beta - hydroxysteroid dehydrogenase ( 17beta - HSD ) catalyzes the last step in the biosynthesis of the potent androgen testosterone ( T ) by selectively reducing the C17 ketone of 4 - androstene - 3 , 17 - dione ( delta4 - dione ) , with NADPH as cofactor . This enzyme is thus an interesting therapeutic target for androgen - sensitive diseases . Using an efficient convergent chemical approach we synthesized a phosphorylated version of the best delta4 - dione / adenosine hybrid inhibitor of type 3 17beta - HSD previously reported . An appropriately protected P06681 ' phosphorylated adenosine was first prepared and linked by esterification to the steroid delta4 - dione bearing an alkyl spacer . After three deprotection steps , the phosphorylated bisubstrate inhibitor was obtained . The inhibitory potency of this compound was evaluated on homogenated P29320 - 293 cells overexpressing type 3 17beta - HSD and compared to the best non - phosphorylated bisubstrate inhibitor . Unexpectedly , the phosphorylated derivative was slightly less potent than the non - phosphorylated bisubstrate inhibitor of type 3 17beta - HSD . Two hypotheses are discussed to explain this result : 1 ) the phosphorylated adenosine moiety does not interact optimally with the cofactor - binding site and 2 ) the bisubstrate inhibitors , phosphorylated or not , interact only with the substrate - binding site of type 3 17beta - HSD .",
"P18089 gene insertion / deletion polymorphism and artery compliance . BACKGROUND : The P18089 gene insertion / deletion ( I / D ) polymorphism is associated with various cardiovascular and metabolic phenotypes . Large ( C1 ) and small ( P06681 ) artery compliance , assessed by pulse wave analysis , is considered as sensitive markers or risk factors for cardiovascular disease . Therefore whether the P18089 I / D polymorphism is associated with C1 and P06681 need to be investigated . METHODS : A total of 227 men and 243 women were enrolled in a Chinese family - based study . C1 and P06681 were measured by pulse wave analysis . P18089 genotypes were determined by polymerase chain reaction . Statistical methods included generalized estimation equations and quantitative transmission disequilibrium test . RESULTS : The II ( 31 . 9 % ) , ID ( 46 . 8 % ) and DD ( 21 . 3 % ) genotype frequencies were in Hardy - Weinberg equilibrium ( P = 0 . 73 ) . The covariates selected by stepwise regression for C1 and P06681 were age , systolic pressure and gender . The population based association analysis showed that C1 and P06681 were not associated with P18089 genotype both before ( C1 : P = 0 . 28 ; P06681 : P = 0 . 27 ) and after ( C1 : P = 0 . 58 ; P06681 : P = 0 . 18 ) the adjustment . The family - based analyses of 128 informative offspring showed that transmission of the D - allele was not associated with C1 or P06681 , both before ( C1 : P = 0 . 42 ; P06681 : P = 0 . 85 ) and after ( C1 : P = 0 . 31 ; P06681 : P = 0 . 82 ) the adjustment . CONCLUSION : The study do not support that the P18089 gene I / D polymorphism has a major gene effect on C1 or P06681 in the Chinese population of current sample size .",
"Characterization of de novo synthesized GPCRs supported in nanolipoprotein discs . The protein family known as G - protein coupled receptors ( GPCRs ) comprises an important class of membrane - associated proteins , which remains a difficult family of proteins to characterize because their function requires a native - like lipid membrane environment . This paper focuses on applying a single step method leading to the formation of nanolipoprotein particles ( NLPs ) capable of solubilizing functional GPCRs for biophysical characterization . NLPs were used to demonstrate increased solubility for multiple GPCRs such as the Neurokinin 1 Receptor ( P25103 ) , the Adrenergic Receptor â2 ( P07550 ) and the Dopamine Receptor D1 ( P21728 ) . All three GPCRs showed affinity for their specific ligands using a simple dot blot assay . The P25103 was characterized in greater detail to demonstrate correct folding of the ligand pocket with nanomolar specificity . Electron paramagnetic resonance ( EPR ) spectroscopy validated the correct folding of the P25103 binding pocket for Substance P ( SP ) . Fluorescence correlation spectroscopy ( FCS ) was used to identify SP - bound P25103 - containing NLPs and measure their dissociation rate in an aqueous environment . The dissociation constant was found to be 83 nM and was consistent with dot blot assays . This study represents a unique combinational approach involving the single step de novo production of a functional GPCR combined with biophysical techniques to demonstrate receptor association with the NLPs and binding affinity to specific ligands . Such a combined approach provides a novel path forward to screen and characterize GPCRs for drug discovery as well as structural studies outside of the complex cellular environment .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK69___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state ."
] |
[
"___MASK10___",
"___MASK11___",
"___MASK13___",
"___MASK67___",
"___MASK68___",
"___MASK69___",
"___MASK70___",
"___MASK75___",
"___MASK91___"
] |
___MASK70___
|
MH_train_423
|
interacts_with DB00281?
|
[
"___MASK76___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"Substance P promotes expansion of human mesenteric preadipocytes through proliferative and antiapoptotic pathways . White adipose tissue is intimately involved in the regulation of immunity and inflammation . We reported that human mesenteric preadipocytes express the DB05875 ( SP ) - mediated neurokinin - 1 receptor ( P25103 ) , which signals proinflammatory responses . Here we tested the hypothesis that SP promotes proliferation and survival of human mesenteric preadipocytes and investigated responsible mechanism ( s ) . Preadipocytes were isolated from mesenteric fat biopsies during gastric bypass surgery . Proliferative and antiapoptotic responses were delineated in 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 5 -( 3 - carboxymethoxyphenyl )- 2 -( 4 - sulfophenyl )- 2H - tetrazolium ( MTS ) , bromodeoxyuridine ( BrdU ) , caspase - 3 , and TUNEL assays , as well as Western immunoanalysis . SP ( 10 (- 7 ) M ) increased MTS and proliferation ( BrdU ) and time dependently ( 15 - 30 min ) induced Akt , P01133 receptor , IGF receptor , integrin alphaVbeta3 , phosphatidylinositol 3 - kinase , and PKC - theta phosphorylation . Furthermore , pharmacological antagonism of Akt and PKC - theta activation significantly attenuated SP - induced preadipocyte proliferation . Exposure of preadipocytes to the proapoptotic P48023 ( P48023 , 100 microM ) resulted in nuclear DNA fragmentation ( TUNEL assay ) , as well as increased cleaved poly ( ADP - ribose ) polymerase , cleaved caspase - 7 , and caspase - 3 expression . Cotreatment with SP almost completely abolished these responses in a P25103 - dependent fashion . SP ( 10 (- 7 ) M ) also time dependently stimulated expression 4E binding protein 1 and phosphorylation of P08133 S6 kinase , which increased protein translation efficiency . SP increases preadipocyte viability , reduces apoptosis , and stimulates proliferation , possibly via cell cycle upregulation and increased protein translation efficiency . SP - induced proliferative and antiapoptotic pathways in fat depots may contribute to development of the creeping fat and inflammation characteristic of Crohn ' s disease .",
"Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms . Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level . A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour , but only limited genetic evidence for positive selection has been presented . To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset , studying single nucleotide polymorphisms ( SNPs ) , and analyzed 55 genes in detail . We identified eight genes that are associated with the melanin pathway ( Q9UMX9 , Q04671 , P17643 , P40126 , P21583 , P00533 , P14416 and Q03181 ) and presented significant differences in genetic variation between Europeans , Africans and Asians . In six of these genes we detected , by means of the EHH test , variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( Q04671 , P17643 and P21583 ) and in Asians ( Q04671 , P40126 , P21583 , P00533 and P14416 ) , whereas signals were scarce in Africans ( P40126 , P00533 and P14416 ) . Furthermore , a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed . Overall , our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians , whereas dark skin color seems of unique origin , reflecting the ancestral state in humans .",
"DB00281 inhibits tyrosine kinase activity of the epidermal growth factor receptor and suppresses proliferation of corneal epithelial cells . BACKGROUND : Although lidocaine is recognized as an excellent topical corneal analgesic , its toxic effect on corneal epithelial cells limits its use during corneal epithelial wound healing . Mechanism of the impairment of corneal reepithelialization with lidocaine , however , has not been evaluated . The authors ' previous study revealed that lidocaine inhibits the activity of tyrosine kinase receptors through the interaction with specific amino acid sequences around autophosphorylation sites , including acidic , basic , and aromatic amino acids . P00533 ( P00533 ) , a tyrosine kinase receptor with an important role in epithelial cell proliferation after corneal wounding , also possesses these amino acids sequences around autophosphorylation sites . The authors hypothesized that lidocaine would suppress tyrosine kinase activity of P00533 and would impair corneal epithelial cell proliferation . METHODS : To investigate the effect of lidocaine ( 4 microM - 40 mM ) on epidermal growth factor ( P01133 ) - stimulated autophosphorylation of P00533 , the authors studied purified P00533 in microtubes . They cultured human corneal epithelial cells ( HCECs ) with P01133 and lidocaine to investigate the effect of lidocaine on cell proliferation and on autophosphorylation of P00533 in HCECs . RESULTS : DB00281 ( > or = 400 microM ) significantly suppressed P01133 - stimulated autophosphorylation of the purified P00533 . In the HCEC study , P01133 alone stimulated cell proliferation and increased autophosphorylation of P00533 in HCECs . DB00281 ( > or = 400 microM ) significantly suppressed both the proliferation of HCECs promoted by P01133 and P01133 - stimulated autophosphorylation of P00533 . CONCLUSION : DB00281 directly inhibits tyrosine kinase activity of P00533 and suppresses the corneal epithelial cell proliferation .",
"The antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor . Local anesthetics suppress proliferation in several cancer cells . The mechanism of the suppression , however , is unknown . Our previous study shows that lidocaine , at the level of tissue concentration under topical or local administration , has a direct inhibitory effect on the activity of epidermal growth factor receptor ( P00533 ) , which is a potential target for antiproliferation in cancer cells . Therefore , we hypothesized that lidocaine would suppress the proliferation of cancer cells through the inhibition of P00533 activity . We investigated the effects of lidocaine ( 40 - 4000 microM ) on proliferation of a human tongue cancer cell line , CAL27 , which has a high level of P00533 expression , and also examined the effect of lidocaine on epidermal growth factor ( P01133 ) - stimulated autophosphorylation of P00533 in CAL27 cells . A clinical concentration of lidocaine ( 400 microM ) suppressed both serum - induced and P01133 - induced proliferation of CAL27 cells and inhibited P01133 - stimulated tyrosine kinase activity of P00533 without cytotoxicity . A larger concentration of lidocaine ( 4000 microM ) showed cytotoxicity with an antiproliferative effect . We suggest that the inhibition of P01133 - stimulated P00533 activity is one of the mechanisms of the antiproliferative effect of lidocaine on CAL27 cells . DB00281 administered topically within the oral cavity for cancer pain relief may suppress the proliferation of human tongue cancer cells .",
"Transforming growth factor - alpha directly augments histidine decarboxylase and vesicular monoamine transporter 2 production in rat enterochromaffin - like cells . For the production and vesicle storage of histamine , Enterochromaffin - like ( ECL ) cells express histidine decarboxylase ( HDC ) and vesicular monoamine transporter 2 ( Q05940 ) . Although HDC and Q05940 show dynamic changes during gastric ulcer healing , the control system of their expression has not been fully investigated . In the present study , we investigated the effect of transforming growth factor - alpha ( TGF - alpha ) and proinflammatory cytokines on HDC and Q05940 expression in rat ECL cells . Time course changes in the expression of TGF - alpha during the healing of acetic acid - induced ulcers were studied . P01133 receptor ( P00533 ) expression was also examined in ECL cells , whereas the direct effects of TGF - alpha and proinflammatory cytokines on HDC and Q05940 expression in ECL cells were investigated using in vivo and in vitro models . During the process of ulcer healing , expression of TGF - alpha mRNA was markedly augmented . Furthermore , P00533 was identified in isolated ECL cells . TGF - alpha stimulated HDC and Q05940 mRNA expression and protein production and also increased histamine release from ECL cells . Selective P00533 tyrosine kinase inhibitor tyrphostin AG1478 almost completely inhibited HDC and Q05940 gene expression induced by TGF - alpha in vivo and in vitro . During gastric mucosal injury , TGF - alpha was found to stimulate ECL cell functions by increasing HDC and Q05940 expression .",
"___MASK54___ binding to human and rat dopamine and 5 - HT receptors . ___MASK54___ ( ___MASK54___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK54___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK54___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK54___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"Dual P00533 and P42345 targeting in squamous cell carcinoma models , and development of early markers of efficacy . The epidermal growth factor receptor ( P00533 ) is a validated target in squamous cell carcinoma ( SCC ) of the head and neck . Most patients , however , do not respond or develop resistance to this agent . P42345 ( P42345 ) is involved in the pathogenesis of SCC of the head and neck ( SCCHN ) . This study aimed to determine if targeting P42345 in combination with P00533 is effective in SCC , and to develop early pharmacodynamic markers of efficacy . Two SCC cell lines , one resistant ( HEP2 ) and one of intermediate susceptibility ( Detroit 562 ) to P00533 inhibitors , were xenografted in vivo and treated with an P42345 inhibitor ( temsirolimus ) , an P00533 inhibitor ( erlotinib ) or a combination of both . ___MASK60___ exerted superior growth arrest in both cell lines than erlotinib . The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line . Immunohistochemical assessment of pharmacodynamic effects in fine - needle aspiration ( FNA ) biopsies early after treatment using phospho MAPK , Phospho - P70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination , the only group where regressions were seen . In conclusion , an P42345 inhibitor showed antitumor activity in P00533 - resistant SCC cell lines . Marked antitumor effects were associated with dual pathway inhibition , which were detected by early FNA biopsies .",
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK52___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .",
"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK79___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK94___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK46___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"O15105 but not O43541 cooperates with oncogenic ras to cause malignant conversion in a mouse model for squamous cell carcinoma . O15105 and O43541 are inhibitory Smads that block transforming growth factor - beta ( TGF - beta ) superfamily signal transduction . O15105 is overexpressed in chemically induced mouse epidermal tumors , where oncogenic activation of c - ras is a frequent event . To test the role of O15105 overexpression in tumor progression , we used retroviruses to transduce O15105 or O43541 and v - ras ( Ha ) into primary mouse keratinocytes . By itself , O15105 transiently enhanced keratinocyte proliferation , blocked normal differentiation , and induced keratin 8 , a marker of malignant conversion , but did not cause tumor formation . O15105 extended the in vitro life span , suppressed senescence , and increased transformation frequency 3 - fold of primary keratinocytes coexpressing v - ras ( Ha ) . O15105 / v - ras ( Ha ) coinfected keratinocytes rapidly progressed to squamous cell carcinomas in vivo , whereas pBabe / v - ras ( Ha )- or O43541 / v - ras ( Ha )- transduced keratinocytes formed only benign papillomas . O15105 / v - ras ( Ha ) tumors had elevated proliferation and defective nuclear localizaton of Q15796 , P84022 , and Q99717 , whereas only Q99717 was altered in O43541 / v - ras ( Ha ) tumors . O15105 overexpression in vitro induced epidermal growth factor ( P01133 ) - like growth factors TGF - alpha , heparin binding - P01133 , amphiregulin , and P01133 receptor tyrosine phosphorylation as well as the P01133 - Q15814 growth factor cripto - 1 . TGF - alpha and cripto - 1 were also overexpressed in O15105 / v - ras ( Ha ) tumors . These results suggest that O15105 overexpression accelerates tumor progression through inhibition of TGF - beta superfamily signaling and up - regulation of the P01133 - like superfamily of growth factors . This is the first demonstration that O15105 overexpression can cause malignant conversion in a multistage cancer model and suggests that it may have an important role in the pathogenesis of human cancer .",
"5 - Q13049 receptor induces P29323 phosphorylation and proliferation through ADAM - 17 tumor necrosis factor - alpha - converting enzyme ( P78536 ) activation and heparin - bound epidermal growth factor - like growth factor ( HB - P01133 ) shedding in mesangial cells . In this study , we present multiple lines of evidence to support a critical role for heparin - bound P01133 ( epidermal growth factor ) - like growth factor ( HB - P01133 ) and tumor necrosis factor - alpha - converting enzyme ( P78536 ) ( P78536 ) in the transactivation of P01133 receptor ( P00533 ) , P29323 phosphorylation , and cellular proliferation induced by the 5 - HT ( 2A ) receptor in renal mesangial cells . 5 - hydroxy - tryptamine ( 5 - HT ) resulted in rapid activation of P78536 , HB - P01133 shedding , P00533 activation , P29323 phosphorylation , and longer term increases in DNA content in mesangial cells . P29323 phosphorylation was attenuated by 1 ) neutralizing P00533 antibodies and the P00533 kinase inhibitor , AG1478 , 2 ) neutralizing HB - P01133 , but not amphiregulin , antibodies , heparin , or CM197 , and 3 ) pharmacological inhibitors of matrix - degrading metalloproteinases or P78536 small interfering RNA . Exogenously administered HB - P01133 stimulated P29323 phosphorylation . Additionally , P78536 was co - immunoprecipitated with HB - P01133 . Small interfering RNA against P78536 also blocked 5 - HT - induced increases in P29323 phosphorylation , HB - P01133 shedding , and DNA content . In aggregate , this work supports a pathway map that can be depicted as follows : 5 - HT --> 5 - HT ( 2A ) receptor --> P78536 --> HB - P01133 shedding --> P00533 --> P29323 --> increased DNA content . To our knowledge , this is the first time that P78536 has been implicated in 5 - HT - induced P00533 transactivation or in proliferation induced by a G protein - coupled receptor in native cells in culture .",
"[ ___MASK93___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK93___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"Q08431 inhibits inflammasome - induced IL - 1β production and limits postischemic cerebral injury . Milk fat globule - P01133 8 ( Q08431 ) plays important , nonredundant roles in several biological processes , including apoptotic cell clearance , angiogenesis , and adaptive immunity . Several recent studies have reported a potential role for Q08431 in regulation of the innate immune response ; however , the precise mechanisms underlying this role are poorly understood . Here , we show that Q08431 is an endogenous inhibitor of inflammasome - induced IL - 1β production . Q08431 inhibited necrotic cell - induced and DB00171 - dependent IL - 1β production by macrophages through mediation of integrin β ( 3 ) and Q99572 receptor interactions in primed cells . Itgb3 deficiency in macrophages abrogated the inhibitory effect of Q08431 on DB00171 - induced IL - 1β production . In a setting of postischemic cerebral injury in mice , Q08431 deficiency was associated with enhanced IL - 1β production and larger infarct size ; the latter was abolished after treatment with IL - 1 receptor antagonist . Q08431 supplementation significantly dampened caspase - 1 activation and IL - 1β production and reduced infarct size in wild - type mice , but did not limit cerebral necrosis in Il1b - , Itgb3 - , or P2rx7 - deficient animals . In conclusion , we demonstrated that Q08431 regulates innate immunity through inhibition of inflammasome - induced IL - 1β production .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK32___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"Protein kinase Cdelta and calmodulin regulate epidermal growth factor receptor recycling from early endosomes through Arp2 / 3 complex and cortactin . The intracellular trafficking of the epidermal growth factor receptor ( P00533 ) is regulated by a cross - talk between calmodulin ( P62158 ) and protein kinase Cdelta ( PKCdelta ) . On inhibition of P62158 , PKCdelta promotes the formation of enlarged early endosomes and blocks P00533 recycling and degradation . Here , we show that PKCdelta impairs P00533 trafficking due to the formation of an F - actin coat surrounding early endosomes . The PKCdelta - induced polymerization of actin is orchestrated by the Arp2 / 3 complex and requires the interaction of cortactin with PKCdelta . Accordingly , inhibition of actin polymerization by using cytochalasin D or by overexpression of active cofilin , restored the normal morphology of the organelle and the recycling of P00533 . Similar results were obtained after down - regulation of cortactin and the sequestration of the Arp2 / 3 complex . Furthermore we demonstrate an interaction of cortactin with P62158 and PKCdelta , the latter being dependent on P62158 inhibition . In summary , this study provides the first evidence that P62158 and PKCdelta organize actin dynamics in the early endosomal compartment , thereby regulating the intracellular trafficking of P00533 ."
] |
[
"___MASK32___",
"___MASK46___",
"___MASK52___",
"___MASK54___",
"___MASK60___",
"___MASK76___",
"___MASK79___",
"___MASK93___",
"___MASK94___"
] |
___MASK46___
|
MH_train_424
|
interacts_with DB00790?
|
[
"G protein - coupled receptor kinase 2 mediates endothelin - 1 - induced insulin resistance via the inhibition of both Galphaq / 11 and insulin receptor substrate - 1 pathways in 3T3 - Q9NUQ9 adipocytes . G protein - coupled receptor kinases ( GRKs ) regulate seven - transmembrane receptors ( 7TMRs ) by phosphorylating agonist - activated 7TMRs . Recently , we have reported that P25098 can function as a negative regulator of insulin action by interfering with G protein - q / 11 alpha - subunit ( Galphaq / 11 ) signaling , causing decreased glucose transporter 4 ( P14672 ) translocation . We have also reported that chronic endothelin - 1 ( ET - 1 ) treatment leads to heterologous desensitization of insulin signaling with decreased tyrosine phosphorylation of insulin receptor substrate ( P41252 ) - 1 and Galphaq / 11 , and decreased insulin - stimulated glucose transport in 3T3 - Q9NUQ9 adipocytes . In the current study , we have investigated the role of P25098 in chronic ET - 1 - induced insulin resistance . P01308 - induced P14672 translocation was inhibited by pretreatment with ET - 1 for 24 h , and we found that this inhibitory effect was rescued by microinjection of anti - P25098 antibody or P25098 short interfering RNA . We further found that P25098 mediates the inhibitory effects of ET - 1 by two distinct mechanisms . Firstly , adenovirus - mediated overexpression of either wild - type ( WT ) - or kinase - deficient ( KD ) - P25098 inhibited Galphaq / 11 signaling , including tyrosine phosphorylation of Galphaq / 11 and cdc42 - associated phosphatidylinositol 3 - kinase activity . Secondly , ET - 1 treatment caused DB00133 / DB00156 phosphorylation of P35568 and P35568 protein degradation . Overexpression of KD - P25098 , but not WT - P25098 , inhibited ET - 1 - induced serine 612 phosphorylation of P35568 and restored activation of this pathway . Taken together , these results suggest that P25098 mediates ET - 1 - induced insulin resistance by 1 ) inhibition of Galphaq / 11 activation , and this effect is independent of P25098 kinase activity , and 2 ) P25098 kinase activity - mediated P35568 serine phosphorylation and degradation .",
"The use of microcalorimetry and HPLC for the determination of degradation kinetics and thermodynamic parameters of DB00790 Erbumine in aqueous solutions . DB00790 Erbumine ( O15534 ) is one of the newly used angiotensin - converting enzyme inhibitors ( P12821 inhibitors ) and is used for the treatment of patients with hypertension and symptomatic heart failure . It has two main degradation pathways , i . e . the degradation by hydrolysis and the degradation by cyclization . An isothermal heat conduction microcalorimetry ( MC ) and high pressure liquid chromatography ( HPLC ) were used for the characterization of aqueous solutions of O15534 and its stability properties . The rates of heat evolved during degradation of perindopril were measured by MC as a function of temperature and pH and from these data rate constant and change in enthalpy of the reactions were determined . With the HPLC method the concentration of perindopril and its degradation products were measured as a function of time in aqueous solutions of different pH that were stored at different temperatures . We demonstrated that reactions of degradation of perindopril at observed conditions follow the first order kinetics . The Arrhenius equation for each pH was determined . At pH 6 . 8 only one degradation pathway is present , i . e . the degradation by hydrolysis . Degradation constants for this pathway calculated from MC data are in good agreement with those obtained from HPLC . MC as a non - specific technique was shown to be useful in studies of O15534 when one reaction was present in the sample and also when more chemical and physical processes were simultaneously running .",
"The role of vascular endothelial growth factor and matrix metalloproteinases in canine lymphoma : in vivo and in vitro study . BACKGROUND : Canine lymphoma represents the most frequent haematopoietic cancer and it shares some similarities with human non - Hodgkin lymphoma . Matrix metalloproteinases ( MMPs ) and vascular endothelial growth factor ( P15692 ) play a coordinated role during invasion and proliferation of malignant cells ; however , little is known about their role in canine haematologic malignancies . The aim of this study was to investigate the mRNA and protein expression of P15692 and the most relevant MMPs in canine lymphoma . Lymph node aspirates from 26 B - cell and 21 T - cell lymphomas were collected . The protein expression levels of P14780 , P08253 and P15692 were evaluated by immunocytochemistry , and the mRNA levels of P08253 , P14780 , P50281 , P01033 , P16035 , O95980 , P15692 and P15692 - 164 were measured using quantitative RT - PCR . RESULTS : P50281 , P01033 and O95980 mRNA levels were significantly higher in T - cell lymphomas than in B - cell lymphomas . Higher mRNA and protein levels of P14780 and P15692 were observed in T - cell lymphomas than in B - cell lymphomas and healthy control lymph nodes . A positive correlation was found between P14780 and P15692 in T - cell lymphomas . Moreover , P14780 , P50281 , P01033 and P15692 were expressed at the highest levels in high - grade T - cell lymphomas . CONCLUSIONS : This study provides new information on the expression of different MMPs and P15692 in canine lymphoma , suggesting a possible correlation between different MMPs and P15692 , immunophenotype and prognosis .",
"Regulation of matrix metalloproteinases ( MMP ) - 2 /- 9 expression in eosinophilic chronic rhinosinusitis -- cell culture by interleukin - 5 and - 13 ? BACKGROUND : Eosinophils are a prominent immunological feature of chronic rhinosinusitis ( CRS ) . Cytokines in the respiratory mucosa may be the key to upper airway pathophysiology . Matrix metalloproteinases ( MMP ) represent an entire group of DB01593 dependent endopeptidases with the potential to alter the extracellular matrix ( Q13201 ) . In this study epithelial cultures of CRS were treated with interleukin ( IL ) - 5 or P35225 and subsequent levels of metalloproteinases were determined . MATERIALS AND METHODS : The cells for CRS culture were obtained from patients undergoing functional endoscopic sinus surgery . After 8 - 72 hours incubation with 0 . 2 - 0 . 4 ng / ml P05113 or 3 - 6 ng / ml P35225 , the expression of the P08253 and - 9 in the CRS cultures was analysed . RESULTS : After 72 hours incubation with P05113 , the relative levels of P08253 showed no significant alteration in protein expression in comparison with the control groups . Incubation with P35225 revealed a statistically insignificant decrease of the relative P14780 expression in ECRS compared to the control group ( p > 0 . 1 ) . CONCLUSION : Alterations of P08253 and - 9 expression may play a role in ECRS , but the association with P05113 and P35225 remains unclear .",
"DB04216 abrogates P05231 / P40763 signaling and inhibits glioblastoma cell line growth and migration . Evidence has suggested that P40763 functions as an oncogene in gliomagenesis . As a consequence , changes in the inflammatory microenvironment are thought to promote tumor development . Regardless of its origin , cancer - related inflammation has many tumor - promoting effects , such as the promotion of cell cycle progression , cell proliferation , cell migration and cell survival . Given that P05231 , a major cancer - related inflammatory cytokine , regulates P40763 activation and is upregulated in glioblastoma , we sought to investigate the inhibitory effects of the chemopreventive flavonoid quercetin on glioblastoma cell proliferation and migration triggered by P05231 , and to determine the underlying mechanisms of action . In this study , we show that quercetin is a potent inhibitor of the P05231 - induced P40763 signaling pathway in T98G and U87 glioblastoma cells . Exposure to quercetin resulted in the reduction of P42704 , P23458 and P40763 activation by P05231 , as well as a marked decrease of the proliferative and migratory properties of glioblastoma cells induced by P05231 . Interestingly , quercetin also modulated the expression of two target genes regulated by P40763 , i . e . cyclin D1 and matrix metalloproteinase - 2 ( P08253 ) . Moreover , quercetin reduced the recruitment of P40763 at the cyclin D1 promoter and inhibited Rb phosphorylation in the presence of P05231 . Overall , these results provide new insight into the role of quercetin as a blocker of the P40763 activation pathway stimulated by P05231 , with a potential role in the prevention and treatment of glioblastoma .",
"Causation , prevention and reversal of vascular endothelial dysfunction . P01308 Resistance along with endothelial dysfunction give rise to a constellation of syndromes designated as P41252 / O14974 metabolic syndrome . Endothelial dysfunction starts early in life much before the development of structural atherosclerosis . Recent insights into vascular biology enable us to understand the molecular mechanisms underlying endothelial dysfunction , and the scope and need for prevention of \" pre - clinical \" coronary atherosclerosis through lifestyle modification ; diet , exercise and stress management . Diminished production of nitric oxide ( NO ) and / or increased inactivation of NO through oxidative stress ( reactive oxygen species ROS and reactive nitrogen species ( RNS ) are the basis of endothelial dysfunction hence increasing the bioavailability of NO and decreasing its inactivation is the aim of prevention and reversal of endothelial dysfunction . P01308 regulates constitutive NOS gene expression in endothelial cells in vivo ; vasodilation is an important component of P01308 - stimulated whole body glucose uptake . Successful strategies are : Q07869 alpha and gamma agonists which increase NO production in endothelium ; anti - oxidants such as vit . E and C ; supplementation with L - arginine , tetrahydrobiopterin - BH4 or sepiapterin ( precursor of BH4 ) , SOD mimetic tempol , statins which apart from lowering cholesterol improve NO production , selective beta1 adrenoreceptor antagonists such as nebivolol ; suppression of angiotensin - mediated endothelin production by P12821 inhibitors and ATR blockers ; P21554 receptor blockers , PKCb inhibitors , nitric oxide donors ( glyceryl trinitrate and isosorbide dinitrate ) , dietary supplements of EPA / DB01708 and regular physical exercise and control of mental stress .",
"P10275 coregulator Q96L73 - alpha interacts with death receptor - 6 revealed by the yeast two - hybrid . Q96L73 - alpha is a newly identified androgen receptor coactivator . In order to further elucidate its precise role in cells , using the Q96L73 - alpha fragment containing four P20941 and one Q01105 conserved domains as bait we revealed an Q96L73 - alpha - P20941 - Q01105 - interacting protein , death receptor - 6 ( O75509 ) , in the yeast two - hybrid screening . O75509 is the member of P01375 receptor family and has a death domain in its intracellular cytoplasmic portion ( DR6cp ) to mediate the cell apoptosis . The interaction between Q96L73 - alpha - P20941 - Q01105 and DR6cp was confirmed in vitro and in vivo . Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between Q96L73 - alpha and O75509 .",
"A role for plasma transforming growth factor - beta and matrix metalloproteinases in aortic aneurysm surveillance in Marfan syndrome ? BACKGROUND : We have previously shown that the angiotensin - converting enzyme ( P12821 ) inhibitor perindopril reduced aortic diameter by 3 - 7mm in Marfan syndrome ( MFS ) patients . Excessive signalling by the transforming growth factor - beta ( TGF - beta ) has been implicated in the development of aortic dilatation . We hypothesised that reduction in aortic diameter would correlate with reduction in plasma TGF - beta and matrix metalloproteinase ( MMP ) levels . METHODS : 17 MFS patients ( aged 33 +/- 5 ( mean +/- SD ) ) on standard beta - blocker therapy were randomised to also receive perindopril ( n = 10 ) or placebo ( n = 7 ) for 24 weeks in a double blind study . Aortic root diameters were assessed at four sites via transthoracic echocardiography . Venous blood samples were analysed for latent and active TGF - beta , P08253 and P08254 levels . RESULTS : DB00790 significantly reduced aortic root diameters relative to placebo in both end - systole and end - diastole ( by 1 . 2 - 3mm / m ( 2 ) , p < 0 . 001 ) . In addition , compared to placebo perindopril significantly reduced latent TGF - beta levels by 14 . 0 +/- 4 . 5ng / ml ( p = 0 . 01 ) , active TGF - beta levels by 4 +/- 1ng / ml ( p = 0 . 02 ) , P08253 levels by 22 +/- 6ng / ml ( p < 0 . 001 ) , and P08254 levels by 5 +/- 1ng / ml ( p < 0 . 001 ) . There were moderately strong correlations between the pre / post intervention change in aortic diameters and the change in both latent ( r = 0 . 49 - 0 . 76 , p = 0 . 001 - 0 . 04 ) and active TGF - beta ( r = 0 . 59 - 0 . 73 , p = 0 . 002 - 0 . 02 ) , P08253 ( r = 0 . 63 - 0 . 75 , p = 0 . 001 - 0 . 007 ) , and P08254 plasma levels ( r = 0 . 81 - 0 . 83 , p < 0 . 0001 ) . CONCLUSIONS : Plasma TGF - beta , P08253 and P08254 should be further explored in longitudinal trials as potential prognostic indicators of progression of aortic dilatation and response to therapy in MFS .",
"Dual effect of angiotensin - converting enzyme inhibition on angiogenesis in type 1 diabetic mice . OBJECTIVE : We analyzed the beneficial therapeutic effect of angiotensin converting enzyme inhibitor ( ACEI ) on both retinal and hind limb neovascularization in diabetic mice . METHODS AND RESULTS : Diabetic mice ( streptozotocin , 40 mg / kg ) were treated with or without ACEI ( DB00790 , 3 mg / kg per day ) or AT1 receptor blocker ( DB00796 , 20 mg / kg ) for 4 months . Hind limb ischemia was then induced by right femoral artery ligature for 1 additional month . In the ischemic leg , angiographic score , capillary density , and foot perfusion were increased by 2 . 7 , 2 . 0 - fold , and 1 . 6 - fold , respectively , in ACEI - treated diabetic mice compared with untreated diabetic animals ( P < 0 . 01 ) . ACEI also raised vascular endothelial growth factor ( P15692 ) protein level by 1 . 4 - fold in ischemic diabetic leg . This ACEI pro - angiogenic effect was totally blunted in diabetic bradykinin B2 receptor - deficient animals , suggesting that it was mediated by the bradykinin pathway . In the diabetic retina , angiotensinogen and P12821 mRNA levels were increased by 2 . 8 - fold and 4 . 1 - fold , respectively ( P < 0 . 01 versus nondiabetic mice ) , highlighting a local activation of renin - angiotensin system . Diabetes also raised P15692 protein level by 1 . 5 - fold ( P < 0 . 05 versus nondiabetic mice ) . Treatments with ACEI and AT1 receptor blocker hampered diabetes - induced P15692 upregulation and retinal neovascularization . CONCLUSIONS : P12821 inhibition improved neovascularization in the diabetic ischemic leg through activation of bradykinin signaling , whereas it reduced vessel growth in the diabetic retina through inhibition of overacting Ang II pathway .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK3___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"Inflammatory profiles in nasal mucosa of patients with persistent vs intermittent allergic rhinitis . BACKGROUND : To date there is little information on the inflammatory profiles of patients suffering from persistent ( O15534 ) and intermittent allergic rhinitis ( Q92932 ) . Also , it is not clear whether differences exist in eosinophilic inflammation and / or T - helper cell sub - populations and their markers . The aim of this study was to primarily evaluate the inflammatory profiles of patients with moderate / severe O15534 and Q92932 . METHODS : Inferior nasal turbinate tissue was obtained from 12 O15534 , 12 Q92932 and 12 nonallergic nonrhinitic ( control ) patients , and symptoms ( visual analogue scales , VAS ) and impairment of life was monitored . All tissues were assessed for eosinophil and mast cell numbers by immunohistochemistry ; P05113 , P12724 and IgE concentrations by immunoassay ; mRNA for transcription factors GATA - 3 , T - bet , Q9BZS1 and RORc by quantitative real - time polymerase chain reaction ; and IgE - induced release of LTC ( 4 )/ D ( 4 )/ E ( 4 ) and P52209 ( 2 ) in vitro . RESULTS : Eosinophils and mast cells were significantly increased in patients with O15534 and patients with Q92932 compared to control subjects ; by patients with O15534 demonstrating even significantly greater increase of both cell types than patients with Q92932 . Similarly , P12724 P05113 , GATA - 3 mRNA expression and IgE - induced release of LTC4 / D ( 4 )/ E ( 4 ) and P52209 ( 2 ) from mast cells were significantly increased in patients with O15534 compared to patients with Q92932 . In contrast , the expression of T - bet , Q9BZS1 or RORc mRNA was not significantly different in the O15534 , Q92932 or control patients . CONCLUSION : The findings from the present study suggest that O15534 is characterized by a significantly greater eosinophilic and predominantly Th2 cell - mediated nasal inflammatory profile compared to Q92932 .",
"DB00790 decreases P wave dispersion in patients with stage 1 hypertension . INTRODUCTION : P12821 inhibitors prevent atrial fibrillation episodes by effective control of blood pressure and improving electrical and structural remodelling in the atria . Increased P wave dispersion ( P35670 ) is a non - invasive electrocardiographic marker for paroxysmal atrial fibrillation . The aim of the study was to evaluate the effect of perindopril treatment on P35670 in hypertensive patients . METHODS : Forty - eight hypertensive patients ( mean age 57 . 4 +/- 11 . 8 years , 18 men ) were included . Blood pressure values were determined and 12 - lead electrocardiograms were recorded at the beginning and at the first week , first month , third month and sixth month of the perindopril treatment . The difference between maximum and minimum P wave durations was calculated as P35670 . RESULTS : PWDs were significantly shortened at the first , third and sixth months ( 41 . 7 +/- 8 . 8 ms , Q04695 +/- 6 . 9 ms and 38 . 3 +/- 7 . 1 ms , respectively ) compared with baseline and first - week measurements ( 54 . 3 +/- 9 . 2 ms and 49 . 0 +/- 9 . 1 ms , respectively , p < 0 . 001 ) . Baseline P35670 was correlated with body mass index ( r = 0 . 32 , p = 0 . 026 ) , while P35670 at the sixth month of treatment was significantly correlated with left atrial volume index ( r = 0 . 30 , p = 0 . 042 ) . Multiple linear regression analysis revealed that P35670 at the sixth month was related to baseline P35670 ( p = 0 . 001 ) . CONCLUSION : DB00790 treatment significantly reduced P35670 in hypertensive patients .",
"An P12821 inhibitor reduces Th2 cytokines and TGF - beta1 and TGF - beta2 isoforms in murine lupus nephritis . BACKGROUND : P12821 ( P12821 ) inhibitors , such as captopril , are used to control hypertension . In patients and animals with primary nephropathies , these agents improve renal function more than that would be expected from their control of hypertension . Here , we examine the effects of treatment with captopril on lupus nephritis and discuss the potential mechanism ( s ) by which this agent exerts its renoprotective effects . METHODS : Lupus - prone , NZB / NZW F1 and MRL - lpr / lpr , mice were treated with captopril or with a control antihypertensive agent , verapamil . Mice were monitored for nephritis , and their sera and tissues analyzed for cytokine and transforming growth factor - beta ( TGF - beta ) expression . RESULTS : DB01197 treatment delayed the onset of proteinuria when administered to prenephritic mice , whereas verapamil did not . DB01197 treatment also retarded disease progression when given to lupus mice that had early disease , and even reversed severe proteinuria in at least some older animals with advanced disease . It reduced chronic renal lesions , but had no effect on autoantibody production . The improvement in renal disease correlated with reduced TGF - beta expression , particularly of the TGF - beta1 and TGF - beta2 isoforms , in the kidneys . Interestingly , in vivo or in vitro exposure to captopril reduced splenic levels of type 2 cytokines , interleukin ( IL ) - 4 and P22301 , suggesting a possible role of the immune system in captopril - mediated disease modulation . CONCLUSION : Since type 2 cytokines are known to promote lupus glomerulosclerosis , decreased P05112 and P22301 production in captopril - treated mice may be related to this agent ' s renoprotective effects . We argue here that P12821 inhibitors not only act as selective TGF - beta inhibitors , but also as selective immunomodulators , to improve lupus nephritis .",
"Inhibition of the renin - angiotensin system improves physiological outcomes in mice with mild or severe cancer cachexia . Cancer cachexia describes the progressive skeletal muscle wasting and weakness associated with many cancers . Cachexia reduces mobility and quality of life and accounts for 20 - 30 % of all cancer - related deaths . Activation of the renin - angiotensin system causes skeletal muscle wasting and weakness . We tested the hypothesis that treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , perindopril , would enhance whole body and skeletal muscle function in cachectic mice bearing Colon - 26 ( C - 26 ) tumors . CD2F1 mice received a subcutaneous injection of phosphate buffered saline or C - 26 tumor cells inducing either a mild or severe cachexia . The following day , one cohort of C - 26 mice began receiving perindopril in their drinking water ( 4 mg kg (- 1 ) day (- 1 ) ) for 21 days . In mild and severe cachexia , perindopril increased measures of whole body function ( grip strength and rotarod ) and reduced fatigue in isolated contracting diaphragm muscle strips ( p < 0 . 05 ) . In severely cachectic mice , perindopril reduced tumor growth , improved locomotor activity and reduced fatigue of tibialis anterior muscles in situ ( p < 0 . 05 ) , which was associated with increased oxidative enzyme capacity ( succinate deyhydrogenase , p < 0 . 05 ) . DB00790 attenuated the increase in Q969Q1 and P05231 mRNA expression and enhanced Akt phosphorylation in severely cachectic mice but neither body nor muscle mass was increased . These findings support the therapeutic potential of P12821 inhibition for enhancing whole body function and reducing fatigue of respiratory muscles in early and late stage cancer cachexia and should be confirmed in future clinical trials . Since P12821 inhibition alone did not enhance body or muscle mass , co - treatment with an anabolic agent may be required to address these aspects of cancer cachexia .",
"Matrix metallopeptidase 2 ( P08253 ) mediates Q29983 ( Q29983 ) shedding in renal cell carcinoma . INTRODUCTION : The MHC class i chain - related molecule A ( Q29983 ) is a ligand for the natural killer group 2 , member D ( P26718 ) immunoreceptor activation . The engagement of tumor cell surface Q29983 to P26718 stimulates the NK and T cell antitumor immunity . Shedding of Q29983 by tumor cells facilitates tumor immune evasion , which might partially contribute to tumor progression . MATERIAL AND METHODS : Inmunohistochemistry was performed on both normal and neoplastic renal tissue . Human renal carcinoma cell lines 786 - 0 and ACHIN were transfected and target sequences to silence human P08253 by shRNA expression were established . The degree of Q29983 shedding was measured and quantitative real - time PCR and Western - blot analysis were performed . RESULTS : The membrane type matrix metalloproteinase 2 ( P08253 ) mediated the Q29983 shedding , which was blocked by suppression of P08253 expression . Concomitantly , P08253 over - expression enhanced the Q29983 shedding , indicating that P08253 was involved in the renal cell carcinoma - associated proteolytic release of soluble Q29983 ( sMICA ) , which facilitated the tumor immune escape . CONCLUSIONS : These findings suggested that P08253 might be a new potential target for tumor immune therapy . Elucidation of the mechanisms by which tumors shed Q29983 could be of a great importance for cancer treatment in order to reinforce the NK and T cell antitumor immunity .",
"Bayesian meta - analysis of tissue angiotensin - converting enzyme inhibitors for reduction of adverse cardiovascular events in patients with diabetes mellitus and preserved left ventricular function . The role of angiotensin - converting enzyme ( P12821 ) inhibitors in diabetic patients with preserved ventricular function is uncertain . Tissue P12821 inhibitors have been defined by increased lipophilicity and structural characteristics that result in greater tissue - specific P12821 binding when compared with plasma P12821 inhibitors . A Bayesian meta - analysis of randomized trials was conducted to evaluate tissue P12821 inhibitors in prevention of cardiovascular disease among patients with diabetes mellitus and preserved left ventricular function . Four trials were selected that evaluated 2 different P12821 inhibitors and included 10 , 328 patients ( 43 , 517 patient - years ) . The DB00790 Substudy in Coronary Artery Disease and Diabetes ( PERSUADE ) and the DB00790 Protection Against Recurrent Stroke Study ( PROGRESS ) compared the effects of perindopril vs a placebo , and the Heart Outcomes Prevention Evaluation ( HOPE ) and the Non - P01308 - Dependent Diabetes , Hypertension , Microalbuminuria , Proteinuria , Cardiovascular Events , and Ramipril ( DIABHYCAR ) study investigated the impact of ramipril vs a placebo . Bayesian meta - analysis of sequential trials and sensitivity analysis of therapeutic response were subsequently computed . Bayesian meta - analysis determined reduced risk of cardiovascular mortality ( PB =. 991 ) , myocardial infarction ( PB =. 999 ) , and the need for invasive coronary revascularization ( PB =. 995 ) when compared with placebo . Total mortality was also decreased ( PB =. 967 ) , while the risk of stroke ( PB =. 907 ) and hospitalization for heart failure ( PB =. 923 ) were impacted . Bayesian meta - analysis of randomized trials suggests that tissue P12821 inhibitors decrease the probability that diabetic patients with preserved left ventricular function will experience myocardial infarctions and cardiovascular death and reduce overall mortality .",
"Early and delayed castrations confer a similar survival advantage in TRAMP mice . The most appropriate time to introduce androgen deprivation therapy for prostate cancer remains controversial . Our aim was to evaluate the effects of early versus delayed surgical castration on prostate cancer progression and survival in the transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model . TRAMP mice were randomly divided into three groups : the early castration group ( on which castration was performed at the age of 4 weeks ) , the delayed castration group ( on which castration was performed when abdominal tumours could be palpated ) , and the sham - castrated group . Mice were monitored daily throughout their lives until cancer - related death or the development of an obviously moribund appearance , at which time the individual mouse was killed . P10275 expression in prostate tumours was also evaluated . The results shows that the average lifespan in early castration , delayed castration and sham - castrated groups were 54 . 1 weeks , 59 . 9 weeks and Q04695 weeks , respectively . Both early castration and delayed castration conferred a statistically significant survival advantage when compared with the sham - castrated group ( P < 0 . 001 ) . However , the difference in lifespan between the early castration group and the delayed castration group was not statistically significant ( P = 0 . 85 ) . The increase in lifespan in the TRAMP mice that received either early or delayed castration correlated with lower G / B value ( genitourinary tract weight / body weight ) at death than the sham - castrated mice . In conclusion , early and delayed castrations in TRAMP mice prolonged survival to a similar extent . This finding may provide a guide for clinical practice in prostate cancer therapy .",
"Pharmacological and parametrical investigation of prepulse inhibition of startle and prepulse elicited reactions in Wistar rats . Prepulse inhibition ( PPI ) is the inhibition of an acoustic startle response ( ASR ) that is observed when a weak prepulse is presented shortly before a startling stimulus . Here we studied in Wistar rats the dependence of PPI on variations of the interstimulus interval ( ISI ; from 25 - 1020ms ) after treatment with various drugs that are known to disrupt PPI . The motor response to the prepulse itself ( prepulse elicited reaction , O15534 ) was also studied . The direct dopamine receptor agonist apomorphine , the non - competitive DB01221 glutamate receptor antagonist MK - 801 , and the cannabinoid P21554 receptor agonist Q08050 55 , 212 - 2 all reduced PPI , depending on the ISI , with different effects on the O15534 and / or pulse alone . The serotonin 2A receptor agonist DOI tended to reduce PPI . The cannabinoid P21554 receptor antagonist AM 251 did neither affect PPI nor the responses to prepulses or startling noise pulses . Taken together this study supports the current notion of a pharmacologically complex pattern of regulation of PPI at different ISIs and suggests that the O15534 is a miniature ASR that does , however , not predict the level of PPI .",
"Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with ___MASK82___ , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20 - week - old Zucker obese and 16 - week - old ZDF rats were treated with ___MASK82___ ( 25 mg / kg / day ) or Enalapril ( 20 mg / kg / day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75 - 175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with ___MASK82___ or Enalapril .",
"P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK89___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .",
"Exenatide blocks P23458 - P42224 in pancreatic beta cells . Exenatide ( Ex - 4 ) is an antidiabetic drug that acts through the glucagon - like peptide 1 receptor and has recently been approved for the treatment of type 2 diabetes mellitus . Ex - 4 also has been shown to affect beta cell gene expression and increase beta cell mass in rodent models of type 1 diabetes mellitus , but the mechanisms are not fully understood . We therefore analyzed the pathways affected by Ex - 4 in human islets by using oligonucleotide microarrays and the PathwayStudio software ( Ariadne Genomics , Rockville , MD ) . We identified the P23458 - P42224 pathway as a novel target of Ex - 4 and confirmed the Ex - 4 - mediated down - regulation of P23458 and P42224 by quantitative reverse transcription - polymerase chain reaction in human islets and P01308 - 1 cells . P23458 - P42224 is the major signaling pathway mediating the interferon gamma effects on beta cell apoptosis in type 1 diabetes mellitus . Thus , these findings suggest that Ex - 4 treatment may also be beneficial in type 1 diabetes mellitus , where it may help protect beta cells from cytokine - induced cell death by inhibiting P23458 - P42224 .",
"Inhibition of central angiotensin converting enzyme ameliorates scopolamine induced memory impairment in mice : role of cholinergic neurotransmission , cerebral blood flow and brain energy metabolism . Evidences indicate that inhibition of central P00797 angiotensin system ( DB01367 ) ameliorates memory impairment in animals and humans . Earlier we have reported involvement of central angiotensin converting enzyme ( P12821 ) in streptozotocin induced neurodegeneration and memory impairment . The present study investigated the role of central P12821 in cholinergic neurotransmission , brain energy metabolism and cerebral blood flow ( Q03701 ) in model of memory impairment induced by injection of scopolamine in mice . DB00790 ( 0 . 05 and 0 . 1 mg / kg , PO ) was given orally for one week before administration of scopolamine ( 3mg / kg , IP ) . Then , memory function was evaluated by Morris water maze and passive avoidance tests . Q03701 was measured by laser Doppler flowmetry . Biochemical and molecular parameters were estimated after the completion of behavioral studies . DB00747 caused impairment in memory which was associated with reduced Q03701 , acetylcholine ( ACh ) level and elevated acetylcholinesterase ( P22303 ) activity and malondialdehyde ( MDA ) level . DB00790 ameliorated scopolamine induced amnesia in both the behavioral paradigms . Further , perindopril prevented elevation of P22303 and MDA level in mice brain . There was a significant increase in Q03701 and ACh level in perindopril treated mice . However , scopolamine had no significant effect on DB00171 level and mRNA expression of angiotensin receptors and P12821 in cortex and hippocampus . But , perindopril significantly decreased P12821 activity in brain without affecting its mRNA expression . The study clearly showed the interaction between P12821 and cholinergic neurotransmission and beneficial effect of perindopril can be attributed to improvement in central cholinergic neurotransmission and Q03701 .",
"[ An effect of perindopril on the level of tumor necrosis factor - alpha and matrix metalloproteinase - 9 in peripheral blood in the acute period of atherothrombotic ischemic stroke and myocardial infarction ] . Twenty - nine patients with acute atherothrombotic ischemic stroke and 36 patients with acute Q - wave myocardial infarction have been studied . Each group has been stratified into 2 subgroups : patients of subgroups A received an P12821 inhibitor perindopril in the complex therapy from the 1st day of disease . Patients of subgroups B were not assigned to this drug . Along with routine tests , the level of tumor necrosis factor - alpha and matrix metalloproteinase - 9 ( P14780 ) measured with ELISA using test - systems ( Q02223 Diagnostics , USA ) and reagents ( R & D , England ) have been determined . The administration of perindopril did not cause side - effects , including arterial hypotonia after the first dosage , in patients in the acute period of atherothrombotic ischemic stroke and myocardial infarction . DB00790 may decrease the activity of P14780 in these patients and produces an anticytokine effect . Some similar mechanisms of ischemic lesions of the heart and the brain and a commonness of biochemical \" response \" to the same medical intervention ( the administration of an P12821 inhibitor perindopril ) in patients of both groups were found . The results support the pathogenetic validity of perindopril therapy in the secondary prevention of ischemic stroke and myocardial infarction .",
"A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re - vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly - developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 - based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically - used drugs operating on the P00797 - Angiotensin - DB04630 - System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point - of - no - return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling - reversing drugs to pathways other than RAAS , a specific inhibitor of 11β - hydroxy - steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy - associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization - induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling - reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects .",
"Cardiac protective effect of Astragalus on viral myocarditis mice : comparison with DB00790 . In clinical practice , Astragali Radix ( Astragalus ) , the root of Astragalus membranaceus Bunge , has been widely applied to treat patients with viral diseases , including viral myocarditis in China . The present study was designed to evaluate the protective effects of Astragalus on the function of sarcoplasmic reticulum calcium ATPase ( P16615 ) activity and endothelin system at acute and chronic periods of myocarditis mice induced by CVB ( 3 ) infection . Astragalus feeding ( 2 . 2 mg / kg / day ) could significantly increase the survival rate , alleviate pathological alterations and serum cardiac troponin I ( cTnI ) , as well as restore impaired SERCA activity at the acute stage . Low affinity and capacity of ETR were reversed with Astragalus after the first CVB ( 3 ) inoculation up to 7 days and after the second virus inoculation up to 150 days . In the meantime , the contents of cardiac ET - 1 and P01160 were reduced . Comparison the myocarditis mice treated with DB00790 ( 0 . 44 mg / kg / day ) , an P12821 inhibitor , shows that Astragalus achieved a similar effect on survival rate , P16615 and ET system . These results indicated that the beneficial effects of Astragalus and DB00790 for treating viral myocarditis might be partly mediated by preserving the functions of SERCA 2 activity and ET system .",
"P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell - surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration - response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed .",
"___MASK32___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK32___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK32___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK32___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"DB02901 interacts with P00533 / MAPK signalling and modulates P00533 levels in androgen receptor - positive LNCaP prostate cancer cells . P10275 ( AR ) signalling plays a pivotal role in prostate cancer pathogenesis and progression . However , androgen - mediated AR signalling is yet to be fully understood . P00533 and Q96HU1 kinase signalling pathways play predominant roles in AR function . Therefore , we investigated the interaction of P00533 signalling and AR activity in AR - positive LNCaP cells . We found that 5alpha - dihydrotestosterone ( DB02901 ) and P01133 had a synergistic effect on AR activity as detected by a luciferase reporter system , although P01133 alone did not activate AR . Both P27361 / 2 and p38 were involved in DB02901 and DB02901 / P01133 - induced AR activation as detected by specific MEK and p38 inhibitors . Furthermore , 24 - h treatment of the cells with DB02901 resulted in ubiquitination and down - regulation of the P00533 . This effect could be inhibited by the anti - androgen flutamide , suggesting an androgen - dependent mechanism . On the other hand , DB02901 - treatment strongly increased AR levels in LNCaP cells . These data suggest a complex regulatory loop between activated AR and P00533 . In conclusion , activation of AR by both DB02901 and P01133 / DB02901 involves the Q96HU1 kinase pathway . Long - term activation of AR results in increase of AR levels , which through so far unknown regulatory mechanisms results in ubiquitination and degradation of the P00533 .",
"Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK32___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK32___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK32___ .",
"Different effects of perindopril and enalapril on monocyte cytokine release in coronary artery disease patients with normal blood pressure . BACKGROUND : Favorable effects of angiotensin - converting enzyme ( P12821 ) inhibitor treatment on the incidence of cardiovascular and cerebrovascular mortality and morbidity are not limited to patients with elevated blood pressure . As suggested by our previous results , the physicochemical and pharmacokinetic differences between drugs may markedly contribute to the strength of pleiotropic effects of P12821 inhibitors . METHODS : The present study was aimed at comparing the effects of serum - and tissue - type P12821 inhibitors on monocyte release of proinflammatory cytokines in normotensive patients with stable coronary artery disease . The participants were randomized to 90 - day treatment with enalapril ( 20 mg daily , n = 29 ) , perindopril ( 4 mg daily , n = 27 ) or placebo ( n = 28 ) . Plasma levels of lipids , glucose , insulin and high sensitivity P02741 ( hsCRP ) , as well as monocyte release of proinflammatory cytokines were determined before and after 30 days of therapy , and at the end of the treatment . RESULTS : Lipopolysaccharide - stimulated monocytes from normotensive patients with stable coronary artery disease released significantly more P01375 - α , interleukin - 1β and monocyte chemoattractant protein - 1 in comparison with monocytes from 23 matched control subjects . Their baseline hsCRP levels were also higher . DB00790 reversed the disease - induced changes in cytokine release and reduced plasma hsCRP , while the effect of enalapril was much more limited . The effect on both drugs on cytokine release was stronger in insulin - resistant than insulin - sensitive subjects . CONCLUSIONS : Our results indicate that perindopril is superior to enalapril in producing monocyte - suppressing and systemic anti - inflammatory effects in normotensive patients with coronary artery disease . This action may contribute to the clinical effectiveness of tissue P12821 inhibitors in the therapy of atherosclerosis - related disorders , particularly in insulin - resistant subjects .",
"Analgesic and Anti - Inflammatory Activities of Methanol Extract of Cissus repens in Mice . The aim of this study was to investigate possible analgesic and anti - inflammatory mechanisms of the CR ( MeOH ) . Analgesic effect was evaluated in two models including acetic acid - induced writhing response and formalin - induced paw licking . The anti - inflammatory effect was evaluated by λ - carrageenan - induced mouse paw edema and histopathologic analyses . The results showed that CR ( MeOH ) ( 500 mg / kg ) decreased writhing response in the acetic acid assay and licking time in the formalin test . CR ( MeOH ) ( 100 and 500 mg / kg ) significantly decreased edema paw volume at 4th to 5th hours after λ - carrageenan had been injected . Histopathologically , CR ( MeOH ) abated the level of tissue destruction and swelling of the edema paws . These results were indicated that anti - inflammatory mechanism of CR ( MeOH ) may be due to declined levels of NO and MDA in the edema paw through increasing the activities of SOD , GPx , and GRd in the liver . Additionally , CR ( MeOH ) also decreased IL - 1β , P05231 , NFκB , P01375 - α , P35354 , and P35228 levels . The contents of two active ingredients , ursolic acid and lupeol , were quantitatively determined . This paper demonstrated possible mechanisms for the analgesic and anti - inflammatory effects of CR ( MeOH ) and provided evidence for the classical treatment of Cissus repens in inflammatory diseases .",
"Vascular endothelial growth factor expression and glomerular endothelial cell loss in the remnant kidney model . BACKGROUND : Vascular endothelial growth factor ( P15692 ) is constitutively expressed in the glomerulus where it may have a role in the maintenance of capillary endothelial cell integrity . The present study sought to examine changes in P15692 expression in a model of progressive renal disease and to assess the effects of angiotensin converting enzyme ( P12821 ) inhibition . METHODS : Subtotal nephrectomized ( STNx ) rats were randomly assigned to receive vehicle ( n = 10 ) or the P12821 inhibitor perindopril ( 8 mg / l drinking water ) for 12 weeks duration ( n = 10 ) . Sham - operated rats were used as controls ( n = 10 ) . Glomerular capillary endothelial cell density was evaluated by immunostaining for the pan - endothelial cell marker Q06609 - 1 and P15692 expression was assessed by quantitative in situ hybridization . RESULTS : In STNx rats glomerular capillary endothelial cell density was reduced to 19 % that of sham rats ( P < 0 . 01 ) with a concomitant reduction in glomerular P15692 expression , also to 19 % of sham rats ( P < 0 . 01 ) . DB00790 treatment was associated with normalization of both capillary endothelial cell density and glomerular P15692 mRNA . CONCLUSIONS : Reduction in glomerular P15692 expression is a feature of the renal pathology that follows subtotal nephrectomy . In the context of the known functions of this growth factor , these findings suggest that diminution in P15692 may contribute to the demonstrated loss of glomerular endothelium that develops in this model of progressive renal disease .",
"Functional role of wogonin in anti - angiogenesis . Constitutive activation of the Janus kinase ( JAK ) / signal transducer and activator of transcription ( P35610 ) pathway occurs commonly in cancer cells and endothelial cells , and contributes to angiogenesis . Wogonin is a compound with many biologically relevant properties . We previously reported that wogonin blocked P05231 - induced angiogenesis through suppression of P15692 expression , an important regulator of angiogenesis . However , the pathway involved in the suppressive effect of wogonin on P05231 - induced P15692 has not been completely clarified . This study aimed to investigate the molecular mechanisms participating in the suppression of wogonin on P05231 - induced P15692 in vitro , focusing on IL - 6R / P23458 / P40763 / P15692 pathway . Both P40763 siRNA and wogonin treatment resulted in an abolition of the expression of P15692 . Moreover , our data revealed that wogonin treatment after P40763 knock - down did not further suppress P15692 expression . The addition of IL - 6R siRNA or wogonin resulted in a decrease in the expression level of the phosphorylated P23458 protein . Furthermore , wogonin significantly decreased the amount of phosphorylated P40763 . Finally , by EMSA , wogonin suppressed P05231 - induced P40763 binding activity in a concentration - dependent manner . Taken together , our results show that wogonin suppresses P05231 - induced P15692 by modulating the IL - 6R / P23458 / P40763 signaling pathway . Based on this study , we suggest that wogonin may provide a new potential therapeutic option for treatment of P05231 - related pathological angiogenesis .",
"Clock gene Per1 regulates the production of P13500 and interleukin - 6 through p38 , P45983 and NF - κB activation in spinal astrocytes . It has been previously reported that spinal clock genes controlled under circadian rhythm contribute to the regulation of astrocytic function , which in turn is involved in diverse processes such as nociceptive transduction and the induction of inflammation . However , how clock genes expressed in spinal cord astrocytes are associated with the modulation of the inflammatory response is poorly understood . In the current study , the role of Period1 ( Per1 ) , one of clock genes , in the expression of chemokine ( C - C motif ) ligand 2 ( P13500 ) and interleukin - 6 ( P05231 ) , which are typical pro - inflammatory mediators produced by spinal astrocytes , was investigated . It was found that the knockdown of Per1 by using RNA interference led to a significant increase of the expression of P13500 and P05231 in cultured rat spinal astrocytes . Moreover , the silencing of the Per1 gene also increased the phosphorylation of p38 , c - Jun N - terminal kinase ( JNK ) 1 and IκBα , and led to the translocation of p65 from the cytosol to the nucleus . The induction of P13500 and P05231 was significantly inhibited by treatment with the inhibitors of p38 , JNK , and NF - κB . By contrast , the overexpression of O15534 by transfection vector significantly blocked the expression of P13500 and P05231 , and the activation of p38 , JNK , and NF - κB . Together , these results suggest that down - regulation of Per1 induced the phosphorylation of p38 and P45983 and the subsequent activation of NF - κB , and that these events contribute to neuroinflammatory state in the spinal cord via the induction of the release of inflammatory mediators .",
"Genetic susceptibility to aseptic loosening following total hip arthroplasty : a systematic review . Introduction Aseptic loosening is the most common cause of total hip arthroplasty ( DB00382 ) failure and revision surgery . Genetic polymorphisms could be determinant factors for implant loosening . Source of data We performed a comprehensive search of Medline , CINAHL , Googlescholar , Embase and Cochrane databases , using various combinations of the keyword terms ' aseptic loosening ' , ' gene ' , ' hip arthoplasty ' , ' genetics ' , ' loosening ' . Twelve studies detailing the genetic investigation of patients with aseptic loosening of a DB00382 were identified . Areas of agreement SNPs of GNAS1 , P01375 - 238 A allele , P01375 - α promoter ( - 308G → A ) transition , P05231 - 174 G allele , interleukin ( IL ) - 6 ( - 597 ) and ( - 572 ) , P03956 - promoting gene , C / C genotype for the P03956 , P50281 , P08253 , transforming growth factor - beta1 signal sequence ( 29T → C ) transitions , A / A genotype for the O00300 - 163 , and P11226 were overexpressed in patients with aseptic loosening and periprosthetic osteolysis . Areas of controversy Data from single centre studies do not allow one to compare the results of different studies . Conclusion Several gene pathways and genes contribute to the genetic susceptibility to aseptic loosening following DB00382 . Further studies will enhance the understanding of prosthesis failure , and may inform and direct pharmaceutical interventions . Growing points Further multi - centre prospective studies are necessary to confirm the general validity of the findings reported . Single - centre findings should be replicated in other centres and populations to open new avenues for pre - surgical genetic testing and to investigate immune response modulation in DB00382 . Areas timely for developing research Research in this field could lead to better understanding of mechanisms behind aseptic osteolysis , and improve the results of DB00382 .",
"P00797 - angiotensin system is involved in the mechanism of increased serum asymmetric dimethylarginine in essential hypertension . Endothelium - dependent / nitric oxide ( NO ) - mediated vasodilation is impaired in hypertensive individuals . DB01686 ( DB01686 ) , an endogenous inhibitor of NO synthase , is synthesized by many types of cells including vascular endothelial cells . The serum level of DB01686 is elevated in patients with essential hypertension , but the mechanism for this increase is unknown . Therefore , the present study examined whether the renin - angiotensin system ( DB01367 ) is involved . Patients with essential hypertension [ systolic blood pressure ( BP ) > 160 mmHg and / or diastolic BP > 95 mmHg ] were randomized to an angiotensin - converting enzyme ( P12821 ) inhibitor treatment group ( perindopril , 4mg / day for 4 weeks , n = 7 ) , an angiotensin II type 1 ( AT1 ) receptor antagonist treatment group ( losartan , 50 mg / day for 4 weeks , n = 7 ) or a beta - blocker treatment group ( bisoprolol , 5 mg / day for 4 weeks , n = 7 ) . Before and after the treatment , BP , serum concentration of DB01686 and plasma concentration of P04275 ( P04275 , a biological marker of endothelial injury ) were measured . DB00790 , losartan and bisoprolol decreased BP to a similar extent , and either perindopril or losartan , but not bisoprolol , significantly decreased serum DB01686 and plasma P04275 . These findings suggest that the DB01367 may contribute to the mechanism of increased serum DB01686 as well as to the endothelial injury observed in hypertensive patients . The vasculoprotective actions of P12821 inhibitors or AT1 receptor antagonists may be explained at least in part by amelioration of the endothelial injury through a decrease in the serum DB01686 concentration .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK36___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"DB00790 : possible use in cancer therapy . Since angiogenesis is essential for the growth of any solid tumor , emerging efforts are being made to develop antiangiogenic therapy . To date , however , no antiangiogenic agent has become widely available for the clinical setting . Angiotensin I - converting enzyme ( P12821 ) inhibitors are commonly used as antihypertensive agents and it has recently been suggested that they decrease the risk of cancer . Studies have found that an P12821 inhibitor , perindopril , is a potent inhibitor of experimental tumor development and angiogenesis at a clinically comparable dose . The potent angiogenic factor , vascular endothelial growth factor ( P15692 ) , is significantly suppressed by perindopril and also inhibits P15692 - induced tumor growth . In vitro studies showed that perindopril is not cytotoxic to either tumor cells or endothelial cells . Since perindopril is already in widespread clinical use without serious side effects , it may represent a potential new strategy for anticancer therapy .",
"Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .",
"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK47___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .",
"Transmembrane proteases in cell growth and invasion : new contributors to angiogenesis ? Transmembrane proteases ( TPs ) are proteins anchored in the plasma membrane with their catalytic site exposed to the external surface of the membrane . TPs are widely expressed , and their dysregulated expression is associated with cancer , infection , inflammation , autoimmune and cardiovascular diseases , all diseases where angiogenesis is part of the pathology . TPs participate in extracellular proteolysis ( degradation of extracellular matrix components , regulation of chemokine activity , release of membrane - anchored cytokines , cytokine receptors and adhesion molecules ) and influence cell functions ( growth , secretion of angiogenic molecules , motility ) . Recent attention has been focused on the ADAM - 17 ( a disintegrin and metalloprotease ) / P78536 / CD156q , the P50281 ( membrane - type - 1 matrix metallo proteinase ) / P50281 , and the ectopeptidases aminopeptidase N ( P15144 / P15144 ) , dipeptidyl peptidase IV ( DPPIV / P27487 ) and angiotensin - converting enzyme ( P12821 / CD143 ) , that appear to have a critical role in angiogenesis . This article summarizes current knowledge on these TPs , and reviews recent investigations that document their participation during angiogenic - related events . Through their multiple roles , TPs may thereby provide critical links in angiogenesis .",
"Investigation of mechanisms mediating 8 - OH - DPAT - induced impairment of spatial memory : involvement of P08908 receptors in the dorsal hippocampus in rats . The purpose of this study was to identify mechanisms that mediate the impairment of spatial memory induced by 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , a P08908 / P34969 receptor agonist , in the eight - arm radial maze in rats . WAY - 100635 and NAN - 190 , P08908 receptor antagonists , reversed the impairment of spatial memory induced by systemic injection of 8 - OH - DPAT ( 1 mg / kg , i . p . ) . On the other hand , the alpha1 - adrenoceptor antagonist prazosin and a selective P34969 receptor antagonist SB269970 had no effect on 8 - OH - DPAT - induced impairment of spatial memory . Bilateral microinjection of 8 - OH - DPAT ( 4 microg / side ) impaired spatial memory when injected into the dorsal hippocampus ( DH ) . Contrastingly , spatial memory was unaffected by microinjections of 8 - OH - DPAT into the other six areas examined : ventral hippocampus ( VH ) , central amygdaloid nucleus ( P12821 ) , lateral hypothalamus ( LH ) , nucleus accumbens ( NAc ) , and dorsal ( DR ) and median ( MR ) raphe nucleus . Furthermore , NAN - 190 significantly reversed the impairment of spatial memory induced by intra - DH injection of 8 - OH - DPAT . These findings suggest that P08908 receptors in the DH play an important role in the mechanisms underlying the 8 - OH - DPAT - induced impairment of spatial memory in rats .",
"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK33___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"Surfactin exhibits neuroprotective effects by inhibiting amyloid β - mediated microglial activation . Microglial - mediated neuroinflammation and neurotoxicity contribute to the pathogenesis of neurodegenerative diseases including Alzheimer ' s disease ; therefore , control of microglial activation and subsequent suppression of neurotoxic pro - inflammatory molecules could provide a potential therapeutic approach for the treatment of such diseases . In this study , we investigated the effects of surfactin , a surfactant from Bacillus subtilis , on oligomeric amyloid β ( Aβ ) - induced microglial activation and neurotoxicity . Surfactin significantly suppressed expression of P14780 , P35228 and P35354 , as well as production of ROS , NO , DB00917 , P01375 - α , IL - 1β , P05231 and P13500 in Aβ - stimulated BV - 2 microglial cells . Moreover , surfactin markedly inhibited Aβ - induced nuclear translocation and activation of NF - κB as well as phosphorylation of JNK and p38 MAPK . Furthermore , surfactin protected hippocampal HT22 cells from indirect neuronal toxicity mediated by Aβ - treated microglial cells , but had no effect on Aβ - induced direct toxicity to HT22 cells . These results suggest that surfactin impairs the Aβ - induced inflammatory response of microglial cells and confers protection against indirect neurotoxicity to hippocampal cells . Our findings indicate that surfactin may have therapeutic potential for ameliorating Alzheimer ' s disease as well as other neurodegenerative disorders which involve neuroinflammation .",
"P00797 - angiotensin system modulation : the weight of evidence . Modulation of the renin - angiotensin system is considered to be the most complete way to manage high - risk patients including those with hypertension . P12821 ( P12821 ) inhibitors are effective at reducing the morbidity and mortality of patients with overt clinical heart failure , asymptomatic left ventricular dysfunction , and uncomplicated myocardial infarction . Furthermore , recent trials like the Heart Outcomes Prevention Evaluations ( HOPE ) study and the EUropean trial on Reduction Of cardiac events with DB00790 in stable coronary Artery disease ( EUROPA ) support extending the use of P12821 inhibitors to the routine / first - line treatment of patients with an increased global cardiovascular risk . Although some investigators have seen the development of angiotensin II receptor blockers ( ARBs ) as a more effective and tolerable way of reproducing the benefits of P12821 inhibition , there remain important concerns regarding the distinct pharmacologic profiles and modes of action of these two classes of drugs . Careful evaluation of data from recent large - scale studies revealed that , unlike P12821 inhibitors , ARBs are either neutral or may actually increase rates of myocardial infarction despite similar levels of blood pressure reduction . The fact that this effect is most apparent when ARBs are compared with placebo in the absence of concomitant P12821 inhibitors suggests that differential effects on the angiotensin II type 2 ( AT ( 2 ) ) receptors may be important . Other important pharmacologic differences are also known to be present and may be of direct relevance . The weight of available evidence therefore supports the use of appropriate P12821 inhibitor regimens , although not ARBs , in the treatment of global cardiovascular risk .",
"Novel marine phenazines as potential cancer chemopreventive and anti - inflammatory agents . Two new ( 1 and 2 ) and one known phenazine derivative ( lavanducyanin , 3 ) were isolated and identified from the fermentation broth of a marine - derived Streptomyces sp . ( strain CNS284 ) . In mammalian cell culture studies , compounds 1 , 2 and 3 inhibited P01375 - α - induced NFκB activity ( IC₅₀ values of 4 . 1 , 24 . 2 , and 16 . 3 μM , respectively ) and LPS - induced nitric oxide production ( IC₅₀ values of > 48 . 6 , 15 . 1 , and 8 . 0 μM , respectively ) . PGE₂ production was blocked with greater efficacy ( IC₅₀ values of 7 . 5 , 0 . 89 , and 0 . 63 μM , respectively ) , possibly due to inhibition of cyclooxygenases in addition to the expression of P35354 . Treatment of cultured HL - 60 cells led to dose - dependent accumulation in the subG1 compartment of the cell cycle , as a result of apoptosis . These data provide greater insight on the biological potential of phenazine derivatives , and some guidance on how various substituents may alter potential anti - inflammatory and anti - cancer effects .",
"___MASK47___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK47___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .",
"Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK25___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .",
"DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .",
"Increased expression of the renin - angiotensin system and mast cell density but not of angiotensin - converting enzyme II in late stages of human heart failure . BACKGROUND : The activation of the renin - angiotensin system ( DB01367 ) contributes to the progression of left ventricular dysfunction . A novel human homologue of the angiotensin - converting enzyme ( P12821 ) , named Q9BYF1 , has been described but its role in human heart failure ( HF ) has not been elucidated . Besides , there is controversy as to whether the major angiotensin II - forming - activity in heart is P12821 or chymase released from mast cells . Furthermore , long - term blockade of nitric oxide ( NO ) synthesis has been shown to increase P12821 activity . To assess the locally activated vasoactive mediators that may contribute to the ventricular deterioration process , we sought to simultaneously analyze their expression in failing hearts . METHODS : We analyzed left ventricular biopsies from 30 patients with heart failure undergoing heart transplantation and 12 organ donors . The mRNA levels of P12821 , Q9BYF1 , chymase and endothelial nitric oxide synthase ( P29474 ) , were quantified by real - time polymerase chain reaction and mast cell density was assessed by immunohistochemistry . The mRNA levels of the atrial natriuretic peptide ( P01160 ) and the brain natriuretic peptide ( DB04899 ) were also quantified as controls . RESULTS : There was higher P12821 and chymase mRNA expression and mast cell density in failing than in control myocardium and no changes in Q9BYF1 expression were detected . P29474 mRNA levels were lower in failing hearts . Both P01160 and DB04899 expression were higher in pathological than in control samples . CONCLUSIONS : These data document a decompensation of vasoactive systems that may contribute to the progressive impairment of the myocardial function in HF . On the other hand , Q9BYF1 mRNA expression is not altered in human end - stage HF .",
"NAADP links histamine H1 receptors to secretion of P04275 in human endothelial cells . A variety of endothelial agonist - induced responses are mediated by rises in intracellular Ca ( 2 +) , suggesting that different Ca ( 2 +) signatures could fine - tune specific inflammatory and thrombotic activities . In search of new intracellular mechanisms modulating endothelial effector functions , we identified nicotinic acid adenine dinucleotide phosphate ( NAADP ) as a crucial second messenger in histamine - induced Ca ( 2 +) release via H1 receptors ( P35367 ) . NAADP is a potent intracellular messenger mobilizing Ca ( 2 +) from lysosome - like acidic compartments , functionally coupled to the endoplasmic reticulum . Using the human EA . hy926 endothelial cell line and primary human umbilical vein endothelial cells , we show that selective P35367 activation increases intracellular NAADP levels and that P35367 - induced calcium release involves both acidic organelles and the endoplasmic reticulum . To assess that NAADP links P35367 to Ca ( 2 +)- signaling we used both microinjection of self - inactivating concentrations of NAADP and the specific NAADP receptor antagonist , Ned - 19 , both of which completely abolished P35367 - induced but not thrombin - induced Ca ( 2 +) mobilization . Interestingly , P35367 - mediated P04275 ( P04275 ) secretion was completely inhibited by treatment with Ned - 19 and by siRNA knockdown of 2 - pore channel NAADP receptors , whereas thrombin - induced P04275 secretion failed to be affected . These findings demonstrate a novel and specific Ca ( 2 +)- signaling mechanism activated through P35367 in human endothelial cells , which reveals an obligatory role of NAADP in the control of P04275 secretion .",
"___MASK82___ reduces neointima formation in a rat model of balloon injury . BACKGROUND : Processes of restenosis , following arterial injury , are complex involving different cell types producing various cytokines and enzymes . Among those enzymes , smooth muscle cell - derived matrix metalloproteinases ( MMPs ) are thought to take part in cell migration , degrading of extracellular matrix , and neointima formation . P14780 , also known as gelatinase B , is expressed immediately after vascular injury and its expression and activity can be inhibited by statins . Using an established in vivo model of vascular injury , we investigated the effect of the P04035 inhibitor rosuvastatin on P14780 expression and neointima formation . MATERIALS AND METHODS : 14 - week old male Sprague Dawley rats underwent balloon injury of the common carotid artery . Half of the animals received rosuvastatin ( 20 mg / kg body weight / day ) via oral gavage , beginning 3 days prior to injury . Gelatinase activity and neointima formation were analyzed 3 days and 14 days after balloon injury , respectively . 14 days after vascular injury , proliferative activity was assessed by staining for Ki67 . RESULTS : After 14 days , animals in the rosuvastatin group showed a decrease in total neointima formation ( 0 . 194 ± 0 . 01 mm2 versus 0 . 124 ± 0 . 02 mm2 , p < 0 . 05 ) as well as a reduced intima / media ratio ( 1 . 26 ± 0 . 1 versus 0 . 75 ± 0 . 09 , p < 0 . 05 ) . Balloon injury resulted in increased activity of P14780 3 days after intervention for both rosuvastatin treated animals and controls with no significant difference observed between the groups . There was a trend towards a reduction in the number of Ki67 - positive cells 14 days after injury . CONCLUSIONS : ___MASK82___ attenuates neointima formation without affecting early P14780 activity in a rat model of vascular injury .",
"Role of angiotensin II in the remodeling induced by a chronic increase in flow in rat mesenteric resistance arteries . Angiotensin II is a potent growth factor involved in arterial wall homeostasis . In resistance arteries , chronic increases in blood flow induce a rise in diameter associated with arterial wall hypertrophy . Nevertheless , the role of angiotensin II in this remodeling is unknown . We investigated the effect of blocking angiotensin II production or receptor activation on flow - induced remodeling of mesenteric resistance arteries . Arteries were ligated in vivo to generate high - flow arteries compared with normal flow ( control ) vessels located at a distance . Arteries were isolated after 1 week for in vitro analysis . Arterial diameter , media surface , endothelial NO synthase expression , superoxide production , and extracellular signal - regulated kinase 1 / 2 phosphorylation were higher in high - flow than in control arteries . P12821 inhibition ( perindopril ) and angiotensin II type 1 receptor blockade ( candesartan ) prevented arterial wall hypertrophy without affecting diameter enlargement . The nonselective vasodilator hydralazine had no effect on remodeling . Although perindopril and candesartan increased endothelial NO synthase expression in high - flow arteries , hypertrophy remained in rats treated with N ( G )- nitro - l - arginine methyl ester and mice lacking endothelial NO synthase . DB00790 and candesartan reduced oxidative stress in high - flow arteries , but superoxide scavenging did not prevent hypertrophy . Both Tempol and the absence of endothelial NO synthase prevented the rise in diameter in high - flow vessels . P27361 / 2 activation in high - flow arteries was prevented by perindopril and candesartan and not by hydralazine . P27361 / 2 inhibition in vivo ( U0126 ) prevented hypertrophy in high - flow arteries . Thus , a chronic rise in blood flow in resistance arteries induces a diameter enlargement involving NO and superoxide , whereas hypertrophy was associated with extracellular signal - regulated kinase 1 / 2 activation by angiotensin II .",
"Progressive encephalomyelitis with rigidity presenting as a stiff - person syndrome . Diagnosis criteria of stiff - person syndrome ( P49903 ) include progressive , fluctuating muscular rigidity and spasms with normal neurological examination . The presence of unusual features such as prominent limb rigidity with segmental signs and contracture , evidence of brainstem dysfunction , profound autonomic disturbances , P04141 pleiocytosis or Q9BWK5 abnormalities in patients with P49903 presentation allows to classify these patients as progressive encephalomyelitis with rigidity ( O15534 ) . We report a 50 year - old woman suffering from severe painful spasms of abdominal wall and limb muscles . Neurological examination showed pyramidal signs . EMG disclosed continuous muscle activity with superimposed discharges . Treatment with high doses of diazepam and baclofen led to moderate improvement of generalised stiffness . However , the right arm became more rigid with oedema and vasomotor changes . Subsequently , bilateral nystagmus and internuclear opthalmplegia appeared . There was mild P04141 pleiocytosis . Associated auto - immune thyroiditis was found with positive anti - microsome antibodies and decreased thyroid hormones . Search for profound neoplasm was negative . The patient had three subacute bouts then she improved with methylprednisolone . The initial clinical presentation mimicking a P49903 with subsequent diffuse involvement of the central nervous system and a striking localisation of a severe rigidity to one arm allowed to suspect the diagnosis of O15534 . The relationship between P49903 and O15534 remains unclear because of the rarity of these disorders . The observation reported in this paper gives evidence that both the disorders are probably two clinical presentations of the same pathogenic process .",
"P12821 activity is involved in the mechanism of increased endogenous nitric oxide synthase inhibitor in patients with type 2 diabetes mellitus . The renin - angiotensin system plays an important role in the elevation of asymmetric dimethylarginine ( DB01686 ) , an endogenous inhibitor of nitric oxide synthase , in hypertensive patients , so the present study was designed to examine whether angiotensin - converting enzyme ( P12821 ) activity is also involved in the mechanism of DB01686 elevation in type 2 diabetes mellitus ( NIDDM ) . A crossover study was performed to determine if P12821 inhibition with perindopril ( 4 mg / day ) for 4 weeks decreases serum DB01686 concentration and plasma P04275 ( P04275 ) level ( a marker of endothelial injury ) in 11 patients with NIDDM . None of the patients was treated with insulin or oral hypoglycemic drugs , and none had major diabetic complications . Before the protocol began , serum DB01686 and plasma P04275 were significantly higher in the 11 NIDDM patients , when compared with 8 control subjects without diabetes . DB00790 did not affect blood pressure or glucose metabolism , but did significantly decrease serum DB01686 and plasma P04275 . These results suggest that endothelial injury associated with DB01686 elevation may be present even in patients with non - complicated NIDDM , and that increased activity of P12821 may be involved in such endothelial dysfunction .",
"[ Thrombotic complications following the treatment of multiple myeloma with new agents ] . Patients with multiple myeloma ( MM ) are at an increased risk of venous and arterial thrombosis . The risk factors and pathomechanisms for thrombotic complications in multiple myeloma patients can be divided into the disease - related and treatment - specific risk factors . With the introduction of novel therapies , including talidomide , lenalidomide and bortezomib , the outcomes of the patients with newly diagnosed or previously treated multiple myeloma have improved , however the treatment affected the prothrombotic and anticoagulant processes . The risk of venous thromboembolism ( VTE ) in patients receiving immunomodulatory agent - based regimens ( thalidomide or lenalidomide ) , especially when used in combination with high - dose deamethasone - and / or anthracycline - based chemiotherapy is high . The proposed mechanisms for prothrombotic state include changes in P04275 , factor VIII , thrombomodulin , P25116 and P35354 epression , and some abnormalities in transcription factors and genetic risk factors . Moreover , dysregulation of anticoagulation and impairment of fibrinolysis may also contribute to hypercoagulability state . The incidence of VTE in bortezomib - containing regimens is very low . It may be due to inhibitory effect of bortezomib on platelet aggregation and NF - kappa / beta . This article presents the latest outlook upon the pathogenesis of thrombotic complications in multiple myeloma patients undergoing the therapy with new agents .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK62___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK62___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"Granulocyte macrophage - colony stimulating factor increases the expression of histamine and histamine receptors in monocytes / macrophages in relation to arteriosclerosis . OBJECTIVE : To study the effect of granulocyte macrophage - colony - stimulating factor ( GM - P04141 ) on histamine metabolism in arteriosclerosis , the expression of histidine decarboxylase ( HDC ; histamine - producing enzyme ) , histamine receptors 1 and 2 ( P35367 and P25021 ) , and GM - P04141 was investigated in human and mouse arteriosclerotic carotid arteries . Furthermore , the molecular mechanisms of GM - P04141 - induced HDC and P35367 expression in monocytic U937 cells were investigated . METHODS AND RESULTS : Immunohistochemistry showed that atherosclerotic human coronary and mouse ligated carotid arteries contained HDC - expressing macrophages . Gene expression of HDC , P35367 , P25021 , and GM - P04141 was also detected in the lesions . In U937 cells , GM - P04141 enhanced histamine secretion and gene expression of HDC and P35367 . A promoter assay showed that GM - P04141 enhanced gene transcription of HDC and P35367 but not P25021 . CONCLUSIONS : The present results indicate that HDC and HHR are expressed in arteriosclerotic lesion , and that GM - P04141 induces HDC and P35367 expression in monocytes . Locally produced histamine might participate in atherogenesis by affecting the expression of atherosclerosis - related genes in monocytes and smooth muscle cells . The presence of histamine - producing macrophages and gene expression of histamine receptors and GM - P04141 was demonstrated in arteriosclerotic lesions . In monocytic U937 cells , GM - P04141 upregulated the expression of histamine and P35367 . Coordinated expression of histamine and its receptors by GM - P04141 would participate in atherogenesis by affecting monocytic and SMC gene expression ."
] |
[
"___MASK25___",
"___MASK32___",
"___MASK33___",
"___MASK36___",
"___MASK3___",
"___MASK47___",
"___MASK62___",
"___MASK82___",
"___MASK89___"
] |
___MASK33___
|
MH_train_425
|
interacts_with DB00674?
|
[
"Hyperecho - turbo spin - echo sequences at 3T : clinical application in neuroradiology . BACKGROUND AND PURPOSE : Hyperecho - turbo spin - echo ( hyperTSE ) sequences were developed to reduce the specific absorption rate ( SAR ) , especially at high fields such as 3T and above . The purpose of this study was to quantitatively and qualitatively assess the detection of neuroradiologic pathologies by hyperTSE in comparison with standard turbo spin - echo ( TSE180 degrees ) sequences . MATERIALS AND METHODS : TSE180 degrees and hyperTSE images with parameters adapted for equal P24752 contrast were acquired on a 3T whole - body system in 51 patients with 54 cerebral pathologies . Region - of - interest analysis was performed of signal intensities of pathologies , normal white and gray matter , P04141 , and the SD of noise . Signal intensity - to - noise ratios ( SNRs ) and contrast - to - noise ratios ( CNRs ) for healthy tissues and pathologies were determined . A qualitative rating concerning artifacts , lesion conspicuity , and image quality was performed by 2 experienced neuroradiologists . RESULTS : HyperTSE sequences were equivalent to standard TSE180 degrees sequences for the P21554 of pathologies and of the contrast between gray and white matter . The SNR of gray and white matter and P04141 were also the same . The CNRs of the pathologies in hyperTSE and TSE180 degrees images were strongly correlated with each other ( r = 0 . 93 , P = . 001 ) . The visual rating of images revealed no significant differences between hyperTSE and TSE180 degrees . CONCLUSION : HyperTSE sequences proved to be qualitatively and quantitatively equivalent to TSE180 degrees sequences in the detection of high - and low - signal - intensity lesions . They provide equal P21554 of pathologies and of gray minus white matter and reduce the imaging restrictions of conventional TSE180 degrees imposed by SAR limitations at 3T .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK69___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"Inhibitors of Q06187 and Q08881 : state of the new drugs for cancer , autoimmunity and inflammatory diseases . Q06187 and Q08881 are cytoplasmic tyrosine kinases of crucial importance for B and T cell development , with loss - of - function mutations causing X - linked agammaglobulinemia and susceptibility to severe , frequently lethal , Epstein - Barr virus infection , respectively . Over the last few years , considerable efforts have been made in order to develop small - molecule inhibitors for these kinases to treat lymphocyte malignancies , autoimmunity or allergy / hypersensitivity . The rationale is that even if complete lack of Q06187 or Q08881 during development causes severe immunodeficiency , inactivation after birth may result in a less severe phenotype . Moreover , therapy can be transient or only partially block the activity of Q06187 or Q08881 . Furthermore , a drug - induced B cell deficiency is treatable by gamma globulin substitution therapy . The newly developed Q06187 inhibitor P05154 - 32765 , recently renamed ___MASK98___ , has already entered several clinical trials for various forms of non - Hodgkin lymphoma as well as for multiple myeloma . Experimental animal studies have demonstrated highly promising treatment effects also in autoimmunity . Q08881 inhibitors are still under the early developmental phase , but it can be expected that such drugs will also become very useful . In this study , we present Q06187 and Q08881 with their signalling pathways and review the development of the corresponding inhibitors .",
"AACR - 91st meeting . Dendritic cell vaccine strategies . Inevitably , the sessions on dendritic cells at the AACR Annual Meeting were some of the most consistently well attended . Interest has been intense for several years , largely since the technical obstacles to the routine culture of these cells and their precursors , both from animal and human sources , were removed in the early 1990s . Several important advances were presented towards further optimizing dendritic cell - based immunotherapy in general . Groups reported on improved culture conditions , as well as more efficient means of obtaining larger quantities of dendritic cells or their precursors . As expected , there were several strong reports on the beneficial bioactivity of cytokines , such as IL - 12 , GM - P04141 , and P60568 . In addition , enticing work continues with Flt3 - ligand and has begun with progenipoietin , a more recently identified hematopoietic growth factor . As shown in this year ' s sessions , the clinical promise of tumor lysate and apoptotic bodies continues to move steadily from the bench to the clinic . Finally , although dendritic cells are excellent antigen - presenters , work to determine if they could be engineered to be even more effective continues . As a result , several reports were given on gene - modifying this type of immune cell .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Murine bone marrow - derived macrophages differentiated with GM - P04141 become foam cells by PI3Kγ - dependent fluid - phase pinocytosis of native LDL . Accumulation of cholesterol by macrophage uptake of LDL is a key event in the formation of atherosclerotic plaques . Previous research has shown that granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) is present in atherosclerotic plaques and promotes aortic lipid accumulation . However , it has not been determined whether murine GM - P04141 - differentiated macrophages take up LDL to become foam cells . GM - P04141 - differentiated macrophages from P01130 - null mice were incubated with LDL , resulting in massive macrophage cholesterol accumulation . Incubation of P01130 - null or wild - type macrophages with increasing concentrations of ¹²⁵I - LDL showed nonsaturable macrophage LDL uptake that was linearly related to the amount of LDL added , indicating that LDL uptake was mediated by fluid - phase pinocytosis . Previous studies suggest that phosphoinositide 3 - kinases ( PI3K ) mediate macrophage fluid - phase pinocytosis , although the isoform mediating this process has not been determined . Because PI3Kγ is known to promote aortic lipid accumulation , we investigated its role in mediating macrophage fluid - phase pinocytosis of LDL . Wild - type macrophages incubated with LDL and the PI3Kγ inhibitor AS605240 or PI3Kγ - null macrophages incubated with LDL showed an ∼ 50 % reduction in LDL uptake and cholesterol accumulation compared with wild - type macrophages incubated with LDL only . These results show that GM - P04141 - differentiated murine macrophages become foam cells by fluid - phase pinocytosis of LDL and identify PI3Kγ as contributing to this process .",
"A Type II Arabinogalactan from Anoectochilus formosanus for G - P04141 Production in Macrophages and Leukopenia Improvement in Q86TM3 - Bearing Mice Treated with DB00544 . Anoectochilus formosanus is an herb well known in Asian countries . The polysaccharide isolated from A . formosanus consists of type II arabinogalactan ( AGAF ) , with branched 3 , 6 - Gal as the major moiety . In this study , AGAF was examined for the granulocyte colony - stimulating factor ( DB00099 ) production and related protein expression in RAW 264 . 7 murine macrophages . The signaling pathway of G - P04141 production involves AGAF and mitogen - activated protein kinases ( MAPKs ) inhibitors and pattern - recognition receptor antibodies . AGAF was evaluated to ease the leukopenia in Q86TM3 - colon - cancer - bearing mice treated with 5 - fluorouracil ( DB00544 ) . The results of this study showed that AGAF was a stimulant for O60603 and Q9BXN2 and that it induced G - P04141 production , through p38 and P29323 MAPK , and NF - κ B pathways . In vivo examination showed that the oral administration of AGAF mitigated the side effects of leukopenia caused by DB00544 in colon - cancer - bearing mice . In conclusion , the botanic type II AGAF in this study was a potent G - P04141 inducer in vivo and in vitro .",
"Differential regulation of cystic fibrosis transmembrane conductance regulator by interferon gamma in mast cells and epithelial cells . P13569 ( P13569 ) is a P13569 in epithelial cells ; recently , we identified it in mast cells . Previous work that we confirmed showed that interferon gamma ( IFNgamma ) down - regulated P13569 expression in epithelial cells ( T84 ) , but by contrast , we found that IFNgamma up - regulated P13569 mRNA and protein expression in rat and human mast cells . IFNgamma up - regulation of P13569 in mast cells was inhibited by p38 and extracellular signal - regulated kinase ( P29323 ) kinase inhibitors but not a Janus tyrosine kinase ( JAK ) 2 inhibitor , whereas in T84 cells IFNgamma - mediated down - regulation of P13569 was O60674 - dependent and P29323 - and p38 - independent . Furthermore , IFNgamma down - regulation of P13569 in T84 epithelial cells was P42224 - dependent , but up - regulation of P13569 in mast cells was P42224 - independent . Thus , differential regulatory pathways of P13569 expression in mast cells and epithelial cells exist that depend upon either p38 / P29323 or JAK / P35610 pathways , respectively . Surprisingly , IFNgamma treatment of mast cells inhibited Cl (-) efflux , in contrast to up - regulation of P13569 / mRNA and protein expression . However , down - regulation of Cl (-) flux correlated with IFNgamma - mediated inhibition of mediator secretion . This and other work suggests that the effect of IFNgamma on P13569 expression in mast cells is important for their function .",
"___MASK98___ inhibits P11274 and NF - κB signaling and reduces tumor proliferation in tissue - resident cells of patients with CLL . Chronic lymphocytic leukemia ( CLL ) cells depend on microenvironmental factors for proliferation and survival . In particular , tissue - resident CLL cells show prominent activation of both B - cell receptor ( P11274 ) and NF - κB pathways . We evaluated the in vivo effects of ibrutinib , a Q06187 ( Q06187 ) inhibitor on tumor cell activation and proliferation in the blood , lymph node , and bone marrow of patients with CLL . Applying validated pathway - specific gene signatures , we detected a rapid and sustained downregulation of P11274 and NF - κB signaling in CLL cells from both the peripheral blood and tissue compartments during ibrutinib treatment . ___MASK98___ reduced phosphorylation of PLCγ2 and P29323 and decreased nuclear protein expression of NF - κB p50 . ___MASK98___ significantly decreased tumor proliferation and expression of surface activation markers Q07108 and P42081 , independent of prognostic factors such as IGHV mutational status , chromosome 17p deletion , or prior treatment history . Interestingly , stronger inhibition of P11274 signaling in lymph node resident CLL cells after one dose of ibrutinib was associated with a higher rate of nodal response at the end of cycle 2 . Together , these data validate on - target effects of Q06187 inhibition in the tissue compartments and demonstrate that ibrutinib effectively inhibits pathways that promote tumor cell activation and proliferation in vivo . This study is registered at www . clinicaltrials . gov as # NCT01500733 .",
"DB00674 ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine : involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic - P27361 / 2 systems . DB00674 , a drug used to treat Alzheimer ' s disease , inhibits acetylcholinesterase ( P22303 ) and allosterically modulates nicotinic acetylcholine receptors ( nAChRs ) resulting in stimulation of catecholamine neurotransmission . In this study , we investigated whether galantamine exerts cognitive - improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine ( Meth ) psychosis . The mice treated with Meth ( 1 mg / kg . d ) for 7 d showed memory impairment in a novel object recognition test . DB00674 ( 3 mg / kg ) ameliorated the memory impairment , and it increased the extracellular dopamine release in the prefrontal cortex ( P27918 ) of Meth - treated mice . Donepezil , an P22303 inhibitor ( 1 mg / kg ) increased the extracellular ACh release in the P27918 , whereas it had no effect on the memory impairment in Meth - treated mice . The nAChR antagonist , mecamylamine , and dopamine D1 receptor antagonist , P35240 23390 , blocked the ameliorating effect of galantamine on Meth - induced memory impairment , whereas the muscarinic AChR antagonist , scopolamine , had no effect . The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine . DB00674 attenuated the defect of the novelty - induced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . The ameliorating effect of galantamine on recognition memory in Meth - treated mice was negated by microinjection of an P29323 inhibitor , PD98059 , into the P27918 . These results suggest that the ameliorating effect of galantamine on Meth - induced memory impairment is associated with indirect activation of dopamine D1 receptor - P27361 / 2 following augmentation with dopaminergic neurotransmission in the P27918 through the allosteric activation of nAChRs . DB00674 could be a useful therapeutic agent for treating cognitive deficits in schizophrenia / Meth psychosis , as well as Alzheimer ' s disease .",
"Inhibition of matrix metalloproteinase - 9 expression by docosahexaenoic acid mediated by heme oxygenase 1 in 12 - O - tetradecanoylphorbol - 13 - acetate - induced MCF - 7 human breast cancer cells . P14780 ( P14780 ) plays a crucial role in tumor metastasis . Previous studies showed that polyunsaturated fatty acids exhibit an anti - cancer effect in various human carcinoma cells , but the effect of docosahexaenoic acid ( DB01708 ) and linoleic acid ( LA ) on metastasis of breast cancer cells is not fully clarified . We studied the anti - metastasis potential of DB01708 and LA in 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) - induced MCF - 7 cells . We found that TPA ( 100 ng / ml ) induced P14780 enzyme activity both dose - and time - dependently , and 200 μM DB01708 and LA significantly inhibited P14780 mRNA and protein expression , enzyme activity , cell migration , and invasion . Treatment with PD98059 ( 10 μM ) , wortmannin ( 10 μM ) , and GF109203X ( 0 . 5 μM ) decreased TPA - induced P14780 protein expression and enzyme activity . TPA - induced activation of P27361 , Akt , and PKCδ was attenuated by DB01708 , whereas LA attenuated only P27361 activation . GF109203X also suppressed P27361 activation . EMSA showed that DB01708 , LA , PD98059 , and wortmannin decreased TPA - induced NF - κB and AP - 1 DNA - binding activity . Furthermore , DB01708 rather than LA dose - dependently increased P09601 expression . P09601 siRNA alleviated the inhibition by DB01708 of TPA - induced P14780 protein expression and enzyme activity in MCF - 7 cells , and P09601 knockdown reversed the DB01708 inhibition of cell migration . These results suggest that DB01708 and LA have both similar and divergent signaling pathways in the suppression of TPA - induced MCF - 7 metastasis .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK17___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK97___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK97___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK97___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .",
"Induction of high mobility group box 1 release from serotonin - stimulated human umbilical vein endothelial cells . High mobility group box 1 ( P09429 ) is a non - histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis . The P09429 functions as a potent proinflammatory cytokine in the extracellular spaces . Recently , P09429 has been implicated in the progression of atherosclerosis . However , the association between P09429 and the development of atherosclerosis is poorly understood . Therefore , we examined whether serotonin ( 5 - HT ) , a key factor involved in the development of atherosclerosis , induced P09429 release in human umbilical vein endothelial cells ( HUVECs ) . We found that 5 - HT induced the release of P09429 but not of P27361 / 2 and JNK from HUVECs via the 5 - HT receptor ( P28222 ) / p38 mitogen - activated protein kinase ( MAPK ) signaling pathway . The p38MAPK inhibitor SB203580 and the P28222 antagonist GR55526 markedly inhibited P09429 release from 5 - HT - stimulated HUVECs . The vascular endothelial growth factor ( P15692 ) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis . We found that P09429 induced P15692 production in macrophage - like RAW264 . 7 cells . P09429 induced the activation of p38MAPK , P27361 / 2 and Akt . The P19957 - kinase inhibitor LY294002 significantly inhibited P15692 production in P09429 - stimulated macrophages , while other kinase inhibitors did not . These results suggest that P09429 release may contribute as a risk factor in the development and progression of atherosclerosis .",
"___MASK18___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"Brain 5 - HT and inhibition of aggressive behavior in animals : 5 - HIAA and receptor subtypes . Evolutionary constant serotonin ( 5 - HT ) neuronal systems evolved along medial brain structures ; yet , wide variations in functionality characterize serotonergic systems in mediating aggressive responses in species ranging from lobsters , ants , electric fish , and rodents to primates . So far , the attempts to correlate cerebrospinal fluid ( P04141 ) 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels with measures of aggression have revealed inverse , direct , or no correlations in different nonhuman primate species . It is difficult to harmonize the occasional correlations between P04141 5 - HIAA and adaptive aggressive acts in nonhuman primates ( a ) with clinically diagnosed suicidal or impulsive individuals , and ( b ) with the biochemical , anatomical , and presumably functional differentiation of 5 - HT pathways and receptor subtypes . Eltoprazine , a mixed P08908 / B agonist , and meta - trifluoro - methylphenyl - piperazine HCl ( TFMPP ) , a more selective P28222 agonist , specifically decrease aggressive behavior in several animal species and situations in both sexes without detriment to other social , exploratory , or motoric activities . A definite role for P08908 , 5 - HT2 , and 5 - Q9H205 receptor subtypes in the mechanisms mediating aggressive behaviors has to await the development of selective agonists and antagonists , respectively .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK63___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK63___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK63___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK63___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK63___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK63___ increased the protein expression of hepatic P05181 and ___MASK63___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK63___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK63___ and RFP - induced hepatotoxicity .",
"N - arachidonoyl - L - serine is neuroprotective after traumatic brain injury by reducing apoptosis . N - arachidonoyl - L - serine ( AraS ) is a brain component structurally related to the endocannabinoid family . We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto - parietal skull and the mechanisms involved . A single injection of AraS following injury led to a significant improvement in functional outcome , and to reduced edema and lesion volume compared with vehicle . Specific antagonists to CB2 receptors , transient receptor potential vanilloid 1 ( Q8NER1 ) or large conductance calcium - activated potassium ( BK ) channels reversed these effects . Specific binding assays did not indicate binding of AraS to the Q9Y2T6 cannabinoid receptor . N - arachidonoyl - L - serine blocked the attenuation in phosphorylated extracellular - signal - regulated kinase 1 / 2 ( P29323 ) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices . Increased levels of the prosurvival factor Bcl - xL were evident 24 hours after injury in AraS - treated mice , followed by a 30 % reduction in caspase - 3 activity , measured 3 days after injury . Treatment with a CB2 antagonist , but not with a P21554 antagonist , reversed this effect . Our results suggest that administration of AraS leads to neuroprotection via P29323 and Akt phosphorylation and induction of their downstream antiapoptotic pathways . These protective effects are related mostly to indirect signaling via the CB2R and Q8NER1 channels but not through P21554 or Q9Y2T6 receptors .",
"Tumor - derived exosomes promote tumor progression and T - cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor - derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30 - 100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0 . 05 ) . TW03 - derived exosomes impaired T - cell function by inhibiting T - cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome - stimulated T - cells . TW03 - derived exosomes increased the proinflammatory cytokines IL - 1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8 + T - cells . Furthermore , five commonly over - expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa - miR - 24 - 3p , hsa - miR - 891a , hsa - miR - 106a - 5p , hsa - miR - 20a - 5p , and hsa - miR - 1908 . These over - expressed miRNA clusters down - regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor - derived exosomes and identify a unique intercellular mechanism mediated by tumor - derived exosomes to modulate T - cell function in NPC .",
"P14780 leads to claudin - 5 degradation via the NF - κB pathway in BALB / c mice with eosinophilic meningoencephalitis caused by Angiostrongylus cantonensis . The epithelial barrier regulates the movement of ions , macromolecules , immune cells and pathogens . The objective of this study was to investigate the role of the matrix metalloproteinase ( MMP ) - 9 in the degradation of tight junction protein during infection with rat nematode lungworm Angiostrongylus cantonensis . The results showed that phosphorylation of IκB and NF - κB was increased in mice with eosinophilic meningoencephalitis . Treatment with MG132 reduced the phosphorylation of NF - κB and the activity of P14780 , indicating upregulation of P14780 through the NF - κB signaling pathway . O00501 was reduced in the brain but elevated in the cerebrospinal fluid ( P04141 ) , implying that A . cantonensis infection caused tight junction breakdown and led to claudin - 5 release into the P04141 . Degradation of claudin - 5 coincided with alteration of the blood - P04141 barrier permeability and treatment with the MMP inhibitor DB02255 attenuated the degradation of claudin - 5 . These results suggested that degradation of claudin - 5 was caused by P14780 in angiostrongyliasis meningoencephalitis . O00501 could be used for the pathophysiologic evaluation of the blood - P04141 barrier breakdown and tight junction disruption after infection with A . cantonensis .",
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK72___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"Perfluorocarbons and Gilbert syndrome ( phenotype ) in the Q99618 Health Study Population . BACKGROUND : Gilbert syndrome ( GS ) is an inherited defect of bilirubin conjugation , most commonly caused by a gene mutation for the enzyme P22309 . GS is known to affect the metabolism and excretion of drugs and xenobiotics . Perfluorocarbon compounds ( PFCs ) are bio - persistent environmental contaminants that affect metabolic regulation . In this study , we examined the associations of GS phenotype and serum PFCs in the Q99618 Health Study Population . MATERIALS AND METHODS : Using 2005 - 2006 data from a large P27918 - exposure population survey , we compared serum PFCs concentrations between GS and non GS clinical phenotypes , in a cross sectional design , adjusting for standard risk factors , including age , BMI , smoking status , socioeconomic status and gender . RESULTS : Among 10 P27918 compounds considered , only perfluorohexanoic acid ( PFHxA ) was seen at a significantly higher concentration in GS men and women . CONCLUSION : PFHxA exposure may be associated with GS . Our findings do not support increased exposure in GS for other PFCs .",
"Different cholinesterase inhibitor effects on P04141 cholinesterases in Alzheimer patients . BACKGROUND : The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) activities and protein levels , in the cerebrospinal fluid ( P04141 ) of Alzheimer disease ( AD ) patients . METHODS AND FINDINGS : AD patients aged 50 - 85 years were randomized to open - label treatment with oral rivastigmine , donepezil or galantamine for 13 weeks . P22303 and BuChE activities were assayed by Ellman ' s colorimetric method . Protein levels were assessed by enzyme - linked immunosorbent assay ( ELISA ) . Primary analyses were based on the Completer population ( randomized patients who completed Week 13 assessments ) . 63 patients were randomized to treatment . DB00989 was associated with decreased P22303 activity by 42 . 6 % and decreased P22303 protein levels by 9 . 3 % , and decreased BuChE activity by 45 . 6 % and decreased BuChE protein levels by 21 . 8 % . DB00674 decreased P22303 activity by 2 . 1 % and BuChE activity by 0 . 5 % , but increased P22303 protein levels by 51 . 2 % and BuChE protein levels by 10 . 5 % . Donepezil increased P22303 and BuChE activities by 11 . 8 % and 2 . 8 % , respectively . Donepezil caused a 215 . 2 % increase in P22303 and 0 . 4 % increase in BuChE protein levels . Changes in mean P22303 - Readthrough / Synaptic ratios , which might reflect underlying neurodegenerative processes , were 1 . 4 , 0 . 6 , and 0 . 4 for rivastigmine , donepezil and galantamine , respectively . CONCLUSION : The findings suggest pharmacologically - induced differences between rivastigmine , donepezil and galantamine . DB00989 provides sustained inhibition of P22303 and BuChE , while donepezil and galantamine do not inhibit BuChE and are associated with increases in P04141 P22303 protein levels . The clinical implications require evaluation .",
"[ ___MASK9___ sodium ( Photofrin - II ) ] . ___MASK9___ sodium ( ___MASK9___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK9___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP3A ) , a phase II enzyme ( P22309 / 6 / 9 ) , two drug transporters ( P - gp and Q9Y6L6 ) and a component of the renal function ( Videau et al . 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat . The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC - MS / MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated . The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1 / 2 with omeprazole / omeprazole - sulfone , midazolam / 1 '- hydroxymidazolam or 4 - hydroxymidazolam and / or dextromethorphan / 3 - methoxymorphinan , CYP2C6 / 11 with tolbutamide / 4 - hydroxytolbutamide , CYP2D1 / 2 with omeprazole / 5 - hydroxyomeprazole or dextromethorphan / dextrorphan , and P19224 / 7 with acetaminophen / acetaminophen - glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP2C11 and CYP2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK38___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK38___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK38___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK38___ among adults with ADHD .",
"Enhanced IgE allergic response to Aspergillus fumigatus in P13569 -/- mice . To gain insight into aberrant cytokine regulation in cystic fibrosis ( CF ) , we compared the phenotypic manifestations of allergen challenge in gut - corrected P13569 - deficient mice with background - matched C57Bl6 ( B6 ) mice . Aspergillus fumigatus ( Af ) antigen was used to mimic allergic bronchopulmonary aspergillosis , a peculiar hyper - IgE syndrome with a high prevalence in CF patients . P13569 -/- , C57BL / 6 and FVB / NJ mice were sensitized with Af antigen by serial intraperitoneal injections . Control mice were mock sensitized with PBS . Challenges were performed by inhalation of Af antigen aerosol . After Af antigen challenge , histologic analysis showed goblet cell hyperplasia and lymphocytic infiltration in both strains . However , total serum IgE levels were markedly elevated in CF mice . Sensitized CF mice showed a five - fold greater IgE response to sensitization as compared with B6 - and FVB - sensitized controls . Additional littermate controls to fully normalize for B6 - FVB admixture in the strain background confirmed the role of P13569 mutation in the hyper - IgE syndrome . Cytokine mRNA levels of P05113 and GM - P04141 in the bronchoalveolar lavage ( BAL ) fluid , and BAL cell differentials indicated that P13569 mutation caused a shift from an P05113 - predominant to an P05112 - predominant cytokine profile . This system models a very specific type of airway inflammation in CF and could provide insights into pathogenesis and treatment of the disease .",
"Detection of anti - isoniazid and anti - cytochrome P450 antibodies in patients with isoniazid - induced liver failure . Isoniazid ( ___MASK63___ ) - induced hepatotoxicity remains one of the most common causes of drug - induced idiosyncratic liver injury and liver failure . This form of liver injury is not believed to be immune - mediated because it is not usually associated with fever or rash , does not recur more rapidly on rechallenge , and previous studies have failed to identify anti - ___MASK63___ antibodies ( Abs ) . In this study , we found Abs present in sera of 15 of 19 cases of ___MASK63___ - induced liver failure . Anti - ___MASK63___ Abs were present in 8 sera ; 11 had anti - cytochrome P450 ( CYP ) 2E1 Abs , 14 had Abs against P05181 modified by ___MASK63___ , 14 had anti - P08684 antibodies , and 10 had anti - P11712 Abs . ___MASK63___ was found to form covalent adducts with P05181 , P08684 , and P11712 . None of these Abs were detected in sera from ___MASK63___ - treated controls without significant liver injury . The presence of a range of antidrug and autoAbs has been observed in other drug - induced liver injury that is presumed to be immune mediated . CONCLUSION : These data provide strong evidence that ___MASK63___ induces an immune response that causes ___MASK63___ - induced liver injury .",
"Induction of lymphokine - activated cytotoxic T lymphocytes stimulated by dendritic cells and autologous tumor from a patient with gastric cancer and their effects in vitro . BACKGROUND / AIMS : The purpose of the study was to generate lymphokine - activated cytotoxic T lymphocytes stimulated by dendritic cells ( DC ) and autologous tumor from a patient with gastric cancer and to clarify their cytotoxic effects in vitro . METHODOLOGY : DC was induced by interleukin - 4 ( P05112 ) and granulocyte - macrophage - colony - stimulating factor ( GM - P04141 ) from the peripheral blood mononuclear cells ( PBMC ) . Then , PBMC was incubated with mitomycin C - treated tumor cells and DC , and following that was activated with P60568 and anti - CD3 . Induction of DC and cytotoxic T cells ( CTL ) were confirmed by the analyses of the cell surface antigens , killing activities , and blocking tests . RESULTS : Induction of DC and cytotoxic T cells ( CTL ) was confirmed by the analyses of the cell surface antigens , killing activities , and blocking tests . In vitro study demonstrated that lymphokine - activated lymphocytes pulsed by DCs and autologous tumor contained the largest population of CTLs , the greatest production of P01579 , and the greatest Q06187 activity . CONCLUSIONS : Those results indicated that CTLs could be generated in vitro from a patient with gastric cancer more successfully by this method than by conventional methods , suggesting the possibility of a new immunotherapy for the treatment of gastric cancer .",
"Gossypin up - regulates P01130 through activation of P29323 pathway : a signaling mechanism for the hypocholesterolemic effect . Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease . This study aims to elucidate the effect of gossypin on cholesterol metabolism in HepG2 cells . Results indicated that gossypin significantly reduced the total cholesterol concentration in a dose - dependent manner . There was a time - and dose - dependent increase in the expression of low - density lipoprotein receptor ( P01130 ) protein . However , 3 - hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase , the rate - limiting enzyme in cholesterol synthesis , was not affected by gossypin . Moreover , gossypin had no effect on nuclear sterol regulatory element binding proteins ( SREBP ) - 2 abundance . The activity of gossypin on P01130 expression was inhibited by the extracellular signal - regulated kinase ( P29323 ) inhibitor PD98059 . Western blotting analysis revealed that gossypin treatment dose - and time - dependently increased P29323 activation and preceded the up - regulation of P01130 expression . Collectively , these new findings identify gossypin as a new hypocholesterolemic agent that up - regulates P01130 expression independent of Q12772 but is dependent on P29323 activation ."
] |
[
"___MASK17___",
"___MASK18___",
"___MASK38___",
"___MASK63___",
"___MASK69___",
"___MASK72___",
"___MASK97___",
"___MASK98___",
"___MASK9___"
] |
___MASK72___
|
MH_train_426
|
interacts_with DB00482?
|
[
"A triple combination of atorvastatin , celecoxib and tipifarnib strongly inhibits pancreatic cancer cells and xenograft pancreatic tumors . Because K - Ras mutation and cyclooxygenase - 2 ( P35354 ) overexpression are hallmarks of majority of pancreatic cancer patients , an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets , should be considered . In the present study , we assessed the effects of atorvastatin ( Lipitor ) , celecoxib ( DB00482 ) and tipifarnib ( DB04960 ) on the growth of human pancreatic cancer . In the in vitro studies , we found that treatment of human pancreatic tumor cells with a combination of atorvastatin , celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs . We also found that treatment of Panc - 1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1 / 2 and Akt . In an animal model of xenograft tumors in severe combined immunodeficient ( SCID ) mice , we found that daily i . p . injections of a combination of atorvastatin , celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs . The results of our study indicate that a combination of atorvastatin , celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer .",
"Approach to angiogenesis inhibition based on cyclooxygenase - 2 . Two cyclooxygenase ( P36551 ) isoforms have been identified : P23219 and P35354 . P23219 is the constitutively expressed form of the enzyme and is ubiquitous in its distribution . P35354 is inducible and is present in inflammatory foci , tumors , and neovasculature . Expression of P35354 appears to be important in tumor promotion , growth , and metastasis . It is up - regulated in a variety of premalignant disorders and malignancies . P36551 inhibitors have a major role in the treatment of inflammation and pain . Epidemiologic evidence in patients who take nonsteroidal anti - inflammatory drugs links P36551 inhibition with decreases in malignant esophageal , stomach , colon , lung , and breast tumors . Nonselective P36551 inhibitors have demonstrated efficacy in control of familial adenomatous polyposis , a disorder associated with the development of thousands of benign intestinal polyps . The selective P35354 inhibitor celecoxib ( DB00482 , Pharmacia ) has been shown to reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis as an adjunct to usual care . Celecoxib has recently been approved for this indication and offers the potential for equivalent or greater efficacy than that seen with nonselective P36551 inhibitors but without the gastrointestinal mucosal toxicity and the inhibition of platelet function associated with those agents . Angiogenesis is a feature of both benign and malignant disease . Because P35354 is up - regulated in the neovasculature of the rheumatoid pannus and in malignant tumors and their surrounding stroma , selective P35354 inhibitors may be able to modify the progression of these disorders through the control of angiogenesis .",
"Drug insight : cyclo - oxygenase 2 inhibitors and cardiovascular risk -- where are we now ? Cyclo - oxygenase ( P36551 ) 1 mediates the production of thromboxane A2 in platelets , leading to platelet aggregation and vasoconstriction . Conversely , P35354 catalyzes endothelial prostacyclin synthesis , which effectively counteracts thromboxane A2 , triggering vasodilation and platelet inhibition . Selective P35354 inhibitors decrease prostacyclin production , potentially disrupting homeostasis and creating a prothrombotic state . The VIGOR study findings of increased cardiovascular risk with rofecoxib were subsequently confirmed by large meta - analyses , observational studies and recent APPROVe trial publication . The P25054 trial findings of increased cardiovascular risk with DB00482 ( celecoxib ) conflict with those in the ADAPT trial , the upcoming PreSAP publication , a case - control study by Graham et al . and prior large clinical trials , meta - analyses and observational studies of this drug . Therefore , while an adverse class effect is a possibility for P35354 inhibitors , the published data are inconsistent . Baseline cardiovascular risk in patients might contribute significantly to these findings . In light of the negative Vioxx ( rofecoxib ) publicity , however , P35354 inhibitors might forever remain underinvestigated . The relative selectivity of these compounds for P35354 is extremely variable , casting significant doubt on the class - effect hypothesis . Improved endothelial function has also been reported with celecoxib , leading to endothelium - dependent vasodilation , and associated decreases in P02741 and LDL cholesterol . The addition of meloxicam to low - dose aspirin and heparin has improved clinical outcomes after acute coronary syndromes . These are the first studies suggesting improvement in endothelial function and reduction of inflammation with P35354 inhibition . Thus , more randomized controlled trials are needed to study the relative cardiovascular effects of different P35354 inhibitors , alone and in combination with aspirin .",
"Phospholipase A₂ activities in skin physiology and pathology . Skin inflammatory diseases are most commonly treated with corticosteroids , especially topical preparations , benefitting from high potency and unparalleled formulation flexibility . However , these benefits are limited due to side effects , especially under long - term use . Non - steroidal anti - inflammatory drugs ( NSAIDs ) which block the P36551 pathways have been used as safer alternatives to corticosteroids , and much effort and resources have been invested in developing P36551 inhibitors . However , synthetic NSAIDs are less potent than steroids , have limited formulation flexibility and have their own safety issues , thereby yielding unsatisfactory results , with some high - profile drugs ( e . g . , the P35354 inhibitors Vioxx , DB00482 ) being withdrawn from the market due to safety concerns . The potency and safety challenges of NSAIDs are related to inter - eicosanoid dynamics , pertaining to their pro - versus anti - inflammatory action , homeostatic functions and tissue - specific activities . Instead , the upstream control of phospholipase A2 ( P04054 ) enzymatic activity , which hydrolyzes cell membrane phospholipids to initiate the eicosanoid production , has been considered for inhibiting eicosanoid activation while maintaining the intricate balance needed for their homeostatic functions . Yet , PLA ( 2 ) inhibitors have hardly been tested for treating skin inflammatory / allergic conditions . In this article we review the involvement of PLA ( 2 ) s in skin physiology and pathology , and discuss the prospect of PLA ( 2 ) inhibition for the treatment of dermatological diseases .",
"Inflammation induces mitochondrial dysfunction and dopaminergic neurodegeneration in the nigrostriatal system . Evidence suggests that chronic inflammation , mitochondrial dysfunction , and oxidative stress play significant and perhaps synergistic roles in Parkinson ' s disease ( PD ) , where the primary pathology is significant loss of the dopaminergic neurons in the substantia nigra . The use of anti - inflammatory drugs for PD treatment has been proposed , and inhibition of cyclo - oxygenase - 2 ( P35354 ) or activation of peroxisome proliferator - activated receptor gamma ( P37231 ) yields neuroprotection in MPTP - induced PD . Lipopolysaccharide ( LPS ) induces inflammation - driven dopaminergic neurodegeneration . We tested the hypothesis that celecoxib ( DB00482 , P35354 inhibitor ) or pioglitazone ( Actos , P37231 agonist ) will reduce the LPS - induced inflammatory response , spare mitochondrial bioenergetics , and improve nigral dopaminergic neuronal survival . Rats were treated with vehicle , celecoxib , or pioglitazone and were intrastriatally injected with LPS . Inflammation , mitochondrial dysfunction , oxidative stress , decreased dopamine , and nigral dopaminergic neuronal loss were observed post - LPS . Celecoxib and pioglitazone provided neuroprotective properties by decreasing inflammation and restoring mitochondrial function . Pioglitazone also attenuated oxidative stress and partially restored striatal dopamine as well as demonstrated dopaminergic neuroprotection and reduced nigral microglial activation . In summary , intrastriatal LPS served as a model for inflammation - induced dopaminergic neurodegeneration , anti - inflammatory drugs provided protective properties , and pioglitazone or celecoxib may have therapeutic potential for the treatment of neuro - inflammation and PD .",
"___MASK96___ inhibits RhoC function and limits head and neck cancer metastasis . OBJECTIVE : RhoC oncogene is a well characterized marker of metastasis in a majority of invasive cancers , including HNSCC . Elevated RhoC expression has been found to be associated with distant metastasis . Statins are a class of drugs that are used to reduce cholesterol levels by inhibiting P04035 activity which in turns prevents mevalonate synthesis , which is a precursor for synthesis of cholesterol and prenylation . Interestingly , the proper function of Rho proteins depends on prenylation . Significantly , it has been reported that metastasis in human melanoma can be reduced by atorvastatin which inhibits RhoC activity by preventing its geranylgeranylation . Given that RhoC is a key oncogene involved in metastasis , we hypothesized ___MASK96___ can reduce head and neck metastasis by inhibiting RhoC activity . METHODS : In vitro and in vivo studies were carried out to evaluate the ability of ___MASK96___ to inhibit RhoC function and HNSCC metastasis . Cell motility , proliferation , cell invasion , and colony formation assays were performed according to the standard protocols . RESULTS : ___MASK96___ treatment significantly reduced the active form of RhoC in vitro and diminished cell motility , invasion , proliferation and colony formation . Importantly , we observed a significant decrease in p - P27361 / 2 and p - P40763 in ___MASK96___ treated cell lines . In vivo experiments revealed inhibition of angiogenesis and lung metastases with ___MASK96___ therapy . CONCLUSIONS : This study is the first of its kind to establish a potential role of ___MASK96___ in head and neck cancer therapy . These findings suggest that ___MASK96___ can be a potential low risk adjuvant therapy to minimize metastases in aggressive forms of HNSCC .",
"P35354 inhibitors : a story of greed , deception and death . In 1999 , drug manufacturers introduced a class of NSAIDs called P35354 inhibitors or coxibs . The drugs were avidly promoted directly to the consumers and became bestsellers from the start . Arthritis sufferers were eager to take medications that eased joint pain with less risk of causing gastrointestinal pain , bleeding and other side - effects . In the year after their introduction , doctors wrote over 100 million prescriptions for celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) . DB00482 is the sixth best - selling drug , with sales of more than US $ 4 billion since its debut in 1999 . Vioxx had sales of US $ 2 . 6 billion in 2001 . However , the coxibs increase the risk of heart attacks and strokes , and their price , in the USA , is obscene . The manufacturers faced a possibly complicit , toothless and bloodless FDA , and used every maneuvering to fleece the patients . We must now reflect on attitudes that we thought only belong to the tobacco industry . Fortunately , safe and active alternatives exist .",
"P35354 inhibition attenuates antibody responses against human papillomavirus - like particles . Vaccination to generate protective humoral immunity against infectious disease is becoming increasingly important due to emerging strains of virus , poorly immunogenic vaccines , and the threat of bioterrorism . We demonstrate that cyclooxygenase - 2 ( Cox - 2 ) is crucial for optimal Ab responses to a model vaccine , human papillomavirus type 16 virus - like particles ( HPV 16 VLPs ) . Cox - 2 - deficient mice produce 70 % less IgG , 50 % fewer Ab - secreting cells , and 10 - fold less neutralizing Ab to HPV 16 VLP vaccination compared with wild - type mice . The reduction in Ab production by Cox - 2 (-/-) mice was partially due to a decrease in class switching . SC - 58125 , a structural analog of the Cox - 2 - selective inhibitor DB00482 reduced by approximately 70 % human memory B cell differentiation to HPV 16 VLP IgG - secreting cells . The widespread use of nonsteroidal anti - inflammatory drugs and Cox - 2 - selective inhibitory drugs may therefore reduce vaccine efficacy , especially when vaccines are poorly immunogenic or the target population is poorly responsive to immunization .",
"Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .",
"Neuroprotective and anti - inflammatory activities of atorvastatin in a rat chronic constriction injury model . ___MASK96___ is an P04035 inhibitor used to treat hypercholesterolemic conditions associated with hypertension . This study aims to investigate the anti - inflammatory and neuroprotective effects of atorvastatin on peripheral neuropathic pain . Peripheral neuropathic pain was induced by chronic constriction injury ( CCI ) in Sprague - Dawley rats . Rats were divided into 3 groups including sham - operated , CCI , and atorvastatin - treated . ___MASK96___ ( 10 mg / kg ) or phosphate - buffered saline was orally administered for 2 weeks . All animals were assessed by neurobehavioral tests before surgery and at days 3 , 7 , 14 after surgery . Inflammatory and neuroprotective factors were evaluated by Western blot analysis . P29474 , P35354 and P35228 in the sciatic nerve were also studied using immunohistochemistry . ___MASK96___ attenuated CCI - induced nociceptive sensitization and thermal hyperalgesia in a time - dependent manner . ___MASK96___ improved CCI - induced neurobehavioral / inflammatory activity by inhibition of TGF - beta , pIkB / IkB , NFkB , P35354 , P35228 , EP1 and EP4 in the sciatic nerve . ___MASK96___ was also found to increase neuroprotection factors pAkt / Akt , P29474 and P15692 . Taken together , these data indicate that atorvastatin could protect the sciatic nerve against CCI - induced neuroinflammation and nociception .",
"___MASK62___ : kinetic and dynamic profile in the treatment of pain . ___MASK62___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK62___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK62___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK62___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"[ A pop - up menu linked to a computerized drug prescribing system . Prescribing pattern ' s feedback via a simple and quick method ] . It takes time for a GP to acquire sufficient experience of a new drug to be able to prescribe competently . This article describes a project studying the use of computerized records to afford a group of GP ' s swift feedback on recently introduced drugs of special interest . In the south - east of Sweden a network of primary health care centers has been created in two neighboring counties . The pharmacies of the region are also taking part . When new drugs of particular interest are introduced , each participating GP will automatically see a pop - up menu , asking questions pertaining to each computer - assisted prescription . In the pharmacies , patients are given a questionnaire regarding their expectations with respect to the drug . In this way it will be possible to provide the individual GP swift feedback from a large number of colleagues and patients concerning the drug ' s effectiveness in clinical practice . We have now been studying the P35354 inhibitors rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) . Results show that a pop - up menu used in this way provides the general practitioner quick feed - back on prescribing behavior as well as drug effectiveness in clinical practice .",
"A structural and in vitro characterization of asoprisnil : a selective progesterone receptor modulator . Selective progesterone receptor modulators ( SPRMs ) have been suggested as therapeutic agents for treatment of gynecological disorders . One such SPRM , asoprisnil , was recently in clinical trials for treatment of uterine fibroids and endometriosis . We present the crystal structures of progesterone receptor ( PR ) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor ( NCoR ) and Q9Y618 . This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors . These structures show PR in a different conformation than PR complexed with progesterone ( P4 ) . We profiled asoprisnil in PR - dependent assays to understand further the PR - mediated mechanism of action . We confirmed previous findings that asoprisnil demonstrated antagonism , but not agonism , in a PR - B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay . Asoprisnil , but not DB00834 , weakly recruited the coactivators Q15788 and Q9Y6Q9 . However , asoprisnil strongly recruited the corepressor NCoR in a manner similar to DB00834 . Unlike DB00834 , NCoR binding to asoprisnil - bound PR could be displaced with equal affinity by NCoR or Q15596 peptides . We further showed that it weakly activated T47D cell gene expression of Sgk - 1 and O60437 and antagonized P4 - induced expression of both genes . In rat leiomyoma ELT3 cells , asoprisnil demonstrated partial P4 - like inhibition of cyclooxygenase ( P36551 ) enzymatic activity and P35354 gene expression . In the rat uterotrophic assay , asoprisnil demonstrated no P4 - like ability to oppose estrogen . Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to DB00834 or P4 , and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus .",
"P35354 independent effects of cyclooxygenase - 2 inhibitors on oxidative stress and intracellular glutathione content in normal and malignant human B - cells . We recently reported that inhibition of P35354 ( Cox - 2 ) reduced human B - CLL proliferation and survival . Herein , we investigated the mechanisms whereby small molecule Cox - 2 selective inhibitors , SC - 58125 ( a DB00482 analog ) and CAY10404 blunt survival of human B - cell lymphomas and chronic lymphocytic leukemia B - cells . SC - 58125 and OSU03012 ( a DB00482 analog that lacks Cox - 2 inhibitory activity ) both decreased intracellular glutathione ( DB00143 ) content in malignant human B - cells , as well as in Cox - 2 deficient mouse B - cells . This new finding supports Cox - 2 independent effects of SC - 58125 . Interestingly , SC - 58125 also significantly increased B - cell reactive oxygen species ( ROS ) production , suggesting that ROS are a pathway that reduces malignant cell survival . Addition of DB00143 ethyl ester protected B lymphomas from the increased mitochondrial membrane permeability and reduced survival induced by SC - 58125 . Moreover , the SC - 58125 - mediated DB00143 depletion resulted in elevated steady - state levels of the glutamate cysteine ligase catalytic subunit mRNA and protein . These new findings of increased ROS and diminished DB00143 levels following SC - 58125 exposure support novel mechanisms whereby a Cox - 2 selective inhibitor reduces malignant B - cell survival . These observations also support the concept that certain Cox - 2 selective inhibitors may have therapeutic value in combination with other drugs to kill malignant B lineage cells .",
"DB00917 produced by lung cancer suppresses immune function through T - regulatory cells and can be blocked by the P35354 inhibitor DB00482 .",
"Current application of selective P35354 inhibitors in cancer prevention and treatment . The multistep process of carcinogenesis , which can take many years , provides many opportunities for intervention to inhibit disease progression . Effective chemoprevention agents may reduce the risk of cancer by inhibiting the initiation stage of carcinoma through induction of apoptosis or DNA repair in cells harboring mutations , or they may act to prevent promotion of tumor growth . Similarly , chemoprevention may entail blocking cancer progression to an invasive phenotype . Over the past decade , in vitro , preclinical , and clinical data have supported the hypothesis that cyclooxygenase ( P36551 ) - 2 plays a central role in oncogenesis and that treatment with P35354 inhibitors offers an effective chemoprevention strategy , as exemplified by the activity of celecoxib ( DB00482 ) in familial adenomatous polyposis . These P35354 data have contributed to initiation of clinical trials testing P35354 inhibitors for the chemoprevention of a wide variety of cancers that overexpress P35354 .",
"Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib - pairs in 64 sib - ships from families ascertained by early - onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib - pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation .",
"P35354 inhibitors -- IBC conference . 12 - 13 April 1999 , Coronado , CA , USA . The introduction of celecoxib ( DB00482 , Figure 1 ; GD Searle and Co ) as the first cyclooxygenase ( P36551 ) 2 selective inhibitor in the US and the expected introduction of rofecoxib ( Vioxx ; Merck and Co Inc ) as the first P35354 inhibitor with an acute pain indication , has prompted interest in this class of drugs as a possible therapeutic improvement on dual P23219 / P35354 inhibitor NSAIDs , currently on the market . Recognition that the P35354 enzyme may have a broader role than pain and inflammation has led to studies investigating the efficacy of P35354 inhibitors for Alzheimer ' s disease ( AD ) , stroke , cardiovascular disease and colon cancer . Speakers at the second annual conference sponsored by IBC , addressed issues ranging from the basic concepts of P35354 specificity versus selectivity , pathways and regulatory factors related to P35354 expression , the principles underlying the possible broad implications of the P35354 mechanisms , as well as summaries of recently completed clinical trials supporting the clinical efficacy and safety of P35354 inhibitors in humans . The timeliness of this meeting is emphasized by the recent approval of rofecoxib by the FDA Arthritis Advisory panel and the initial reports in the media of toxicity attributed to celecoxib . Preclinical and limited clinical data presented suggest possible therapeutic roles for selective P35354 inhibitors in neurodegeneration due to both AD and stroke , the prevention and treatment of colon cancer , prevention of premature labor , as well as pain and inflammation .",
"Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .",
"P35354 inhibitors in glioma therapy . The cyclooxygenase enzyme is a prostaglandin synthase that has two isoforms , cyclooxygenase - 1 ( P23219 ) and cyclooxygenase - 2 ( P35354 ) . Upregulation of the P35354 isoform in many cancers has led to investigation regarding the potential role of this enzyme in oncogenesis . The Food and Drug Administration has approved celecoxib ( DB00482 ) for patients with familial adenomatous polyposis ( FAP ) based on a study that showed a reduction in the number of polyps in such patients when treated with high doses of this drug . We are investigating the potential role of P35354 inhibitors in the treatment of recurrent malignant gliomas in combination with retinoids . In this article the rationale for using this combination therapy in patients with malignant gliomas is presented .",
"Lipoperoxidation and cyclooxygenases 1 and 2 inhibitory compounds from Iryanthera juruensis . Plants from Iryanthera genus have been traditionally used as food supplements by South American Indians . The MeOH extract of leaves of Iryanthera juruensis , one of the plants endemic to the Amazon region and consumed in Brazil , and the hexane extract from its seeds inhibited lipid peroxidation ( P22079 ) and cyclooxygenase ( P23219 and - 2 ) ) enzymes in in vitro assays . Further analyses of these extracts yielded 5 - deoxyflavones ( 1 - 5 ) from the leaf extract and sargachromenol ( 6 ) , sargaquinoic acid ( 7 ) , a novel juruenolic acid ( 8 ) , omega - arylalkanoic acids ( 9a - c ) , and the lignan guaiacin ( 10 ) from the seed extract . Compounds 3 - 5 inhibited P22079 by 86 % , 77 % , and 88 % at 10 ppm , respectively , and compounds 6 and 9a - c showed inhibition at 76 % and 78 % at 100 ppm , respectively . However , compounds 7 and 8 were inactive and lignan 10 exhibited P22079 inhibitory activity by 99 % at 100 ppm compared to commercial antioxidants butylated hydroxyanisole ( BHA ) , butylated hydroxytoluene ( BHT ) , and vitamin E . The flavones 1 - 5 also inhibited P23219 and - 2 enzymes by 50 - 65 % at 100 ppm . DB04088 showed high but nonselective inhibition of P23219 and P35354 enzymes , when compared to aspirin and DB00482 , a nonsteroidal anti - inflammatory drug ( NSAID ) . Compounds 7 and 10 inhibited P23219 by 60 % and 65 % and P35354 by 37 % and 18 % , respectively , whereas compounds 8 and 9a - c showed little or no activity against these enzymes .",
"The role of celecoxib in Rad51 expression and cell survival affected by gefitinib in human non - small cell lung cancer cells . Celecoxib ( DB00482 ) is a cyclooxygenase - 2 ( P35354 ) selective inhibitor and gefitinib ( DB00317 ( R ) , ZD1839 ) is a selective epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor for human non - small cell lung cancer ( NSCLC ) . The addition of celecoxib to gefitinib to prolong the survival of patients with NSCLC still remains controversial and needs to be investigated . The Rad51 protein is essential for homologous recombination repair , and is overexpressed in chemo - or radioresistant carcinomas . In this study , we characterize the role of celecoxib in the cytotoxicity , P27361 / 2 activation and Rad51 expression affected by gefitinib in NSCLC cells . We show that celecoxib can enhance the cytotoxicity induced by gefitinib in NSCLC cells . Treatment with celecoxib alone has no effect on the P27361 / 2 activation , Rad51 mRNA and protein levels , however , combined treatment with gefitinib results in a significant reduction of phospho - P27361 / 2 and Rad51 protein levels , and triggers the degradation of Rad51 via a 26S proteasome - dependent pathway . Expression of constitutively active Q02750 / 2 vectors ( Q02750 / 2 - CA ) significantly rescues the decreased P27361 / 2 activity , and restores Rad51 protein levels and cell survival under co - treatment with gefitinib and celecoxib . Furthermore , blocking P27361 / 2 activation by U0126 ( Q02750 / 2 inhibitor ) and knocking down Rad51 expression by transfection with small interfering RNA of Rad51 can enhance the cytotoxicity of celecoxib .",
"Selective inhibition of P35354 is beneficial to mice infected intranasally with VSV . Cyclooxygenase ( P36551 ) is the key enzyme for prostaglandin ( PG ) synthesis . PGs are mediators of many critical physiological and inflammatory responses . There are two isoforms , P23219 and P35354 , both of which are constitutively expressed in the central nervous system ( CNS ) . Studies have shown that P23219 and P35354 are involved in physiological and pathological conditions of the brain . However , little is known about the role ( s ) of P36551 in the host defense system against a viral infection in the CNS . In this report , we used Vesicular Stomatitis Virus ( VSV ) induced acute encephalitis to distinguish between the contribution ( s ) of the two isoforms . P35354 activity was inhibited with a P35354 selective drug , celecoxib ( DB00482 ) , and P23219 was antagonized with SC560 . We found that inhibition of P35354 led to decreased viral titers , while P23219 antagonism did not have the same effect at day 1 post infection . 5 - lipooxygenase ( P09917 ) expression and neutrophil recruitment in the CNS were increased in celecoxib - inhibited mice . Furthermore , mice treated with celecoxib expressed more DB00435 Synthase - 1 ( Q8WY41 ) , a crucial component of the innate immune system in the restriction of VSV propagation . The expression of type 1 cytokines , P01579 and IL - 12 , were also increased in celecoxib - treated mice .",
"Celecoxib - induced upper gastrointestinal hemorrhage and ulceration . P35354 inhibitors are a new class of nonsteroidal anti - inflammatory drugs with a reported benefit of less gastric and duodenal ulceration and hemorrhage . We describe a 67 - year - old man taking a higher than usual dose of celecoxib ( DB00482 ) for osteoarthritis with resultant gastric erosions , ulceration , and a significant gastrointestinal ( GI ) hemorrhage .",
"Membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib . Both membranous glomerulopathy and acute interstitial nephritis have been reported to occur following treatment with non - steroidal anti - inflammatory drugs . We report the first cases of membranous glomerulopathy and acute interstitial nephritis following treatment with celecoxib ( DB00482 ) , a selective P35354 inhibitor . The rapid and complete resolution of both conditions following discontinuation of DB00482 strongly implicates this agent in disease pathogenesis . These cases enlarge the spectrum of potential renal toxicities of the P35354 - specific non - steroidal anti - inflammatory drugs .",
"Correlation between tumor volume response to radiotherapy and expression of biological markers in patients with cervical squamous cell carcinoma . OBJECTIVE : To determine the factors associated with tumor volume response to radiotherapy ( RT ) in cervical cancer patients , and the relationship between the tumor volume response and alteration of the expression of biological markers during RT . METHODS : Twenty consecutive patients with cervical squamous cell carcinoma who received definitive RT were enrolled . Tumor volumes were calculated by Q9BWK5 examinations performed at the start of RT ( pre - RT ) , at the fourth week of RT ( mid - RT ) , and 1 month after RT completion ( post - RT ) . Two serial punch biopsies were performed at pre - and mid - RT , and immunohistochemical staining was performed for cyclooxygenase ( P36551 ) - 2 and epidermal growth factor receptor ( P00533 ) . RESULTS : For the pre - RT evaluation , fourteen ( 70 % ) and eleven ( 55 % ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . Among the seven patients whose median percentage residual tumor at mid - RT ( P30518 ) was greater than 0 . 5 , seven ( 100 % , p = 0 . 0515 ) and five ( 71 . 4 % , p = 0 . 3742 ) patients showed positive immunoreactivity for P35354 and P00533 , respectively . The logistic regression analysis showed that positive immunoreactivity for both P35354 and P00533 at pre - RT were associated with P30518 ( p = 0 . 0782 ) . For the mid - RT evaluation , eight cases showed an interval increase in the distribution of immunoreactivity for P35354 , and six out of the eight patients had a P30518 greater than 0 . 5 ( p = 0 . 2222 ) . CONCLUSION : The poor mid - RT tumor response was associated with the coexpression of P35354 and P00533 .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK73___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK73___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK73___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"P11511 inhibitors and cyclooxygenase - 2 ( P35354 ) inhibitors in endometriosis : new questions -- old answers ? The medical treatment of endometriosis needs to be optimized . Therapeutic management strategies for endometriosis - associated pain or recurrent disease are primarily aimed at downregulating ovarian function or antagonizing the effect of estrogen in ectopic endometrial implants . In this context , basic research is providing important results for the development of new , specific treatment modalities . P11511 overexpression has recently been detected in endometriotic tissue . P11511 ( p450arom ) is responsible for converting C19 androgens into estrogen in several types of human tissue . P11511 activity causes local estrogen biosynthesis , which , in turn , stimulates prostaglandin E2 production by upregulating cyclooxygenase - 2 ( P35354 ) . Thus , a positive feedback cycle develops between the two systems . Another abnormality in endometriosis , the deficient 17beta - hydroxysteroiddehydrogenase type II ( 17beta - HSD - Type - II ) expression , impairs the inactivation of estradiol to estrone . In contrast to the eutopic endometrium , these molecular aberrations increase the amount of local estradiol and prostaglandin E2 in endometriosis . In several human cell lines , prostaglandin and estrogen concentrations are associated with proliferation , migration , angiogenesis , apoptosis resistance and even invasiveness . Consequently , aromatase and P35354 are thought to be promising new therapeutic targets . Thus , specific aromatase inhibitors ( e . g . DB01006 / DB01006 , DB01217 / Arimidex or Exemestan / Aromasin ) or selective P35354 inhibitors ( e . g . Celecoxib / DB00482 , DB00533 / Vioxx , DB00580 / Bextra ) are of great interest and should be studied in clinical trials in premenopausal woman with endometriosis to expand the spectrum of currently available treatment options .",
"A real time quantitative PCR analysis and correlation of P23219 and P35354 enzymes in inflamed dental pulps following administration of three different NSAIDs . Dental pain is encountered daily by clinicians . Nonsteroidal anti - inflammatory drugs ( NSAIDs ) commonly used for pain management are traditionally cyclooxygenase - 1 ( P23219 ) and cyclooxygenase - 2 ( P35354 ) inhibitors , and more recently selective P35354 inhibitors . This study was designed to identify and quantify P23219 and P35354 gene expression level in inflamed rat molar pulps after administration of three NSAIDs : DB00482 , Vioxx , and DB01050 . Fifty male Wistar rats had their first and second molar pulps exposed and sealed with Cavit for 4 days . Rats were randomly divided into the three drug groups and two control groups . RNA was isolated from the rat pulps . Real Time Quantitative Reverse Transcriptase - Polymerase Chain Reaction assay , a relatively new PCR technique , was used to quantify P23219 and P35354 mRNA . Statistical analysis demonstrated no significant differences in P23219 and P35354 levels among the drug groups . However , Vioxx and DB01050 significantly reduced P35354 expression levels compared to inflamed ( positive control ) pulps ( p < 0 . 05 ) .",
"[ Moclobemide ( ___MASK14___ ) , the first P21397 - inhibitor : really something new ? ] .",
"[ The effects of DB00482 on mammary tumorigenesis and aging in P04626 / neu transgenic mice ] . It is well known that cyclooxygenase - 2 ( P35354 ) plays an important role in the development of many tumors including breast cancer . Our study was concerned with evaluating the effects of the selective P35354 inhibitor , celecoxib , on mammary tumorigenesis and aging in P04626 / neu transgenic mice ( 24 ) . Celecoxib ( celebrex ) 25 mg / kg was administered 5 times a week from the age of 2 months . Twenty - four intact females were in control . Monitoring kept track of tumor detection time , size , presence of lung metastases , food and water consumption , estral function , body weight and temperature . No significant differences between the two groups were reported as far as life - span , tumor growth rate , size and number of metastases to the lung is concerned . To sum up , celecoxib treatment failed to produce any significant effect on carcinogenesis in P04626 / neu transgenic mice .",
"Functional characterization of a novel serotonin receptor ( 5 - HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full - length cDNA , coding for a novel serotonin receptor ( 5 - HTap2 ) . The receptor protein bears the characteristics of G protein - coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5 - HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5 - HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [ 3H ] LSD binding was : methiothepin > metergoline > 5 - CT > PAPP > 5 - HT > ketanserin > NAN - 190 > 8 - OH - DPAT > clozapine . RT - PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5 - HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5 - HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg - laying behavior .",
"P35354 inhibitors and DB00482 : safe or suspect ?",
"Enhancement of 5 - fluorouracil efficacy on high P35354 expressing HCA - 7 cells by low dose indomethacin and NS - 398 but not on low P35354 expressing HT - 29 cells . The antiproliferative effect of 5 - fluorouracil ( ___MASK78___ ) in the presence of low dose non - steroidal anti - inflammatory drugs ( NSAIDs ) on high cyclooxygenase - 2 ( P35354 ) - expressing HCA - 7 and low P35354 - expressing HT - 29 colon carcinoma cell lines was investigated . Pharmacogenetic parameters were studied to characterize the ___MASK78___ sensitivity of the two cell lines . P04818 ( TS ) and methylenetetrahydrofolate reductase ( P42898 ) polymorphisms were determined by PCR analysis . Cell proliferation was measured by P50991 assay , cell cycle distribution and apoptosis by FACS analysis . Cyclooxygenase expression was detected by Western blot and also by fluorescence microscopy . Prostaglandin E ( 2 ) ( PGE ( 2 ) ) levels were investigated with ELISA kit . The HT - 29 cell line was found to be homozygous for TS 2R and 1494ins6 and T homozygous for P42898 677 polymorphisms predicting high ___MASK78___ sensitivity ( IC ( 50 ) : 10 microM ) . TS 3R homozygosity , TS 1496del6 and P42898 677CT heterozygosity may explain the modest ___MASK78___ sensitivity ( IC ( 50 ) : 1 . 1 mM ) of the HCA - 7 cell line . Indomethacin and NS - 398 ( 10 microM and 1 . 77 microM , respectively ) reduced the PGE ( 2 ) level in HCA - 7 cells ( > 90 % ) . Low concentrations of NSAIDs without antiproliferative potency increased the S - phase arrest and enhanced the cytotoxic action of ___MASK78___ only in HCA - 7 cells after 48 - hours treatment . The presented data suggested that the enhancement of ___MASK78___ cytotoxicity by indomethacin or NS - 398 applied in low dose is related to the potency of NSAIDs to modulate the cell - cycle distribution and the apoptosis ; however , it seems that this effect might be dependent on cell phenotype , namely on the P35354 expression .",
"Microscopic modes and free energies of 3 - phosphoinositide - dependent kinase - 1 ( PDK1 ) binding with celecoxib and other inhibitors . Celecoxib , also known as DB00482 ( approved by FDA in 1998 ) and remembered as the fastest - selling drug in history , was used as a cyclooxygenase - 2 ( P35354 ) selective inhibitor having both anti - inflammatory and anticancer activities . Most recent studies have revealed that the apoptotic activity of celecoxib ( and its derivatives ) is actually independent of the P35354 inhibitory activity and that celecoxib also inhibits the kinase activity of 3 - phosphoinositide - dependent protein kinase - 1 ( PDK1 ) , suggesting that the well - known anticancer activity of celecoxib is not due to the inhibition of P35354 , but possibly is due to the inhibition of PDK1 . It is highly desirable to develop new celecoxib derivatives as PDK1 - specifc inhibitors to avoid the side effects of P35354 inhibitors . To understand how PDK1 binds with celecoxib and its derivatives , we have performed extensive molecular docking and combined molecular dynamics ( MD ) simulations and molecular mechanics / Poisson - Boltzmann surface area ( MM - PBSA ) binding free energy calculations on eight representative PDK1 inhibitors , leading to the finding of a new , more favorable binding mode which is remarkably different from the previously proposed binding mode . Based on the determined most stable binding structures , the calculated binding free energies are all in good agreement with the corresponding experimental data , and the biological activity data available for celecoxib and its derivatives can be better interpreted . The obtained new insights , concerning both the binding mode and computational protocol , will be valuable not only for future rational design of novel , more potent PDK1 - specific inhibitors as promising anticancer therapeutics , but also for rational design of drugs targeting other proteins .",
"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK32___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK32___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .",
"Compositions for treatment of cancer and inflammation . Celecoxib ( DB00482 , Pfizer , NY , USA ) is a worldwide top branded P35354 - specific inhibitor . It was shown to provide relief of arthritic pain and inflammation and has recently been under investigation for the prevention and treatment of cancer . However , recent studies showed that long term use of high doses of celecoxib is associated with an increased cardiovascular toxicity . We discovered that the addition of curcumin , a natural P35354 inhibitor , to celecoxib synergistically ( up to 1000 % ) augments the growth inhibitory effects of celecoxib in in - vitro and in - vivo models of arthritis and cancer , thus rendering effective action of the drug at up to tenfold lower dose . This may pave the way for a novel strategy to treat arthritis and cancer because its effect [ 1 ] can be achieved in the serum of patients receiving standard anti inflammatory or anti - neoplastic dosages of celecoxib , and [ 2 ] involves a regimen with a very low profile of side effects . Preliminary data suggest that the combination is not limited only to celecoxib and that addition of curcumin to other NSAIDs such as sulindac , synergistically augments neoplastic cell growth inhibition . Based on these finding we received an IRB approval to evaluate celecoxib + curcumin in patients with osteoarthritis , pancreatic cancer and metastatic CRC . We hope to complete these novel human clinical trials , in 12 - 18 months .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK66___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"Targeting angiogenic processes by combination rofecoxib and ionizing radiation . Tumor growth and angiogenesis are interdependent . Cyclooxygenase ( P36551 ) catalyzes the synthesis of prostaglandins from arachidonic acid . Nonsteroidal antiinflammatory drugs ( NSAIDs ) inhibit P36551 - mediated synthesis of prostaglandins . P23219 is constitutively expressed in a wide range of tissues , whereas P35354 is cytokine inducible . Enhanced P35354 expression has been attributed a key role in the development of inflammation and related processes observed in pathologically altered disease states . Two specific P35354 inhibitors , namely rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) , both oral agents and U . S . Food and Drug Administration approved , have been shown preclinically and clinically to have efficacy comparable to that of NSAIDs for relief of pain and inflammation in osteoarthritis , with decreased risk of gastrointestinal damage . Little is known about how angiogenesis is affected by the combination of rofecoxib and radiation . We have evaluated the combination of rofecoxib , at various concentrations , and radiation on cytokine - induced angiogenesis in vitro . We have found that rofecoxib inhibited endothelial cell proliferation , migration , and tube formation ( differentiation ) at clinically relevant doses . In combination with radiation , inhibition of endothelial cell function further increased twofold . The combination of rofecoxib and radiation suggests a complementary strategy with clinical ramifications to target angiogenesis - dependent malignancies .",
"Mechanisms of Kv2 . 1 channel inhibition by celecoxib -- modification of gating and channel block . BACKGROUND AND PURPOSE : Selective cyclooxygenase - 2 ( P35354 ) inhibitors such as rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) were developed as NSAIDs with reduced gastric side effects . Celecoxib has now been shown to affect cellular physiology via an unexpected , P36551 - independent , pathway - by inhibiting K ( v ) 2 . 1 and other ion channels . In this study , we investigated the mechanism of the action of celecoxib on K ( v ) 2 . 1 channels . EXPERIMENTAL APPROACH : The mode of action of celecoxib on rat K ( v ) 2 . 1 channels was studied by whole - cell patch - clamping to record currents from channels expressed in P29320 - 293 cells . KEY RESULTS : Celecoxib reduced current through K ( v ) 2 . 1 channels when applied from the extracellular side . At low concentrations ( < or = 3 microM ) , celecoxib accelerated kinetics of activation , deactivation and inactivation . Recovery of rat K ( v ) 2 . 1 channels from inactivation could be characterized by two components , with celecoxib selectively accelerating the slow component of recovery at < or = 10 microM . At > 3 microM , celecoxib led to closed - channel block with relative slowing of activation . At 30 microM , it additionally induced open - channel block that manifested in use - dependent inhibition and slower recovery from inactivation . CONCLUSIONS AND IMPLICATIONS : Celecoxib reduced current through K ( v ) 2 . 1 channels by modifying gating and inducing closed - and open - channel block , with the three effects manifesting at different concentrations . These data will help to elucidate the mechanisms of action of this widely prescribed drug on ion channels and those underlying its neurological , cardiovascular and other effects .",
"Glial response to lipopolysaccharide : possible role of endothelins . Glial inflammation plays a major role in the development of neurodegenerative diseases . Although endothelins ( ETs ) are known as modulators of inflammation in the periphery , little is known about their possible role in brain inflammation . Previously , we demonstrated that all three endothelins ( ET - 1 , P20800 and P14138 ) enhanced unstimulated synthesis of the glial pro - inflammatory mediators , prostaglandin E₂ ( PGE₂ ) and nitric oxide ( NO ) . In the present study , glial cells were stimulated in an in vitro model of inflammation by incubation with the bacterial endotoxin lipopolysaccharide ( LPS ) . Indeed , the present study shows that ETs regulate basal and LPS - induced glial inflammation in an opposite fashion . Here we demonstrate that ETs significantly inhibited the LPS - induced glial synthesis of PGE₂ and NO , and each of the selective antagonists for P25101 and ETB receptors ( BQ123 and BQ788 respectively ) , significantly inhibited the ETs effects in LPS - treated cells . Similar results were observed when expression of key enzymes namely , cyclooxygenase - 2 ( P35354 ) and inducible nitric oxide synthase ( P35228 ) in PG and NO synthesis respectively , was measured . ET - 1 significantly enhanced the expression of both P35354 and P35228 . Whereas , it inhibited the LPS - induced expression of both enzymes . These observations suggest a novel neuro - immune feedback pathway through which inflammatory mediators ' synthesis is initially enhanced by ETs and are eventually blocked by the same neuropeptide when excessive production of inflammatory mediators occurs following an inflammatory insult .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"Enhanced killing of chemo - resistant breast cancer cells via controlled aggravation of ER stress . Moderate activity of the endoplasmic reticulum ( ER ) stress response system exerts anti - apoptotic function and supports tumor cell survival and chemoresistance , whereas its more severe aggravation may exceed the protective capacity of this system and turn on its pro - apoptotic module . In this study , we investigated whether the combination of two pharmacologic agents with known ability to trigger ER stress via different mechanisms would synergize and lead to enhanced tumor cell death . We combined the HIV protease inhibitor nelfinavir ( DB00220 ) and the cyclooxygenase 2 ( P35354 ) inhibitor celecoxib ( DB00482 ) and investigated their combined effect on ER stress and on the viability of breast cancer cells . We found that this drug combination aggravated ER stress and caused pronounced toxicity in human breast cancer cell lines , inclusive of variants that were highly resistant to other therapeutic treatments , such as doxorubicin , paclitaxel , or trastuzumab . The anti - tumor effects of celecoxib were mimicked at increased potency by its non - coxib analog , 2 , 5 - dimethyl - celecoxib ( Q6UXB2 ) , but were substantially weaker in the case of unmethylated - celecoxib ( UMC ) , a derivative with superior P35354 inhibitory efficacy . We conclude that the anti - tumor effects of nelfinavir can be enhanced by celecoxib analogs in a P35354 independent fashion via the aggravation of ER stress , and such drug combinations should be considered as a beneficial adjunct to the treatment of drug - resistant breast cancers .",
"Regional expression and role of cyclooxygenase - 2 following experimental traumatic brain injury . Prostaglandins , potent mediators of inflammation , are generated from arachidonic acid ( AA ) via the action of cyclooxygenase - 1 and - 2 ( P23219 and P35354 ) . In this study , we report that lateral cortical impact injury in rats significantly increases P35354 protein levels both in the cortex surrounding the injury site and the ipsilateral hippocampus . P35354 protein level was elevated as early as 3 h postinjury and persisted for up to 3 days . Increases in immunoreactivity were detected not only in the adjacent cortex and hippocampus , but were also observed in the contralateral cortex and hippocampus , the ipsilateral piriform cortex and the ipsilateral amygdaloid complex . P35354 immunoreactive cells appear morphologically normal and do not present any of the characteristic features of apoptosis . Double immunostaining experiments using either a neuron - specific or an astroglial - specific marker show that the expression of P35354 is localized almost exclusively in neuronal cells . Administration of the P35354 inhibitor 4 -[ 5 -( 4 - methylphenyl )- 3 -( trifluoromethyl )- 1H - pyrazol - 1 - yl ] benzenesulfona mide ( celecoxib , marketed as DB00482 ) worsens motor , but not cognitive , performance , suggesting that P35354 induction following traumatic brain injury may play a protective role .",
"P35354 but not mPGES - 1 contributes to renal DB00917 induction and diabetic proteinuria in mice with type - 1 diabetes . DB00917 ( DB00917 ) has been implicated to play a pathogenic role in diabetic nephropathy ( DN ) but its source remains unlcear . To elucidate whether mPGES - 1 , the best characterized DB00917 synthase , was involved in the development of DN , we examined the renal phenotype of mPGES - 1 KO mice subjected to Q11206 - induced type - 1 diabetes . After Q11206 treatment , mPGES - 1 WT and KO mice presented the similar onset of diabetes as shown by similar elevation of blood glucose . Meanwhile , both genotypes of mice exhibited similar increases of urinary and renal DB00917 production . In parallel with this comparable diabetic status , the kidney injury indices including the urinary albumin excretion , kidney weight and the kidney histology ( DB00233 staining ) did not show any difference between the two genotypes . By Western - blotting and quantitative qRT - PCR , mPGES - 1 , Q9H7Z7 , Q15185 and 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) remain unaltered following six weeks of diabetes . Finally , a selective P35354 inhibitor celecoxib ( 50 mg / kg / day ) was applied to the Q11206 - treated KO mice , which resulted in significant reduction of urinary albumin excretion ( KO / Q11206 : 141 . 5 ± 38 . 4 vs . KO / Q11206 + DB00482 : 48 . 7 ± 20 . 8 ug / 24 h , p < 0 . 05 ) and the blockade of renal DB00917 induction ( kidney : KO / Q11206 : 588 . 7 ± 89 . 2 vs . KO / Q11206 + DB00482 : 340 . 8 ± 58 . 7 ug / 24 h , p < 0 . 05 ; urine : KO / Q11206 1667 . 6 ± 421 . 4 vs . KO / Q11206 + DB00482 813 . 6 ± 199 . 9 pg / 24 h , p < 0 . 05 ) , without affecting the blood glucose levels and urine volume . Taken together , our data suggests that an as yet unidentified prostaglanind E synthase but not mPGES - 1 may couple with P35354 to mediate increased renal DB00917 sythsesis in DN .",
"Dual carbonic anhydrase -- cyclooxygenase - 2 inhibitors . Cyclooxygenase is a key enzyme responsible for metabolisation of arachidonic acid into prostaglandins and thromboxane . This enzyme is the target of non steroidal anti - inflammatory drugs ( NSAIDs ) , used against inflammation and pain . The inducible P35354 was associated with inflammatory conditions , whereas the constitutive form ( P23219 ) was responsible for the beneficial effects of the PGs . This observation led to the development of P35354 inhibitors or \" coxibs \" of which rofecoxib ( Vioxx ) characterized by a methylsulfone moiety and the sulfonamides celecoxib ( DB00482 ) and valdecoxib ( Bextra ) . Initially described as P35354 \" selective \" inhibitors , recent reports revealed a nanomolar inhibition activity of the sulfonamide P35354 inhibitors for several carbonic anhydrase ( CA ) isoforms , confirmed by X - ray crystal structures for the adducts of celecoxib and valdecoxib with isozyme CA II . This dual activity may help to explain differences in clinical observation between sulfonamide and methylsulfone P35354 inhibitors . Moreover , the inhibition of CA isozymes , critical for the development and invasion of cancer cells , such as CA II , IX and XII , may constitute an important mechanism of antitumor action of such sulfonamide compounds .",
"A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK47___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .",
"Inhibition of delayed rectifier potassium channels and induction of arrhythmia : a novel effect of celecoxib and the mechanism underlying it . Selective inhibitors of cyclooxygenase - 2 ( P35354 ) , such as rofecoxib ( Vioxx ) , celecoxib ( DB00482 ) , and valdecoxib ( Bextra ) , have been developed for treating arthritis and other musculoskeletal complaints . Selective inhibition of P35354 over P23219 results in preferential decrease in prostacyclin production over thromboxane A2 production , thus leading to less gastric effects than those seen with nonselective P36551 inhibitors such as acetylsalicylic acid ( aspirin ) . Here we show a novel effect of celecoxib via a mechanism that is independent of P35354 inhibition . The drug inhibited the delayed rectifier ( Kv2 ) potassium channels from Drosophila , rats , and humans and led to pronounced arrhythmia in Drosophila heart and arrhythmic beating of rat heart cells in culture . These effects occurred despite the genomic absence of cyclooxygenases in Drosophila and the failure of acetylsalicylic acid , a potent inhibitor of both P23219 and P35354 , to inhibit rat Kv2 . 1 channels . A genetically null mutant of Drosophila Shab ( Kv2 ) channels reproduced the cardiac effect of celecoxib , and the drug was unable to further enhance the effect of the mutation . These observations reveal an unanticipated effect of celecoxib on Drosophila hearts and on heart cells from rats , implicating the inhibition of Kv2 channels as the mechanism underlying this effect .",
"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK84___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .",
"Celecoxib exhibits the greatest potency amongst cyclooxygenase ( P36551 ) inhibitors for growth inhibition of P35354 - negative hematopoietic and epithelial cell lines . P35354 ( P35354 ) is an important cellular target for both therapy and / or prevention of inflammatory disorders and cancer . The advent of selective P35354 inhibitors now allows a more precise and safer treatment approach . The screening of an array of cancer cell lines for growth inhibitory effects of P35354 - selective and - nonselective inhibitors , including celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) , produced two unanticipated findings . Firstly , the antiproliferative effects of celecoxib were noted to be of very similar magnitude for both hematopoietic and epithelial cancer cell lines . Most hematopoietic cell lines had no detectable P35354 expression by reverse transcription - PCR , and none expressed P35354 protein . In addition , P35354 - negative epithelial lines were found to have IC50s for celecoxib that were very similar to their P35354 + counterparts . Thus , important antiproliferative effects were observed that were independent of both the cell lineage and P35354 status . Secondly , it was also observed that P35354 inhibitor drugs , celecoxib and rofecoxib , with similar P35354 - selectivity and clinical efficacy for inflammatory indications , differed significantly in their in vitro antiproliferative effects on cancer cell lines . IC50s of 35 - 65 microM were observed for celecoxib across this entire panel of cell lines . Finally , no difference in the mode or degree of cytotoxicity was apparent between cell lines , because similar levels of apoptosis were observed in P35354 + and - negative cell lines after treatment with celecoxib , with correspondingly lower levels after rofecoxib treatment . These data are important in that they provide the first direct comparison of epithelial and hematopoietic cancer cell lines , as well as a direct comparison of the in vitro anticancer effects of the two clinically available P35354 inhibitors .",
"DB00762 , cisplatin / carboplatin , and P35354 inhibition in small - cell lung cancer . Recent findings indicate significant prolongation of survival and time to disease progression with irinotecan ( CPT - 11 , Camptosar ) / cisplatin vs etoposide / cisplatin in extensive - stage small - cell lung cancer , and a larger - scale phase III trial has been planned to provide more definitive data on the benefits of the irinotecan / cisplatin combination in this setting . Early - phase studies indicate that the activity of carboplatin ( DB00958 ) in small - cell lung cancer is comparable to that of cisplatin , and that combining irinotecan on a day 1 and 8 schedule with split - dose carboplatin is feasible . Inhibition of the cyclooxygenase - 2 ( P35354 ) enzyme , which is active in tumorigenesis , may augment efficacy and reduce toxicity of platinum / irinotecan combinations . A phase II trial has been designed to compare irinotecan / carboplatin and irinotecan / cisplatin combinations with or without the P35354 inhibitor celecoxib ( DB00482 ) in patients with extensive - stage small - cell lung cancer . Results of these trials will help define the roles of platinum / irinotecan combinations and P35354 inhibition in treatment for small - cell lung cancer .",
"Preventive but not curative efficacy of celecoxib on bladder carcinogenesis in a rat model . To evaluate the effect of a cyclooxygenase 2 inhibitor , celecoxib ( P19835 ) , on bladder cancer inhibition in a rat model , when used as preventive versus as curative treatment . The study comprised 52 male Wistar rats , divided in 5 groups , during a 20 - week protocol : control : vehicle , carcinogen : 0 . 05 % of N - butyl - N -( 4 - hydroxybutyl ) nitrosamine ( BBN ) , P19835 : 10 mg / kg / day of the selective P35354 inhibitor DB00482 , preventive P19835 ( P19835 + BBN - P ) , and curative P19835 ( BBN + P19835 - C ) groups . Although tumor growth was markedly inhibited by the preventive application of P19835 , it was even aggravated by the curative treatment . The incidence of gross bladder carcinoma was : control 0 / 8 ( 0 % ) , BBN 13 / 20 ( 65 % ) , P19835 0 / 8 ( 0 % ) , P19835 + BBN - P 1 / 8 ( 12 . 5 % ) , and BBN + P19835 - C 6 / 8 ( 75 % ) . The number and volume of carcinomas were significantly lower in the P19835 + BBN - P versus BBN , accompanied by an ample reduction in hyperplasia , dysplasia , and papillary tumors as well as P35354 immunostaining . In spite of the reduction of tumor volumes in the curative BBN + P19835 - C group , tumor malignancy was augmented . An anti - inflammatory and antioxidant profile was encountered only in the group under preventive treatment . In conclusion , preventive , but not curative , celecoxib treatment promoted a striking inhibitory effect on bladder cancer development , reinforcing the potential role of chemopreventive strategies based on cyclooxygenase 2 inhibition .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( DB01050 ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"Initial experience combining cyclooxygenase - 2 inhibition with chemoradiation for locally advanced pancreatic cancer . Pancreatic cancer is a lethal disease that is resistant to chemotherapy and radiotherapy . Gemcitabine has recently been shown to be an improvement over 5 - fluorouracil in patients with advanced disease . It is also a potent radiosensitizer , which has led to the investigation of gemcitabine with concurrent radiotherapy . However , preliminary results indicate that there are significant limitations to this approach in this challenging disease . Pancreatic cancer cells have alterations in many molecular signaling pathways that may be responsible for their resistance to cytotoxic therapy and aggressive behavior . P35354 ( P35354 ) is commonly overexpressed in pancreatic tumors , and preclinical evidence indicates that selective P35354 inhibition enhances both chemotherapy and radiotherapy response , without affecting normal tissue damage . We have initiated preclinical studies as well as a phase I clinical protocol evaluating the combination of gemcitabine and celecoxib ( DB00482 ) with radiotherapy . In preclinical studies , celecelecoxib strongly enhanced the antitumor efficacy of chemoradiation . However , preliminary observations from both the preclinical experiments as well as the clinical protocol have revealed more toxicity with this combination than with gemcitabine and radiotherapy alone . These observations require further study , but are cause for concern when combining gemcitabine , radiotherapy , and celecoxib .",
"What ' s all the fuss ? Safety concerns about P35354 inhibitors rofecoxib ( Vioxx ) and celecoxib ( DB00482 ) .",
"Concerted activation of ETS protein P50549 by P52701 coactivators , the acetyltransferase p300 and the receptor tyrosine kinase P04626 / Neu . Activator of thyroid and retinoic acid receptor ( Q9Y6Q9 ) is overexpressed in approximately 60 % of primary human breast tumors and belongs to the P52701 steroid receptor coactivator family . In this study , we identified a novel interaction partner of Q9Y6Q9 , the ETS transcription factor P50549 that is also heavily implicated in mammary tumor formation . Q9Y6Q9 and related P52701 family members ( steroid receptor coactivator - 1 and glucocorticoid receptor - interacting protein - 1 ( Q9Y3R0 ) ) augment P50549 - mediated transcription . Although Q9Y6Q9 and Q9Y3R0 can acetylate P50549 , this posttranslational modification of P50549 is not required for its stimulation by Q9Y6Q9 or Q9Y3R0 . In addition , Q9Y6Q9 collaborates with the p300 coactivator , a joint interaction partner of Q9Y6Q9 and P50549 , to stimulate P50549 function and the ability of p300 to acetylate P50549 is indispensable for this collaboration . Furthermore , the receptor tyrosine kinase P04626 / Neu , an oncoprotein particularly found overexpressed in breast tumors , cooperates with both Q9Y6Q9 and p300 to stimulate P50549 - mediated transcription . Thus , oncogenic P04626 / Neu and Q9Y6Q9 may synergize to orchestrate mammary tumorigenesis through the dysregulation of the transcription factor P50549 and its target genes .",
"[ Selective inhibitors of type 2 cyclooxygenase : less renal effects than the classical non - steroidal anti - inflammatory agents ] . Prostaglandins play an important role in the regulation of renal hemodynamics and sodium excretion . Thus , the administration of non - steroidal anti - inflammatory drugs ( NSAIDs ) induces a renal vasoconstriction and sodium and potassium retention . In some high risk patients , this may lead to acute renal failure . The anti - inflammatory and renal effects of conventional NSAIDs are mediated by the non - selective inhibition of two cyclo - oxygenases , P23219 and P35354 . Recently , highly selective P35354 inhibitors have been developed such as celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) . These drugs were designed to preserve the analgesic and anti - inflammatory properties of NSAIDs while reducing their gastro - intestinal and renal side effects . Selective P35354 inhibitors have indeed less gastro - intestinal side - effects . However , their renal profile is comparable to that of non - selective inhibitors as they induce a decrease in glomerular filtration rate and a sodium and potassium retention . Thus , despite the good gastro - intestinal safety profile of selective P35354 , one should be careful with the use of these agents in high risk patients as they may induce similar renal complications as non - selective NSAIDs .",
"A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice . AIMS : The new cyclooxygenase - 2 ( P35354 ) selective inhibitors , celecoxib ( DB00482 ) and rofecoxib ( Vioxx ) , have been widely prescribed since their launch . No reviews currently appear in the literature of prescribing patterns in Australia . This paper describes a self - audit of the clinical use of selective P35354 inhibitor therapy undertaken with rural general practitioners ( GPs ) in Australia . METHODS : A structured audit form was developed and distributed to interested GPs . The form was self - administered and focused on issues about P35354 inhibitors and the types of patients who were receiving them , e . g . indications , patient demographics , risk factors and drug interactions . RESULTS : A total of 627 patients were recruited ( 569 celecoxib and 58 rofecoxib ) . A range of doses was prescribed . Osteoarthritis was the most common indication ( 68 . 1 % ) . Risk factors known for the nonselective nonsteroidal anti - inflammatory drugs were identified in 65 . 1 % of patients , with the most common being advanced age , hypertension and previous peptic ulcer disease . Potential drug interactions were common . A variety of reasons for initiation of therapy was identified ; these included perceived increased efficacy , safety and failure of other treatment . CONCLUSIONS : These results show that P35354 inhibitors are being prescribed for patients with multiple risk factors that may place the patient at increased risk of adverse drug reactions to a P35354 inhibitor . The perception of improved safety and efficacy was common and is of concern . Limitations of the study include the reliance on self - reporting .",
"Rosiglitazone : a disappointing Q9Y2W7 . Dr Steven Nissen is a heart specialist and currently holds the position of chairman of cardiovascular medicine at the Cleveland Clinic , OH , USA . DB00117 work has involved the development of miniaturised ultrasound imaging devices that can be threaded into a patient ' s heart that allow measurement of the size and composition of plaques , which indicate early artery damage . The ability to characterize and measure the size of plaques provided a novel , effective method to evaluate the efficacy of anticholesterol medications , and for the past two decades Dr Nissen has been using these and other techniques to examine the efficacy of drugs . He has also developed a strong interest in drug safety . DB00117 work linked P35354 inhibitors such as DB00482 and Vioxx ( Merck , NJ , USA ) with heart attacks , and prevented Merck ' s similar product , Arcoxia , from being approved . He also highlighted the serious heart attack risk associated with the experimental drug Pargluva and the drug was subsequently not approved by the US FDA . More recently , Dr Nissen ' s work has focused on the drug rosiglitazone , which was shown to have high cardiovascular risks and has since been given a FDA warning . Here , Dr Nissen discusses the publication of the rosiglitazone meta - analysis and why he considers work in this area to be crucially important for patients .",
"In vitro effects and ex vivo binding of an P00533 - specific immunotoxin on rhabdomyosarcoma cells . PURPOSE : Rhabdomyosarcoma ( RMS ) is a rare and aggressive soft tissue sarcoma with limited treatment options and a high failure rate during standard therapy . New therapeutic strategies based on targeted immunotherapy are therefore much in demand . The epidermal growth factor receptor ( P00533 ) has all the characteristics of an ideal target . It is overexpressed in up to 80 % of embryonal RMS and up to 50 % of alveolar RMS tumors . We therefore tested the activity of the P00533 - specific recombinant immunotoxin ( IT ) 425 ( scFv )- P25101 ' against P00533 (+) RMS cells in vitro and ex vivo . METHODS : We tested the specific binding and internalization behavior of 425 ( scFv )- P25101 ' in RMS cell lines in vitro by flow cytometry , compared to the corresponding imaging probe 425 ( scFv )- P60880 monitored by live cell imaging . The cytotoxic activity of 425 ( scFv )- P25101 ' was tested using cell viability and apoptosis assays . Specific binding of the IT was confirmed on formalin - fixed paraffin - embedded tissue samples from two RMS patients . RESULTS : We confirmed the specific binding of 425 ( scFv )- P25101 ' to RMS cells in vitro and ex vivo . Both the IT and the corresponding imaging probe were rapidly internalized . The IT killed P00533 (+) RMS cells in a dose - dependent manner , while showing no effect against control cells . It showed specific apoptotic activity against one selected RMS cell line . CONCLUSIONS : This is the first study showing the promising therapeutic potential of a recombinant , P00533 - targeting , P25101 '- based IT on RMS cells . We confirmed the selective killing with IC50 values of up to 50 pM , and immunohistochemical staining confirmed the specific ex vivo binding to primary RMS material .",
"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .",
"[ Pharma - clinics . The drug of the month . Celecoxib ( DB00482 ) ] . Celecoxib ( DB00482 , Pharmacia ) is a potent and selective inhibitor of the P35354 isoform of cyclooxygenase which is used as nonsteroidal anti - inflammatory drug ( NSAID ) . Its current indications are osteoarthritis and rheumatoid arthritis . The usual recommended daily dosage of celecoxib is 200 mg ( in one or two intakes per day ) , to be increased up to 400 mg ( two intakes per day ) if necessary . Its clinical efficacy seems to be similar to that of other NSAIDs . However , its safety profile , especially gastro - intestinal tolerance and perhaps renal safety , is much better because of the P35354 selectivity .",
"Detection of overexpressed P35354 in precancerous lesions of hamster pancreas and lungs by molecular imaging : implications for early diagnosis and prevention . The enzyme cyclooxygenase - 2 ( P35354 ) is overexpressed in many cancers , cardiovascular disease , neurodegenerative disorders , and arthritis . Selective inhibitors of P35354 have been developed as therapeutics or preventive agents for these diseases . However , recent reports have revealed a significant increase in cardiovascular mortality in long - term users of the P35354 inhibitors Vioxx and DB00482 , emphasizing the need for noninvasive tests that allow the identification of individuals whose P35354 levels are overexpressed prior to assignment to treatment with these drugs . In this study , we have prepared a radioiodinated analogue of the selective P35354 inhibitor celecoxib , and verified its binding to the P35354 enzyme in vitro . Biodistribution studies in hamsters demonstrated significantly higher levels of radiotracer in animals treated with the tobacco carcinogen NNK in lung , pancreas , and liver . Assessment of P35354 levels by whole - body planar nuclear imaging two hours after injection of the radiotracer was suggestive of a distinct increase in P35354 in the pancreas and liver of a hamster treated for 10 weeks with NNK , in the lungs and liver of a second animal , and in the liver only , in two additional animals from the same treatment group . Immunostains showed selective overexpression of P35354 in pre - neoplastic lesions of the pancreas and lungs in only those animals that showed tracer accumulation in these organs and in the livers of all NNK - treated hamsters . Immunostains for P23219 yielded detectable reactions in the intestinal epithelium but not in pancreas , lungs , or liver , supporting the specificity of the tracer for P35354 . Our data provide proof of principle for the hypothesis that molecular imaging with radiolabeled P35354 inhibitors can be used for the noninvasive monitoring of overexpressed P35354 levels ."
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___MASK47___
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interacts_with DB00594?
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"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Two different P01579 nonresponsive variants derived from the B - cell lymphoma 70Z / 3 . The kappa immunoglobulin ( Igk ) light chain locus is transcriptionally silent in the mouse B - cell lymphoma 70Z / 3 . However , exposure to lipopolysaccharide ( LPS ) or interferon - gamma ( IFN ) causes a marked increase in Igk transcription . By immunoselection , we isolated two variants that are nonresponsive to IFN . One variant , AT7 . 2 , has retained its response to LPS ( IFN - LPS + ) , whereas the other , P01008 . 3 , is also nonresponsive to LPS ( IFN - LPS - ) . Stable transfection of an intact Igk gene does not rescue the phenotype of either variant . Both variants have intact Igk genes and neither is deficient in the binding or uptake of IFN . Nuclear extracts from LPS - treated wild - type 70Z / 3 cells show strong increases in three transcription factors : P09086 , NF - kappa B , and kBF - A . Remarkably , when the IFN - LPS - variant is treated with LPS , all three transcription factors are still observed in the nuclear extracts . Treatment of wild - type cells with either LPS or IFN also causes a decrease in nuclear complexes that bind to two other regions of the Igk intron enhancer , the octenh and the E kappa MHCIC regions . Both of these changes are also observed after LPS or IFN treatment of the IFN - LPS - variant . Thus , this variant transduces the IFN and LPS signals at least into the nuclear compartment , but still fails to activate Igk transcription . In contrast , the IFN - LPS + variant decreases neither the octenh nor the E kappa MHCIC binding complexes in response to IFN . This variant may be defective in transducing the IFN signal to the nucleus . These variants will be useful in studying the activation of Igk transcription and the IFN signaling pathway in B cells .",
"[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK80___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .",
"Whole genome expression analysis for biologic rational pathway modeling : application in cancer prognosis and therapy prediction . Using semi - quantitative microarray technology , almost every one of the approximately 30 000 human genes can be analyzed simultaneously with a low rate of false - positives , a high specificity , and a high quantification accuracy . This is supported by data from comparative studies of microarrays and reverse - transcription PCR for established cancer genes including those for epidermal growth factor receptor ( P00533 ) , human epidermal growth factor receptor - 2 ( P04626 / P04626 ) , estrogen receptor ( P03372 ) , progesterone receptor ( P06401 ) , urokinase - type plasminogen activator ( P00749 ) , and plasminogen activator inhibitor - 1 ( P05121 ) . As such , semi - quantitative expression data provide an almost completely comprehensive background of biological knowledge that can be applied to cancer diagnostics . In clinical terms , expression profiling may be able to provide significant information regarding ( i ) the identification of high - risk patients requiring aggressive chemotherapy ; ( ii ) the pathway control of therapy predictive parameters ( e . g . P03372 and P04626 ) ; ( iii ) the discovery of targets for biologically rational therapeutics ( e . g . capecitabine and trastuzumab ) ; ( iv ) additional support for decisions about switching therapy ; ( v ) target discovery ; and ( vi ) the prediction of the course of new therapies in clinical trials . In conclusion , whole genome expression analysis might be able to determine important genes related to cancer progression and adjuvant chemotherapy resistance , especially in the context of new approaches involving primary systemic chemotherapy . In this review , we will survey the current progress in whole genome expression analyses for cancer prognosis and prediction . Special emphasis is given to the approach of combining biostatistical analysis of expression data with knowledge of biochemical and genetic pathways .",
"Comparative study of the expression of DNA mismatch repair genes , the adenomatous polyposis coli gene and growth arrest DNA damage genes in melanoma recurrences and metastases . The main goal of this study was to examine the expression of DNA mismatch repair genes ( P40692 , P43246 , P54277 and P54278 ) , the adenomatous polyposis coli ( P25054 ) gene and growth arrest DNA damage inducible ( GADD ) genes ( O75807 , P24522 and P35638 ) in the different stages of melanoma recurrences and metastases , and to identify any mutual consistencies in their expression pattern . All the cases of primary melanoma examined showed a reduced expression of DNA repair genes . These results demonstrate that disturbances of DNA repair begin in the early stages of melanoma . No significant differences were found in the expression of these markers between cutaneous melanomas and their recurrences and metastases ( P > 0 . 05 ) . Eighteen significant correlations between markers were found in the primary melanomas , and 10 significant correlations were observed in the first recurrences of melanoma . In contrast , 27 statistically significant relationships were demonstrated in metastatic lymph nodes . The different correlations found in primary and metastatic tumours confirmed the hypothetical difference in marker interaction in the diagnostic groups investigated . Our results suggest that DNA repair genes may play an important role in the recurrence and metastasis of melanomas .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"Proliferative effects of Chishao on Schwann cells are FGF - uPA , and P29323 - and JNK - dependent . This study evaluated the proliferative effects of chishao on RSC96 , Schwann cells . A dose - dependent proliferative effect of chishao was obtained by methylthiazol tetrazolium ( MTT ) , proliferating cell nuclear antigen ( P12004 ) Western blotting , and wound healing assays in Schwann cells administered with chishao ( 0 - 500 mg / ml ) , except at 500 mg / ml concentration . The chishao - treated cells also showed a dose - dependent activated fibroblast growth factor - 2 ( P09038 ) signaling with increased urokinase plasminogen activator ( uPA ) and decreased plasminogen activator inhibitor - 1 ( P05121 ) , enhanced proliferative proteins , extracellular signal regulated kinase ( P29323 ) and c - Jun N - terminal kinase ( JNK ) - signaling . Using mitogen - actvated protein kinase ( MAPK ) - signaling chemical inhibitors , U0126 , SB203580 , and SP600125 , the proliferative effects of chishao on RSC cells were identified to be P29323 - and JNK - signaling dependent . Based on the results , applying appropriate doses of chishao to Schwann cells would be a potential approach for enhancing neuron regeneration .",
"Induction of endoplasmic reticulum stress by sorafenib and activation of NF - κB by lestaurtinib as a novel resistance mechanism in Hodgkin lymphoma cell lines . Hodgkin - Reed / Sternberg ( HRS ) cells of classical Hodgkin lymphoma show aberrant expression and activation of several receptor tyrosine kinases ( RTK ) in the majority of cases . Therefore , we tested whether tyrosine kinase inhibitors ( TKI ) already in clinical use or late stages of clinical trials have antiproliferative effects on HRS cell lines and evaluated the targets , affected signaling pathways , and mechanisms of cell death and resistance . DB00398 and lestaurtinib had antiproliferative effects on HRS cell lines at concentrations achievable in patients . DB00398 inhibited platelet - derived growth factor receptor ( P09619 ) α , P04629 and Q04912 , caused decreases in total and phosphorylated amounts of several signaling molecules , and provoked caspase - 3 - independent cell death , most likely due to endoplasmic reticulum stress as indicated by upregulation of O75807 and P35638 and phosphorylation of Q9NZJ5 . Lestaurtinib inhibited P04629 , PDGFRα , Q04912 , and O60674 and had only a cytostatic effect . Besides deactivation , lestaurtinib also caused activation of signaling pathways . It caused increases in P32971 and P50591 expression , and P32971 / P28908 signaling likely led to the observed concomitant activation of extracellular signal - regulated kinase 1 / 2 and the alternative NF - κB pathway . These data disclose the possible use of sorafenib for the treatment of Hodgkin lymphoma and highlight NF - κB activation as a potential novel mechanism of resistance toward TKIs .",
"Amelioration of experimental colitis by Na - H exchanger - 1 inhibitor amiloride is associated with reversal of IL - 1ss and P29323 mitogen - activated protein kinase . OBJECTIVE : Na - H exchanger - 1 ( P19634 ) is induced in experimental colitis . It has not yet been established whether its inhibition ameliorates colitis . The effects of amiloride , an inhibitor of P19634 , on colitis were examined in this study . Levels of mitogen - activated protein ( Q96HU1 ) kinases P29323 , p38 and interleukin 1ss which participate in intestinal inflammation were also examined in the colonic smooth muscle of rats with colitis . MATERIAL AND METHODS : Colitis was induced in Sprague - Dawley male rats by intrarectal administration of trinitrobenzenesulphonic acid ( TNBS ) and treated daily with amiloride ( 3 , 5 , and 10 mg / kg b . w . ( body - weight ) , orally ) starting 1 h before induction of colitis . The animals were sacrificed on day 5 post - TNBS . Controls received phosphate buffered saline in a similar manner . RESULTS : The highest dose of amiloride ( 10 mg / kg ) was lethal . The lowest dose ( 3 mg / kg ) was tolerated and was used in this study . DB00594 significantly reversed the colitis - reduced contractility and induction of P05164 activity , P19634 , IL - 1ss and P29323 , but not of p38 in inflamed colonic smooth muscle . Splenomegaly , increased colonic mass and decreased sodium pump activity were significantly reversed by amiloride treatment . There was no recovery of b . w . loss in the treated colitic animals . Urine output was increased , whereas food and water intake remained unchanged following amiloride treatment . CONCLUSIONS : These findings suggest that the beneficial effects of P19634 inhibition in experimental colitis are mediated through IL - 1ss and P29323 Q96HU1 kinase .",
"Pan - Q07869 agonist beneficial effects in overweight mice fed a high - fat high - sucrose diet . OBJECTIVE : We analyzed the effect of peroxisome proliferator - activated receptor ( Q07869 ) agonists on adipose tissue morphology , adiponectin expression , and its relation to glucose and insulin levels in C57BL / 6 mice fed a high - fat high - sucrose ( HFHS ) diet . METHODS : Male C57BL / 6 mice received one of five diets : standard chow , HFHS chow , or HFHS plus rosiglitazone ( P37231 agonist ) , fenofibrate ( Q07869 agonist ) , or bezafibrate ( pan - Q07869 agonist ) . Diets were administered for 11 wk and medications from week 6 to week 11 . DB09341 intolerance ( GI ) and insulin resistance were evaluated by oral glucose tolerance testing and homeostasis model assessment for insulin resistance , respectively . Adipocyte diameter was analyzed in epididymal , inguinal , and retroperitoneal fat pads and by adiponectin immunostain . RESULTS : Mice fed the HFHS chow had hyperglycemia , GI , insulin resistance , increased fat pad weight , adipocyte hypertrophy , and decreased adiponectin immunostaining . Rosiglitazone improved GI , insulin sensitiveness , and adiponectin immunostaining , but it resulted in body weight gain , hyperphagia , and adipocyte and heart hypertrophy . Fenofibrate improved all parameters except for fasting glucose and GI . ___MASK69___ was the most efficient in decreasing body weight and glucose intolerance . CONCLUSION : Activation of Q07869 , - delta , and - gamma together is better than the activation of Q07869 or - gamma alone , because bezafibrate showed a wider range of action on metabolic , morphologic , and biometric alterations due to an HFHS diet in mice .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . ___MASK80___ dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK14___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK11___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK11___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .",
"Elk3 from hamster -- a ternary complex factor with strong transcriptional repressor activity . Elk3 belongs to the Ets family of transcription factors , which are regulated by the Ras / mitogen - activated protein kinase - signaling pathway . In the absence of Ras , this protein is a strong inhibitor of transcription and may be directly involved in regulation of growth by downregulating the transcription of genes that are activated during entry into P55008 . We have isolated the Cricetulus griseus Elk3 gene from the Chinese hamster ovary ( CHO ) cell line and investigated the transcriptional potential of this factor . Transient transfections revealed that , in addition to its regulation of the c - fos promoter , Elk3 from CHO cells seems to inhibit other promoters controlling expression of proteins involved in P55008 / S phase progression ; P12004 D1 and P00374 . As has been described for the Elk3 homologs Net ( Mouse ) and Sap - 2 ( Human ) , the results of the present study further indicate that hamster Elk3 is a target of the Ras - Raf - MAPK pathway , and cotransfections with constitutively active H - ras relieves its negative transcriptional activity . No cells stably expressing exogenous Elk3 could be obtained , possibly due to an unspecified toxic or growth retarding effect . These findings support a possible role for Elk3 in growth regulation and reveal a high degree of homology for this protein across species .",
"___MASK66___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .",
"Receptor - bound uPA is reversibly protected from inhibition by low molecular weight inhibitors . P00749 ( uPA ) plays a ubiquitous role in cell migration and invasiveness . DB00594 , a competitive inhibitor of uPA , can inhibit endothelial cell ( EC ) outgrowth during angiogenesis . To address the question of whether amiloride blocked angiogenesis by inhibiting uPA , we undertook a study of uPA expression in sprouting EC in vitro and the effects of amiloride on both enzymatic and morphogenetic activity . As expected , amiloride inhibited soluble uPA ( suPA ) with an IC ( 50 ) of 45 - 85 microm , however , receptor - bound uPA ( rbuPA ) from the sprouting EC was insensitive to amiloride . Removal of uPA from its receptors confers sensitivity to inhibition by amiloride suggesting that a reversible conformational change may mediate the insensitivity of rbuPA to amiloride and its analogs . In summary , we found no evidence to support the hypothesis that amiloride blocks capillary outgrowth by inhibition of uPA , but were able to successfully demonstrate a functional difference between two physiological forms of this important matrix - degrading enzyme .",
"Acid - sensing ion channels promote the inflammation and migration of cultured rat microglia . Microglia , the major immune cells in central nervous system , act as the surveillance and scavenger of immune defense and inflammatory response . Previous studies suggest that there might be close relationship between acid - sensing ion channels ( ASICs ) and inflammation , however , the exact role of ASICs in microglia during inflammation remains elusive . In the present study , we identified the existence of ASICs in the primary cultured rat microglia and explored their functions . By using reverse transcriptase polymerase chain reaction ( RT - PCR ) , quantitative real - time PCR ( qPCR ) , western blotting , and immunofluorescence experiments , we demonstrated that P78348 , ASIC2a , and Q9UHC3 were existed in cultured and in situ rat microglia . After lipopolysaccharide ( LPS ) stimulation , the expressions of microglial P78348 and ASIC2a were upregulated . Meanwhile , ASIC - like currents and acid - induced elevation of intracellular calcium were increased , which could be inhibited by the nonspecific ASICs antagonist amiloride and specific homomeric ASIC1a blocker PcTx1 . In addition , both inhibitors reduced the expression of inflammatory cytokines , including inducible nitric oxide synthase and cyclooxygenase 2 stimulated by LPS . Furthermore , we also observed significant increase in the expression of P78348 and ASIC2a in scrape - stimulated microglial migration . DB00594 and PcTx1 prevented the migration by inhibiting P29323 phosphorylation . Taken together , these results suggest that ASICs participate in neuroinflammatory response , which will provide a novel therapeutic strategy for controlling the inflammation - relevant neuronal diseases .",
"Desipramine induces apoptosis in rat glioma cells via endoplasmic reticulum stress - dependent P35638 pathway . Various antidepressants , mainly tricyclic antidepressants ( TCAs ) and selective serotonin reuptake inhibitors ( SSRIs ) , have exhibited potent anticancer properties in different cancer cell types . In the present study , desipramine ( DB01151 ) , a representative of TCAs , was examined with respect to its apoptosis - inducing activity in rat P13671 glioma cells and the underlying mechanism of action . DB01151 induced typical apoptotic morphology of chromatin condensation in rat glioma P13671 cells and activated intracellular caspase 9 and caspase 3 with no change in mitochondrial membrane potential . Simultaneously , DB01151 significantly elevated expression of endoplasmic reticulum stress regulator P35638 / P35638 and its targeting molecule O75807 . However , knockdown of P35638 by P35638 - specific short interfering RNA ( siRNA ) could decrease the activity of intracellular caspase 3 and the cytotoxicity of DB01151 to P13671 cells . These results revealed that the P35638 - dependent endoplasmic reticulum ( ER ) stress pathway is responsible for DB01151 - induced apoptosis in P13671 cells .",
"Co - culture with Sertoli cells promotes proliferation and migration of umbilical cord DB05914 . Human umbilical cord DB05914 ( hUCMSCs ) have been recently used in transplant therapy . The proliferation and migration of MSCs are the determinants of the efficiency of O60682 transplant therapy . Sertoli cells are a kind of \" nurse \" cells that support the development of sperm cells . Recent studies show that Sertoli cells promote proliferation of endothelial cells and neural stem cells in co - culture . We hypothesized that co - culture of UCMSCs with Sertoli cells may also promote proliferation and migration of UCMSCs . To examine this hypothesis , we isolated UCMSCs from human cords and Sertoli cells from mouse testes , and co - cultured them using a Transwell system . We found that UCMSCs exhibited strong proliferation ability and potential to differentiate to other cell lineages such as osteocytes and adipocytes . The presence of Sertoli cells in co - culture significantly enhanced the proliferation and migration potential of UCMSCs ( P < 0 . 01 ) . Moreover , these phenotypic changes were accompanied with upregulation of multiple genes involved in cell proliferation and migration including phospho - Akt , Mdm2 , phospho - P06493 , P12004 D1 , P12004 D3 as well as P61073 , phospho - Q8TCB0 MAPK and phospho - p38 MAPK . These findings indicate that Sertoli cells boost UCMSC proliferation and migration potential .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK45___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . ___MASK80___ ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , DB06271 ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"Choroid plexus papilloma in an infant . A case of choroid plexus papilloma ( CPP ) associated with overproduction of cerebrospinal fluid ( P04141 ) in an infant is reported . The tumor was totally resected . Histologically , it was diagnosed as CPP with several mitosis , however , there were no other features indicating malignancy . P02766 immunoreactivity was found in the tumor cells on P04141 cytological examination as well as in surgical specimens . Though the percentage of P12004 was high ( 10 . 8 % ) , it was not higher than other benign CPPs ( mean score : 18 . 2 % ) . There was no recurrence or dissemination on follow - up CT or Q9BWK5 1 year after surgery . The patient has grown normally after surgery without a shunting procedure .",
"Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .",
"___MASK21___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK21___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"[ DB00594 attenuates hypoxia - induced proliferation of rats pulmonary artery smooth muscle cells by suppressing Na +/ H + exchanger - 1 ] . AIM : To study the influence of Na +/ H + exchange inhibitor amiloride on hypoxia - induced proliferation in rats pulmonary artery smooth muscle cells ( PASMCs ) , also observe the change of Na +/ H + exchanger - 1 ( P19634 ) activity and expression . METHODS : Rats PASMGs were cultured in normoxia ( 21 % O2 ) or hypoxia ( 2 % O2 ) for 24 hours , as well as administered amiloride with various concentrations , cultured for 24 hours , then determined MTT OD values and rates of P12004 positive cells to investigate cells proliferation , moreover intracellular pH was determined by interactive Laser Cytometer , and Na +/ H + exchanger - 1 mRNA expression was determined by RT - PCR . RESULTS : Hypoxic exposure heightened intracellular pH and mRNA expression of P19634 in PASMCs , however , 3 . 123 - 50 micromol / L amiloride depressed them gradually . Additionally , hypoxic exposure raised MTT OD value and rates of P12004 positive cells , similarly , the above two indexes descended gradually with presence of 3 . 125 - 50 micromol / L amiloride . CONCLUSION : Na +/ H + exchange inhibitor amiloride can suppress hypoxia - induced proliferation in pulmonary artery smooth muscle cells , which is due to depress activity and expression of P19634 .",
"P01236 activates mitogen - activated protein kinase signaling and corticotropin releasing hormone transcription in rat hypothalamic neurons . P01236 ( PRL ) modulates maternal behavior and mediates hypothalamic pituitary adrenal axis inhibition during lactation via PRL receptors in the brain . To identify mechanisms mediating these effects , we examined the effects of PRL on signaling and P06850 transcription in hypothalamic neurons in vivo and in vitro . Western blot of hypothalamic proteins from rats receiving intracerebroventricular PRL injection revealed increases in phosphorylation of the MAPK and P29323 . Double - staining immunohistochemistry demonstrated phosphorylated P29323 localization in parvocellular P06850 neurons as well as magnocellular vasopressin and oxytocin neurons of the hypothalamic paraventricular ( PVN ) and supraoptic nuclei . PRL also induced P29323 phosphorylation in vitro in the hypothalamic cell line , 4B , which expresses PRL receptors , and in primary hypothalamic neuronal cultures . Using reporter gene assays in 4B cells , or quantitative RT - PCR for primary transcript in hypothalamic cell cultures , PRL potentiated forskolin - stimulated P06850 transcription through activation of the P29323 / MAPK pathway . The effect of PRL in hypothalamic cell cultures was unaffected by tetrodotoxin , suggesting a direct effect on P06850 neurons . The data show that PRL activates the P29323 / MAPK pathway and facilitates P06850 transcription in P06850 neurons , suggesting that the inhibitory effect of PRL on hypothalamo - pituitary - adrenal axis activity reported in vivo is indirect and probably mediated through modulation of afferent pathways to the PVN . In addition , the prominent stimulatory action of PRL on the P29323 / MAPK pathway in the hypothalamic PVN and supraoptic nucleus is likely to mediate neuroplasticity of the neuroendocrine system during lactation .",
"Granulocyte - colony stimulating factor ( DB00099 ) induces mechanical hyperalgesia via spinal activation of Q96HU1 kinases and PI3K in mice . Granulocyte - colony stimulating factor ( DB00099 ) is a current pharmacological approach to increase peripheral neutrophil counts after anti - tumor therapies . Pain is most relevant side effect of G - P04141 in healthy volunteers and cancer patients . Therefore , the mechanisms of G - P04141 - induced hyperalgesia were investigated focusing on the role of spinal mitogen - activated protein ( Q96HU1 ) kinases P29323 ( extracellular signal - regulated kinase ) , JNK ( Jun N - terminal Kinase ) and p38 , and PI ( 3 ) K ( phosphatidylinositol 3 - kinase ) . G - P04141 induced dose ( 30 - 300 ng / paw ) - dependent mechanical hyperalgesia , which was inhibited by local post - treatment with morphine . This effect of morphine was reversed by naloxone ( opioid receptor antagonist ) . Furthermore , G - P04141 - induced hyperalgesia was inhibited in a dose - dependent manner by intrathecal pre - treatment with P29323 ( PD98059 ) , JNK ( SB600125 ) , p38 ( SB202190 ) or PI ( 3 ) K ( wortmanin ) inhibitors . The co - treatment with Q96HU1 kinase and PI ( 3 ) K inhibitors , at doses that were ineffective as single treatment , significantly inhibited G - P04141 - induced hyperalgesia . Concluding , in addition to systemic opioids , peripheral opioids as well as spinal treatment with Q96HU1 kinases and PI ( 3 ) K inhibitors also reduce G - P04141 - induced pain .",
"Reduced Q13873 expression induces GM - P04141 translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension . Idiopathic pulmonary arterial hypertension ( PAH [ IPAH ] ) is an insidious and potentially fatal disease linked to a mutation or reduced expression of bone morphogenetic protein receptor 2 ( Q13873 ) . Because intravascular inflammatory cells are recruited in IPAH pathogenesis , we hypothesized that reduced Q13873 enhances production of the potent chemokine granulocyte macrophage colony - stimulating factor ( GM - P04141 ) in response to an inflammatory perturbation . When human pulmonary artery ( PA ) endothelial cells deficient in Q13873 were stimulated with tumor necrosis factor ( P01375 ) , a twofold increase in GM - P04141 was observed and related to enhanced messenger RNA ( mRNA ) translation . The mechanism was associated with disruption of stress granule formation . Specifically , loss of Q13873 induced prolonged phospho - p38 mitogen - activated protein kinase ( MAPK ) in response to P01375 , and this increased O75807 - P50391 phosphatase activity , dephosphorylating eukaryotic translation initiation factor ( eIF2α ) , and derepressing GM - P04141 mRNA translation . Lungs from IPAH patients versus unused donor controls revealed heightened PA expression of GM - P04141 co - distributing with increased P01375 and expanded populations of hematopoietic and endothelial GM - P04141 receptor α ( GM - CSFRα ) - positive cells . Moreover , a 3 - wk infusion of GM - P04141 in mice increased hypoxia - induced PAH , in association with increased perivascular macrophages and muscularized distal arteries , whereas blockade of GM - P04141 repressed these features . Thus , reduced Q13873 can subvert a stress granule response , heighten GM - P04141 mRNA translation , increase inflammatory cell recruitment , and exacerbate PAH .",
"Functional network reconstruction reveals somatic stemness genetic maps and dedifferentiation - like transcriptome reprogramming induced by P23769 . Somatic stem cell transplantation holds great promise in regenerative medicine . The best - characterized adult stem cells are DB05914 ( MSCs ) , neural stem cells ( NSCs ) , and CD133 (+) hematopoietic stem cells ( HSCs ) . The applications of HSCs are hampered since these cells are difficult to maintain in an undifferentiated state in vitro . Understanding genes responsible for stem cell properties and their interactions will help on this issue . The construction of stem cell genetic networks will also help to develop rational strategies to revert somatic cells back to a stem - like state . We performed a systemic study on human CD133 (+) HSCs , NSCs , MSCs , and embryonic stem cells and two different progenies of CD133 (+) HSCs , microvascular endothelial cells ( MVECs ) and peripheral blood mononuclear cells . Genes abundant in each or in all three somatic stem cells were identified . We also observed complex genetic networks functioning in postnatal stem cells , in which several genes , such as Q06124 and P00374 , acted as hubs to maintain the stability and connectivity of the whole genetic network . Eighty - seven P19526 genes , including Q15389 and P23769 , were independently identified by comparing P28906 (+) P20138 (-) P28907 (-) hematopoietic stem cells with P28906 (+) precursors and various matured progenies . Introducing P23769 into MVECs resulted in dedifferentiation - like transcriptome reprogramming , with P19526 genes ( such as Q15389 ) being up and endothelial genes ( such as P29323 ) being down . This study provides a foundation for a more detailed understanding of human somatic stem cells . Expressing the newly discovered stem cell genes in matured cells might lead to a global reversion of somatic transcriptome to a stem - like status .",
"Co - expression of Q03405 and P61073 promotes tumor growth and metastasis in small cell lung cancer . P00749 receptor ( Q03405 ) and C - X - C - chemokine receptor - 4 ( P61073 ) are considered as key molecules in invasion and metastasis of several cancers via extracellular matrix degeneration and assist tumor metastasis to specific sites by chemotaxis . However , the combined effect of Q03405 and P61073 on small cell lung cancer ( SCLC ) , the most aggressive type of lung cancer , is not clear . In this study , we detected the expression of Q03405 and P61073 in SCLC tissue samples ( n = 50 ) by immunohistochemistry . The tumors with high expression of both Q03405 and P61073 ( 12 / 50 ) had larger size , higher lymph node ( LN ) metastasis and worse prognosis of patients than those with low expression of Q03405 and P61073 ( 38 / 50 ) ( P < 0 . 05 ) . We further identified and isolated the both Q03405 and P61073 positive expression subpopulation cells ( Q03405 (+) P61073 (+) cells ) from the SCLC cell line H446 by flow cytometry . The Q03405 (+) P61073 (+) cancer cells showed a higher invasive and migrating capacity in the transwell and wound healing assays compared with other subpopulation cells ( P < 0 . 05 ) . Q03405 (+) P61073 (+) cells injected subcutaneously in nude mice markedly increased tumor growth and induced lung metastasis , while other subpopulation cells did not . In conclusion , these data suggest that Q03405 and P61073 co - expression predicts worse prognosis of SCLC patients . Q03405 (+) P61073 (+) cells promote the tumor growth and play a potential role in metastasis of SCLC .",
"P00749 ( uPA ) stimulates triglyceride synthesis in Huh7 hepatoma cells via p38 - dependent upregulation of Q96PD7 . OBJECTIVE : The liver is the central organ of fatty acid and triglyceride metabolism . Oxidation and synthesis of fatty acids and triglycerides is under the control of peroxisome - proliferator - activated receptors ( Q07869 ) α . Impairment of these receptors ' function contributes to the accumulation of triglycerides in the liver resulting in non - alcoholic fatty liver disease . P00749 ( uPA ) was shown to regulate gene expression in the liver involving PPARγ transcriptional activity . In this study we questioned whether uPA modulates triglyceride metabolism in the liver , and investigated the mechanisms involved in the observed processes . METHODS AND RESULTS : Huh7 hepatoma cells were incubated with increasing concentrations of uPA for 24 h uPA dose - dependently increased the cellular triglyceride mass , and this effect resulted from increased de novo triglyceride synthesis mediated by the enzyme diglyceride acyltransferase 2 ( Q96PD7 ) . Also , the amount of free fatty acids was highly up regulated by uPA through activation of the transcription factor P36956 . Chemical activation of PPARα further increased uPA - stimulated triglyceride synthesis , whereas inhibition of p38 , an upstream activator of PPARα , completely abolished the stimulatory effect of uPA on both triglyceride synthesis and Q96PD7 upregulation . The effect of uPA on triglyceride synthesis in Huh7 cells was mediated via binding to its receptor , the Q03405 . In vivo studies in Q03405 (-/-) mice demonstrated that no lipid droplets were observed in their livers compared to C57BL / 6 mice and the triglyceride levels were significantly lower . CONCLUSION : This study presents a new biological function of the uPA / Q03405 system in the metabolism of triglycerides and might present a new target for an early therapeutic intervention for NAFLD .",
"___MASK80___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK80___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK80___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .",
"Enhanced integrated stress response promotes myelinating oligodendrocyte survival in response to interferon - gamma . The T - cell - derived , pleiotropic cytokine interferon ( IFN ) - gamma is believed to play a key regulatory role in immune - mediated demyelinating disorders of the central nervous system , including multiple sclerosis and experimental autoimmune encephalomyelitis . Our previous work has demonstrated that the endoplasmic reticulum ( ER ) stress response modulates the response of oligodendrocytes to this cytokine . The ER stress response activates the pancreatic ER kinase , which coordinates an adaptive program known as the integrated stress response by phosphorylating translation initiation factor 2alpha ( eIF2alpha ) . In this study , we found that growth arrest and DNA damage 34 ( O75807 ) , a stress - inducible regulatory subunit of a phosphatase complex that dephosphorylates eIF2alpha , was selectively up - regulated in myelinating oligodendrocytes in mice that ectopically expressed P01579 in the central nervous system . We also found that a O75807 mutant strain of mice displayed increased levels of phosphorylated eIF2alpha ( p - eIF2alpha ) in myelinating oligodendrocytes when exposure to P01579 , as well as diminished oligodendrocyte loss and hypomyelination . Furthermore , treatment with salubrinal , a small chemical compound that specifically inhibits protein phosphatase 1 ( P50391 )- O75807 phosphatase activity , increased the levels of p - eIF2alpha and ameliorated hypomyelination and oligodendrocyte loss in cultured hippocampal slices exposed to P01579 . Thus , our data provide evidence that an enhanced integrated stress response could promote oligodendrocyte survival in immune - mediated demyelination diseases .",
"DB08816 increases adenosine plasma concentration in patients with an acute coronary syndrome . OBJECTIVES : This study aimed to investigate the impact of ticagrelor on adenosine plasma concentration ( P25054 ) in acute coronary syndrome ( ACS ) patients . BACKGROUND : DB08816 is a direct - acting Q9H244 - adenosine diphosphate receptor blocker . The clinical benefit of ticagrelor compared with clopidogrel in ACS patients suggests that the drug has non - platelet - directed properties . Animal and in vitro models suggested that the \" pleiotropic \" properties of ticagrelor may be related to an interaction with adenosine metabolism . METHODS : We prospectively randomized 60 ACS patients to receive ticagrelor or clopidogrel . The P25054 was measured by liquid chromatography . To assess the mechanism of P25054 variation , we measured adenosine deaminase concentration , adenosine uptake by red blood cells , and cyclic adenosine monophosphate production by cells overexpressing adenosine receptors . The Q9H244 - adenosine diphosphate receptor blockade was assessed by the vasodilator - stimulated phosphoprotein index . RESULTS : Patients receiving ticagrelor had significantly higher P25054 than patients receiving clopidogrel ( 1 . 5 μM [ interquartile range : 0 . 98 to 1 . 7 μM ] vs . 0 . 68 μM [ interquartile range : 0 . 49 to 0 . 78 μM ] ; p < 0 . 01 ) . The P25054 was not correlated with vasodilator - stimulated phosphoprotein ( p = 0 . 16 ) . Serum - containing ticagrelor inhibited adenosine uptake by red blood cells compared with clopidogrel or controls ( p < 0 . 01 for both comparisons ) . DB00640 deaminase activity was similar in serum of patients receiving clopidogrel or ticagrelor ( p = 0 . 1 ) . DB08816 and clopidogrel had no direct impact on adenosine receptors ( p = not significant ) . CONCLUSIONS : DB08816 increases P25054 in ACS patients compared with clopidogrel by inhibiting adenosine uptake by red blood cells .",
"Human non - synonymous single nucleotide polymorphisms can influence ubiquitin - mediated protein degradation . Ubiquitin - mediated proteolysis plays a critical role in the degradation of proteins important in the cellular processes , such as cell cycle / division , differentiation and development , DNA repair , transcriptional regulation , and signaling . It is carried out by a complex cascade of enzymes that contain a high degree of specificity to motifs found in many proteins with rapid turnover . For example , the PEST motifs are hydrophilic stretches of amino acids that serve as signals for proteolytic degradation . In this study , we propose that amino acid altering non - synonymous single nucleotide polymorphisms ( nsSNP ) result in the abolishment or creation of putative PEST motifs , and thus lead to abnormal stabilization or degradation of the proteins . Using a web - based algorithm , PESTFind , we analyzed a total of 253 nsSNPs from proteins involved in cell cycle ( n = 24 ) , DNA repair ( n = 128 ) , and TGFbeta signaling pathway ( n = 101 ) . Fifteen nsSNPs were located within putative PEST sequences , and 9 / 15 ( 60 % ) either created or abolished these PEST motifs . PEST motifs were abolished in the presence of nsSNPs in P30281 , P54278 , Q9NR33 , SITPEC , and P37231 and putative PEST motifs were created in Q969S2 , P98170 , MLL2 , and O75807 . Although experimental analyses are required to confirm these results , they suggest that nsSNPs can induce changes in ubiquitin - mediated protein degradation .",
"Tumor - derived exosomes promote tumor progression and T - cell dysfunction through the regulation of enriched exosomal microRNAs in human nasopharyngeal carcinoma . Tumor - derived exosomes contain biologically active proteins and messenger and microRNAs ( miRNAs ) . These particles serve as vehicles of intercellular communication and are emerging mediators of tumorigenesis and immune escape . Here , we isolated 30 - 100 nm exosomes from the serum of patients with nasopharyngeal carcinoma ( NPC ) or the supernatant of TW03 cells . Increased circulating exosome concentrations were correlated with advanced lymphoid node stage and poor prognosis in NPC patients ( P < 0 . 05 ) . TW03 - derived exosomes impaired T - cell function by inhibiting T - cell proliferation and Th1 and Th17 differentiation and promoting Treg induction by NPC cells in vitro . These results are associated with decreases in P29323 , P42224 , and P40763 phosphorylation and increases in P42229 phosphorylation in exosome - stimulated T - cells . TW03 - derived exosomes increased the proinflammatory cytokines IL - 1β , P05231 , and P22301 but decreased IFNγ , P60568 , and Q16552 release from P01730 + or CD8 + T - cells . Furthermore , five commonly over - expressed miRNAs were identified in the exosomes from patient sera or NPC cells : hsa - miR - 24 - 3p , hsa - miR - 891a , hsa - miR - 106a - 5p , hsa - miR - 20a - 5p , and hsa - miR - 1908 . These over - expressed miRNA clusters down - regulated the Q9P0L2 signaling pathway to alter cell proliferation and differentiation . Overall , these observations reveal the clinical relevance and prognostic value of tumor - derived exosomes and identify a unique intercellular mechanism mediated by tumor - derived exosomes to modulate T - cell function in NPC .",
"P07204 functions as a plasminogen receptor to modulate angiogenesis . P00749 ( uPA ) activates plasminogen ( Plg ) through a major pericellular proteolytic system involved in cell migration and angiogenesis ; however , the Plg receptor that participates in uPA - mediated Plg activation has not yet been identified . In this study , we demonstrated that thrombomodulin ( TM ) , a type I transmembrane glycoprotein , is a novel Plg receptor that plays a role in pericellular proteolysis and cell migration . Plg activation at the cell surface and the extent of its cell migration - and invasion - promoting effect are cellular TM expression dependent . Direct binding of Plg and the recombinant TM extracellular domain , with a KD of 0 . 1 - 0 . 3 μM , was determined through surface plasmon resonance analysis . Colocalization of TM , Plg , and the uPA receptor within plasma membrane lipid rafts , at the leading edge of migrating endothelial cells , was demonstrated and was also shown to overlap with areas of major pericellular proteolysis . Moreover , the roles of TM and Plg in neoangiogenesis were demonstrated in vivo through the skin wound - healing model . In conclusion , we propose that TM is a novel Plg receptor that regulates uPA / uPA receptor - mediated Plg activation and pericellular proteolysis within lipid rafts at the leading edge of migrating cells during angiogenesis .",
"Advances in our understanding of the molecular basis of disorders of platelet function . Genetic defects of platelet function give rise to mucocutaneous bleeding of varying severity because platelets fail to fulfil their haemostatic role after vessel injury . Abnormalities of pathways involving glycoprotein ( GP ) mediators of adhesion ( Bernard - Soulier syndrome , platelet - type von Willebrand disease ) and aggregation ( Glanzmann thrombasthenia ) are the most studied and affect the GPIb - IX - V complex and integrin αIIbβ3 , respectively . Leukocyte adhesion deficiency - III combines Glanzmann thrombasthenia with infections and defects of kindlin - 3 , a mediator of integrin activation . Agonist - specific deficiencies in platelet aggregation relate to mutations of primary receptors for ADP ( P2Y ( 12 ) ) , thromboxane A ( 2 ) ( TXA2R ) and collagen ( Q9HCN6 ) ; however , selective abnormalities of intracellular signalling pathways remain better understood in mouse models . Defects of secretion from δ - granules are accompanied by pigment defects in the Hermansky - Pudlak and Chediak - Higashi syndromes ; they concern multiple genes and protein complexes involved in secretory organelle biogenesis and function . Quebec syndrome is linked to a tandem duplication of the urokinase plasminogen activator ( P00749 ) gene while locus assignment to chromosome 3p has advanced the search for the gene ( s ) responsible for α - granule deficiency in the gray platelet syndrome . Defects of α - granule biosynthesis also involve germline Q9H267 mutations in the ARC ( arthrogryposis , renal dysfunction and cholestasis ) syndrome . A mutation in transmembrane protein 16F ( Q4KMQ2 ) has been linked to a defective procoagulant activity and phosphatidylserine expression in the Scott syndrome . Cytoskeletal dysfunction ( with platelet anisotrophy ) occurs not only in the Wiskott - Aldrich syndrome but also in filamin A deficiency or P35579 - related disease while P15976 mutations or Q01196 haploinsufficiency can affect expression of multiple platelet proteins .",
"DB00594 derivatives induce apoptosis by depleting ER Ca ( 2 +) stores in vascular endothelial cells . BACKGROUND AND PURPOSE : DB00594 derivatives are blockers of the Na (+)/ H (+) exchanger ( NHE ) and at micromolar concentrations have protective effects on cardiac and brain ischaemia / reperfusion injury but at higher concentrations also induce apoptosis . Here , we aimed to elucidate the mechanism related to this cytotoxic action . EXPERIMENTAL APPROACH : We quantified the expression of genes associated with endoplasmic reticulum ( ER ) stress and measured changes in luminal ER Ca ( 2 +) concentration ( [ Ca ( 2 +)]( ER ) ) with a ' cameleon ' indicator , D1ER . KEY RESULTS : DB00594 derivatives induced apoptosis in vascular endothelial cells , an effect that increased at alkaline extracellular pH . The potency order for cytotoxicity was 5 -( N , N - hexamethylene )- amiloride ( HMA ) > 5 -( N - methyl - N - isobutyl ) amiloride > 5 -( N - ethyl - N - isopropyl ) amiloride ( EIPA ) >> amiloride . HMA dose - dependently increased the transcription of the ER stress genes P35638 and O75807 and rapidly depleted [ Ca ( 2 +)]( ER ) , mimicking the effects of the sarco / endoplasmic reticulum ATPase ( SERCA ) inhibitor thapsigargin . The P19634 - specific inhibitor HOE 694 inhibited NHE activity by 87 % but did not alter [ Ca ( 2 +)]( ER ) . The decrease in [ Ca ( 2 +)]( ER ) evoked by amiloride derivatives was also observed in HeLa cells and was mirrored by an increase in cytosolic Ca ( 2 +) concentration . CONCLUSIONS AND IMPLICATIONS : DB00594 derivatives disrupt ER and cytosolic Ca ( 2 +) homeostasis by a mechanism unrelated to NHE inhibition , most likely by interfering with the activity of SERCA . We propose that ER Ca ( 2 +) depletion and subsequent ER stress provide a rationale framework for the apoptotic effects of amiloride derivatives .",
"G protein - coupled receptor kinase - 3 - deficient mice exhibit WHIM syndrome features and attenuated inflammatory responses . Chemokine receptor interactions coordinate leukocyte migration in inflammation . Chemokine receptors are GPCRs that when activated , are phosphorylated by GRKs to turn off G protein - mediated signaling yet recruit additional signaling machinery . Recently , P35626 was identified as a negative regulator of P48061 / P61073 signaling that is defective in human WHIM syndrome . Here , we report that P35626 -/- mice exhibit numerous features of human WHIM , such as impaired P48061 - mediated desensitization , enhanced P61073 signaling to P29323 activation , altered granulocyte migration , and a mild myelokathexis . Moreover , P35626 -/- protects mice from two acute models of inflammatory arthritis ( K / BxN serum transfer and CAIA ) . In these granulocyte - dependent disease models , protection of P35626 -/- mice is mediated by retention of cells in the marrow , fewer circulating granulocytes in the peripheral blood , and reduced granulocytes in the joints during active inflammation . In contrast to WHIM , P35626 -/- mice have minimal hypogammaglobulinemia and a peripheral leukocytosis with increased lymphocytes and absent neutropenia . Thus , we conclude that the loss of P35626 - mediated regulation of P48061 / P61073 signaling contributes to some , but not all , of the complete WHIM phenotype and that P35626 inhibition may be beneficial in the treatment of inflammatory arthritis .",
"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK69___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .",
"___MASK66___ - targeted liposomes loaded with CPT - 11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma . Medullary thyroid carcinoma ( P04629 ) is a rare endocrine tumor that frequently metastasizes , but treatment with irinotecan ( CPT - 11 ) is limited because of side effects . P04629 is known to overexpress the somatostatin receptor subtype 2 ( P30874 ) . ___MASK66___ ( Oct ) is a somatostatin analogue that has a high binding affinity for SSTR and can be used as a tumor - targeting ligand . We prepared Oct - targeted liposomes loaded with CPT - 11 using Oct - poly ( ethylene glycol ) ( PEG ) - lipid and evaluated Oct - mediated association and cytotoxicity of the liposomes with an P04629 cell line TT . The association of higher concentrations of modified Oct - targeted liposomes with TT cells was significantly higher than PEGylated liposomes and was significantly inhibited by empty Oct - targeted liposomes but not by free Oct . With exposure for 96 h , the cytotoxicity of Oct - targeted liposomal CPT - 11 ( IC50 : 1 . 05 ± 0 . 47 μM ) was higher than free CPT - 11 ( IC50 : 3 . 76 ± 0 . 61 μM ) or PEGylated liposomal CPT - 11 ( IC50 : 3 . 05 ± 0 . 28 μM ) . In addition , empty Oct - targeted liposomes showed significantly higher cytotoxicity than empty nontargeted liposomes at a concentration where free Oct did not show cytotoxicity , suggesting that Oct as a ligand showed cytotoxicity . Moreover , Oct - targeted liposomal CPT - 11 led to significantly higher antitumor activity and prolonged the survival time compared with nontargeted liposomal and free CPT - 11 at a one - third dose and lower administration times with free CPT - 11 . These findings indicated that Oct - targeted liposomes loaded with CPT - 11 may offer considerable potential for P04629 chemotherapy because cytotoxicity of both CPT - 11 and Oct was enhanced by effective cellular uptake via P30874 .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK92___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"___MASK66___ is the favorable alternative for cisplatin resistance reversal of ovarian cancer in vitro and in nude mice in vivo . This study aimed to observe the effects of octreotide ( O75051 ) on cisplatin resistance reversal of cancer cells in vitro and in nude mice in vivo . MTT method and flow cytometry were used to investigate the effect of cisplatin , O75051 or the combination of these two compounds on the proliferation and apoptosis of SKOV3 - O60220 cells . The size and weight of xenograft tumors from the nude mice model were measured . Real - time PCR was used to detect the mRNA expression of P30874 , P08183 , Q92887 , Q86UG4 - pi and P00533 in SKOV3 / O60220 cells following the different treatment . At the concentration of 2 . 5 - 20 g / ml , O75051 significantly reduced IC50 ( p < 0 . 05 ) and promoted apoptosis ( p < 0 . 05 ) of SKOV3 - O60220 cells ' response to cisplatin . Unchanged expression was found in P30874 on the SKOV3 / O60220 cell in vitro after O75051 treatment , but increased expression in vivo ( p < 0 . 05 ) . O75051 increased Q86UG4 - pi expression ( p < 0 . 05 ) and reduced Q92887 and P00533 expression ( p < 0 . 05 ) in a dose - dependent manner . The similar results were obtained in mice in vivo experiment , except the reduced expression of Q86UG4 - pi . It is suggested that O75051 could inhibit ovarian cancer proliferation and promote apoptosis , via the cell surface P30874 , and reverse cisplatin resistance through inhibition of Q92887 , P00533 , and even Q86UG4 - pi expressions .",
"High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK11___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .",
"Inhibition of a thrombin anion - binding exosite - 2 mutant by the glycosaminoglycan - dependent serpins protein C inhibitor and heparin cofactor II . Antithrombin ( P01008 ) , heparin cofactor II ( HCII ) and protein C inhibitor ( P05154 ; also named plasminogen activator inhibitor - 3 ) are serine protease inhibitors ( serpins ) whose thrombin inhibition activity is accelerated in the presence of glycosaminoglycans . We compared the inhibition properties of P05154 and HCII to P01008 using R93A / R97A / R101A thrombin , an anion - binding exosite - 2 ( exosite - 2 ) mutant that has greatly reduced heparin - binding properties . ___MASK80___ - enhanced P05154 inhibition of R93A / R97A / R101A thrombin was only approximately 2 - fold compared to 40 - fold enhancement with wild - type recombinant thrombin . P07204 ( TM ) ( with or without the chondroitin sulfate moiety ) accelerated P05154 inhibition of both wild - type and R93A / R97A / R101A thrombins . HCII achieved the same maximum activity in the presence of heparin with both wild - type and R93A / R97A / R101A thrombins ; however , the optimum heparin concentration was 20 times greater than the reaction with wild - type thrombin , indicative of a decrease in heparin affinity . Dermatan sulfate ( DSO4 ) - catalyzed HCII thrombin inhibition was unchanged in R93A / R97A / R101A thrombin compared to wild - type recombinant thrombin . These results suggest that P05154 is similar to P01008 and depends upon ternary complex formation with heparin and these specific thrombin exosite - 2 residues to accelerate thrombin inhibition . In contrast , HCII does not require DB00125 ( 93 ) , DB00125 ( 97 ) and DB00125 ( 101 ) of thrombin exosite - 2 and further supports the hypothesis that HCII uses an allosteric process following glycosaminoglycan binding to inhibit thrombin .",
"Modulation of mitogen - activated protein kinase cascades by differentiation - 1 protein : acquired drug resistance of hormone independent prostate cancer cells . PURPOSE : The inhibitor of differentiation - 1 protein ( Id - 1 ) is over expressed in multidrug resistance prostate cancer cells . We determined the effect of Id - 1 expression and its underlying pathways on the development of multidrug resistance in prostate cancer . MATERIALS AND METHODS : P01008 cells were transfected with the Id - 1 gene or a blank vector . Id - 1 mRNA expression was determined by reverse transcriptase - polymerase chain reaction and Id - 1 protein content was detected by immunoblot and flow cytometry . Cellular cytotoxicity was determined by MTT ( microculture 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyl tetrazolium bromide ) assay ( Sigma Chemical Co . , St . Louis , Missouri ) . The activation and expression of mitogen - activated protein kinase ( MAPK ) were measured by transactivation assay and Western blotting , respectively . RESULTS : Id - 1 overproduction drove P01008 cells to become resistant to chemotherapeutic agents but did not induce mdr - 1 gene expression . The p38MAPK and c - jun N - terminal kinase ( JNK ) pathways were suppressed , which correlated with increased Id - 1 expression . No significant change in extracellular signal - regulated kinase ( P29323 ) activation was observed in Id - 1 transfectants compared with that of P01008 or vector control . Treatment of Id - 1 expressing cells with p38MAPK and JNK inhibitors resulted in decreased doxorubicin induced apoptosis . In contrast , Id - 1 expressing cells treated with P29323 inhibitor made cells more sensitive to drug induced apoptosis . CONCLUSIONS : Up - regulation of Id - 1 was found in prostate cancer multidrug resistant cells . Sustained P29323 activation , and JNK and p38MAPK inhibition by Id - 1 in cells may confer drug resistance . These changes in MAPKs could be a mechanism for the acquisition of multidrug resistance in prostate cancer .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs ."
] |
[
"___MASK11___",
"___MASK14___",
"___MASK21___",
"___MASK45___",
"___MASK66___",
"___MASK69___",
"___MASK80___",
"___MASK92___"
] |
___MASK80___
|
MH_train_428
|
interacts_with DB01241?
|
[
"___MASK3___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK3___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK4___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"___MASK98___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK98___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK98___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK98___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK98___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"Cloning of chick cellular retinol - binding protein , type II and comparison to that of some mammals : expression of the gene at different developmental stages , and possible involvement of RXRs and Q07869 . We cloned chick cellular retinol - binding protein , type two ( P09455 II ) cDNA and compared it with those of some mammals . The deduced amino acid sequence showed that chick P09455 II was one amino acid greater in size than those of mammals , and the nucleotide sequence of chick P09455 II shared 72 % - 75 % similarity with those of mammals . RNA blot hybridization analysis showed that P09455 II transcript of 0 . 7 kb was first detected in the duodenum of day - 18 embryonic chick , and exhibited a rapid increase during 24 hr around the hatching . Northern blot hybridization also revealed that the transcripts of two types of retinoid X receptors ( RXR alpha and RXR gamma ) and peroxisome proliferator - activated receptor ( Q07869 ) were expressed in the chick duodenum at hatching . The organ culture of day 16 embryonic chick duodenum showed that the addition of 9 - cis retinoic acid in the medium caused a significant increase in P09455 II mRNA levels . In addition , arachidonic acid , from which putative ligands for Q07869 were supposed to be generated , was accumulated around hatching in the duodenum . The results may suggest that the abrupt increase of the P09455 II gene expression in the chick duodenum around hatching may be related with RXRs and / or Q07869 .",
"Anti - allergic function and regulatory mechanisms of KR62980 in allergen - induced airway inflammation . The ligand - activated transcription factor , peroxisome proliferator - activated receptor ( Q07869 ) gamma , and its ligands inhibit pro - inflammatory cytokine production by immune cells , thus exerting anti - inflammatory activity . As a non - thiazolidinedione PPARgamma ligand , KR62980 has anti - diabetic and anti - adipogenic activities , but its anti - inflammatory function has yet to be characterized . In this study , we investigated the functions and mechanisms of KR62980 in the activation and differentiation of P01730 + T helper ( Th ) cells by comparing its effects with those of a thiazolidinedione PPARgamma ligand , rosiglitazone . KR62980 dose - dependently and significantly suppressed TCR - triggered Th cell proliferation by suppressing P60568 / IL - 2Ralpha - mediated signaling . Both KR62980 and rosiglitazone suppressed IFNgamma production in a dose - dependent manner , whereas P05112 gene expression was specifically suppressed by only KR62980 . In addition , sustained KR62980 treatment diminished Th2 cytokine production by inhibiting c - Maf expression . In vivo administration of KR62980 in a model of allergic asthma significantly attenuated eotaxin - induced eosinophil infiltration , allergic cytokine production and collagen deposition in the lung . KR62980 also decreased goblet cell hyperplasia in the airway and mucous cell metaplasia in nasal epithelium , concurrent with decreases of allergic Th2 cytokines and Q16552 in the draining lymph node . In conclusion , a novel PPARgamma ligand , KR62980 , suppresses in vitro Th2 cell differentiation and attenuates in vivo OVA - induced airway inflammation , suggesting a beneficial role for KR62980 in the treatment of allergic asthma and allergic rhinitis .",
"___MASK41___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"The peroxisome proliferator - activated receptor ( Q07869 ) β / δ agonist GW501516 inhibits P05231 - induced signal transducer and activator of transcription 3 ( P40763 ) activation and insulin resistance in human liver cells . AIM / HYPOTHESIS : P05231 induces insulin resistance by activating signal transducer and activator of transcription 3 ( P40763 ) and upregulating the transcription of its target gene O14543 . Here we examined whether the peroxisome proliferator - activated receptor ( Q07869 ) β / δ agonist GW501516 prevented activation of the P05231 - P40763 - suppressor of cytokine signalling 3 ( O14543 ) pathway and insulin resistance in human hepatic HepG2 cells . METHODS : Studies were conducted with human HepG2 cells and livers from mice null for Pparβ / δ ( also known as Ppard ) and wild - type mice . RESULTS : GW501516 prevented P05231 - dependent reduction in insulin - stimulated v - akt murine thymoma viral oncogene homologue 1 ( AKT ) phosphorylation and in P35568 and Q9Y4H2 protein levels . In addition , treatment with this drug abolished P05231 - induced P40763 phosphorylation of Tyr⁷⁰⁵ and Ser⁷²⁷ and prevented the increase in O14543 caused by this cytokine . Moreover , GW501516 prevented P05231 - dependent induction of extracellular - related kinase 1 / 2 ( P27361 / 2 ) , a serine - threonine protein kinase involved in serine P40763 phosphorylation ; the livers of Pparβ / δ - null mice showed increased Tyr⁷⁰⁵ - and Ser⁷²⁷ - P40763 as well as phospho - P27361 / 2 levels . Furthermore , drug treatment prevented the P05231 - dependent reduction in phosphorylated AMP - activated protein kinase ( AMPK ) , a kinase reported to inhibit P40763 phosphorylation on Tyr⁷⁰⁵ . In agreement with the recovery in phospho - AMPK levels observed following GW501516 treatment , this drug increased the AMP / DB00171 ratio and decreased the DB00171 / ADP ratio . CONCLUSIONS / INTERPRETATION : Overall , our findings show that the PPARβ / δ activator GW501516 prevents P05231 - induced P40763 activation by inhibiting P27361 / 2 phosphorylation and preventing the reduction in phospho - AMPK levels . These effects of GW501516 may contribute to the prevention of cytokine - induced insulin resistance in hepatic cells .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK100___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK100___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK100___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK100___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK100___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK100___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK100___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK100___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK100___ in the treatment of changes in hypervigilance following severe stress .",
"Combined Effects of Q07869 γ Agonists and Epidermal Growth Factor Receptor Inhibitors in Human Proximal Tubule Cells . We aimed to determine whether epidermal growth factor receptor ( P00533 ) inhibition , in addition to a peroxisome proliferator - activated receptor gamma ( Q07869 γ ) agonist , prevents high - glucose - induced proximal tubular fibrosis , inflammation , and sodium and water retention in human proximal tubule cells exposed to normal glucose ; high glucose ; high glucose with the Q07869 γ agonist pioglitazone or with the P - P00533 inhibitor , gefitinib ; or high glucose with both pioglitazone and gefitinib . We have shown that high glucose increases AP - 1 and NF κ B binding activity , downstream phosphorylation of P00533 and Erk1 / 2 , and fibronectin and collagen IV expression . Pioglitazone reversed these effects but upregulated P48764 and P29972 expression . Gefitinib inhibited high glucose induced fibronectin and collagen IV , and P00533 and Erk1 / 2 phosphorylation and reversed pioglitazone - induced increases in P48764 and P29972 expression . Our data suggests that combination of an P00533 inhibitor and a Q07869 γ agonist mitigates high - glucose - induced fibrosis and inflammation and reverses the upregulation of transporters and channels involved in sodium and water retention in human proximal tubule cells . Hence P00533 blockade may hold promise , not only in limiting tubulointerstitial pathology in diabetic nephropathy , but also in limiting the sodium and water retention observed in patients with diabetes and exacerbated by Q07869 γ agonists .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK39___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK59___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"A novel class of substituted spiro [ quinazoline - 2 , 1 '- cyclohexane ] derivatives as effective Q07869 - 1 inhibitors : molecular modeling , synthesis , cytotoxic and enzyme assay evaluation . Molecular docking simulation study was carried out to design a novel series of spiro [ ( 2H , 3H ) quinazoline - 2 , 1 '- cyclohexan ] - 4 ( 1H )- one derivatives as a new class of effective P09874 inhibitors . Spiro [ 2H - 3 , 1 - benzoxazine - 2 , 1 '- cyclohexan ] - 4 ( 1H )- one ( 5 ) was the starting compound to synthesize the target proposed analogues . The derivatives that showed the top scores and had the best fitting in the binding sites of the target protein were selected to evaluate their in vitro anti - proliferative activity against the cultured human breast carcinoma cell line ( MCF - 7 ) using doxorubicin as a standard drug . Additionally , the compounds that exhibited the highest cytotoxic efficiency were further subjected to P09874 enzyme assay taking 3 - aminobenzamide as the reference drug . The structures of the novel derivatives were confirmed on the bases of microanalytical and spectral data .",
"Thiazolidinedione drugs down - regulate P61073 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor gamma - dependent manner . Peroxisome proliferator activated receptor ( Q07869 ) gamma is a nuclear receptor involved primarily in lipid and glucose metabolism . PPARgamma is also expressed in several cancer types , and has been suggested to play a role in tumor progression . PPARgamma agonists have been shown to reduce the growth of colorectal carcinoma cells in culture and in xenograft models . Furthermore , the PPARgamma agonist thiazolidinedione has been shown to reduce metastasis in a murine model of rectal cancer . Since the chemokine receptor P61073 has emerged as an important player in tumorigenesis , particularly in the process of metastasis , we sought to determine if PPARgamma agonists might act in part by reducing P61073 expression . We found that rosiglitazone , a thiazolidinedione PPARgamma agonist used primarily in the treatment of type 2 diabetes , significantly reduced cell - surface expression of P61073 protein on HT - 29 human colorectal carcinoma cells . This effect occurred at concentrations as low as 1 nM , and was first evident after 8 h of drug exposure . P61073 mRNA was also down - regulated after treatment with rosiglitazone , indicating that the effect occurs at the level of transcription . Four other thiazolidinedione compounds ( ciglitazone , pioglitazone , troglitazone , and MCC555 ) also significantly reduced P61073 expression . To confirm the involvement of PPARgamma in thiazolidinedione - induced P61073 down - regulation , we used PPARgamma antagonists GW9662 and T0070907 , both of which completely blocked the effect of rosiglitazone on P61073 expression . Furthermore , HT - 29 cells in which PPARgamma expression was reduced using shRNA were less responsive to rosiglitazone . In conclusion , we have shown that thiazolidinedione compounds reduce P61073 mRNA and cell - surface protein expression in a PPARgamma - dependent manner .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Q07869 gamma ligands , rosiglitazone and pioglitazone , inhibit P09038 - and P15692 - mediated angiogenesis . OBJECTIVE : To study the effect of peroxisome proliferator - activated receptor - gamma ( Q07869 gamma ) agonists , pioglitazone and rosiglitazone , on vascular endothelial growth factor ( P15692 ) - and basic fibroblast growth factor ( P09038 ) - induced angiogenesis and on endothelial cell migration . METHODS : Chick chorioallantoic membrane ( P62158 ) model was used to evaluate the efficacy of pioglitazone and rosiglitazone on P15692 - and P09038 - induced angiogenesis . In addition , the effect of pioglitazone and rosiglitazone on endothelial cell migration was evaluated using 8 mm pore filter to a feeder layer containing vitronectin as chemoattractant . RESULTS : Pioglitazone and rosiglitazone inhibited the pro - angiogenic effects of P09038 and P15692 in the P62158 model significantly ( P < 0 . 001 ) to the same extent . Endothelial cell migration was also inhibited by both pioglitazone and rosiglitazone ( P < 0 . 001 ) . CONCLUSIONS : These results suggest that Q07869 gamma ligands , pioglitazone and rosiglitazone , in addition to their important regulatory role in adipogenesis and inflammation , possess anti - angiogenic properties . Thus , Q07869 gamma ligands may be useful in the treatment of diabetic retinopathy , macular degeneration , and other ocular disorders and may lower the risk to develop cancer in diabetic patients .",
"Q07869 gene variants influence progression of coronary atherosclerosis and risk of coronary artery disease . BACKGROUND : Q07869 ( PPARalpha ) regulates the expression of genes involved in lipid metabolism and inflammation , making it a candidate gene for atherosclerosis and ischemic heart disease ( IHD ) . METHODS AND RESULTS : We investigated the association between the leucine 162 to valine ( L162V ) polymorphism and a G to C transversion in intron 7 of the PPARalpha gene and progression of atherosclerosis in the DB01241 Coronary Angiography Trial ( LOCAT ) , a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study ( Q9NP85 ) , a prospective study of healthy middle - aged men in the United Kingdom . There was no association with plasma lipid concentrations in either study . Both polymorphisms influenced progression of atherosclerosis and risk of IHD . V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis . Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes . The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele . Homozygotes for the intron 7 C allele had increased risk of IHD , an effect modulated by the L162V polymorphism CONCLUSIONS : The PPARalpha gene affects progression of atherosclerosis and risk of IHD . Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK69___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK97___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Obesity and breast cancer : the roles of peroxisome proliferator - activated receptor - γ and plasminogen activator inhibitor - 1 . Breast cancer is the most prominent cancer among females in the United States . There are a number of risk factors associated with development of breast cancer , including consumption of a high - fat diet and obesity . P00747 activator inhibitor - 1 ( P05121 ) is a cytokine upregulated in obesity whose expression is correlated with a poor prognosis in breast cancer . As a key mediator of adipogenesis and regulator of adipokine production , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) is involved in P05121 expression from adipose tissue . We summarize the current knowledge linking Q07869 - γ and P05121 expression to high - fat diet and obesity in the risk of breast cancer .",
"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations ."
] |
[
"___MASK100___",
"___MASK39___",
"___MASK3___",
"___MASK41___",
"___MASK4___",
"___MASK59___",
"___MASK69___",
"___MASK97___",
"___MASK98___"
] |
___MASK59___
|
MH_train_429
|
interacts_with DB06288?
|
[
"DB06288 promotes cognitive flexibility in rats : the role of P34969 receptors . The antagonism of P34969 receptors may contribute to the antidepressant and procognitive actions of the atypical antipsychotic drug , amisulpride . It has been previously demonstrated that the selective P34969 receptor antagonist reversed restraint stress - induced cognitive impairments in a rat model of frontal - dependent attentional set - shifting task ( ASST ) . Therefore , the first aim of the present study was to assess the effectiveness of amisulpride against stress - evoked cognitive inflexibility . The second goal was to elucidate whether the pro - cognitive effect of amisulpride could be due to the compound ' s action at P34969 receptors . Rats repeatedly exposed ( 1 h daily for 7 days ) to restraint stress demonstrated impaired performance on the extra - dimensional ( ED ) set - shifting stage of the ASST . DB06288 ( 3 mg / kg ) given to stressed rats 30 min before testing reversed this restraint - induced cognitive inflexibility and improved ED performance of the unstressed control group . The P34969 receptor agonist , AS19 ( 10 mg / kg ) , abolished the pro - cognitive efficacy of amisulpride ( 3 mg / kg ) . The present study suggests that the antagonism of P34969 receptors may contribute to the mechanisms underlining the pro - cognitive action of amisulpride . These results may have therapeutic implications in frontal - like deficits associated with stress - related disorders .",
"Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .",
"Serotonin directly stimulates luteinizing hormone - releasing hormone release from GT1 cells via P34969 receptors . DB00044 - releasing hormone ( P01148 release , which serves as the primary drive to the hypothalamic - pituitary gonadal axis , is controlled by many neuromediators . Serotonin has been implicated in this regulation . However , it is unclear whether the central effect of serotonin on P01148 secretion is exerted directly on P01148 neurosecretory neurons or indirectly via multisynaptic pathways . The present studies were undertaken in order to examine whether P01148 secretion from immortalized P01148 cell lines is directly regulated by serotonin and , if so , to identify the receptor subtype involved . 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , a P08908 / 7 receptor agonist , stimulated P01148 release from GT1 - 1 cells . This effect was blocked by ritanserin , a 5 - HT2 / 7 receptor antagonist , but not by SDZ - 216 - 525 , a P08908 antagonist . Basal P01148 release was not affected by the 5 - HT2 agonist DOI . Reverse transcription and polymerase chain reaction technique ( RT - PCR ) was used in order to identify P08908 and P34969 receptor mRNA in immortalized P01148 cell lines . GT1 - 1 cells express mRNA for the P34969 , but not the P08908 receptor subtypes . These results demonstrate a direct stimulatory effect of serotonin on P01148 release via P34969 receptor .",
"Role of monoamine oxidases in the exaggerated 5 - hydroxytryptamine - induced tension development of human isolated preeclamptic umbilical artery . We investigated the role ( s ) of monoamine oxidases ( MAOs ) on the altered 5 - hydroxytryptamine ( 5 - HT , serotonin ) - induced tension development of the isolated umbilical artery of preeclamptic pregnancy of Chinese women . An enhanced 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy was observed when compared with that of normal pregnancy . The enhanced component of 5 - HT - induced tension development was eradicated by clorgyline ( a P21397 inhibitor ) . Blockade of P29474 ( endothelial isoform nitric oxide synthase ) ( N ( omega )- nitro - L - arginine methyl ester ) , 5 - HT transporter ( citalopram ) , 5 - HT receptor subtypes ( 5HT2B , SB 204741 ; P28335 , RS 102221 ; P34969 , SB 269970 ) , and endothelium denudation of the umbilical artery of normal pregnancy mimicked the enhanced 5 - HT - induced tension development as observed in the preeclamptic tissues . In contrast , no apparent changes in 5 - HT - induced tension development of the umbilical artery of preeclamptic pregnancy were observed with the same pharmacological manipulations . A decreased protein expression levels of P21397 and P29474 ( no P35228 and P27338 expression was detected ) and no change in caveolin - 1 and 5 - HT transporter expression were demonstrated in the umbilical artery ( endothelium intact ) lysate of preeclamptic pregnancy , compared to that of the umbilical artery of normal pregnancy . Thus , in the umbilical artery of preeclamptic pregnancy , a decrease of P21397 and P29474 protein expression levels are probably associated with , or responsible for , the exaggerated 5 - HT - induced tension development .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK62___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .",
"Phosphodiesterase - 4 influences the PKA phosphorylation status and membrane translocation of G - protein receptor kinase 2 ( P25098 ) in P29320 - 293beta2 cells and cardiac myocytes . Membrane - recruitment of P25098 ( G - protein receptor kinase 2 ) provides a fundamental step in the desensitization process controlling GPCRs ( G - protein - coupled receptors ) , such as the beta2AR ( beta2 - adrenergic receptor ) . In the present paper , we show that challenge of P29320 - 293beta2 [ human embryonic kidney cells stably overexpressing the FLAG - tagged beta2AR - GFP ( green fluorescent protein ) ] cells with the beta - adrenoceptor agonist , isoprenaline , causes P25098 to become phosphorylated by PKA ( DB02527 - dependent protein kinase ) . This action is facilitated when DB02527 - specific DB05876 ( phosphodiesterase - 4 ) activity is selectively inactivated , either chemically with rolipram or by siRNA ( small interfering RNA ) - mediated knockdown of Q07343 and Q08499 . DB05876 - selective inhibition by rolipram facilitates the isoprenaline - induced membrane translocation of P25098 , phosphorylation of the beta2AR by P25098 , membrane translocation of beta - arrestin and internalization of beta2ARs . DB05876 - selective inhibition also enhances the ability of isoprenaline to trigger the PKA phosphorylation of P25098 in cardiac myocytes . In the absence of isoprenaline , rolipram - induced inhibition of DB05876 activity in P29320 - 293beta2 cells acts to stimulate PKA phosphorylation of P25098 , with consequential effects on P25098 membrane recruitment and P25098 - mediated phosphorylation of the beta2AR . We propose that a key role for DB05876 enzymes is : ( i ) to gate the action of PKA on P25098 , influencing the rate of P25098 phosphorylation of the beta2AR and consequential recruitment of beta - arrestin subsequent to beta - adrenoceptor agonist challenge , and ( ii ) to protect P25098 from inappropriate membrane recruitment in unstimulated cells through its phosphorylation by PKA in response to fluctuations in basal levels of DB02527 .",
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK56___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK56___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .",
"Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \" dominant negative \" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK22___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"___MASK79___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK79___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"Serotonin P34969 receptors coupled to induction of interleukin - 6 in human microglial MC - 3 cells . Brain serotonin 5 - HT ( 7 ) receptors are known to be expressed in neurons and astrocytes . We now report the presence of these receptors in a third type of cell , microglial cells . 5 - Hydroxytryptamine ( 5 - HT ) , 5 - carboxamidotryptamine ( 5 - CT ) , 5 - methoxytryptamine ( 5 - MeOT ) and 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) induced concentration - dependent stimulations of DB02527 accumulation in the human microglial MC - 3 cell line . The maximal effect of 5 - HT was 3 . 4 +/- 0 . 3 - fold stimulation ( mean +/- S . E . M . , n = 5 ) above basal levels . The rank order of agonist potency ( pEC50 values ) was 5 - CT ( 7 . 09 ) > 5 - HT ( 6 . 13 ) > or = 5 - MeOT ( 5 . 78 ) >> 8 - OH - DPAT ( ca . 5 ) . The effect of 5 - CT was inhibited in a concentration - dependent manner by the selective P34969 receptor antagonist SB - 269970 ( pA2 value 9 . 03 ) . Western blot analysis revealed the presence of immunoreactive bands corresponding to the human P34969 receptor in extracts of MC - 3 cells . The presence of two splice variants of the P34969 receptor ( P34969 ( a / b ) ) was visualized by reverse transcriptase - polymerase chain reaction ( RT - PCR ) analysis with specific primers . In real - time PCR studies , the mRNA for interleukin - 6 ( P05231 ) was found to be increased by 2 . 5 - fold in MC - 3 cells after 1 h incubation with 5 - CT ( 1 microM ) and this effect was fully blocked by the P34969 receptor antagonist SB - 269970 ( 1 microM ) . These data show that functional P34969 receptors are present in human microglial MC - 3 cells , suggesting that they are involved in neuroinflammatory processes .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK12___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"The impact of biological agents interfering with receptor / ligand binding in the immune system . We herein discuss the impact of biological agents based on the ability of monoclonal antibodies to target specific molecules . This approach has given to clinical immunologists a spectrum of drugs able to manipulate the immune system . In the first session , we discuss drugs targeting T - cell function by : ( 1 ) targeting P10747 mediated costimulation ( DB01281 and DB06681 ) ; ( 2 ) interfering with interleukin - 2 receptor ( DB00074 and DB00111 ) ; ( 3 ) blocking cell adhesion and homing ( DB00092 , DB00095 , DB00108 ) . The second session is dedicated to drugs targeting cytokines or their receptors . The best known and largely experimented case is represented by drugs targeting tumor necrosis factor ( P01375 ) ( DB00065 , Adalilumab , Certolizumab ) or its p75 receptor ( DB00005 ) . However , newer products are now available to target other inflammatory cytokines including P05231 , P10145 , IL - 12 , P40933 , Q14116 , IL - 23 . These agents have the potential to become powerful tools in the control of several immune - mediated diseases , especially auto - immune and inflammatory ones . They traslate into reality the prediction that antibodies will eventually become \" magic bullets which seek their own target \" ( P . Ehrich , 1906 ) .",
"Comparison of the effects of aging on P34969 and P08908 receptors in discrete regions of the circadian timing system in hamsters . The circadian timekeeping system exhibits many functional changes with aging , including a loss of sensitivity to time cues such as systemic injections of the serotonergic agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) . In order to elucidate the neurochemical mechanisms responsible for this age - related loss of sensitivity of the circadian pacemaker to serotonin agonists , the present study used quantitative autoradiography to determine whether aging decreases serotonin receptor populations in male Syrian hamsters . Four neuroanatomical regions that regulate circadian timekeeping were studied ( the suprachiasmatic nuclei [ SCN ] , the lateral geniculate nuclei [ P81274 ] , and the median raphe nucleus [ MRN ] and dorsal raphe nucleus [ DRN ] ) . The specific binding of [ 3H ] 8 - OH - DPAT to serotonin7 ( P34969 ) and serotonin1A ( P08908 ) receptors was investigated by competitive inhibition with ritanserin and pindolol , respectively . The results showed that the SCN , IGL , MRN , and DRN of the male Syrian hamster exhibited specific binding of [ 3H ] 8 - OH - DPAT to both the P34969 and P08908 receptors , and that the latter receptor subtype is more abundant in all of these regions . At 17 - 19 months of age , a 50 % decrease in P34969 receptors was found in the DRN but not in any other regions . No significant age - related changes in P08908 receptors were observed in any regions examined . The finding that a marked decrease in P34969 receptors occurs in the DRN at the age previously characterized by loss of sensitivity to 8 - OH - DPAT suggests that this region and this receptor subtype play important roles in 8 - OH - DPAT induction of circadian phase shifts in vivo and that they constitute an important locus of aging in the circadian timing system .",
"Activation of P34969 receptor stimulates neurite elongation through P42345 , Cdc42 and actin filaments dynamics . Recent studies have indicated that the serotonin receptor subtype 7 ( 5 - HT7R ) plays a crucial role in shaping neuronal morphology during embryonic and early postnatal life . Here we show that pharmacological stimulation of 5 - HT7R using a highly selective agonist , LP - 211 , enhances neurite outgrowth in neuronal primary cultures from the cortex , hippocampus and striatal complex of embryonic mouse brain , through multiple signal transduction pathways . All these signaling systems , involving P42345 , the Rho GTPase Cdc42 , Cdk5 , and P29323 , are known to converge on the reorganization of cytoskeletal proteins that subserve neurite outgrowth . Indeed , our data indicate that neurite elongation stimulated by 5 - HT7R is modulated by drugs affecting actin polymerization . In addition , we show , by 2D Western blot analyses , that treatment of neuronal cultures with LP - 211 alters the expression profile of cofilin , an actin binding protein involved in microfilaments dynamics . Furthermore , by using microfluidic chambers that physically separate axons from the soma and dendrites , we demonstrate that agonist - dependent activation of 5 - HT7R stimulates axonal elongation . Our results identify for the first time several signal transduction pathways , activated by stimulation of 5 - HT7R , that converge to promote cytoskeleton reorganization and consequent modulation of axonal elongation . Therefore , the activation of 5 - HT7R might represent one of the key elements regulating CNS connectivity and plasticity during development .",
"Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK11___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .",
"Effect of chronic ___MASK44___ treatment on the prostate of C57Bl / 6 mice . ___MASK44___ is a potent and selective inhibitor of phosphodiesterase - 5 ( O76074 ) and is considered first - line therapy for erectile dysfunction . Nowadays , ___MASK44___ is used extensively throughout the world on patients with pulmonary hypertension . However , few studies have evaluated the possible side effects of chronic ___MASK44___ treatment on the male reproductive system , specifically in the prostate . In the present study , it was demonstrated via morphological and ultrastructural analysis that chronic treatment with ___MASK44___ induced an enhancement of the glandular activity of the prostate . In addition , mice treated with ___MASK44___ showed a significant increase in testosterone serum levels . However , no statistically significant differences were observed in nitric oxide serum levels , or in sGC , P29474 , PSA and TGF - β prostatic expression . In conclusion , the present study suggests that chronic use of ___MASK44___ does not cause evident prostatic damage , and therefore , can be used pharmacologically to treat a variety of disorders .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK41___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK100___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"DB06288 is a potent P34969 antagonist : relevance for antidepressant actions in vivo . RATIONALE : DB06288 is approved for clinical use in treating schizophrenia in a number of European countries and also for treating dysthymia , a mild form of depression , in Italy . DB06288 has also been demonstrated to be an antidepressant for patients with major depression in many clinical trials . In part because of the selective D ( 2 )/ D ( 3 ) receptor antagonist properties of amisulpride , it has long been widely assumed that dopaminergic modulation is the proximal event responsible for mediating its antidepressant and antipsychotic properties . OBJECTIVES : The purpose of these studies was to determine if amisulpride ' s antidepressant actions are mediated by off - target interactions with other receptors . MATERIALS AND METHODS : We performed experiments that : ( 1 ) examined the pharmacological profile of amisulpride at a large number of central nervous system ( CNS ) molecular targets and , ( 2 ) after finding high potency antagonist affinity for human 5 - HT ( 7a ) serotonin receptors , characterized the actions of amisulpride as an antidepressant in wild - type and 5 - HT ( 7 ) receptor knockout mice . RESULTS : We discovered that amisulpride was a potent competitive antagonist at 5 - HT ( 7a ) receptors and that interactions with no other molecular target investigated in this paper could explain its antidepressant actions in vivo . Significantly , and in contrast to their wild - type littermates , 5 - HT ( 7 ) receptor knockout mice did not respond to amisulpride in two widely used rodent models of depression , the tail suspension test and the forced swim test . CONCLUSIONS : These results indicate that 5 - HT ( 7a ) receptor antagonism , and not D ( 2 )/ D ( 3 ) receptor antagonism , likely underlies the antidepressant actions of amisulpride .",
"Novel P34969 receptor inverse agonists . Synthesis and molecular modeling of arylpiperazine - and 1 , 2 , 3 , 4 - tetrahydroisoquinoline - based arylsulfonamides . A series of arylpiperazine - and 1 , 2 , 3 , 4 - tetrahydroisoquinoline - based arylsulfonamides was synthesized and evaluated for their interactions with the constitutively active P34969 receptor . Effects on basal adenylate cyclase activity were measured using P29320 - 293 cells expressing the rat P34969 . All ligands produced a decrease of adenylate cyclase activity , indicative of their inverse agonism . Additionally , computational studies with a set of 22 inverse agonists , including these novel inverse agonists and inverse agonists known from literature , resulted in a pharmacophore model and a CoMFA model ( R2 = 0 . 97 , SE = 0 . 18 ) . Docking of inverse agonists at the binding site of a model of the helical parts of the P34969 receptor , based on the alpha carbon template for 7 - TM GPCRs , revealed interesting molecular interactions and a possible explanation for observed structure - activity relationships ."
] |
[
"___MASK100___",
"___MASK11___",
"___MASK12___",
"___MASK22___",
"___MASK41___",
"___MASK44___",
"___MASK56___",
"___MASK62___",
"___MASK79___"
] |
___MASK56___
|
MH_train_430
|
interacts_with DB00966?
|
[
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK14___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK14___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"P37231 regulates P12830 expression and inhibits growth and invasion of prostate cancer . P37231 ( PPARgamma ) might not be permissive to ligand activation in prostate cancer cells . Association of PPARgamma with repressing factors or posttranslational modifications in PPARgamma protein could explain the lack of effect of PPARgamma ligands in a recent randomized clinical trial . Using cells and prostate cancer xenograft mouse models , we demonstrate in this study that a combination treatment using the PPARgamma agonist pioglitazone and the histone deacetylase inhibitor valproic acid is more efficient at inhibiting prostate tumor growth than each individual therapy . We show that the combination treatment impairs the bone - invasive potential of prostate cancer cells in mice . In addition , we demonstrate that expression of P12830 , a protein involved in the control of cell migration and invasion , is highly up - regulated in the presence of valproic acid and pioglitazone . We show that P12830 expression responds only to the combination treatment and not to single PPARgamma agonists , defining a new class of PPARgamma target genes . These results open up new therapeutic perspectives in the treatment of prostate cancer .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK20___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK69___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"Potential utility of telmisartan , an angiotensin II type 1 receptor blocker with peroxisome proliferator - activated receptor - gamma ( P37231 ) - modulating activity for the treatment of cardiometabolic disorders . The metabolic syndrome is strongly associated with insulin resistance and consists of a constellation of factors such as hypertension and hyperlipidemia that raise the risk for cardiovascular diseases and diabetes mellitus . There is widespread agreement that the renin - angiotensin system ( DB01367 ) plays a pivotal role in the pathogenesis of insulin resistance and cardiovascular disease in diabetes . Indeed , large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular end - organ protection . Thus the blockade of the DB01367 may be a promising strategy for the treatment of the patients with the metabolic syndrome . Although several types of angiotensin II type 1 ( AT ( 1 ) ) receptor blockers ( ARBs ) are commercially available for the treatment of patients with hypertension , we have recently found that telmisartan ( DB00966 ) could have the strongest binding affinity to AT ( 1 ) receptor . Further , telmisartan is reported to act as a partial agonist of peroxisome proliferator - activated receptor - gamma ( P37231 ) . These observations suggest that , due to its unique P37231 - modulating activity , telmisartan may be one of the most promising sartans for the treatment of cardiometabolic disorders . In this paper , we reviewed the potential utility of telmisartan in insulin resistance and vascular complications in diabetes .",
"Telmisartan , its potential therapeutic implications in cardiometabolic disorders . There is a growing body of evidence that the renin - angiotensin system ( DB01367 ) plays a pivotal role in the pathogenesis of cardiovascular diseases . Indeed , large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular - organ protection . Although several types of angiotensin II type 1 ( AT ( 1 ) ) receptor blockers ( ARBs ) are commercially available for the treatment of patients with hypertension , we have recently found that telmisartan ( DB00966 ) could have the strongest binding affinity to AT ( 1 ) receptor . Telmisartan will be a promising cardiometabolic sartan due to its unique peroxisome proliferator - activated receptor - gamma ( P37231 ) - inducing properties as well . In this review , we focused on telmisartan , and discussed its potential therapeutic implications in cardiometabolic disorders .",
"P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK73___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK73___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"The expression of the solute carriers Q14973 and O75051 - 1 is regulated by cholesterol in HepG2 cells . Drug disposition and response are greatly determined by the activities of drug - metabolizing enzymes and transporters . While the knowledge in terms of CYP enzymes and efflux ABC transporters ( such as P08183 , P - glycoprotein ) is quite extensive , influx transporters are increasingly being unveiled as key contributors to the process of drug disposition . There is little information on the regulation of these proteins in human cells , especially as regards the effect of endogenous compounds . In this study , we analysed the expression of P08684 and three uptake transporters Q14973 ( Q14973 ) , P46721 / P46721 ( P46721 ) and O75051 - 1 ( O15245 ) in HepG2 cells following treatment with cholesterol . While P08684 and P46721 expression was unaffected , cholesterol treatment led to increased levels of Q14973 and O75051 - 1 mRNAs . Alterations in the functional characteristics and / or expression levels of drug transporters in the liver may conceivably contribute to the variability in drug oral bioavailability often observed in the clinical settings .",
"Managing the underlying cause of cystic fibrosis : a future role for potentiators and correctors . Cystic fibrosis ( CF ) , a severe genetic disease , is caused by mutations that alter the structure and function of P13569 , a plasma membrane channel permeable to chloride and bicarbonate . Defective anion transport in CF irreversibly damages the lungs , pancreas , liver , and other organs . CF mutations cause loss of P13569 function in multiple ways . In particular , class 3 mutations such as p . Gly551Asp strongly decrease the time spent by P13569 in the open state ( gating defect ) . Instead , class 2 mutations impair the maturation of P13569 protein and its transport from the endoplasmic reticulum to the plasma membrane ( trafficking defect ) . The deletion of phenylalanine 508 ( p . Phe508del ) , the most frequent mutation among CF patients ( 70 - 90 % ) , destabilizes the P13569 protein , thus causing both a trafficking and a gating defect . These two defects can be overcome with drug - like molecules generically called correctors and potentiators , respectively . The potentiator Kalydeco ™ ( also known as ___MASK66___ or VX - 770 ) , developed by Vertex Pharmaceuticals , has been recently approved by the US FDA and the European Medicines Agency ( P15941 ) for the treatment of CF patients carrying at least one P13569 allele with the p . Gly551Asp mutation ( 2 - 5 % of all patients ) . In contrast , the corrector VX - 809 , which significantly improves p . Phe508del - P13569 trafficking in vitro , is still under study in clinical trials . Because of multiple defects caused by the p . Phe508del mutation , it is probable that rescue of the mutant protein will require combined treatment with correctors having different mechanisms of action . This review evaluates the status of experimental and clinical research in pharmacotherapy for the CF basic defect .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK55___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK55___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"___MASK94___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK94___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK94___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK94___ inhibits activated T cells . We show that in vitro , ___MASK94___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK94___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK94___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK94___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK94___ to treat chronic inflammatory disease .",
"Transforming growth factor - beta ( TGF - beta ) activates cytosolic phospholipase A2alpha ( cPLA2alpha ) - mediated prostaglandin E2 ( PGE ) 2 / EP1 and peroxisome proliferator - activated receptor - gamma ( P37231 ) / Smad signaling pathways in human liver cancer cells . A novel mechanism for subversion of TGF - beta - induced mitoinhibition . Transforming growth factor - beta ( TGF - beta ) potently inhibits the growth of human epithelial cells . However , neoplastic epithelial cells become resistant to TGF - beta - mediated mitoinhibition , and the mechanisms for this alteration during tumorigenesis are not fully understood . This study was designed to determine whether there is an association between the cytosolic phospholipase A2alpha ( cPLA2alpha ) - controlled eicosanoid metabolism and the growth response to TGF - beta in human liver cancer cells . TGF - beta treatment induced simultaneous Smad - mediated gene transcription and phosphorylation of cPLA2alpha . Whereas Smad activation inhibited tumor cell growth , phosphorylation of P47712 alpha promoted growth and counteracted Smad - mediated mitoinhibition . TGF - beta1 failed to prevent the growth of cells with high basal expression of cPLA2alpha , but inhibition of P47712 alpha , cyclooxygenase - 2 ( P35354 ) , or EP1 receptor restored mitoinhibition by TGF - beta1 in these cells . These results suggest that resistance of tumor cells to TGF - beta - mediated mitoinhibition involves activation of cPLA2alpha / P35354 / EP1 signaling . Furthermore , the TGF - beta1 - induced Smad transcriptional activity and mitoinhibition were blocked by overexpression of cPLA2alpha or peroxisome proliferator - activated receptor - gamma ( P37231 ) but enhanced by depletion of cPLA2alpha or P37231 . These findings , along with the observations that cPLA2alpha activates P37231 and that P37231 binds P84022 , illustrate novel cPLA2alpha / P35354 / EP1 and cPLA2alpha / P37231 / Smad signaling pathways that counteract the mitoinhibition by TGF - beta in human cancer cells .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK2___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK2___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"hGH - V gene expression and promoter activity under glucose and 5 - azacytidine ( 5azaC ) effects . The metabolic conditions affecting placental development depend on nutritional state , genetic constitution and other external factors . The secretion of human placental growth hormone ( hGH - V ) had shown to be dependent of glucose , but the regulatory effects of this metabolite on hGH - V promoter activity and gene expression in presence of 5 - azacytidine had not been studied . In this work we compared the hGH - V promoter activity and the endogenous mRNA expression in human placental choriocarcinoma cell line JAR in the presence of glucose and demethylating genome conditions . High glucose concentration in culture medium diminished hGH - V mRNA endogenous levels in JAR cells whereas the expression of hGH - V from transfected PACs was slightly higher ; but in the presence of 5azaC a higher hGH - V gene expression from both the endogenous and the transfected ones was obtained . A drastic diminution of promoter analysis was shown when cells had no glucose ( J0 cells ) or in presence of 5azaC ; the placental transcription factors that showed modified binding capacity were DB09106 - 2 , P37231 , H4TF - 1 and O75051 - 1 . Our results suggest that in vitro suppressive glucose effect dictates a metabolic context to hGH - V gene expression and promoter regulation whereas a genomic methylation - dependent background is necessary to maintain placental transcription factors able to bind and regulate proximal promoter region of hGH - V in placental cells .",
"P37231 ( PPARgamma ) and immunoregulation : enhancement of regulatory T cells through PPARgamma - dependent and - independent mechanisms . Peroxisome proliferator - activated receptor ( Q07869 ) gamma is a nuclear hormone receptor primarily characterized for its effect on insulin metabolism . PPARgamma ligands , used to treat human type 2 diabetes , also down - regulate most immune system cells including APCs and pathogenic T cells . These effects putatively underlie the efficacy of PPARgamma ligands in treating animal models of autoimmunity , leading to projections of therapeutic potential in human autoimmunity . However , the relationship between PPARgamma ligands and P01730 + CD25 + regulatory T cells ( Tregs ) has not been examined . Specifically , no studies have examined the role of Tregs in mediating the in vivo immunoregulatory effects of PPARgamma ligands , and there have been no investigations of the use of PPARgamma ligands to treat autoimmunity in the absence of Tregs . We now characterize the novel relationship between ciglitazone , a thiazolidinedione class of PPARgamma ligand , and both murine natural Tregs ( nTregs ) and inducible Tregs ( iTregs ) . In vitro , ciglitazone significantly enhances generation of iTregs in a PPARgamma - independent manner . Surprisingly , and contrary to the current paradigm , we find that , in a model of graft - vs - host disease , the immunotherapeutic effect of ciglitazone requires the presence of nTregs that express PPARgamma . Overall , our results indicate that , unlike its down - regulatory effect on other cells of the immune system , ciglitazone has an enhancing effect on both iTregs and nTregs , and this finding may have important implications for using PPARgamma ligands in treating human autoimmune disease .",
"The P37231 Agonist 15 - Deoxy - Delta - Prostaglandin J ( 2 ) Attenuates Microglial Production of IL - 12 Family Cytokines : Potential Relevance to Alzheimer ' s Disease . Accumulation of amyloid - beta peptide ( Abeta ) appears to contribute to the pathogenesis of Alzheimer ' s disease ( AD ) . Therapeutic hope for the prevention or removal of Abeta deposits has been placed in strategies involving immunization against the Abeta peptide . Initial Abeta immunization studies in animal models of AD showed great promise . However , when this strategy was attempted in human subjects with AD , an unacceptable degree of meningoencephalitis occurred . It is generally believed that this adverse outcome resulted from a T - cell response to Abeta . Specifically , P01730 (+) Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Abeta immunization in the treatment of AD . Interleukin ( IL ) - 12 and IL - 23 play critical roles in the development of Th1 and Th17 cells , respectively . In the present study , Abeta ( 1 - 42 ) synergistically elevated the expression of IL - 12 and IL - 23 triggered by inflammatory activation of microglia , and the peroxisome proliferator - activated receptor ( Q07869 ) - gamma agonist 15 - deoxy - Delta ( 12 , 14 )- PGJ ( 2 ) ( 15d - PGJ ( 2 ) ) effectively blocked the elevation of these proinflammatory cytokines . Furthermore , 15d - PGJ ( 2 ) suppressed the Abeta - related synergistic induction of P08571 , MyD88 , and O60603 , molecules that play critical roles in neuroinflammatory conditions . Collectively , these studies suggest that P37231 agonists may be effective in modulating the development of AD .",
"P37231 controls Muc1 transcription in trophoblasts . The nuclear receptor peroxisome proliferator - activated receptor gamma ( PPARgamma ) is essential for placental development . Here , we show that the mucin gene Muc1 is a PPARgamma target , whose expression is lost in PPARgamma null placentas . During differentiation of trophoblast stem cells , PPARgamma is strongly induced , and Muc1 expression is upregulated by the PPARgamma agonist rosiglitazone . Muc1 promoter is activated strongly and specifically by liganded PPARgamma but not PPARalpha or PPARdelta . A Q07869 binding site ( DR1 ) in the proximal Muc1 promoter acts as a basal silencer in the absence of PPARgamma , and its cooperation with a composite upstream enhancer element is both necessary and sufficient for PPARgamma - dependent induction of Muc1 . In the placenta , P15941 protein is localized exclusively to the apical surface of the labyrinthine trophoblast around maternal blood sinuses , resembling its luminal localization on secretory epithelia . Last , variably penetrant maternal blood sinus dilation in Muc1 - deficient placentas suggests that Muc1 regulation by PPARgamma contributes to normal placental development but also that the essential functions of PPARgamma in the organ are mediated by other targets .",
"Functional changes in rheumatoid fibroblast - like synovial cells through activation of peroxisome proliferator - activated receptor gamma - mediated signalling pathway . P37231 ( PPARgamma ) is a ligand dependent transcriptional factor known to be a regulator of adipogenesis . Recent studies have also shown that stimulation of PPARgamma inhibits the transcriptional activities of other nuclear factors and down - regulates proinflammatory cytokine synthesis in T cells and monocytes . We examined , in the present study , the functional significance of PPARgamma expressed in fibroblast - like synovial cells ( FLS ) isolated from patients with rheumatoid arthritis ( RA ) . Incubation of FLS with a synthetic PPARgamma ligand , troglitazone , inhibited endogenous production of P01375 , P05231 and P10145 , as well as matrix metalloprotease - 3 ( P08254 ) , without inducing apoptosis of the cells . The gelatinase activity of FLS culture media was also inhibited by troglitazone . Electrophoretic mobility shift assay ( EMSA ) showed a significant reduction in the DNA binding activity of NF - kappaB in troglitazone - treated FLS in response to P01375 or IL - 1beta . Moreover , long - term cultivation of FLS with troglitazone resulted in morphological changes with marked lipid accumulation in these cells . Our results show a negative regulatory function for PPARgamma on cytokine and MMP production together with inhibition of cytokine - mediated inflammatory responses in rheumatoid synovial cells . Our results also suggest that FLS could differentiate into adipocyte - like cells in the presence of proper stimulatory signals including PPARgamma .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK8___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"Peroxisome proliferator - activated receptor - gamma - independent repression of collagenase gene expression by 2 - cyano - 3 , 12 - dioxooleana - 1 , 9 - dien - 28 - oic acid and prostaglandin 15 - deoxy - delta ( 12 , 14 ) J2 : a role for Smad signaling . Matrix metalloproteinases ( MMPs ) degrade extracellular matrix components , and overexpression of these enzymes contributes to tissue destruction in arthritis . Of particular importance are the collagenases , P03956 and P45452 , which have high activity against the interstitial collagens in cartilage . In this study , we address the mechanisms of two inhibitors of collagenase gene expression , the synthetic triterpenoid 2 - cyano - 3 , 12 - dioxooleana - 1 , 9 - dien - 28 - oic acid ( CDDO ) and 15 - deoxy - delta ( 12 , 14 )- prostaglandin J2 ( 15 - dPGJ2 ) . Although both inhibitors are ligands for the nuclear hormone receptor peroxisome proliferator - activated receptor - gamma ( P37231 ) , a connection between P37231 and collagenase gene expression has yet to be established . Here , we test the hypothesis that CDDO and 15 - dPGJ2 use P37231 to repress MMP gene expression . Our findings with the P37231 antagonist 2 -[ 4 -[ 2 -[ 3 -( 2 , 4 - difluorophenyl )- 1 - heptylureido ] ethyl ] rsqb ]- phenylsulfanyl ] - 2 - methylpropionic acid ( GW9662 ) and mouse embryonic fibroblasts lacking P37231 demonstrate that CDDO and 15 - dPGJ2 use P37231 - independent mechanisms to inhibit collagenase gene expression . To address a potential P37231 - independent mechanism leading to the repression of MMPs by CDDO , we tested the effect of CDDO on the transforming growth factor - beta ( TGF - beta ) signaling pathway . We found that CDDO requires Smads ( transcription factors activated by TGF - beta ) for the repression of P03956 . Specifically , P03956 is inhibited neither by CDDO in the absence of TGF - beta receptor - activated P84022 nor when a negative regulator , O15105 , attenuates TGF - beta signaling . We conclude that CDDO represses MMP gene expression through a novel P37231 - independent mechanism that requires Smad signaling ."
] |
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"___MASK14___",
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"___MASK69___",
"___MASK73___",
"___MASK8___",
"___MASK94___"
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___MASK73___
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MH_train_431
|
interacts_with DB00169?
|
[
"DB00169 and its nuclear receptor increase the expression and activity of the human proton - coupled folate transporter . Folates are essential for nucleic acid synthesis and are particularly required in rapidly proliferating tissues , such as intestinal epithelium and hemopoietic cells . Availability of dietary folates is determined by their absorption across the intestinal epithelium , mediated by the proton - coupled folate transporter ( Q96NT5 ) at the apical enterocyte membranes . Whereas transport properties of Q96NT5 are well characterized , regulation of Q96NT5 gene expression remains less elucidated . We have studied the mechanisms that regulate Q96NT5 promoter activity and expression in intestine - derived cells . Q96NT5 mRNA levels are increased in Caco - 2 cells treated with 1 , 25 - dihydroxyvitamin D ( 3 ) ( vitamin D ( 3 ) ) in a dose - dependent fashion , and the duodenal rat Pcft mRNA expression is induced by vitamin D ( 3 ) ex vivo . The Q96NT5 promoter region is transactivated by the vitamin D receptor ( P11473 ) and its heterodimeric partner retinoid X receptor - alpha ( RXRalpha ) in the presence of vitamin D ( 3 ) . In silico analyses predicted a P11473 response element ( VDRE ) in the Q96NT5 promoter region - 1694 /- 1680 . DNA binding assays showed direct and specific binding of the P11473 : RXRalpha heterodimer to the Q96NT5 (- 1694 /- 1680 ) , and chromatin immunoprecipitations verified that this interaction occurs within living cells . Mutational promoter analyses confirmed that the Q96NT5 (- 1694 /- 1680 ) motif mediates a transcriptional response to vitamin D ( 3 ) . In functional support of this regulatory mechanism , treatment with vitamin D ( 3 ) significantly increased the uptake of [( 3 ) H ] folic acid into Caco - 2 cells at pH 5 . 5 . In conclusion , vitamin D ( 3 ) and P11473 increase intestinal Q96NT5 expression , resulting in enhanced cellular folate uptake . Pharmacological treatment of patients with vitamin D ( 3 ) may have the added therapeutic benefit of enhancing the intestinal absorption of folates .",
"FGF - 8b increases angiogenic capacity and tumor growth of androgen - regulated S115 breast cancer cells . P55075 ( P55075 ) is a secreted heparin - binding protein , which has transforming potential . Alternative splicing of the mouse Fgf - 8 gene potentially codes for eight protein isoforms ( a - h ) which differ in their transforming capacity in transfected cells . S115 mouse mammary tumor cells express a transformed phenotype and secrete P55075 in an androgen - dependent manner . In order to study the role of P55075 isoforms in the induction of transformed phenotype of breast cancer cells , we over - expressed P55075 isoforms a , b and e in S115 cells . Over - expression of FGF - 8b , but not FGF - 8a or FGF - 8e , induced androgen and anchorage independent growth of S115 cells . FGF - 8b - transfected S115 cells formed rapidly growing tumors with increased vascularization when injected s . c . into nude mice . FGF - 8a also slightly increased tumor growth and probably tumor vascularization but FGF - 8e was not found to have any effects . The angiogenic activity of FGF - 8b and heparin - binding growth factor fraction ( HBGF ) of S115 cell conditioned media was tested in in vitro and in vivo models for angiogenesis using immortomouse brain capillary endothelial cells ( IBEC ) and chorion allantoic membrane ( P62158 ) assays . Recombinant FGF - 8b protein was able to stimulate proliferation , migration , and vessel - like tube formation of IBECs . In addition , stimulatory effect of S115 - HBGF on IBE cell proliferation was evident . A positive angiogenic response to FGF - 8b was also seen in P62158 assay . The results demonstrate that the expression of Fgf - 8b is able to promote vessel formation . Angiogenic capacity probably markedly contributes to the ability of FGF - 8b to increase tumor growth of androgen - regulated S115 mouse breast cancer cells .",
"Polymorphisms of chemokine receptors and P29474 in Brazilian patients with sickle cell disease . Sickle cell disease ( O00767 ) is an inherited disorder that presents extremely variable clinical manifestations . For the past few decades , it has been approached as an inflammatory disorder , and several researchers have tried to determine the factors involved in such characteristic . In order to contribute to the identification of the genetic differences underlying this phenotypic diversity in O00767 , we proposed to study the distribution of polymorphic variants of the genes encoding the chemokine receptors P41597 and P51681 , as well as three polymorphisms in the NOS3 gene , in Brazilian O00767 patients . These genes are involved in the development of inflammatory immune reactions , a feature believed to be of extreme importance in O00767 pathology . Our results indicate that the polymorphisms studied here are not directly associated with severe clinical manifestations in O00767 patients . Nevertheless , we observed a tendency for the development of a severe clinical course in carriers of the variant alleles P41597 - 64I and CCR5delta32 and in homozygotes for the - 786C variant of the NOS3 gene . Further studies should be carried out in order to assess the role of such variants in the clinical picture of O00767 .",
"DB00169 suppresses the androgen - stimulated growth of mouse mammary carcinoma SC - 3 cells by transcriptional repression of fibroblast growth factor 8 . Active metabolites of vitamin A and D are well known to act as growth inhibitors in hormone - related prostate and breast cancers . When various concentrations of 1alpha , 25 - dihydroxyvitamin D3 ( vitamin D3 ) , all - trans - retinoic acid ( DB00755 ) and 9 - cis retinoic acid ( 9 - cis RA ) were examined , the androgen - stimulated growth of mouse mammary carcinoma SC - 3 cells was inhibited by vitamin D3 alone in a dose - dependent manner . A flow cytometer analysis showed that vitamin D3 leads SC - 3 cells to relative P55008 - growth arrest after 72 h . Characterization of vitamin D3 - responsive genes using an oligonucleotide microarray demonstrated that 220 genes were upregulated at more than threefold , and 84 genes were downregulated to less than one - third , compared with the testosterone - stimulated SC - 3 cells . Neither cyclin - dependent kinase inhibitors ( CDKIs ) nor the antiapoptotic bcl - 2 gene were induced in vitamin D3 - responsive genes , with the exception of a slight induction of p15 ( INK4B ) . Importantly , fgf8 was markedly repressed in response to vitamin D3 . The exogenous addition of P55075 canceled the growth suppression by vitamin D3 in SC - 3 cells , suggesting that the repression of fgf8 is an indispensable step in vitamin D3 - mediated growth inhibition . In reporter assays using the ARE - containing artificial construct and the natural androgen - regulated PSA promoter , co - transfection of the vitamin D receptor ( P11473 ) and androgen receptor ( AR ) suppressed AR - stimulated promoter activity . In addition , vitamin D3 also suppressed androgen - stimulated promoter activity in the stably transfected SC - 3 cells . Moreover , P11473 repressed the core promoter activity of fgf8 in COS1 cells and in the SC - 3 cells . All these findings strongly suggest that vitamin D3 serves as a negative regulator for both androgen - related and fgf8 transcriptions .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . ___MASK31___ is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . DB01267 was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"The genomic clone P08908 which resembles a beta - adrenergic receptor sequence encodes the P08908 receptor . The recent cloning of the complementary DNAs and / or genes for several receptors linked to guanine nucleotide regulatory proteins including the adrenergic receptors ( alpha 1 , alpha 2A , alpha 2B , beta 1 , beta 2 ) , several subtypes of the muscarinic cholinergic receptors , and the visual ' receptor ' rhodopsin has revealed considerable similarity in the primary structure of these proteins . In addition , all of these proteins contain seven putative transmembrane alpha - helices . We have previously described a genomic clone , P08908 , isolated by cross - hybridization at reduced stringency with a full length beta 2 - adrenergic receptor probe . This clone contains an intronless gene which , because of its striking sequence resemblance to the adrenergic receptors , is presumed to encode a G - protein - coupled receptor . Previous attempts to identify this putative receptor by expression studies have failed . We now report that the protein product of the genomic clone , Q96NT5 , transiently expressed in monkey kidney cells has all the typical ligand - binding characteristics of the 5 - hydroxytryptamine ( P08908 ) receptor .",
"Association of common genetic variants with risperidone adverse events in a Spanish schizophrenic population . ___MASK31___ non - compliance is often high due to undesirable side effects , whose development is in part genetically determined . Studies with genetic variants involved in the pharmacokinetics and pharmacodynamics of risperidone have yielded inconsistent results . Thus , the aim of this study was to investigate the putative association of genetic markers with the occurrence of four frequently observed adverse events secondary to risperidone treatment : sleepiness , weight gain , extrapyramidal symptoms and sexual adverse events . A series of 111 schizophrenia inpatients were genotyped for genetic variants previously associated with or potentially involved in risperidone response . Presence of adverse events was the main variable and potential confounding factors were considered . Allele 16Gly of P07550 was significantly associated with a higher risk of sexual adverse events . There were other non - significant trends for P35462 9Gly and P31645 S alleles . Our results , although preliminary , provide new candidate variants of potential use in risperidone safety prediction .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( DB00755 ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and DB00755 .",
"Induction of P33151 in rat placental trophoblasts by P15692 through a NO - dependent pathway . Vascular endothelial - cadherin ( P33151 ) , a calcium - dependent homotypic adhesion molecule , contributes to endothelial assembly and P15692 - mediated survival during angiogenesis . In human term placentas , villous vessels and extravillous cytotrophoblasts express P33151 . Therefore , the purpose of this study was to examine if P15692 modulated placental development by increasing the expression of P33151 in rat placentas . Placental tissues from rats on gestation days 14 ( G14 ) , 18 ( G18 ) and 21 ( Q96NT5 ) were used . Western blot analysis and immunohistochemistry were performed to detect the protein abundance and the distribution of P33151 . A nitric oxide analyzer was used to measure the released nitric oxide ( NO ) from placental explant culture . With the progression of pregnancy , the abundance of P33151 and the intensity of the immunoreactive staining for P33151 in endovascular trophoblasts and labyrinth trophoblasts were decreased . In explant culture , P15692 ( 0 . 01 - 1 . 0 ng / ml ) increased the protein abundance of P33151 . SNP ( an NO donor ) or L - arginine ( substrate for P29474 ) induced the expression of P33151 with the increase of NO production . L - NAME ( a NOS inhibitor ) reduced the P15692 - increased expression and L - arginine reversed the inhibitory effect of L - NAME . In conclusion , P15692 plays an important role in placental development by the induction of P33151 in trophoblasts , which , in part , maintains the survival of labyrinth trophoblast in rat placentas .",
"Inhibition of DB00169 metabolism enhances P11473 signalling in androgen - independent prostate cancer cells . Induction of growth arrest and differentiation by 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 -( OH )( 2 ) D ( 3 ) ) occurs in non - malignant cell types but is often reduced in cancer cells . For example , androgen - independent prostate cancer cells , DU - 145 and PC - 3 , are relatively insensitive to the anti - proliferative action of 1 , 25 -( OH )( 2 ) D ( 3 ) . This appears to be due to increased 1 , 25 -( OH )( 2 ) D ( 3 )- metabolism , as a result of Q07973 enzyme - induction , which in turn leads to decreased anti - proliferative efficacy . In the in vitro rat kidney mitochondria assay , the 2 -( 4 - hydroxybenzyl )- 6 - methoxy - 3 , 4 - dihydro - 2H - naphthalen - 1 - one ( 4 ) was found to be a potent inhibitor of Vitamin D ( 3 ) metabolising enzymes ( IC ( 50 ) 3 . 5 microM ) , and was shown to be a more potent inhibitor than the broad spectrum P450 inhibitor ketoconazole ( IC ( 50 ) 20 microM ) . The combination of the inhibitor and 1 , 25 -( OH )( 2 ) D ( 3 ) caused a greater inhibition of proliferation in DU - 145 cells than when treated with both agents alone . Examination of the regulation of P11473 target gene mRNA in DU - 145 cells revealed that co - treatment of 1 , 25 -( OH )( 2 ) D ( 3 ) plus inhibitor of Vitamin D ( 3 ) metabolising enzymes co - ordinately upregulated Q07973 , P38936 ( waf1 / cip1 ) and GADD45alpha .",
"Synergism between bosutinib ( ___MASK52___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"DB00169 modulation of plasminogen activator inhibitor type - 1 in human breast carcinomas under organ culture . DB00013 plasminogen activator ( uPA ) , its cell - bound receptor ( Q03405 ) and its main inhibitor plasminogen activator type 1 ( P05121 ) are present primarily in stromal cells in invasive breast carcinoma . The purpose of this study was to investigate the regulation by 1 , 25 dihydroxyvitamin - D3 ( VD3 ) of these invasion - associated markers expressed in breast cancer tumors under organ culture , which preserves the interacting network of tumor and stromal cells . Breast carcinoma slices ( 30 cases ) , obtained using the Krumdieck tissue slicer , cultured for 48 h in the presence or absence of 100 nM vitamin D3 , were embedded in formalin - fixed paraffin . uPA , Q03405 , P05121 and VD3 receptor ( P11473 ) were analyzed by immunohistochemistry , and their expression , detected in tumor cells and fibroblasts of the specimens , was not statistically changed by culture conditions . The proportion of cases expressing uPA , Q03405 and P05121 was not affected by VD3 in epithelial cells , but the fraction of cases displaying strong P05121 reactivity in fibroblasts was reduced ( P = 0 . 016 ) compared with control slices . Fibroblasts isolated from invasive ductal carcinomas and from normal breast tissues expressed higher P11473 mRNA levels than epithelial cells . In cultured tumor fibroblasts , P05121 immunostaining and mRNA levels were reduced by VD3 - limiting fibroblast contribution to invasion .",
"Human chromosome 3 and pig chromosome 13 show complete synteny conservation but extensive gene - order differences . A comparative map of human chromosome 3 ( HSA 3 ) and pig chromosome 13 ( SSC 13 ) was constructed using physically assigned pig sequence - tagged sites ( STSs ) . Pig STSs representing 11 HSA 3 genes , including v - P04049 murine leukemia viral oncogene homolog 1 ( P04049 ) , retinoic acid beta receptor ( P10826 ) , cholecystokinin ( CCK ) , pituitary transcription factor 1 ( P28069 ) , ceruloplasmin ( CP ) , guanine nucleotide binding protein , alpha - inhibiting polypeptide 2 ( P04899 ) , sucrase - isomaltase ( SI ) , rhodopsin ( P08100 ) , dopamine receptor D3 ( P35462 ) , growth - associated protein 43 ( P17677 ) , and somatostatin ( P61278 ) , were developed . Ten pig STSs were regionally mapped using a somatic cell hybrid panel ( SCHP ) to SSC 13 with 80 - 100 % concordance . Large - insert probes were obtained by screening a pig yeast artificial chromosome ( YAC ) library with primers for each STS . Several YACs were identified for P35462 , P17677 , P28069 , P08100 , SI , and P61278 for fluorescence in situ hybridization ( Q5TCZ1 ) mapping . Single gene and bi - color Q5TCZ1 with each pairwise combination were used to further define the gene order on SSC 13 . While these data confirm chromosome painting results showing that HSA 3 probes hybridize to a major portion of SSC 13 , they also demonstrate extensive gene - order differences between man and pig within this large conserved synteny group . Interestingly , several conserved chromosomal regions have been detected between pig and mouse that are not conserved between man and mouse , suggesting that the SSC 13 gene arrangement may be the closest to that of the ancestral eutherian chromosome .",
"MAPK inhibition by 1alpha , 25 ( OH ) 2 - DB00169 in breast cancer cells . Evidence on the participation of the P11473 and Src . 1alpha , 25 - Dihydroxyvitamin D ( 3 ) [ 1alpha , 25 ( OH )( 2 ) D ( 3 ) ] , the hormonally active form of Vitamin D ( 3 ) , has been shown to be a potent negative growth regulator of breast cancer cells both in vitro and in vivo . 1alpha , 25 ( OH )( 2 ) D ( 3 ) acts through two different mechanisms . In addition to regulating gene transcription via its specific intracellular receptor ( Vitamin D receptor , P11473 ) , 1alpha , 25 ( OH )( 2 ) D ( 3 ) induces , rapid , non - transcriptional responses involving activation of transmembrane signal transduction pathways . The mechanisms that mediate the antiproliferative effects of 1alpha , 25 ( OH )( 2 ) D ( 3 ) in breast cancer cells are not fully understood . Particularly , there is no information about the early non - genomic signal transduction effectors modulated by the hormone . The present study shows that 1alpha , 25 ( OH )( 2 ) D ( 3 ) rapidly inhibits serum induced activation of P27361 and P28482 Q96HU1 kinases . The non - receptor tyrosine kinase Src is involved in the pathway leading to activation of P29323 1 / 2 by serum . Furthermore , 1alpha , 25 ( OH )( 2 ) D ( 3 ) increases the tyrosine - phosphorylated state of Src as well as it inhibits its kinase activity and induces the association of the P11473 with Src . These data suggest that 1alpha , 25 ( OH )( 2 ) D ( 3 ) inhibits MAPK by inactivating Src tyrosine kinase through a so far unknown mechanism that seems to be mediated by the P11473 .",
"Chemokine production and leukocyte recruitment to the lungs of Paracoccidioides brasiliensis - infected mice is modulated by interferon - gamma . Chemokines and chemokine receptors play a role in cell recruitment during granulomatous inflammatory reactions . Here , we evaluated the expression of chemokines and chemokine receptors and their regulation by P01579 in the course of Paracoccidioides brasiliensis ( Pb ) infection in mice . We found an association between KC and MIP - 1alpha ( P10147 ) production and neutrophil infiltration in the lungs of Pb - infected mice during the early acute phase of infection . High levels of RANTES / P13501 , P13500 / P13500 , P02778 / P02778 , and Mig / Q07325 simultaneously with mononuclear cell infiltration in the lungs was found . In the absence of P01579 ( GKO mice ) we observed increased production of KC and MIP - 1alpha and chronic neutrophilia . Moreover , we found a change in the chemokine receptor profiles expressed by wild - type ( WT ) versus GKO animals . Increased expression of P49682 and P51681 , and low levels of P51677 and CCR4 were observed in the lungs of Pb - infected WT mice , whereas the opposite effect was observed in the lungs of GKO mice . Consistent with these results , infected cells from WT mice preferentially migrated in response to P02778 ( P49682 ligand ) , while those from GKO mice migrated in response to eotaxin / P51671 ( P51677 ligand ) . These results suggest that P01579 modulates the expression of chemokines and chemokine receptors as well as the kind of cells that infiltrate the lungs of Pb - infected mice .",
"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Differential ligand - dependent interactions between the AF - 2 activating domain of nuclear receptors and the putative transcriptional intermediary factors mSUG1 and O15164 . Using a yeast two - hybrid system we report the isolation of a novel mouse protein , mSUG1 , that interacts with retinoic acid receptor alpha ( RAR alpha ) both in yeast cells and in vitro in a ligand - and AF - 2 activating domain ( AF - 2 AD ) - dependent manner and show that it is a structural and functional homologue of the essential yeast protein P62195 . mSUG1 also efficiently interacts with other nuclear receptors , including oestrogen ( ER ) , thyroid hormone ( TR ) , DB00169 ( P11473 ) and retinoid X ( RXR ) receptors . By comparing the interaction properties of these receptors with mSUG1 and O15164 , we demonstrate that : ( i ) RXR alpha efficiently interacts with O15164 , but not with mSUG1 , whereas TR alpha interacts much more efficiently with mSUG1 than with O15164 , and RAR alpha , P11473 and ER efficiently interact with mSUG1 and O15164 ; ( ii ) the amphipathic alpha - helix core of the AF - 2 AD is differentially involved in interactions of RAR alpha with mSUG1 and O15164 ; ( iii ) the AF - 2 AD cores of RAR alpha and ER are similarly involved in their interaction with O15164 , but not with mSUG1 . Thus , the interaction interfaces between the different receptors and either mSUG1 or O15164 may vary depending on the nature of the receptor and the putative mediator of its AF - 2 function . We discuss the possibility that mSUG1 and O15164 may mediate the transcriptional activity of the AF - 2 of nuclear receptors through different mechanisms .",
"___MASK100___ and sirolimus antagonize tacrolimus based calcineurin inhibition via competition for FK - binding protein 12 . The calcineurin inhibitors cyclosporin A and tacrolimus and the inhibitors of the P42345 , sirolimus and everolimus bind immunophilins that are required for their immunosuppressive action . In contrast to cyclosporin A , tacrolimus and the P42345 inhibitors ( MTIs ) share common immunophilins , the FK506 - binding proteins ( FKBPs ) . We investigated the immunosuppressive interactions of MTIs on tacrolimus based immune suppression , since insights in immunological drug - drug interactions can be very relevant for optimization of immunosuppressive regimens in allograft transplantation medicine . Isolated peripheral blood mononuclear cells from healthy volunteers were incubated with combinations of MTIs and calcineurin inhibitors and when monitored for calcineurin activity and P60568 excretion after mitogen stimulation , tacrolimus IC ( 50 ) concentrations shifted to higher concentrations in the presence of MTIs . This antagonism was absent for cyclosporin A , reproducible for 10 healthy volunteers ( p < 0 . 001 ) and stronger for sirolimus than for everolimus . When cell lysate was treated with and without MTI , tacrolimus and P62942 , P62942 could increase calcineurin inhibition by tacrolimus and reverse the MTI antagonism for both MTIs . These results demonstrate that P62942 can be rate limiting for calcineurin inhibition at high tacrolimus concentrations and that the antagonism of sirolimus and everolimus on tacrolimus based immune suppression is mediated via saturation of P62942 .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK78___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"___MASK100___ ( RAD001 ) : an P42345 inhibitor for the treatment of metastatic renal cell carcinoma . The recent introduction of drugs that inhibit angiogenesis or the P42345 has provided new options for the treatment of metastatic renal cell carcinoma , a disease which often has a poor prognosis . Chemotherapy and cytokine therapy are largely ineffective . The 5 - year survival rate is under 10 % . ___MASK100___ , an immunosuppressive drug widely used for the prevention of allograft rejection and an P42345 inhibitor , is one of the latest drugs undergoing clinical trials in metastatic renal cell carcinoma . It has been tested in patients with progressive disease after therapy with tyrosine kinase receptor inhibitors ( sunitinib , sorafenib or both ) , which interfere with signaling pathways , such as the P15692 pathway . Clinical efficacy results ( progression - free survival ) for everolimus are promising and the safety profile is good .",
"MAPK and P12931 - kinases control P18146 and NF - kappa B inductions by changes in mechanical environment in osteoblasts . Bone loss occurs in microgravity whereas an increase in bone mass is observed after skeletal loading . This tissue adaptation involves changes in osteoblastic proliferation and differentiation whose mechanisms remain largely unknown . In this context , we investigated the expression and the nuclear translocation of Egr - 1 and NF - kappa B , in a simulated microgravity model ( clinostat ) and in a model of mechanical strain ( Flexcell ) . We performed RT - PCR and immunocytochemistry analyses at baseline and up to 2 h after stimulation ( a mitogenic regimen , 1 % stretch , 0 . 05 Hz , 10 min , or clinorotation 50 rpm , 10 min ) in osteoblastic ROS17 / 2 . 8 cells . Egr - 1 induction as well as NF - kappa B nuclear translocation were activated by mechanical changes . PKC downregulation and P23219 / 2 inhibition did not alter these inductions . In contrast , P27361 / 2 , p38 ( MAPK ) and src - kinases pathways were differentially involved in both models . Thus , we demonstrated that changes in the mechanical environment induced an activation of Egr - 1 and NF - kappa B with specific kinetics and involved various transduction pathways including MAPKs and src - kinases . These could partially explain the later alterations of proliferation observed .",
"DB00169 : a transcriptional modulator of the interferon - gamma gene . 1Alpha , 25 - dihydroxyvitamin D3 [ 1 , 25 -( OH ) 2D3 ] exerts several effects on the immune system , by regulating lymphocyte proliferation , differentiation of monocytes and secretion of cytokines as P60568 , granulocyte - macrophage colony - stimulating factor and P01579 in T cells . Here , we analyze the effect of 1 , 25 -( OH ) 2D3 on P01579 gene transcription . Transient transfection assays in Jurkat T cells indicate that activation of the P01579 promoter is down - regulated by 1 , 25 -( OH ) 2D3 . This effect is enhanced by retinoid X receptor ( RXR ) , and a functional vitamin D3 receptor ( P11473 ) DNA - binding domain in necessary for repression . We delineated two important promoter regions mainly involved in this modulation . The first of these is situated at the level of a promoter - silencer previously characterized and binds the heterodimer P11473 - RXR in electrophoretic mobility shift assay . Residual negative regulation was also detected at the level of the promoter fragment - 108 to + 64 bp from the transcription start site and , surprisingly , the activity of the P01579 enhancer from - 108 to - 36 bp in the context of a heterologous promoter was not affected by 1 , 25 -( OH ) 2D3 . Moreover , binding activity for P11473 - RXR has been detected in the P01579 minimal promoter , suggesting a possible mechanism of interference with transcription initiation / progression . The overall data indicate that direct modulation of the P01579 promoter activity is one of the possible mechanisms involved in the repressive effect of 1 , 25 -( OH ) 2D3 on P01579 gene expression .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"The 1alpha , 25 - dihydroxy P11473 preferentially recruits the coactivator Q15788 during up - regulation of the osteocalcin gene . Binding of 1alpha , 25 - dihydroxy DB00169 to the C - terminal domain ( LBD ) of its receptor ( P11473 ) , induces a conformational change that enables interaction of P11473 with transcriptional coactivators such as the members of the P52701 / P12931 family or the DRIP ( Vitamin D interacting complex ) / Mediator complex . These interactions are critical for P11473 - mediated transcriptional enhancement of target genes . Recent reports indicate that nuclear receptors , including P11473 , interact with P52701 / P12931 members and the DRIP / Mediator complex in a sequential , cyclical , and mutually exclusive manner when bound to a target promoter , exhibiting also a high exchange rate . Here , we present an overview of how these coactivators are recruited to the bone - specific osteocalcin ( OC ) gene in response to short and long exposures to 1alpha , 25 - dihydroxy DB00169 . We find that in intact osteoblastic cells P11473 and Q15788 rapidly bind to the OC promoter in response to the ligand . This recruitment correlates with transcriptional enhancement of the OC gene and with increased histone acetylation at the OC promoter . In contrast , binding of the Q15648 subunit , which anchors the DRIP / Mediator complex to the P11473 , is detected at the OC promoter after several hours of incubation with 1alpha , 25 - dihydroxy DB00169 . Together , our results indicate that P11473 preferentially recruits Q15788 to enhance basal bone - specific OC gene transcription . We propose a model where specific protein - DNA and protein - protein interactions that occur within the context of the OC gene promoter in osteoblastic cells stabilize the preferential association of the P11473 - Q15788 complex .",
"Synergy between vitamin D ( 3 ) and Toll - like receptor agonists regulates human dendritic cell response during maturation . Human dendritic cells ( DC ) can be differentiated from blood monocytes in the presence of GM - P04141 and P05112 and matured by lipopolysaccharide ( LPS ) . DB00169 inhibits the maturation of human DC measured by changes in surface expression of HLA - DR , P08571 , P25942 , P33681 , Q01151 , and P42081 . We here examine the function of vitamin D3 during DC maturation . One of the earliest changes to LPS - induced maturation was an increase in Q01151 expression . DB00169 inhibited the increase in expression of HLA - DR , P25942 , P33681 , Q01151 , and P42081 and the decrease in expression of P08571 , which was paralleled morphologically by vitamin D3 - induced inhibition of dendritic cell differentiation . DB00169 acted in synergy with the TLR agonists LPS and peptidoglycan ( Q9UQ90 ) in inducing P05231 , P10145 , and P22301 , whereas vitamin D3 completely inhibited LPS - induced secretion of IL - 12 . The synergy occurred at concentrations where neither vitamin D3 nor the TLR agonists alone induced measurable cytokine secretion . Both LPS and Q9UQ90 enhanced the level of the vitamin D3 receptor ( P11473 ) . Taken together , these data demonstrated that vitamin D3 and TLR agonists acted in synergy to alter secretion of cytokines from human DC in a direction that may provide an anti - inflammatory environment .",
"Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .",
"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"27 - hydroxycholesterol is an endogenous ligand for liver X receptor in cholesterol - loaded cells . The nuclear receptors liver X receptor alpha ( LXRalpha ) ( Q13133 ) and LXRbeta ( P55055 ) are important regulators of genes involved in lipid metabolism , including O95477 , P45844 , and sterol regulatory element - binding protein - 1c ( SREBP - 1c ) . Although it has been demonstrated that oxysterols are LXR ligands , little is known about the identity of the physiological activators of these receptors . Here we confirm earlier studies demonstrating a dose - dependent induction of O95477 and P45844 in human monocyte - derived macrophages by cholesterol loading . In addition , we show that formation of 27 - hydroxycholesterol and cholestenoic acid , products of Q02318 action on cholesterol , is dependent on the dose of cholesterol used to load the cells . Other proposed LXR ligands , including 20 ( S )- hydroxycholesterol , 22 ( R )- hydroxycholesterol , and 24 ( S ), 25 - epoxycholesterol , could not be detected under these conditions . A role for Q02318 in regulation of cholesterol - induced genes was demonstrated by the following findings . 1 ) Introduction of Q02318 into P29320 - 293 cells conferred an induction of P45844 and SREBP - 1c ; 2 ) upon cholesterol loading , Q02318 - expressing cells induce these genes to a greater extent than in control cells ; 3 ) in Q02318 - deficient human skin fibroblasts , the induction of O95477 in response to cholesterol loading was ablated ; and 4 ) in a coactivator association assay , 27 - hydroxycholesterol functionally activated LXR . We conclude that 27 - hydroxylation of cholesterol is an important pathway for LXR activation in response to cholesterol overload .",
"Regulation of interleukin - 6 promoter activation in gastric epithelial cells infected with Helicobacter pylori . The regulation of Helicobacter pylori induced interleukin ( IL ) - 6 in the gastric epithelium remains unclear . Primary gastric epithelial cells and MKN28 cells were cocultured with H . pylori and its isogenic cag pathogenicity island ( P05121 ) mutant and / or oipA mutants . H . pylori infection - induced P05231 mRNA expression and P05231 protein production , which was further enhanced by the cag P05121 and OipA . Luciferase reporter gene assays and electrophoretic mobility shift assays showed that full P05231 transcription required binding sites for nuclear factor - kappaB ( NF - kappaB ) , DB02527 response element ( CRE ) , CCAAT / enhancer binding protein ( C / EBP ) , and activator protein ( AP ) - 1 . The cag P05121 and OipA were involved in binding to NF - kappaB , AP - 1 , CRE , and C / EBP sites . The cag P05121 activated the extracellular signal - regulated kinase ( P29323 ) and Jun N - terminal kinase ( JNK ) pathways ; OipA activated the p38 pathway . Transfection of dominant negative G - protein confirmed roles for Raf , Rac1 , and RhoA in P05231 induction . Overall , the cag P05121 - related P05231 signal transduction pathway involved the Ras / Raf / Q02750 / 2 / P29323 / AP - 1 / CRE pathway and the JNK / AP - 1 / CRE pathway ; the OipA - related pathway is p38 / AP - 1 / CRE and both the cag P05121 and OipA appear to be involved in the RhoA / Rac1 / NF - kappaB pathway . Combination of different pathways by the cag P05121 and OipA will lead to the maximum P05231 induction .",
"A mechanism underlying the effects of polyunsaturated fatty acids on breast cancer . Breast cancer is the most frequent cancer in women . Evidence suggests that the polyunsaturated fatty acids ( PUFAs ) , eicosapentaenoic acid ( EPA ) , and docosahexaenoic acid ( DB01708 ) affect breast cancer proliferation , differentiation and prognosis . However , the mechanism still remains unclear . In this study , the expression of transient receptor potential canonical ( TRPC ) 3 was detected throughout the cell cytoplasm and at the cell surface of MCF - 7 cells . Ca ( 2 +) entry was induced in these cells via activated Q13507 by either the diacylglycerol analogue ( OAG ) or by intracellular Ca ( 2 +) store depletion . TRPC - mediated Ca ( 2 +) entry was inhibited by PUFAs including arachidonic acid ( AA ) and linolenic acid ( LA ) but not saturated fatty acids . Overexpression of the PUFA degradation enzyme , cyclooxygenase 2 ( P35354 ) , enhanced capacitative Ca ( 2 +) entry . In addition , inhibition of P35354 reduced [ Ca ( 2 +)]( i ) . Nevertheless , inhibition of TRPC reduced the cell cycle S phase and cell migration , implicating a functional role for TRP - mediated Ca ( 2 +) entry in cell proliferation and invasion . Exogenous PUFA as well as a Q13507 antagonist consistently attenuated breast cancer cell proliferation and migration , suggesting a mechanism in which PUFA restrains the breast cancer partly via its inhibition of TRPC channels . Additionally , our results also suggest that Q13507 appears as a new mediator of breast cancer cell migration / invasion and represents a potential target for a new class of anticancer agent .",
"The deltaccr5 mutation conferring protection against HIV - 1 in Caucasian populations has a single and recent origin in Northeastern Europe . The chemokine receptor P51681 is encoded by the P51681 gene located on the P38936 . 3 region of human chromosome 3 , and constitutes the major co - receptor for the macrophage - tropic strains of HIV - 1 . A mutant allele of the P51681 gene , Delta ccr5 , was shown to provide to homozygotes with a strong resistance against infection by HIV . The frequency of the Delta ccr5 allele was investigated in 18 European populations . A North to South gradient was found , with the highest allele frequencies in Finnish and Mordvinian populations ( 16 % ) , and the lowest in Sardinia ( 4 % ) . Highly polymorphic microsatellites ( IRI3 . 1 , D3S4579 and IRI3 . 2 , D3S4580 ) located respectively 11 kb upstream and 68 kb downstream of the P51681 gene deletion were used to determine the haplotype of the chromosomes carrying the Delta ccr5 variant . A strong linkage disequilibrium was found between Delta ccr5 and specific alleles of the IRI3 . 1 and IRI3 . 2 microsatellites : > 95 % of the Delta ccr5 chromosomes carried the IRI3 . 1 - 0 allele , while 88 % carried the IRI3 . 2 - 0 allele . These alleles were found respectively in only 2 or 1 . 5 % of the chromosomes carrying a wild - type P51681 gene . From these data , it was inferred that most , if not all Delta ccr5 alleles originate from a single mutation event , and that this mutation event probably took place a few thousand years ago in Northeastern Europe . The high frequency of the Delta ccr5 allele in Caucasian populations can not be explained easily by random genetic drift , suggesting that a selection advantage is or has been associated with homo - or heterozygous carriers of the Delta ccr5 allele .",
"Functional characterization of a novel serotonin receptor ( 5 - HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full - length cDNA , coding for a novel serotonin receptor ( 5 - HTap2 ) . The receptor protein bears the characteristics of G protein - coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5 - HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5 - HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [ 3H ] LSD binding was : methiothepin > metergoline > 5 - CT > PAPP > 5 - HT > ketanserin > NAN - 190 > 8 - OH - DPAT > clozapine . RT - PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5 - HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5 - HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg - laying behavior .",
"Q13507 - like protein and vitamin D receptor mediate DB00136 - induced Q5T124 influx in muscle cells . 1alpha , 25 - Dihydroxy - Vitamin - D3 ( 1alpha , 25 ( OH ) 2 - DB00169 ) stimulates in skeletal muscle cells Ca2 + release from inner stores and influx through both voltage - dependent and store - operated Ca2 + ( Q5T124 , CCE ) channels . We investigated the involvement of TRPC proteins and Vitamin D receptor ( P11473 ) in CCE induced by DB00136 in chick muscle cells . Two fragments were amplified by RT - PCR , exhibiting approximately 80 % sequence homology with mammalian Q13507 / 6 / 7 . Northern and Western blots employing a Q13507 - probe and anti - Q13507 antibodies , respectively , confirmed endogenous expression of a Q13507 - like protein of 140 kDa . Spectrofluorimetric measurements in Fura - 2 loaded cells showed reduced CCE and Mn2 + entry in response to either thapsigargin or DB00136 upon transfection with anti - Q13507 / 6 / 7 antisense oligodeoxynucleotides ( ODNs ) . Transfection with anti - P11473 antisense ODNs diminished DB00136 - dependent Ca2 + and Mn2 + influx . Co - immunoprecipitation of Q13507 - like protein and P11473 under non - denaturating conditions was observed . We propose that endogenous Q13507 - like proteins and the P11473 participate in the modulation of CCE by DB00136 in muscle cells , which could be mediated by an interaction between these proteins .",
"___MASK12___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"Testing Hardy - Weinberg equilibrium using family data from complex surveys . Genetic data collected during the second phase of the Third National Health and Nutrition Examination Survey ( NHANES III ) enable us to investigate the association of a wide variety of health factors with regard to genetic variation . The classic question when looking into the genetic variations in a population is whether the population is in the state of Hardy - Weinberg Equilibrium ( HWE ) . Our objective was to develop test procedures using family data from complex surveys such as NHANES III . We developed six Pearson chi ( 2 ) based tests for a diallelic locus of autosomal genes . The finite sample properties of the proposed test procedures were evaluated via Monte Carlo simulation studies and the Rao - Scott first order corrected test was recommended . Test procedures were applied to three loci from NHANES III genetic databases , i . e . , P07550 , P01137 , and P11473 . HWE was shown to hold at 0 . 05 level for all three loci when only families with genotypic information available for two parents and for one or more children were used in the analysis .",
"Characterization of vitamin D production by human ocular barrier cells . PURPOSE : DB00169 is a secosteroid mainly synthesized from the conversion of the skin precursor 7 - dehydrocholesterol ( 7DHC ) to vitamin D3 by ultraviolet ( UV ) B sunlight . Extrarenal synthesis of vitamin D3 has been reported in many tissues and cells , including barrier sites . This study characterizes the expression of components of vitamin D3 signaling in human ocular barrier cells . METHODS : Primary human scleral fibroblasts ( HSF ) , human corneal endothelial ( HCEC - 12 ) , nonpigmented ciliary body epithelial ( ODM - 2 ) , and adult retinal pigment epithelial ( ARPE - 19 ) cell lines were analyzed for the expression of vitamin D receptor ( P11473 ) , the vitamin D3 activating enzymes 1α - hydroxylase ( O15528 ) , 25 - hydroxylases ( Q02318 and Q6VVX0 ) , the vitamin D3 inactivating enzyme 24 - hydroxylase ( Q07973 ) , and the endocytic receptors cubilin and megalin using a combination of RT - PCR , immunocytochemistry , and enzyme immunoassay ( EIA ) . RESULTS : The HSF , HCEC - 12 , ODM - 2 , and ARPE - 19 express mRNA and protein for all vitamin D3 synthesizing and metabolizing components . The cell types tested , except HSF , are able to convert inactive 25 - hydroxyvitamin D3 ( 25 [ OH ] D3 ) into active 1 , 25 - hydroxyvitamin D3 ( 1 , 25 [ OH ] 2D3 ) . CONCLUSIONS : This novel study demonstrated that ocular barrier epithelial cells express the machinery for vitamin D3 and can produce 1 , 25 ( OH ) 2D3 . We suggest that vitamin D3 might have a role in immune regulation and barrier function in ocular barrier epithelial cells .",
"The effect of 1 , 25 - dihydroxyvitamin D3 on lymphoma cell lines and expression of vitamin D receptor in lymphoma . 1 , 25 ( OH ) 2D3 promotes differentiation and has an antiproliferative effect in a variety of cell lines derived from the immunohaematopoetic system . alpha - Calcidol which is metabolised to 1 , 25 ( OH ) 2D3 has been shown to produce tumour regression in follicular low grade non - Hodgkin ' s lymphoma ( Q9NZ71 ) and the dose limiting toxicity is hypercalcaemia . The cellular action of 1 , 25 ( OH ) 2D3 is mediated by binding to an intracellular protein , the vitamin D receptor ( P11473 ) . We have evaluated the activity of 1 , 25 ( OH ) 2D3 and its non - calcaemogenic analogue MC903 in the SU - DHL4 and SU - DUL5 B cell lines which carry the 14 ; 18 translocation characteristic of follicular Q9NZ71 , and also the expression of the P11473 in a range of B cell NHLs . Both agents induced differentiation and had an antiproliferative effect on the SU - DHL4 and SU - DUL5 cell lines . However this occurred at a relatively high concentration ( 10 (- 7 ) M ) which exceeds the physiological concentration of 1 , 25 ( OH ) 2D3 by approximately 10 ( 3 )- 10 ( 4 )- fold . Expression of the P11473 was low in each cell line and in the low grade lymphoma tumour samples . To account for the observed clinical response to 1 alpha OHD3 ( alpha - calcidol ) in follicular Q9NZ71 a network is suggested whereby 1 , 25 ( OH ) 2D3 modulates the activity of P01730 + T cells which have previously been shown to promote follicle centre cell proliferation . DB00169 analogues may enable serum levels to be achieved which produce a direct action on follicular lymphoma cells without disturbing calcium metabolism .",
"Differential effects of selective HDAC inhibitors on macrophage inflammatory responses to the O00206 agonist LPS . Broad - spectrum inhibitors of HDACs are therapeutic in many inflammatory disease models but exacerbated disease in a mouse model of atherosclerosis . HDAC inhibitors have anti - and proinflammatory effects on macrophages in vitro . We report here that several broad - spectrum HDAC inhibitors , including P32119 and ___MASK29___ , suppressed the LPS - induced mRNA expression of the proinflammatory mediators Edn - 1 , Ccl - 7 / P80098 , and Il - 12p40 but amplified the expression of the proatherogenic factors Cox - 2 and Pai - 1 / serpine1 in primary mouse BMM . Similar effects were also apparent in LPS - stimulated TEPM and HMDM . The pro - and anti - inflammatory effects of P32119 were separable over a concentration range , implying that individual HDACs have differential effects on macrophage inflammatory responses . The Q13547 - selective inhibitor , MS - 275 , retained proinflammatory effects ( amplification of LPS - induced expression of Cox - 2 and Pai - 1 in BMM ) but suppressed only some inflammatory responses . In contrast , 17a ( a reportedly Q9UBN7 - selective inhibitor ) retained anti - inflammatory but not proinflammatory properties . Despite this , Q9UBN7 (-/-) macrophages showed normal LPS - induced expression of HDAC - dependent inflammatory genes , arguing that the anti - inflammatory effects of 17a are not a result of inhibition of Q9UBN7 alone . Thus , 17a provides a tool to identify individual HDACs with proinflammatory properties .",
"Neuroprotective profile of novel P12931 kinase inhibitors in rodent models of cerebral ischemia . Src kinase signaling has been implicated in multiple mechanisms of ischemic injury , including vascular endothelial growth factor ( P15692 ) - mediated vascular permeability that leads to vasogenic edema , a major clinical complication in stroke and brain trauma . Here we report the effects of two novel Src kinase inhibitors , 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 3 -( 4 - methyl - 1 - piperazinyl ) propoxy ]- 3 - quinolinecarbonitrile ( ___MASK52___ ) and 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 4 -( 4 - methypiperazin - 1 - yl ) but - 1 - ynyl ]- 3 - quinolinecarbonitrile ( SKS - 927 ) , on ischemia - induced brain infarction and short - and long - term neurological deficits . Two well established transient [ transient middle cerebral artery occlusion ( tMCAO ) ] and permanent [ permanent middle cerebral artery occlusion ( pMCAO ) ] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario . Brain penetration of Src inhibitors , their effect on blood - brain barrier integrity and P15692 signaling in human endothelial cells were also evaluated . Our results demonstrate that both agents potently block P15692 - mediated signaling in human endothelial cells , penetrate rat brain upon systemic administration , and inhibit postischemic Src activation and vascular leakage . Treatment with ___MASK52___ or SKS - 927 ( at the doses of 3 - 30 mg / kg i . v . ) resulted in a dose - dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4 - to 6 - h after tMCAO . Src blockade after pMCAO resulted in accelerated improvement in recovery from motor , sensory , and reflex deficits during a long - term ( 3 weeks ) testing period poststroke . These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke .",
"Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .",
"Screening of candidate genes for primary open angle glaucoma . PURPOSE : Primary open - angle glaucoma ( POAG ) is one of the leading causes of irreversible blindness in the world . To make progress in understanding POAG , it is necessary to identify more POAG - causing genes . METHODS : Using haplotype analysis , we found that mutational region is located on chromosome 2 in two families . Furthermore , we screened 11 candidate genes on chromosome 2 by protein - protein interaction ( PPI ) analysis , including mutS homolog 6 ( P52701 ) , mutS homolog 2 ( P43246 ) , v - rel reticuloendotheliosis viral oncogene homolog ( Q04864 ) , endothelial DB00233 domain protein 1 ( Q99814 ) , vaccinia related kinase 2 ( Q86Y07 ) , F - box protein 11 ( Q86XK2 ) , P01133 containing fibulin - like extracellular matrix protein 1 ( Q12805 ) , reticulon 4 ( Q9NQC3 ) , P62820 , member DB01367 oncogene family ( P62820 ) , ARP2 actin - related protein 2 homolog ( P61160 ) , and calmodulin 2 ( phosphorylase kinase , delta ; P62158 ) . These 11 genes are all predicted to be related to trabecular meshwork changes and progressive loss of retinal ganglion cells in POAG patients . RESULTS : According to our study , Q86XK2 and Q86Y07 may interact with tumor protein p53 to regulate mitochondrial membrane permeability , mitochondrial membrane organization , and apoptosis . P43246 is responsible for repairing DNA mismatches and Q9NQC3 is for neuronal regeneration . Therefore , they are supposed to play a negative role in cellular process in POAG . P62158 may be involved in retinal ganglion cell death and oxidative damage to cell communication . CONCLUSIONS : The results demonstrate that the genes above may be associated with pathogenesis of POAG .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK3___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"___MASK100___ inhibits anti - HLA I antibody - mediated endothelial cell signaling , migration and proliferation more potently than sirolimus . Antibody ( Ab ) crosslinking of HLA I molecules on the surface of endothelial cells triggers proliferative and pro - survival intracellular signaling , which is implicated in the process of chronic allograft rejection , also known as transplant vasculopathy ( TV ) . The purpose of this study was to investigate the role of mammalian target of rapamycin ( P42345 ) in HLA I Ab - induced signaling cascades . ___MASK100___ provides a tool to establish how the P42345 signal network regulates HLA I - mediated migration , proliferation and survival . We found that everolimus inhibits P42345 complex 1 ( mTORC1 ) by disassociating Q8N122 from P42345 , thereby preventing class I - induced phosphorylation of P42345 , p70S6K , S6RP and Q13541 , and resultant class I - stimulated cell migration and proliferation . Furthermore , we found that everolimus inhibits class I - mediated mTORC2 activation ( 1 ) by disassociating Rictor and Sin1 from P42345 ; ( 2 ) by preventing class I - stimulated Akt phosphorylation and ( 3 ) by preventing class I - mediated P29323 phosphorylation . These results suggest that everolimus is more effective than sirolimus at antagonizing both mTORC1 and mTORC2 , the latter of which is critical in endothelial cell functional changes leading to TV in solid organ transplantation after HLA I crosslinking . Our findings point to a potential therapeutic effect of everolimus in prevention of chronic Ab - mediated rejection .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK32___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK32___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"Effects of the dopamine D3 receptor ( P35462 ) gene polymorphisms on risperidone response : a pharmacogenetic study . Previous observations of the anatomical distribution and pharmacological profile of the dopamine D ( 3 ) receptor ( P35462 ) have indicated its potential role in antipsychotic drug action . ___MASK31___ , an effective first - line atypical antipsychotic agent , exhibits a relatively high affinity for this receptor . Recent studies have reported an association of the Ser9Gly polymorphism in the P35462 gene with therapeutic response to risperidone , but the results were inconsistent . We therefore postulated that the Ser9Gly polymorphism might be in linkage disequilibrium with an undetected variant that exerts a direct influence on risperidone efficacy . The present study genotyped eight single nucleotide polymorphisms ( SNPs ) distributed throughout the P35462 gene and examined five of these for association with treatment outcome , following an 8 - week period of risperidone monotherapy in 130 schizophrenic patients from mainland China . Clinical symptoms were assessed before and after the treatment period , using the Brief Psychiatry Rating Scale ( BPRS ) . The confounding effects of non - genetic factors were estimated and the baseline symptom score was included as a covariate for adjustment . Neither was any association observed between the five polymorphisms and improvement in total BPRS scores nor was any combined effect of these variants detected in the haplotype analysis . The current results indicate that genetic variations within the P35462 gene may not contribute significantly to interindividual differences in the therapeutic efficacy of risperidone .",
"A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma . Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis . Consistent heterogeneity in chromosome number was found , and most cell lines showed a near - triploid chromosome complement . Several cell lines showed deletions of the P04637 ( alias p53 ) , CDKN2A ( alias p16 ) , and P40337 genes . Multiplex fluorescence in situ hybridization ( M - Q5TCZ1 ) analysis revealed chromosome 3 translocated to several other partners chromosomes , as well as breakage events commonly affecting chromosomes 1 , 5 , 8 , 10 , and 17 . The most common abnormality detected with comparative genomic hybridization ( CGH ) was deletions of chromosome 3p , with loss of the Q9NS23 , P49789 , and p44S10 loci frequently involved . CGH gain of 5q showed overrepresentation of the P18146 and P07333 genes . Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the P00533 , O15164 , and P35250 genes . Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of P11802 and SAS loci . M - Q5TCZ1 revealed several other recurrent translocations , and CGH findings included loss of 9p , 14q , and 18q and gain of 8q , 12 , and 20 . Further genomic microarray changes included loss of Q13126 , IGH @ , P28222 , and Q13485 ( previously Q13485 ) and gains of MYC and P11387 . An excellent correlation was observed between the genomic array and Q5TCZ1 data , demonstrating that this technique is effective and accurate . The aberrations detected here may reflect important pathways in renal cancer pathogenesis .",
"Promyelocytic leukemia nuclear bodies support a late step in DNA double - strand break repair by homologous recombination . The P29590 protein and P29590 nuclear bodies ( P29590 - NB ) are implicated in multiple cellular functions relevant to tumor suppression , including DNA damage response . In most cases of acute promyelocytic leukemia , the P29590 and retinoic acid receptor alpha ( P10276 ) genes are translocated , resulting in expression of oncogenic P29590 - RARα fusion proteins . P29590 - NB fail to form normally , and promyelocytes remain in an undifferentiated , abnormally proliferative state . We examined the involvement of P29590 protein and P29590 - NB in homologous recombinational repair ( HRR ) of chromosomal DNA double - strand breaks . Transient overexpression of wild - type P29590 protein isoforms produced hugely enlarged or aggregated P29590 - NB and reduced HRR by ~ 2 - fold , suggesting that HRR depends to some extent upon normal P29590 - NB structure . Knockdown of P29590 by RNA interference sharply attenuated formation of P29590 - NB and reduced HRR by up to 20 - fold . However , P29590 - knockdown cells showed apparently normal induction of P16104 phosphorylation and Q06609 foci after DNA damage by ionizing radiation . These findings indicate that early steps in HRR , including recognition of DNA double - strand breaks , initial processing of ends , and assembly of single - stranded DNA / Q06609 nucleoprotein filaments , do not depend upon P29590 - NB . The HRR deficit in P29590 - depleted cells thus reflects inhibition of later steps in the repair pathway . Expression of P29590 - RARα fusion proteins disrupted P29590 - NB structure and reduced HRR by up to 10 - fold , raising the possibility that defective HRR and resulting genomic instability may figure in the pathogenesis , progression and relapse of acute promyelocytic leukemia .",
"DNA methylation - related vitamin D receptor insensitivity in breast cancer . Calcitriol ( 1α , 25 ( OH )( 2 )- DB00169 ) binds to the vitamin D receptor ( P11473 ) and regulates differentiation of the normal mammary gland , and may therefore be useful in breast cancer treatment or prevention . Many breast cancer cells are , however , resistant to Calcitriol . In this study , we investigated the resistance mechanism and the role of epigenetic silencing of P11473 by promoter hypermethylation . Bisulfite sequencing of the P11473 promoter region revealed methylated CpG islands at - 700 base pairs ( bp ) upstream and near the transcription start site . P11473 CpG islands were demethylated by 5 ' deoxy - azacytidine treatment , and this was accompanied by a parallel increase in P11473 mRNA levels in breast cancer cell lines . Quantitative methylation - specific PCR analyses confirmed hypermethylation of these CpG islands in primary tumors , and its absence in normal breast tissue . P11473 transcripts detected in breast cancers were predominantly 5 '- truncated , while normal breast tissue expressed full - length transcripts . Consistent with this observation , genes containing the P11473 - responsive element ( VDRE ) , such as cytochrome p450 hydroxylases , P38936 or C / EBP were underexpressed in breast cancers compared to normal breast samples . Expression of the active longer transcripts of P11473 was restored with 5 ' deoxy - DB00928 ( AZA ) treatment , with a concurrent increase in expression of VDRE - containing genes . Thus , promoter methylation - mediated silencing of expression of the functional variants of P11473 may contribute to reduced expression of downstream effectors of the P11473 pathway and subsequent Calcitriol insensitivity in breast cancer . These data suggest that pharmacological reversal of P11473 methylation may re - establish breast cancer cell susceptibility to differentiation therapy using Calcitriol .",
"DB00169 derivatives with adamantane or lactone ring side chains are cell type - selective vitamin D receptor modulators . The vitamin D receptor ( P11473 ) mediates the biological actions of 1 , 25 - dihydroxyvitamin D ( 3 ) [ 1 , 25 ( OH )( 2 ) D ( 3 ) ] , the active form of vitamin D , which regulates calcium homeostasis , immunity , cellular differentiation , and other physiological processes . We investigated the effects of three 1 , 25 ( OH )( 2 ) D ( 3 ) derivatives on P11473 function . AD47 has an adamantane ring and LAC67a and LAC67b have lactone ring substituents at the side chain position . These vitamin D derivatives bind to P11473 but do not stabilize an active cofactor conformation . In a P11473 transfection assay , AD47 and LAC67b act as partial agonists and all three compounds inhibit P11473 activation by 1 , 25 ( OH )( 2 ) D ( 3 ) . The derivatives enhanced the heterodimerization of P11473 with the retinoid X receptor , an effect unrelated to agonist / antagonist activity . AD47 and LAC67b weakly induced recruitment of the Q15788 cofactor to P11473 , and all three derivatives inhibited the recruitment of P52701 family cofactors to P11473 induced by 1 , 25 ( OH )( 2 ) D ( 3 ) . It is noteworthy that AD47 induced Q15648 recruitment as effectively as 1 , 25 ( OH )( 2 ) D ( 3 ) , whereas LAC67a and LAC67b were not effective . We examined the expression of endogenous P11473 target genes and the nuclear protein levels of P11473 and cofactors in several cell lines , including cells derived from intestine , bone , and monocytes , and found that the vitamin D ( 3 ) derivatives act as cell type - selective P11473 modulators . The data indicate that side chain modification is useful in the development of P11473 antagonists and tissue - selective modulators . Further elucidation of the molecular mechanisms of action of selective P11473 modulators will be essential for their clinical application .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK31___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"Enhancement of the P11362 signaling in the P11362 - P08908 heteroreceptor complex in midbrain raphe 5 - HT neuron systems . Relevance for neuroplasticity and depression . New findings show existence of P11362 - P08908 heteroreceptor complexes in 5 - HT nerve cells of the dorsal and median raphe nuclei of the rat midbrain and hippocampus . Synergistic receptor - receptor interactions in these receptor complexes indicated their enhancing role in hippocampal plasticity . The existence of P11362 - P08908 heteroreceptor complexes also in midbrain raphe 5 - HT nerve cells open up the possibility that antidepressant drugs by increasing extracellular 5 - HT levels can cause an activation of the P09038 / P11362 mechanism in these nerve cells as well . Therefore , the agonist modulation of the P11362 - P08908 heteroreceptor complexes and their specific role is now determined in rat medullary raphe RN33B cells and in the caudal midline raphe area of the midbrain rich in 5 - HT nerve cells . The combined i . c . v . treatment with P09038 and the P08908 agonist 8 - OHDPAT synergistically increased P11362 and P27361 / 2 phosphorylation in the raphe midline area of the midbrain and in the RN33B cells . Cotreatment with P09038 and the P08908 agonist induced RN33B cell differentiation as seen from development of an increased number and length of extensions per cell and their increased 5 - HT immunoreactivity . These signaling and differentiation events were dependent on the receptor interface since they were blocked by incubation with TMV but not by TMII of the P08908 receptor . Taken together , the P08908 autoreceptors by being part of a P11362 - P08908 heteroreceptor complex in the midbrain raphe 5 - HT nerve cells appears to have also a trophic role in the central 5 - HT neuron systems besides playing a key role in reducing the firing of these neurons .",
"Selective targeting of the repressive transcription factors P25490 and cMyc to disrupt quiescent human immunodeficiency viruses . Quiescent HIV - 1 infection of resting P01730 (+) T cells is an obstacle to eradication of HIV - 1 infection . These reservoirs are maintained , in part , by repressive complexes that bind to the HIV - 1 long terminal repeat ( LTR ) and recruit histone deacetylases ( HDACs ). cMyc and P25490 are two transcription factors that are recruited as part of well - described , distinct complexes to the HIV - 1 LTR and in turn recruit HDACs . In prior studies , depletion of single factors that recruit Q13547 in various cell lines was sufficient to upregulate LTR activity . We used short hairpin RNAs ( shRNAs ) to test the effect of targeted disruption of a single transcription factor on quiescent proviruses in T cell lines . In this study , we found that depletion of P25490 significantly increases mRNA and protein expression from the HIV - 1 promoter in some contexts , but does not affect Q13547 , Q92769 , O15379 , or acetylated histone 3 occupancy of the HIV - 1 LTR . Conversely , depletion of cMyc or cMyc and P25490 does not significantly alter the level of transcription from the LTR or affect recruitment of HDACs to the HIV - 1 LTR . Furthermore , global inhibition of HDACs with the HDAC inhibitor suberoylanilide hydroxamic acid ( ___MASK29___ ) enhanced the increase in LTR transcription in cells that were depleted of P25490 . These findings show that despite prior isolated findings , redundancy in repressors of HIV - 1 LTR expression will require selective targeting of multiple restrictive mechanisms to comprehensively induce the escape of quiescent proviruses from latency .",
"Clonal differences in expression of 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase , of 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase , and of the vitamin D receptor in human colon carcinoma cells : effects of epidermal growth factor and 1alpha , 25 - dihydroxyvitamin D ( 3 ) . Human colon carcinoma cells express 25 - hydroxyvitamin D ( 3 )- 1alpha - hydroxylase ( O15528 ) and thus produce the vitamin D receptor ( P11473 ) ligand 1alpha , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 - D3 ) , which can be metabolized by 25 - hydroxyvitamin D ( 3 )- 24 - hydroxylase ( Q07973 ) . Expression of P11473 , O15528 , and Q07973 determines the efficacy of the antimitotic action of 1 , 25 - D3 and is distinctly related to the degree of differentiation of cancerous lesions . In the present study we addressed the question of whether the effects of epidermal growth factor ( P01133 ) and of 1 , 25 - D3 on P11473 , O15528 , and Q07973 gene expression in human colon carcinoma cell lines also depend on the degree of cellular differentiation . We were able to show that slowly dividing , highly differentiated Caco - 2 / 15 cells responded in a dose - dependent manner to both P01133 and 1 , 25 - D3 by up - regulation of P11473 and O15528 expression , whereas in highly proliferative , less differentiated cell lines , such as Caco - 2 / AQ and COGA - 1A and - 1E , negative regulation was observed . Q07973 mRNA was inducible in all clones by 1 , 25 - D3 but not by P01133 . From the observed clonal differences in the regulatory effects of P01133 and 1 , 25 - D3 on P11473 and O15528 gene expression we suggest that P11473 - mediated growth inhibition by 1 , 25 - D3 would be efficient only in highly differentiated carcinomas even when under mitogenic stimulation by P01133 .",
"Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc - dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan - HDAC inhibitor ___MASK29___ ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil - tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down - regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and ___MASK29___ . Tubacin in combination with ___MASK29___ or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan - caspase inhibitor Z - VAD - fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 , an early marker of DNA double - strand breaks . Tubacin enhances DNA damage induced by etoposide or ___MASK29___ as indicated by increased accumulation of γ P16104 and activation of the checkpoint kinase Chk2 . Tubacin induces the expression of P35638 ( P35638 / P35638 ) , a transcription factor up - regulated in response to cellular stress . P35638 induction is further increased when tubacin is combined with ___MASK29___ . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti - cancer agents in transformed cells .",
"Effects of angico extract ( Anadenanthera colubrina var . cebil ) in cutaneous wound healing in rats . PURPOSE : To study the effects of the angico extract ( Anadenanthera colubrina var . cebil ) on the healing of rat skin . METHODS : Twenty adult rats were divided into four groups of five animals each , the G4 , G7 , G14 and Q96NT5 , which corresponds to the respective postoperative days . Each group received two incisions on skin and subcutaneous tissue in the right and left antimere of the thoracic region , separated by a distance of 2 cm . The right lesion was treated daily with saline and the left with the angico alcoholic extract ( 5 % ) . At the end of each experimental period , animals were euthanized and fragments of the wound area , together with the edges were removed , fixed in 10 % formaldehyde solution and processed for paraffin embedding . In the histological sections with 5 µm of thickness , were carried out immunohistochemical methods for detection of blood vessels ( P15692 ) and stained with hematoxylin and eosin for morphological analysis . Statistical analysis was done by Q9UNW9 and Tukey test ( p < 0 . 05 ) . RESULTS : Morphological analysis showed larger fibroblasts and a higher concentration of collagen fibers in days 7 and 14 in wounds treated with the angico extract . Morphometric analysis demonstrated a significant increase in the number of blood vessels in both the seventh and 14th days ( p < 0 . 01 ) in wounds treated with the angico extract . CONCLUSION : The angico alcoholic extract ( Anadenanthera colubrina var . cebil ) induces the acceleration of wound healing in skin wounds of rats .",
"DB00169 down - regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen - associated molecular patterns . Toll - like receptors ( TLR ) represent an ancient front - line defence system that enables the host organism to sense the presence of microbial components within minutes . As inducers of inflammation , TLR act as important triggers of distinct entities such as sepsis or autoimmune disease exacerbation . We report here that vitamin D3 [ 1alpha , 25 - dihydroxycholecalciferol , 1 , 25 ( OH )( 2 ) D3 ] suppresses the expression of O60603 and O00206 protein and mRNA in human monocytes in a time - and dose - dependent fashion . Despite 1 , 25 ( OH )( 2 ) D3 - induced up - regulation of P08571 , challenge of human monocytes with either LPS or lipoteichoic acid resulted in impaired P01375 and procoagulatory tissue factor ( CD142 ) production , emphasizing the critical role of TLR in the induction of inflammation . Moreover , reduced TLR levels in 1 , 25 ( OH )( 2 ) D3 - treated phagocytes were accompanied by impaired NF - kappaB / RelA translocation to the nucleus and by reduced p38 and Q8NFH3 / 44 ( extracellular signal - regulated kinase 1 / 2 ) phosphorylation upon TLR - ligand engagement . Both TLR down - regulation and P08571 up - regulation were substantially inhibited by the vitamin D receptor ( P11473 ) antagonist ZK 159222 , indicating that the immunomodulatory effect of 1 , 25 ( OH )( 2 ) D3 on innate immunity receptors requires P11473 transcription factor activation . Our data provide strong evidence that 1 , 25 ( OH )( 2 ) D3 primes monocytes to respond less effectively to bacterial cell wall components in a P11473 - dependent mechanism , most likely due to decreased levels of O60603 and O00206 .",
"Dysregulation of vitamin D3 synthesis leads to enhanced cholangiocarcinoma growth . BACKGROUND : Cholangiocarcinoma is a deadly biliary tumour with limited treatment strategies . Vitamin ( 1 , 25 ( OH ) 2D ) has anti - proliferative effects on several cancers . DB00169 is synthesized by the enzyme , O15528 , and signals via the nuclear vitamin D3 receptor . The enzyme , Q07973 , degrades vitamin D3 . AIMS : ( i ) Measure the expression of O15528 , Q07973 , and vitamin D3 receptor in human nonmalignant and cholangiocarcinoma lines and biopsy control or tumour samples ; and ( ii ) evaluate the effects of vitamin D3 on vitamin D3 synthesis and cholangiocarcinoma growth . METHODS : In vitro studies were performed in malignant and nonmalignant cholangiocytes . P11473 , Q07973 and Q02318 expression was measured in cell lines and biopsy samples . Cell lines were stimulated with vehicle or vitamin D3 from 30min to 48h . Cell viability was assessed by MTS assays and BrdU incorporation . P11473 , Q07973 and O15528 expression was measured in cholangiocarcinoma cells stimulated with vehicle or vitamin D3 . RESULTS : In cholangiocarcinoma lines and biopsy samples , vitamin D3 receptor and Q07973 expression increased compared to controls , whereas O15528 expression was decreased or unchanged . DB00169 induced nuclear translocation of vitamin D3 receptor in cholangiocarcinoma and decreased cholangiocarcinoma growth . CONCLUSION : Treatment with vitamin D3 decreased Q07973 , whereas O15528 expression increased . Modulation of vitamin D3 synthesis may be important in the management of cholangiocarcinoma .",
"Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization ."
] |
[
"___MASK100___",
"___MASK12___",
"___MASK29___",
"___MASK31___",
"___MASK32___",
"___MASK3___",
"___MASK52___",
"___MASK78___"
] |
___MASK3___
|
MH_train_432
|
interacts_with DB00051?
|
[
"Inhibitors of DB00171 - binding cassette transporters suppress interleukin - 12 p40 production and major histocompatibility complex II up - regulation in macrophages . DB00171 - binding cassette ( DB01048 ) transporters are a large family of proteins whose role is to translocate various substances across biological membranes . They include the Tangier disease protein ABC1 , sulfonylurea receptors ( Q09428 ) , multidrug resistance protein ( MDR ) , and cystic fibrosis transmembrane regulator ( P13569 ) . In the current study , we investigated the involvement of ABC transporters in the regulation of lipopolysaccharide ( LPS ) and / or interferon ( IFN ) - gamma - induced interleukin ( IL ) - 12 p40 and tumor necrosis factor ( P01375 ) - alpha production , nitric oxide formation , as well as major histocompatibility complex II up - regulation in macrophages . The general ABC transporter inhibitor glibenclamide suppressed both IL - 12 p40 and nitric oxide production . However , glibenclamide failed to affect the production of P01375 . The selective ABC1 inhibitors 4 , 4 '- diisothiocyanostilbene - 2 , 2 '- disulfonic acid and sulfobromophthalein mimicked the suppressive effect of glibenclamide on IL - 12 p40 production . On the other hand , both the MDR inhibitor verapamil and P13569 blocker 2 , 2 '- iminodibenzoic acid failed to suppress the production of IL - 12 p40 . Furthermore , selective inhibitors and activators of SURs were without effect . In agreement with the pharmacological data , macrophages expressed mRNA for ABC1 , but not SURs or P13569 . Intracellular levels of IL - 12 p40 were decreased by glibenclamide , suggesting that glibenclamide does not affect IL - 12 p40 secretion . The effect of glibenclamide did not involve an interference with the activation of the p38 and Q8NFH3 / 44 mitogen - activated protein kinases or c - Jun kinase . ___MASK36___ also suppressed P01579 - induced up - regulation of major histocompatibility complex II . Taken together , our results indicate that ABC proteins regulate LPS and / or P01579 - induced macrophage activation .",
"P01375 inhibitors to treat ulcerative colitis in a metastatic breast cancer patient : a case report and literature review . DB00051 ( P00813 ) is a tumor necrosis factor ( P01375 ) inhibitor , used for the treatment of inflammatory bowel disease . Previous studies have reported an increased risk of cancer following exposure to P01375 inhibitors , but little has been reported for patients with cancer receiving P01375 - inhibitor treatment . We present a female patient with metastatic breast cancer and ulcerative colitis ( UC ) who was treated with P00813 . A 54 - year - old African American female with a past history of left - sided breast cancer ( BC ) diagnosed at age 30 was initially treated with left - breast lumpectomy , axillary dissection , followed by chemotherapy and radiation therapy . Years after initial diagnosis , she developed recurrent , bilateral BC and had bilateral mastectomy . Subsequent restaging computed tomography ( CT ) scan demonstrated distant metastases to the bone and lymph nodes . Three years into her treatment of metastatic breast cancer , she was diagnosed with UC by colonoscopy . Her UC was not controlled for 5 mo with 5 - aminosalicylates . Subcutaneous P00813 was started and resulted in dramatic improvement of UC . Four months after starting P00813 , along with ongoing chemotherapy , restaging CT scan showed resolution of the previously seen metastatic lymph nodes . Bone scan and follow - up positron emission tomography / CT scans performed every 6 mo indicated the stability of healed metastatic bone lesions for the past 3 years on P00813 . While P01375 - α inhibitors could theoretically promote further metastases in patients with prior cancer , this is the first report of a patient with metastatic breast cancer in whom the cancer has remained stable for 3 years after P00813 initiation for UC .",
"Influence of anti - tumor necrosis factor therapy ( DB00051 ) on regulatory T cells and dendritic cells in rheumatoid arthritis . OBJECTIVE : To investigate whether anti - P01375 therapy could have an effect on dendritic cells ( DCs ) and regulatory T cells in rheumatoid arthritis ( RA ) patients . METHODS : A four - colour flow cytometric technique was used to measure P01730 + CD25 + T cells i . e . P01730 + CD25high + ( regulatory T cells ) and P01730 + CD25low + ( activated T cells ) ) , DCs as well as the in vitro , intracellular , lipopolysaccharide - stimulated cytokine production of DCs . RESULTS : Clinical and laboratory parameters of disease activity decreased after anti - P01375 treatment . Before anti - P01375 therapy , RA patients demonstrated a decreased count of Th2 - promoting lymphoid DCs as compared to controls and after anti - P01375 therapy this decrease was sustained . Intracellular cytokine production was only found in the myeloid DCs population and there was a higher production of P01375 and IL1 - b as compared to healthy controls . Treatment did not alter this cytokine production . Before anti - P01375 therapy , the percentage P01730 + CD25 + T cells was significantly elevated in RA patients than in healthy controls . CONCLUSION : These results demonstrate anti - P01375 to be a potent anti - inflammatory drug , as mirrored by the decrease in clinical and biological parameters as well as the decrease in activated P01730 + T cells . However , in this study no demonstrable effect on DCs and regulatory T cells was found .",
"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .",
"Severe Guillain - Barré syndrome in a patient receiving anti - P01375 therapy . Consequence or coincidence . A case - based review . The adverse effects of anti - tumour necrosis factor alpha ( TNFα ) drugs include an increase in the risk of infections , congestive heart failure , lupus - like syndrome , and the onset or worsening of various demyelinating diseases such as , multiple sclerosis , optic neuritis , and Guillain - Barrè syndrome ( GBS ) , among others . We describe the case of a patient who developed GBS while she was on treatment with adalimumab . A 50 - year - old woman with rheumatoid arthritis ( RA ) was admitted to the hospital due to progressive severe bilateral symmetric weakness of the legs , which quickly extended to the upper limbs and to the respiratory muscles . DB00051 was started 13 months before . GBS was diagnosed and the anti - TNFα therapy discontinued . The serological test for Campylobacter jejuni was positive . She required invasive mechanical ventilatory support for 9 months . Twelve months later , the patient was using a wheelchair following a rehabilitation programme , and at 24 months she was walking a few steps with assistive devices . The relevant literature on the relationship between GBS and anti - TNFα is reviewed . Twenty three cases of GBS occurring during anti - TNFα therapy have been reported so far in the literature . In several cases , there was no clear temporal association , more than half had a possible previous infection , and in two cases the drug was reintroduced without recurrence of GBS . Our case , which is best explained by C . jejuni infection , as well as some of the cases described are probably not a direct result of anti - TNFα treatment , but an accidental coincidence . We also discuss the potential therapeutic options after anti - TNFα discontinuation .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK94___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"DB00051 for the treatment of Crohn ' s disease . The advent of biologic therapy for Crohn ' s disease has revolutionized our approach to disease management and redefined our goals . DB00065 ( Remicade ) , an intravenously delivered murine - chimeric monoclonal antibody against P01375 was released in 1998 and shown to have significant benefits in patients with refractory luminal and fistulizing Crohn ' s disease . Since then other anti - P01375 strategies have undergone investigation with variable results . DB00051 ( Humira ) , a self administered , subcutaneous , fully human monoclonal antibody against P01375 represents the next generation of therapy . It has demonstrated efficacy for induction and maintenance of remission in patients with moderate - to - severe Crohn ' s in three large double - blind , placebo - controlled , randomized trials . In addition it has demonstrated steroid - sparing properties and the ability to reduce hospitalizations and improve quality of life . It is anticipated , given its clinical efficacy , its fully human nature , and the convenience of self administration that it will have a significant effect on the management of Crohn ' s disease .",
"Altered gene expression by low - dose arsenic exposure in humans and cultured cardiomyocytes : assessment by real - time PCR arrays . Chronic arsenic exposure results in higher risk of skin , lung , and bladder cancer , as well as cardiovascular disease and diabetes . The purpose of this study was to investigate the effects on expression of selected genes in the blood lymphocytes from 159 people exposed chronically to arsenic in their drinking water using a novel RT - PCR TaqMan low - density array ( TLDA ) . We found that expression of tumor necrosis factor - α ( P01375 - α ) , which activates both inflammation and NF - κB - dependent survival pathways , was strongly associated with water and urinary arsenic levels . Expression of P22460 , which encodes a potassium ion channel protein , was positively associated with water and toe nail arsenic levels . Expression of 2 and 11 genes were positively associated with nail and urinary arsenic , respectively . Because arsenic exposure has been reported to be associated with long QT intervals and vascular disease in humans , we also used this TLDA for analysis of gene expression in human cardiomyocytes exposed to arsenic in vitro . Expression of the ion - channel genes CACNA1 , Q12809 , P51787 and P15382 were down - regulated by 1 - μM arsenic . Alteration of some common pathways , including those involved in oxidative stress , inflammatory signaling , and ion - channel function , may underlay the seemingly disparate array of arsenic - associated diseases , such as cancer , cardiovascular disease , and diabetes .",
"P01375 and its inhibitors in cancer . P01375 ( P01375 ) - alpha is implicated in the same time in apoptosis and in cell proliferation . P01375 not only acts as pro - inflammatory cytokine conducing to wide spectrum of human diseases including inflammatory diseases , but can also induce tumor development . The molecular mechanisms of P01375 functions have been intensively investigated . In this review we covered P01375 , the molecule , its signaling pathway , and its therapeutic functions . We provide a particular insight in its paradoxical role in tumor promotion and in its use as anti - tumor agent . This review considers also the recent findings regarding P01375 inhibitors , their pharmacokinetics , and their pharmacodynamics . Six P01375 inhibitors have been considered here : DB00065 , DB00051 , Golimumab , DB08904 , CDP571 , DB00005 , and Thalidomide . We discussed the clinical relevance of their functions in treatment of several diseases such as advanced inflammatory rheumatic and bowel disease , with a focus in cancer treatment . Targeting P01375 by these drugs has many side effects like malignancies development , and the long - term sequels are not very well explored . Their efficacy and their safety were discussed , underscoring the necessity of close patients monitoring and of their caution use .",
"DB00051 - induced lupus erythematosus with central nervous system involvement in a patient with Crohn ' s disease . The anti - tumor necrosis factor ( P01375 ) agents are drugs that in recent years turned out to be a mainstay of therapy for the treatment of inflammatory bowel disease . Nevertheless , they have several adverse effects such as infectious complications and immunogenicity . One of the most common immunogenic effects is the development of autoantibodies , mainly anti - nuclear antibodies and anti - double - stranded DNA antibodies , only rarely associated with overt clinical manifestations of systemic lupus erythematosus . DB00051 is a fully humanized monoclonal antibody widely used for the treatment of Crohn ' s disease and supposed to have less immunogenic activity and a safer profile than other anti - P01375 agents . The occurrence of systemic lupus erythematosus with involvement of the central nervous system appears to be a very rare complication of such drugs , and no cases have been reported in the medical literature in patients treated with adalimumab . We report a case of a 53 years - old woman with ileo - colic Crohn ' s disease where the treatment with adalimumab was complicated by systemic lupus erythematosus with central nervous system vasculitis .",
"DB00051 ( Humira ™ ) : a promising monoclonal anti - tumor necrosis factor alpha in ophthalmology . P01375 alpha ( P01375 - α ) is a key soluble mediator involved in the inflammatory cascade of many disorders including uveitis . Among the anti - P01375 - α agents , one of the most used in immune - mediated diseases , such as inflammatory arthropathies , is adalimumab ( Humira ™ , Abbott Pharmaceutical Inc . ) , a fully humanized antibody . The purpose of this review is to analyze the main pharmacological and clinical aspects of adalimumab and its efficacy both in systemic and ocular inflammatory disorders . DB00051 was effective in treating several autoimmune diseases , such as rheumatoid arthritis , ankylosing spondylitis , and psoriatic arthritis . In recent years , adalimumab has been used successfully in refractory cases of intraocular inflammation . Moreover , this biological agent showed good safety and efficacy profiles in ocular use including childhood uveitis . Switching from other anti - P01375 - α agents to adalimumab may offer several advantages , such as easier administration , better patient compliance , and lower rate of adverse events . DB00051 is a promising drug for the therapy of uveitis , although further studies are needed on its application in uveitis .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK5___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"Upregulation of cell - surface - associated plasminogen activation in cultured keratinocytes by interleukin - 1 beta and tumor necrosis factor - alpha . Keratinocytes synthesize and secrete urokinase - type plasminogen activator ( uPA ) which is bound in an autocrine manner to a specific receptor ( uPA - R ) at the keratinocyte surface . P00747 that is also bound to specific membrane binding sites is readily activated by uPA - R - bound uPA . Thus , plasmin is provided for proteolysis of pericellular glycoproteins . The expression of uPA and the uPA - R is confined to migrating keratinocytes during epidermal wound healing , rather than to keratinocytes of the normal epidermis . The regulatory factors of uPA / uPA - R expression in keratinocytes remained largely elusive . Proinflammatory cytokines , such as tumor necrosis factor - alpha ( P01375 ) or interleukin - 1 beta ( P01584 ) , are present in epidermal wounds . We have therefore tested P01584 and P01375 for their influence on surface - associated plasminogen activation in a human keratinocyte cell line ( HaCaT ) as well as in primary cultures of normal human epidermal keratinocytes . Both cytokines induced the secretion of uPA into the culture supernatants and a concomitant increase in uPA activity as well as in uPA and uPA - R antigen at the cell surface . The increase was preceded by an increase in specific mRNA . The induction was accompanied by an accelerated uPA - dependent and plasmin - mediated detachment of HaCaT cells from the culture substratum . Taken together , the proinflammatory cytokines P01584 and P01375 induced a coordinated increase in uPA and uPA - R as well as increased pericellular plasmin - mediated proteolysis in human epidermal keratinocytes . This function might be an element of the molecular cell biological events during epidermal wound healing .",
"The efficacy and safety of a third anti - P01375 monoclonal antibody in Crohn ' s disease after failure of two other anti - P01375 antibodies . BACKGROUND : DB00051 ( P00813 ) and certolizumab pegol ( CZP ) have demonstrated efficacy in Crohn ' s disease ( CD ) patients previously treated with infliximab ( IFX ) . AIM : To assess the efficacy and tolerability of a third anti - P01375 in CD after failure of and / or intolerance to two different anti - P01375 antibodies . METHODS : Crohn ' s disease patients who received P00813 or CZP after loss of response and / or intolerance to two anti - P01375 agent were included in this retrospective study . Data were collected using a standardized questionnaire . Clinical response , duration , safety and reasons for discontinuation were assessed . RESULTS : Sixty - seven patients treated with CZP ( n = 40 ) or P00813 ( n = 27 ) were included . A clinical response was observed in 41 ( 61 % ) at week 6 and 34 patients ( 51 % ) at week 20 . The probability of remaining under treatment at 3 months , 6 months and 9 months was 68 % , 60 % and 45 % , respectively . At the end of follow - up , the third anti - P01375 had been stopped in 36 patients for intolerance ( n = 13 ) , or failure ( n = 23 ) . Two deaths were observed . CONCLUSIONS : The treatment with a third anti - P01375 ( CZP or P00813 ) agent of CD patients , who have experienced loss of response and / or intolerance to two anti - P01375 antibodies , has favourable short - term and long - term efficacy . It is an option to be considered in patients with no other therapeutic options .",
"[ Biologics in the early treatment of ankylosing spondylitis and related forms of spondyloarthritis ] . New pathogenetic insights have identified the key role of P01375 in inflammatory rheumatic diseases and have revolutionized the therapy of spondyloarthritides . P01375 - antagonists specifically inhibit the pro - inflammatory effects of P01375 . Clinical studies with infliximab ( Remicade ) , DB00005 ( Enbrel ) or DB00051 ( Humira ) in ankylosing spondylitis or related diseases demonstrate superior efficacy to conventional drugs like non - steroidal antirheumatic drugs or traditional disease modifying antirheumatic drugs .",
"Efficacy of adalimumab for pediatric Vogt - Koyanagi - Harada syndrome . Pediatric Vogt - Koyanagi - Harada syndrome ( VKH ) is rare , with limited cases of corticosteroid - sparing immunosuppression use reported . A 15 - year - old Hispanic girl was referred for bilateral intraocular inflammation . Her initial best corrected visual acuity ( BCVA ) was 20 / 30 in the right eye and 20 / 200 in the left eye , with granulomatous keratic precipitates , anterior chamber and vitreous cell , optic disc edema , and nummular depigmented chorioretinal lesions on examination consistent with VKH after an unrevealing work - up . Inflammation was recurrent despite oral prednisone and methotrexate . DB00051 , a P01375 inhibitor , led to rapid resolution of inflammation , successful dose reduction of prednisone and methotrexate , and final BCVA of 20 / 25 in the right eye and 20 / 40 in the left at 26 - month follow - up .",
"The therapeutic potential of P01375 antagonists for skin psoriasis comorbidities . IMPORTANCE OF THE FIELD : Alopecia , psoriatic arthritis , the metabolic syndrome , inflammatory bowel diseases and cardiovascular diseases may occur as skin psoriatic comorbidities . P01375 antagonists are used to treat psoriasis . DB00051 is one of the recognized active agents for this indication . AREAS COVERED IN THIS REVIEW : The current peer - reviewed publications and presentation of original findings . WHAT THE READER WILL GAIN : DB00051 is active on recalcitrant psoriasis and some of its comorbidities , particularly arthropathies and Crohn ' s disease . However , the progression of the radiological alterations is limited with regression of the bony erosions . Psoriatic enthesopathy also regresses . Mortality associated with psoriasis arthropathy is on the decline . Crohn ' s disease , the most frequent inflammatory bowel comorbidity of psoriasis , is responsive to adalimumab . The effect of adalimumab on the metabolic syndrome and cardiovascular involvement is more erratic . The spectacular effects of adalimumab may be associated with some adverse effects . In particular , despite a marked reduction in the psoriasis area - and - severity index ( PASI ) score some new acute lesions of cutaneous psoriasis may develop corresponding to paradoxical psoriasis . Other potential adverse effects include infections , granulomas , rapid growth of cancers and occurrence of lymphomas . TAKE HOME MESSAGE : DB00051 frequently controls moderate - to - severe forms of cutaneous psoriasis and some of its comorbidities .",
"[ The importance of biologicals in the treatment of SoJIA ] . Systemic onset juvenile idiopathic arthritis ( SoJIA ) remains difficult to treat . In addition to conventional antirheumatic therapy with non - steroidal antirheumatic drugs ( NSARDs ) , steroids or disease - modifying antirheumatic drugs ( DMARDs ) , biologicals offer a new therapeutic approach for this disease in that they are able to target pathogenically relevant cytokines and effector cells . Some biologicals are already approved for use in children with rheumatic disease . In order to assess the currently available data on the use of biologicals in SoJIA , we performed a Medline search for the period 2005 to March 2010 , including the MeSH terms \" SoJIA \" , \" systemic juvenile idiopathic arthritis \" and \" biologicals \" , as well as an NIH study registry search . At Present there are scant and unconvincing data on the use of DB00005 or DB00051 for the treatment of SoJIA . No results are published on the use of DB00065 or other new P01375 inhibitors . The inhibition of IL - 1 or P05231 shows promising results . Data on the efficacy of DB01281 is limited due to very low numbers of SoJIA patients in the studies . Further studies on the use of biologicals in SoJIA while taking individual factors into consideration are required . The long - term safety of all biologicals should be investigated in prospective registers .",
"How rapidly should remission be achieved ? The major goal of therapy in inflammatory bowel disease is to induce remission . Remission has multiple definitions - clinical remission , where the patient ' s symptoms have remitted , and endoscopic remission , in which there has been complete mucosal healing . Mucosal healing is a harder endpoint of remission but may be more difficult to achieve . In clinical trials we are forced to use activity indices such as the Crohn ' s disease activity index that may not completely reflect the endoscopic and histologic state of the bowel . Ideally we would like to see remission as quickly as possible to improve patient quality of life . The time to remission varies between different therapeutic approaches . Steroids tend to have a rapid clinical effect with remission seen in some patients as early as two weeks . In early anti - P01375 trials , a single dose of infliximab lead to 27 % remission at two weeks compared to 4 % of placebo patients . DB00051 and certolizumab have similar reports of early induction of remission . DB00244 in Crohn ' s disease has inconsistent and delayed remission rates , whereas in ulcerative colitis , response and remission rates are more consistent in the three - week time frame . DB00993 and 6 - mercaptopurine have delayed onset of action but may induce remission as early as six weeks if dosing is optimized . In this presentation induction of clinical remission and mucosal healing in Crohn ' s disease and ulcerative colitis will be discussed . The impact of early remission on disease course will also be reviewed .",
"Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing P04626 . In an attempt to treat cancer patients with P04626 overexpressing tumors , we developed a chimeric antigen receptor ( CAR ) based on the widely used humanized monoclonal antibody ( mAb ) ___MASK83___ ( Herceptin ) . An optimized CAR vector containing P10747 , 4 - 1BB , and CD3zeta signaling moieties was assembled in a gamma - retroviral vector and used to transduce autologous peripheral blood lymphocytes ( PBLs ) from a patient with colon cancer metastatic to the lungs and liver , refractory to multiple standard treatments . The gene transfer efficiency into autologous T cells was 79 % CAR (+) in CD3 (+) cells and these cells demonstrated high - specific reactivity in in vitro coculture assays . Following completion of nonmyeloablative conditioning , the patient received 10 ( 10 ) cells intravenously . Within 15 minutes after cell infusion the patient experienced respiratory distress , and displayed a dramatic pulmonary infiltrate on chest X - ray . She was intubated and despite intensive medical intervention the patient died 5 days after treatment . Serum samples after cell infusion showed marked increases in interferon - gamma ( P01579 ) , granulocyte macrophage - colony stimulating factor ( GM - P04141 ) , tumor necrosis factor - alpha ( P01375 ) , interleukin - 6 ( P05231 ) , and P22301 , consistent with a cytokine storm . We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of P04626 on lung epithelial cells .",
"Binding characteristics of tumor necrosis factor receptor - Fc fusion proteins vs anti - tumor necrosis factor mAbs . P01375 ( P01375 ) antagonists are efficacious in the treatment of various autoimmune diseases . Two classes of P01375 antagonists are currently commercially available : soluble P01375 receptor - Fc fusion proteins ( etanercept ) and anti - P01375 mAbs ( adalimumab and infliximab ) . The classes differ in molecular structures and mechanisms of action . The interactions between P01375 antagonists with P01375 molecules were characterized . The anti - P01375 mAbs , but not the soluble P01375 receptor , formed visible lines of precipitation in Ouchterlony assays . The molecular weights of complexes formed by P01375 ( 52 kDa ) with either etanercept ( 130 kDa ) , adalimumab ( 150 kDa ) , or infliximab ( average 165 kDa ) were determined by size exclusion chromatography - light - scattering assays . DB00005 and P01375 formed complexes of 180 and 300 kDa , representing one and two etanercept monomers bound to a P01375 trimer , respectively . DB00051 and infliximab formed a variety of complexes with P01375 with molecular weights as high as 4 , 000 and 14 , 000 kDa , respectively , suggesting the presence of complexes with a wide range of sizes and stoichiometries . The absence of large complex formation with the binding of soluble receptor - fusion proteins to P01375 may account for the different clinical efficacy and safety profiles of the two classes of P01375 antagonists .",
"DB00051 for early rheumatoid arthritis . Rheumatoid arthritis affects 1 % of the population and can result in joint destruction , reduced quality of life and function , loss of work productivity and , in severe cases , early mortality . Recent advances with optimal therapeutic strategies , including early initiation of treatment , tight control of the disease activity aiming for remission of the disease and the advent of biological therapies , have led to improved outcomes for patients with rheumatoid arthritis . It is generally agreed that the best outcomes for patients with rheumatoid arthritis occur when treatment is started early . DB00051 is a new fully humanized monoclonal antibody that blocks the adverse effects of excess P01375 . New studies using this agent early in the course of rheumatoid arthritis indicate superior rates of remission for patients with this disease .",
"Differential effect of DB03932 , pravastatin , and fluvastatin on production of Q14116 and expression of P05362 and P25942 in human monocytes . A novel , proinflammatory cytokine , interleukin ( IL ) - 18 production was detected in the medium of human monocytes treated with 3 - hydroxy - 3 - methylglutaryl coenzyme - A ( HMG - DB01992 ) reductase inhibitors , pravastatin , and fluvastatin ( 0 . 1 and 1 muM ) but not with the statin - derived lymphocyte function - associated antigen - 1 ( LFA - 1 ) inhibitor DB03932 , which did not inhibit P04035 . ___MASK53___ and fluvastatin also induced the production of Q14116 , tumor necrosis factor alpha ( P01375 ) and interferon - gamma ( P01579 ) in human peripheral blood mononuclear cells ( PBMC ) in contrast to DB03932 . Q14116 production by PBMC is located upstream of the cytokine cascade activated by these statins . The Q14116 - induced cytokine production was demonstrated to be dependent on adhesion molecule expression on monocytes . In the absence and presence of lower concentrations ( 0 . 1 and 1 ng / ml ) of Q14116 , pravastatin and fluvastatin inhibited the expression of intercellular adhesion molecule ( ICAM ) - 1 and induced the expression of P25942 , whereas DB03932 had no effect . In the presence of higher concentrations ( 5 , 10 , and 100 ng / ml ) of Q14116 , pravastatin , fluvastatin , and DB03932 similarly inhibited the expression of P05362 and P25942 as well as the production of IL - 12 , P01375 , and P01579 in PBMC . The effects of pravastatin and fluvastatin but not DB03932 were abolished by the addition of mevalonate , indicating the involvement of P04035 in the action of pravastatin and fluvastatin . Thus , the effects of DB03932 were distinct from those of pravastatin and fluvastatin in the presence of lower concentrations of Q14116 . It was concluded that DB03932 has the inhibitory effect on an Q14116 - initiated immune response without any activation on monocytes .",
"Morphea associated with the use of adalimumab : a case report and review of the literature . Therapy with P01375 blockers may induce cutaneous adverse events , but the development of morphea , a localized scleroderma lesion , is extremely infrequent . We describe a 37 - year - old man with ankylosing spondylitis treated with adalimumab who developed morphea lesions in the lower limbs after 12 months of treatment . DB00051 was discontinued , which resulted in progressive improvement in the skin lesions , with only mild hyperpigmentation remaining . We also review reports of morphea and other adverse cutaneous events related to anti - P01375 treatment .",
"P01375 - Alpha Inhibitors for Chronic Urticaria : Experience in 20 Patients . Patients with severe chronic urticaria may not respond to antihistamines , and other systemic treatment options may either be ineffective or associated with unacceptable side effects . We present data on efficacy and safety of adalimumab and etanercept in 20 adult patients with chronic urticaria . Twelve ( 60 % ) patients obtained complete or almost complete resolution of urticaria after onset of therapy with either adalimumab or etanercept . Further three patients ( 15 % ) experienced partial response . Duration of treatment ranged between 2 and 39 months . Those responding completely or almost completely had a durable response with a mean of 11 months . Six patients ( 30 % ) experienced side effects and five patients had mild recurrent upper respiratory infections , whereas one patient experienced severe CNS toxicity that could be related to treatment with P01375 inhibitor . DB00051 and etanercept may be effective and relatively safe treatment options in a significant proportion of patients with chronic urticaria who do not respond sufficiently to high - dose antihistamines or in whom standard immunosuppressive drugs are ineffective or associated with unacceptable side effects .",
"Efficacy and complications of adalimumab treatment for medically - refractory Crohn ' s disease : analysis of nationwide experience in Scotland ( 2004 - 2008 ) . BACKGROUND : DB00051 is a second generation humanized anti - tumour necrosis factor ( P01375 ) monoclonal antibody with established efficacy in Crohn ' s disease ( CD ) . AIMS : To evaluate the efficacy and safety of adalimumab on a nationwide clinical setting . METHODS : We used the Scottish Society of Gastroenterology network to identify and follow up the clinical outcomes of patients with CD treated with adalimumab over a 4 - year period ( 2004 - 2008 ) . RESULTS : A total of 98 patients received adalimumab - 100 . 5 patient follow - up years were recorded ( 64 . 3 % females ; median age at diagnosis of 20 . 7 years ; 88 . 8 % treated with 80 / 40 mg induction regimen . Eighty eight ( 89 . 8 % ) had previous infliximab with 29 ( 32 . 9 % ) primary nonresponders ; 32 ( 32 . 6 % ) were corticosteroid - dependent ; 47 ( 47 . 9 % ) were intolerant / resistant to most immunosuppressive therapies ( two or more ) . In all , 60 % of patients were in clinical remission at 1 - year follow - up , with 30 % and 55 % requiring dose escalation to weekly therapy at 1 - and 2 - year follow - up respectively . Overall , 29 ( 29 . 6 % ) patients developed complications with eight nonfatal serious ( 8 . 2 % ) adverse events and 2 ( 2 . 0 % ) case fatalities ( sepsis following perforation and disseminated colorectal cancer , respectively ) . CONCLUSIONS : DB00051 is efficacious in severe and refractory CD in the clinical setting , although there remain significant therapy - and disease - related risks of serious complications .",
"Aqueous Humor Levels of Different Interleukins 1 - β , 2 , 6 and 10 , Tumor Necrosis Factor - α and Vascular Endothelial Growth Factor in Uveitis Treated with DB00051 . PURPOSE : To assess changes in aqueous humor levels of different interleukins ( IL ) , tumor necrosis factor ( P01375 ) - α and vascular endothelial growth factor ( P15692 ) in patients with uveitis treated with adalimumab . METHODS : In this study , 24 aqueous humor samples including 12 pre - and post - treatment samples from 6 patients with uveitis treated with subcutaneous adalimumab and 12 samples from patients with cataracts ( serving as controls ) were evaluated . The levels of IL - 1β , P60568 , P05231 , P22301 , P01375 - α and P15692 were measured using a Luminex (®) 200 ™ flow cytometer ( Merckmillipore , Merck KGaA , Darmstadt , Alemania ) and a highly sensitive ELISA system . RESULTS : The levels of IL - 1β , P60568 , P05231 and P22301 in the aqueous humor before and after treatment with adalimumab did not show significant differences . Aqueous P15692 levels significantly reduced after treatment with adalimumab ( P = 0 . 028 ) . Aqueous P01375 - α levels did not significantly change after treatment with adalimumab , however the post - treatment level was significantly higher in patients as compared to control subjects ( P = 0 . 032 ) . P60568 showed significantly higher levels in uveitis patients before treatment as compared to controls ( P = 0 . 024 ) , while its post - treatment levels were almost normalized . CONCLUSION : Decrease in the aqueous humor levels of P15692 and P60568 after treatment with systemic adalimumab indicates that anti - P01375 - α therapy induces modifications of some inflammatory mediators involved in the pathogenesis of uveitis . Aqueous humor samples may be useful to assess the effect of adalimumab on intraocular inflammation through measurement of cytokines .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK100___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK100___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK100___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK100___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK100___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"DB00051 : new indication . Severe Crohn ' s disease : a second P01375 alpha antagonist , subcutaneous administration .",
"Transcriptional profiles during the differentiation and maturation of monocyte - derived dendritic cells , analyzed using focused microarrays . Dendritic cells ( DC ) are professional antigen - presenting cells capable of initiating primary immune responses . They have been intensively studied and are used in both basic immunology research and clinical immunotherapy . However , the genetic pathways leading to DC differentiation and maturation remain poorly understood . Using focused microarrays with oligonucletotide probes for 120 genes encoding co - stimulatory molecules , chemokines , chemokine receptors , cytokines , cytokine receptors , TLRs , and several other related molecules , we analyzed the kinetics of gene expression for the overall differentiation process of monocytes into mature DC . In parallel , we compared the transcriptional profiles in DC maturation in the presence of LPS , P01375 or trimeric P29965 . We found similar transcriptional profiles for early immature DC and immature DC , respectively generated by culturing monocytes with GM - P04141 and P05112 for three or six days . We identified sets of common and stimuli - specific genes , the expression of which changed following stimulation with LPS , P01375 or P29965 . A dynamic analysis of the entire DC differentiation and maturation process showed that some important inflammatory and constitutive chemokines are transcribed in both immature and mature DC . The correlative expression kinetics of the gene pairs P14778 / P27930 , P40933 / Q13261 , Q9NNX6 / P13598 and Q9NNX6 / P32942 imply that they all play crucial roles in mediating DC functions . Thus , our analysis with focused microarrays shed light on the transcriptional kinetics of DC differentiation and maturation , and this method may also prove useful for identifying novel marker genes involved in DC functions .",
"P40933 affects serotonin system and exerts antidepressive effects through IL15Rα receptor . Contrary to the reduction of depressive - like behavior observed in several strains of cytokine receptor knockout mice , mice lacking the specific receptor for interleukin ( IL ) - 15 showed increased immobility in tail suspension and modified forced swimming tests . There was also a reduction in social interactions . The hippocampus of the IL15Rα knockout mice had decreased mRNA for 5 - HT ( 1A ) , increased mRNA for 5 - HT ( 2C ) , and region - specific changes of serotonin reuptake transporter ( P31645 ) immunoreactivity . ___MASK43___ ( the classic antidepressant ___MASK43___ , which inhibits 5 - HT ( 2C ) and P31645 ) reduced the immobility of the IL15Rα knockout mice in comparison with their pretreatment baseline . Together with the unchanged performance of the IL15Rα knockout mice on the rotarod , this response to fluoxetine indicates that the immobility reflects depression . Wildtype mice responded to P40933 treatment with improvement of immobility induced by forced swimming , whereas the knockout mice failed to respond . Thus , the cognate P40933 receptor is necessary for the antidepressive activity of P40933 . In ex vivo studies , P40933 decreased synaptosomal uptake of 5 - HT , and modulated the expression of 5 - HT ( 2C ) and P31645 in cultured neurons in a dose - and time - dependent manner . Thus , the effect of P40933 on serotonin transmission may underlie the depressive - like behavior of IL15Rα knockout mice . We speculate that P40933 is essential to maintain neurochemical homeostasis and thereby plays a role in preventing neuropsychiatric symptoms .",
"DB00051 treatment for life threatening pulmonary artery aneurysm in Behçet disease : a case report . Behçet ' s disease ( BD ) is a multisystem disorder characterized by vasculitis . Pulmonary vascular problems such as pulmonary artery aneurysms ( PAA ) are reported to indicate poor prognosis and high mortality . We describe a 43 - year - old man who presented with life threatening bilateral PAA and thromboembolic disease due to BD . He was treated with prednisone and pulse cyclophosphamide and was poorly responsive to the conventional immunosuppression . The introduction of adalimumab therapy stabilized his PAA . We report that the inhibition of P01375 using the neutralizing monoclonal antibody adalimumab has the potential to induce rapid , complete , and long - lasting remission in a life - threatening manifestation of BD .",
"Disease duration did not influence the rates of loss of efficacy of the anti - P01375 therapy in Latin American Crohn ’ s disease patients . BACKGROUND / AIMS : The efficacy of both DB00065 ( IFX ) and DB00051 ( P00813 ) can be reduced over time . The aim of this study was to analyze the incidence of loss of efficacy ( LOE ) of both IFX and P00813 , and outline the influence of disease duration on its occurrence . METHODS : Retrospective , multicenter , observational cohort study , with CD patients treated with anti - P01375 therapy . LOE was defined as the need for steroids , occurrence of major abdominal surgery during treatment , dose increase , interval shortening or switching of the anti - P01375 agent . Patients were allocated in three subgroups based on disease duration ( DD ) : < 24 months , between 24 and 60 months and > 60 months . RESULTS : 175 patients were included in the study ( 117 under IFX and 58 under P00813 therapy ) . LOE occurred in 32 % of patients with DD < 24 months , in 33 . 3 % with DD between 24 and 60 months and in 31 . 3 % of subjects with DD over 60 months ( p = 0 . 975 ) . CONCLUSIONS : Disease duration ( DD ) did not influence LOE rates . These results suggest that in real - world observational practice , patients with early CD might have the same rates of LOE than patients with a disease prolonging for a longer duration .",
"Anterior optic neuropathy associated with adalimumab . PURPOSE : Our purpose was to report a case of anterior optic neuropathy with pupillary edema in a patient treated with the P01375 - antagonist adalimumab . METHODS : We report the case of a 60 - year - old woman with optic neuropathy in 1 eye after 6 months of treatment with adalimumab . RESULTS : The patient developed decreased visual acuity of the left eye . The ocular findings were left optic disc swelling and bleeding at the rim , superior visual field depression in both eyes and left afferent pupillary defect . DB00051 was discontinued and the visual acuity recovered slowly . CONCLUSIONS : Like infliximab , the modern P01375 antagonist adalimumab is associated with optic neuropathy . Ophthalmologists should thus be alert when seeing patients treated with adalimumab .",
"Steroid - induced inflammatory neuropathy in a patient on tumor necrosis factor - α antagonist therapy . We describe a patient on the tumor necrosis factor - α antagonist , adalimumab , for 2 years for rheumatoid arthitis , who developed a rapidly progressive inflammatory neuropathy shortly after starting oral steroids . DB00051 was stopped at onset of neurologic symptoms . Electrophysiology showed demyelination , which persisted at 6 month follow - up , cerebrospinal fluid analysis showed persistent albuminocytologic dissociation , and magnetic resonance studies revealed enlarged and enhancing nerve roots . Treatment with intravenous immunoglobulins resulted in slow , progressive improvement . P01375 - α antagonists have previously been implicated in acquired demyelinating neuropathies . In this patient , we hypothesize that adalimumab may have caused an initially asymptomatic chronic inflammatory demyelinating polyneuropathy , which became symptomatic shortly after initiation of steroid therapy . This case may raise the issue of the safety of steroids in conjunction with antitumor necrosis factor - α therapy in susceptible patients .",
"Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .",
"Update on the management of inflammatory bowel disease : specific role of adalimumab . Anti - tumor necrosis factor alpha ( P01375 - α ) medications are a class of biologics employed in the treatment of patients with inflammatory bowel disease ( Q9UKU7 ) . DB00051 is the first fully human monoclonal immunoglobulin directed against P01375 - α , which binds with high affinity and specificity to membrane and soluble P01375 . DB00051 administered subcutaneously has demonstrated efficacy in the treatment of rheumatoid arthritis , ankylosing spondylitis , psoriatic arthritis , and severe chronic psoriasis . Studies have shown that adalimumab is effective for inducing and maintaining remission of moderate - to - severe active Crohn ' s disease ( CD ) patients at an induction dose of 160 / 80 mg ( week 0 and 2 ) and at a maintenance dose of 40 mg every other week . The efficacy of adalimumab as a second - line therapy has also been documented for patients with loss of response or intolerance to infliximab . DB00051 is also superior to placebo for inducing and maintaining complete perianal fistula closure . It also seems effective for reducing extraintestinal manifestations . The safety profile is similar to that of other anti - P01375 therapy in CD patients , with lower immunogenicity and rate of adverse injection reactions than infliximab . DB00051 is not approved for the treatment of ulcerative colitis ( UC ) . Recently , however , the results of the first randomized , controlled trial on adalimumab for UC showed that adalimumab at 160 / 80 mg induction dose was safe and effective for inducing remission and clinical response after 8 weeks in patients with moderately - to - severely active UC failing treatment with corticosteroids and / or immunosuppressants . More data are necessary to clarify the therapeutic role of adalimumab in UC . This review of the literature summarizes available data on the efficacy and safety profile adalimumab in patients with Q9UKU7 .",
"Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .",
"[ Effectiveness and safety of biological therapy with adalimumab ] . DB00051 is a human , recombinant antibody , which is effective in patients with rheumatoid arthritis , polyarticular juvenile idiopathic arthritis , psoriasis , arthritis psoriatica , spondylitis ankylopoetica , as well as with Crohn - disease . DB00051 has got a high affinity binding to tumor necrosis factor ( P01375 - alfa ) , this way it inhibits the interactions with P01375 and its receptors ( soluble and membrane associated ) . It is well tolerated and safe , it improves the the quality of life . Possible side effects can be decreased by the careful observation and usual control of patients . The authors discuss in detail the publications on adalimumab in the above mentioned diseases .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK44___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK85___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"Emerging biologic drugs for the treatment of rheumatoid arthritis . This article reviews the role of emerging biologic drugs for the treatment of rheumatoid arthritis ( RA ) . Besides anti - tumor necrosis factor ( P01375 ) - alpha and anti - interleukin ( IL ) - 1 agents ( DB00065 , DB00051 , DB00005 and DB00026 ) whose clinical efficacy is now established , new drugs have been proposed for the therapy of rheumatoid arthritis patients not responding to conventional treatments . These approaches include the blockade of B - cell activity with anti - P11836 monoclonal antibody ( DB00073 ) and the inhibition of T - cell activation with fusion protein DB01281 . Moreover , promising results have been obtained in animal models utilizing suppressors of cytokine signaling ( Q9NSE2 ) and dominant - negative P01375 variants to inactivate P01375 signaling .",
"The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .",
"Influence of body mass index , comorbidities and prior systemic therapies on the response of psoriasis to adalimumab : an exploratory analysis from the APHRODITE data . DB00051 is a fully human monoclonal antibody directed against tumor necrosis factor ( P01375 ) - alpha , which is effective for the treatment of psoriasis and psoriatic arthritis ( PsA ) . The aim of this study is to determine whether the response of psoriasis to adalimumab treatment might be influenced by certain particular factors , such as body mass index ( BMI ) , history of biologic therapy , blood hypertension and metabolic comorbidities . For this reason , an exploratory analysis was conducted on 144 patients with psoriasis and concomitant PsA treated with adalimumab 40 mg every other week , evaluating the influence of such factors on the Psoriasis Area and Severity Index ( PASI ) response rate at week 12 . Our preliminary results suggest that the response rate at week 12 , in terms of both PASI - 50 and PASI - 75 , appeared to be independent of the presence of hypertension and / or metabolic comorbidities . The PASI - 50 response was observed more frequently in patients with BMI less than 30 as compared to obese patients ( 79 % vs 58 % , p = 0 . 02 ) . Previous use of anti - P01375 biologics did not appear to affect per se the rate of responders , although it was associated with a lower PASI - 75 rate among responders .",
"Molecular differences in anticytokine therapies . Biologic agents that inhibit proinflammatory cytokines have made a profound impact on the treatment of rheumatoid arthritis ( RA ) . Of the agents that are currently approved by the US Food and Drug Administration ( FDA ) for this indication , etanercept and infliximab neutralize tumor necrosis factor ( P01375 ) , and anakinra inhibits interleukin - 1 ( IL - 1 ) . DB00051 , which was just recently approved by the FDA , is also a P01375 inhibitor . Despite their common ability to inhibit cytokine bioactivity , the molecular structures and mechanisms of action of these biologic agents are significantly different . The P01375 - binding moiety of etanercept is derived from soluble P01375 receptor subunits . DB00065 is a chimeric ( mouse - human ) monoclonal antibody to P01375 , while adalimumab is a fully human anti - P01375 monoclonal antibody . DB00026 has yet another mechanism of action : it is an IL - 1 receptor antagonist . The molecular characteristics of these agents may be relevant to clinical efficacy and safety . These agents are still relatively new : to date , the longest reporting time is 5 years , for etanercept . Additional long - term data will be required to determine the relative benefits and drawbacks of different molecular characteristics in these anticytokine agents .",
"DB00051 - associated antiphospholipid syndrome : a case report and review of the literature . This study aims for the presentation of the first reported case of adalimumab - associated antiphospholipid syndrome ( APS ) and review of the literature on adalimumab - induced vasculitis and APS . A case of APS associated with adalimumab use in a 67 - year - old woman is reported . The English medical literature was reviewed for antitumor necrosis factor ( P01375 ) agents and their association with APS and vasculitis . DB00051 is a fully humanized monoclonal antibody targeted against P01375 alpha that is widely used in the treatment of rheumatoid arthritis , juvenile idiopathic arthritis , ankylosing spondylitis , psoriatic arthritis , psoriasis , and Crohn ' s disease . Literature review reveals several cases of anti - P01375 - induced vasculitis including cases associated with adalimumab . We report the first case of adalimumab - induced APS in a 67 - year - old woman who developed APS and vasculitis associated with de novo positive anti - cardiolipin ( aCL ) antibody following the third dose of adalimumab therapy for the treatment of spondyloarthropathy . This is the first case demonstrating that a short course of adalimumab therapy may induce immunoglobulin M aCL autoantibodies leading to APS . With the growing use of anti - P01375 medications in immune - mediated and inflammatory diseases , adalimumab and other anti - P01375 medications should be considered as a possible explanation for APS .",
"Role of novel biological therapies in psoriatic arthritis : effects on joints and skin . Psoriatic arthritis ( PsA ) is a partly debilitating disease that may affect small and large joints and the spine . Patients with PsA are divided into different subgroups according to joint involvement and their disease may be classified as part of the spectrum of spondyloarthritides or seronegative rheumatoid arthritis . Traditional treatment comprises nonsteroidal anti - inflammatory drugs , systemic and intra - articular corticosteroids and disease - modifying antirheumatic drugs such as sulfasalazine , methotrexate and cyclosporin . On the basis of the very recent studies performed in the US and Germany , patients with severe disease can be treated with anti - tumour necrosis factor ( P01375 ) therapy . Biologicals such as etanercept and infliximab have been used successfully to treat PsA . While etanercept is a 75kD P01375 receptor fusion protein that binds to TNFalpha and TNFbeta , infliximab is a chimeric monoclonal antibody that binds to TNFalpha both in its soluble form in the serum and on the cell membrane . DB00051 is a fully humanised antibody recognising TNFalpha that has not been tested in PsA to date . Another biological agent , alefacept , is directed against the adhesion molecule lymphocyte function - associated antigen ( LFA ) - 2 , which is known to interfere with T - cell activation . DB00092 has been shown to be efficacious in a limited number of patients with PsA . Taken together , there has been definite recent progress in the treatment of PsA . Severely affected patients may especially have substantial benefit from therapy with biologicals directed against TNFalpha and other targets .",
"Osteonecrosis of the jaw in a Crohn ' s disease patient following a course of Bisphosphonate and DB00051 therapy : a case report . BACKGROUND : Bisphosphonates have a widespread indication for osteoporosis and are also applied in cancer patients with skeletal - related conditions . Bisphosphonate - associated osteonecrosis of the jaw ( BRONJ ) is a feared side effect which is hard to treat and often affects patient ' s quality of life in an extensive manner . DB00051 ( Humira ® ) , a fully human recombinant antibody specific for tumor necrosis factor - α , is approved for treatment in patients with Inflammatory Bowel Disease like ulcerative colitis or Crohn ' s disease . CASE PRESENTATION : In March 2013 , a 36 - year - old female presented with right - sided perimandibular swelling , recurrent facial pain and exposed necrotic bone after previous extraction of tooth 47 . She had the medical history of Crohn ' s disease for more than one decade with chronic active enterocolitis , fistula disease as well as previous oral manifestation and was currently treated with DB00051 since September 2008 . Due to steroid - induced osteoporosis , diagnosed in 2004 , she received oral Bisphosphonates ( Risedronate ) from 2004 until 2007 followed by two infusions of DB00399 in 2008 and 2009 . CONCLUSION : This patient with a medical history of Crohn ' s disease and gastrointestinal remission under DB00051 therapy presented with osteonecrosis of the jaw after suspended oral and intravenous Bisphosphonate therapy implicating that the biologic therapy with an anti - P01375 - α antibody might promote the manifestation of osteonecrosis and compromise oral healing capacity .",
"Effective long - term control of refractory hidradenitis suppurativa with adalimumab after failure of conventional therapy . BACKGROUND : Hidradenitis suppurativa is a chronic suppurative condition featuring inflammatory nodules , fistulas and scars . It occurs predominantly in the axillae and groin . The disease is poorly responsive to any treatment and is connected with significant morbidity . Systemic therapy , including oral antibiotics , retinoids and antiandrogens , usually has only limited effect . Surgical treatment of affected areas is necessary in advanced stages . OBJECTIVES : Several reports support the beneficial effect of tumor necrosis factor - α ( P01375 - α ) antagonists for the treatment of severe hidradenitis suppurativa . By contrast with data on infliximab and etanercept , data describing the potential positive influence of adalimumab on disease outcome are limited and refer to only small cohorts of patients . METHODS : Eight patients with severe , recalcitrant hidradenitis were treated for 1 year with adalimumab in a standard regimen and were subsequently followed for 1 year . RESULTS : All patients improved within 4 - 6 weeks and laboratory parameters of P02741 ( CRP ) and leukocyte count reduced significantly during treatment . Three patients demonstrated long - lasting improvement and five showed recurrences several months after discontinuation of the therapy . The average recurrence - free interval was 9 . 5 months . CONCLUSIONS : DB00051 is suitable for the long - term treatment of hidradenitis suppurativa and presents a further conservative treatment approach .",
"DB00051 specifically induces CD3 (+) P01730 (+) CD25 ( high ) Foxp3 (+) CD127 (-) T - regulatory cells and decreases vascular endothelial growth factor plasma levels in refractory immuno - mediated uveitis : a non - randomized pilot intervention study . AIM : To explore immunoregulatory and anti - inflammatory pathways specifically targeted by a subcutaneous anti - TNFαdrug - adalimumab - which might be relevant for controlling refractory uveitis . DESIGN : Non - randomized pilot intervention study on the effects of adalimumab on Treg populations and plasma P15692 levels in refractory uveitis patients . Inflammatory and immunological parameters were measured in 12 patients before therapy , and 1 and 6 months after therapy , and analyzed in the context of ophthalmological outcomes . The results were compared with those obtained in 10 systemic prednisone - treated uveitis patients . RESULTS : After 1 month of treatment , all patients responded , with 67 % of adalimumab group and 80 % of the corticosteroid group achieving inactivity ( P = 0 . 5 ) . Unlike steroid - treated patients , a significant increase in T - regulatory P01730 (+) CD25 ( high ) Foxp3 (+) CD127 (-) cells was observed in adalimumab patients after 1 month of treatment , and maintained after 6 months ( P = 0 . 003 ) . A significant adalimumab - specific drop in plasma P15692 was observed after 1 and 6 months of treatment ( P = 0 . 019 ) . In every single patient , Tregs but not P15692 correlated with disease activity . CONCLUSIONS : In refractory uveitis patients treated with adalimumab , clinical efficacy may be mediated through upregulation of Tregs in addition to modulation of P15692 - mediated inflammatory pathways . These biological properties , which were not observed in patients treated with corticosteroids , may reflect the specificity of P01375 - αtargeting .",
"Efficacy of adalimumab in plaque psoriasis : experience on 28 patients . Psoriasis is a common , chronic inflammatory skin disease with arthritis that may occur in a percentage of patients that varies between 5 % and 42 % . Many systemic agents as cyclosporine , methotrexate , acitretin , and photochemotherapy have been used for the treatment of patients affected by moderate - to - severe plaque psoriasis although they present side effects ( ie , cumulative organ toxicity and lack of efficacy over time ) that limit long - term use . Significant therapeutical improvement has been obtained introducing biological therapies , designed to modify and regulate immunological processes by targeting specific molecules involved in the immunopathogenesis of psoriasis . DB00051 is a fully human recombinant antibody against tumor necrosis factor - alpha ( P01375 ) . To date , there is not much data available on the efficacy and safety of adalimumab in patients affected by moderate - to - severe plaque psoriasis . The authors report our first experience on the efficacy and safety of adalimumab in monotherapy at a dose of 40 mg every - other - week for the treatment of plaque psoriasis in patients with or without arthritis . Twenty - eight patients were treated for a period of 48 months . It was observed an improvement of the psoriasis condition as well as of patients ' quality of life and mood state .",
"[ A 47 - year - old dog breeder with chronic polyarthritis , weight loss and high fever ] . A 47 - year - old dog breeder had suffered from unclassified polyarthritis for four years . During immunomodulatory therapy of an assumed seronegative chronic polyarthritis with Leflunomid and DB00051 he developed severe systemic inflammatory disease with high fever , weight loss , and severe arthralgia . Fever and arthralgias temporarily improved under antibiotic therapy , although a causative organism had not been found . The clinical picture led to the differential diagnosis of Whipple ' s disease , but DB00233 - positive macrophages were not detected in duodenal biopsies . The diagnosis was finally based on a positive PCR result for Tropheryma whipplii , typical clinical symptoms and a complete response on adequate antibiotic long - term treatment with cotrimoxazol . The diagnosis of Whipple ' s disease was possibly masked by the initial antibiotic therapies . Therapies with immunomodulators , P01375 - inhibitors , and corticosteroids may transform an infection with Tropheryma whipplii , normally in a subacute stage , into a septic , life - threatening disease .",
"Safety and efficacy of adalimumab ( D2E7 ) in Crohn ' s disease patients with an attenuated response to infliximab . OBJECTIVES : Although infliximab is highly effective in the treatment of Crohn ' s disease ( CD ) , attenuated response to infliximab may develop over time in a subgroup of patients . The aim of our study was to examine the safety and efficacy of adalimumab ( D2E7 ) , a fully humanized anti - P01375 Ab , in CD patients who had experienced an attenuated response to infliximab . METHODS : Fifteen patients with active CD who experienced an attenuated response to infliximab were treated with adalimumab over a 6 - month period . Patients , received a loading dose of 80 mg subcutaneously followed by 40 mg every 2 wk . The clinical response to adalimumab was classified as complete response , partial response , or nonresponse . RESULTS : Two patients received the loading dose of adalimumab but did not have adequate follow - up evaluations . Of the remaining 13 patients , 7 ( 54 % ) had a complete response , 4 ( 31 % ) had a partial response , and 2 ( 15 % ) were nonresponders . In six patients , the maintenance dose was increased in order to maintain clinical response . Eight of 11 ( 73 % ) patients on concurrent corticosteroids were able to discontinue or significantly decrease the dose of the steroids . DB00051 was well tolerated without signs or symptoms of allergic reaction except in two patients who developed an injection site reaction . CONCLUSIONS : Our preliminary data suggest that adalimumab may be a safe and effective therapy for patients with CD who have experienced an attenuated response to infliximab .",
"DB00051 for the induction and maintenance of clinical remission in Japanese patients with Crohn ' s disease . BACKGROUND AND AIMS : DB00051 has been shown to be efficacious and well - tolerated in Western patients with Crohn ' s disease . These 2 randomized , double - blind clinical trials evaluated adalimumab efficacy and safety in Japanese patients with moderate to severe Crohn ' s disease . METHODS : 90 patients enrolled in the induction trial and were randomized to receive adalimumab 160 / 80 mg , adalimumab 80 / 40 mg or placebo at Weeks 0 / 2 . At Week 4 , patients who achieved a decrease in CDAI ≥ 70 points versus Baseline entered the maintenance trial and were randomized to adalimumab 40 mg every other week or placebo for 52 weeks . All other patients received 4 more weeks of blinded adalimumab before entering the open - label portion of the maintenance trial . At / after Week 4 of the maintenance trial , blinded patients who flared / failed to respond entered the open - label portion . Open - label maintenance patients received adalimumab 40 mg every other week with the option of 80 mg every other week for flare / non - response . RESULTS : Clinical remission rates at Week 4 in the induction trial were 33 . 3 % , 17 . 6 % and 13 . 0 % in the adalimumab 160 / 80 mg , adalimumab 80 / 40 mg and placebo groups , respectively . Maintenance remission rates were 38 . 1 % for adalimumab and 9 . 1 % for placebo at Week 52 . Anti - P01375 naïve patients achieved greater efficacy than anti - P01375 exposed patients . Patients randomized to adalimumab achieved greater quality of life improvement versus placebo . There were no clinically relevant differences in safety between adalimumab and placebo . CONCLUSIONS : DB00051 is effective and well - tolerated for inducing and maintaining clinical remission in Japanese patients with moderate to severe Crohn ' s disease .",
"Oral tuberculosis associated with a treatment with anti - rheumatic drugs . BACKGROUND : The use of immunosuppressive medication is a dominant risk factor for infection in patients with rheumatoid arthritis ( RA ) . DB00563 ( MTX ) is one of the traditional disease - modifying antirheumatic drugs . DB00051 [ a human anti - tumor necrosis factor - alpha ( anti - P01375 ) monoclonal antibody ] represent an important advance in the treatment of RA and has been recently come in use . P01375 plays a role in the host defense against Mycobacterium tuberculosis and notably in granuloma formation . Infections occur at a high rate among those who use one or the combination of the two medications . METHOD : We examined a female patient that was referred to our department for evaluation and treatment of a granular lesion on the soft palate and uvula , complaining of mild dysphagia . The patient was treated for 4 months with MTX and adalimumab for RA before the oral lesion appeared . RESULTS : The histopathological examination of a specimen of the oral lesion , taken by biopsy , showed a chronic inflammation characterized by tuberculous granulomas . Polymerase chain reaction test and culture of a new specimen was positive for M . tuberculosis . CONCLUSIONS : The therapeutic use of MTX or / and adalimumab for the treatment of RA or few others diseases , can cause oral tuberculosis .",
"DB00051 in the treatment of rheumatoid arthritis . DB00051 ( P00813 ) , a fully human monoclonal antibody against P01375 - α is indicated for the treatment of rheumatoid arthritis ( RA ) , psoriatic arthritis , ankylosing spondylitis , juvenile idiopathic arthritis , Crohn ' s disease , ulcerative colitis and psoriasis . In RA , it may be prescribed in combination with methotrexate or other disease - modifying antirheumatic drugs or as monotherapy . Studies comparing P00813 with other P01375 - α inhibitors are limited and are based mainly on meta - analyses of randomised controlled trials and large observational cohorts . In this study , the effectiveness and safety of P00813 is compared with that of etanercept and infliximab .",
"Varicella zoster virus encephalitis during treatment with anti - tumor necrosis factor - alpha agent in a psoriatic arthritis patient . The introduction of targeted immunotherapies has greatly improved the therapeutic options of several inflammatory diseases such as psoriatic arthritis . However treatment - related opportunistic infections and viral reactivations may still occur . We describe a case of varicella zoster virus ( VZV ) encephalitis due to the reactivation of latent VZV infection during a long therapy with the anti - tumor necrosis factor - alpha ( P01375 ) drug DB00051 . The low incidence of VZV encephalitis in patients treated with biological agents does not justify VZV serological screening in these subjects , but careful monitoring of the patients is recommended to recognize early signs and symptoms of herpes zoster to start prompt antiviral therapy to prevent associated complications .",
"Inorganic lead enhances cytokine - induced elevation of matrix metalloproteinase P14780 expression in glial cells . Inorganic lead ( Pb ) is a ubiquitous environmental contaminant that produces a variety of deleterious effects in the central nervous system ( CNS ) . Matrix metalloproteinases ( MMPs ) , specifically P14780 , induced by inflammatory cytokines , are increasingly being implicated in CNS pathology . The present study demonstrates that low concentrations of either pro - inflammatory cytokines ( P01375 and IL - 1beta ) or Pb did not influence the P14780 expression in a glial cell line ( P13671 ) when added separately . However , combined administration of Pb and cytokines induced a marked synergized elevation of P14780 expression in spite of a reduction in the number of glial cells . These results demonstrate a possible new mechanism by which Pb may induce neuropathological processes .",
"DB00051 - induced noncaseating granuloma in the bone marrow of a patient being treated for rheumatoid arthritis . Sarcoidosis is a multisystemic disease characterized by noncaseating granulomatous infiltration , primarily of the lungs and lymphatic system . While reports of the efficacy of adalimumab in the treatment of refractory sarcoidosis have been mixed , the more widely used infliximab has demonstrated clear efficacy in this disease . The association between tumor necrosis factor ( P01375 ) - inhibitors and noncaseating granulomas in the lung has been reported in literature . With the exception of one patient treated with adalimumab , who developed pulmonary granuloma , the remaining patients described in literature were treated with etanercept . The current case study is , to our knowledge , the first to describe adalimumab - induced noncaseating granulomas in the bone marrow of a patient being treated for rheumatoid arthritis and suggests that although P01375 - inhibitors are used in the treatment of granulomatous disorders , their use should be carefully monitored as , in rare cases , P01375 - inhibitors may leave sufficient cytokine activation to support granuloma formation .",
"DB00051 for treatment of moderate to severe psoriasis and psoriatic arthritis . Psoriasis and psoriatic arthritis are common diseases associated with considerable morbidity and disability . Their pathophysiology comprises similar processes leading to inflammation of skin , entheses , and joints . Although traditional systemic agents can be effective , their use may be limited by lack of efficacy and concerns regarding adverse effects . The objective of this study was to assess the efficacy and safety of adalimumab , a fully human antitumor necrosis factor ( anti - P01375 ) monoclonal antibody , over 16 weeks . The present authors report their personal experience in 15 patients with severe plaque psoriasis and psoriatic arthritis , refractory to other treatments , in which a decisive regression of joint / skin involvement was obtained . Psoriasis and psoriatic arthritis are chronic inflammatory disorders resulting from a combination of genetic and environmental factors .",
"DB00051 could suppress the activity of non alcoholic steatohepatitis ( NASH ) . The prevalence of non - alcoholic steatohepatitis ( NASH ) is increasing . NASH confers an increased risk of liver - related morbidity and mortality with a substantial risk of developing liver cirrhosis . At present , there is no established medical treatment for NASH . The pathogenesis of NASH is incompletely understood . Several lines of evidence suggest that P01375 may be involved in the pathogenesis of NASH by promoting liver inflammation , insulin resistance and hepatocyte apoptosis . Anti - P01375 therapy has not been evaluated for the treatment of NASH . We report here on a patient with NASH who has experienced rapid normalization of liver biochemistry during treatment of an associated rheumatoid arthritis with the humanized anti - P01375 antibody adalimumab . This observation suggests that pilot studies may be warranted to evaluate the role of adalimumab for the treatment of NASH .",
"DB00051 in ankylosing spondylitis : an evidence - based review of its place in therapy . INTRODUCTION : Ankylosing spondylitis ( AS ) is an idiopathic chronic inflammatory disease that has prominent effects on the spine and peripheral joints . In addition , extraarticular manifestations such as enthesitis and acute anterior uveitis may be clinically important . In recent years , the therapy of AS has changed , largely due to the introduction of inhibitors of the proinflammatory cytokine tumor necrosis factor ( P01375 ) . DB00051 , a human monoclonal antibody specifically for P01375 , is the most recent of the P01375 blocking agents that have been approved for the treatment of active , nonsteroidal antiinflammatory drug ( NSAID ) - refractory patients with AS . AIMS : To evaluate the evidence for the therapeutic value of adalimumab in ankylosing spondylitis . EVIDENCE REVIEW : There is clear evidence that adalimumab , administered 40 mg subcutaneously every 2 weeks , substantially improves the signs and symptoms of NSAID - refractory , active AS when compared with placebo treatment . There is ample evidence that adalimumab causes significant improvements in physical health status and overall AS - specific , health - related quality of life and physical functioning , which consequently leads to better work productivity . There is substantial evidence that adalimumab improves spinal and sacroiliac joint inflammation in AS patients . Initial results from clinical trials suggest that there is no increased risk of serious infections or malignancies in adalimumab - treated patients with AS . The most common adverse events were injection - site reactions . Limited economic evidence suggests that adalimumab 40 mg may be cost effective when used according to current valid treatment guidelines . PLACE IN THERAPY : DB00051 is an effective treatment for patients with active AS .",
"[ Efficiency and safety of human monoclonal antibodies to P01375 in children with juvenile idiopathic arthritis in primary and secondary ineffectiveness of other biologicals ] . PURPOSE : To evaluate the safety and efficiency of adalimumab in children with severe refractory JIA with primary inefficiency , partial effect or loss of the effectiveness of other biologicals . PATIENTS AND METHODS : The article presents the results of the retrospective observational study of the efficacy and safety of adalimumab in 68 patients aged 10 ( 3 , 17 ) years with various embodiments of JIA , with the primary inefficiency or partial or loss of the effectiveness of other biologicals . JIA diagnosis established on the basis of criteria ILAR ( International League of Associations for Rheumatology ) . RESULTS : Efficacy was assessed during 1 year in 68 and 2 years -- in 56 patients . At the 24th week we observed the improvement by criteria AKR 30 , 50 . 70 in 100 , 91 and 74 % of patients , respectively , and at the 52th week -- in 100 , 96 and 90 % , respectively . Inactive disease status was recorded in 55 . 8 , 66 . 1 and 98 . 2 % of study participants after 6 months , 1 and 2 years , respectively . Remission was achieved in 55 . 8 and 96 . 4 % of patients after 1 and 2 years of observation , respectively . CONCLUSIONS : DB00051 was effective and well tolerated by patients with primary inefficiency , partial and loss of efficiency of other biologicals . In clinical practice , patients with non - systemic JIA transition to the second P01375 blocker can restore the biological effect of the first drug without increasing the frequency of infectious AEs .",
"DB00051 plus methotrexate or standard therapy is more effective than methotrexate or standard therapies alone in the treatment of fatigue in patients with active , inadequately treated rheumatoid arthritis . OBJECTIVES : Fatigue is an important systemic symptom of rheumatoid arthritis ( RA ) but has rarely been evaluated consistently after initiation of treatment in RA patients . This study examined the effects of adalimumab ( HUMIRA , Abbott Laboratories , Abbott Park , IL , USA ) , a fully human , anti - tumor necrosis factor ( anti - P01375 ) monoclonal antibody , on reducing fatigue in patients with RA . METHODS : A total of 1526 patients with RA were enrolled in 3 randomized , placebo - controlled clinical trials of adalimumab versus placebo plus methotrexate ( MTX ) or placebo plus standard antirheumatic therapies . Fatigue was assessed with the Functional Assessment of Chronic Illness Therapy ( FACIT ) fatigue scale questionnaire ( which has been validated in RA ) at baseline , mid - study , and at the end of the study . Logistic regression models were constructed using baseline demographic variables to test for treatment effect . In addition , sensitivity analyses were performed to determine the robustness of the data . RESULTS : At baseline in the 3 trials , patients ' fatigue ranged from 27 . 9 - 29 . 7 , representing considerable fatigue on the FACIT fatigue scale . Fatigue was significantly and consistently reduced in adalimumab - treated patients in the 3 clinical trials . Relative to placebo plus MTX , the adalimumab 40 - mg - every - other - week dosage group reported statistically significantly less fatigue at all time points post - baseline . Improvements between adalimumab and placebo ranged from 3 - 7 points across all 3 trials , with a 3 - 4 - point change representing a minimum clinically important difference . CONCLUSION : DB00051 treatment was shown to significantly reduce fatigue in patients with moderate to severe RA . Changes in fatigue in all 3 trials were found to be clinically important ."
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___MASK83___
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MH_train_433
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interacts_with DB00136?
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[
"A cardiac pathway of cyclic GMP - independent signaling of guanylyl cyclase A , the receptor for atrial natriuretic peptide . Cardiac atrial natriuretic peptide ( P01160 ) regulates arterial blood pressure , moderates cardiomyocyte growth , and stimulates angiogenesis and metabolism . P01160 binds to the transmembrane guanylyl cyclase ( GC ) receptor , P16066 , to exert its diverse functions . This process involves a cGMP - dependent signaling pathway preventing pathological [ Ca ( 2 +)]( i ) increases in myocytes . In chronic cardiac hypertrophy , however , P01160 levels are markedly increased and P16066 / cGMP responses to P01160 are blunted due to receptor desensitization . Here we show that , in this situation , P01160 binding to P16066 stimulates a unique cGMP - independent signaling pathway in cardiac myocytes , resulting in pathologically elevated intracellular Ca ( 2 +) levels . This pathway involves the activation of Ca ( 2 +)- permeable transient receptor potential canonical 3 / 6 ( Q13507 / P13671 ) cation channels by P16066 , which forms a stable complex with Q13507 / P13671 channels . Our results indicate that the resulting cation influx activates voltage - dependent L - type Ca ( 2 +) channels and ultimately increases myocyte Ca ( 2 )(+)( i ) levels . These observations reveal a dual role of the P01160 / P16066 - signaling pathway in the regulation of cardiac myocyte Ca ( 2 +)( i ) homeostasis . Under physiological conditions , activation of a cGMP - dependent pathway moderates the Ca ( 2 +)( i )- enhancing action of hypertrophic factors such as angiotensin II . By contrast , a cGMP - independent pathway predominates under pathophysiological conditions when P16066 is desensitized by high P01160 levels . The concomitant rise in [ Ca ( 2 +)]( i ) might increase the propensity to cardiac hypertrophy and arrhythmias .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Identification of novel small compounds that restore P12830 expression and inhibit tumor cell motility and invasiveness . Tumor dissemination and invasive behavior are associated with a majority of cancer - related mortality cases . Loss of P12830 , which is caused by several tumor - promoting factors , is associated with metastasis and poor prognosis in many neoplasms . In this study , we aimed to identify small molecule compounds that restore the expression of P12830 , because these molecules are most likely to suppress tumor malignancy by restoring P12830 function and / or by inhibiting signals that suppress P12830 expression . Here , we developed a fluorescence screen system based on P12830 expression . A pilot drug library screen revealed that methotrexate ( MTX ) strongly induces P12830 expression in a colorectal cancer cell line , SW620 . From the screen for 9600 compounds , we identified 9 hit compounds , which restored the expression of P12830 in SW620 and / or a melanoma cell line , SK - P61006 - 28 . We confirmed that MTX and the other identified compounds transcriptionally promote P12830 expression . Among these , 2 compounds suppressed migration / invasion capacity in colorectal cancer cells and 3 in melanoma cells . A compound reduced SW620 migration and invasion with subtle effects on cell viability in SW620 , SK - P61006 - 28 , and a non - tumor cell line , HaCaT , with decrease in AKT and P27361 / 2 protein levels . One of the other compounds reduced SK - P61006 - 28 cell migration and invasion and affected the viability only of SW620 and SK - P61006 - 28 cells but not HaCaT cells . These results suggest that these compounds would be attractive lead molecules as anti - metastasis agents .",
"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .",
"Cystatin D is a candidate tumor suppressor gene induced by vitamin D in human colon cancer cells . The active vitamin D metabolite 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] has wide but not fully understood antitumor activity . A previous transcriptomic analysis of DB00136 action on human colon cancer cells revealed cystatin D ( P28325 ) , which encodes an inhibitor of several cysteine proteases of the cathepsin family , as a candidate target gene . Here we report that DB00136 induced vitamin D receptor ( P11473 ) binding to , and activation of , the P28325 promoter and increased P28325 RNA and protein levels in human colon cancer cells . In cells lacking endogenous cystatin D , ectopic cystatin D expression inhibited both proliferation in vitro and xenograft tumor growth in vivo . Furthermore , cystatin D inhibited migration and anchorage - independent growth , antagonized the Wnt / beta - catenin signaling pathway , and repressed c - MYC expression . Cystatin D repressed expression of the epithelial - mesenchymal transition inducers O95863 , O43623 , P37275 , and O60315 and , conversely , induced P12830 and other adhesion proteins . P28325 knockdown using shRNA abrogated the antiproliferative effect of DB00136 , attenuated P12830 expression , and increased c - MYC expression . In human colorectal tumors , expression of cystatin D correlated with expression of P11473 and P12830 , and loss of cystatin D correlated with poor tumor differentiation . Based on these data , we propose that P28325 has tumor suppressor activity that may contribute to the antitumoral action of DB00136 in colon cancer .",
"Vitamin D increases plasma renin activity independently of plasma Ca2 + via hypovolemia and β - adrenergic activity . 1 , 25 - Dihydroxycholechalciferol ( calcitriol ) and 19 - nor - 1 , 25 - dihydroxyvitamin D2 ( paricalcitol ) are vitamin D receptor ( P11473 ) agonists . Previous data suggest P11473 agonists may actually increase renin - angiotensin activity , and this has always been assumed to be mediated by hypercalcemia . We hypothesized that calcitriol and paricalcitol would increase plasma renin activity ( P06703 ) independently of plasma Ca ( 2 +) via hypercalciuria - mediated polyuria , hypovolemia , and subsequent increased β - adrenergic sympathetic activity . We found that both calcitriol and paricalcitol increased P06703 threefold ( P < 0 . 01 ) . Calcitriol caused hypercalcemia , but paricalcitol did not . Both calcitriol and paricalcitol caused hypercalciuria ( 9 - and 7 - fold vs . control , P < 0 . 01 ) and polyuria ( increasing 2 . 6 - and 2 . 2 - fold vs . control , P < 0 . 01 ) . Paricalcitol increased renal calcium - sensing receptor ( P41180 ) expression , suggesting a potential cause of paricalcitol - mediated hypercalciuria and polyuria . Volume replacement completely normalized calcitriol - stimulated P06703 and lowered plasma epinephrine by 43 % ( P < 0 . 05 ) . β - Adrenergic blockade also normalized calcitriol - stimulated P06703 . P35354 inhibition had no effect on calcitriol - stimulated P06703 . Our data demonstrate that vitamin D increases P06703 independently of plasma Ca ( 2 +) via hypercalciuria , polyuria , hypovolemia , and increased β - adrenergic activity .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK80___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"P98164 - mediated endocytosis of vitamin D binding protein correlates with DB00146 actions in human mammary cells . The major circulating form of vitamin D is DB00146 [ DB00146 ] , which is delivered to target tissues in complex with the serum vitamin D binding protein ( DBP ) . We recently observed that mammary cells can metabolize DB00146 to DB00136 [ 1 , 25 ( OH )( 2 ) D3 ] , the vitamin D receptor ( P11473 ) ligand , and the objective of our study was to elucidate the mechanisms by which the DB00146 - DBP complex is internalized by mammary cells prior to metabolism . Using fluorescent microscopy and temperature - shift techniques , we found that T - 47D breast cancer cells rapidly internalize DBP via endocytosis , which is blunted by receptor - associated protein , a specific inhibitor of megalin - mediated endocytosis . Endocytosis of DBP was associated with activation of P11473 by DB00146 but not 1 , 25 ( OH )( 2 ) D3 ( as measured by induction of the P11473 target gene , Q07973 ) . We also found that megalin and its endocytic partner , cubilin , are coexpressed in normal murine mammary tissue , in nontransformed human mammary epithelial cell lines , and in some established human breast cancer cell lines . To our knowledge , our studies are the first to demonstrate that mammary - derived cells express megalin and cubilin , which contribute to the endocytic uptake of DB00146 - DBP and activation of the P11473 pathway .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"A histone deacetylase inhibitor , largazole , decreases liver fibrosis and angiogenesis by inhibiting transforming growth factor - β and vascular endothelial growth factor signalling . BACKGROUND & AIMS : Largazole is a novel histone deacetylase ( HDAC ) inhibitor . This study investigated the effects of largazole against liver fibrosis . METHODS : The in vitro effects of largazole were examined using hepatic stellate cells ( HSCs ) . In vivo effects of largazole were studied using a mouse liver fibrotic model induced by CCl4 . RESULTS : Largazole augmented acetylation of histone H3 ( H3 ) and histone H4 ( H4 ) in HSCs . It directly inhibited the activation of HSCs owing to HDAC inhibitory activity as the antifibrotic effect of largazole was significantly decreased in cells with Q13547 , Q92769 and O15379 knockdown . Largazole also induced apoptosis of HSCs . Largazole not only inhibited the expression of TGFβR2 , but also reduced phosphorylation of Q15796 and Akt induced by TGF - β1 . Largazole also inhibited the expression of vascular endothelial growth factor ( P15692 ) and its receptor . P15692 - induced proliferation of HSCs and activation of Akt and p38MAPK were also suppressed by largazole . In vivo , largazole reduced the expression of collagen I , α - smooth muscle actin and tissue inhibitor of metalloproteinase - 1 in CCl4 - induced fibrosis , and these antifibrotic effects were associated with increased acetylation of H3 and H4 . Largazole also induced HSCs to undergo apoptosis in vivo , which was correlated with downregulation of bcl - 2 and bcl - xL . Furthermore , largazole inhibited angiogenesis in vivo as evidenced by reduced expression of P28906 , P15692 and VEGFR . In addition to its antifibrotic activity , the drug reduced inflammatory activity in CCl4 - induced liver fibrosis . CONCLUSIONS : Our findings revealed a novel role of largazole in the treatment of liver fibrosis . Through multiple mechanisms , largazole could be a potentially effective antifibrotic agent .",
"Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK65___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK65___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .",
"Inhibition by 1alpha , 25 - dihydroxyvitamin D3 of activin A - induced differentiation of murine erythroleukemic P12259 - 5 cells . DB00136 ( 1alpha , 25 -( OH ) 2D3 ) and other vitamin D3 ( VD3 ) analogs enhanced the inhibitory effect of Activin A on murine erythroleukemia ( P61006 ) cell proliferation and differentiation in a dose - dependent manner . 1alpha , 25 -( OH ) 2D3 inhibited differentiation more potently than proliferation by one order of magnitude . The VD3 analog study demonstrated either effect of VD3 on P61006 cells via vitamin D receptor ( P11473 ) , as evidenced from the close relationship with the reported affinities for P11473 . The effects of 1alpha , 25 -( OH ) 2D3 were preceded by the suppression of ornithine decarboxylase ( ODC ) activity , a rate - limiting enzyme in polyamine metabolism . Difluoromethylornithine ( DB06243 ) , an inhibitor of ODC , inhibited P61006 cell proliferation , which was reversed by the simultaneous addition of putrescine , a product of ODC , but did not affect differentiation . 1alpha , 25 -( OH ) 2D3 inhibited cell differentiation during the phenotype - expression stage as reflected by the inhibition of beta - globin gene expression , while it inhibited proliferation in the commitment stage . Furthermore , it seems unlikely that the different effects of VD3 on proliferation and differentiation may be a result of upregulation of P11473 or nongenomic action . In summary , it was suggested that 1alpha , 25 -( OH ) 2D3 inhibited Activin A - induced P61006 cell proliferation and differentiation by distinct mechanisms and inhibited the proliferation by inhibiting ODC activity . We demonstrated the presence of 1alpha , 25 -( OH ) 2D3 action on leukemic cells at physiological concentration , which was distinct from the pharmacological effect of VD3 reported thus far .",
"Mutation of the calmodulin binding motif IQ of the L - type Ca ( v ) 1 . 2 Ca2 + channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation - contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca ( 2 +)/ calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca ( v ) 1 . 2 channel and induces Ca ( 2 +)- dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca ( v ) 1 . 2 ( I1624E ) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca ( v ) 1 . 2 ( Q401N2 ) allele by tamoxifen - induced cardiac - specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca ( v ) 1 . 2 ( I1624E ) hearts , the activity of phospho - P62158 kinase II and phospho - MAPK was increased . CMs expressed reduced levels of Ca ( v ) 1 . 2 ( I1624E ) channel protein and I ( Ca ) . The Ca ( v ) 1 . 2 ( I1624E ) channel showed \" CDI \" kinetics . Despite a lower sarcoplasmic reticulum Ca ( 2 +) content , cellular contractility and global Ca ( 2 +) transients remained unchanged because the EC coupling gain was up - regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca ( v ) 1 . 2 ( I1624E ) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death .",
"___MASK67___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK67___ , in the USA in 2003 .",
"The p16 - cyclin D / Cdk4 - P06400 pathway as a functional unit frequently altered in melanoma pathogenesis . The p16Ink4 / CDKN2 , D - type cyclins , their partners Cdk4 / Cdk6 , and P06400 constitute a P55008 regulatory pathway commonly targeted in tumorigenesis . Genetic , immunochemical , and functional cell cycle analyses showed abnormalities of this pathway in each of 22 human melanoma cell lines examined . Normal melanocytes and all melanoma lines expressed Cdk4 , Cdk6 , and cyclins D1 and D3 . The tumor suppressors p16Ink4 / CDKN2 and P06400 were lost in 17 and 4 cases , respectively , due to various genetic mechanisms , including transcriptional block of p16 and nonsense mutations of P06400 . Ectopic expression of p16 prevented S - phase entry of Rb +/ p16 - but not Rb - deficient melanoma lines . The SK29 - P61006 - 1 cell line harboring an R24C mutation in Cdk4 expressed wild - type P06400 and overabundant p16 , the latter preventing endogenous Cdk6 but not Cdk4 from associating with cyclin D1 . Microinjection of cyclin D1 - neutralizing antibody arrested the SK29 - P61006 - 1 cells in P55008 , whereas pl6 did not , indicating that the cyclin D1 / Cdk4 - R24C complex is required for P55008 progression , and the resistance of the complex to p16 in vivo . These data strongly support the candidacy of Cdk4 as a novel proto - oncogene , provide further evidence for the p16 - cyclin D / Cdk - P06400 pathway as a functional unit , and suggest that deregulation of this checkpoint may represent a common step in the multistep progression of sporadic malignant melanomas .",
"Molecular profile of osteoprogenitor cells seeded on allograft bone . In order to optimize and modulate bone formation it is essential to understand the expression patterns of key bone - specific growth factors , as osteoprogenitor cells undergo the processes of proliferation , differentiation and maturation . This study reports the sequential expression of bone - related growth and transcription factors when bone marrow - derived osteoprogenitor cells from C57BL mice were cultured on allograft bone discs . Mineralization and osteocalcin protein levels were used to track osteogenic differentiation and maturation . Bone - related growth factors , such as Bmp - 2 , Bmp - 7 , Ctnnb - 1 , Fgf - 2 , Igf - 1 , Vegf - a and Tgf - β1 , and transcription factors , such as Runx - 2 and osteocalcin , were examined by enzyme - linked immunosorbent assay ( ELISA ) and reverse transcription polymerase chain reaction ( RT - PCR ) . Total density of mineralized bone was significantly increased 7 . 6 ± 0 . 7 % in allografts cultured with cells , compared with a 0 . 5 ± 2 . 0 % increase in the controls without cells ( p < 0 . 01 ) . P02818 protein levels peaked at day 4 . Protein expression showed peaks of P12643 and TGF - β1 on day 2 , with P15692 peaking on day 8 , and DB01277 decreasing on day 2 . mRNA for Pdgf - a peaked on day 2 ; Bmp - 2 on days 4 and 16 ; Ctnnb - 1 on days 8 and 20 ; Vegf - a , Fgf - 2 , Runx - 2 and Igf - 1 on day 12 ; Tgf - β1 on day 16 ; and Pdgf - b on day 20 . Osteogenic growth factors correlated with Runx - 2 and Ctnnb - 1 , whereas a predominant vascular growth factor , Vegf - a , did not follow this pattern . Specific bone - related genes and proteins were expressed in a time - dependent manner when osteoprogenitor cells were cultured on cortico - cancellous bone discs in vitro .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"Overexpression of SnoN / SkiL , amplified at the 3q26 . 2 locus , in ovarian cancers : a role in ovarian pathogenesis . High - resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26 . 2 encompassing SnoN / SkiL , a coregulator of SMAD / TGFbeta signaling . SnoN RNA transcripts were elevated in approximately 80 % of advanced stage serous epithelial ovarian cancers . In both immortalized normal ( TIOSE ) and ovarian carcinoma cell lines ( OVCA ) , SnoN RNA levels were increased by TGFbeta stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGFbeta - induced increases in SnoN RNA . In TIOSE , SnoN protein levels were reduced 15min post TGFbeta - stimulation , likely by proteosome - mediated degradation . In contrast , in OVCA , SnoN levels were elevated 3h post - stimulation potentially as a result of inhibition of the proteosome . To elucidate the role of SnoN in ovarian tumorigenesis , we explored the effects of both increasing and decreasing SnoN levels . In both TIOSE and OVCA , SnoN siRNA decreased cell growth between 20 and 50 % concurrent with increased P38936 levels . In TIOSE , transient expression of SnoN repressed TGFbeta induction of P05121 promoters with little effect on the P38936 promoter or resultant cell growth . In contrast to the effects of transient expression , stable expression of SnoN in TIOSE led to growth arrest through induction of senescence . Collectively , these results implicate SnoN levels in multiple roles during ovarian carcinogenesis : promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non - transformed ovarian epithelial cells .",
"Broadening of transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model to represent late stage androgen depletion independent cancer . BACKGROUND : The transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model closely mimics PC - progression as it occurs in humans . However , the timing of disease incidence and progression ( especially late stage ) makes it logistically difficult to conduct experiments synchronously and economically . The development and characterization of androgen depletion independent ( ADI ) TRAMP sublines are reported . METHODS : Sublines were derived from androgen - sensitive TRAMP - C1 and TRAMP - P06681 cell lines by androgen deprivation in vitro and in vivo . Epithelial origin ( cytokeratin ) and expression of late stage biomarkers ( P12830 and KAI - 1 ) were evaluated using immunohistochemistry . P10275 ( AR ) status was assessed through quantitative real time PCR , Western blotting , and immunohistochemistry . Coexpression of AR and P12830 was also evaluated . Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays . Proliferation / survival of sublines in response to androgen was assessed by WST - 1 assay . In vivo growth of subcutaneous tumors was assessed in castrated and sham - castrated C57BL / 6 mice . RESULTS : The sublines were epithelial and displayed ADI in vitro and in vivo . Compared to the parental lines , these showed ( 1 ) significantly faster growth rates in vitro and in vivo independent of androgen depletion , ( 2 ) greater tumorigenic , and invasive potential in vitro . All showed substantial downregulation in expression levels of tumor suppressor , P12830 , and metastatis suppressor , KAI - 1 . Interestingly , the percentage of cells expressing AR with downregulated P12830 was higher in ADI cells , suggesting a possible interaction between the two pathways . CONCLUSIONS : The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness .",
"Performance of in silico analysis in predicting the effect of non - synonymous variants in inherited steroid metabolic diseases . BACKGROUND : Unclassified genetic variants are commonly encountered in molecular diagnostic service . In silico analyses using web - based predictive programs may provide information on the nature of the genetic variants , and help to prioritize novel variants for in vitro functional characterization . The objective of this study was to compare the performance of three such programs in genes related to steroid metabolism . METHODS : The effects of non - synonymous benign and pathogenic sequence variants in the P05108 , P15538 , P19099 , P05093 , P11511 , P08686 , Q9UBM7 , P26439 , P80365 , P37058 , P16435 , and P31213 genes listed in the Human Gene Mutation Database and dbSNP were tested by SIFT , PolyPhen - 2 and P27169 - P . Their concordance , sensitivity , specificity , positive and negative predictive values and accuracy were assessed , using the reported phenotype and the in vitro functional data as gold standards . RESULTS : 797 sequence variants were tested . SIFT and PolyPhen - 2 had high concordance , with PolyPhen - 2 being slightly superior to SIFT in all assessments . P27169 - P behaved differently , with one - third of the variants unclassified . CONCLUSIONS : SIFT and PolyPhen - 2 behaved similarly while P27169 - P behaved differently in predicting pathogenicity in genes related to steroid metabolism . Molecular pathologists should verify the performance of these programs before considering them in clinical decision making , and be aware that these programmes can not replace in vitro function studies . Clinicians and patients should also be informed about the limitations of genetic testing , particularly when a novel variant is encountered .",
"The genes encoding cytokines P60568 , P22301 and P29460 are primary DB00136 target genes . A number of studies have described the effects of DB00136 in immune system . Most of the known effects of DB00136 are indirect since only two functional VDREs that regulate transcription of cytokine gene has been reported until today . In this study we have examined a possibility of direct transcriptional regulation of P60568 , P22301 and P29460 genes in activated Jurkat or THP - 1 cells via liganded P11473 by using gene expression analysis and chromatin immunoprecipitation assays . According to our data the P60568 , P22301 and P29460 genes respond to DB00136 treatment by 3 - 6 h . In addition , all of these genes contain several genomic regions that recruit P11473 in a ligand dependent fashion . These data suggest that the above cytokines are under direct transcriptional regulation by DB00136 .",
"Role of TGFbeta / Smad signaling in gremlin induction of human trabecular meshwork extracellular matrix proteins . PURPOSE : The bone morphogenic protein ( BMP ) antagonist gremlin is elevated in glaucomatous trabecular meshwork ( TM ) cells and tissues and elevates intraocular pressure ( IOP ) . Gremlin also blocks P12644 inhibition of transforming growth factor ( TGF ) - β2 induction of TM extracellular matrix ( Q13201 ) proteins . The purpose of this study was to determine whether Gremlin regulates Q13201 proteins in cultured human TM cells . METHODS : Human TM cells were treated with recombinant gremlin to determine the effects on Q13201 gene and protein expression . Expression of the Q13201 genes FN , COL1 , P05121 , and P15502 was examined in cultured human TM cells by quantitative RT - PCR and Western immunoblot analysis . TM cells were pretreated with TGFBR inhibitors ( LY364947 , SB431542 or P36897 / P61812 siRNAs ) , inhibitors of the Smad signaling pathway ( SIS3 or Q15796 / 3 / 4 siRNAs ) , or P29279 siRNA to identify the signaling pathway ( s ) involved in gremlin induction of Q13201 gene and protein expression . RESULTS : All Q13201 genes analyzed ( FN , COL1 , P05121 , and P15502 ) were induced by gremlin . This gremlin induction of Q13201 genes and protein expression was blocked by inhibitors of TGFBR and the canonical Q15796 / 3 / 4 and P29279 signaling pathways . CONCLUSIONS : Gremlin employs canonical TGFβ2 / Smad signaling to induce Q13201 genes and proteins in cultured human TM cells . Gremlin also induces both TGFβ2 and P29279 , which can act downstream to mediate some of these Q13201 changes in TM cells .",
"20 - Hydroxycholecalciferol , product of vitamin D3 hydroxylation by P450scc , decreases NF - kappaB activity by increasing IkappaB alpha levels in human keratinocytes . The side chain of vitamin D3 is hydroxylated in a sequential manner by cytochrome P450scc ( P05108 ) to form 20 - hydroxycholecalciferol , which can induce growth arrest and differentiation of both primary and immortalized epidermal keratinocytes . Since nuclear factor - kappaB ( NF - kappaB ) plays a pivotal role in the regulation of cell proliferation , differentiation and apoptosis , we examined the capability of 20 - hydroxycholecalciferol to modulate the activity of NF - kappaB , using DB00136 ( calcitriol ) as a positive control . 20 - hydroxycholecalciferol inhibits the activation of NFkappaB DNA binding activity as well as NF - kappaB - driven reporter gene activity in keratinocytes . Also , 20 - hydroxycholecalciferol induced significant increases in the mRNA and protein levels of the NF - kappaB inhibitor protein , IkappaB alpha , in a time dependent manner , while no changes in total NF - kappaB - p65 mRNA or protein levels were observed . Another measure of NF - kappaB activity , p65 translocation from the cytoplasm into the nucleus was also inhibited in extracts of 20 - hydroxycholecalciferol treated keratinocytes . Increased IkappaB alpha was concomitantly observed in cytosolic extracts of 20 - hydroxycholecalciferol treated keratinocytes , as determined by immunoblotting and immunofluorescent staining . In keratinocytes lacking vitamin D receptor ( P11473 ) , 20 - hydroxycholecalciferol did not affect IkappaB alpha mRNA levels , indicating that it requires P11473 for its action on NF - kappaB activity . Comparison of the effects of calcitrol , hormonally active form of vitamin D3 , with 20 - hydrocholecalciferol show that both agents have a similar potency in inhibiting NF - kappaB . Since NF - kappaB is a major transcription factor for the induction of inflammatory mediators , our findings indicate that 20 - hydroxycholecalciferol may be an effective therapeutic agent for inflammatory and hyperproliferative skin diseases .",
"Long pentraxin - 3 as an epithelial - stromal fibroblast growth factor - targeting inhibitor in prostate cancer . Fibroblast growth factors ( FGFs ) exert autocrine / paracrine functions in prostate cancer by stimulating angiogenesis and tumour growth . Here dihydrotestosterone ( DB02901 ) up - regulates P09038 and FGF8b production in murine TRAMP - P06681 prostate cancer cells , activating a FGF - dependent autocrine loop of stimulation . The soluble pattern recognition receptor long pentraxin - 3 ( PTX3 ) acts as a natural FGF antagonist that binds P09038 and FGF8b via its N - terminal domain . We demonstrate that recombinant PTX3 protein and the PTX3 - derived pentapeptide Ac - ARPCA - NH2 abolish the mitogenic response of murine TRAMP - P06681 cells and human LNCaP prostate cancer cells to DB02901 and FGFs . Also , PTX3 hampers the angiogenic activity of DB02901 - activated TRAMP - P06681 cells on the chick embryo chorioallantoic membrane ( P62158 ) . Accordingly , human PTX3 overexpression inhibits the mitogenic activity exerted by DB02901 or FGFs on hPTX3_TRAMP - P06681 cell transfectants and their angiogenic activity . Also , hPTX3_TRAMP - P06681 cells show a dramatic decrease of their angiogenic and tumourigenic potential when grafted in syngeneic or immunodeficient athymic male mice . A similar inhibitory effect is observed when TRAMP - P06681 cells overexpress only the FGF - binding N - terminal PTX3 domain . In keeping with the anti - tumour activity of PTX3 in experimental prostate cancer , immunohistochemical analysis of prostate needle biopsies from primary prostate adenocarcinoma patients shows that parenchymal PTX3 expression , abundant in basal cells of normal glands , is lost in high - grade prostatic intraepithelial neoplasia and in invasive tumour areas . These results identify PTX3 as a potent FGF antagonist endowed with anti - angiogenic and anti - neoplastic activity in prostate cancer .",
"P02818 promotes differentiation of osteoclast progenitors from murine long - term bone marrow cultures . Murine long - term bone marrow cultures ( LTBMCs ) were used to generate hematopoietic cells free from marrow stromal cells . These progenitor cells were treated with GM - P04141 ( 5 U / ml ) with or without rat bone osteocalcin or rat serum albumin in either alpha - MEM with 2 % heat - inactivated horse serum alone ( alpha ) or supplemented with 10 % L - cell - conditioned medium ( as a source of P09603 ) ( Q6PL24 ) . Few substrate - attached cells survived in basal alpha medium , but when treated with Q6PL24 medium or GM - P04141 , they survived and proliferated . P02818 did not significantly affect survival or proliferation . Subcultures of cells treated with GM - P04141 had large numbers of multinucleated cells , more than half of which were tartrate - resistant acid phosphatase - positive ( TRAP ) . P02818 further promoted the development of TRAP - positive multinucleated cells ; a dose of 0 . 7 microgram / ml osteocalcin promoted osteoclastic differentiation by 60 % . Using a novel microphotometric assay , we detected significantly more tartrate - resistant acid phosphatase activity in the osteocalcin plus GM - P04141 group ( 75 . 6 +/- 14 . 2 ) than in GM - P04141 alone ( 53 . 3 +/- 7 . 3 ) . In the absence of P09603 , GM - P04141 stimulated tartrate - resistant acid phosphatase activity , but osteocalcin did not have an additional effect . These studies indicate that osteocalcin promotes osteoclastic differentiation of a stromal - free subpopulation of hematopoietic progenitors in the presence of GM - P04141 and L - cell - conditioned medium . These results are consistent with the hypothesis that this bone - matrix constituent plays a role in bone resorption .",
"P00797 and prorenin have no direct effect on aldosterone synthesis in the human adrenocortical cell lines H295R and HAC15 . INTRODUCTION : Transgenic rats expressing the human ( pro ) renin receptor ( h ( P ) RR ) have elevated plasma aldosterone levels despite unaltered levels , in plasma and adrenal , of renin and angiotensin II . MATERIALS AND METHODS : To investigate whether renin / prorenin -( P ) RR interaction underlies these elevated aldosterone levels , the effect of ( pro ) renin on steroidogenesis was compared with that of angiotensin II in two ( P ) RR - expressing human adrenocortical cell lines , H295R and HAC15 . Angiotensin II rapidly induced extracellular signal - regulated kinase ( P29323 ) phosphorylation and increased the expression of STAR , P08686 , P19099 , and P05093 at 6 and 24 hours , whereas the expression of P05108 and P26439 remained unaltered . Incubation with renin or prorenin at nanomolar concentrations had no effect on the expression of any of the steroidogenic enzymes tested , nor resulted in P29323 phosphorylation . Angiotensin II , but not renin or prorenin , induced aldosterone production . CONCLUSION : Although the ( P ) RR is present in adrenocortical cells , renin and prorenin do not elicit P29323 phosphorylation nor directly affect steroid production via this receptor at nanomolar concentrations . Thus , direct ( pro ) renin -( P ) RR interaction is unlikely to contribute to the elevated aldosterone levels in human ( P ) RR transgenic rats . This conclusion also implies that the aldosterone rise that often occurs during prolonged renin - angiotensin system blockade is rather due to the angiotensin II ' escape ' during such blockade .",
"DB00136 induces capacitative calcium entry involving a Q13507 protein in skeletal muscle and osteoblastic cells . This work describes the involvement of TRPC proteins in capacitative calcium entry ( CCE ) induced by 1alpha , 25 - dihydroxy - vitamin - D3 [ DB00136 ] in chick skeletal muscle and in rat osteoblast - like cells ( ROS 17 / 2 . 8 ) and the role of the vitamin D receptor ( P11473 ) in this non - genomic rapid response mediated by the hormone . We propose that an endogenous Q13507 protein mediates DB00136 modulation of CCE in these cells , which seems to implicate P11473 - Q13507 association and the participation of an INAD - like scaffold protein .",
"1Alpha , 25 ( OH ) 2D3 - induced transrepression by vitamin D receptor through E - box - type elements in the human parathyroid hormone gene promoter . Although transactivation by the liganded vitamin D receptor ( P11473 ) is well described at the molecular level , the precise molecular mechanism of negative regulation by the liganded P11473 remains to be elucidated . We have previously reported a novel class of negative vitamin D response element ( nVDRE ) called 1alphanVDRE in the human 25 ( OH ) D31alpha - hydroxylase [ 1alpha ( OH ) ase ] gene by DB00136 - bound P11473 . This element was composed of two E - box - type motifs that bound to VDIR for transactivation , which was attenuated by liganded P11473 . Here , we explore the possible functions of VDIR and E - box motifs in the human ( h ) PTH and hPTHrP gene promoters . Functional mapping of the DB05829 and hPTHrP promoters identified E - box - type elements acting as nVDREs in both the DB05829 promoter ( hPTHnVDRE ; - 87 to - 60 bp ) and in the hPTHrP promoter ( hPTHrPnVDRE ; - 850 to - 600 bp ; - 463 to - 104 bp ) in a mouse renal tubule cell line . The hPTHnVDRE alone was enough to direct ligand - induced transrepression mediated through P11473 / retinoid X receptor and VDIR . Direct DNA binding of hPTHnVDRE to VDIR , but not P11473 / retinoid X receptor , was observed and ligand - induced transrepression was coupled with recruitment of P11473 and histone deacetylase 2 ( Q92769 ) to the DB05829 promoter . These results suggest that negative regulation of the DB05829 gene by liganded P11473 is mediated by VDIR directly binding to the E - box - type nVDRE at the promoter , together with recruitment of an HDAC corepressor for ligand - induced transrepression .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK68___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK68___ who were treated with a single dose of mifepristone .",
"The role of selectins and P05107 in leukotriene B4 - mediated white blood cell emigration in human skin grafts transplanted on SCID mice . The purpose of this study was to examine the role of selectins and P05107 cell adhesion molecules ( CAMs ) in inflammation induced by injection of leukotriene B4 ( LTB4 ) into human skin . To accomplish this , the expression of CAMs and the ability of specific antibodies against CAMs to block white blood cell ( WBC ) transmigration were studied in an in vivo model consisting of human skin transplanted onto mice with the severe combined immune deficiency ( SCID ) mutation . The results indicate that LTB4 - induced WBC transmigration in the human / SCID model is rapid and pronounced ; however , it is not accompanied by a significant upregulation of the baseline expression of endothelial P16109 , P16581 , P05362 or P19320 . An anti - murine P05107 mAb markedly inhibited white cell infiltration ( 89 % inhibition ) confirming the importance of beta 2 integrins in the process . The role of selectins was also examined . P61006 - 14 , a bioactive antibody against murine P14151 inhibited transmigration by 66 % . A significant , but smaller , effect ( 39 % inhibition ) was observed by blocking P16581 function . These results indicate that LTB4 - induced inflammation does not require upregulation of endothelial P62158 expression and , in contrast to P01375 alpha - induced transmigration , is only partially blocked by anti - P16581 antibodies .",
"Nuclear factor of activated T cells ( NFAT ) as a molecular target for 1alpha , 25 - dihydroxyvitamin D3 - mediated effects . The molecular basis of the immunomodulatory properties of 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) remains elusive . We demonstrate here that DB00136 - mediated suppressive effects on the inducible expression of cytokine genes in human T cells may , in part , be due to diminished activity of the transcription factor NFAT . The vitamin D3 receptor ( P11473 ) and its heterodimeric partner retinoid X receptor alpha ( RXR alpha ) specifically bound to the distal NFAT site in the human P60568 promoter , and this binding was abolished by mutating unique regions in the NFAT oligonucleotide . In vitro inhibition of NFAT complex formation was noted when P11473 - RXR alpha heterodimers were added to DNA binding reactions containing nuclear extracts from activated B or T cells , whereas in vitro NFkappaB complex formation was not significantly influenced . Furthermore , DB00136 treatment of activated T cells resulted in decreased formation of NFAT complexes detected upon incubation of nuclear extracts from these cells with 32P - labeled probe . Transient expression of both P11473 and RXR alpha , but not of a single component , was capable of inhibiting expression of a NFAT - driven reporter gene in stimulated jurkat cells in a ligand - dependent manner . These results suggest that NFAT plays a crucial role in DB00136 - mediated immunosuppressive activity .",
"A concise and efficient route to 2alpha -( omega - hydroxyalkoxy )- 1alpha , 25 - dihydroxyvi tam in D3 : remarkably high affinity to vitamin D receptor . [ reaction : see text ] A convenient and potentially valuable synthetic approach to the novel 2alpha - functionalized 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] derivatives ( 1a - c ) , which are the P06681 - epimer of ED - 71 and its analogues , has been developed . The C2alpha - modified ring A precursors ( 1 , 7 - enynes 16 , n = 0 , 1 , and 2 ) were constructed stereoselectively starting from D - glucose in high yield . In the synthesized 2alpha -( omega - hydroxyalkoxy )- DB00136 derivatives , 1a and 1b showed a greater binding affinity to vitamin D receptor ( P11473 ) , up to 1 . 8 times that of the native hormone .",
"A P35354 metabolite of the endogenous cannabinoid , 2 - arachidonyl glycerol , mediates suppression of P60568 secretion in activated Jurkat T cells . Previous studies from this laboratory have demonstrated that a P35354 metabolite of the endogenous cannabinoid , 2 - arachidonyl glycerol ( 2 - AG ) , inhibits P60568 secretion in activated T cells through PPARgamma activation independent of the cannabinoid receptors , P21554 / CB2 . Because numerous cyclooxygenase ( P36551 ) products have been shown to activate PPARgamma , the primary purpose of the present studies was to determine the role of P36551 metabolism in the inhibition of P60568 secretion by 2 - AG . Pretreatment with nonselective and P35354 - specific inhibitors completely abrogated 2 - AG - mediated suppression of P60568 secretion . In contrast , pretreatment with P23219 - specific inhibitors had no effect upon 2 - AG - mediated inhibition of P60568 secretion . Interestingly , the current studies also demonstrate that while the potency of 2 - AG is comparable between human Jurkat T cells and murine splenocytes , anandamide ( AEA ) is markedly more potent in suppressing P60568 production in Jurkat T cells compared to murine splenocytes . Additionally , the present studies also demonstrate that P35354 protein is readily detectable in resting Jurkat T cells , which is in contrast to resting murine splenocytes in which P35354 protein is virtually undetectable . Furthermore , P35354 protein and mRNA levels are significantly increased over basal levels by 2h following activation of Jurkat cells , whereas increases in P35354 protein in murine splenocytes are not observed until 4h after cellular activation . These studies suggest that the potency of AEA in the suppression of P60568 secretion may correlate with P35354 protein levels in different T cell models . The present studies are also significant in that they demonstrate 2 - AG - mediated inhibition of P60568 secretion is dependent upon P35354 metabolism .",
"Prox1 and Q99958 act as regulators of lymphangiogenesis and angiogenesis in oral squamous cell carcinoma . Prospero homeobox 1 ( Prox1 ) and forkhead box ( FOX ) P06681 regulate angiogenesis and / or lymphangiogenesis . However , the detailed role and function of Prox1 and Q99958 in cancer remains controversial . In the present study , we examined the expression of Prox1 and Q99958 proteins in specimens from 163 cases with oral squamous cell carcinoma ( OSCC ) . Furthermore , the role of Prox1 and Q99958 in cancer cell growth and invasion was evaluated in cultured OSCC cells . Prox1 expression was significantly associated with local progression of the tumor ( P = 0 . 0023 ) , clinical stage ( P < 0 . 0001 ) , lymphovessel density ( LVD ) ( P < 0 . 0001 ) , nodal metastasis ( P < 0 . 0001 ) , and worse prognosis ( P < 0 . 0001 ) . Immunoreactivity of Q99958 was strongly correlated with microvessel density ( P53602 ) ( P < 0 . 0001 ) and poor prognosis ( P = 0 . 0076 ) . In vitro analysis demonstrated that Prox1 regulates cell growth , proliferation , invasion , and lymphangiogenesis by activating vascular endothelial growth factor ( P15692 ) - C expression . Furthermore , Q99958 enhanced the expression level of Prox1 and promoted angiogenesis by enhancement of P15692 expression . Our results suggested that Prox1 and Q99958 play key roles in OSCC progression and that further studies focusing on these proteins may yield useful insights for diagnosis and therapy of OSCC .",
"Perinuclear localization of cytosolic phospholipase A ( 2 ) alpha is important but not obligatory for coupling with cyclooxygenases . In response to Ca ( 2 +) signaling , cytosolic phospholipase A ( 2 ) alpha ( cPLA ( 2 ) alpha ) translocates from the cytosol to the perinuclear membrane , where downstream eicosanoid - synthetic enzymes , such as cyclooxygenase ( P36551 ) , are localized . Although the spatiotemporal perinuclear colocalization of cPLA ( 2 ) alpha and COXs has been proposed to be critical for their functional coupling leading to prostanoid production , definitive evidence for this paradigm has remained elusive . To circumstantiate this issue , we took advantage of a chimeric cPLA ( 2 ) alpha mutant harboring the P06681 domain of protein kinase Calpha , which translocates to the plasma membrane following cell activation . Transfection analyses of the native or chimeric cPLA ( 2 ) alpha in combination with P23219 or P35354 revealed that , even though the arachidonate - releasing capacities of native and mutant cPLA ( 2 ) alpha were comparable , prostaglandin production by mutant cPLA ( 2 ) alpha was markedly impaired as compared with that by native cPLA ( 2 ) alpha . We thus conclude that the perinuclear localization of cPLA ( 2 ) alpha is preferential , even if not obligatory , for efficient coupling with COXs .",
"TRP expression pattern and the functional importance of Q13507 in primary human T - cells . TRP proteins form ion channels which are activated following receptor stimulation . In T - cell lines , expression data of TRP proteins have been published . However , almost no data about TRP expression is available in primary human T - cells . Using RT - PCR and quantitative RT - PCR , we compare the expression of TRP mRNA in 1 ) human peripheral blood lymphocytes , which are a mix of mostly mono - nuclear blood lymphocytes but contain other leucocytes , 2 ) a pure human P01730 + T - helper cell population in the resting ( = naïve ) and activated ( = effector ) state , and 3 ) two commonly used P01730 + Jurkat T - cell lines , E6 - 1 and parental . To mimic physiological cell stimulation , we analyzed TRP expression in primary human cells in a quantitative way over several days following formation of an immunological synapse through stimulation with antibody - coated beads . The TRP expression profile of primary human T - cells was significantly different from Jurkat T - cells . Among the TRP mRNAs of the TRPC , TRPM , and TRPV family , we found consistent expression of P48995 , Q13507 , Q8NER1 , O94759 , and Q96QT4 in primary human P01730 + T - cells of all analyzed blood donors . Among these , Q13507 and O94759 were strongly up - regulated following stimulation , but with different kinetics . We found that Q13507 modulates Ca² +- dependent proliferation of primary P01730 + T - cells indicating that Q13507 may be involved in Ca² + homeostasis in T - cells besides the well - established STIM and ORAI proteins which are responsible for store - operated Ca² + entry .",
"[ Gene polymorphism of the vitamin D receptor , vitamin D - binding protein and calcium - sensing receptor in respect of calcium - phosphate disturbances in chronic dialysis patients ] . Dialysed patients suffering from chronic kidney disease ( CKD ) show varied levels of concentration of parathyroid hormone ( PTH ) in the blood . One of the factors in charge of regulating levels of PTH concentration is DB00136 [ 1 , 25 -( OH ) 2D3 ] . Its deficiency in advanced stages of CKD is common . Vitamin D supplementation is not always effective in reaching levels of PTH concentration recommended by KDIGO for the dialysed patients . That suggests , among other things , disturbances in 1 , 25 -( OH ) 2D3 , reaching its place of target effect and having the desired final result . Disturbances of vitamin D target pathway can be genetically conditioned , hence the aim of this paper is to describe the distribution of polymorphic variants of vitamin D - binding protein gene ( VDBP ) , vitamin D receptor gene ( P11473 ) and gene of the calcium - sensing receptor ( P41180 ) with respect to PTH concentrations in serum and response to cinacalcet treatment in patients with secondary hyperparathyroidism in view of the differences in demographical , clinical and laboratory data of the dialysed patients .",
"The calcium - sensing receptor -- a driver of colon cell differentiation . Dietary Ca ( 2 +) reduces colon cell proliferation and carcinogenesis , but it becomes ineffective or even tumor - promoting during carcinogenesis . It appears that Ca ( 2 +) and the colon cell P41180 together brake the massive cell production in normal colon crypts . The rapid proliferation of the transit - amplifying ( TA ) progeny of the colon stem cells at the bases of the crypts is driven by the \" Wnt \" signaling mechanism that stimulates proliferogenic genes and prevents apoptogenesis . It appears that TA cell cycling stops and terminal differentiation starts when the cells reach a higher level in the crypt where there is enough external Ca ( 2 +) to stimulate the expression of CaSRs , the signals from which stimulate the expression of P12830 . At this point the P25054 ( adenomatous polyposis coli ) protein appears and some of it enters the nucleus . There it removes the apoptogenesis shield and stops the beta - cateninTcf - 4 complex from driving further TA cell proliferation by releasing beta - catenin from the nucleus , and delivering it to cytoplasmic APCaxinGSK - 3beta complexes for ultimate proteasomal destruction . Cytoplasmic beta - catenin is prevented from returning to the nucleus by destruction in APCaxinGSK - 3beta complexes or locked by the emerging P12830 into adherens junctions which link the cell to proliferatively shut - down functioning cells with P25054 - dependent cytoskeletons moving up and out of the crypt . A common first step in colon carcinogenesis is the loss of functional P25054 which results in the retention of proliferogenic nuclear beta - cateninTcf - 4 . This drives the eventual appearance of mutation accumulating , apoptosis - resistant clones the proliferation of which can not be inhibited by external Ca ( 2 +) because of P41180 - disabling gene mutations .",
"Exposure to an organophosphate ( ___MASK65___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK65___ ( ___MASK65___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK65___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK65___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK65___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .",
"Differential display cloning of a novel human histone deacetylase ( O15379 ) cDNA from PHA - activated immune cells . The nucleosomal histones can be modified through reversible acetylation by histone acetyltransferases ( HATs ) and deacetylases ( HDACs ) . HATs induce nucleosomal relaxation and allow DNA - binding by transcriptional activators . HDACs from corepressor complexes which negatively regulate cell growth . However , the HDAC inhibitors butyrate and Trichostatin A block T cell proliferation , suggesting that not all effects of HDACs lead to repression . Using mRNA differential display and 5 ' RACE we isolated human O15379 , a novel gene that is upregulated in PHA - activated T cell clones . O15379 is homologous to other human HDACs and yeast RPD3 . In peripheral blood mononuclear cells ( PBMCs ) , activation by PHA , PMA and alpha - CD3 increased HDAC mRNA but no effect was seen with P01579 , LPS , or P05112 . In contrast , P04141 downregulated PBMC levels of O15379 mRNA . All HDACs were found to be ubiquitously expressed in immune and non - immune tissues . In human myeloid leukemia THP - 1 cells , O15379 transfection resulted in increased size , aberrant nuclear morphology and cell cycle G2 / M cell accumulation . Functional activity of the expressed O15379 protein was confirmed in alpha - O15379 antibody immunoprecipitates by a histone deacetylase assay . Our study suggests the participation of HDACs in cell cycle progression and activation .",
"The biological activities of 1alpha , 25 - dihydroxyvitamin D3 and its synthetic analog 1alpha , 25 - dihydroxy - 16 - ene - vitamin D3 in normal human osteoblastic cells and human osteosarcoma SaOS - 2 cells are modulated by 17 - beta estradiol and dependent on stage of differentiation . We compared the effects of 1alpha , 25 - dihydroxyvitamin D3 [ DB00136 ] and its analog , 1alpha , 25 - dihydroxy - 16 - ene - vitamin D3 [ 1alpha , 25 ( OH ) 2 - 16 - ene - D3 ] , as well as their interactions with 17 - beta estradiol ( E2 ) on osteoblastic function in our human normal ( HOB ) and osteosarcoma SaOS - 2 cell models representing two different stages of differentiation , the more differentiated HOB + DEX cells and SaOS + DEX cells , and the corresponding less differentiated HOB - DEX and SaOS - DEX cells . The differential effects of DB00136 and 1alpha , 25 ( OH ) 2 - 16 - ene - D3 and the modulation by E2 on ALP activity in HOB - DEX and HOB + DEX cells were small but significant . The most significant effects were seen in SaOS + DEX cells , in which 1alpha , 25 ( OH ) 2 - 16 - ene - D3 was 100 - fold more potent than DB00136 , the maximal enhancement being exerted at 0 . 1 nM and 10 nM , respectively . E2 enhanced the stimulatory effects of both compounds , with ALP being increased 2 - fold at 0 . 1 nM ( p < 0 . 001 ) . P02818 ( OC ) production in HOB - DEX cells was stimulated 1 . 3 to 1 . 4 - fold by DB00136 and 1alpha , 25 ( OH ) 2 - 16 - ene - D3 at a concentration of 0 . 01 nM , with E2 inhibiting the effect of 1alpha , 25 ( OH ) 2 - 16 - ene - D3 . In SaOS - DEX and SaOS + DEX cells , DB00136 and 1alpha , 25 ( OH ) 2 - 16 - ene - D3 stimulated OC production 1 . 6 - fold at 0 . 1 nM with E2 slightly enhancing the effect of DB00136 . Western blot analysis of DB00136 receptor ( P11473 ) levels showed that in SaOS + DEX cells , the effect of DB00136 was larger than that of 1alpha , 25 ( OH ) 2 - 16 - ene - D3 . These results show that 1alpha , 25 ( OH ) 2 - 16 - ene - D3 is biologically active in human osteoblasts .",
"Antagonistic action of novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone analogs on differentiation of human leukemia cells ( HL - 60 ) induced by 1alpha , 25 - dihydroxyvitamin D3 . We examined the effects of two novel 1alpha , 25 - dihydroxyvitamin D3 - 26 , 23 - lactone ( 1alpha , 25 - lactone ) analogues on human promyelocytic leukemia cell ( HL - 60 ) differentiation using the evaluation system of the vitamin D nuclear receptor ( P11473 ) / vitamin D - responsive element ( DRE ) - mediated genomic action stimulated by 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) and its analogues . We found that the 1alpha , 25 - lactone analogues ( 23S ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9647 ) , and ( 23R ) - 25 - dehydro - 1alpha - hydroxyvitamin - D3 - 26 , 23 - lactone ( TEI - 9648 ) bound much more strongly to the P11473 than the natural ( 23S , 25R ) - DB00136 - 26 , 23 - lactone , but did not induce cell differentiation even at high concentrations ( 10 (- 6 ) M ) . Intriguingly , the differentiation of HL - 60 cells induced by DB00136 was inhibited by either TEI - 9647 or TEI - 9648 but not by the natural lactone . In contrast , retinoic acid or 12 - O - tetradecanoylphorbol - 13 - acetate - induced HL - 60 cell differentiation was not blocked by TEI - 9647 or TEI - 9648 . In separate studies , TEI - 9647 ( 10 (- 7 ) M ) was found to be an effective antagonist of both DB00136 ( 10 (- 8 ) M ) mediated induction of P38936 ( P38936 , CIP1 ) in HL - 60 cells and activation of the luciferase reporter assay in COS - 7 cells transfected with cDNA containing the DRE of the rat DB00146 - 24 - hydroxylase gene and cDNA of the human P11473 . Collectively the results strongly suggest that our novel 1alpha , 25 - lactone analogues , TEI - 9647 and TEI - 9648 , are specific antagonists of 1alpha , 25 ( OH ) 2D3 action , specifically P11473 / DRE - mediated genomic action . As such , they represent the first examples of antagonists , which act on the nuclear P11473 .",
"Inhibition of histone deacetylase causes emphysema . In patients with chronic obstructive pulmonary disease ( P48444 ) , histone deacetylase ( HDAC ) expression and activity are reduced in the lung tissue . However , whether HDAC activity controls the maintenance of the lung alveolar septal structures has not been investigated . To explore the consequences of HDAC inhibition and address the question of whether HDAC inhibition causes lung cell apoptosis and emphysema , male Sprague - Dawley rats and human pulmonary microvascular endothelial cells ( HPMVEC ) were treated with trichostatin A ( P32119 ) , a specific inhibitor of HDACs . Chronic P32119 treatment increased the alveolar air space area , mean linear intercept , and the number of caspase - 3 - positive cells in rat lungs . P32119 suppressed hypoxia - inducible factor - 1α ( HIF - 1α ) , P15692 , and lysyl oxidase ( P28300 ) and increased microtubule - associated protein - 1 light chain 3 ( LC3 ) , p53 , and miR34a microRNA expression in both rat lungs and cultured HPMVEC . Gene silencing of Q92769 using small interfering RNA ( siRNA ) in cultured HPMVEC resulted in the suppression of HIF - 1α , P15692 , and P28300 and an increase of p53 expression . These data indicate that HDAC inhibition causes emphysema and that HDAC - dependent mechanisms contribute to the maintenance of the adult lung structure . Our results also suggest that the increase in apoptosis , as a consequence of HDAC inhibition , is associated with decreased P15692 and HIF - 1α expression .",
"Detection of melamine in infant formula and grain powder by surface - assisted laser desorption / ionization mass spectrometry . We have developed a method for the determination of melamine ( P61006 ) , ammeline ( Q9BXJ7 ) , and ammelide ( AMD ) by surface - assisted laser desorption / ionization mass spectrometry ( SALDI - MS ) using gold nanoparticles ( Au NPs ) . The major peaks for P61006 , Q9BXJ7 , and AMD at m / z 127 . 07 , 128 . 05 , and 129 . 04 are assigned to the [ P61006 + H ] (+) , [ Q9BXJ7 + H ] (+) , and [ AMD + H ] (+) ions . Because the three tested compounds adsorb weakly onto the surfaces of the Au NPs through Au - N bonding , they can be easily concentrated from complex samples by applying a simple trapping / centrifugation process . The SALDI - MS method provides limits of detection of 5 , 10 , and 300 nM for P61006 , Q9BXJ7 , and AMD , respectively , at a signal - to - noise ratio of 3 . The signal variation for 150 - shot average spectra of the three analytes within the same spot was 15 % , and the batch - to - batch variation was 20 % . We have validated the practicality of this approach by the analysis of these three analytes in infant formula and grain powder . This simple and rapid SALDI - MS approach holds great potential for screening of P61006 in foods .",
"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .",
"Osteoclast progenitors from cats with and without tooth resorption respond differently to 1 , 25 - dihydroxyvitamin D and interleukin - 6 . Both vitamin D and inflammatory cytokines can stimulate osteoclast formation and activity . We studied the effect of DB00136 ( 1 , 25 ( OH )( 2 ) D ) , and interleukin - 6 ( P05231 ) , on the formation and activity of feline osteoclasts , using peripheral blood mononuclear cells ( PBMCs ) from cats with and without tooth resorption ( TR (+) and TR (-) ) as a source of osteoclast precursors . The formation of osteoclast - like cells ( defined as multinucleated , tartrate - resistant acid phosphatase - positive cells ) was assessed at 7 and 14 days . In the presence of P09603 and O14788 , with and without P05231 , more osteoclasts were formed from TR (-) PBMCs than from TR (+) PBMCs on plastic . More osteoclasts were formed from TR (+) PBMCs on bone slices in the presence of P09603 / O14788 with 1 , 25 ( OH )( 2 ) D . This opposite effect may be due to a higher expression of the vitamin D receptor ( P11473 ) in TR (+) osteoclasts and precursors on bone . Formation of resorption pits was analyzed and confirmed with scanning electron microscopy . In conclusion , we propose that TR (+) PBMCs when cultured on bone are sensitive to 1 , 25 ( OH )( 2 ) D , whereas the differentiation of TR (-) PMBCs on bone seem more sensitive to P05231 , suggesting that osteoclast precursors from cats with and without tooth resorption respond differently to osteoclast stimulating factors .",
"Role of vitamin D receptor in the antiproliferative effects of calcitriol in tumor - derived endothelial cells and tumor angiogenesis in vivo . Calcitriol ( DB00136 ) , the major active form of vitamin D , is antiproliferative in tumor cells and tumor - derived endothelial cells ( TDEC ) . These actions of calcitriol are mediated at least in part by vitamin D receptor ( P11473 ) , which is expressed in many tissues including endothelial cells . To investigate the role of P11473 in calcitriol effects on tumor vasculature , we established TRAMP - 2 tumors subcutaneously into either P11473 wild - type ( WT ) or knockout ( KO ) mice . Within 30 days post - inoculation , tumors in KO mice were larger than those in WT ( P < 0 . 001 ) . TDEC from WT expressed P11473 and were able to transactivate a reporter gene whereas TDEC from KO mice were not . Treatment with calcitriol resulted in growth inhibition in TDEC expressing P11473 . However , TDEC from KO mice were relatively resistant , suggesting that calcitriol - mediated growth inhibition on TDEC is P11473 - dependent . Further analysis of the TRAMP - P06681 tumor sections revealed that the vessels in KO mice were enlarged and had less pericyte coverage compared with WT ( P < 0 . 001 ) . Contrast - enhanced magnetic resonance imaging showed an increase in vascular volume of TRAMP tumors grown in P11473 KO mice compared with WT mice ( P < 0 . 001 ) and FITC - dextran permeability assay suggested a higher extent of vascular leakage in tumors from KO mice . Using ELISA and Western blot analysis , there was an increase of hypoxia - inducible factor - 1alpha , vascular endothelial growth factor , angiopoietin 1 , and platelet - derived growth factor - BB levels observed in tumors from KO mice . These results indicate that calcitriol - mediated antiproliferative effects on TDEC are P11473 - dependent and loss of P11473 can lead to abnormal tumor angiogenesis .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK4___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK39___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"Program death - 1 engagement upon TCR activation has distinct effects on costimulation and cytokine - driven proliferation : attenuation of Q9Y6W8 , P05112 , and Q9HBE4 , but not P10747 , P13232 , and P40933 responses . The program death 1 ( P18621 ) receptor and its ligands , P18621 ligand ( PD - L ) 1 and Q9BQ51 , define a novel regulatory pathway with potential inhibitory effects on T , B , and monocyte responses . In the present study , we show that human P01730 (+) T cells express P18621 , Q9NZQ7 , and Q9BQ51 upon activation , and Abs to the receptor can be agonists or antagonists of the pathway . Under optimal conditions of stimulation , Q9Y6W8 but not P10747 costimulation can be prevented by P18621 engagement . P60568 levels induced by costimulation are critical in determining the outcome of the P18621 engagement . Thus , low to marginal P60568 levels produced upon Q9Y6W8 costimulation account for the greater sensitivity of this pathway to P18621 - mediated inhibition . Interestingly , exogenous P60568 , P13232 , and P40933 but not P05112 and Q9HBE4 can rescue P18621 inhibition , suggesting that among these cytokines only those that activate P42229 can rescue P18621 inhibition . As P42229 has been implicated in the maintenance of IL - 2Ralpha expression , these results suggest that P13232 and P40933 restore proliferation under conditions of P18621 engagement by enhancing high - affinity IL - 2R expression and hence , P60568 responsiveness .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK32___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK65___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK65___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK65___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .",
"___MASK92___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK92___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK26___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"In vitro affinity reduction of biologic response modifiers from production buffy coat platelets exposed to recombinant protein receptors . BACKGROUND : Recent studies link biologic response modifiers found in donor platelet ( Q02083 ) concentrates to transfusion reactions . We tested a novel method to deplete BRMs from Q02083 concentrates using apheresis . STUDY DESIGN AND METHODS : Whole blood from 25 donors was treated to yield PLTs for in vitro measurements on Days 2 , 5 , and 7 . On Day 7 , PLTs were filtrated through columns with either antibody - coated agarose or rh - megalin bound to antibody - coated agarose . In addition , we also tested the naked matrix ( agarose ) and another apheresis surface containing rh - cubilin bound to agarose . P98164 and cubilin are parts of the protein complex mediating P51531 endocytosis in the human kidney . RESULTS : Compared to before filtration ( 951 × 10 ( 9 ) ± 41 × 10 ( 9 ) cells / L ) , Q02083 numbers decreased slightly after filtration over both naked ( 859 × 10 ( 9 ) ± 38 × 10 ( 9 ) ) and antibody - coated ( 848 × 10 ( 9 ) ± 41 × 10 ( 9 ) ) matrices ( both p < 0 . 001 vs . before ) . Concentrations of interleukin ( IL ) - 1β , IL - 12 ( p40 ) , IL - 12 ( P08133 ) , and P13232 all decreased by approximately 40 % even in the absence of a recombinant surface . After filtration over rh - cubilin , but not rh - megalin , concentrations of IFN - γ , IL - 1β , tumor necrosis factor - α , IL - 12 , and P13232 all further decreased by 30 % to 50 % . CONCLUSION : In a pilot study of in vitro apheresis to deplete BRMs , we found that cell numbers and function remained largely unaffected by filtration . Significant reductions in BRMs occurred already with agarose . However , apheresis with the multiligand receptor rh - cubilin was able to further decrease concentrations .",
"DB00136 inhibits transcriptional potential of nuclear factor kappa B in breast cancer cells . 1alpha , 25 - Dihydroxyvitamin D ( 3 ) ( VD ( 3 ) ) , the biologically active form of vitamin D , may have either pro - or anti - inflammatory activities because of its diverse actions on nuclear factor kappa B ( NF - kappaB ) . Previous studies indicated that VD ( 3 ) can either activate or inhibit NF - kappaB via Akt - induced I kappaB alpha phosphorylation and increase in I kappaB alpha synthesis respectively . At present , the relevant contribution of each mechanism has not been fully explored . We observed a VD ( 3 )- mediated NF - kappaB inhibitory effect in vitamin D receptor ( P11473 ) - positive MCF - 7 breast cancer cells . We showed that VD ( 3 ) induced P11473 - dependent I kappaB alpha expression but still able to lead on transient NF - kappaB p65 nuclear translocation through Akt - induced I kappaB alpha phosphorylation . Upon TNFalpha stimulation , VD ( 3 ) was not capable to inhibit I kappaB alpha degradation , p65 nuclear translocation and p65 / p50 - DNA binding . Here , we found that VD ( 3 ) strongly repressed p65 transactivation in MCF - 7 cells using Gal4 - p65 chimeras system . P11473 was required for the VD ( 3 )- mediated transrepression and mutations in P11473 affected its suppressive ability . We also demonstrated that neither inhibition of p65 phosphorylation nor acetylation was responsible for the transrepression . In fact , we found that treatment of MCF - 7 cells with histone deacetylase inhibitors abrogated VD ( 3 )- induced p65 transrepression . In addition , knockdown of two nuclear corepressors O15379 and Q9Y618 relieved p65 transactivation and particular TNFalpha - triggered gene expression . In conclusion , the reduction of gene activation by VD ( 3 ) in breast cancer cells was caused by the interference of the transactivation potential of NF - kappaB p65 subunit . Our studies provide a scientific background for rational use of vitamin D in the prevention and treatment of inflammatory diseases .",
"Evidence that Q13507 is a molecular component of the DB00136 - activated capacitative calcium entry ( CCE ) in muscle and osteoblast cells . In chick skeletal muscle and in rat osteoblast - like cells ( ROS 17 / 2 . 8 ) , 1alpha , 25 - dihydroxy - Vitamin - D ( 3 ) [ 1alpha , 25 ( OH )( 2 ) D ( 3 ) ] stimulates release of Ca ( 2 +) from inner stores and extracellular cation influx through both voltage - dependent and capacitative Ca ( 2 +) entry ( CCE ) channels . We investigated the involvement of TRPC proteins in CCE induced by 1alpha , 25 ( OH )( 2 ) D ( 3 ) . Two fragments were amplified by RT - PCR , exhibiting > 85 % sequence homology with human Q13507 . Northern and Western blots employing Q13507 - probes and anti - Q13507 antibodies , respectively , confirmed endogenous expression of a Q13507 - like protein . Both cell types transfected with anti - Q13507 antisense oligodeoxynucleotides showed reduced CCE and Mn ( 2 +) entry induced by either thapsigargin or 1alpha , 25 ( OH )( 2 ) D ( 3 ) . In muscle cells , anti - P11473 antisense inhibited steroid - induced Ca ( 2 +) and Mn ( 2 +) influx and co - immunoprecipitation of Q13507 and P11473 was observed , suggesting an association between both proteins and a functional role of the receptor in 1alpha , 25 ( OH )( 2 ) D ( 3 ) activation of CCE . In osteoblasts , two PCR fragments showing high homology with human INAD - like sequences were obtained . Northern blot and antisense functional assays suggested the involvement of the INAD - like protein in CCE regulation by the hormone . Therefore , we propose that an endogenous Q13507 protein mediates 1alpha , 25 ( OH )( 2 ) D ( 3 ) modulation of CCE in muscle and osteoblastic cells , which seems to implicate P11473 - Q13507 association and the participation of a INAD - like scaffold protein .",
"Tissue expression of Q13507 and Q9Y210 in hypertensive Munich Wistar Frömter rats showing proteinuria . BACKGROUND : We investigated whether alterations of transient receptor potential canonical ( TRPC ) channel expression may be observed in tissues from Munich Wistar Frömter ( MWF ) rats showing proteinuria compared to control Wistar rats . METHODS : TRPC expression was investigated in tissue from MWF and Wistar rats using quantitative real time PCR , immunoblotting , and immunohistochemistry . RESULTS : Compared to Wistar rats MWF rats showed significantly increased systolic blood pressure and significantly higher left ventricle weight ( each p < 0 . 01 ) . Quantitative real time PCR revealed that Q13507 transcripts were significantly higher in kidney cortex from MWF rats compared to Wistar rats ( p < 0 . 01 ) . Q13507 transcripts were not significantly different in kidney medulla nor in aorta from both groups ( p = n . s . ) . Furthermore , Q9Y210 transcripts were significantly lower in kidney cortex from MWF rats compared to Wistar rats ( p < 0 . 001 ) . Immunoblotting showed that Q13507 channel protein expression was also significantly higher in kidney cortex from MWF rats compared to Wistar rats ( p < 0 . 01 ) . There was a significant correlation of Q13507 mRNA and a specific marker for endothelium , P04275 ( P04275 ; Spearman r = 0 . 564 ; p < 0 . 01 ) . We observed a significant correlation between the Q13507 transcripts to Q9Y210 transcripts ratio in kidney cortex and urinary albumin excretion ( Spearman r = 0 . 785 , p < 0 . 001 ) . CONCLUSION : Altered TRPC expression pattern in kidney cortex is associated with kidney damage in MWF rats showing hypertension and albuminuria ."
] |
[
"___MASK26___",
"___MASK32___",
"___MASK39___",
"___MASK4___",
"___MASK65___",
"___MASK67___",
"___MASK68___",
"___MASK80___",
"___MASK92___"
] |
___MASK26___
|
MH_train_434
|
interacts_with DB06603?
|
[
"The relationship of CD133 , histone deacetylase 1 and thrombospondin - 1 in gastric cancer . BACKGROUND / AIM : Gastric cancer is one of the most common types of cancer . Cancer stem cells ( CSCs ) have been reported to play important roles in multiple cancer types . This study investigated the correlation between cluster of differentiation 133 ( CD133 ) , histone deacetylase 1 ( Q13547 ) and thrombospondin - 1 ( P07996 ) expression in advanced gastric cancer . MATERIALS AND METHODS : The study included 65 patients with gastric cancer with recurrence after surgery . Expression of CD133 , Q13547 and P07996 was examined by immunohistochemistry . Prognostic factors were investigated by multivariate analysis using Cox ' s proportional hazard model . RESULTS : Clinicopathological variables , including survival , of patients positive for CD133 expression ( n = 6 , 23 % ) , were compared with those without CD133 expression ( n = 20 , 77 % ) . Positive Q13547 expression and P07996 expression were observed in 34 ( 52 % ) and 17 ( 26 % ) patients , respectively . Using univariate analysis , positive expression of CD133 and negative expression of P07996 predicted significantly worse prognosis . Multivariate analysis revealed CD133 - positive and P07996 - negative expression were independent prognostic indicators . CONCLUSION : CD133 expression and P07996 expression were prognostic factors , and a negative relationship between HDAC and P07996 was observed in advanced gastric cancer . These biomarkers may help determine postoperative treatment in patients with gastric cancer .",
"DB00169 upregulated protein 1 suppresses P01375 - α - induced NF - κB activation in hepatocarcinogenesis . Vitamin D ( 3 ) upregulated protein 1 ( Q9H3M7 ) is a candidate tumor suppressor , the expression of which is dramatically reduced in various tumor tissues . In this study , we found that Q9H3M7 expression is suppressed during human hepatic carcinogenesis , and mice lacking Q9H3M7 are much more susceptible to diethylnitrosamine - induced hepatocarcinogenesis compared with wild type mice . Q9H3M7 - deficient tumors proliferated significantly more than wild type tumors and had corresponding changes in the expression of key cell cycle regulatory proteins . In addition , the hepatomitogen - induced response was associated with a considerable increase in the release of P01375 - α and subsequent enhancement of NF - κB activation in Q9H3M7 - deficient mice . When cells were treated with P01375 - α , the Q9H3M7 level was markedly reduced , concomitant with elevated NF - κB activation . Furthermore , the overexpression of Q9H3M7 resulted in the robust suppression of P01375 - α - activated NF - κB activity via association with Q13547 and O15379 . These results indicate that Q9H3M7 negatively regulates hepatocarcinogenesis by suppressing P01375 - α - induced NF - κB activation .",
"Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK66___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .",
"Differential radiosensitisation by ZD1839 ( ___MASK80___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK80___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .",
"P38398 , Q9BXW9 and Chk1 are potential molecular targets for the modulation of a radiation - induced DNA damage response in bystander cells . Radiotherapy is an important treatment option for many human cancers . Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers . The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects . This study aims to elucidate radiation - induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting . Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine ( BrdU ) nuclear foci detection at sites of single stranded DNA . γ P16104 co - localised with these BrdU foci . P38398 and Q9BXW9 foci formed in T98G bystander cells . Using ATR mutant F02 - 98 hTERT and Q13315 deficient GM05849 fibroblasts it could be shown that ATR but not Q13315 was required for the recruitment of Q9BXW9 to sites of replication associated DNA damage in bystander cells whereas P38398 bystander foci were Q13315 - dependent . Phospho - Chk1 foci formation was observed in T98G bystander cells . Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor P55089 - 01 but increased radioresistance of bystander cells . This study identifies P38398 , Q9BXW9 and Chk1 as potential targets for the modulation of radiation response in bystander cells . It adds to our understanding of the key molecular events propagating out - of - field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation .",
"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK82___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .",
"The distal zinc finger domain of Q01196 / Q13465 / EVI1 is an oligomerization domain involved in induction of hematopoietic differentiation defects in primary cells in vitro . Q01196 / Q13465 / EVI1 ( AME ) is a chimeric transcription factor produced by the ( 3 ; 21 ) ( q26 ; q22 ) translocation . This chromosomal translocation is associated with de novo and therapy - related acute myeloid leukemia and with the blast crisis of chronic myelogenous leukemia . AME is obtained by in - frame fusion of the Q01196 and Q13465 / EVI1 ( ME ) genes . The mechanisms by which AME induces a neoplastic transformation in bone marrow cells are unknown . AME interacts with the corepressors CtBP and Q13547 , and it was shown that AME is a repressor in contrast to the parent transcription factors Q01196 and ME , which are transcription activators . Studies with murine bone marrow progenitors indicated that the introduction of a point mutation that destroys the CtBP - binding consensus impairs but does not abolish the disruption of cell differentiation and replication associated with AME expression , suggesting that additional events are required . Several chimeric proteins , such as Q01196 / Q06455 , P11274 / P00519 , and P29590 / RARa , are characterized by the presence of a self - interaction domain critical for transformation . We report that AME is also able to oligomerize and displays a complex pattern of self - interaction that involves at least three oligomerization regions , one of which is the distal zinc finger domain . Although the deletion of this short domain does not preclude the self - interaction of AME , it significantly reduces the differentiation defects caused in vitro by AME in primary murine bone marrow progenitors . The addition of a point mutation that inhibits CtBP binding completely abrogates the effects of AME on differentiation , suggesting that AME induces hematopoietic differentiation defects through at least two separate but cooperating pathways .",
"DB06603 synergizes with bortezomib to induce endoplasmic reticulum stress and ubiquitinated protein accumulation in renal cancer cells . BACKGROUND : Inducing endoplasmic reticulum ( ER ) stress is a novel strategy used to treat malignancies . Inhibition of histone deacetylase ( HDAC ) 6 by the HDAC inhibitor DB06603 hinders the refolding of unfolded proteins by increasing the acetylation of heat shock protein 90 . We investigated whether combining DB06603 with the proteasome inhibitor bortezomib would kill cancer cells effectively by inhibiting the degradation of these unfolded proteins , thereby causing ubiquitinated proteins to accumulate and induce ER stress . METHODS : Caki - 1 , ACHN , and 769 - P cells were treated with DB06603 and / or bortezomib . Cell viability , clonogenicity , and induction of apoptosis were evaluated . The in vivo efficacy of the combination was evaluated using a murine subcutaneous xenograft model . The combination - induced ER stress and ubiquitinated protein accumulation were assessed . RESULTS : The combination of DB06603 and bortezomib induced apoptosis and inhibited renal cancer growth synergistically ( combination indexes < 1 ) . It also suppressed colony formation significantly ( p < 0 . 05 ) . In a murine subcutaneous tumor model , a 10 - day treatment was well tolerated and inhibited tumor growth significantly ( p < 0 . 05 ) . Enhanced acetylation of the Q9UBN7 substrate alpha - tubulin was consistent with the suppression of Q9UBN7 activity by DB06603 , and the combination was shown to induce ER stress and ubiquitinated protein accumulation synergistically . CONCLUSIONS : DB06603 inhibits renal cancer growth by synergizing with bortezomib to induce ER stress and ubiquitinated protein accumulation . The current study provides a basis for testing the combination in patients with advanced renal cancer .",
"Rac1 modulates acute and subacute genotoxin - induced hepatic stress responses , fibrosis and liver aging . To investigate the importance of the Ras - homologous GTPase Rac1 for the hepatic response to genotoxic insults and liver aging , rac1 was deleted in liver of mice by Mx1 - Cre - based recombination . Knockout of rac1 caused complex changes in basal as well as doxorubicin and ionizing radiation - induced mRNA expression of various genotoxic stress response - related genes , including hspa1b , rad51 , wrn and xpc . Rac1 deletion protected the liver from acute toxicity following doxorubicin treatment . Moreover , the level of S139 phosphorylated histone P16104 ( γ P16104 ) , which is indicative of DNA damage , and mRNA expression of pro - inflammatory ( P05231 ) and pro - fibrotic ( P29279 , TGFβ , αSMA ) factors were mitigated in rac1 knockout animals . By contrast , lack of rac1 promoted subacute hepatotoxicity , which was determined 3 weeks after injection of multiple low doses of doxorubicin by assaying the γ P16104 level , mitotic index and pro - fibrotic gene expression . Regarding ionizing radiation , rac1 deficiency had no major effects on DNA damage induction or acute pro - inflammatory and pro - fibrotic stress responses . Mice lacking hepatic rac1 for extended period of time ( 15 months ) revealed increased mRNA expression of fibrosis - related factors ( P29279 , TGFβ , collagen , P03956 ) and fibrotic tissue remodeling . In addition , protein expression of the senescence marker p16 was enhanced in the absence of rac1 . Taken together , the data provide evidence that Rac1 is required for doxorubicin - induced DNA damage induction . It is also involved in both the acute and delayed inflammatory and fibrotic stress response in the liver following doxorubicin , but not ionizing radiation , treatment and , furthermore , protects against endogenous liver aging .",
"Role of acetylation and extracellular location of heat shock protein 90alpha in tumor cell invasion . Heat shock protein ( hsp ) 90 is an DB00171 - dependent molecular chaperone that maintains the active conformation of client oncoproteins in cancer cells . An isoform , hsp90alpha , promotes extracellular maturation of matrix metalloproteinase ( MMP ) - 2 , involved in tumor invasion and metastasis . Knockdown of histone deacetylase ( HDAC ) 6 , which deacetylates lysine residues in hsp90 , induces reversible hyperacetylation and attenuates DB00171 binding and chaperone function of hsp90 . Here , using mass spectrometry , we identified seven lysine residues in hsp90alpha that are hyperacetylated after treatment of eukaryotic cells with a pan - HDAC inhibitor that also inhibits Q9UBN7 . Depending on the specific lysine residue in the middle domain involved , although acetylation affects DB00171 , cochaperone , and client protein binding to hsp90alpha , acetylation of all seven lysines increased the binding of hsp90alpha to 17 - allyl - amino - demethoxy geldanamycin . Notably , after treatment with the pan - HDAC inhibitor DB06603 ( LBH589 ) , the extracellular hsp90alpha was hyperacetylated and it bound to P08253 , which was associated with increased in vitro tumor cell invasiveness . Treatment with antiacetylated hsp90alpha antibody inhibited in vitro invasion by tumor cells . Thus , reversible hyperacetylation modulates the intracellular and extracellular chaperone function of hsp90 , and targeting extracellular hyperacetylated hsp90alpha may undermine tumor invasion and metastasis .",
"Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK66___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .",
"___MASK96___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"The HDAC inhibitor LBH589 induces P29323 - dependent prometaphase arrest in prostate cancer via Q9UBN7 inactivation and down - regulation . Histone deacetylase inhibitors ( HDACIs ) have potent anti - cancer activity in a variety of cancer models . Understanding the molecular mechanisms involved in the therapeutic responsiveness of HDACI is needed before its clinical application . This study aimed to determine if a potent HDACI , LBH589 ( DB06603 ) , had differential therapeutic responsiveness towards LNCaP and PC - 3 prostate cancer ( PCa ) cells . The former showed prometaphase arrest with subsequent apoptosis upon LBH589 treatment , while the latter was less sensitive and had late G2 arrest . The LBH589 treatment down - regulated Q9UBN7 and sustained P29323 activation , and contributed to prometaphase arrest . Mechanistically , LBH589 inhibited Q9UBN7 activity , caused its dissociation from protein phosphatase PP1α , and increased 14 - 3 - 3ζ acetylation . Acetylated 14 - 3 - 3ζ released its mask effect on serine 259 of c - Raf and serine 216 of Cdc25C subsequent to de - phosphorylation by PP1α , which contributed to P29323 activation . Enhanced P29323 activity by LBH589 further down - regulated Q9UBN7 protein levels and sustained P29323 activation by free - forward regulation . The sustained Cdc25C and P29323 activation resulted in early M - phase ( prometaphase ) arrest and subsequent apoptosis in the most sensitive LNCaP cells but not in PC - 3 cells . This study provides pre - clinical evidence that Q9UBN7 may serve as a sensitive therapeutic target in the treatment of prostate cancer with HDACI LBH589 for clinical translation . This study also posits a novel mechanism of Q9UBN7 participation in regulating the c - Raf - P50391 - P29323 signaling pathway and contributing to M phase cell - cycle transition .",
"P25021 overexpression induces U937 cell differentiation despite triggered mechanisms to attenuate DB02527 signalling . Knowing that cell - surface receptors that recognize and respond to extracellular stimuli are key components for the regular communication between individual cells required for the survival of any living organism , the aim of the present work was to investigate the effect of P25021 overexpression on the U937 signal transduction pathway and its consequences on cell proliferation and differentiation . The overexpression of P25021 led to an increase in DB02527 basal levels , a leftward shift of agonist concentration - response curves , and similar maximal response to agonist treatment , suggesting that overexpressed H2Rs act as functional spare receptors . In this system cells triggered several mechanisms tending to restore DB02527 basal levels to those of the naïve cells . P25021 overexpression induced PDE activity stimulation and P25098 overexpression . In spite of the onset of these regulatory mechanisms , H2 agonist and rolipram treatments induced the terminal differentiation of the P25021 overexpressed clone , conversely to the naïve cells . Present findings show that stably P25021 overexpression alters DB02527 signalling as the result of not only the amounts of second messenger generated but also the activation or upregulation of various components of signalling cascade , leading to an adapted biologically unique system . This adaptation may represent an advantage or a disadvantage , depending on the biological system , but in any case , the existence of compensatory mechanisms should be considered when a clinical treatment is designed .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK66___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .",
"Activation of histamine H4 receptor inhibits TNFα / IMD - 0354 - induced apoptosis in human salivary NS - SV - AC cells . Apoptosis is involved in the pathogenesis of Sjögren ' s syndrome ( SS ) , an autoimmune disease affecting exocrine glands . Our recent studies revealed diminished histamine H4 receptor ( H₄R ) expression and impaired histamine transport in the salivary gland epithelial cells in SS . The aim was now to test if nanomolar histamine and high - affinity H₄R signaling affect apoptosis of human salivary gland epithelial cell . Simian virus 40 - immortalized acinar NS - SV - AC cells were cultured in serum - free keratinocyte medium ± histamine H₄R agonist HST - 10 . Expression and internalization of H₄R were studied by immunofluorescence staining ± clathrin inhibitor methyl - β - cyclodextrin ( MβCD ) . Apoptosis induced using tumor necrosis factor - α with nuclear factor - κB inhibitor IMD - 0354 was studied using phase contrast microscopy , Western blot , flow cytometry and polymerase chain reaction ( qRT - PCR ) . HST - 10 - stimulated H₄R internalization was inhibited by MβCD . Western blotting revealed diminished phosphorylated c - Jun N - terminal kinase JNK , but unchanged levels of phosphorylated extracellular signal regulated kinase pERK1 / 2 in H₄R - stimulated samples compared to controls . qRT - PCR showed up - regulated expression of anti - apoptotic B cell lymphoma - extra large / Bcl - xL mRNAs and proteins , whereas pro - apoptotic Bcl - 2 - associated X protein / Q07812 remained unchanged in Q9H3N8 - stimulated samples . H₄R stimulation diminished cleavage of PARP and flow cytometry showed significant dose - dependent inhibitory effect of H₄R stimulation on apoptosis . As far as we know this is the first study showing inhibitory effect of H₄R activation on apoptosis of human salivary gland cells . Diminished H₄R - mediated activation may contribute to loss of immune tolerance in autoimmune diseases and in SS in particular .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK19___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK19___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK19___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK19___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK19___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"Increasing P16070 +/ P25063 (-) tumor stem cells , and upregulation of P35354 and Q9UBN7 , as major functions of P04626 in breast tumorigenesis . BACKGROUND : Cancer cells are believed to arise primarily from stem cells . P16070 +/ P25063 (-) have been identified as markers for human breast cancer stem cells . Although , P04626 is a well known breast cancer oncogene , the mechanisms of action of this gene are not completely understood . Previously , we have derived immortal ( M13SV1 ) , weakly tumorigenic ( M13SV1R2 ) and highly tumorigenic ( M13SV1R2N1 ) cell lines from a breast epithelial cell type with stem cell phenotypes after successive SV40 large T - antigen transfection , X - ray irradiation and ectopic expression of P04626 / C - erbB2 / neu . Recently , we found that M13SV1R2 cells became non - tumorigenic after growing in a growth factor / hormone - deprived medium ( R2d cells ) . RESULTS : In this study , we developed M13SV1R2N1 under the same growth factor / hormone - deprived condition ( R2N1d cells ) . This provides an opportunity to analyze P04626 effect on gene expression associated with tumorigenesis by comparative study of R2d and R2N1d cells with homogeneous genetic background except P04626 expression . The results reveal distinct characters of R2N1d cells that can be ascribed to P04626 : 1 ) development of fast - growing tumors ; 2 ) high frequency of P16070 +/ P25063 (-) cells ( ~ 50 % for R2N1d vs . ~ 10 % for R2d ) ; 3 ) enhanced expression of P35354 , Q9UBN7 mediated , respectively , by MAPK and PI3K / Akt pathways , and many genes associated with inflammation , metastasis , and angiogenesis . Furthermore , P04626 expression can be down regulated in non - adhering R2N1d cells . These cells showed longer latent period and lower rate of tumor development compared with adhering cells . CONCLUSIONS : P04626 may induce breast cancer by increasing the frequency of tumor stem cells and upregulating the expression of P35354 and Q9UBN7 that play pivotal roles in tumor progression .",
"Low - density lipoprotein - induced expression of interleukin - 6 , a marker of human mesangial cell inflammation : effects of oxidation and modulation by lovastatin . Low - density lipoprotein ( LDL ) may contribute to the pathogenesis of glomerulosclerosis by stimulating a mesangial cell inflammatory response . P05231 ( P05231 ) is a marker of active inflammation and ongoing glomerular injury . Therefore , we investigated the effects of native and oxidized LDL on human mesangial cell production of P05231 and a possible modulation of this inflammatory response by lovastatin , which has been shown to ameliorate experimental glomerulosclerosis . Human mesangial cells were exposed for 6 or 24 h to culture medium containing either native LDL alone or a LDL mixture containing 5 or 20 % oxidized LDL . We found that native LDL stimulated 6 h mRNA expression and secretion of P05231 . This effect was further enhanced , in a dose - related manner , when mesangial cells were exposed to increasing concentrations of oxidized LDL . ___MASK96___ markedly inhibited mesangial cell expression of P05231 mRNA and reduced P05231 secretion . The inhibitory effects of lovastatin were overridden at least partially by exogenous mevalonate . We conclude that LDL , and particularly oxidized LDL , might contribute to the pathogenesis of glomerular disease by modulating the inflammatory response of human mesangial cells , as assessed by the stimulation of P05231 expression . Moreover , this inflammatory response can be prevented by lovastatin , providing a potential direct anti - inflammatory mechanism by which P04035 inhibitors may attenuate lipid - induced glomerular injury .",
"Biological differences between in vitro produced bovine embryos and parthenotes . Parthenotes may represent an alternate ethical source of stem cells , once biological differences between parthenotes and embryos can be understood . In this study , we analyzed development , trophectoderm ( TE ) differentiation , apoptosis / necrosis , and ploidy in parthenotes and in vitro produced bovine embryos . Subsequently , using real - time PCR , we analyzed the expression of genes expected to underlie the observed differences at the blastocyst stage . In vitro matured oocytes were either fertilized or activated with ionomycin + 6 - DMAP and cultured in simple medium . Parthenotes showed enhanced blastocyst development and diploidy and reduced TE cell counts . Apoptotic and necrotic indexes did not vary , but parthenotes evidenced a higher relative proportion of apoptotic cells between inner cell mass and TE . The pluripotence - related Q01860 and the methylation Q9Y6K1 genes were downregulated in parthenotes . Among pregnancy recognition genes , TP - 1 was upregulated in parthenotes , while O00264 and PLAC8 did not change . Expression of p66 ( shc ) and Q07812 / P10415 ratio were higher , and p53 lower , in parthenotes . Among metabolism genes , P11166 was downregulated , while P15121 , P35354 , O95479 , and P10599 were upregulated in parthenotes , and P22732 did not differ . Among genes involved in compaction / blastulation , P17302 was downregulated in parthenotes , but no differences were detected within P05023 and CDH1 . Within parthenotes , the expression levels of P11166 , TP - 1 , and O95479 , and possibly P15121 , resemble patterns described in female embryos . The pro - apoptotic profile is more pronounced in parthenotes than in embryos , which may differ in their way to channel apoptotic stimuli , through p66 ( shc ) and p53 respectively , and in their mechanisms to control pluripotency and de novo methylation .",
"P35372 mutant , T394A , abolishes opioid - mediated adenylyl cyclase superactivation . This study was to characterize the effects of a point - mutant at C - terminal of mu opioid receptor ( MOR ) , namely MOR T394A , in chronic opioid - induced cellular responses . After 18 h of exposure to [ D - Ala , N - Me - DB00120 , DB00145 - ol ] enkephalin ( DAMGO ) , adenylyl cyclase ( AC ) superactivation , a hallmark for the cellular adaptive response after chronic opioid stimulation , was observed in the cells expressing wild - type receptor , but was totally abolished in the cells expressing MOR T394A . Receptor phosphorylation was also attenuated in cells with MOR T394A after prolonged preexposure to agonist . Furthermore , Q96HU1 kinase kinase - 1 ( Q02750 ) overexpression was able to rescue AC superactivation in cells with MOR T394A , but showed no effect in the wild - type MOR - expressing cells . These results indicated that the amino acid T394 at C - terminus of MOR played a critical role in chronic agonist - induced AC superactivation and receptor phosphorylation .",
"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .",
"Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , DB02546 ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .",
"Comparison of the cytotoxicity of cladribine and clofarabine when combined with fludarabine and busulfan in AML cells : Enhancement of cytotoxicity with epigenetic modulators . Clofarabine ( Clo ) , fludarabine ( Flu ) , and busulfan ( Bu ) combinations are efficacious in hematopoietic stem cell transplantation for myeloid leukemia . We sought to determine whether the more affordable drug cladribine ( Clad ) can provide a viable alternative to Clo , with or without DB06603 ( Pano ) and DB01262 ( P22760 ) . Both Clad + Flu + Bu and Clo + Flu + Bu combinations showed synergistic cytotoxicity in KBM3 / Bu250 ( 6 ) , HL60 , and OCI - Q13950 cell lines . Cell exposure to these drug combinations resulted in 60 % - 80 % inhibition of proliferation ; activation of the Q13315 pathway ; increase in histone modifications ; decrease in O15379 , P56524 , Q9UQL6 and SirT7 proteins ; decrease in mitochondrial membrane potential ; activation of apoptosis and stress signaling pathways ; and downregulation of the AKT pathway . These drug combinations activated DNA - damage response and apoptosis in primary cell samples from AML patients . At lower concentrations of Clad / Clo , Flu , and Bu , inclusion of Pano and P22760 enhanced cell killing , increased histone modifications and DNA demethylation , and increased the levels of P16 / INK4a , P15 / INK4b and P21 / Waf1 / Cip1 proteins . The observed DNA demethylating activity of Clad and Clo may complement P22760 activity ; increase demethylation of the gene promoters for Q8N474 , Q9UBP4 , and Q9Y5W5 ; and cause degradation of β - catenin in cells exposed to Clad / Clo + Flu + Bu + P22760 + Pano . The overlapping activities of Clad / Clo + Flu + Bu , Pano , and P22760 in DNA - damage formation and repair , histone modifications , DNA demethylation , and apoptosis may underlie their synergism . Our results provide a basis for supplanting Clo with Clad and for including epigenetic modifiers in the pre - hematopoietic stem cell transplantation conditioning regimen for myeloid leukemia patients .",
"Regulation of P40763 by histone deacetylase - 3 in diffuse large B - cell lymphoma : implications for therapy . Diffuse large B - cell lymphoma ( DLBCL ) with an activated B - cell ( DB01048 ) gene - expression profile has been shown to have a poorer prognosis compared with tumors with a germinal center B - cell type . ABC cell lines have constitutive activation of P40763 ; however , the mechanisms regulating P40763 signaling in lymphoma are unknown . In studies of class - I histone deacetylase ( HDAC ) expression , we found overexpression of O15379 in phospho P40763 - positive DLBCL and the O15379 was found to be complexed with P40763 . Inhibition of HDAC activity by DB06603 ( LBH589 ) increased p300 - mediated P40763 ( Lys685 ) acetylation with increased nuclear export of P40763 to the cytoplasm . HDAC inhibition abolished P40763 ( Tyr705 ) phosphorylation with minimal effect on P40763 ( Ser727 ) and O60674 tyrosine activity . pSTAT3 ( Tyr705 )- positive DLBCLs were more sensitive to HDAC inhibition with LBH589 compared with pSTAT3 ( Tyr705 )- negative DLBCLs . This cytotoxicity was associated with downregulation of the direct P40763 target Mcl - 1 . O15379 knockdown upregulated P40763 ( Lys685 ) acetylation but prevented P40763 ( Tyr705 ) phosphorylation and inhibited survival of pSTAT3 - positive DLBCL cells . These studies provide the rationale for targeting P40763 - positive DLBCL tumors with HDAC inhibitors .",
"The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 phosphorylation . ___MASK66___ ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low - concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .",
"Combination therapy for hepatocellular carcinoma : additive preclinical efficacy of the HDAC inhibitor DB06603 with sorafenib . BACKGROUND & AIMS : Hepatocellular carcinoma ( HCC ) is a heterogeneous cancer in which sorafenib is the only approved systemic therapy . Histone deacetylases ( HDAC ) are commonly dysregulated in cancer and therefore represent promising targets for therapies , however their role in HCC pathogenesis is still unknown . We analyzed the expression of 11 HDACs in human HCCs and assessed the efficacy of the pan - HDAC inhibitor DB06603 alone and in combination with sorafenib in preclinical models of liver cancer . METHODS : Gene expression and copy number changes were analyzed in a cohort of 334 human HCCs , while the effects of DB06603 and sorafenib were evaluated in three liver cancer cell lines and a murine xenograft model . RESULTS : Aberrant HDAC expression was identified and validated in 91 and 243 HCCs , respectively . Upregulation of O15379 and Q9UQL6 mRNAs was significantly correlated with DNA copy number gains . Inhibiting HDACs with DB06603 led to strong anti - tumoral effects in vitro and vivo , enhanced by the addition of sorafenib . Cell viability and proliferation declined , while apoptosis and autophagy increased . DB06603 increased histone H3 and HSP90 acetylation , downregulated O15392 ( survivin ) and upregulated CDH1 . Combination therapy with DB06603 and sorafenib significantly decreased vessel density , and most significantly decreased tumor volume and increased survival in HCC xenografts . CONCLUSIONS : Aberrant expression of several HDACs and copy number gains of O15379 and Q9UQL6 occur in HCC . Treatment with DB06603 combined with sorafenib demonstrated the highest preclinical efficacy in HCC models , providing the rationale for clinical studies with this novel combination .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK59___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"DB00188 prevents the expression of P45452 and the degradation of collagen type 2 in human chondrocytes . The structural backbone of extracellular matrix in cartilage is the collagen fibril , which is mainly composed of type II collagen . A measurable increase in type II collagen denaturation and degradation has been found in early Osteoarthritis ( OA ) . Pro - inflammatory cytokine such as P01375 - α produced in OA cartilage induced the expression of matrix metalloproteinase - 13 ( P45452 ) , which targets and degrades type II collagen . DB00188 is a proteasome inhibitor approved by the FDA for treatment of multiple myeloma and mantel cell lymphoma . The effects of bortezomib in OA have not been reported before . In this study , we found that bortezomib is able to suppress the degradation of type II collagen induced by P01375 - α in human chondrocytes . Mechanistically , bortezomib treatment inhibits the expression of P10914 through blunting O60674 / P42224 pathway , thereby prevents the induction of P45452 as well as the degradation of type II collagen . Our findings suggest the therapeutic potentials of bortezomib in patients with OA .",
"Gefitinib ( ' ___MASK80___ ' , ZD1839 ) inhibits the growth response of bladder tumour cell lines to epidermal growth factor and induces P16035 . The effect of P01133 stimulation and its inhibition with gefitinib ( ' ___MASK80___ ' , ZD1839 ) , an epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor , has been investigated in two P00533 - positive human bladder tumour cell lines , RT112 and RT4 . The growth of RT112 cells in a medium containing 10 % foetal bovine serum was inhibited by 50 % with 10 microM gefitinib , whereas this dose completely inhibited RT4 cell growth . Cells were more sensitive to growth inhibition in the serum - free medium . Increased growth of cells in the serum - free medium was observed with 10 or 50 ng x ml (- 1 ) P01133 and the proliferative effect of P01133 stimulation in both cell lines was inhibited in the presence of 1 microM , but not 0 . 1 microM gefitinib . Zymography of the conditioned medium from RT112 cells treated with P01133 and gefitinib showed a decrease in matrix metalloproteinase 2 ( P08253 ) concentrations . Western blot analysis showed that tissue inhibitor of metalloproteinase 1 ( P01033 ) increased in the conditioned medium from RT112 cells treated with P01133 , and this was partially inhibited with both 1 and 5 microM gefitinib . Conversely , P16035 decreased with P01133 stimulation and this was reversed with gefitinib . Tissue inhibitor of metalloproteinase 1 had no effect on the growth of either cell line . These studies show alterations in the balance of MMPs and their inhibitors in P01133 - stimulated bladder tumour cells , which are reversed by gefitinib , suggesting gefitinib should be investigated for its effect on human bladder tumours .",
"In vitro and in vivo interactions between the Q9UBN7 inhibitor ricolinostat ( ACY1215 ) and the irreversible proteasome inhibitor carfilzomib in non - Hodgkin lymphoma cells . Interactions between the Q9UBN7 inhibitor ricolinostat ( ACY1215 ) and the irreversible proteasome inhibitor carfilzomib were examined in non - Hodgkin lymphoma ( Q9NZ71 ) models , including diffuse large B - cell lymphoma ( DLBCL ) , mantle cell lymphoma ( Q8WXI8 ) , and double - hit lymphoma cells . Marked in vitro synergism was observed in multiple cell types associated with activation of cellular stress pathways ( e . g . , P45983 / 2 , P27361 / 2 , and p38 ) accompanied by increases in DNA damage ( γH2A . X ) , G2 - M arrest , and the pronounced induction of mitochondrial injury and apoptosis . Combination treatment with carfilzomib and ricolinostat increased reactive oxygen species ( ROS ) , whereas the antioxidant TBAP attenuated DNA damage , JNK activation , and cell death . Similar interactions occurred in bortezomib - resistant and double - hit DLBCL , Q8WXI8 , and primary DLBCL cells , but not in normal P28906 (+) cells . However , ricolinostat did not potentiate inhibition of chymotryptic activity by carfilzomib . shRNA knockdown of P45983 ( but not Q02750 / 2 ) , or pharmacologic inhibition of p38 , significantly reduced carfilzomib - ricolinostat lethality , indicating a functional contribution of these stress pathways to apoptosis . Combined exposure to carfilzomib and ricolinostat also markedly downregulated the cargo - loading protein P54727 . Moreover , P54727 knockdown significantly increased carfilzomib - and ricolinostat - mediated lethality , suggesting a role for this event in cell death . Finally , combined in vivo treatment with carfilzomib and ricolinostat was well tolerated and significantly suppressed tumor growth and increased survival in an Q8WXI8 xenograft model . Collectively , these findings indicate that carfilzomib and ricolinostat interact synergistically in Q9NZ71 cells through multiple stress - related mechanisms , and suggest that this strategy warrants further consideration in Q9NZ71 .",
"mu - Opioid receptor agonists differentially regulate the expression of miR - 190 and Q13562 . The agonists of mu - opioid receptor ( P35372 ) induce extracellular signal - regulated kinase ( P29323 ) phosphorylation through different pathways : morphine uses the protein kinase C ( PKC ) - pathway , whereas fentanyl functions in a beta - arrestin2 - dependent manner . In addition , the two pathways result in the different cellular location of phosphorylated P29323 and the activation of different sets of transcriptional factors . In the current study , the influence of the two pathways on the expression of microRNAs ( miRNAs ) was investigated . After treating the primary culture of rat hippocampal neurons and the mouse hippocampi with morphine or fentanyl for 3 days , seven miRNAs regulated by one or two of the agonists were identified . One of the identified miRNAs , miR - 190 , was down - regulated by fentanyl but not by morphine . This down - regulation was attenuated by 1 , 4 - diamino - 2 , 3 - dicyano - 1 , 4 - bis ( methylthio ) butadiene ( U0126 ) , which blocks the phosphorylation of P29323 . When fentanyl - induced but not morphine - induced P29323 phosphorylation was blocked in the primary cultures from beta - arrestin2 (-/-) mouse , fentanyl did not decrease the expression of miR - 190 . However , a PKC inhibitor that blocked morphine - induced P29323 phosphorylation specifically had no effect on the miR - 190 down - regulation . Therefore the decrease in miR - 190 expression resulted from the agonist - selective P29323 phosphorylation . In addition , the expressional changes in one of the miR - 190 targets , neurogenic differentiation 1 ( Q13562 ) , correlated with those in miR - 190 expression , suggesting the P35372 could regulate the Q13562 pathways via the control of miR - 190 expression .",
"Synergism between bosutinib ( ___MASK12___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"Treatment with DB06603 induces glucose - regulated protein 78 acetylation and endoplasmic reticulum stress in breast cancer cells . Increased levels of misfolded polypeptides in the endoplasmic reticulum ( ER ) triggers the dissociation of glucose - regulated protein 78 ( P11021 ) from the three transmembrane ER - stress mediators , i . e . , protein kinase RNA - like ER kinase ( Q9NZJ5 ) , activating transcription factor - 6 ( P18850 ) , and inositol - requiring enzyme 1alpha , which results in the adaptive unfolded protein response ( UPR ) . In the present studies , we determined that histone deacetylase - 6 ( Q9UBN7 ) binds and deacetylates P11021 . Following treatment with the pan - histone deacetylase inhibitor DB06603 ( Novartis Pharmaceuticals ) , or knockdown of Q9UBN7 by short hairpin RNA , P11021 is acetylated in 11 lysine residues , which dissociates P11021 from Q9NZJ5 . This is associated with the activation of a lethal UPR in human breast cancer cells . Coimmunoprecipitation studies showed that binding of Q9UBN7 to P11021 requires the second catalytic and COOH - terminal BUZ domains of Q9UBN7 . Treatment with DB06603 increased the levels of phosphorylated - eukaryotic translation initiation factor ( p - eIF2alpha ) , P18848 , and CAAT / enhancer binding protein homologous protein ( P35638 ) . DB06603 treatment also increased the proapoptotic Q13323 , O43521 , Q07812 , and Q16611 levels , as well as increased the activity of caspase - 7 . Knockdown of P11021 sensitized MCF - 7 cells to bortezomib and DB06603 - induced UPR and cell death . These findings indicate that enforced acetylation and decreased binding of P11021 to Q9NZJ5 is mechanistically linked to DB06603 - induced UPR and cell death of breast cancer cells . Mol Cancer Ther ; 9 ( 4 ) ; 942 - 52 . ( c ) 2010 AACR .",
"Syntenic conservation between humans and cattle . I . Human chromosome 9 . Bovine X hamster hybrid somatic cells have been used to investigate the syntenic relationship of nine loci in the bovine that have homologous loci on human chromosome 9 . Six loci , P00352 , P05062 , P01031 , P15291 , P06396 , and P02760 , were assigned to the previously identified bovine syntenic group U18 represented by P21399 , whereas the other three loci , P00519 , P00966 , and P11021 , mapped to a new , previously unidentified autosomal syntenic group . Additionally , a secondary locus , P42684 , which cross - hybridized with the P00519 probe , was mapped to bovine syntenic group U1 with the HSA 1 loci P52209 and P06733 . The results predict that P21399 will map proximal to P00352 ; P11021 distal to P02760 and P01031 ; P06396 proximal to P00568 , P00519 , and P00966 on HSA 9 ; P11021 to MMU 2 ; and P02760 and P06396 to MMU 4 .",
"Repression of O15392 / survivin by O43524 / O43524 sensitizes human neuroblastoma cells to DNA damage - induced apoptosis . The phosphatidylinositol 3 - kinase ( PI3K ) - protein kinase B ( P31749 ) pathway regulates survival and chemotherapy resistance of neuronal cells , and its deregulation in neuroblastoma ( NB ) tumors predicts an adverse clinical outcome . Here , we show that inhibition of PI3K - P31749 signaling in human NB cells induces nuclear translocation of O43524 / O43524 , represses the prosurvival protein O15392 / Survivin , and sensitizes to DNA - damaging agents . To specifically address whether O43524 contributes to Survivin regulation , we introduced a 4 - hydroxy - tamoxifen - regulated O43524 ( A3 ) ERtm allele into NB cells . Conditional O43524 activation repressed Survivin transcription and protein expression . Transgenic Survivin exerted a significant antiapoptotic effect and prevented the accumulation of Bim and Bax at mitochondria , the loss of mitochondrial membrane potential as well as the release of cytochrome c during O43524 - induced apoptosis . In concordance , Survivin knockdown by retroviral short hairpin RNA technology accelerated O43524 - induced apoptosis . Low - dose activation of O43524 sensitized to the DNA - damaging agents doxorubicin and etoposide , whereas the overexpression of Survivin diminished O43524 sensitization to these drugs . These results suggest that repression of Survivin by O43524 facilitates O43524 - induced apoptosis and sensitizes to cell death induced by DNA - damaging agents , which supports the central role of PI3K - P31749 - O43524 signaling in drug resistance of human NB .",
"Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .",
"Histone deacetylase inhibitor treatment dramatically reduces cholesterol accumulation in Niemann - Pick type C1 mutant human fibroblasts . Niemann - Pick type C ( NPC ) disease is predominantly caused by mutations in the O15118 protein that affect intracellular cholesterol trafficking and cause accumulation of unesterified cholesterol and other lipids in lysosomal storage organelles . We report the use of a series of small molecule histone deacetylase ( HDAC ) inhibitors in tissue culture models of NPC human fibroblasts . Some HDAC inhibitors lead to a dramatic correction in the NPC phenotype in cells with either one or two copies of the O15118 ( I1061T ) mutation , and for several of the inhibitors , correction is associated with increased expression of O15118 protein . Increased O15118 ( I1061T ) protein levels may partially account for the correction of the phenotype , because this mutant can promote cholesterol efflux if it is delivered to late endosomes and lysosomes . The HDAC inhibitor treatment is ineffective in an P61916 mutant human fibroblast line . Analysis of the isoform selectivity of the compounds used implicates Q13547 and / or Q92769 as likely targets for the observed correction , although other HDACs may also play a role . LBH589 ( DB06603 ) is an orally available HDAC inhibitor that crosses the blood - brain barrier and is currently in phase III clinical trials for several types of cancer . It restores cholesterol homeostasis in cultured O15118 mutant fibroblasts to almost normal levels within 72 h when used at 40 nM . The findings that HDAC inhibitors can correct cholesterol storage defects in human O15118 mutant cells provide the potential basis for treatment options for NPC disease .",
"O15379 represses the expression of P26718 ligands ULBPs in epithelial tumour cells : potential implications for the immunosurveillance of cancer . The expression of the P26718 ligands on cancer cells leads to their recognition and elimination by host immune responses mediated by natural killer and T cells . UL16 - binding proteins ( ULBPs ) are P26718 ligands , which are scarcely expressed in epithelial tumours , favouring their evasion from the immune system . Herein , we investigated the epigenetic mechanisms underlying the repression of ULBPs in epithelial cancer cells . We show that Q9BZM6 - 3 expression is increased in tumour cells after exposure to the inhibitor of histone deacetylases ( HDACs ) trichostatin A ( P32119 ) , which enhances the natural killer cell - mediated cytotoxicity of HeLa cells . Our experiments showed that the transcription factor Sp3 is crucial in the activation of the Q9BZM6 promoter by P32119 . Furthermore , by small interfering RNA - mediated knockdown and overexpression of Q13547 - 3 , we showed that O15379 is a repressor of ULBPs expression in epithelial cancer cells . Remarkably , P32119 treatment caused the complete release of O15379 from the Q9BZM6 - 3 promoters . O15379 is recruited to the Q9BZM6 promoter through its interaction with Sp3 and P32119 treatment interfered with this association . Together , we describe a new mechanism by which cancer cells may evade the immune response through the epigenetic modulation of the ULBPs expression and provide a model in which HDAC inhibitors may favour the elimination of transformed cells by increasing the immunogenicity of epithelial tumours .",
"Determination of the class and isoform selectivity of small - molecule histone deacetylase inhibitors . The human HDAC ( histone deacetylase ) family , a well - validated anticancer target , plays a key role in the control of gene expression through regulation of transcription . While HDACs can be subdivided into three main classes , the class I , class II and class III HDACs ( sirtuins ) , it is presently unclear whether inhibiting multiple HDACs using pan - HDAC inhibitors , or targeting specific isoforms that show aberrant levels in tumours , will prove more effective as an anticancer strategy in the clinic . To address the above issues , we have tested a number of clinically relevant HDACis ( HDAC inhibitors ) against a panel of rhHDAC ( recombinant human HDAC ) isoforms . Eight rhHDACs were expressed using a baculoviral system , and a Fluor de Lystrade mark ( Biomol International ) HDAC assay was optimized for each purified isoform . The potency and selectivity of ten HDACs on class I isoforms ( rhHDAC1 , rhHDAC2 , rhHDAC3 and rhHDAC8 ) and class II HDAC isoforms ( rhHDAC4 , rhHDAC6 , rhHDAC7 and rhHDAC9 ) was determined . MS - 275 was Q13547 - selective , DB05651 was Q13547 - and Q92769 - selective , apicidin was Q92769 - and O15379 - selective and valproic acid was a specific inhibitor of class I HDACs . The hydroxamic acid - derived compounds ( trichostatin A , DB00238 - LAQ824 , DB06603 , ITF2357 , vorinostat and belinostat ) were potent pan - HDAC inhibitors . The growth - inhibitory effect of the HDACis on HeLa cells showed that both pan - HDAC and class - I - specific inhibitors inhibited cell growth . The results also showed that both pan - HDAC and class - I - specific inhibitor treatment resulted in increased acetylation of histones , but only pan - HDAC inhibitor treatment resulted in increased tubulin acetylation , which is in agreement with their activity towards the Q9UBN7 isoform .",
"DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .",
"The microtubule - associated histone deacetylase 6 ( Q9UBN7 ) regulates epidermal growth factor receptor ( P00533 ) endocytic trafficking and degradation . Q9UBN7 ( Q9UBN7 ) is a microtubule - associated deacetylase with tubulin deacetylase activity , and it binds dynein motors . Recent studies revealed that microtubule acetylation affects the affinity and processivity of microtubule motors . These unique properties implicate a role for Q9UBN7 in intracellular organelle transport . Here , we show that Q9UBN7 associates with the endosomal compartments and controls epidermal growth factor receptor ( P00533 ) trafficking and degradation . We found that loss of Q9UBN7 promoted P00533 degradation . Mechanistically , Q9UBN7 deficiency did not cause aberrant P00533 internalization and recycling . Rather , it resulted in accelerated segregation of P00533 from early endosomes and premature delivery of P00533 to the late endosomal and lysosomal compartments . The deregulated P00533 endocytic trafficking was accompanied by an increase in microtubule - dependent movement of P00533 - bearing vesicles , revealing a novel regulation of P00533 vesicular trafficking and degradation by the microtubule deacetylase Q9UBN7 .",
"Deciphering the molecular and biologic processes that mediate histone deacetylase inhibitor - induced thrombocytopenia . Histone deacetylase inhibitor ( HDACI ) - induced thrombocytopenia ( DB01520 ) is a major dose - limiting toxicity of this new class of drugs . Using preclinical models to study the molecular and biologic events that underpin this effect of HDACI , we found that C57BL / 6 mice treated with both the Q13547 / 2 - selective HDACI romidepsin and the pan - HDACI DB06603 developed significant DB01520 . HDACI - induced DB01520 was not due to myelosuppression or reduced platelet lifespan , but to decreased platelet release from megakaryocytes . Cultured primary murine megakaryocytes showed reductions in proplatelet extensions after HDACI exposure and a dose - dependent increase in the phosphorylation of myosin light chain 2 ( MLC2 ) . Phosphorylation of MLC to phospho - MLC ( pMLC ) and subsequent proplatelet formation in megakaryocytes is regulated by the Rho - GTPase proteins Rac1 , P60953 , and RhoA . Primary mouse megakaryocytes and the human megakaryoblastic cell line Meg - 01 showed reductions in Rac1 , P60953 , and RhoA protein levels after treatment with HDACIs . We were able to overcome HDACI - induced DB01520 by administering the mouse - specific thrombopoietin ( P07202 ) mimetic AMP - 4 , which improved platelet numbers to levels similar to untreated controls . Our report provides the first detailed account of the molecular and biologic processes involved in HDACI - mediated DB01520 . Moreover , our preclinical studies provide evidence that dose - limiting DB01520 induced by HDACIs may be circumvented using a P07202 mimetic .",
"Loss of protein phosphatase 6 in mouse keratinocytes increases susceptibility to ultraviolet - B - induced carcinogenesis . We previously reported that deficiency in the gene encoding the catalytic subunit of protein phosphatase 6 ( Ppp6c ) predisposes mouse skin tissue to papilloma formation initiated by DMBA . Here , we demonstrate that Ppp6c loss acts as a tumor promoter in UVB - induced squamous cell carcinogenesis . Following UVB irradiation , mice with Ppp6c - deficient keratinocytes showed a higher incidence of skin squamous cell carcinoma than did control mice . Time course experiments showed that following UVB irradiation , Ppp6c - deficient keratinocytes upregulated expression of p53 , PUMA , Q07812 , and cleaved caspase - 3 proteins . UVB - induced tumors in Ppp6c - deficient keratinocytes exhibited a high frequency of both p53 - and γ P16104 - positive cells , suggestive of DNA damage . Epidemiological and molecular data strongly suggest that UVB from sunlight induces p53 gene mutations in keratinocytes and is the primary causative agent of human skin cancers . Our analysis suggests that PP6 deficiency underlies molecular events that drive outgrowth of initiated keratinocytes harboring UVB - induced mutated p53 . Understanding PP6 function in preventing UV - induced tumorigenesis could suggest strategies to prevent and treat this condition .",
"R306465 is a novel potent inhibitor of class I histone deacetylases with broad - spectrum antitumoral activity against solid and haematological malignancies . R306465 is a novel hydroxamate - based histone deacetylase ( HDAC ) inhibitor with broad - spectrum antitumour activity against solid and haematological malignancies in preclinical models . R306465 was found to be a potent inhibitor of Q13547 and - 8 ( class I ) in vitro . It rapidly induced histone 3 ( H3 ) acetylation and strongly upregulated expression of p21waf1 , cip1 , a downstream component of Q13547 signalling , in A2780 ovarian carcinoma cells . R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of Q9UBN7 ( class IIb ) confirmed by the absence of downregulation of Hsp90 chaperone c - raf protein expression and tubulin acetylation . This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards Q9UBN7 ( e . g . vorinostat ) or had a broader HDAC inhibition spectrum ( e . g . DB06603 ) . R306465 potently inhibited cell proliferation of all main solid tumour indications , including ovarian , lung , colon , breast and prostate cancer cell lines , with IC50 values ranging from 30 to 300 nM . Haematological cell lines , including acute lymphoblastic leukaemia , acute myeloid leukaemia , chronic lymphoblastic leukaemia , chronic myeloid leukaemia , lymphoma and myeloma , were potently inhibited at a similar concentration range . R306465 induced apoptosis and inhibited angiogenesis in cell - based assays and had potent oral in vivo antitumoral activity in xenograft models . Once - daily oral administration of R306465 at well - tolerated doses inhibited the growth of A2780 ovarian , H460 lung and HCT116 colon carcinomas in immunodeficient mice . The high activity of R306465 in cell - based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies .",
"P01579 and P42224 arrest monocyte migration and modulate P31749 / P60953 pathways . Positive regulation of cell migration by chemotactic factors and downstream signaling pathways has been extensively investigated . In contrast , little is known about factors and mechanisms that induce migration arrest , a process important for retention of cells at inflammatory sites and homeostatic regulation of cell trafficking . In this study , we found that P01579 directly inhibited monocyte migration by suppressing remodeling of the actin cytoskeleton and cell polarization in response to the chemokine P13500 . Inhibition was dependent on P42224 and downstream genes , whereas P40763 promoted migration . P01579 altered monocyte responses to P13500 by modulating the activity of Pyk2 , JNK , and the GTPases Rac and Cdc42 , and inhibiting P13500 - induced activation of the downstream P38936 - activated kinase that regulates the cytoskeleton and cell polarization . These results identify a new role for P01579 in arresting monocyte chemotaxis by a mechanism that involves modulation of cytoskeleton remodeling . Crosstalk between Jak - P35610 and Rac / Cdc42 GTPase - mediated signaling pathways provides a molecular mechanism by which cytokines can regulate cell migration .",
"Significance of interleukin - 6 signaling in the resistance of pharyngeal cancer to irradiation and the epidermal growth factor receptor inhibitor . PURPOSE : Tumor eradication by chemoradiotherapy for pharyngeal cancer has not been particularly successful . Targeting epithelial growth factor receptor ( P00533 ) could be a potential treatment strategy providing additional benefits , but only a subset of these tumors gives a clinically significant response to P00533 inhibitors . The aim has been to identify the role of interleukin - 6 ( P05231 ) signaling and its predictive power in the treatment response of pharyngeal cancer . METHODS AND MATERIALS : Human pharyngeal cancer cell lines , including the hypopharyngeal cancer cell line FaDu and its derived cell line FaDu - C225 - R , were selected . Changes in tumor growth , response to treatment , and responsible signaling pathway were investigated in vitro . Furthermore , 95 pharyngeal cancer tissue specimens were analyzed by immunohistochemical staining , and correlations were made between levels of P05231 , P05231 receptor ( IL - 6R ) , p - AKT , and p - P40763 expression and the clinical outcome of patients . RESULTS : In vitro , either extrinsic P05231 stimulation of cancer cells or intrinsically activated P05231 signaling detected in FADu - C225 - R cells results in resistance to irradiation and P00533 inhibitor . Blocking P05231 signaling attenuated aggressive tumor behavior and sensitized the cells to treatments . The responsible mechanisms included decreased p - P40763 , less nuclear translocation of P00533 , and subsequently attenuated epithelial - mesenchymal transition . Regarding clinical data , staining of p - P40763 and P05231 was significantly linked with lower response rates to treatments and shorter survival in pharyngeal cancer patients . CONCLUSIONS : P05231 and p - P40763 may be significant predictors of pharyngeal carcinoma , and regulating P05231 signaling can be considered a promising therapeutic approach .",
"Histone deacetylase inhibitors as potential therapeutic approaches for chordoma : an immunohistochemical and functional analysis . Chordomas are rare malignancies of the axial skeleton . Therapy is mainly restricted to surgery . This study investigates histone deacetylase ( HDAC ) inhibitors as potential therapeutics for chordomas . Immunohistochemistry ( IHC ) was performed using the HDAC 1 - 6 antibodies on 50 chordoma samples ( 34 primary tumors , 16 recurrences ) from 44 patients ( 27 male , 17 female ) . Pan - HDAC - inhibitors DB02546 ( DB02546 ) , DB06603 ( LBH - 589 ) , and Belinostat ( PXD101 ) were tested for their efficacy in the chordoma cell line MUG - Chor1 via Western blot , cell cycle analysis , caspase 3 / 7 activity ( MUG - Chor1 , UCh - 1 ) , cleaved caspase - 3 , and PARP cleavage . p - Values below 0 . 05 were considered significant . IHC was negative for Q13547 , positive for Q92769 in most ( n = 36 ; 72 % ) , and for HDACs 3 - 6 in all specimens available ( n = 43 ; 86 % ) . Q9UBN7 expression was strongest . DB02546 and LBH - 589 , but not PXD101 caused a significant increase of G2 / M phase cells and of cleaved caspase - 3 ( p = 0 . 0003 , and p = 0 . 0014 after 72 h , respectively ) , and a peak of caspase 3 / 7 activity . PARP cleavage confirmed apoptosis . The presented chordoma series expressed HDACs 2 - 6 with strongest expression of Q9UBN7 . DB02546 and LBH - 589 significantly increased apoptosis and changed cell cycle distribution in vitro . HDAC - inhibitors should be further evaluated as therapeutic options for chordoma .",
"Expression of Npc1 in glial cells corrects sterility in Npc1 (-/-) mice . Niemann - Pick type C1 ( NPC ) disease is an autosomal recessive neurodegenerative disorder . One feature of the mouse model of O15118 is it ' s infertility . We have made transgenic mice which express the Npc1 protein exclusively in fibrillary astrocytes , using the glial fibrillary acidic protein ( P14136 ) promoter . This selective expression of Npc1 corrects sterility in P14136 - Npc1 (-/-) , Npc1 (-/-) mice . Counts of acidophils in the pituitary of P14136 - Npc1E , Npc1 (-/-) mice , as compared Npc1 (-/-) mice , and measurements of dopamine D2 receptor ( P14416 ) mRNA in the pituitary , suggest mechanisms for fertility enhancement . We conclude that the correction of sterility in P14136 - Npc1E , Npc1 (-/-) mice is a result of restoring hypothalamic control of the pituitary .",
"Epigenetics , an early event in the modulation of gene expression by inositol hexaphosphate in ethylnitrosourea exposed mouse lungs . Mechanisms of anticancer effects of inositol hexaphosphate are not fully understood . Epigenetic changes are the early changes in tumorigenesis . DNA methyl transferases , methyl CpG binding proteins , methyl CpG DNA binding domain protein , and histone deacetylases are the major molecules involved in epigenetics . We have shown the effects of IP6 at the molecular level in mouse lungs before the tumor is developed . After 3 mo of ENU exposure , there was no tumor formation , but there was hyperplasia and lymphocytic infiltration in the lungs . Inflammation and DNA damage repair enzymes P35354 and P40692 appear to be upregulated , whereas tumor suppressor gene p16 was downregulated by ENU . On the other hand , ENU exposure more or less upregulated the epigenetic events such as the expressions of P26358 , MeCP2 , Q9UIS9 , and Q13547 . This alteration was reduced by IP6 administration . Results were supported by modulation of global DNA methylation and the modulation of promoter CpG methylation of p16 , P40692 , and P35354 genes . Hence , this study indicates the possible role of epigenetics at the early stage of tumor development and in the regulation of gene expression by IP6 before the onset of ENU - induced lung tumors .",
"An oncogenic form of the Flt - 1 kinase has a tubulogenic potential in a sinusoidal endothelial cell line . We have previously reported a constitutively activated form of the Flt - 1 kinase ( P11274 - FLTm ) molecularly engineered based on the structural backbone of the activated tyrosine kinase P11274 - P00519 . Here we show that it can induce not only growth stimulation but also tubulogenic differentiation of non - tubulogenic NP31 ( non parenchymal ) sinusoidal endothelial cells of rat liver in basement membrane matrix . Tubules formed in vitro were accompanied by fenestration structures and allowed circulation when transplanted into syngeneic animals . This biological response was not observed in other activated forms of kinases constructed in a similar fashion , which include Trk ( P11274 - P04629 ) , P35968 ( P11274 - P35968 ) , and the parental P11274 - P00519 . Interestingly , formation of fine tubules was accomplished with lower but not higher expression levels of P11274 - FLTm . Compared to NP cells in primary culture NP31 is deficient in expression of alpha1 integrin subunit , which was restored by expression of P11274 - FLTm that had tubulogenic ability . Matrix - induced tyrosine phosphorylation of an adaptor protein Shc with recruitment of Grb - 2 was observed even when tubulogenesis was nearly completed at P55008 stage of the cell cycle in 2 - 3 weeks . Activation of matrix metalloproteinase 2 ( P08253 ) and expression of urokinase type plasminogen activator ( uPA ) was observed with cellular invasion into matrix at the depth of 200 - 300 microm . Inhibitors for Q96HU1 kinase activator Q02750 and for serine proteases showed deleterious effects on the tubulogenesis . We suppose that matrix ligand - induced integrin signals cooperate with a low level of Flt - 1 kinase activity to promote tubulogenic behaviors of endothelial cells in this system .",
"Senescence - associated secretory phenotype in a mouse model of bleomycin - induced lung injury . DB00290 produces DNA damage , apoptosis and senescence , all of which play crucial roles in the development of pulmonary fibrosis . Recently , close attention has been paid to a DNA damage - induced phenotypic change ( senescence - associated secretory phenotype ; SASP ) as a trigger for the secretion of various mediators which modify the processes of tissue injury , inflammation , repair and fibrosis . We characterized the SASP in a murine model of bleomycin - induced lung injury . Mice were intratracheally administered bleomycin or control saline , and the lungs were obtained on days 7 , 14 and 21 . The occurrence of DNA damage and the SASP in the lungs was examined by immunostaining . γ P16104 immunostaining of the bleomycin - treated lungs revealed double - strand breaks ( DSBs ) , largely within P12830 - positive , β4 - integirn - positive alveolar epithelial cells . The DSBs were associated with phosphorylation of Q13315 / ATR , a central signal transducer mediating the DNA damage response , and upregulation of the cyclin - dependent kinase inhibitor P38936 ( CIP1 ) . The DSBs persisted for at least 21 days after the bleomycin exposure , although it began to wane after 7 days . A subpopulation of the γ P16104 - positive , DNA - damaged cells exhibited the SASP , characterized by overexpression of P05231 , TNFα , P08253 and P14780 , in association with the phosphorylation of IKKα / β and p38 MAPK . Persistent DNA damage and the SASP are induced in the process of bleomycin - induced lung injury and repair , suggesting that these events play an important role in the regulation of inflammation and tissue remodeling in bleomycin - induced pneumopathy .",
"Autophagic impairment contributes to systemic inflammation - induced dopaminergic neuron loss in the midbrain . BACKGROUND : Neuroinflammation plays an important role in the pathogenesis of Parkinson ' s disease ( PD ) , inducing and accelerating dopaminergic ( DA ) neuron loss . Autophagy , a critical mechanism for clearing misfolded or aggregated proteins such as α - synuclein ( α - O15061 ) , may affect DA neuron survival in the midbrain . However , whether autophagy contributes to neuroinflammation - induced toxicity in DA neurons remains unknown . RESULTS : Intraperitoneal injection of lipopolysaccharide ( LPS , 5 mg / kg ) into young ( 3 - month - old ) and aged ( 16 - month - old ) male C57BL / 6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of α - O15061 in the midbrain . The autophagic substrate - p62 ( Q13501 ) persistently increased , whereas LC3 - II and Q9UBN7 exhibited early increases followed by a decline . In vitro studies further demonstrated that P01375 - α induced cell death in PC12 cells . Moreover , a sublethal dose of P01375 - α ( 50 ng / ml ) increased the expression of LC3 - II , p62 , and α - O15061 , implying that P01375 - α triggered autophagic impairment in cells . CONCLUSION : Neuroinflammation may cause autophagic impairment , which could in turn result in DA neuron degeneration in midbrain .",
"The effect of Q13315 and P27361 / 2 inhibition on mitoxantrone - induced cell death of leukaemic cells . The relationship between signal pathways Q02750 / 2 - P27361 / 2 and Q13315 - p53 in the response to DNA damage is not well understood . The aim of our study was to investigate the effect of mitoxantrone and two protein kinase inhibitors - caffeine ( inhibitor of Q13315 kinase ) and U0126 ( inhibitor of Q02750 / 2 kinase ) - on Q14C87 - 4 and Jurkat leukaemic cell lines . In this work we show that the inhibition of Q02750 / 2 is associated with an increased mortality of cells after mitoxantrone treatment . Inhibition of Q13315 by caffeine delayed mitoxantrone - induced cell death in Q14C87 - 4 cells . Mitoxantrone itself induced cell - cycle arrest and accumulation of the cells in late S and G2 / M phase . Inhibition of Q13315 , but not of Q02750 / 2 , abrogated mitoxantrone - induced cell - cycle arrest . Inhibition of Q02750 / 2 did not change mitoxantroneinduced up - regulation of p53 and P38936 , but inhibition of Q13315 markedly decreased up - regulation of p53 and P38936 , and p53 phosphorylation on serine 15 and serine 392 . It can be concluded that : 1 ) mitoxantrone - induced phosphorylation of p53 on serine 15 and serine 392 is Q13315 dependent and Q02750 / 2 - P27361 / 2 independent . 2 ) Q13315 inhibition by caffeine prevents G2 cell arrest and in p53 - positive cells Q14C87 - 4 delays the onset of mitoxantrone - induced cell death . 3 ) Inhibition of Q02750 / 2 - P27361 / 2 cascade potentiates the cytostatic effect of mitoxantrone regardless of the p53 status .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK14___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"The interplay between G protein - coupled receptor kinase 2 ( P25098 ) and histone deacetylase 6 ( Q9UBN7 ) at the crossroads of epithelial cell motility . G protein - coupled receptor kinase 2 ( P25098 ) is emerging as a key integrative node in cell migration control . In addition to its canonical role in the desensitization of G protein - coupled receptors involved in chemotaxis , novel recently identified P25098 substrates and interacting partners appear to mediate the P25098 - dependent modulation of diverse molecular processes involved in motility , such as gradient sensing , cell polarity or cytoskeletal reorganization . We have recently identified an interaction between P25098 and histone deacetylase 6 ( Q9UBN7 ) , a major cytoplasmic α - tubulin deacetylase involved in cell motility and adhesion . P25098 dynamically associates with and phosphorylates Q9UBN7 to stimulate its α - tubulin deacetylase activity at specific cellular localizations such as the leading edge of migrating cells , thus promoting local tubulin deacetylation and enhanced motility . This P25098 - Q9UBN7 functional interaction may have important implications in pathological contexts related to aberrant epithelial cell migration .",
"A 3 - D model for P08908 - receptor agonists based on stereoselective methyl - substituted and conformationally restricted analogues of 8 - hydroxy - 2 -( dipropylamino ) tetralin . The enantiomers of cis - and trans - 1 , 2 , 3 , 4 , 4a , 5 , 10 , 10a - octahydro - 9 - hydroxy - 1 - propylbenzo [ g ] quinolines ( 10 and 11 , respectively ) and the enantiomers of trans - 1 , 2 , 3 , 4 , 4a , 5 , 6 , 10b - octahydro - 10 - hydroxy - 4 - propylbenzo [ f ] quinoline ( 12 ) have been synthesized and their stereochemical and conformational characteristics have been studied by use of X - ray crystallography and molecular mechanics ( P08253 ) calculations . The compounds , which are conformationally restricted analogues of the potent 5 - hydroxytryptamine ( 5 - HT ) receptor agonist 8 - hydroxy - 2 - ( dipropylamino ) tetralin ( 8 - OH - DPAT ; 1 ) have been evaluated for central 5 - HT and dopamine receptor stimulating activity by use of biochemical and behavioral tests in rats . In addition , we have evaluated the ability of these compounds and a number of previously reported analogues to displace [ 3H ] - 8 - OH - DPAT from P08908 - binding sites . The enantiomers of 12 behave as potent P08908 - receptor agonists , whereas the octahydrobenzo [ g ] quinoline derivatives are much less potent or inactive . In general , the affinities of the compounds correlate well with their agonist potencies . The set of compounds under study is accommodated by a novel computer - graphics - derived model for P08908 - receptor agonism . The model consists of a flexible pharmacophore and a partial receptor - excluded volume .",
"Revelation of p53 - independent function of Q13330 in DNA damage response via modulation of the P38936 P38936 - proliferating cell nuclear antigen pathway . Although metastasis - associated protein 1 ( Q13330 ) , a component of the nucleosome remodeling and deacetylase ( NuRD ) complex , is a DNA - damage response protein and regulates p53 - dependent DNA repair , it remains unknown whether Q13330 also participates in p53 - independent DNA damage response . Here , we provide evidence that Q13330 is a p53 - independent transcriptional corepressor of P38936 ( P38936 ) , and the underlying mechanism involves recruitment of Q13330 - histone deacetylase 2 ( Q92769 ) complexes onto two selective regions of the P38936 ( P38936 ) promoter . Accordingly , Q13330 depletion , despite its effect on p53 down - regulation , superinduces P38936 ( P38936 ) , increases P38936 ( P38936 ) binding to proliferating cell nuclear antigen ( P12004 ) , and decreases the nuclear accumulation of P12004 in response to ionizing radiation . In support of a p53 - independent role of Q13330 in DNA damage response , we further demonstrate that induced expression of Q13330 in p53 - null cells inhibits P38936 ( P38936 ) promoter activity and P38936 ( P38936 ) binding to P12004 . Consequently , Q13330 expression in p53 - null cells results in increased induction of gamma P16104 foci and DNA double strand break repair , and decreased DNA damage sensitivity following ionizing radiation treatment . These findings uncover a new target of Q13330 and the existence of an additional p53 - independent role of Q13330 in DNA damage response , at least in part , by modulating the P38936 ( P38936 )- P12004 pathway , and thus , linking two previously unconnected NuRD complex and DNA - damage response pathways .",
"9 - Hydroxystearic acid interferes with P01133 signalling in a human colon adenocarcinoma . The epidermal growth factor has long been known to be strictly correlated with the highly proliferating activities of cancer cells and primary tumors . Moreover , in the nucleus , the epidermal growth factor / epidermal growth factor receptor complex ( P01133 / P00533 ) functions as a transcriptional regulator that activates the cyclin D1 gene . 9 - hydroxystearic acid ( 9 - HSA ) induces cell proliferation arrest and differentiation in HT29 colon cancer cells by inhibiting histone deacetylase 1 ( Q13547 ) . 9 - HSA - treated HT29 , when stimulated with P01133 , are not responsive and surprisingly undergo a further arrest . In order to understand the mechanisms of this effect , we analyzed the degree of internalization of the P01133 / P00533 complex and its interactions with Q13547 . It appears that Q13547 , as modified by 9 - HSA , is unable to associate with cyclin D1 , interfering with the cell proliferation program , and sequesters the P01133 / P00533 complex interrupting the transduction of the mitogenic signal .",
"Targeting phosphoinositide 3 - kinase : moving towards therapy . Phosphoinositide 3 - kinases ( PI3K ) orchestrate cell responses including mitogenic signaling , cell survival and growth , metabolic control , vesicular trafficking , degranulation , cytoskeletal rearrangement and migration . Deregulation of the PI3K pathway occurs by activating mutations in growth factor receptors or the P42336 locus coding for P42336 , by loss of function of the lipid phosphatase and tensin homolog deleted in chromosome ten ( P60484 / MMAC / TEP1 ) , by the up - regulation of protein kinase B ( P31749 / Akt ) , or the impairment of the tuberous sclerosis complex ( Q92574 / 2 ) . All these events are linked to growth and proliferation , and have thus prompted a significant interest in the pharmaceutical targeting of the PI3K pathway in cancer . Genetic targeting of P48736 ( P48736 ) and O00329 ( O00329 ) in mice has underlined a central role of these PI3K isoforms in inflammation and allergy , as they modulate chemotaxis of leukocytes and degranulation in mast cells . Proof - of - concept molecules selective for P48736 have already successfully alleviated disease progress in murine models of rheumatoid arthritis and lupus erythematosus . As targeting PI3K moves forward to therapy of chronic , non - fatal disease , safety concerns for PI3K inhibitors increase . Many of the present inhibitor series interfere with target of rapamycin ( TOR ) , DNA - dependent protein kinase ( DNA - PK ( cs ) ) and activity of the ataxia telangiectasia mutated gene product ( Q13315 ) . Here we review the current disease - relevant knowledge for isoform - specific PI3K function in the above mentioned diseases , and review the progress of > 400 recent patents covering pharmaceutical targeting of PI3K . Currently , several drugs targeting the PI3K pathway have entered clinical trials ( phase I ) for solid tumors and suppression of tissue damage after myocardial infarction ( phases I , II ) .",
"PD98059 - inhibited invasion of Dunning rat prostate cancer cells involves suppression of motility but not P08253 or uPA secretion . Up - regulation of extracellular - regulated kinases 1 / 2 ( P27361 / 2 ) has been implicated in tumor progression and metastasis in many types of cancer . We have previously shown that P27361 / 2 is necessary for invasiveness of Dunning rat prostatic adenocarcinoma cell lines in which levels of activated P27361 / 2 correlate with the metastatic potential . Here , we further examined the biological effects of elevated P27361 / 2 in the highly metastatic Dunning cell line , Q03164 , in which the abilities to invade and metastasize are enhanced relative to its progenitor strain . Inhibition of P27361 / 2 activation by the Q02750 inhibitor , PD98059 , dose - dependently reduced Q03164 cell invasiveness and motility with similar IC50 values . On the other hand , the abilities of Q03164 cells to adhere to the extracellular matrix , phosphorylate myosin regulatory light chain and secrete matrix - degrading enzymes , matrix metalloproteinase ( MMP ) - 2 and urokinase plasminogen activator ( uPA ) were marginally , if at all , affected by PD98059 treatment . These data indicated that the inhibitory effect of PD98059 on the invasiveness of Q03164 cells was primarily due to the suppression of cell motility , and the up - regulation of P27361 / 2 is , at least in part , responsible for the enhanced cellular motility and invasiveness of the Q03164 cells .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK84___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"[ Numerical impairments in genes in breast cancer : a multiplex ligation - dependent probe amplification study ] . OBJECTIVE : To analyze breast cancer samples using the new technique multiplex ligation - dependent probe amplification ( MLPA ) assay . MATERIAL AND METHODS ; DB03843 - fixed paraffin - embedded breast carcinoma samples from 65 patients were examined . After manual microdissection , DNA was isolated using a commercial kit ( \" QIAGEN \" ) and analyzed with SALSA MLPA P10721 P078 - B1 Breast Tumour ( \" MRC - Holland \" ) . Capillary electrophoresis provided results . RESULTS : MLPA assay was successful in all examined samples . The amplification and deletion frequencies of the analyzed genes were in line with the literature data . The technique requires conventional work - related skills in a molecular genetic laboratory and , as a whole , presents no problems with its usage . The interpretation of results is devoid of subjective meaning due to exclusively their mathematical analysis . MLPA assay provides an insight into numerical impairments in the following genes : P04626 , MYC , Q9BUZ4 , Q7Z589 ( Q7Z589 ) , Q13443 , O14920 , P24864 , P11388 , CDH1 , Q99741 , P03372 , O75976 , P00533 , Q86UE4 , P24385 , O15392 , MED1 , P11362 , P10636 , Q9GZV8 , and O14965 . CONCLUSION : MLPA is an easy - to - use and promising method for multiplex genetic analysis of tumor cells in breast cancer .",
"Transcription of the activating receptor P26718 in natural killer cells is regulated by P40763 tyrosine phosphorylation . P40763 ( P40763 ) is considered a negative regulator of inflammation , as inhibition of P40763 signaling enhances antitumor immunity . However , P40763 activation is a key oncogenic pathway in natural killer ( NK ) - lineage large granular lymphomas , and we recently reported enhanced proliferation and function of human NK cells activated with Q9HBE4 , which signals primarily through P40763 . These Q9HBE4 - expanded NK cells also have increased P26718 expression , which led us to focus our investigation on whether P40763 regulates P26718 . In this study , we show that modulation of P40763 phosphorylation with cytokines and small - molecule inhibitors correlates with P26718 expression on human NK cells , leading to altered NK - cell degranulation . Moreover , P26718 expression on murine NK cells having conditional P40763 ablation is lower than on NK cells from wild - type mice , and human NK cells carrying dominant - negative P40763 mutations have decreased baseline P26718 expression and blunted responses to P22301 and Q9HBE4 . Lastly , we show binding of P40763 to a predicted P40763 binding site upstream of the P26718 gene , which is enhanced by P22301 and Q9HBE4 and decreased by P40763 inhibition . Taken together , these data show that P26718 expression in NK cells is regulated at the transcriptional level by P40763 , resulting in a functional NK cell defect in patients with P40763 mutations ."
] |
[
"___MASK12___",
"___MASK14___",
"___MASK19___",
"___MASK59___",
"___MASK66___",
"___MASK80___",
"___MASK82___",
"___MASK84___",
"___MASK96___"
] |
___MASK80___
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MH_train_435
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interacts_with DB04817?
|
[
"Expression of cyclooxygenase - 2 ( P35354 ) in tumour and stroma compartments in cervical cancer : clinical implications . This study aims at investigating the relationship between cyclooxygenase - 2 expression in tumour vs stroma inflammatory compartment and its possible clinical role . The study included 99 stage IB - IV cervical cancer patients : immunostaining of tumour tissue sections was performed with rabbit antiserum against cyclooxygenase - 2 . CD3 , P01730 , CD8 , CD25 , Mast Cell Tryptase monoclonal antibodies were used to characterise stroma inflammatory cells in nine cervical tumours . An inverse relation was found between cyclooxygenase - 2 levels ( cyclooxygenase - 2 IDV ) of tumour vs stroma compartment ( r =- 0 . 44 , P < 0 . 0001 ) . The percentage of cases showing high tumour / stromal cyclooxygenase - 2 IDV ratio was significantly higher in patients who did not respond to treatment ( 93 . 3 % ) with respect to patients with partial ( 60 . 5 % ) , and complete ( 43 . 7 % ) response ( P = 0 . 009 ) . Cases with a high tumour / stroma cyclooxygenase - 2 IDV ratio had a shorter overall survival rate than cases with a low tumour / stroma cyclooxygenase - 2 IDV ( P < 0 . 0001 ) . In the multivariate analysis advanced stage and the status of tumour / stroma cyclooxygenase - 2 IDV ratio retained an independent negative prognostic role . The proportion of CD3 (+) , P01730 (+) , and CD25 (+) cells was significantly lower in tumours with high tumour / stroma cyclooxygenase - 2 IDV ratio , while a higher percentage of mast cells was detected in tumours showing high tumour / stroma cyclooxygenase - 2 IDV ratio . Our study showed the usefulness of assessing cyclooxygenase - 2 status both in tumour and stroma compartment in order to identify cervical cancer patients endowed with a very poor chance of response to neoadjuvant therapy and unfavourable prognosis .",
"Activation of serotonin receptor - 2B rescues small - for - size liver graft failure in mice . The implantation of grafts below 30 % of the normal liver volume is associated with a high risk of failure known as small - for - size ( SFS ) syndrome . Strategies to rescue small grafts may have a dramatic impact on organ shortage . Serotonin is a potent growth factor for the liver . The goal of this study was to determine whether enhanced serotonin signaling could prevent the deleterious effects of SFS syndrome . We performed 30 % normal liver volume transplantations in wild - type C57 / BL6 and interleukin - 6 ( P05231 ) (-/-) mice . Some animals received α - methyl - 5 - HT ( DOI ) , an agonist of serotonin receptor - 2 ( P41595 ) . Endpoints included long - term survival , serum and hepatic markers of liver injury and regeneration , assessment of hepatic microcirculation by intravital fluorescence microscopy and scanning electron microscopy , and transcript levels of a variety of serotonin receptors , tumor necrosis factor α , and P05231 . All recipients of small grafts ( controls ) died within 2 - 4 days of transplantation , whereas half of those receiving DOI survived permanently . Control animals disclosed major liver injury , including diffuse microvesicular steatosis in hepatocytes , impairment of microcirculation , and a failure of regeneration , whereas these parameters were dramatically improved in animals subjected to DOI . Blockage of P41595 blunted the protective effects of DOI . Whereas P05231 levels were higher in DOI - treated animals , P05231 (-/-) mice were still protected by DOI , suggesting a protective pathway independent of P05231 . CONCLUSION : Serotonin through its action on receptor - 2B protects SFS liver grafts from injury and prevents microcirculation and regeneration . The mechanism of hepato - protection is independent of P05231 .",
"A comparative study of the antipyretic effects of indomethacin and dipyrone in rats . OBJECTIVE : Compare the antipyretic effects of dipyrone and indomethacin . MATERIALS AND METHODS : Fever was induced in rats by i . v . LPS or i . c . v . interleukins ( IL ) , prostaglandins ( PG ) , arachidonic acid ( AA ) , pre - formed pyrogenic factor ( PFPF ) , tumour necrosis factor - alpha ( P01375 ) or corticotrophin releasing hormone ( P06850 ) . DB04817 and indomethacin were administered i . p . , arginine vasopressin V1 - receptor antagonist , d ( CH2 ) 5 DB00135 ( Me ) AVP , into the ventral septal area . Cyclooxygenase ( P23219 /- 2 ) blocking activity was assessed in transfected COS - 7 cells . P06850 release from isolated hypothalami was determined by ELISA . RESULTS : Indomethacin or dipyrone reduced LPS , IL - 1beta , P05231 or P01375 induced fever and P06850 release from rat hypothalamus . Only dipyrone inhibited P10145 , PFPF or PGF2alpha fever . Only indomethacin inhibited fever induced by AA or IL - 1beta , plus AA . Neither antipyretic affected fever caused by DB00917 or P06850 . d ( CH2 ) 5Tyr ( Me ) AVP only blocked antipyresis induced by indomethacin . DB04817 at a very high concentration ( 10 mM ) inhibited only P23219 , while indomethacin ( 0 . 1 microM ) blocked P23219 and P35354 in COS - 7 cells . CONCLUSION : The antipyretic effect of dipyrone differs from that of indomethacin in that it does not depend on AVP release or inhibition of PG synthesis .",
"___MASK88___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK88___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"P35372 mutant , T394A , abolishes opioid - mediated adenylyl cyclase superactivation . This study was to characterize the effects of a point - mutant at C - terminal of mu opioid receptor ( MOR ) , namely MOR T394A , in chronic opioid - induced cellular responses . After 18 h of exposure to [ D - Ala , N - Me - DB00120 , DB00145 - ol ] enkephalin ( DAMGO ) , adenylyl cyclase ( AC ) superactivation , a hallmark for the cellular adaptive response after chronic opioid stimulation , was observed in the cells expressing wild - type receptor , but was totally abolished in the cells expressing MOR T394A . Receptor phosphorylation was also attenuated in cells with MOR T394A after prolonged preexposure to agonist . Furthermore , Q96HU1 kinase kinase - 1 ( Q02750 ) overexpression was able to rescue AC superactivation in cells with MOR T394A , but showed no effect in the wild - type MOR - expressing cells . These results indicated that the amino acid T394 at C - terminus of MOR played a critical role in chronic agonist - induced AC superactivation and receptor phosphorylation .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK18___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"IL - 1beta induces P15692 , independently of DB00917 induction , mainly through the P19957 - K / P42345 pathway in renal mesangial cells . Vascular endothelial growth factor ( P15692 ) could play a relevant role in angiogenesis associated with chronic allograft nephropathy . Interleukin - 1beta ( IL - 1beta ) has a key role in inflammatory response . It induces prostaglandin ( PG ) E2 , which is involved in P15692 release by some normal and tumor cells . In the present work , we studied the effect of IL - 1beta on P15692 release by rat mesangial cells , the transduction signal , and whether or not DB00917 is involved in this effect . IL - 1beta induced a time - dependent formation of P15692 ( analyzed by enzyme - linked immunosorbent assay ) and DB00917 ( analyzed by enzyme immunoassay ) . The latter correlated with microsomal - PGE - synthase ( mPGES ) - 1 expression rather than with cyclooxygenase ( P36551 ) - 2 in terms of protein , determined by Western blotting . No effect of IL - 1beta on P23219 , cytosolic O14684 , or Q9H7Z7 expression was observed . Indomethacin exerted a nonsignificant effect on IL - 1beta - induced P15692 , and exogenously added DB00917 exhibited a nonsignificant stimulatory effect on P15692 formation . SB 203580 , a p38 mitogen - activated protein kinase inhibitor , weakly inhibited the induction of P15692 by IL - 1beta in a concentration - dependent manner , whereas LY 294002 , a phosphoinoside 3 - kinase ( P19957 - K ) inhibitor , and rapamycin , a mammalian target of rapamycin ( P42345 ) inhibitor , strongly inhibited both IL - 1beta - and tumor necrosis factor - alpha - induced P15692 formation in a concentration - dependent manner . ___MASK45___ also decreased glomerular P15692 levels in the anti - Thy1 . 1 model of experimental glomerulonephritis . In conclusion , the P19957 - K - P42345 pathway seems to be essential in cytokine - induced release of P15692 in mesangial cells .",
"Histone deacetylase inhibitors suppress the induction of c - Jun and its target genes including P35354 . P35354 ( P35354 ) is considered to be a target for anticancer therapy . Histone deacetylase ( HDAC ) inhibitors exhibit antitumor activity , but the mechanisms of action are incompletely understood . We investigated whether HDAC inhibitors blocked AP - 1 - mediated activation of P35354 transcription . Trichostatin A and suberoylanilide hydroxamic acid , two structurally related inhibitors of HDAC activity , blocked AP - 1 - mediated induction of P35354 expression and prostaglandin E2 biosynthesis . Chromatin immunoprecipitation assays indicated that HDAC inhibitors suppressed c - Jun binding to the P35354 promoter and thereby blocked transcription . The observed reduction in binding reflected reduced levels of c - Jun . HDAC inhibitors suppressed the induction of c - jun transcription by blocking the recruitment of the preinitiation complex ( RNA polymerase II and Q00403 ) to the c - jun promoter . O15379 but not Q13547 or Q92769 was required for AP - 1 - mediated stimulation of c - jun expression . Because HDAC inhibitors suppressed the induction of c - jun gene expression , resulting in reduced P35354 transcription , it was important to determine whether other known AP - 1 target genes were also modulated . P12004 D1 and collagenase - 1 are AP - 1 - dependent genes that have been implicated in carcinogenesis . HDAC inhibitors suppressed the induction of both cyclin D1 and collagenase - 1 transcription by inhibiting the binding of c - Jun to the respective promoters . Taken together , these results suggest that HDAC inhibitors block the induction of c - jun transcription by inhibiting the recruitment of the preinitiation complex to the c - jun promoter . This led , in turn , to reduced expression of several activator protein - 1 - dependent genes ( P35354 , cyclin D1 , collagenase - 1 ) . These findings provide new insights into the mechanisms underlying the antitumor activity of HDAC inhibitors .",
"Synthesis and biological evaluation of novel pyrrolidine - 2 , 5 - dione derivatives as potential antidepressant agents . Part 1 . A series of 3 -( 1H - indol - 3 - yl ) pyrrolidine - 2 , 5 - dione derivatives was synthesized and their biological activity was evaluated . The chemical structures of the newly prepared compounds were confirmed by ( 1 ) H NMR , ( 13 ) C NMR and P19957 - HRMS spectra data . All tested compounds proved to be potent P08908 receptor and serotonin transporter protein ( P31645 ) ligands . Among them , compounds 15 , 18 , 19 and 30 showed significant affinity for P08908 and P31645 . Computer docking simulations carried out for compounds 15 , 31 and 32 to models of P08908 receptor and P31645 confirm the results of biological tests . Due to high affinity for the P08908 receptor and moderate affinity for P31645 , compounds 31 , 32 , 35 , and 37 were evaluated for their affinity for D2L , P50406 , P34969 and 5 - Q13049 receptors . In vivo tests , in turn , resulted in determining the functional activity of compounds 15 , 18 , 19 and 30 to the P08908 receptor . The results of these tests indicate that all of the ligands possess properties characteristic of P08908 receptor agonists .",
"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .",
"The p65 ( RelA ) subunit of NF - kappaB interacts with the histone deacetylase ( HDAC ) corepressors Q13547 and Q92769 to negatively regulate gene expression . Regulation of NF - kappaB transactivation function is controlled at several levels , including interactions with coactivator proteins . Here we show that the transactivation function of NF - kappaB is also regulated through interaction of the p65 ( RelA ) subunit with histone deacetylase ( HDAC ) corepressor proteins . Our results show that inhibition of HDAC activity with trichostatin A ( P32119 ) results in an increase in both basal and induced expression of an integrated NF - kappaB - dependent reporter gene . Chromatin immunoprecipitation ( ChIP ) assays show that P32119 treatment causes hyperacetylation of the wild - type integrated NF - kappaB - dependent reporter but not of a mutant version in which the NF - kappaB binding sites were mutated . Expression of Q13547 and Q92769 repressed tumor necrosis factor ( P01375 ) - induced NF - kappaB - dependent gene expression . Consistent with this , we show that Q13547 and Q92769 target NF - kappaB through a direct association of Q13547 with the Rel homology domain of p65 . Q92769 does not interact with NF - kappaB directly but can regulate NF - kappaB activity through its association with Q13547 . Finally , we show that inhibition of HDAC activity with P32119 causes an increase in both basal and P01375 - induced expression of the NF - kappaB - regulated interleukin - 8 ( P10145 ) gene . Similar to the wild - type integrated NF - kappaB - dependent reporter , ChIP assays showed that P32119 treatment resulted in hyperacetylation of the P10145 promoter . These data indicate that the transactivation function of NF - kappaB is regulated in part through its association with HDAC corepressor proteins . Moreover , it suggests that the association of NF - kappaB with the Q13547 and Q92769 corepressor proteins functions to repress expression of NF - kappaB - regulated genes as well as to control the induced level of expression of these genes .",
"DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK53___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"Selective inhibitors of Q02750 / ERK44 / 42 and p38 mitogen - activated protein kinases potentiate apoptosis induction by sulindac sulfide in human colon carcinoma cells . The nonsteroidal anti - inflammatory drug ( NSAID ) sulindac prevents experimental colon cancer and can regress precancerous polyps in humans . Sulindac sulfide inhibits cyclooxygenase ( P36551 ) - mediated prostaglandin synthesis and retards the growth of cultured colon cell lines primarily by inducing apoptosis . Given the known role of mitogen - activated protein kinase ( MAPK ) in signal transduction and the regulation of cell survival and death , we determined the effect of sulindac sulfide on MAPK activation , P35354 expression , and apoptosis induction in HCA - 7 human colon cancer cells . Sulindac sulfide treatment was associated with activation of ERKp44 / 42 and p38 MAPK in a dosage - and time - dependent manner , and also activated upstream MEK . Similar results were seen in HCT - 15 cells and also with the selective P35354 inhibitor NS398 . ERKp44 / 42 and p38 activation were accompanied by an induction of P35354 protein expression . Selective inhibitors of sulindac sulfide - induced ERKp44 / 42 ( PD98059 ) and p38 MAPK ( SB203580 ) activation also suppressed the induction of P35354 by this NSAID . Furthermore , both MAPK inhibitors significantly augmented sulindac sulfide - induced apoptosis , as did suppression of constitutive P35354 using antisense oligonucleotides . In conclusion , MEK / P29323 and p38 MAPK activation mediate P35354 induction by sulindac sulfide . Selective inhibitors of these MAPKs potentiate apoptosis induction by this NSAID , suggesting a novel strategy for the prevention or treatment of colorectal cancer .",
"Inhibition of Akt / P31749 by a P35354 inhibitor induces apoptosis in gastric cancer cells . BACKGROUND / AIM : Inhibition of cyclooxygenase - 2 has been proposed to be a potential mechanism for the chemoprevention of gastrointestinal tumors by nonsteroidal anti - inflammatory drugs . This study investigates the mechanisms by which the cyclooxygenase - 2 inhibitor SC236 induces apoptosis of gastric cancer cell lines and its downstream signaling pathway . METHODS : Two gastric cancer cell lines , AGS and MKN28 , were treated with SC236 and assessed for cell growth and apoptosis . The involvement of mitogen - activated protein kinase and Akt kinase / protein kinase B ( Akt / P31749 ) pathways and their downstream signalings were studied in the AGS cell line . RESULTS : SC236 treatment induced apoptosis in gastric cancer cells and caused activation of p38 and stress - activated protein kinase / jun kinase , but down - regulated Akt / P31749 . The specific p38 inhibitor SB203580 and the dominant - negative stress - activated protein kinase / jun kinase both failed , while the constitutively active form of Akt / P31749 was able to block SC236 - induced apoptosis . SC236 - induced apoptosis was coupled with release of cytochrome c and activation of caspases . CONCLUSION : One of the pathways involved in SC - 236 - induced apoptosis in gastric cancer cells is through downregulation of Akt and then release of cytochrome c .",
"High mobility group box protein - 1 promotes cerebral edema after traumatic brain injury via activation of toll - like receptor 4 . Traumatic brain injury ( TBI ) is a major cause of mortality and morbidity worldwide . Cerebral edema , a life - threatening medical complication , contributes to elevated intracranial pressure ( ICP ) and a poor clinical prognosis after TBI . Unfortunately , treatment options to reduce post - traumatic edema remain suboptimal , due in part , to a dearth of viable therapeutic targets . Herein , we tested the hypothesis that cerebral innate immune responses contribute to edema development after TBI . Our results demonstrate that high - mobility group box protein 1 ( P09429 ) was released from necrotic neurons via a Q13224 - mediated mechanism . P09429 was clinically associated with elevated ICP in patients and functionally promoted cerebral edema after TBI in mice . The detrimental effects of P09429 were mediated , at least in part , via activation of microglial toll - like receptor 4 ( O00206 ) and the subsequent expression of the astrocytic water channel , aquaporin - 4 ( P55087 ) . Genetic or pharmacological ( VGX - 1027 ) O00206 inhibition attenuated the neuroinflammatory response and limited post - traumatic edema with a delayed , clinically implementable therapeutic window . Human and rodent tissue culture studies further defined the cellular mechanisms demonstrating neuronal P09429 initiates the microglial release of interleukin - 6 ( P05231 ) in a O00206 dependent mechanism . In turn , microglial P05231 increased the astrocytic expression of P55087 . Taken together , these data implicate microglia as key mediators of post - traumatic brain edema and suggest P09429 - O00206 signaling promotes neurovascular dysfunction after TBI .",
"P28335 receptor involvement in female rat lordosis behavior . Adult , hormone - primed , ovariectomized rats ( P05231 - 344 ) with bilateral implants within the ventromedial nucleus of the hypothalamus ( VMN ) , were injected with 0 . 5 microgram estradiol benzoate followed 48 h later with 500 microgram progesterone . This priming produced rats with 2 different levels of sexual receptivity . Rats with a lordosis to mount ratio ( L / M ) >/= 0 . 5 were used to examine the potential lordosis - inhibiting effects of the 5 - Q13049 receptor antagonist , R (+)- a - ( 2 , 3 - dimethoxyphenyl ) - 1 -[ 2 ( 4 - fluoro - phenylethyl )]- 4 - piperidine - methanol ( MDL 100 , 907 ) , and the P28335 receptor antagonist , 5 - methyl - 1 -( 3 - pyridylcarbamoyl )- 1 , 2 , 3 , 5 - tetrahydropyrrolo [ 2 , 3 - f ] indole ( SB 206553 ) . Rats with low sexual receptivity ( L / M < 0 . 5 ) were bilaterally infused with the 5 - Q13049 / 2C receptor agonist , (+/-)- 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane HCl ( DOI ) , or DOI plus either MDL 100 , 907 or SB 206553 to determine if either drug would attenuate the lordosis - facilitating effects of DOI . The P28335 receptor antagonist , but not the 5 - Q13049 receptor antagonist , effectively inhibited lordosis behavior . Similarly , SB 206553 was more effective than MDL 100 , 907 in reducing the DOI - induced increase in lordosis responding . However , both drugs limited the duration of lordosis responding initiated by DOI . These results are consistent with prior suggestions that 5 - Q13049 / 2C receptors within the VMN are involved in the modulation of lordosis behavior and lead to the suggestion that P28335 , rather than 5 - Q13049 , receptors are primarily responsible for the effects of 5 - HT2 receptor - active drugs on lordosis behavior .",
"P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .",
"The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 phosphorylation . ___MASK26___ ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low - concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .",
"Involvement of the rapamycin - sensitive pathway in the insulin regulation of muscle protein synthesis in streptozotocin - diabetic rats . P01308 resistance in 3 - day streptozotocin ( Q11206 ) - treated rats was manifested by the lack of antiproteolytic action of insulin as well as by a reduction of its stimulatory effect on protein synthesis ( - 60 % compared with the control group ) in epitrochlearis muscle incubated in vitro . In the present study , we have investigated the diabetes - associated alterations in the insulin signalling cascade , especially the phosphatidylinositol - 3 kinase ( P19957 kinase ) / P08133 S6 kinase ( P08133 ( S6K ) ) pathway , in rat skeletal muscle . LY 294002 , a specific inhibitor of P19957 kinase , markedly decreased the basal rate of protein synthesis and completely prevented insulin - mediated stimulation of this process both in control and diabetic rats . Thus , P19957 kinase is required for insulin - stimulated muscle protein synthesis in diabetic rats as in the controls . ___MASK45___ , an inhibitor of mammalian target of rapamycin ( P42345 ) , had no effect on the basal rate of protein synthesis in either of the experimental groups . In control rats , the stimulatory action of insulin on muscle protein synthesis was diminished by 36 % in the presence of rapamycin , whereas in diabetic muscles this reduction amounted to 68 % . The rapamycin - sensitive pathway makes a relatively greater contribution to the stimulatory effect of insulin on muscle protein synthesis in diabetic rats compared with the controls , due presumably to the preferential decrease in the rapamycin - insensitive component of protein synthesis . Neither basal nor insulin - stimulated P08133 ( S6K ) activity , a signalling element lying downstream of P42345 , were modified by Q11206 - diabetes .",
"Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .",
"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK8___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK8___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK8___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK8___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK30___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK30___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK30___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK30___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK30___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK26___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .",
"Development of new drugs for P48444 . Chronic obstructive pulmonary disease ( P48444 ) is an increasing global health problem and cause of death . P48444 is a chronic inflammatory disease predominantly affecting small airways and lung parenchyma that leads to progressive airway obstruction . However , current therapies fail to prevent either disease progression or mortality . The mainstay of current drug therapy is long - acting bronchodilators . Several once daily inhaled β ( 2 )- agonists and muscarinic antagonists ( and combinations ) are now in development . No treatments effectively suppress chronic inflammation in P48444 lungs . With better understanding of the inflammatory and destructive process in the pathophysiology of P48444 , several new therapeutic targets have been identified . Several mediator antagonists or inhibitors tested in P48444 have so far been disappointing , but P25025 antagonists that block pulmonary neutrophil and monocyte recruitment are more promising . Broad spectrum anti - inflammatory drugs may be more effective , and include inhibitors of the proinflammatory enzymes phosphodiesterase - 4 , p38 mitogen - activated protein kinase , Janus kinases , NF - κB kinase and P19957 kinase - γ and - δ , but side effects after oral administration are a major limitation so that in future inhaled delivery may be necessary . A new promising approach is reversal of corticosteroid resistance through increasing histone deacetylase - 2 ( Q92769 ) activity . This might be achieved by existing treatments such as theophylline , nortriptyline and macrolides , or more selectively by P19957 kinase - δ inhibitors . Thus although there have been major advances in the development of long - acting bronchodilators for P48444 , it has proved difficult to find anti - inflammatory treatments that are safe and effective .",
"Pharmacological characterization of mitogen - activated protein kinase activation by recombinant human P28335 , 5 - Q13049 , and P41595 receptors . The type 2 serotonin ( 5 - HT ( 2 ) ) receptor subfamily is known to couple to phosphoinositide hydrolysis ( PI ) and the subsequent mobilization of intracellular Ca ( 2 +) , as well as the release of arachidonic acid ( AA ) . Less is known of 5 - HT ( 2 )- mediated activation of the mitogen - activated protein kinase ( MAPK ) or extracellular signal - regulated kinase ( P27361 / 2 ) signaling . The present study measured the relative efficacies and potencies of 5 - HT agonists to activate P28482 in non - neuronal cells expressing recombinant human 5 - HT ( 2A ) , 5 - HT ( 2B ) , and 5 - HT ( 2C ( ISV )) receptors . 5 - HT agonists stimulated P28482 activity via all three 5 - HT ( 2 ) subtypes . There were no meaningful differences in the potencies or relative efficacies of these agonists to affect P28482 activity vs . PI accumulation or Ca ( 2 +) mobilization , suggesting that these pathways may be sequentially linked . Indeed , P28482 activity was very sensitive to PKC inhibition and calcium chelation and insensitive to tyrosine kinase and P19957 - kinase inhibition . 5 - HT ( 2 ) receptors efficiently couple to MAPK activation via sequential PI hydrolysis , and Ca ( 2 +) mobilization . This profile differs from reports of \" agonist - directed trafficking of receptor stimulus \" between PI / Ca ( 2 +) and AA pathways activated by 5 - HT ( 2 ) receptors .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK86___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"Novel bioactive metabolites of dipyrone ( metamizol ) . DB04817 is a common antipyretic drug and the most popular non - opioid analgesic in many countries . In spite of its long and widespread use , molecular details of its fate in the body are not fully known . We administered dipyrone orally to mice . Two unknown metabolites were found , viz . the arachidonoyl amides of the known major dipyrone metabolites , 4 - methylaminoantipyrine ( 2 ) and 4 - aminoantipyrine ( 3 ) . They were identified by P19957 - LC - MS / MS after extraction from the CNS , and comparison with reference substances prepared synthetically . The arachidonoyl amides were positively tested for cannabis receptor binding ( CB ( 1 ) and CB ( 2 ) ) and cyclooxygenase inhibition ( P23219 and P35354 in tissues and as isolated enzymes ) , suggesting that the endogenous cannabinoid system may play a role in the effects of dipyrone against pain .",
"___MASK45___ unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . ___MASK45___ ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .",
"Platelet - derived growth factor mediated altered expression and regulation of ornithine decarboxylase in H - ras - transformed cell lines . This study demonstrates a novel link between alterations in platelet - derived growth factor ( PDGF ) regulation of ornithine decarboxylase ( ODC ) expression during malignant conversion . H - ras - transformed cell lines exhibited PDGF - mediated alterations in ODC gene expression . These alterations involved transcriptional , posttranscriptional , and cycloheximide - mediated events . PDGF - mediated alterations in ODC gene expression in Q13224 cells ( capable of only benign tumour formation ) were ras - dependent , involved a tyrosine kinase activity and mitogen - activated protein ( Q96HU1 ) kinase - mediated signalling events , and were independent of both protein kinase C ( PKC ) events and pertussis toxin - sensitive ( Q03393 ) G - protein - mediated signalling . PDGF - mediated alterations in ODC gene expression in P06681 cells [ capable of malignant progression ( metastasis formation ) ] were ras - dependent , required a tyrosine kinase activity , involved both Q96HU1 kinase - mediated events and phosphatidylinositol - 3 - kinase ( P19957 - kinase ) - mediated events , and were dependent upon Q03393 G - protein - mediated signalling but independent of PKC - mediated events . PDGF - mediated regulation of ODC gene expression changes in response to H - ras - mediated cellular transformation and malignant progression .",
"Evaluation of the endogenous cannabinoid system in mediating the behavioral effects of dipyrone ( metamizol ) in mice . DB04817 is a common nonopioid analgesic and antipyretic , which , in many countries , is available over the counter and is more widely used than paracetamol or aspirin . However , the exact mechanisms by which dipyrone acts remain inconclusive . Two novel arachidonoyl - conjugated metabolites are formed in mice following the administration of dipyrone that are dependent on the activity of fatty acid amide hydrolase ( FAAH ) , which also represents the major catabolic enzyme of the endogenous cannabinoid ligand anandamide . These arachidonoyl metabolites not only inhibit cyclooxygenase ( P23219 / P35354 ) but also bind to cannabinoid receptors at low micromolar concentrations . The relative contributions of cannabinoid receptors and FAAH in the overall behavioral response to dipyrone remain untested . Accordingly , the two primary objectives of the present study were to determine whether the behavioral effects of dipyrone would ( a ) be blocked by cannabinoid receptor antagonists and ( b ) occur in FAAH mice . Here , we report that thermal antinociceptive , hypothermic , and locomotor suppressive actions of dipyrone are mediated by a noncannabinoid receptor mechanism of action and occurred after acute or repeated administration irrespective of FAAH . These findings indicate that FAAH - dependent arachidonoyl metabolites and cannabinoid receptors are not requisites by which dipyrone exerts these pharmacological effects under noninflammatory conditions .",
"DB00131 - activated protein kinase regulates platelet - derived growth factor - BB - induced vascular smooth muscle cell migration . Migration of vascular smooth muscle cells ( VSMCs ) is essential for repair of vascular injury , development of atherosclerotic lesions and restenosis after angioplasty or by - pass graft surgery . It has been reported that platelet - derived growth factor ( PDGF ) - BB induces VSMC migration via the Q8TCB0 / Q8NFH3 mitogen - activated protein ( Q96HU1 ) kinase pathway and the phosphatidylinositol 3 ( P19957 ) - kinase / Akt pathway . DB00131 - activated protein kinase ( AMPK ) is generally known to regulate multiple metabolic pathway . In the present study , we investigated the involvement of AMPK in DB00102 - induced migration of VSMCs using , a VSMC line , A10 cells . DB00102 induced phosphorylation of AMPK - α at DB00156 - 172 residue . Treatment of A10 cells with compound C , an AMPK inhibitor , suppressed DB00102 - induced migration in a concentration - dependent manner ( 0 . 01 - 1μM ) . Compound C truly attenuated DB00102 induced phosphorylation of acetyl - DB01992 carboxylase , a downstream substance of AMPK . Downregulation of AMPK - α expression by the siRNA appeared an anti - migratory effect on DB00102 - induced migration . DB00102 - induced phosphorylation of c - Raf , Q02750 / 2 or Q8TCB0 / Q8NFH3 Q96HU1 kinase , and phosphorylation of P19957 - kinase or Akt were markedly suppressed by compound C . In conclusion , our results strongly suggest that DB00102 induces activation of AMPK in VSMCs , and subsequently regulates the migration via both the Q8TCB0 / Q8NFH3 Q96HU1 kinase pathway and the P19957 - kinase / Akt pathway .",
"Expression of P35354 and DB01221 receptor genes at the cochlea and midbrain in salicylate - induced tinnitus . OBJECTIVE / HYPOTHESIS : The expression of the genes for cyclooxygenase ( P36551 ) and DB01221 receptor ( NR ) has seldom been reported in tinnitus . We hypothesized that expression of P35354 and NR was altered in the cochlea and midbrain in salicylate - induced tinnitus . STUDY DESIGN : Experimental study on mice . METHODS : We evaluated the tinnitus score and mRNA expression levels of P35354 and NR subtype 2B ( Q13224 ) in the cochlea and midbrain in response to intraperitoneal injections of salicylate for 4 days . RESULTS : At day 4 of tinnitus induction , the mean weights of the whole body and midbrain did not change greatly in both control and salicylate groups . The tinnitus score was not elevated from day 1 to day 4 in the control group , but increased day by day in the salicylate group . The mRNA expression level of P35354 decreased slightly in the salicylate group in the cochlea ( 1 . 1 ± 0 . 33 vs . 1 . 3 ± 0 . 49 , P = . 0752 ) and in the midbrain ( 0 . 9 ± 0 . 10 versus 1 . 0 ± 0 . 35 , P = . 0489 ) . Inversely , the expression levels of the Q13224 gene increased moderately in the salicylate group in the cochlea ( 3 . 7 ± 0 . 47 versus 2 . 3 ± 1 . 13 , P < 0 . 0001 ) and in the midbrain ( 1 . 6 ± 0 . 64 versus 1 . 0 ± 0 . 44 , P = . 0007 ) . CONCLUSIONS : Salicylate induced tinnitus and altered the expression of the P35354 and Q13224 genes in the cochlea and midbrain of mice . These findings might contribute to further understanding of pathophysiology and therapy of tinnitus .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK47___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK47___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects ."
] |
[
"___MASK18___",
"___MASK26___",
"___MASK30___",
"___MASK45___",
"___MASK47___",
"___MASK53___",
"___MASK86___",
"___MASK88___",
"___MASK8___"
] |
___MASK45___
|
MH_train_436
|
interacts_with DB00315?
|
[
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"___MASK12___ treatment ameliorates murine chronic graft - versus - host disease . Chronic graft - versus - host disease ( cGVHD ) is a life - threatening impediment to allogeneic hematopoietic stem cell transplantation , and current therapies do not completely prevent and / or treat cGVHD . P01730 + T cells and B cells mediate cGVHD ; therefore , targeting these populations may inhibit cGVHD pathogenesis . ___MASK12___ is an FDA - approved irreversible inhibitor of Bruton ' s tyrosine kinase ( Q06187 ) and P60568 inducible T cell kinase ( Q08881 ) that targets Th2 cells and B cells and produces durable remissions in B cell malignancies with minimal toxicity . Here , we evaluated whether ibrutinib could reverse established cGVHD in 2 complementary murine models , a model interrogating T cell - driven sclerodermatous cGVHD and an alloantibody - driven multiorgan system cGVHD model that induces bronchiolar obliterans ( BO ) . In the T cell - mediated sclerodermatous cGVHD model , ibrutinib treatment delayed progression , improved survival , and ameliorated clinical and pathological manifestations . In the alloantibody - driven cGVHD model , ibrutinib treatment restored pulmonary function and reduced germinal center reactions and tissue immunoglobulin deposition . Animals lacking Q06187 and Q08881 did not develop cGVHD , indicating that these molecules are critical to cGVHD development . Furthermore , ibrutinib treatment reduced activation of T and B cells from patients with active cGVHD . Our data demonstrate that B cells and T cells drive cGVHD and suggest that ibrutinib has potential as a therapeutic agent , warranting consideration for cGVHD clinical trials .",
"Cortical spreading depression - associated hyperemia in rats : involvement of serotonin . We investigated whether the vasoactive neurotransmitter serotonin ( 5 - HT ) is involved in cortical spreading depression ( Q9Y600 ) - associated hyperemia in the rat . We focused on the 5 - HT2 receptor , which is engaged in 5 - HT induced small arteriolar relaxation in cats , as well as on the P28221 / 1B receptor , the binding site of the potent antimigraine drug sumatriptan . In male barbiturate anaesthetized Wistar rats ( n = 25 ) CSDs were elicited by brain topical application of 1 M DB00761 , and the DC - potential and regional cerebral blood flow ( rCBF , by Laser Doppler flowmetry ) were measured over the same hemisphere through dura and thinned bone , respectively . Intravenous application of 8 mg / kg of the 5 - Q13049 / 2C receptor antagonist ritanserin ( group I ; n = 8 ) significantly reduced the hyperperfusion amplitude during Q9Y600 by approximately 44 % ( p < 0 . 05 , from 342 +/- 124 to 194 +/- 97 % , baseline before Q9Y600 = 100 % ) , and prolonged its duration by approx . 30 % . Vehicle alone ( group II ; n = 4 ) did not affect Q9Y600 hyperperfusion . The highly selective P28221 / 1B receptor agonist DB00315 was given in two doses : 100 micrograms / kg i . v . ( n = 5 ) had no effect on Q9Y600 hyperperfusion , while 800 micrograms / kg ( n = 5 ) increased hyperperfusion significantly ( p < 0 . 05 , from 224 +/- 86 to 310 +/- 148 % ) . We conclude that serotonin is , probably via 5 - HT2 receptors , involved in the modulation of the regional cerebral blood flow increase during Q9Y600 . Novel highly selective receptor antagonists may help to discriminate the differential contribution of various 5 - HT receptor subspecies .",
"Genetic variation in three candidate genes and nicotine dependence , withdrawal and smoking cessation in hospitalized patients . AIMS : This study evaluates the relationship of six polymorphisms found in the P32297 , P14416 and P21964 genes with nicotine dependence , the ability to quit smoking and the occurrence of withdrawal symptoms after short - term use of nicotine patch in hospitalized patients . MATERIALS & METHODS : The study included 233 participants from a double - blind , placebo - controlled trial of nicotine patch substitution with a 6 - month follow - up period . ___MASK92___ dependence was assessed by the Fagerström Test for ___MASK92___ Dependence ( FTND ) questionnaire , withdrawal symptoms by the Minnesota ___MASK92___ Withdrawal Scale questionnaire and smoking cessation by self - reported abstinence at 1 week , 1 month and 6 months after treatment . RESULTS : After correcting for multiple testing , three polymorphisms in the P14416 gene ( Taq1A , Taq1B and Pro319Pro ) were significantly associated with nicotine dependence ( p = 0 . 018 , p = 0 . 048 and p = 0 . 006 , respectively ) . Using a cutoff point for the FTND score , the P32297 Tyr215Tyr ( rs1051730 ) polymorphism was also associated with nicotine dependence ( p = 0 . 037 and p = 0 . 074 after correction for multiple testing ) . No association of any of the studied polymorphisms was observed with either smoking cessation or the occurrence of withdrawal symptoms . CONCLUSION : This study confirms the reported association of the P32297 locus with nicotine dependence and shows the involvement of two independent P14416 polymorphisms in nicotine dependence .",
"Fluorescence energy transfer analysis of calmodulin - peptide complexes . The interactions between calmodulin and the tryptophan residues of synthetic peptides corresponding to the calmodulin binding domains of skeletal muscle myosin light - chain kinase and the plasma membrane calcium pump were examined . The single tryptophan residue contained in each peptide became relatively immobilized and inaccessible to iodide ion upon binding to calmodulin , indicating that the indole side chain was inserted into a hydrophobic cleft in the surface of calmodulin . Fluorescence energy transfer from peptidyl tryptophan residues to an AEDANS moiety attached to cysteine - 26 of spinach calmodulin was measured . Included in these analyses was a tryptophan - containing peptide analog of the calmodulin binding domain of neuromodulin . These data indicated that the indole ring of each peptide inserted 32 - 35 A away from cysteine - 26 and may therefore interact with the carboxyl - terminal lobe of P62158 in its \" bent \" conformation [ Persechini & Kretsinger ( 1988a ) J . Cardiovasc . Pharmacol . 12 ( Suppl 5 ) , S1 - P28222 ; Ikura et al . ( 1992 ) Science 256 , 632 - 638 ; Vorherr et al . ( 1992 ) Eur . J . Biochem . 204 , 931 - 937 ] . The interchange of tryptophan - 3 and phenylalanine - 21 of the calcium pump peptide increased the efficiency of energy transfer to the AEDANS - moiety approximately 12 - fold , reducing the calculated distance to 20 A . These data suggest that phenylalanine - 21 of the calcium pump peptide interacts with the hydrophobic cleft in the amino - terminal lobe of P62158 .",
"___MASK23___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"[ The cluster headache : a clinical model of immunologic receptor pathology ? ] . It is well established that cluster headache shows impaired functions at their neuroimmunomodulatory system level . Defect in receptor expression for 5 - HT , IL - 1 and P60568 have been found in these patients . Sumatriptan , a molecule with agonistic activity for P28221 receptor , truncates cluster headache attacks in 74 % of patients . Flow cytometric analysis of monocytes expressing 5 - HT receptor in cluster headache patients showed different trends clearly correlated with the clinical response to sumatriptan . Our findings strongly support the concept that cluster headache patients who are non responders to sumatriptan could present a block in their 5 - HT receptor possibly due to specific autoantibodies for this receptor site .",
"The tolerability and pharmacokinetics of the novel antimigraine compound DB00315 in healthy male volunteers . 1 . DB00315 is a novel and selective agonist at P28221 receptors , with central and peripheral actions , currently in development for the acute oral treatment of migraine . 2 . The pharmacokinetic and tolerability profiles of single oral doses from 1 - 50 mg DB00315 were investigated in 12 healthy male volunteers in a double - blind , placebo - controlled , dose - escalating study . 3 . DB00315 was well tolerated with most adverse experiences of mild and transient nature . 4 . Absorption was rapid with dose - independent kinetics . Median tmax was 2 - 4 h although 50 - 85 % of eventual Cmax was attained within 1 h . The t1 / 2 was 2 . 5 - 3 h with a high apparent plasma clearance ( CL / F > 2000 ml min - 1 ) and apparent volume of distribution ( Vz / F ) of 400 - 500 l . 5 . Three metabolites were detected in plasma and urine , one of which , the N - desmethyl metabolite , has P28221 agonist activity . 6 . DB00315 showed no clinically significant effects on blood pressure , heart rate , ECG or laboratory variables at any dose and demonstrated a tolerability and pharmacokinetic profile compatible with an acute oral migraine treatment .",
"Acute migraine therapy : the newer drugs . In 1996 , our knowledge of acute antimigraine therapy expanded in three major areas . First , large surveys have confirmed the remarkable efficacy profile of sumatriptan in clinical practice . No satisfying clinical , pharmacokinetic or genetic explanations were found for its major shortcomings : nonresponders , headache recurrence and noncardiac chest symptoms . Second , the novel P28222 / D agonists zolmitriptan ( DB00315 ) , rizatriptan ( MK - 462 ) , eletriptan ( UK - 116 , 044 ) , avitriptan ( BMS - 180048 ) and alniditan ( R091274 ) were all proved superior to placebo for attack treatment , but their advantages over sumatriptan are yet to be analysed in more detail . A higher lipophilicity explains ( except for alniditan ) their greater oral bioavailability and better central nervous system penetration . A central action now proved experimentally in animals and in humans for P28222 / D agonists such as zolmitriptan may be advantageous for the antimigraine efficacy , but it could also increase sedation . Third , an endothelin ( Ro470203 , DB00559 ) and a neurokinin 1 ( RPR100893 ) receptor antagonist were found to be ineffective in migraine . Both compounds are potent inhibitors of neurogenic plasma extravasation in rat dura mater , which might suggest that this pharmacological property does not necessarily predict efficacy in aborting migraine attacks .",
"The clinical effectiveness of DB00315 in the acute treatment of migraine . Efficacy with currently marketed antimigraine compounds is less than optimal . DB00315 is a novel and selective P28221 receptor agonist in development for the acute treatment of migraine . It shows evidence of both central and peripheral activity within the trigemino - vascular system and it is rapidly absorbed following oral administration . In clinical studies in migraine patients , a headache response at 2 hours has been observed in 65 - 81 % of patients at doses above 1 mg . Favourable response rates are reported as early as 1 hour post - dose and efficacy rates continue to improve up to 4 hours . Headache recurrence is reported by 25 - 35 % of patients and DB00315 is also effective in relieving the non - headache symptoms of migraine .",
"DB00315 , a new central and peripherally acting P28221 receptor agonist in the acute oral treatment of migraine : a double - blind , placebo - controlled , dose - range finding study . DB00315 is a novel , centrally and peripherally , acting 5 - hydroxytryptamine1D receptor agonist . We investigated the efficacy and safety of 1 , 5 , and 25 mg of oral DB00315 in the acute treatment of migraine in a randomized , double - blind , placebo - controlled , parallel - group clinical trial involving 84 patients . The proportion of patients in whom the headache improved within 2 hours from moderate or severe to mild or no pain ( primary efficacy measure ) was 15 % for placebo - treated patients and 27 % ( 1 mg ) , 62 % ( 5 mg ) , and 81 % ( 25 mg ) for patients treated with DB00315 . Treatment differences compared with placebo were 12 % ( 95 % CI - 12 , 37 ; p = 0 . 460 ) for 1 mg DB00315 , 47 % ( CI 21 , 73 ; p < 0 . 005 ) for 5 mg DB00315 , and 66 % ( CI 43 , 89 ; p < 0 . 001 ) for 25 mg DB00315 . Photophobia and nausea also showed improvement after DB00315 . Adverse events were generally mild and transient in all treatment groups . There were no clinically significant changes in ECG recordings , blood pressure , or laboratory tests . Oral DB00315 ( 5 and 25 mg ) is highly effective and well tolerated in the acute treatment of migraine . The response rates and treatment differences compared with placebo in this study suggest possible superiority over existing antimigraine therapies . This needs to be confirmed in formal comparative trials .",
"[ Clinical efficacy of zolmitriptan in migraine ] . Zolmitriptan ( previously known as DB00315 ) is a serotoninergic P28222 / D agonist with high oral bioavailability with a double , central and peripheral , action mechanism . Evaluation of its clinical efficacy was developed in a program of clinical studies ( search and confirmation of dosis , comparative and long term studies ) and through analysis of efficacy in different clinical situations . Zolmitriptan shows a high effectiveness in the treatment of migraine crisis , significantly reduces the headaches by 2 hours of its administration , reduce the symptoms associated with migraine ( nausea , photophobia and phonophobia ) and improves the quality of life of the migraine patient . The efficacy is independent of the type of migraine characteristics of the patient as well as of the administration of other concomitant medications . The dosis of 2 . 5 mg of zolmitriptan has been found to be the optimum considering both efficacy and tolerability .",
"Evidence for a spinal serotonergic control of the peripheral inflammation in the rat . We investigated the effect of serotonergic agonists and antagonists injected intrathecally by direct punction of the spinal cord at the lumbar level ( between Q15004 - Q9BTT4 ) on peripheral inflammatory edema . Edema was induced by carrageenan injected subcutaneously in one hindpaw 30 min after spinal treatments . Serotonin ( 0 . 1 , 1 , 10 pmol ) caused a graded - inhibition of the inflammatory paw edema . The corticosteroid inhibitor aminoglutethimide ( 100 mg / kg , p . o . 1 . 5 h before spinal treatment ) did not modify this effect . The P08908 agonist buspirone and the P28222 / 1D agonist sumatriptan ( 0 . 1 , 1 . 0 and 10 nmol ) also inhibited paw edema . The 5 - HT1 , 2 antagonist methysergide ( 10 and 100 pmol ) enhanced edema , but higher doses ( 4 and 8 nmol ) diminished edema . NAN - 190 ( 5 - HT1 antagonist ; 1 and 10 nmol ) increased paw edema , while ritanserin ( 5 - HT2 antagonist ; 1 nmol ) inhibited paw edema . ___MASK76___ ( 5 - Q9H205 antagonist ; up to 10 nmol ) did not affect edema , but metoclopramide ( 5 - Q9H205 antagonist / Q13639 agonist ; 5 , 10 and 30 pmol ) inhibited edema . These data suggest that a tonic release of serotonin in the spinal cord may occurs during ongoing peripheral inflammation , modulating the neurogenic component of edema either by an inhibitory action on 5 - HT1 receptors or by a stimulatory action on 5 - HT2 receptors . A disfunction in such mechanism may be involved in the pathophysiology of certain types of headaches or migraine , which seem to depend on neurogenic vasodilation , and may also help to explain the therapeuthic effectiveness of some serotonergic agents in these conditions .",
"5 - Q13049 receptor induces P29323 phosphorylation and proliferation through ADAM - 17 tumor necrosis factor - alpha - converting enzyme ( P78536 ) activation and heparin - bound epidermal growth factor - like growth factor ( HB - P01133 ) shedding in mesangial cells . In this study , we present multiple lines of evidence to support a critical role for heparin - bound P01133 ( epidermal growth factor ) - like growth factor ( HB - P01133 ) and tumor necrosis factor - alpha - converting enzyme ( P78536 ) ( P78536 ) in the transactivation of P01133 receptor ( P00533 ) , P29323 phosphorylation , and cellular proliferation induced by the 5 - HT ( 2A ) receptor in renal mesangial cells . 5 - hydroxy - tryptamine ( 5 - HT ) resulted in rapid activation of P78536 , HB - P01133 shedding , P00533 activation , P29323 phosphorylation , and longer term increases in DNA content in mesangial cells . P29323 phosphorylation was attenuated by 1 ) neutralizing P00533 antibodies and the P00533 kinase inhibitor , AG1478 , 2 ) neutralizing HB - P01133 , but not amphiregulin , antibodies , heparin , or CM197 , and 3 ) pharmacological inhibitors of matrix - degrading metalloproteinases or P78536 small interfering RNA . Exogenously administered HB - P01133 stimulated P29323 phosphorylation . Additionally , P78536 was co - immunoprecipitated with HB - P01133 . Small interfering RNA against P78536 also blocked 5 - HT - induced increases in P29323 phosphorylation , HB - P01133 shedding , and DNA content . In aggregate , this work supports a pathway map that can be depicted as follows : 5 - HT --> 5 - HT ( 2A ) receptor --> P78536 --> HB - P01133 shedding --> P00533 --> P29323 --> increased DNA content . To our knowledge , this is the first time that P78536 has been implicated in 5 - HT - induced P00533 transactivation or in proliferation induced by a G protein - coupled receptor in native cells in culture .",
"A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men . ___MASK92___ is the major addictive substance in cigarettes , and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction . We studied six single - nucleotide polymorphisms ( SNPs ) in the P43681 gene and four SNPs in the P17787 gene with respect to nicotine dependence in a collection of 901 subjects ( 815 siblings and 86 parents ) from 222 nuclear families with multiple nicotine - addicted siblings . The subjects were assessed for addiction by both the Fagerstrom Test for ___MASK92___ Dependence ( FTND ) and the Revised Tolerance Questionnaire ( RTQ ) . Because only 5 . 8 % of female offspring were smokers , only male subjects were included in the final analyses ( 621 men from 206 families ) . Univariate ( single - marker ) family - based association tests ( FBATs ) demonstrated that variant alleles at two SNPs , rs1044396 and rs1044397 , in exon 5 of the P43681 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype ( i . e . , age - adjusted FTND and RTQ scores ) , which was consistent with the results of the global haplotype FBAT . Furthermore , the haplotype - specific FBAT showed a common ( 22 . 5 % ) P43681 haplotype , GCTATA , which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait ( Z =- 3 . 04 , P < . 005 ) and significant decreases of age - adjusted FTND ( Z =- 3 . 31 , P < . 005 ) or RTQ scores ( Z =- 2 . 73 , P =. 006 ) . Our findings provide strong evidence suggesting a common P43681 haplotype might be protective against vulnerability to nicotine addiction in men .",
"Structure functional expression and spatial distribution of a cloned cDNA encoding a rat P28221 - like receptor . Using polymerase chain reaction ( PCR ) a complementary DNA ( cDNA ) encoding a 5 - hydroxytryptamine ( 5 - HT ) receptor was isolated from rat forebrain . The amplified cDNA specifies an open reading frame of 374 amino acids comprising seven putative transmembrane regions . Expression of the cloned cDNA in human embryonic kidney cells ( P29320 293 ) was used to establish the pharmacological profile of the encoded receptor polypeptide . Membranes containing the cloned receptor showed high affinity binding of [ 3H ] - 5 - HT . Competition binding experiments with a variety of serotonin receptor ligands displayed a rank order of affinities corresponding to a P28221 subtype : 5 - CT > 5 - HT = metergoline > CGS 12066 > methysergide > sumatriptan > mianserin = (-) alpha - Me - 5 - HT = yohimbine > 8 - OH - DPAT > or = rauwolscine > spiperone > DOI > propranolol > or = 2 - Me - 5 - HT > or = ICS 205930 . Ketanserin and ritanserin displaced [ 3H ] - 5 - HT - binding in a biphasic manner . In situ hybridization revealed highest expression of the corresponding mRNA in the pyramidal layer of the olfactory tubercle and the nucleus caudatus and accumbens .",
"Candidate gene studies of ADHD : a meta - analytic review . Quantitative genetic studies ( i . e . , twin and adoption studies ) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder ( ADHD ) . Over the past 15 years , considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD . The first aim of the present study was to conduct a comprehensive meta - analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies . The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results . Significant associations were identified for several candidate genes including Q01959 , P21917 , P21918 , P31645 , P28222 , and P60880 . Further , significant heterogeneity was observed for the associations between ADHD and Q01959 , P21917 , P21918 , P09172 , P08913 , P31645 , Q8IWU9 , P21397 , and P60880 , suggesting that future studies should explore potential moderators of these associations ( e . g . , ADHD subtype diagnoses , gender , exposure to environmental risk factors ) . We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK20___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK89___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"Evaluation of the long - term safety and efficacy of DB00315 in the treatment of migraine . DB00315 is an orally active P28221 agonist with both central and peripheral actions that is currently being developed as an acute antimigraine treatment . Several studies have demonstrated the safety and efficacy of DB00315 in the treatment of a single migraine headache . The objectives of this open study are to assess the safety and efficacy of DB00315 when used for a period of up to one year . Patients can treat as many migraine headaches as desired with an oral treatment regimen of DB00315 . An initial 5 mg dose for treatment of the migraine headache may be followed with a second 5 mg dose to treat recurrence should it develop . Safety assessments include electrocardiograms , the frequency , intensity and duration of adverse experiences , and routine haematology , urinalysis and clinical chemistry measures . Data presented here are an interim view of the database as of August 1995 and should be considered as preliminary observations . No clinically significant serious adverse experiences have been reported . The adverse experience and efficacy profile appears to be consistent with previous DB00315 studies and this dosing regimen of DB00315 was well tolerated during multiple exposures . Notably , response rates are as good after both initial and repeated exposure ( up to 5 migraines ) .",
"___MASK92___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .",
"Disabling the mitotic spindle and tumor growth by targeting a cavity - induced allosteric site of survivin . Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis . Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy . P00533 and Her / neu - transformed human tumors in particular exhibit high levels of survivin . The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein . We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces . P28222 , a lead compound identified in the screen , can bind to the survivin protein at the intended target site . Moreover , P28222 alters spindle formation , causing mitotic arrest and cell death , and inhibits tumor growth in vitro and in vivo . Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity . Thus , the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers .",
"The study of genetic polymorphisms related to serotonin in Alzheimer ' s disease : a new perspective in a heterogenic disorder . Genetic and environmental factors have been implicated in the development of Alzheimer ' s disease ( AD ) , the most common form of dementia in the elderly . Mutations in 3 genes mapped on chromosomes 21 , 14 and 1 are related to the rare early onset forms of AD while the epsilon 4 allele of the apolipoprotein E ( P02649 ) gene ( on chromosome 19 ) is the major susceptibility locus for the most common late onset AD ( LOAD ) . Serotonin ( 5 - hydroxytryptamine or 5 - HT ) is a key neurotransmitter implicated in the control of mood , sleep , appetite and a variety of traits and behaviors . Recently , a polymorphism in the transcriptional control region upstream of the 5 - HT transporter ( 5 - HTT ) gene has been studied in several psychiatric diseases and personality traits . It has been demonstrated that the short variant ( s ) of this 5 - HTT gene - linked polymorphic region ( 5 - HTTLPR ) is associated with a different transcriptional efficiency of the 5 - HTT gene promoter resulting in decreased 5 - HTT expression and 5 - HT uptake in lymphocytes . An increased frequency of this 5 - HTTLPR short variant polymorphism in LOAD was recently reported . In addition , another common polymorphic variation in the 5 - Q13049 and P28335 serotonin receptor genes previously analyzed in schizophrenic patients was associated with auditory and visual hallucinations in AD . These observations suggest that the involvement of the serotonin pathway might provide an explanation for some aspects of the affective symptoms commonly observed in AD patients . In summary , research on genetic polymorphisms related to AD and involved in receptors , transporter proteins and the enzymatic machinery of serotonin might enhance our understanding of this devastating neurodegenerative disorder .",
"( N ) - methanocarba - 2MeSADP ( MRS2365 ) is a subtype - specific agonist that induces rapid desensitization of the P47900 receptor of human platelets . DB00640 diphosphate ( ADP ) initiates and maintains sustained aggregation of platelets through simultaneous activation of both the Gq - coupled P47900 receptor and the Gi - coupled Q9H244 receptor . We recently described the synthesis and P47900 receptor - specific agonist activity of ( N ) - methanocarba - 2MeSADP ( MRS2365 ) . Consequences of selective activation of the P47900 receptor by MRS2365 have been further examined in human platelets . Whereas MRS2365 alone only induced shape change , addition of MRS2365 following epinephrine treatment , which activates the Gi / z - linked , alpha2A - adrenergic receptor , resulted in sustained aggregation that was indistinguishable from that observed with ADP . Conversely , the platelet shape change promoted by ADP in the presence of the P08514 / IIIa antagonist eptifibatide was similar to that promoted by MRS2365 . Preaddition of the high affinity P47900 receptor antagonist MRS2500 inhibited the effect of MRS2365 , whereas addition of MRS2500 subsequent to MRS2365 reversed the MRS2365 - induced shape change . Preactivation of the P47900 receptor with MRS2365 for 2 min resulted in marked loss of capacity of ADP to induce aggregation as evidenced by a greater than 20 - fold rightward shift in the concentration effect curve of ADP . This inhibitory effect of P47900 receptor activation was dependent on the concentration of MRS2365 ( EC50 = 34 nm ) . The inhibitory effect of preincubation with MRS2365 was circumvented by activation of the Gq - coupled 5 - Q13049 receptor suggesting that MRS2365 induces loss of the ADP response as a consequence of desensitization of the Gq - coupled P47900 receptor . The time course of MRS2365 - induced loss of aggregation response to epinephrine was similar to that observed with ADP . These results further demonstrate the P47900 receptor selectivity of MRS2365 and illustrate the occurrence of agonist - induced desensitization of the P47900 receptor of human platelets studied in the absence of Q9H244 receptor activation .",
"Serotonin via P34969 receptors activates p38 mitogen - activated protein kinase and protein kinase C epsilon resulting in interleukin - 6 synthesis in human U373 MG astrocytoma cells . Serotonin [ 5 - hydroxytryptamine ( 5 - HT ) ] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes . Previously , it has been demonstrated that 5 - HT may induce interleukin ( IL ) - 6 expression in primary rat hippocampal astrocytes . The present study was undertaken to investigate the molecular pathways underlying this induction of P05231 synthesis . As a model system , we used the human astrocytoma cell line U373 MG , which synthesizes P05231 upon stimulation with various inducers . 5 - HT dose - and time - dependently induced P05231 protein synthesis . We identified several 5 - HT receptors to be expressed on U373 MG cells , including the P28221 , 5 - Q13049 , 5 - Q9H205 and P34969 receptors . In this report , we show that the 5 - HT - induced P05231 release is mediated by the P34969 receptor based on several agonist / antagonists that were used . 5 - HT - induced P05231 synthesis is inhibited by the partially selective P34969 receptor antagonist , pimozide , and the selective antagonist SB269970 . Furthermore , P05231 synthesis was induced by the P34969 receptor agonist carboxamidotryptamin . In addition , we found p38 MAPKs and protein kinase C ( PKC ) epsilon to be involved in 5 - HT - induced P05231 synthesis as specific inhibitors of these enzymes ( SB202190 and RO - 31 - 8425 , respectively ) blocked 5 - HT - induced P05231 synthesis . Furthermore , 5 - HT mediated the phosphorylation of both p38 MAPK as well as the PKC epsilon isoform . The Q8NFH3 / 44 MAPKs , however , were not involved in 5 - HT - induced P05231 synthesis . This study shows , for the first time , a central role of P34969 receptor linked to p38 MAPK and PKC epsilon for the induction of cytokine synthesis in astrocytic cells .",
"A new cell culture - based assay quantifies vitamin K 2 , 3 - epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol - driven Q9BQB6 assay . BACKGROUND : ___MASK96___ directly inhibits the vitamin K 2 , 3 - epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) - driven vitamin K 2 , 3 - epoxide reductase ( Q9BQB6 ) assay . ___MASK96___ inhibits wild - type Q9BQB6 function by the DTT - Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance - associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture - based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild - type and variant Q9BQB6 proteins . METHODS : Human coagulation factor ( F ) IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild - type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : ___MASK96___ dose - response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild - type , Val29Leu , Val45Ala and Leu128Arg variants . The corresponding calculated IC50 values were 24 . 7 , 136 . 4 , 152 . 0 and 1226 . 4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild - type Q9BQB6 . Ranked IC50 values from the cell culture - based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation - associated warfarin resistance .",
"[ ___MASK12___ : A new drug of B - cell malignancies ] . ___MASK12___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK12___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK12___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK13___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"E3 ubiquitin ligase Q13049 negatively regulates tumor suppressor p53 to promote tumorigenesis . P04637 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses , including apoptosis , cell cycle arrest and senescence . To ensure its proper levels and functions in cells , p53 is tightly regulated mainly through post - translational modifications , such as ubiquitination . Here , we identified E3 ubiquitin ligase Q13049 as a novel p53 target gene and negative regulator to regulate p53 - mediated stress responses . In response to stress , such as DNA damage , p53 binds to the p53 responsive element in the promoter of the Q13049 gene and transcriptionally induces the expression of Q13049 in cells . In turn , Q13049 interacts with p53 and promotes p53 degradation through ubiquitination . Thus , Q13049 negatively regulates p53 - mediated apoptosis , cell cycle arrest and senescence in response to stress . Q13049 is frequently overexpressed in different types of human tumors . Q13049 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53 - dependent manner . Taken together , our results demonstrated that as a novel p53 target and a novel negative regulator for p53 , Q13049 has an important role in regulation of p53 and p53 - mediated cellular stress responses . Furthermore , our results also revealed that impairing p53 function is a novel mechanism for Q13049 in tumorigenesis .",
"Constitutive G ( i2 )- dependent activation of adenylyl cyclase type II by the P08908 receptor . Inhibition by anxiolytic partial agonists . The P08908 receptor is implicated in depression and anxiety . This receptor couples to G ( i ) proteins to inhibit adenylyl cyclase ( AC ) activity but can stimulate AC in tissues ( e . g . hippocampus ) that express ACII . The role of ACII in receptor - mediated stimulation of DB02527 formation was examined in P29320 - 293 cells transfected with the P08908 receptor , which mediated inhibition of basal and G ( s )- induced DB02527 formation in the absence of ACII . In cells cotransfected with P08908 receptor and ACII plasmids , P08908 agonists induced a 1 . 5 - fold increase in DB02527 level . Cotransfection of P08908 receptor , ACII , and Galpha ( i2 ) , but not Galpha ( i1 ) , Galpha ( i3 ) , or Galpha ( o ) , resulted in an agonist - independent 6 - fold increase in the basal DB02527 level , suggesting that G ( i2 ) preferentially coupled the receptor to ACII . The P28222 receptor also constitutively activated ACII . Constitutive activity of the P08908 receptor was blocked by pertussis toxin and the Gbetagamma antagonist , betaCT , suggesting an important role for Gbetagamma - mediated activation of ACII . The DB00156 - 149 --> Ala mutation in the second intracellular domain of the P08908 receptor disrupted Gbetagamma - selective activation of ACII . Spontaneous P08908 receptor activity was partially attenuated by P08908 receptor partial agonists with anxiolytic activity ( e . g . buspirone and flesinoxan ) but was not altered by full agonists or antagonists . Thus , anxiolytic activity may involve inhibition of spontaneous P08908 receptor activity .",
"Computer - aided design and synthesis of 5 - substituted tryptamines and their pharmacology at the P28221 receptor : discovery of compounds with potential anti - migraine properties . The design and synthesis of a series of novel 5 - substituted tryptamines with pharmacological activity at P28221 and other monoamine receptors is described . Structural modifications of N - and C - linked ( principally hydantoin ) analogues at the 5 - position were synthesized and their pharmacological activities were utilized to deduce significant steric and electrostatic requirements of the P28221 and 5 - Q13049 receptor subtypes . Conformations of the active molecules were computed which , when overlaid , suggested a pharmacophore hypothesis which was consistent with the affinity and selectivity measured at P28221 and 5 - Q13049 receptors . This pharmacophore is composed of a protonated amine site , an aromatic site , a hydrophobic pocket , and two hydrogen - bonding sites . A \" selectivity site \" was also identified which , if occupied , induced sensitivity for P28221 over 5 - Q13049 in this series of molecules . The development and use of the pharmacophore models in compound design is described . In addition , the physicochemical constraints of molecular size and hydrophobicity required for efficient oral absorption are discussed . Utilizing the pharmacophore model in conjunction with the physicochemical constraints of molecular size and log DpH7 . 4 led to the discovery of DB00315 ( 6 ) , a new selective P28221 agonist with good oral absorption and potential use in the treatment of migraine .",
"Interaction of calmodulin with the serotonin 5 - hydroxytryptamine2A receptor . A putative regulator of G protein coupling and receptor phosphorylation by protein kinase C . The 5 - hydroxytryptamine2A ( 5 - Q13049 ) receptor is a G ( q / 11 )- coupled serotonin receptor that activates phospholipase C and increases diacylglycerol formation . In this report , we demonstrated that calmodulin ( P62158 ) co - immunoprecipitates with the 5 - Q13049 receptor in NIH - 3T3 fibroblasts in an agonist - dependent manner and that the receptor contains two putative P62158 binding regions . The putative P62158 binding regions of the 5 - Q13049 receptor are localized to the second intracellular loop and carboxyl terminus . In an in vitro binding assay peptides encompassing the putative second intracellular loop ( i2 ) and carboxyl - terminal ( ct ) P62158 binding regions bound P62158 in a Ca2 +- dependent manner . The i2 peptide bound with apparent higher affinity and shifted the mobility of P62158 in a nondenaturing gel shift assay . Fluorescence emission spectral analyses of dansyl - P62158 showed apparent K ( D ) values of 65 +/- 30 nM for the i2 peptide and 168 +/- 38 nM for the ct peptide . The ct P62158 - binding domain overlaps with a putative protein kinase C ( PKC ) site , which was readily phosphorylated by PKC in vitro . P62158 binding and phosphorylation of the ct peptide were found to be antagonistic , suggesting a putative role for P62158 in the regulation of 5 - Q13049 receptor phosphorylation and desensitization . Finally , we showed that P62158 decreases 5 - Q13049 receptor - mediated [ 35S ] GTPgammaS binding to NIH - 3T3 cell membranes , supporting a possible role for P62158 in regulating receptor - G protein coupling . These data indicate that the serotonin 5 - Q13049 receptor contains two high affinity P62158 - binding domains that may play important roles in signaling and function .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"Eugenosedin - A ameliorates hyperlipidemia - induced vascular endothelial dysfunction via inhibition of α1 - adrenoceptor / 5 - HT activity and NADPH oxidase expression . Eugenosedin - A ( Eu - A ) effects on vascular endothelial dysfunction and oxidative stress in a hyperlipidemic rat model were investigated . Rats were randomly divided into four groups : two control groups and two treatment groups . The control rats received a regular diet or high fat diet ( HFD ) ; the treatment rats fed received an HFD with 5 mg / kg Eu - A or atorvastatin for 10 weeks . No changes in serotonin levels were observed in the four groups ; norepinephrine levels were enhanced in the HFD group which was attenuated by Eu - A and atorvastatin . In the HFD group , the vascular reactivity was increased by vasoconstrictors ( 5 - nonyloxytryptamine , 5 - HT , and phenylephrine ) and decreased by an endothelium - dependent vasorelaxant , carbachol . Protein levels of α1 - adrenergic receptors ( not P28222 / 2A ) , reactive oxygen species ( ROS ) p47 ( phox ) , p67 ( phox ) , and gp91 ( phox ) , and oxidative damage markers 3 - nitrotyrosine ( 3 - NT ) and 4 - hydroxy - 2 - nonenal ( 4 - HNE ) were increased , but endothelial nitric oxide synthase ( P29474 ) , P - P29474 and vasodilator - stimulated phosphoprotein phosphorylation ( P - P50552 ) were decreased . P04040 and superoxide dismutase ( SOD - 1 and SOD - 2 ) proteins were increased , but glutathione peroxidase ( GPx ) was decreased in the aorta . Eu - A and atorvastatin reduced vasoconstrictor - induced aortic contractions that might be related to P28222 / 2A and α1 - adrenergic receptors inhibitory activities . Eu - A and atorvastatin improved P29474 / P - P29474 , P - P50552 , GPx , and malondialdehyde ( MDA ) levels , and decreased ROS and oxidative damage markers . Taken together , we suggest that Eu - A can ameliorate hyperlipidemia - induced vascular endothelial dysfunction and oxidative dysregulation .",
"P25116 14 - amino acid peptide mediates endothelial hyperadhesivity and neutrophil adhesion by P16109 - dependent mechanism . Thrombin cleaves its receptor at arginine - 41 , resulting in the generation of a new receptor NH2 - terminus with the sequence SFLLRNPNDKYEPF . This peptide ( TRP - 14 ) may signal a variety of thrombin ' s responses . We examined the effects of TRP - 14 in inducing endothelial cell hyperadhesivity and neutrophil ( PMN ) adhesion to endothelial cell monolayers . Human umbilical vein endothelial cells ( HUVECs ) challenged with TRP - 14 ( 10 (- 4 ) to 10 (- 5 ) M ) produced concentration - dependent increases in endothelial adhesivity to PMN . In contrast , position 1 to 2 inverted peptide ( FSLLRNPNDKYEPF ) did not induce the response . The adhesion response was transient ; that is , PMN adhesion increased within 15 minutes and decreased by 75 minutes after TRP - 14 challenge of HUVECs . The transient endothelial adhesiveness paralleled the time course of P16109 expression . TRP - 14 - induced release of P16109 from intracellular stores may be a critical determinant of the response since treatment of endothelial cells with anti - P16109 monoclonal antibody ( mAb ) P55008 prevented the increase in PMN adhesion . Control nonneutralizing anti - P16109 mAb P28222 and mAb P23921 / 1 directed against intercellular adhesion molecule - 1 ( P05362 ) on HUVECs were ineffective . The results indicate that the \" tethered ligand \" of the thrombin receptor created by the proteolytic action of thrombin on its receptor ( i . e . , TRP - 14 ) signals increased endothelial adhesiveness by a P16109 - dependent mechanism . Thrombin - induced PMN adhesion may involve formation of a new NH2 - terminus of the endothelial thrombin receptor with the sequence SFLLRNPNDKYEPF followed by activation of endothelial second messenger pathways and the transient expression of P16109 .",
"A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma . Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis . Consistent heterogeneity in chromosome number was found , and most cell lines showed a near - triploid chromosome complement . Several cell lines showed deletions of the P04637 ( alias p53 ) , CDKN2A ( alias p16 ) , and P40337 genes . Multiplex fluorescence in situ hybridization ( M - Q5TCZ1 ) analysis revealed chromosome 3 translocated to several other partners chromosomes , as well as breakage events commonly affecting chromosomes 1 , 5 , 8 , 10 , and 17 . The most common abnormality detected with comparative genomic hybridization ( CGH ) was deletions of chromosome 3p , with loss of the Q9NS23 , P49789 , and p44S10 loci frequently involved . CGH gain of 5q showed overrepresentation of the P18146 and P07333 genes . Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the P00533 , O15164 , and P35250 genes . Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of P11802 and SAS loci . M - Q5TCZ1 revealed several other recurrent translocations , and CGH findings included loss of 9p , 14q , and 18q and gain of 8q , 12 , and 20 . Further genomic microarray changes included loss of Q13126 , IGH @ , P28222 , and Q13485 ( previously Q13485 ) and gains of MYC and P11387 . An excellent correlation was observed between the genomic array and Q5TCZ1 data , demonstrating that this technique is effective and accurate . The aberrations detected here may reflect important pathways in renal cancer pathogenesis .",
"Evidence that the anxiolytic - like effects of the beta3 receptor agonist DB05395 involve serotoninergic receptor activity . Anxiety disorders are the most common behavioral disorders , and they exhibit high comorbidity rates . The aim of the present study was to confirm the effects of Amibegron , the first selective beta 3 adrenergic agent , on anxiety and to demonstrate that different serotoninergic receptor subtypes are involved in this effect . We administered the serotonin P08908 receptor antagonist WAY - 100635 , the serotonin 5 - Q13049 receptor antagonist Ketanserin and the serotonin 5 - Q9H205 receptor antagonist ___MASK76___ in mice and evaluated their performance in the elevated plus - maze test . Mice administered with Amibegron ( 5 and 10 mg / kg ) showed a dose - dependent prolonged time spent in the open arms and an increase in the number of entries into the open arms during the elevated plus - maze ( EPM ) test . However , in the control mice , administration of WAY , Ketanserin and ___MASK76___ demonstrated no effect on the time spent in the open arms and the number of entries into the open arms . In addition , these treatments all significantly reversed the effect of the Amibegron - induced ( 10 mg / kg ) increase in the time spent in the open arms . However , only WAY and Ketanserin treatments reversed the Amibegron - induced increase in the number of entries into the open arms . In conclusion , Amibegron exerted a significant anxiolytic effect , which was as effective as Diazepam , in mice during the EPM test . This effect of Amibegron may be mediated by interactions with the serotonin P08908 , 5 - Q13049 and 5 - Q9H205 receptors .",
"Clinical safety of DB00315 : aggregated data from patients and volunteers to date . The tolerability of DB00315 , a novel , selective and highly effective P28221 receptor agonist in development for the acute treatment of migraine , has been evaluated in a number of clinical pharmacology and patient studies across the dose range 1 - 50 mg . DB00315 has been well tolerated across the entire dose range and no clinically relevant changes in routine laboratory parameters , blood pressure or ECG recordings have been observed . Adverse experiences reported are generally dose related , mild to moderate and resolve spontaneously . Chest - related symptoms occur infrequently and the cardiovascular safety profile of DB00315 is considered particularly favourable . DB00315 , therefore , possesses a desirable safety profile which is well suited to broad - based outpatient administration .",
"DB00877 unbalances the polarization of human macrophages to M1 . Plasticity is a hallmark of macrophages , and in response to environmental signals these cells undergo different forms of polarized activation , the extremes of which are called classic ( M1 ) and alternative ( M2 ) . DB00877 ( Q96PN7 ) is crucial for survival and functions of myeloid phagocytes , but its effects on macrophage polarization are not yet studied . To address this issue , human macrophages obtained from six normal blood donors were polarized to M1 or M2 in vitro by lipopolysaccharide plus interferon - γ or interleukin - 4 ( P05112 ) , respectively . The presence of Q96PN7 ( 10 ng / ml ) induced macrophage apoptosis in M2 but not in M1 . Beyond the impact on survival in M2 , Q96PN7 reduced P61073 , CD206 and Q9NNX6 expression and stem cell growth factor - β , P55774 and Q99616 release . In contrast , in M1 Q96PN7 increased P42081 and P32248 expression and P05231 , tumour necrosis factor - α and IL - 1β release but reduced CD206 and Q9NNX6 expression and P22301 , vascular endothelial growth factor and P55774 release . In view of the in vitro data , we examined the in vivo effect of Q96PN7 monotherapy ( 0 · 1 mg / kg / day ) in 12 patients who were treated for at least 1 month before islet transplant . Cytokine release by O00206 - stimulated peripheral blood mononuclear cells showed a clear shift to an M1 - like profile . Moreover , macrophage polarization 21 days after treatment showed a significant quantitative shift to M1 . These results suggest a role of mammalian target of rapamycin ( P42345 ) into the molecular mechanisms of macrophage polarization and propose new therapeutic strategies for human M2 - related diseases through P42345 inhibitor treatment .",
"Inhibition of the trigemino - vascular system with P28221 agonist drugs : selectively targeting additional sites of action . Inappropriate activation of the trigemino - vascular system is thought to be important in the pathogenesis of a migraine attack . The P28221 agonist sumatriptan , which is highly effective in the acute treatment of migraine , inhibits trigemino - vascular activation in animals , although its actions are normally limited to peripheral components of the trigemino - vascular system . DB00315 , a novel P28221 agonist drug , which is also highly effective in the acute treatment of migraine , acts not only at these sites , but , additionally within the brainstem , inhibiting trigemino - vascular activation centrally as well as peripherally . This article describes the pre - clinical development of DB00315 and considers , specifically , the approaches taken in the design of a molecule with attributes which facilitate access to brainstem components of the trigeminal pathway and combine this with good oral bioavailability .",
"First report of warfarin dose requirements in patients possessing the P11712 * 12 allele . BACKGROUND : ___MASK96___ is the most frequently prescribed anticoagulant in North America and Europe . It is administered as a racemate , but S - warfarin is principally responsible for its anticoagulant activity . Cytochrome P450 ( CYP ) 2C9 is the enzyme primarily responsible for the metabolism of S - warfarin . Numerous variant alleles of P11712 have been identified . The P11712 * 12 ( rs9332239 ) allele harbors a P489S substitution in P11712 which has been shown to result in a 40 % decline in catalytic activity in vitro . CASES : Four Caucasian patients with a low mean weekly warfarin dose ( MWWD ) were genotyped for P11712 , Q9BQB6 and P02649 variant alleles . None of the four patients carried the common P11712 variant alleles ( * 2 , * 3 , * 5 , * 6 , * 7 , * 8 , * 9 , * 11 , * 13 ) despite a relatively low MWWD ( 23 . 4 ± 7 . 94 mg ) compared to 208 patients carrying the CYP29C9 * 1 genotype ( 32 . 2 ± 12 . 65 mg ) . Given that P11712 * 12 confers decreased in vitro activity to the enzyme , we investigated whether these patients carried this allele . All four patients were P11712 * 12 CT heterozygotes . Individual comparisons with patients possessing the same Q9BQB6 and P02649 genotypes also demonstrated lower dose requirements in the patients that possessed P11712 * 12 allele . CONCLUSIONS : There are no reports of the clinical impact of rs9332239 on P11712 substrates . This is the first report of patients with the rare P11712 * 12 genotype and lower warfarin dose requirements .",
"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK22___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK22___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .",
"' VASPFix ' for measurement of P50552 phosphorylation in platelets and for monitoring effects of Q9H244 antagonists . P50552 ( P50552 ) is phosphorylated and dephosphorylated consequent to increases and decreases in cyclic nucleotide levels . Monitoring changes in P50552 phosphorylation is an established method for indirect measurement of cyclic nucleotides . Here we describe the use of an innovative cocktail , VASPFix , which allows sensitive and reproducible measurement of phosphorylated P50552 ( P50552 - P ) in a simple , single - step procedure using cytometric bead technology . Frozen VASPFix - treated samples are stable for at least six months prior to analysis . We successfully used VASPFix to measure P50552 - P in platelets in both platelet - rich plasma and blood in response to compounds that increase ( dibutyryl DB02527 , adenosine , iloprost , PGE1 ) and decrease ( ADP , PGE1 ) DB02527 , and to determine the effects of certain receptor antagonists on the results obtained . The change in P50552 - P brought about by adding ADP to PGE1 - stimulated platelets is a combination of the effect of ADP at the Q9H244 receptor and of PGE1 at both IP and EP3 receptors . For iloprost - stimulated platelets EP3 receptors are not involved . A procedure in which iloprost , ADP and VASPFix were used to determine effectiveness of clopidogrel and prasugrel in patients was compared with an established commercial procedure that uses PGE1 and ADP ; the latter produced higher platelet reactivity values that were the result of PGE1 interacting with platelet EP3 receptors . We conclude that VASPFix can be used both as a research tool and for clinical investigations and provides better specificity for Q9H244 receptor inhibition . The latter confers a distinct advantage over existing methods used to monitor effects of Q9H244 antagonists on platelet function .",
"High loading dose of clopidogrel is unable to satisfactorily inhibit platelet reactivity in patients with glycoprotein IIIA gene polymorphism : a genetic substudy of PRAGUE - 8 trial . The study aimed to assess the impact of nine polymorphisms of genes encoding platelet receptors , enzymes , and hemostatic factors on clopidogrel efficacy to inhibit platelet reactivity in patients with stable coronary artery disease undergoing elective coronary angiography either with or without ad hoc percutaneous coronary intervention . The study was performed as a genetic substudy of the PRAGUE - 8 trial . Ninety - five patients pretreated with 600 mg clopidogrel at least 6 h prior to coronary angiography were tested . Baseline platelet reactivity to ADP was assessed before the drug was administered . ___MASK22___ efficacy was tested again at 12 and 28 h after administration . Polymorphisms of platelet receptors , glycoprotein ( GP ) Ia ( 807C / T ) , Q9HCN6 ( 13254C / T ) , P05106 ( PlA1 / PlA2 ) , P25116 ( IVSn - 14A / T ) , Q9H244 ( 32C / T ) , Q9H244 ( H1 / H2 ) haplotype , gene variations of cyclooxygenase - 1 , Leiden , and factor II mutations were studied . Flow cytometric tests of vasodilator - stimulated phosphoprotein phosphorylation states were used as a measure of drug efficacy . None of the gene polymorphisms influenced baseline ADP - induced platelet reactivity significantly . Twenty - eight hours after drug administration , differences in suppression of ADP - induced platelet reactivity were observed between polymorphism - positive and polymorphism - negative patients . Inhibition of platelet reactivity , after 600 mg of clopidogrel , was significantly less in carriers of PlA2 ( P = 0 . 009 ) for mean decrease in platelet reactivity index . The proportion of clopidogrel nonresponders ( platelet reactivity index > 50 % ) was apparently higher in PlA2 carriers in comparison with PlA1 / PlA1 patients ( 54 vs . 24 % , P = 0 . 082 ) . A 600 mg loading dose of clopidogrel failed to acceptably inhibit platelet reactivity in patients who were positive for the PlA2 polymorphism .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"GLC756 decreases P01375 via an alpha2 and beta2 adrenoceptor related mechanism . GLC756 , a polyvalent anti - glaucoma drug showed in an endotoxin - induced - uveitis model ( EIU ) in rats a significant tumor necrosis factor - alpha ( P01375 ) decrease in serum , indicating an additional anti - inflammatory potential of this compound . The receptors on which GLC756 binds ( D1 , D2 , D4 , alpha - 1 , alpha - 2 , P08908 , P28335 , P28221 , 5 - HT2 A , beta - 1 , and beta - 2 ) were suggested to play a role . In order to identify a receptor type mediating the P01375 lowering response , GLC756 was combined with various counteracting compounds ( CP ) . For EIU , 8 - week - old Lewis rats were intravenously injected at 160 microg lipopolysaccharide ( LPS ) from Salmonella typhimurium . Before EIU - induction animals received either one of the CP ' s or GLC756 alone , or GLC756 in combination with one of the CP ' s . P01375 was determined in serum 2h post EIU - induction . Treatment with CP ' s alone indicated that agonistic effects on beta - 2 adrenoceptors and antagonistic effects on alpha - 2 , P08908 and P28221 receptors resulted in statistically significant decreased P01375 levels in comparison to the LPS - control group . In combination with GLC756 , the counteracting CP ' s domitor ( alpha - 2 adrenoceptor agonist ) and ICI 118551 ( beta - 2 adrenoceptor antagonist ) inhibited completely the P01375 decreasing effect of GLC756 . Counteracting the P08908 receptor with the P08908 agonist 8 - OH - DPAT could not prevent the P01375 decreasing effect of GLC756 . In conclusion , the antagonistic effect on alpha - 2 adrenoceptors and the agonistic effect on beta - 2 adrenoceptors were identified as mechanism for the P01375 decreasing effect of GLC756 .",
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK76___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"Support for association between ADHD and two candidate genes : NET1 and P21728 . Attention deficit hyperactivity disorder ( ADHD ) is a common , multifactorial disorder with significant genetic contribution . Multiple candidate genes have been studied in ADHD , including the norepinephrine transporter ( NET1 ) and dopamine D1 receptor ( P21728 ) . NET1 is implicated in ADHD because of the efficacy of atomoxetine , a selective noradrenergic reuptake inhibitor , in the treatment of ADHD . P21728 is primarily implicated through mouse models of ADHD . DNA from 163 ADHD probands , 192 parents , and 129 healthy controls was used to investigate possible associations between ADHD and polymorphisms in 12 previously studied candidate genes ( P28222 , 5 - Q13049 , P28335 , P08913 , P43681 , P21964 , Q01959 , P21728 , P21917 , P21918 , NET1 , and P60880 ) . Analyses included case - control and family - based methods , and dimensional measures of behavior , cognition , and anatomic brain magnetic resonance imaging ( Q9BWK5 ) . Of the 12 genes examined , two showed a significant association with ADHD . Transmission disequilibrium test ( P04053 ) analysis revealed significant association of two NET1 single nucleotide polymorphisms ( SNPs ) with ADHD ( P < or = 0 . 009 ) ; case - control analysis revealed significant association of two P21728 SNPs with ADHD ( P < or = 0 . 008 ) . No behavioral , cognitive , or brain Q9BWK5 volume measurement significantly differed across NET1 or P21728 genotypes at an alpha of 0 . 01 . This study provides support for an association between ADHD and polymorphisms in both NET1 and P21728 ; polymorphisms in ten other candidate genes were not associated with ADHD . Because family - based and case - control methods gave divergent results , both should be used in genetic studies of ADHD .",
"Emergence of motor circuit activity . In the developing nervous system , ordered neuronal activity patterns can occur even in the absence of sensory input and to investigate how these arise , we have used the model system of the embryonic chicken spinal motor circuit , focusing on motor neurons of the lateral motor column ( O15467 ) . At the earliest stages of their molecular differentiation , we can detect differences between medial and lateral O15467 neurons in terms of expression of neurotransmitter receptor subunits , including P30532 , P36544 , Q12879 , P39086 , P08908 and P28222 , as well as the Q9H2X9 transporter . Using patch - clamp recordings we also demonstrate that medial and lateral O15467 motor neurons have subtly different activity patterns that reflect the differential expression of neurotransmitter receptor subunits . Using a combination of patch - clamp recordings in single neurons and calcium - imaging of motor neuron populations , we demonstrate that inhibition of nicotinic , muscarinic or GABA - ergic activity , has profound effects of motor circuit activity during the initial stages of neuromuscular junction formation . Finally , by analysing the activity of large populations of motor neurons at different developmental stages , we show that the asynchronous , disordered neuronal activity that occurs at early stages of circuit formation develops into organised , synchronous activity evident at the stage of O15467 neuron muscle innervation . In light of the considerable diversity of neurotransmitter receptor expression , activity patterns in the O15467 are surprisingly similar between neuronal types , however the emergence of patterned activity , in conjunction with the differential expression of transmitter systems likely leads to the development of near - mature patterns of locomotor activity by perinatal ages .",
"[ Molecular pharmacogenetic studies of drug responses to obsessive - compulsive disorder and six functional genes ] . OBJECTIVE : To investigate the associations between the drug responses to obsessive - pulsive disorder ( OCD ) and six functional genes related with serotonin and dopamine . METHODS : One hundred and thirteen OCD nuclear families were collected . The OCD patients were treated with serotonin reuptake inhibitors ( SRIs ) for 8 weeks and the drug responses were assessed using the Yale - Brown obsessive - compulsive scale ( Y - BOCS ) . The patients were divided into drug responders group and non - responders group according to the reducing rate of Y - BOCS score . The genotypes of six genes were determined with the Amp - DB00712 and Amp - RFLP techniques and analyzed by transmission disequilibrium test ( P04053 ) . The six genes are serotonin 2A receptor ( 5 - Q13049 ) , serotonin transporter ( 5 - HTT ) , dopamine D2 receptor ( P14416 ) , dopamine D4 receptor ( P21917 ) , catechol - O - methyltransferase ( P21964 ) and monoamine oxidase A ( P21397 ) . RESULTS : No association was found between the six genes and different drug responses groups . However , there was significant difference between the drug responders and non - responders in homozygosity at the 5 - Q13049 - 1438G / A locus ( chi ( 2 )= 4 . 69 , P = 0 . 03 ) . CONCLUSION : The results suggested that the 5 - Q13049 may play some roles in the effects of drug treatment on OCD ."
] |
[
"___MASK12___",
"___MASK13___",
"___MASK20___",
"___MASK22___",
"___MASK23___",
"___MASK76___",
"___MASK89___",
"___MASK92___",
"___MASK96___"
] |
___MASK76___
|
MH_train_437
|
interacts_with DB00530?
|
[
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"Potentiation of anti - angiogenic activity of heparin by blocking the P01008 - interacting pentasaccharide unit and increasing net anionic charge . ___MASK45___ , a potent anticoagulant used for the prevention of venous thromboembolism , has been recognized as a tumor angiogenesis inhibitor . Its limitation in clinical application for cancer therapy , however , arises from its strong anticoagulant activity , which causes associated adverse effects . In this study , we show the structural correlation of LHT7 , a previously developed heparin - based angiogenesis inhibitor , with its influence on P15692 blockade and its decreased anticoagulant activity . LHT7 was characterized as having average seven molecules of sodium taurocholates conjugated to one molecule of low - molecular - weight heparin ( LMWH ) . This study showed that the conjugation of sodium taurocholates selectively blocked interaction with antithrombin III ( P01008 ) while enhancing the binding with P15692 . This resulted in LHT7 to have negligible anticoagulant activity but potent anti - angiogenic activity . Following up on this finding , we showed that the bidirectional effect of sodium taurocholate conjugation was due to its unique structure , that is , the sterane core hindering the P01008 - binding pentasaccharide unit of LMWH with its bulky and rigid structural characteristics while the terminal sulfate group interacts with P15692 to produce stronger binding . In addition , we showed that LHT7 was localized in the tumor , especially on the endothelial cells . One explanation for this might be that LHT7 was delivered to the tumor via platelets .",
"A unique structure for epidermal growth factor receptor bound to GW572016 ( DB01259 ) : relationships among protein conformation , inhibitor off - rate , and receptor activity in tumor cells . GW572016 ( DB01259 ) is a tyrosine kinase inhibitor in clinical development for cancer that is a potent dual inhibitor of epidermal growth factor receptor ( P00533 , ErbB - 1 ) and ErbB - 2 . We determined the crystal structure of P00533 bound to GW572016 . The compound is bound to an inactive - like conformation of P00533 that is very different from the active - like structure bound by the selective P00533 inhibitor DB00530 ( Tarceva ) described previously . Surprisingly , we found that GW572016 has a very slow off - rate from the purified intracellular domains of P00533 and ErbB - 2 compared with DB00530 and another P00533 selective inhibitor , ZD - 1839 ( DB00317 ) . Treatment of tumor cells with these inhibitors results in down - regulation of receptor tyrosine phosphorylation . We evaluated the duration of the drug effect after washing away free compound and found that the rate of recovery of receptor phosphorylation in the tumor cells reflected the inhibitor off - rate from the purified intracellular domain . The slow off - rate of GW572016 correlates with a prolonged down - regulation of receptor tyrosine phosphorylation in tumor cells . The differences in the off - rates of these drugs and the ability of GW572016 to inhibit ErbB - 2 can be explained by the enzyme - inhibitor structures .",
"A phase II study of erlotinib ( DB00530 ) given in combination with carboplatin in patients with recurrent epithelial ovarian cancer ( NCIC CTG IND . 149 ) . OBJECTIVES : Approximately 50 % of ovarian cancers have elevated levels of epidermal growth factor receptor ( P00533 ) which correlates with a poor prognosis . Preclinical evidence suggests that P00533 tyrosine kinase inhibitors ( TKIs ) , such as erlotinib ( DB00530 ) , may potentiate the anti - tumour effects of cytotoxic agents , including carboplatin . Blocking P00533 could thus potentially reverse drug resistance . The primary objective of the study was to assess the response rate to the addition of erlotinib in patients with recurrent ovarian cancer who were receiving carboplatin . METHODS : Patients enrolled on this study had either local or advanced recurrent ovarian cancer with measurable disease . They may have had up to 2 prior chemotherapy regimens , one of which must have contained platinum , and they must have responded to prior platinum therapy . Patients were stratified by platinum sensitivity and were treated with erlotinib 150 mg daily on a continuous dosing schedule , and carboplatin at an AUC of 5 every 21 days . RESULTS : Fifty patients with recurrent ovarian cancer entered the study , 33 in the platinum - sensitive arm and 17 in the platinum - resistant arm . Of patients evaluable for response , there were 14 partial responses ( PR ) of 30 evaluable for response ( 57 % objective response rate ( ORR ) ) in the platinum - sensitive arm , and 1 PR of 14 evaluable for response ( 7 % ORR ) in the platinum - resistant arm . CONCLUSIONS : The combination of erlotinib and carboplatin was active in patients with platinum - sensitive disease , but not in platinum - resistant disease . The toxicities seen were those expected with carboplatin and erlotinib .",
"Overview of tyrosine kinase inhibitors in clinical breast cancer . Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti - oestrogen therapy , and to tamoxifen in particular , have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors , notably the epidermal growth factor receptor ( P00533 ) and P04626 . Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor ( ER ) signalling . Inhibition of receptor tyrosine kinase activity involved in the P00533 signalling cascade forms the basis for the use of P00533 specific tyrosine kinase inhibitors exemplified by gefitinib ( ZD1839 , DB00317 ) and erlotinib ( DB00530 , Tarceva ) . Such agents have proved promising in pre - clinical studies and are currently in clinical trials in breast cancer , where gefitinib has been studied more extensively to date . Here , we present an overview of the current development of gefitinib in clinical breast cancer . This includes results from our clinical breast cancer trial 1839IL / 0057 that demonstrate the efficacy of gefitinib within ER - positive , tamoxifen - resistant patients with locally advanced / metastatic disease , where parallel decreases in P00533 signal transduction and the Ki67 ( Q86YT6 ) proliferation marker can be detected as predicted from model system studies . We also consider trials examining combination treatment with gefitinib and anti - hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay / prevent onset of anti - hormone resistance .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK6___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"Protein kinase Cdelta and calmodulin regulate epidermal growth factor receptor recycling from early endosomes through Arp2 / 3 complex and cortactin . The intracellular trafficking of the epidermal growth factor receptor ( P00533 ) is regulated by a cross - talk between calmodulin ( P62158 ) and protein kinase Cdelta ( PKCdelta ) . On inhibition of P62158 , PKCdelta promotes the formation of enlarged early endosomes and blocks P00533 recycling and degradation . Here , we show that PKCdelta impairs P00533 trafficking due to the formation of an F - actin coat surrounding early endosomes . The PKCdelta - induced polymerization of actin is orchestrated by the Arp2 / 3 complex and requires the interaction of cortactin with PKCdelta . Accordingly , inhibition of actin polymerization by using cytochalasin D or by overexpression of active cofilin , restored the normal morphology of the organelle and the recycling of P00533 . Similar results were obtained after down - regulation of cortactin and the sequestration of the Arp2 / 3 complex . Furthermore we demonstrate an interaction of cortactin with P62158 and PKCdelta , the latter being dependent on P62158 inhibition . In summary , this study provides the first evidence that P62158 and PKCdelta organize actin dynamics in the early endosomal compartment , thereby regulating the intracellular trafficking of P00533 .",
"20 - HETE in neovascularization . Cytochrome P450 4A / F ( CYP4A / F ) converts arachidonic acid ( AA ) to 20 - HETE by ω - hydroxylation . The contribution of 20 - HETE to the regulation of myogenic response , blood pressure , and mitogenic actions has been well summarized . This review focuses on the emerging role of 20 - HETE in physiological and pathological vascularization . 20 - HETE has been shown to regulate vascular smooth muscle cells ( VSMC ) and endothelial cells ( EC ) by affecting their proliferation , migration , survival , and tube formation . Furthermore , the proliferation , migration , secretion of proangiogenic molecules ( such as HIF - 1α , P15692 , SDF - 1α ) , and tube formation of endothelial progenitor cells ( EPC ) are stimulated by 20 - HETE . These effects are mediated through c - Src - and P00533 - mediated downstream signaling pathways , including MAPK and PI3K / Akt pathways , P29474 uncoupling , and NOX / ROS system activation . Therefore , the CYP4A / F - 20 - HETE system may be a therapeutic target for the treatment of abnormal angiogenic diseases .",
"P00533 tyrosine kinase inhibitors : application in non - small cell lung cancer . Despite treatment advances over the past decade , long - term survival for patients with non - small cell lung cancer ( NSCLC ) remains poor , and treatment options available after second - line therapy are limited . Increased understanding of cancer biology has led to the identification of several potential targets for treatment . The epidermal growth factor receptor ( P00533 ) belongs to a family of plasma membrane receptor tyrosine kinases that controls many important cellular functions , from growth and proliferation to cell death . This receptor is a particularly promising therapeutic target because it often is overexpressed in patients with NSCLC and has been implicated in the pathogenesis as well as the proliferation , invasion , and metastasis of lung cancer and other malignancies . New agents developed to inhibit P00533 function include small - molecule tyrosine kinase inhibitors , monoclonal antibodies to P00533 , and pan - P00533 inhibitors . Completed and ongoing clinical trials have shown that P00533 inhibitors have remarkable efficacy for patients with relapsed NSCLC . Among these , two phase 2 trials have shown that ZD1839 is effective when used as monotherapy . The response rates are comparable with those for docetaxel given in the second - line setting . Another phase 2 trial has shown that DB00530 is effective in the same setting . Data from phase 3 trials indicate that adding an P00533 tyrosine kinase inhibitor to chemotherapy does not provide an additional survival benefit , as compared with standard chemotherapy alone for first - line treatment of NSCLC . It appears that P00533 tyrosine kinase inhibitors are safe and well tolerated by patients with cancer . Further studies will elucidate how these new agents can best be used for NSCLC and other tumor types .",
"Erlotinib : success of a molecularly targeted agent for the treatment of advanced pancreatic cancer . P00533 ( P00533 ) is overexpressed by several solid tumors , including pancreatic cancer , and has become an important target for novel anticancer pharmacotherapy . Erlotinib ( Tarceva , DB00530 ) is an orally available small - molecule inhibitor of the P00533 tyrosine kinase . The addition of erlotinib to gemcitabine has been shown to prolong survival of patients treated for advanced pancreatic cancer in the National Cancer Institute of Canada PA . 3 trial . This survival advantage is small yet noteworthy , in that numerous gemcitabine - containing combinations have failed to show a statistically significant survival advantage over gemcitabine alone . The most frequent toxicities associated with the addition of erlotinib are diarrhea and rash . Erlotinib - induced rash appears to be predictive of outcome . Further clinical studies of erlotinib in the treatment of pancreatic cancer are ongoing .",
"Epithelial growth factor receptor interacting agents . The data reviewed here have further established the promise of anti - P00533 - targeted therapies . This statement is supported by the evidence of antitumor activity of the TK inhibitors ZD1839 and DB00530 against several tumor types and by the ability of the monoclonal antibody IMC - C225 to reverse clinical chemotherapy resistance . These results are further supported by an emerging number of compounds , monoclonal antibodies , and TK inhibitors directed at the P00533 that are in clinical development ( see Fig . 2 , Table 1 ) . Among the TK inhibitors , these compounds can be further categorized by their receptor specificity and reversibility of binding . In the case of anti - P00533 monoclonal antibodies , compounds in clinical development include chimeric , humanized , and bispecific antibodies . The fundamental observation is that these compounds have shown activity in several tumor types , including NSCL cancer , prostate carcinoma , colorectal carcinoma , ovarian carcinoma , renal cell carcinoma , and head and neck cancers . These findings observed with different agents and in different tumor types validate P00533 as a target for cancer therapy . The results of ongoing studies with these agents in diverse indications and tumor types may establish the role of these promising therapies to our current cancer treatments .",
"Structure of the epidermal growth factor receptor kinase domain alone and in complex with a 4 - anilinoquinazoline inhibitor . The crystal structure of the kinase domain from the epidermal growth factor receptor ( EGFRK ) including forty amino acids from the carboxyl - terminal tail has been determined to 2 . 6 - A resolution , both with and without an EGFRK - specific inhibitor currently in Phase III clinical trials as an anti - cancer agent , erlotinib ( DB00530 , CP - 358 , 774 , Tarceva ( TM ) ) . The P00533 family members are distinguished from all other known receptor tyrosine kinases in possessing constitutive kinase activity without a phosphorylation event within their kinase domains . Despite its lack of phosphorylation , we find that the EGFRK activation loop adopts a conformation similar to that of the phosphorylated active form of the kinase domain from the insulin receptor . Surprisingly , key residues of a putative dimerization motif lying between the EGFRK domain and carboxyl - terminal substrate docking sites are found in close contact with the kinase domain . Significant intermolecular contacts involving the carboxyl - terminal tail are discussed with respect to receptor oligomerization .",
"[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK8___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .",
"[ Molecular target - based cancer therapy : epidermal growth factor receptor inhibitors ] . Based on recent progress in cancer biology , numerous molecules that contribute to proliferation , invasion , and metastasis of cancer cells have been identified . The epidermal growth factor receptor ( P00533 ) , a member of cell membrane receptors , is overexpressed by many tumors , and P00533 overexpression correlates with poor prognosis and disease progression . The P00533 is an attractive target for novel anticancer therapy . ZD1839 and DB00530 , highly specific P00533 tyrosine kinase inhibitors , have shown promising antitumor activity against cisplatin - resistant non - small cell lung cancer in phase I and phase II trials . IMC - C225 , a monoclonal antibody against P00533 , has achieved significant disease control in head and neck cancer and colorectal cancer in combination with anticancer agents . These agents are under evaluation in phase III trials . In conclusion , it is expected that P00533 - directed therapies will soon be established as an effective novel treatment for many cancer patients .",
"P13726 expression in human pterygium . PURPOSE : A pterygium shows tumor - like characteristics , such as proliferation , invasion , and epithelial - mesenchymal transition ( EMT ) . Previous reports suggest that tissue factor ( TF ) expression is closely related to the EMT of tumor cells , and subsequent tumor development . In this study , we analyzed the expression and immunolocalization of TF in pterygial and normal conjunctival tissues of humans . METHODS : Eight pterygia and three normal bulbar conjunctivas , surgically removed , were used in this study . DB03843 - fixed , paraffin - embedded tissues were submitted for immunohistochemical analysis with anti - TF antibody . Double staining immunohistochemistry was performed to assess TF and alpha - smooth muscle actin ( α - SMA ) or epidermal growth factor receptor ( P00533 ) expression in the pterygia . RESULTS : Immunoreactivity for TF was detected in all pterygial tissues examined . TF immunoreactivity was localized in the cytoplasm of basal , suprabasal , and superficial epithelial cells . The number of TF - immunopositive cells in pterygial epithelial cells was significantly higher than in normal conjunctival epithelial cells ( p < 0 . 001 ) . TF immunoreactivity was detected in α - SMA - positive or - negative pterygial epithelial cells . P00533 immunoreactivity was detected in pterygial epithelium , which was colocalized with TF . CONCLUSIONS : These results suggest that TF plays a potential role in the pathogenesis and development of a pterygium , and that TF expression might be involved through EMT - dependent and - independent pathways .",
"Growth factors and their receptors : new targets for prostate cancer therapy . Stimulation of the signal transduction pathway of the epidermal growth - factor receptor ( P00533 ) tyrosine kinase family of receptors in tumor cells enhances cellular proliferation , prevents apoptosis , and promotes tumor - cell mobility , adhesion , and invasion . Therapeutic approaches used to target the P00533 and its signal transduction cascade include ( 1 ) monoclonal antibodies ( eg , cetuximab [ IMC - C225 ] ) directed against the extracellular binding domain of the receptor ; and ( 2 ) trastuzumab , a monoclonal antibody binding to the P04626 receptor ; immunotoxin conjugates use an antibody directed against P00533 joined to a cell toxin . All are in clinical trials for a number of cancers , including prostate cancer . Antisense strategies are in preclinical development . Low - molecular - weight inhibitors of the P00533 tyrosine kinase also in clinical development include DB00530 , PD182905 , PKI - 166 , DB05424 , and ZD1839 . ZD1839 has shown encouraging results in patients with prostate cancer in phase 1 trials . mn",
"Combination treatment of glioblastoma multiforme cell lines with the anti - malarial artesunate and the epidermal growth factor receptor tyrosine kinase inhibitor DB00530 . New drugs and combination modalities for otherwise non - responsive brain tumors are urgently required . The anti - malarial artesunate ( O00253 ) and the P00533 tyrosine kinase inhibitor DB00530 reveal profound cytotoxic activity . The effectiveness of a combination treatment and the underlying molecular determinants of cellular response are unknown . In the present investigation , we studied O00253 and DB00530 in glioblastoma multiforme ( GBM ) cell lines . Supra - additive inhibition of cell growth was observed in U - 87MG . DeltaEGFR cells transduced with a deletion - mutant constitutively active P00533 gene , while additive effects were present in cells transduced with wild - type P00533 ( U - 87MG . WT - 2N ) , kinase - deficient P00533 ( U - 87MG . DK - 2N ) , mock vector controls ( U - 87MG . LUX ) , or non - transduced parental U - 87MG cells . Among nine other non - transduced GBM cell lines , supra - additive effects were found in two cell lines ( G - 210GM , G - 599GM ) , while O00253 and DB00530 acted in an additive manner in the other seven cell lines ( G - 211GM , G - 750GM , G - 1163GM , G - 1187GM , G - 1265GM , G - 1301GM , and G - 1408GM ) . Sub - additive or antagonistic effects were not observed . Genomic gains and losses of genetic material in the non - transduced cell lines as assessed by comparative genomic hybridization were correlated with the IC ( 50 ) values for O00253 and DB00530 and subsequently subjected to hierarchical cluster analysis and cluster image mapping . A genomic profile of imbalances was detected that predicted cellular response to O00253 and DB00530 . The genes located at the genomic imbalances of interest may serve as candidate resistance genes of GBM cells towards O00253 and DB00530 . In conclusion , the combination treatment of O00253 and DB00530 resulted in an increased growth inhibition of GBM cell lines as compared to each drug alone .",
"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK20___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .",
"DB00530 OSI Pharmaceuticals . DB00530 ( formerly CP - 358774 ) , a quinazoline derivative , is an orally active epidermal growth factor receptor ( P00533 ) inhibitor which was originally under joint development by Pfizer and OSI Pharmaceuticals ( formerly Oncogene Science ) for the potential treatment of cancer ( eg , ovarian , non - small cell lung cancer ( NSCLC ) and head and neck ) . It is being evaluated in phase II trials [ 304305 ] , [ 372201 ] . On 8 January 2001 , OSI announced that it had signed an agreement with Roche and Genentech for the global co - development and marketing of DB00530 . The agreement with Genentech covers the United States , that with Roche the rest of the world [ 395371 ] , [ 395526 ] . In June 2000 , OSI gained all development and marketing rights for DB00530 following Pfizer ' s merger with Warner - Lambert [ 371439 ] . In September 2000 , Pfizer transferred the IND dossierfor DB00530 to OSI ahead of the timeline agreed in the June 2000 development and marketing rights agreement [ 383786 ] . The phase II trials will assess DB00530 both as a single agent and in combination with existing chemotherapy regimens [ 347783 ] . Phase III trials are expected to be initiated in 2001 [ 347783 ] . In October 2000 , Lehman Brothers predicted that DB00530 would move into pivotal trials in thefirst half of 2001 and that the drug would be launched in 2003 . The analysts also estimated worldwide sales of US $ 66 million , $ 285 million and $ 461 million in 2003 , 2004 and 2005 , respectively , and peak sales in excess of US $ 500 million [ 395189 ] .",
"Rationale for investigation of epidermal growth factor receptor inhibitors in definitive treatment of locally advanced non - small cell lung cancer and head and neck cancer . Designing targeted therapies has become an important field in cancer therapeutics . The epidermal growth factor receptor ( P00533 ) is a molecular target that has gained immense attention as preclinical and clinical studies have supported its potential role for therapy of a variety of cancers , including non - small cell lung cancer ( NSCLC ) and head and neck ( HN ) cancer . Several compounds that specifically inhibit P00533 have been developed , including ZD1839 , C225 , and DB00530 . Interestingly , studies suggesting a potential role for P00533 inhibitors as an adjunct to the current combined - modality approach for therapy of NSCLC and HN cancer have been performed in the preclinical and clinical setting . Therefore , determining the potential of P00533 inhibitors to improve the efficacy of standard combined - modality regimens ( chemotherapy / radiation therapy +/- surgery ) for NSCLC and HN cancer patients is of the utmost importance . An overview of the rationale and the ongoing / proposed studies aimed at determining the role for P00533 inhibitors in combination with radiation therapy for NSCLC and HN cancer patients will be presented .",
"Erlotinib in non - small cell lung cancer : a review . Erlotinib ( Tarceva , DB00530 ; Pfizer , Inc . ) is an orally - active , targeted inhibitor of the epidermal growth factor receptor ( P00533 / P00533 ) , which is part of a key regulatory pathway in cancer . Patients with advanced , incurable non - small cell lung cancer ( NSCLC ) may derive a clinical benefit from first - and second - line chemotherapy , but third - line treatment with available cytotoxic agents is not effective . Remarkably , P00533 / P00533 antagonists have demonstrated activity as second - and even third - line treatment for this disease . Erlotinib is the first of this novel class of drug to demonstrate a statistically significant and clinically relevant difference in overall survival , progression free survival and time to disease related symptoms ( cough , pain , shortness of breath ) compared with treatment with best supportive care in patients who have failed standard first - or second - line chemotherapy . This paper reviews the pharmacology , preclinical and clinical data to support the use of erlotinib in NSCLC .",
"P00533 tyrosine kinase inhibitors in late stage clinical trials . The epidermal growth factor receptor ( P00533 ) is a cell membrane receptor that plays a key role in cancer development and progression . Ligand - activated P00533 - dependent signalling is involved in cell proliferation , apoptosis , angiogenesis and metastatic spread . Targeting the P00533 , therefore , represents a promising molecular approach in cancer treatment . Several anti - P00533 agents are in clinical development . Three drugs are currently in Phase II and III development as single agents , or in combination with other anticancer modalities : IMC - 225 ( cetuximab / Erbitux ; ImClone ) , a chimaeric human - mouse monoclonal IgG ( 1 ) antibody , which blocks ligand binding and functional activation of the P00533 ; DB00530 ( erlotinib / Tarceva ; Genentech / OSI / Roch ) and ZD1839 ( gefitinib / DB00317 ; AstraZeneca ) , two small molecule P00533 - selective inhibitors of tyrosine kinase enzymatic activity , which prevent P00533 autophosphorylation and activation . DB00317 is the first P00533 - targeting agent to be registered as an anticancer drug in Japan , in Australia and in the US for the third - line treatment of chemoresistant non - small cell lung cancer ( NSCLC ) patients . This review will focus on the preclinical background and on the results from the first series of clinical trials with these drugs . Furthermore , continuing clinical trials and a series of open clinical issues for the development of optimal strategies of using P00533 - targeting agents will be discussed .",
"Targeted therapy using novel agents in the treatment of non - small - cell lung cancer . Patients with advanced non - small - cell lung cancer ( NSCLC ) have a poor prognosis and high mortality . The therapeutic improvement caused by the new generation of cytotoxic agents seems to have reached a plateau . The main categories of targeted therapeutics applicable for NSCLC include receptor - targeted therapy , signal transduction or cell - cycle inhibition , angiogenesis inhibitors , gene therapy , and vaccines . Several major classes of agents directed at specific cellular mechanisms exist for the treatment of NSCLC . The anti - epidermal growth factor receptor ( P00533 ) group contains trastuzumab and IMC - C225 , monoclonal antibodies against EGFRs that are overexpressed in many cancers . DB00530 and ZD1839 are inhibitors of P00533 tyrosine kinase , a key enzyme of the signaling pathway . Farnesyl transferase inhibitors , such as SCH66336 , and protein kinase C inhibitors , such as ISIS 3521 , have also shown antitumor activity . Antiangiogenesis agents that have shown promise include TNP - 470 , recombinant endostatin , and angiostatin . Antibodies to vascular endothelial growth factor ( P15692 ) also seem to control tumor progression and may prolong survival . LY317615 , an inhibitor of protein kinase Cb , augmented the tumor growth delay produced by cytotoxic drugs . All of these agents are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy drugs . These new agents are more target specific , less toxic , easier to administer , and may lead to enhanced safety and survival for patients with advanced NSCLC .",
"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .",
"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .",
"Erlotinib ( Tarceva , DB00530 ) antagonizes DB00171 - binding cassette subfamily B member 1 and DB00171 - binding cassette subfamily G member 2 - mediated drug resistance . It has been reported that gefitinib , an epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor ( TKI ) , has the ability to modulate the function of certain DB00171 - binding cassette ( DB01048 ) transporters and to reverse ABC subfamily B member 1 ( P08183 ; P - glycoprotein ) - and ABC subfamily G member 2 ( Q9UNQ0 ; breast cancer resistance protein / mitoxantrone resistance protein ) - mediated multidrug resistance ( MDR ) in cancer cells . However , it is unknown whether other P00533 TKIs have effects similar to that of gefitinib . In the present study , we have investigated the interaction of another P00533 TKI , erlotinib , with selected ABC drug transporters . Our findings show that erlotinib significantly potentiated the sensitivity of established P08183 or Q9UNQ0 substrates and increased the accumulation of paclitaxel or mitoxantrone in P08183 - or Q9UNQ0 - overexpressing cells . Furthermore , erlotinib did not significantly alter the sensitivity of non - P08183 or non - Q9UNQ0 substrates in all cells and was unable to reverse MRP1 - mediated MDR and had no effect on the parental cells . However , erlotinib remarkably inhibited the transport of E ( 2 ) 17 beta G and methotrexate by Q9UNQ0 . In addition , the results of ATPase assays show that erlotinib stimulated the ATPase activity of both P08183 and Q9UNQ0 . Interestingly , erlotinib slightly inhibited the photolabeling of P08183 with [( 125 ) I ] iodoarylazidoprazosin ( IAAP ) at high concentration , but it did not inhibit the photolabeling of Q9UNQ0 with IAAP . Overall , we conclude that erlotinib reverses P08183 - and Q9UNQ0 - mediated MDR in cancer cells through direct inhibition of the drug efflux function of P08183 and Q9UNQ0 . These findings may be useful for cancer combinational therapy with erlotinib in the clinic .",
"Inactivation of Akt by the epidermal growth factor receptor inhibitor erlotinib is mediated by HER - 3 in pancreatic and colorectal tumor cell lines and contributes to erlotinib sensitivity . Signaling through the receptor for epidermal growth factor receptor ( P00533 ) is frequently deregulated in solid tumors . Erlotinib ( Tarceva , DB00530 , OSI Pharmaceuticals , Inc . , Melville , NY ) is a low molecular weight , orally bioavailable inhibitor of the P00533 that has been approved for both non - small cell lung cancer and pancreatic cancers . Previous studies have indicated that sensitivity to P00533 antagonists correlated with HER - 3 signaling for non - small cell lung cancer . Herein , we have sought to understand the signaling pathways that mediate erlotinib sensitivity for pancreatic and colorectal cancers . In a panel of 12 pancreatic tumor cell lines , we find that P00533 is coexpressed with HER - 3 in all cell lines sensitive to erlotinib but not in insensitive cell lines . Erlotinib can block HER - 3 phosphorylation in these sensitive cell lines , suggesting that HER - 3 is transactivated by P00533 . Knockdown of HER - 3 in BxPC3 , an erlotinib - sensitive pancreatic tumor cell line , results in inhibition of the phosphorylation for both Akt and S6 and is associated with a decrease in cell proliferation and reduced sensitivity to erlotinib . Therefore , P00533 transactivation of HER - 3 mediates Akt signaling and can contribute to erlotinib sensitivity for pancreatic tumors . We extended our analysis to a panel of 13 colorectal tumor cell lines and find that , like pancreatic , HER - 3 is coexpressed with P00533 in the most erlotinib - sensitive cell lines but not in erlotinib - insensitive cell lines . These studies suggest that HER - 3 could be used as a biomarker to select patients who are most likely to respond to erlotinib therapy .",
"Interferon - alpha promotes the anti - proliferative effect of Erlotinib ( DB00530 ) on human colon cancer cell lines . Interferon - alpha ( IFNalpha ) treatment is associated with up - regulation of epidermal growth factor receptor ( P00533 / P00533 ) expression and marked growth inhibition while maintaining the sensitivity of the target colon cancer cells to epidermal growth factor ( Gut 2004 ; 53 : 123 ) . We aimed to determine the effect of combining IFNalpha and Erlotinib ( an P00533 / P00533 inhibitor ) on colon cancer cell line growth . Crystal - violet staining and flow cytometry were used to assess cell proliferation and expression of P00533 / P00533 . IFNalpha pre - treatment followed by a combination of IFNalpha plus Erlotinib significantly enhanced the sensitivity of 7 / 9 of colon cancer cell lines by 7 - 43 % . This approach may have clinical implications for improving treatment based on targeting of P00533 / P00533 .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK93___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK93___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"___MASK71___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK71___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .",
"DB01076 may delay cardiac aging by upregulating peroxisome proliferator - activated receptors in rats . AIMS : To investigate the effect of atorvastatin on cardiac aging in rats . MATERIALS : Ninety 20 - month - old Wistar rats were administered oral atorvastatin ( AVT ; 10 or 1 mg · kg (- 1 )· day (- 1 ) ) or saline for 4 months . At the end of the experiment , age - related changes in hearts were measured . RESULTS : Compared with young rats , obvious increases were found in the aging rats in left ventricle thickness , diameter of cardiocytes , collagen deposition , the ratio of type I / type III collagen , β - galactosidase and malondialdehyde ( MDA ) , and obvious decreases were found in superoxide dismutase ( SOD ) , catalase ( CAT ) and nitric oxide synthase ( NOS ) . The treatment with AVT led to significant decreases in the thickness of the left ventricle , diameter of cardiocytes , collagen deposition , I / III collagen ratio , MDA , β - galactosidase and increases in the activity of SOD , CAT and NOS . Some aging - related inflammatory cytokines like interleukin ( IL ) - 1β , tumour necrosis factor ( P01375 ) - α and matrix metalloproteinase ( MMP ) - 9 were found to be overexpressed in the aging rats . AVT treatment could inhibit the expression of IL - 1β , P01375 - α and P14780 on both the mRNA and protein levels , and increase the expression of peroxisome proliferator - activated receptors ( Q07869 - α / β / δ / γ ) . Pretreatment with Q07869 inhibitors attenuated the inhibitory effect of AVT on the expression of inflammatory cytokines . CONCLUSION : AVT may retard the cardiac aging process by upregulating PPARs .",
"YAP modifies cancer cell sensitivity to P00533 and survivin inhibitors and is negatively regulated by the non - receptor type protein tyrosine phosphatase 14 . The Yes - associated protein ( YAP ) is a transcriptional factor involved in tissue development and tumorigenesis . Although YAP has been recognized as a key element of the Hippo signaling pathway , the mechanisms that regulate YAP activities remain to be fully characterized . In this study , we demonstrate that the non - receptor type protein tyrosine phosphatase 14 ( Q15678 ) functions as a negative regulator of YAP . We show that YAP forms a protein complex with Q15678 through the WW domains of YAP and the PPXY motifs of Q15678 . In addition , Q15678 inhibits YAP - mediated transcriptional activities . Knockdown of YAP sensitizes cancer cells to various anti - cancer agents , such as cisplatin , the P00533 tyrosine kinase inhibitor erlotinib and the small - molecule antagonist of survivin , P28222 . YAP - targeted modalities may be used in combination with other cancer drugs to achieve maximal therapeutic effects .",
"Targeting epidermal growth factor receptor : novel therapeutics in the management of cancer . Overexpression of epidermal growth factor receptor ( P00533 ) in epithelial tumors , including head and neck , lung , breast , colon and other solid tumors , has frequently been correlated with poor prognosis , thus stimulating efforts to develop new cancer therapies that target P00533 . Monoclonal antibodies and tyrosine kinase inhibitors specifically targeting P00533 are the most well - studied and hold substantial promise of success . Several compounds of monoclonal antibodies and tyrosine kinase inhibitors targeting P00533 have been studied and clinical trials are now underway to test the safety and efficacy of these targeting strategies in several human tumors . This review will address each of these agents alone or in combination with radiation or chemotherapy and highlight some of these promising developments . Cetuximab ( Erbitux ) is being evaluated in combination with radiation or chemotherapy in Phase III trials . Other compounds such as h - R3 , DB01269 , P50402 - 55900 and ICR - 62 have proved to be effective in targeting malignant cells alone or in combination with traditional therapies . Tyrosine kinase inhibitors targeting the intracellular domain of P00533 , including ZD - 1839 ( gefitinib , DB00317 ) , DB00530 ( Erlotinib / Tarceva ) , PD - 153053 , PD - 168393 and DB05424 , have been studied in clinical setting alone or in combination with radiation or chemotherapy . ZD - 1839 is being studied in a Phase III trial in patients with advanced non - small cell lung cancer . P00533 targeted treatment by monoclonal antibodies and tyrosine kinase inhibitors have been proven to sensitize tumor cells to the effects of chemotherapy and radiation therapy . The synergistic activities and nonoverlapping toxicities of these compounds allow concomitant administration with cytotoxic therapy . Challenges of evaluating P00533 targeted agents exist in selecting the optimal dosages and determining long - term toxicity .",
"Mutant epidermal growth factor receptor up - regulates molecular effectors of tumor invasion . The gene most commonly altered in human glioblastomas is the epidermalgrowth factor receptor ( P00533 ) . We profiled transcripts induced by mutantEGFR to better understand its role in tumor progression . The pattern found suggested enhanced tumor invasion . The highly induced genes included extracellular matrix components , metalloproteases , and a serine protease . We confirmed that mutant P00533 did make glioblastoma cells both more motile and invasive using in vitro assays . Furthermore , inhibitors of P00533 ( DB00530 and Tyrphostin AG1478 ) selectively down - regulated these molecular effectors in glioblastoma cells , eliminating enhanced invasion .",
"Label - free electrochemical measurement of protein tyrosine kinase activity and inhibition based on electro - catalyzed tyrosine signaling . A novel label - free electrochemical method for measuring the activity of protein tyrosine kinases ( PTK ) has been developed . P00533 ( P00533 ) , a typical PTK associated with a large percentage of all solid tumors , was used as the model kinase . Poly ( glu , tyr ) ( 4 : 1 ) peptide , as a substrate of P00533 , was covalently immobilized on the surface of indium tin oxide ( ITO ) electrode by silane chemistry . The tyrosine ( DB00135 ) residue in the polypeptide served as an electrochemical signal reporter . Its voltammetric current was catalyzed by a dissolved electron mediator Os ( bpy )( 3 )( 2 +) ( bpy = 2 , 2 '- bipyridine ) for increased sensitivity . Phosphorylation of the DB00135 led to a loss of its electrochemical current , thus providing a sensing mechanism for PTK activity . Experimental conditions for the silanization of ITO surface and immobilization of polypeptide were investigated in details to facilitate the generation of DB00135 electrochemical signal . The proposed biosensor exhibited high sensitivity and excellent stability . The limit of detection for P00533 was 1 UmL (- 1 ) . Furthermore , this biosensor can also be used for quantitative analysis of kinase inhibition . On the basis of the inhibitor concentration dependent electrochemical signal , the half - maximal inhibition value IC ( 50 ) of three P00533 inhibitors , PD - 153035 , DB00530 and ZD - 1839 , and their corresponding inhibition constants K ( i ) were estimated , which were in agreement with those obtained from the conventional kinase assay . This electrochemical biosensor can be implemented in an array format for the high throughput assay of in vitro PTK activity and PTK inhibitors screening for practical diagnostic application and drug discovery .",
"Interstitial lung disease in patients with non - small - cell lung cancer treated with epidermal growth factor receptor inhibitors . Interstitial lung disease ( ILD ) refers to a diverse range of pulmonary fibrotic disorders and may be hard to accurately diagnose , as distinguishing it from other pulmonary diseases can be difficult . Estimations of the incidence in populations are confounded by the complexity of the different forms of the disorder . In addition , ILD is a comorbid disease of lung cancer and is seen after most forms of chemotherapy and radiotherapy for advanced lung cancer . Incidences of > or = 10 % have been reported ; however , whatever the true incidence , both chemotherapy and radiotherapy enhance the risk of developing ILD . ILD has also been reported with the epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors , including erlotinib ( Tarceva , DB00530 ) and gefitinib ( IRESSA ) . In a large number of gefitinib - treated patients ( n > 185 , 000 ) an incidence of approx 1 % has been observed ( approx 2 % in Japan ; 0 . 3 % in the rest of the world ) . Nevertheless , as with other treatments for advanced non - small - cell lung cancer , the clinical benefit outweighs the risk of ILD . In this article , we review the data on ILD with P00533 inhibitors and other common lung cancer treatments .",
"Molecular weight and biochemical profile of a chemically modified heparin derivative , Suleparoide . Recently , a new chemically modified derivative of heparin ( Suleparoide , Syntex Laboratories Buenos Aires , Argentina ) was introduced for the prophylaxis of thrombosis and treatment of vascular disorders . This agent is claimed to contain a depolymerized , chemically modified , heparin derivative with similar biologic actions as heparan sulfate . To study the pharmacologic profile of this agent , we have defined its molecular weight distribution profile , utilizing a computerized gel permeation chromatographic system equipped with ultraviolet and refractive index detectors . Suleparoide exhibited a normal molecular distribution profile with no contaminants . It exhibited a weight average of 9 . 3 K DA and an apparent peak MW of 8 . 0 K DA . Approximately 50 % of the molecular components were < 5 . 0 K DA and 40 % > 5 . 0 K DA . The results from these studies on the mechanisms show that Suleparoide has anticoagulant activity primarily mediated through ___MASK45___ Cofactor - II ( P05546 ) and because of its novel mechanism of action , further investigations on the biochemical profile of Suleparoide are carried out . Global clotting tests such as Activated Partial P13726 Time ( APTT ) , Heptest and Thrombin Time ( TT ) revealed a concentration dependent effect in all assays . Plasma samples supplemented with Suleparoide exhibited no significant anti - Xa and anti - IIa activities . However , in the P05546 mediated inhibitory assay for IIa , Suleparoide exhibited significant activity . In contrast , the P01008 ( DB11598 ) mediated inhibition of IIa was much weaker .",
"Compensatory increases in Her - 2 / neu activation in response to P00533 tyrosine kinase inhibition in colon cancer cell lines . BACKGROUND : Tyrosine kinase receptors of the ErbB family have become promising targets for anti - neoplastic drugs , but mechanisms of resistance are incompletely understood . To investigate such pathways , we applied a small - molecule , selective P00533 inhibitor , DB00530 , to three well - characterized colon cancer cell lines and studied the alterations of expression and activation of receptors in the erbB family . METHODS : MTT assays were performed to determine the IC ( 50 ) s of GEO , FET , and HCT 116 human colorectal cancer cell lines treated with DB00530 . Plated cells were then exposed to either DB01093 control or 7 microm of DB00530 for treatment durations of 1 , 3 , 5 , 7 , 10 , 14 , 28 , and 56 days . Cell lysates were evaluated by Western blotting , evaluating both total and phosphorylated levels of P00533 , Her - 2 / neu , and erbB - 3 . RESULTS : IC ( 50 ) values for GEO , FET , and HCT 116 cell lines exposed to DB00530 were 12 . 0 , 16 . 0 , and greater than 100 microm , respectively . In all treated cell lines , DB00530 diminished P00533 activation but did not affect total expression compared with controls . In contrast , Her - 2 / neu activation was increased in all cell lines . These changes in P00533 and Her - 2 / neu were identified within 24 h but peaked later in the treatment cycle . ErbB - 3 expression and activation did not follow a consistent pattern between cell lines . CONCLUSIONS : Inhibition of P00533 led to increased activation of Her - 2 / neu . This result suggests a possible mechanism by which cells might escape the proapoptotic signals resulting from P00533 blockade . Our findings suggest concurrent inhibition of multiple members of the erbB family may yield stronger apoptotic responses than single receptor blockade alone .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK97___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Rationale and clinical validation of epidermal growth factor receptor as a target in the treatment of head and neck cancer . Recurrent / metastatic head and neck cancer is an area of high , unmet treatment need . There is a strong rationale for targeting the epidermal growth factor receptor ( P00533 ) in head and neck cancer as most of these tumors express high levels of P00533 relative to normal tissue , with high expression correlating with poor patient outcome . This rationale has been validated in extensive preclinical studies . Two small molecules with P00533 inhibitory activity , gefitinib ( ' DB00317 ' , ZD1839 ) and erlotinib ( ' Tarceva ' , DB00530 ) , and a humanized monoclonal antibody against the P00533 extracellular domain , cetuximab ( ' Erbitux ' , C225 ) , are in clinical trials for advanced head and neck cancer . The initial results of these trials are promising . Gefitinib and erlotinib show activity as monotherapy in patients with recurrent or metastatic head and neck cancer , and have an acceptable safety profile compared with conventional chemotherapy . Gefitinib , which can be given at doses below the maximum tolerated dose , is associated with slightly lower rates of adverse events than erlotinib , which is dosed at the maximum tolerated dose . Combinations of cetuximab with radiotherapy or platinum - based chemotherapy have also shown activity in phase I / II studies . Both gefitinib and cetuximab have entered phase III studies . The results of these trials , which will mature over the next few years , will help determine the optimal use of P00533 agents in head and neck cancers .",
"Phase II clinical trial data with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib ( DB00530 ) in non - small - cell lung cancer . Erlotinib ( DB00530 ; Tarceva ) is an orally available , highly specific epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitor . The results of 3 phase II studies with erlotinib in non - small - cell lung cancer ( NSCLC ) are reviewed herein : ( 1 ) in patients with chemotherapy - resistant , P00533 / P00533 - expressing NSCLC of all histologies , ( 2 ) in patients with bronchoalveolar carcinoma previously untreated or treated with chemotherapy , and ( 3 ) as first - line therapy in elderly patients with NSCLC of all histologies . These studies have evaluated tumor response , survival , and symptom improvement . Erlotinib was given as an oral , continuous daily dose of 150 mg . The drug was well tolerated ; drug - related cutaneous rash and diarrhea were observed in approximately two thirds of patients . Withdrawals caused by toxicity were rare . The response rates were 12 . 3 % , 25 % , and 13 . 3 % , respectively . Mature survival data are available for the first trial . The median survival was 8 . 4 months , and the 1 - year survival rate was 40 % . All responding patients in the first and second trials presented skin rash . In addition , survival correlated with the occurrence and severity of rash in the first trial . No data on the correlation between rash and survival are available for the second and third trials . Erlotinib is active and well tolerated in patients with NSCLC as first - and second - line therapy . Cutaneous rash appears to be a surrogate marker of clinical benefit , but this finding needs to be confirmed in ongoing and future studies .",
"Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 for erlotinib and gefitinib in non - small - cell lung cancer ; P01116 against the use of cetuximab and panitumumab in colorectal cancer ; P04626 ( P04626 / neu ) for trastuzumab in breast cancer ; P11274 - P00519 for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 / RARα for all - trans - retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia .",
"Potential role for epidermal growth factor receptor inhibitors in combined - modality therapy for non - small - cell lung cancer . There has been a surge of interest in the translation of discoveries in molecular biology into clinically relevant therapies in the field of hematology / oncology . The epidermal growth factor receptor ( P00533 ) has been a molecular target of significant interest and investigation , and preclinical and clinical studies support a role for targeted therapy in a variety of cancers , including non - small - cell lung cancer ( NSCLC ) via compounds that specifically inhibit P00533 . ZD1839 , IMC - C225 , and DB00530 are the most clinically developed of these compounds . Interestingly , preclinical studies have demonstrated that P00533 inhibitors may have radiation - sensitizing properties , as well as increased cytotoxic activity in combination with chemotherapeutic agents , suggesting a potential role for P00533 inhibitors as an adjunct to the current combined - modality approach for therapy of Stage III NSCLC . Therefore , clinical trials have been proposed and initiated to address the issue of determining the impact of the addition of P00533 inhibitors to the standard combined - modality regimen ( chemotherapy / radiation therapy +/- surgery ) for Stage III NSCLC . This article reviews preclinical and clinical data supporting the role for P00533 inhibitors alone or in combination with chemotherapy / radiation therapy for locally advanced NSCLC . Also , it will provide an overview of ongoing and proposed clinical studies investigating the potential role for P00533 inhibitors in Stage III NSCLC .",
"Identification of candidate small - molecule therapeutics to cancer by gene - signature perturbation in connectivity mapping . Connectivity mapping is a recently developed technique for discovering the underlying connections between different biological states based on gene - expression similarities . The sscMap method has been shown to provide enhanced sensitivity in mapping meaningful connections leading to testable biological hypotheses and in identifying drug candidates with particular pharmacological and / or toxicological properties . Challenges remain , however , as to how to prioritise the large number of discovered connections in an unbiased manner such that the success rate of any following - up investigation can be maximised . We introduce a new concept , gene - signature perturbation , which aims to test whether an identified connection is stable enough against systematic minor changes ( perturbation ) to the gene - signature . We applied the perturbation method to three independent datasets obtained from the GEO database : acute myeloid leukemia ( AML ) , cervical cancer , and breast cancer treated with letrozole . We demonstrate that the perturbation approach helps to identify meaningful biological connections which suggest the most relevant candidate drugs . In the case of AML , we found that the prevalent compounds were retinoic acids and Q07869 activators . For cervical cancer , our results suggested that potential drugs are likely to involve the P00533 pathway ; and with the breast cancer dataset , we identified candidates that are involved in prostaglandin inhibition . Thus the gene - signature perturbation approach added real values to the whole connectivity mapping process , allowing for increased specificity in the identification of possible therapeutic candidates .",
"Target - based agents against ErbB receptors and their ligands : a novel approach to cancer treatment . The ErbB receptors and their cognate ligands that belong to the epidermal growth factor ( P01133 ) family of peptides are involved in the pathogenesis of different types of carcinomas . In fact , the ErbB receptors and the P01133 - like growth factors are frequently expressed in human tumors . These proteins form a complex system that regulates the proliferation and the survival of cancer cells . Therefore , ErbB receptors and their ligands might represent suitable targets for novel therapeutic approaches in human carcinomas . In this regard , different target - based agents that are directed against the ErbB receptors have been developed in the past two decades . One of these compounds , the humanized anti - ErbB - 2 monoclonal antibody trastuzumab has been approved for the treatment of patients with metastatic breast cancer . The anti - P01133 receptor ( P00533 ) antibody C225 , as well as P00533 tyrosine kinase inhibitors ZD1839 and DB00530 are currently in phase III clinical development . Several other ErbB tyrosine kinase inhibitors are in phase I / II studies . These compounds have generally been shown to have an acceptable toxicity profile and promising anti - tumor activity in heavily pretreated patients . The mechanisms of action of these compounds , as well as the potential therapeutic strategies to improve their efficacy are discussed in this review with particular regard to the combinations of anti - ErbB agents with cytotoxic drugs , or combinations of different ErbB - targeting agents .",
"X - ray cross - complementing group 1 and thymidylate synthase polymorphisms might predict response to chemoradiotherapy in rectal cancer patients . PURPOSE : ___MASK35___ - based chemoradiotherapy before total mesorectal excision is currently the standard treatment of Stage II and III rectal cancer patients . We used known predictive pharmacogenetic biomarkers to identify the responders to preoperative chemoradiotherapy in our series . METHODS AND MATERIALS : A total of 93 Stage II - III rectal cancer patients were genotyped using peripheral blood samples . The genes analyzed were X - ray cross - complementing group 1 ( P18887 ) , P07992 , P42898 , P00533 , Q12882 , and P04818 . The patients were treated with 225 mg / m ( 2 )/ d continuous infusion of 5 - fluorouracil concomitantly with radiotherapy ( 50 . 4 Gy ) followed by total mesorectal excision . The outcomes were measured by tumor regression grade ( TRG ) as a major response ( TRG 1 and TRG 2 ) or as a poor response ( Q9Y512 , TRG4 , and TRG5 ) . RESULTS : The major histopathologic response rate was 47 . 3 % . P18887 G / G carriers had a greater probability of response than G / A carriers ( odds ratio , 4 . 18 ; 95 % confidence interval , 1 . 62 - 10 . 74 , p = . 003 ) Patients with polymorphisms associated with high expression of thymidylate synthase ( 2R / 3G , 3C / 3G , and 3G / 3G ) showed a greater pathologic response rate compared with carriers of low expression ( odds ratio , 2 . 65 ; 95 % confidence interval , 1 . 10 - 6 . 39 , p = . 02 ) No significant differences were seen in the response according to P00533 , P07992 , MTHFR_C677 and MTHFR_A1298 expression . CONCLUSIONS : P18887 G / G and thymidylate synthase ( 2R / 3G , 3C / 3G , and 3G / 3G ) are independent factors of a major response . Germline thymidylate synthase and P18887 polymorphisms might be useful as predictive markers of rectal tumor response to neoadjuvant chemoradiotherapy with 5 - fluorouracil .",
"P04626 up - regulates P26447 and several other prometastatic genes in medulloblastoma . Medulloblastoma is frequently disseminated throughout the central nervous system by the time of diagnosis . Conventional therapeutic approaches have not reduced the high mortality associated with metastatic medulloblastoma and little is known regarding the molecular mechanisms that promote tumor invasion . Previously , we reported that overexpression of P04626 in medulloblastoma is associated with poor prognosis and metastasis . Here , we demonstrate that P04626 overexpression increases the migration of medulloblastoma cells across basement membranes in vitro . Furthermore , using microarray expression profiling , we show that P04626 up - regulates the expression of prometastatic genes in medulloblastoma cells . These include P26447 , which was previously shown to promote metastasis of breast cancer . We demonstrate that P26447 is a direct target of P04626 signaling in medulloblastoma cells via a pathway involving phosphatidylinositol 3 - kinase , P31749 , and extracellular signal - regulated kinase 1 / 2 and that levels of P04626 and P26447 are tightly correlated in samples of primary medulloblastoma . Finally , we show that P04626 - dependent medulloblastoma cell invasion in vitro and prometastatic gene expression in vivo can be blocked using the P00533 tyrosine kinase inhibitor DB00530 . These data identify an P04626 driven prometastatic pathway that may provide a novel target for therapeutic intervention in metastatic medulloblastoma .",
"Targeting epidermal growth factor receptor in lung cancer . Among the most promising agents in clinical development to treat non - small - cell lung cancer ( NSCLC ) are the epidermal growth factor receptor ( P00533 ) targeting agents . A series of recent studies have demonstrated the activity of anti - P00533 targeted therapies for NSCLC . In advanced NSCLC that is refractory to chemotherapy , antitumor responses have been reported with P00533 tyrosine kinase inhibitors ( ZD1839 and DB00530 ) . The role of ZD1839 and DB00530 as possible additions to standard chemotherapy in the first - line setting has also been evaluated , and the studies conducted to date should respond to the question of whether these compounds could provide a survival benefit . Other areas of research involve looking at the role of P00533 tyrosine kinase inhibitors in the neoadjuvant treatment of stage III NSCLC and the planning of chemoprevention studies . These exciting results and plans are further complemented by an emerging number of compounds in clinical development , including both monoclonal antibodies ( ie , IMC - C225 ) and other tyrosine kinase inhibitors , directed at the P00533 .",
"The emerging role of epidermal growth factor receptor inhibitors in ovarian cancer . P00533 ( P00533 ) inhibitors are a new biologically targeted therapy , which may offer new hope in the treatment of patients with advanced or recurrent ovarian cancers . In this review , we summarize and discuss the results of research to date on P00533 inhibitors with particular emphasis on ovarian cancer . We reviewed data identified by searches of MEDLINE , PubMed , and abstracts from the proceedings of the American Society of Clinical Oncology meetings from 1998 to 2006 , with the search terms \" Ovarian Cancer , \" \" P00533 , \" \" gefitinib , ZD1839 , DB00317 , \" \" erlotinib , DB00530 , Tarceva , \" \" DB05424 , \" \" DB01259 , lapatinib , \" \" PKI - 166 , \" \" Q9Y259 569 , \" \" anti - P00533 antibodies , \" \" trastuzumab , Herceptin , \" \" cetuximab , Erbitux , IMC - C225 , \" \" matuzumab , P50402 72000 , \" \" panitumamab , DB01269 , \" \" pertuzumab , \" and \" vandetanib , rINN , DB05294 , DB05294 . \" Phase II trials of both small molecule inhibitors of P00533 - and antibody - based inhibitors are currently ongoing in ovarian cancer and emerging data suggest that their activity in unselected women with advanced or recurrent ovarian cancer is modest , when utilized as a single agent . It is possible that these agents will be highly effective in smaller subsets of patients whose tumors are dependent on P00533 signaling , perhaps through activating mutations in P00533 or its downstream pathway . Targeted therapy with P00533 inhibitors is an untapped potential resource in the treatment of advanced or recurrent ovarian cancer . Ongoing trials will elucidate the most effective strategies to use these agents individually or in combination with traditional chemotherapeutic agents .",
"Anti - epidermal growth factor receptor drugs in cancer therapy . The epidermal growth factor receptor is a cell membrane growth factor receptor that plays a key role in cancer development and progression . P00533 - activated signalling pathways control cell proliferation , apoptosis , angiogenesis and metastatic spread in the majority of human epithelial cancers . Targeting the epidermal growth factor receptor represents a valuable molecular approach to cancer therapy . Promising strategies in clinical development include monoclonal antibodies which block ligand binding and small molecule inhibitors of the tyrosine kinase enzymatic activity which prevent epidermal growth factor receptor autophosphorylation and propagation of downstream intracellular signals . Several anti - epidermal growth factor receptor agents are in clinical development for cancer therapy . Among these , IMC - 225 ( cetuximab ) , a chimeric human - mouse monoclonal IgG1 antibody , DB00530 ( Tarceva ) and ZD1839 ( DB00317 ) , two small molecule epidermal growth factor receptor - selective tyrosine kinase inhibitors , are currently in Phase II and III development as single agents or in combination with conventional therapies , such as radiotherapy or chemotherapy . Results from Phase I - II trials in advanced cancer demonstrate that these drugs have an acceptable tolerability and an interesting clinical activity in patients with a variety of tumour types .",
"Ventilation - induced increases in P00533 ligand mRNA are not altered by intra - amniotic LPS or ureaplasma in preterm lambs . Chorioamnionitis and mechanical ventilation are associated with bronchopulmonary dysplasia ( BPD ) in preterm infants . Mechanical ventilation at birth activates both inflammatory and acute phase responses . These responses can be partially modulated by previous exposure to intra - amniotic ( IA ) LPS or Ureaplasma parvum ( UP ) . P00533 ( P00533 ) ligands participate in lung development , and angiotensin converting enzyme ( P12821 ) 1 and Q9BYF1 contribute to lung inflammation . We asked whether brief mechanical ventilation at birth altered P00533 and P12821 pathways and if antenatal exposure to IA LPS or UP could modulate these effects . Ewes were exposed to IA injections of UP , LPS or saline multiple days prior to preterm delivery at 85 % gestation . Lambs were either immediately euthanized or mechanically ventilated for 2 to 3 hr . IA UP and LPS cause modest changes in the P00533 ligands amphiregulin ( P15514 ) , epiregulin ( O14944 ) , heparin binding epidermal growth factor ( HB - P01133 ) , and betacellulin ( P35070 ) mRNA expression . Mechanical ventilation greatly increased mRNA expression of P15514 , O14944 , and HB - P01133 , with no additional increases resulting from IA LPS or UP . With ventilation P15514 and O14944 mRNA localized to cells in terminal airspace . P00533 mRNA also increased with mechanical ventilation . IA UP and LPS decreased ACE1 mRNA and increased Q9BYF1 mRNA , resulting in a 4 fold change in the ACE1 / Q9BYF1 ratio . Mechanical ventilation with large tidal volumes increased both ACE1 and Q9BYF1 expression . The alterations seen in P12821 with IA exposures and P00533 pathways with mechanical ventilation may contribute to the development of BPD in preterm infants .",
"Biologically targeted treatment of non - small - cell lung cancer : focus on epidermal growth factor receptor . The epidermal growth factor receptor ( P00533 ) has emerged in recent years as a key target of molecular therapy for solid tumors . The postembryonic role of P00533 is normally limited . In cancer , however , abnormal P00533 - tyrosine kinase ( TK ) activity plays a central role in many of the processes involved in tumor progression , such as proliferation , angiogenesis , invasiveness , decreased apoptosis , and loss of differentiation . Several different approaches have been taken to inhibit P00533 - mediated activity in tumor cells , including monoclonal antibodies directed at the ligand - binding portion of the P00533 and small - molecule agents that directly inhibit the intracellular TK domain of P00533 . Two of these TK inhibitors , gefitinib and erlotinib ( DB00530 , Tarceva ) , have shown antitumor activity and good tolerability across several tumor types in early dose - finding clinical trials , particularly for non - small - cell lung cancer ( NSCLC ) . In heavily pretreated patients with advanced NSCLC , gefitinib showed clinically significant tumor responses and symptom relief with good tolerability . Based on these results , gefitinib has now been approved for the third - line treatment of advanced NSCLC . The use of gefitinib in standard treatment programs or combined with other molecular targeted agents may substantially improve the outlook for patients with NSCLC or other types of solid tumors",
"Gefitinib ( ' DB00317 ' , ZD1839 ) and new epidermal growth factor receptor inhibitors . The epidermal growth factor receptor ( P00533 ) is a promising target for cancer therapy and a number of P00533 - targeted agents have been developed . Those most advanced in development are the P00533 tyrosine kinase inhibitors gefitinib ( ' DB00317 ' , ZD1839 ) and erlotinib ( ' Tarceva ' , DB00530 ) , and the monoclonal antibody cetuximab ( ' Erbitux ' , IMC - C225 ) . This review provides a clinical overview of these agents , highlighting their antitumour activities in different tumour types . P00533 - targeted agents are generally well tolerated and are not typically associated with the severe adverse events often seen with cytotoxic chemotherapy . Gefitinib is the agent with the most extensive clinical experience , particularly in non - small - cell lung cancer ( NSCLC ) . Recently , gefitinib became the first - approved P00533 - targeted agent , for use in patients with previously treated advanced NSCLC in Japan , the USA and other countries . Further studies are required to explore the full potential of these novel agents either as monotherapy or combination therapy .",
"Beyond the TRIBUTE trial : integrating P00533 / P00533 tyrosine kinase inhibitors with chemotherapy in advanced NSCLC . Evaluation of : Herbst RS , Prager D , Hermann R et al . : TRIBUTE : a Phase III trial of erlotinib hydrochloride ( DB00530 ) combined with carboplatin and paclitaxel chemotherapy in advanced non - small cell lung cancer . J . Clin . Oncol . 23 , 5892 - 5899 ( 2005 ) . Patients diagnosed with advanced non - small cell lung cancer have limited therapeutic options . A large , randomized , controlled trial of the human epidermal growth factor receptor tyrosine - kinase inhibitor , erlotinib ( Tarceva ) , plus standard first - line chemotherapy did not meet its primary end point of improved survival in the overall population , but did reveal a striking survival benefit in a subset of patients who had never smoked . There are a number of possible explanations for the lack of overall benefit , including the use of an unselected patient population , the need for alternatives to concurrent administration , and a postulated pathophysiological interaction between erlotinib and chemotherapy . Ongoing studies investigating alternative schedules and sequences of administration with chemotherapy will help clinicians to determine how agents such as erlotinib can best be combined with standard cytotoxic agents .",
"Phase II study of carboplatin and erlotinib ( Tarceva , DB00530 ) in patients with recurrent glioblastoma . Targeting the epidermal growth factor receptor ( P00533 ) may be effective in a subset of glioblastoma patients . This phase II study assessed the clinical activity of erlotinib plus carboplatin and to determine molecular predictors of response . The primary endpoint was progression free survival ( PFS ) . Patients with recurrent glioblastoma with no more than two prior relapses received carboplatin intravenously on day 1 of every 28 - day cycle ( target AUC of 6 mg x ml / min ) . Daily erlotinib at 150 mg / day was dose escalated to 200 mg / day , as tolerated . Clinical and Q9BWK5 assessments were made every 4 and 8 weeks , respectively . Tumor tissue was evaluated for P00533 , AKT and phosphatase and tensin homolog ( P60484 ) status . One partial response ( PR ) was observed out of 43 assessable patients . Twenty patients ( 47 % ) had stable disease ( SD ) for an average of 12 weeks . Median PFS was 9 weeks . The 6 - month PFS rate was 14 % . Median overall survival ( OS ) was 30 weeks . This regimen was well tolerated with grade 3 / 4 toxicities of fatigue , leukopenia , thrombocytopenia and rash requiring dose reductions . A recursive partitioning analysis ( RPA ) predicted that patients with KPS > or = 90 treated with more than 1 prior regimen had the highest OS . No correlation was observed between P00533 , Akt or P60484 expression and either PFS or OS . Carboplatin plus erlotinib is well tolerated but has modest activity in unselected patients . Future trials should be stratified based on optimal molecular or clinical characteristics .",
"Rational design of an P01133 - Q14116 fusion protein : implication for developing tumor therapeutics . Q14116 ( Q14116 ) is a proinflammatory cytokine . This protein has a role in regulating immune responses and exhibits significant anti - tumor activities . Epidermal growth factor ( P01133 ) is an important growth factor that plays a central role in the regulation of cell cycle and differentiation . It was proposed that a targeted delivery of Q14116 by generation of Q14116 - P01133 fusion protein might decrease adverse effects and result in enhancing cytotoxic and antitumor activities . In the present study , a fusion protein , consisting of P00533 binding domain fused to human Q14116 mature peptide via a linker peptide of ( DB00145 ( 4 ) DB00133 ) 3 , was constructed and expressed in the insect cell line Sf9 using Bac - to - Bac baculovirus expression system . We showed that the purified recombinant fusion protein induced similar levels of P01579 to that of native Q14116 protein in human PBMC in the presence of ConA . Furthermore , P01133 receptor competitive test in human epithelial cancer A431 cell line showed that P01133 - Q14116 fusion protein can specifically bind with P00533 by competing with native P01133 protein . These suggest that this rationally designed protein can be further developed as novel tumor therapeutics .",
"Phase II study of erlotinib ( DB00530 ) in patients with metastatic colorectal cancer . Erlotinib ( Tarceva , DB00530 ) , a potent epidermal growth factor receptor tyrosine kinase inhibitor ( P00533 ) , was evaluated in a phase II study to assess its activity in patients with metastatic colorectal cancer . In all , 38 patients with metastatic colorectal cancer were treated with erlotinib at a continuous daily oral dose of 150 mg . Radiological evaluation was carried out every 8 weeks and tumour biopsies were performed before treatment and on day 8 . Of 31 evaluable patients , 19 ( 61 % ) had progressive disease and 12 ( 39 % ) had stable disease ( s . d . ) . The median time to progression for those patients having s . d . was 123 days ( range 108 - 329 days ) . The most common adverse events were rash in 34 patients and diarrhoea in 23 patients . Correlative studies were conducted to investigate the effect of erlotinib on downstream signalling . Tumour tissue correlations were based on usable tissue from eight match paired tumour samples pre - and on therapy , and showed a statistically significant decrease in the median intensity of both pEGFR ( P = 0 . 008 ) and phospho - extracellular signal - regulated kinase ( P29323 ) ( P = 0 . 008 ) a week after commencement of treatment . No other statistically significant change in tumour markers was observed . Erlotinib was well tolerated with the most common toxicities being rash and diarrhoea . More than one - third of evaluable patients had s . d . for a minimum of 8 weeks . Correlative studies showed a reduction in phosphorylated P00533 and P29323 in tumour tissue post - treatment .",
"Why the epidermal growth factor receptor ? The rationale for cancer therapy . There is a need for new , selective anticancer agents that differentiate between malignant and nonmalignant cells . The benefits of such agents would include a higher therapeutic index and lower toxicity than conventional therapies . Although expressed in nonmalignant cells , the epidermal growth factor receptor ( P00533 ) is highly expressed in a variety of tumors , and its expression correlates with poor response to treatment , disease progression , and poor survival . Evidence for a role for the P00533 in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor . Activation of the P00533 signaling pathway in cancer cells has been linked with increased cell proliferation , angiogenesis , and metastasis , and decreased apoptosis . Preclinical data show that anti - P00533 therapies can inhibit these effects in vitro and in vivo . In addition , preclinical data confirm that many such agents have the potential to increase the effectiveness of current cytotoxic agents . Following accelerated drug development programs , phase III trials are now under way for a number of P00533 - targeted therapies , including the monoclonal antibody IMC - C225 and the P00533 - tyrosine kinase inhibitors ZD1839 ( DB00317 ) and DB00530 . Thus , the rationale for P00533 - targeted approaches to cancer treatment is apparent and now well established , and there is increasing evidence that they may represent a significant contribution to cancer therapy .",
"Erlotinib ( DB00530 ) - induced inhibition of transitional cell carcinoma of bladder cell line growth is enhanced by interferon - alpha . OBJECTIVE : To examine whether erlotinib gives similar results to gefitinib , a small molecule epidermal growth factor receptor ( P00533 / P00533 ) tyrosine kinase ( TK ) inhibitor that inhibits the growth of human bladder cancer cell lines in vitro , and given that interferon - alpha ( IFNalpha ) promotes an antiproliferative effect of P00533 / P00533 inhibitors on colon cancer cell lines , to also determine the effects of erlotinib alone or together with INFalpha on bladder cancer cell lines , and whether sensitivity is influenced by P00533 / P00533 mutation status . MATERIALS AND METHODS : Seven bladder cancer cell lines were characterized for P00533 / P00533 expression , then treated with erlotinib alone , IFNalpha alone , or IFNalpha plus erlotinib . Cell growth inhibition was assessed by crystal - violet staining and P00533 / P00533 expression by flow cytometry . Synergy was evaluated using the combination index of Chou and Talalay . DNA from these cell lines in the linear growth phase and from 14 bladder cancer tissue samples were tested for P00533 / EGFRTK mutations . RESULTS : Cell - surface P00533 / P00533 expression was present in all seven bladder cancer cell lines . Both erlotinib and IFNalpha independently were significantly antiproliferative , and combined treatment synergistically enhanced the sensitivity in six of the seven cell lines . No bladder cancer cell lines or tissues tested expressed P00533 / EGFRTK mutations . CONCLUSION : Erlotinib inhibits the growth of human bladder cancer cell lines . Enhanced inhibition in the presence of IFNalpha is not determined by the presence of P00533 / EGFRTK mutations . This study might have clinical implications for improving the treatment of bladder cancer .",
"Efficacy and safety of erlotinib HCl , an epidermal growth factor receptor ( P00533 / P00533 ) tyrosine kinase inhibitor , in patients with advanced ovarian carcinoma : results from a phase II multicenter study . The aim of this single - arm , phase II study was to estimate the tumor response rate and safety profile of erlotinib HCl ( erlotinib , Tarceva , DB00530 ) monotherapy in patients with refractory , recurrent , P00533 / P00533 - positive epithelial ovarian tumors , who had failed prior taxane and / or platinum - based chemotherapy . Thirty - four patients received 150 mg erlotinib orally once daily for up to 48 weeks or until disease progression or dose - limiting toxicity . Two patients had partial responses , lasting 8 + and 17 weeks , giving an objective response rate of 6 % ( 95 % confidence interval [ CI ] , 0 . 7 - 19 . 7 % ) . Fifteen patients ( 44 % ) had stable disease , and 17 patients ( 50 % ) had progressive disease . Median overall survival was 8 months ( 95 % CI , 5 . 7 - 12 . 7 months ) , with a 1 - year survival rate of 35 . 3 % ( 95 % CI , 19 . 8 - 53 . 5 % ) . Patients with rash survived significantly longer than those without ( P = 0 . 009 ) , correlating with rash grade . Erlotinib was generally well tolerated . The most frequent erlotinib - related adverse events were rash ( 68 % ) and diarrhea ( 38 % ) . Erlotinib had marginal activity but was generally well tolerated . The safety profile appears more favorable than typically experienced with standard chemotherapeutic agents , which is encouraging in these heavily pretreated patients . Combination of erlotinib with chemotherapy or other targeted agents should be considered .",
"Enhanced sensitivity to the P00533 / epidermal growth factor receptor tyrosine kinase inhibitor erlotinib hydrochloride in chemotherapy - resistant tumor cell lines . PURPOSE : Erlotinib ( Tarceva , DB00530 ) is a potent and specific inhibitor of the P00533 / epidermal growth factor receptor ( P00533 ) tyrosine kinase . In phase II clinical studies , oral erlotinib monotherapy has shown antitumor activity in patients with advanced non - small cell lung cancer , head and neck cancer , and ovarian cancer after the failure of standard chemotherapy . We hypothesized that some tumors treated with multiple cytotoxic therapies may become more dependent on the P00533 / P00533 signaling pathways for survival . EXPERIMENTAL DESIGN : The growth - inhibitory effect of erlotinib was tested on 10 pairs of chemosensitive , parental , and chemoresistant tumor cell lines . RESULTS : Enhanced sensitivity to erlotinib was observed in the doxorubicin - resistant human breast cancer cell line MCF - 7 , paclitaxel - resistant human ovarian carcinoma cell line A2780 , and cisplatin - resistant human cervical carcinoma cell line ME180 . The IC ( 50 ) values of erlotinib in the resistant cell lines were 2 - to 20 - fold lower than those in the corresponding parental cell lines . This enhanced sensitivity to erlotinib correlated with higher P00533 / P00533 and phospho - P00533 / P00533 expression when compared with the corresponding parental cell lines . Acquired resistance to cytotoxic agents was not associated with cross - resistance to erlotinib . AE - ME180 / DB00515 - resistant xenografts showed greater sensitivity to erlotinib than parental ME180 xenografts did . CONCLUSIONS : Our findings suggest that acquired resistance to cytotoxic therapy in some tumors is associated with enhanced sensitivity to P00533 / P00533 inhibitors , which correlates with increased P00533 / P00533 expression . These data may explain some of the observed clinical activity of P00533 / P00533 inhibitors in patients previously treated with multiple therapies . P00533 / P00533 tyrosine kinase inhibitors may be more effective as second - or third - line treatment for certain patients with tumors that were previously treated with multiple chemotherapy regimens .",
"Development of the epidermal growth factor receptor inhibitor Tarceva ( DB00530 ) . The epidermal growth factor receptor ( P00533 ) is a transmembrane receptor involved in the regulation of a complex array of essential biological processes such as cell proliferation and survival . Dysregulation of P00533 signaling network has been frequently reported in multiple human cancers and has been associated with the processes of tumor development , growth , proliferation , metastasis and angiogenesis . Inhibition of the P00533 was associated with antitumor effects in preclinical models . On the bases of these data , therapeutics targeting the P00533 were explore in clinical trials . Tarceva ( DB00530 , OSI Pharmaceuticals , Uniondale , NY ) is a small molecule selective inhibitor of the P00533 tyrosine kinase ( TK ) . In preclinical studies , Tarceva inhibited the phosphorylation of the P00533 in a dose and concentration dependent manner resulting in cell cycle arrest and induction of apoptosis . In in vivo studies , the agent caused tumor growth inhibition and shoved synergistic effects when combined with conventional chemotherapy . Subsequent single agent phase I studies and phase I studies in combination with chemotherapy demonstrated that the agent has a good safety profile and induced tumor growth inhibition in a substantial number of patients with a variety of different solid tumor . Preliminary report from phase II studies confirmed the excellent tolerability of Tarceva as well as showed encouraging preliminary activity . Phase III studies have either been completed or are ongoing in several tumor types such as lung cancer and pancreatic cancer . In summary , Tarceva is a novel inhibitor of the P00533 TK which has shown promising activity in initial studies and is currently undergoing full development as an anticancer drug .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK99___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"Inhibition of proliferation , migration , and matrix metalloprotease production in malignant mesothelioma cells by tyrosine kinase inhibitors . The epidermal growth factor receptor ( P00533 ) is expressed in a variety of human solid tumors , including malignant mesothelioma . P00533 has been implicated in regulation of cell proliferation , survival , angiogenesis , and metastasis , making it an ideal target for drug development . ZD1839 ( gefitinib ) and DB00530 ( erlotinib ) are new , low - molecular - weight , P00533 - selective tyrosine kinase ( TK ) inhibitors , whereas DB05424 is a pan - P00533 family TK inhibitor . In the present study , we used ZD1839 , DB00530 , and DB05424 and investigated the effect of these drugs on proliferation , migration , and matrix metalloprotease ( MMP ) production in three malignant mesothelioma cell lines ( M14K , ZL34 , and SPC212 ) . Using [ 3H ] thymidine incorporation , DNA synthesis assay , we found that all three drugs inhibited transforming growth factor - alpha ( TGF - alpha ) - induced cellular proliferation in a dose - dependent manner . In addition , all three drugs induced apoptosis in ZL34 cells as determined by flow cytometry using annexin - V staining . Furthermore , all three drugs inhibited TGF - alpha - induced cell migration ( chemotaxis ) in a dose - dependent manner as determined by Boyden chamber assay . TGF - alpha - induced P14780 production was also inhibited in a dose - dependent manner as determined by gelatin zymography in three cell lines tested . In conclusion , our study demonstrates inhibitory effectiveness of P00533 - TK inhibitors in malignant mesothelioma cells and suggests that these drugs may be an effective treatment strategy for malignant mesothelioma ."
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___MASK71___
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MH_train_438
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interacts_with DB09052?
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"T cells stimulated by P29965 positive leukemic blasts - pulsed dendritic cells meet optimal functional requirements for adoptive T - cell therapy . Adoptive T - cell immunotherapy may provide complementary therapy for childhood B - cell precursor acute lymphoblastic leukemia ( P03999 - ALL ) . In this study , we have analyzed the functional characteristics of anti - P03999 - ALL effector T cells generated by co - culturing T lymphocytes and dendritic cells ( DC ) from allogeneic human stem cell transplantation ( HSCT ) donors . After 21 - day co - culture with DC pulsed with P29965 + apoptotic P03999 - ALL blasts , T cells presented with both effector and central memory phenotype , and showed high and specific cytotoxic activity against leukemic cells ( average lysis = 77 % ) , mostly mediated by CD8 + T cells . Noticeably , growth of P01730 T cells was maintained ( 45 % of total cells ) , which actively produced Th1 cytokines ( P01579 , P01375 , P60568 ) , but not P05112 , P05113 and P22301 . Anti - P03999 - ALL T cells expressed CD49d and P61073 ( implicated in the recruitment to bone marrow ) , and CD62L and P32248 ( involved in the migration to lymphoid organs ) . In accordance with this profile , T cells significantly migrated in response to the chemokines P48061 and Q99731 . In conclusion , stimulation of T cells with P29965 + P03999 - ALL cells - loaded DC not only elicited the generation of potent and specific anti - leukemic cytotoxic effectors , but also the differentiation of specific and functional Th - 1 P01730 lymphocytes . These effectors are fully equipped to reach leukemia - infiltrated tissues and have characteristics to support and orchestrate the anti - tumor immune - response .",
"Translocation ( 3 ; 5 ) ( Q9Y3Q3 ; q13 ) in a patient with chronic T - cell lymphoproliferative disorder . A 67 - year - old patient with large granular lymphocyte ( LGL ) leukemia is described . At fluorescence - activated cell sorting ( FACS ) analysis of the peripheral blood , the lymphocytes were positive for CD3 , P01730 , P06127 , CD29 , CD45RA , CD57 , and TCR alpha / beta and negative for P09564 , CD8 , CD16 , CD56 , P15391 , P20273 , and TCR gamma / delta . Bone marrow histology and immunohistochemistry did not reveal any lymphocyte infiltration . Cytogenetic examination of peripheral blood cultures showed a clone with the karyotype 46 , XY , t ( 3 ; 5 )( Q9Y3Q3 ; q13 ) . Molecular analysis revealed rearrangement of the gamma - T - cell - receptor chain . The region 3p25 - 3p26 which harbors the von Hippel - Lindau tumor suppressor gene and the P04049 oncogene has been rearranged in a few cases of T - cell leukemia . The translocation in this case has not yet been described and may reflect an alternative mechanism in the pathogenesis of these disorders .",
"Abnormalities of the der ( 12 ) t ( 12 ; 21 ) in P41212 - Q01196 acute lymphoblastic leukemia . P41212 - Q01196 fusion [ t ( 12 ; 21 )( p13 ; q22 ) ] occurs in 25 % of childhood B - cell precursor acute lymphoblastic leukemia ( P03999 - ALL ) and is associated with a favorable outcome . Additional abnormalities involving der ( 21 ) t ( 12 ; 21 ) and nonrearranged chromosome 12 are well characterized but aberrations involving the der ( 12 ) t ( 12 ; 21 ) have rarely been described . Herein , we describe two novel abnormalities affecting the der ( 12 ) t ( 12 ; 21 ) : a deletion ( 20 / 247 , 8 % ) and duplication ( 10 / 247 , 4 % ) . All 30 patients were under 10 years of age , had a median white blood count of 12 . 4 × 10 ( 9 )/ L and 19 . 2 × 10 ( 9 )/ L , respectively , with a good outcome . Deletions of der ( 12 ) t ( 12 ; 21 ) on both sides of the breakpoint were confirmed and mapped : centromeric ( 12p11 . 21 - 12p13 . 2 ) and telomeric ( 21q22 . 12 - 21q22 . 3 ) . The size of these deletions extended from 0 . 4 - 13 . 4 to 0 . 8 - 2 . 5 Mb , respectively . The centromeric deletion encompassed the following genes : O75581 , Q9BZR8 , Q9BY84 , O60519 , and P46527 . We postulate that this deletion occurs at the same time as the translocation because it was present in all P41212 - Q01196 - positive cells . A second abnormality representing duplication of the reciprocal Q01196 - P41212 fusion gene was a secondary event , which we hypothesize arose through mitotic recombination errors . This led to the formation of the following chromosome : der ( 12 )( 21qter → 21q22 . 12 :: 12p13 . 2 - 12p12 . 3 :: 12p12 . 3 → 12qter ) . Both abnormalities affect the reciprocal Q01196 - P41212 fusion product which could either eliminate or amplify its expression and thus contribute to leukemogenesis . However , other consequences such as haploinsufficiency of tumor suppressor genes and amplification of oncogenes could also be driving forces behind these aberrations . In conclusion , this study has defined novel abnormalities in P41212 - Q01196 P03999 - ALL , which implicate new genes involved in leukemogenesis .",
"[ Role of anti - P11836 monoclonal antibody in association with immunomodulatory agents ] . Chimeric monoclonal anti - P11836 antibody ( DB00073 ) has been associated with immunomodulatory agents such as interferon alpha , interleukin - 2 , interleukin - 12 , DB00099 , GM - P04141 and anti - P20273 humanized monoclonal antibody ( DB04958 ) . Synergy with interferon is clearly demonstrated increasing complete response rate and response duration . Other associations are promising but must be tested in randomized prospective trials versus rituximab alone , probably in indolent lymphomas where chemotherapy could be avoided .",
"P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p - Src ) , P04049 , and P29323 . The levels of p - Src and p - Src - progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , ___MASK47___ . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up - regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant - negative P28482 prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor - κB ( NF - κB ) nuclear translocation and NF - κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4 - induced up - regulation of the p53 promoter activity was prevented by preadministration with dominant - negative P28482 or NF - κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 / P28482 / NF - κB signaling pathway contributes to the P4 - induced up - regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .",
"P04035 inhibitors deplete circulating classical and non - classical monocytes following human heart transplantation . BACKGROUND : Monocytes mediate immune responses following solid organ transplantation via cytokine secretion and differentiation to macrophage / dendritic cell lineages . To date , the pleiotropic immunomodulatory effect of statins on human monocytes following human heart transplantation has yet to be elucidated . This study was designed to assess the effects of statin administration on the monocyte repertoire . METHODS : 108 patients were recruited into the study . Clinical data were collected from patients ' notes . Peripheral blood immunophenotype was determined via flow cytometry ( using CD11c , P08571 , CD16 , CD49d , CD64 , P33681 and CD195 ) . RESULTS : There were fewer circulating classical ( p = 0 . 0001 ) and non - classical ( p = 0 . 0013 ) monocytes in patients treated with a statin . CD64 expression was down - regulated ( p = 0 . 011 and p = 0 . 049 ) whereas CD49d expression was up - regulated ( p = 0 . 004 and p = 0 . 022 ) on classical and non - classical monocytes in this group . Patients receiving DB01076 had fewer circulating classical monocytes ( p = 0 . 001 ) compared to patients administered ___MASK18___ . Patients receiving ___MASK18___ had fewer circulating non - classical monocytes ( p = 0 . 029 ) compared to patients administered DB01076 . DISCUSSION : Statin administration alters the circulating monocyte repertoire following heart transplantation , including population size , FcgammaRI and VLA - 4 adhesion molecule expression . Furthermore , different statin treatments are associated with a selective depletion of macrophage or DC ( re ) generating monocytes .",
"P26718 receptor regulates human effector T - cell cytokine production . Although innate immune signals shape the activation of naive T cells , it is unclear how innate signals influence effector T - cell function . This study determined the effects of stimulating the P26718 receptor in conjunction with the TCR on human effector CD8 (+) T cells . Stimulation of CD8 (+) T cells through CD3 and P26718 simultaneously or through a chimeric P26718 receptor , which consists of P26718 fused to the intracellular region of CD3ζ , activated β - catenin and increased expression of β - catenin - induced genes , whereas T cells stimulated through the TCR or a combination of the TCR and P10747 did not . Activation by TCR and P26718 prevented expression and production of anti - inflammatory cytokines P22301 , P15248 , P35225 , and P15692 - α in a β - catenin - and Q07869 γ - dependent manner . P26718 stimulation also modulated the cytokine secretion of T cells activated simultaneously through CD3 and P10747 . These data indicate that activating CD8 (+) T cells through the P26718 receptor along with the TCR modulates signal transduction and the production of anti - inflammatory cytokines . Thus , human effector T cells alter their function depending on which innate receptors are engaged in conjunction with the TCR complex .",
"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK99___ ( ___MASK99___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK99___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK99___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .",
"DB09052 induces autologous T - cell killing of chronic lymphocytic leukemia cells . Chronic lymphocytic leukemia is an incurable B - cell malignancy that is associated with tumor cell - mediated T - cell dysfunction . It therefore represents a challenging disease for T - cell immunotherapeutics . The P15391 / CD3 bi - specific antibody construct blinatumomab ( AMG103 or MT103 ) has been tested clinically in non - Hodgkin ' s lymphoma and acute lymphoblastic leukemia but has not been assessed in chronic lymphocytic leukemia . We investigated whether blinatumomab could overcome T - cell dysfunction in chronic lymphocytic leukemia in vitro . DB09052 was tested on peripheral blood mononuclear cells from 28 patients ( treatment naïve and previously treated ) . T - cell activation and function , as well as cytotoxicity against leukemic tumor cells were measured . DB09052 induced T - cell activation , proliferation , cytokine secretion and granzyme B release in a manner similar to that occurring with stimulation with anti - CD3 / anti - P10747 beads . However , only blinatumomab was able to induce tumor cell death and this was found to require blinatumomab - mediated conjugate formation between T cells and tumor cells . Cytotoxicity of tumor cells was observed at very low T - cell : tumor cell ratios . A three - dimensional model based on confocal microscopy suggested that up to 11 tumor cells could cluster round each T cell . Importantly , blinatumomab induced cytotoxicity against tumor cells in samples from both treatment - naïve and treated patients , and in the presence of co - culture pro - survival signals . The potent cytotoxic action of blinatumomab on tumor cells appears to involve conjugation of T cells with tumor cells at both the activation and effector stages . The efficacy of blinatumomab in vitro suggests that the bi - specific antibody approach may be a powerful immunotherapeutic strategy in chronic lymphocytic leukemia .",
"Levels of NT - proBNP , markers of low - grade inflammation , and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease . P00797 - angiotensin - aldosterone system ( RAAS ) blockade may reduce levels of biomarkers of chronic low - grade inflammation and endothelial dysfunction . We investigated the effect of spironolactone added to standard RAAS blockade on these biomarkers in an analysis of four original studies . MATERIALS AND METHODS : The studies were double - blind , randomised , placebo - controlled studies in 46 type 1 and 23 type 2 diabetic patients with micro - or macroalbuminuria treated with angiotensin - converting enzyme inhibitor ( P12821 inhibitor ) or angiotensin receptor blocker ( ARB ) , and randomised to additional treatment with spironolactone 25 mg and placebo daily for 60 days . OUTCOME MEASURES : Changes in inflammatory ( hsCRP , s - ICAM , P01375 α , P05231 , P10145 , Serum amyloid A , IL1β ) , endothelial dysfunction ( sE - selectin , s - P05362 , s - P19320 , P04275 , p - selectin , s - thrombomodulin ) and NT - proBNP after each treatment period . RESULTS : During spironolactone treatment , u - albumin excretion rate was reduced from 605 ( 411 - 890 ) to 433 ( 295 - 636 ) mg / 24 h , as previously reported . Markers of inflammation and endothelial dysfunction did not change ; only changes in NT - proBNP ( reduced by 14 % , p = 0 . 05 ) and serum amyloid A ( reduced by 62 % , p = 0 . 10 ) were borderline significant . DISCUSSIONS : Our results indicate that the renoprotective effect of spironolactone when added to RAAS blockade is not mediated through anti - inflammatory pathways since markers of inflammation and endothelial dysfunction are not affected during treatment .",
"Involvement of peripheral cannabinoid and opioid receptors in β - caryophyllene - induced antinociception . BACKGROUND : β - caryophyllene ( P03999 ) is a common constitute of the essential oils of numerous spice , food plants and major component in Cannabis . The present study investigated the contribution of peripheral cannabinoid ( CB ) and opioid systems in the antinociception produced by intraplantar ( i . pl . ) injection of P03999 . The interaction between peripheral P03999 and morphine was also examined . METHODS : The antinociceptive effect of i . pl . P03999 was assayed by the capsaicin tests in mice . Antagonists for CB and opioid receptors , and antisera against β - endorphin were injected peripherally prior to i . pl . injection of P03999 . Morphine in combination with P03999 was injected subcutaneously or intrathecally . RESULTS : The i . pl . injection of P03999 dose - dependently attenuated capsaicin - induced nociceptive response . The antinociceptive effect produced by P03999 was prevented by pretreatment with AM630 , a selective CB2 receptor antagonist , but not by AM251 , a selective P21554 receptor antagonist . Pretreatment with naloxone , an opioid receptor antagonist , and β - funaltrexamine , a selective μ - opioid receptor antagonist , reversed the antinociceptive effect of P03999 . Pretreatment with naloxone methiodide , a peripherally acting antagonist for opioid receptors and antisera against β - endorphin , resulted in a significant antagonizing effect on P03999 - induced antinociception . Morphine - induced antinociception was increased by a low dose of P03999 . The increased effect of morphine in combination with P03999 was antagonized significantly by pretreatment with naloxone . CONCLUSIONS : The present results demonstrate that antinociception produced by i . pl . P03999 is mediated by activation of CB2 receptors , which stimulates the local release from keratinocytes of the endogenous opioid β - endorphin . The combined injection of morphine and P03999 may be an alternative in treating chemogenic pain .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Chemoimmunotherapy in acute lymphoblastic leukemia . ALL blast cells express a variety of specific antigens e . g . P15391 , P11836 , P20273 , P20138 , and P31358 , which serve as targets for Monoclonal Antibodies ( MoAbs ) . So far , the most experience is available for anti - P11836 ( rituximab ) , which has been combined with chemotherapy for treatment of mature B - ALL / Burkitt ' s lymphoma . Studies with rituximab have also been completed in B - precursor ALL . Another antigen , P15391 , is of great interest due to a very high rate of expression in ALL . It can be targeted by a bispecific monoclonal antibody , DB09052 , directed against P15391 and CD3 . Smaller studies or case reports are also available for the anti P31358 antibody ( DB00087 ) , for anti P20273 ( DB04958 ) or anti P20138 ( Gemtuzumab ) . Available data demonstrate that MoAb therapy in ALL is a highly promising targeted treatment . However , several details for an optimal treatment approach e . g . the required level of antigen expression , timing , schedule , dosage and stage of disease still need to be defined .",
"[ Molecular target drugs for malignant lymphoma ] . According to revised WHO classification for lymphoid malignancies , biological differences among pathological subtypes of lymphomas could be key points for molecular target therapies . For B cell lymphomas , P11836 , P20273 , P15391 can be molecules for target therapies , whereas there are not so many molecular targets in T cell lymphomas yet . However , novel molecular target drugs are developing from home and abroad . Especially , inhibitors for P42345 , IKK / JAK , HDAC , proteasome , HSP90 , and proapoptotic molecules are developing in clinical trials for B cell - and T cell - lymphomas , and their anti - lymphoma activities will be considerably promising . Moreover , immunomodulatory drugs such as lenalidomide are also tried to investigate the effect on lymphomas . Here , some novel molecular drugs currently under development will be reviewed about their anti - lymphoma effects .",
"DB00207 suppresses P01730 (+) T - cell activation by direct modulation of P42345 activity . Advanced macrolides , such as azithromycin ( AZM ) or clarithromycin ( Q5W186 ) , are antibiotics with immunomodulatory properties . Here we have sought to evaluate their in vitro influence on the activation of P01730 (+) T - cells . Isolated P01730 (+) T - cells were stimulated with agonistic anti - CD3 / anti - P10747 monoclonal antibodies in the presence of 0 . 6 mg / L , 2 . 5 mg / L , 10 mg / L or 40 mg / L AZM or Q5W186 . Cell proliferation , cytokine level in supernatants and cell viability was assessed . Intracellular signaling pathways were evaluated using reporter cell lines , FACS analysis , immunoblotting and in vitro kinase assays . AZM inhibited cell proliferation rate and cytokine secretion of P01730 (+) T - cells in a dose - dependent manner . Similarly , high concentrations of Q5W186 ( 40 mg / L ) also suppressed these T - cell functions . Analysis of molecular signaling pathways revealed that exposure to AZM reduced the phosphorylation of the S6 ribosomal protein , a downstream target of P42345 . This effect was also observed at 40 mg / L Q5W186 . In vitro kinase studies using recombinant P42345 showed that AZM inhibited P42345 activity . In contrast to rapamycin , this inhibition was independent of P62942 . We show for the first time that AZM and to a lesser extent Q5W186 act as immunosuppressive agents on P01730 (+) T - cells by inhibiting P42345 activity . Our results might have implications for the clinical use of macrolides .",
"Monoclonal antibodies in acute lymphoblastic leukemia . With modern intensive combination polychemotherapy , the complete response ( CR ) rate in adults with acute lymphoblastic leukemia ( ALL ) is 80 % to 90 % , and the cure rate is 40 % to 50 % . Hence , there is a need to develop effective salvage therapies and combine novel agents with standard effective chemotherapy . ALL leukemic cells express several surface antigens amenable to target therapies , including P11836 , P20273 , and P15391 . Monoclonal antibodies target these leukemic surface antigens selectively and minimize off - target toxicity . When added to frontline chemotherapy , rituximab , an antibody directed against P11836 , increases cure rates of adults with Burkitt leukemia from 40 % to 80 % and those with pre - B ALL from 35 % to 50 % . Inotuzumab ozogamicin , a P20273 monoclonal antibody bound to calicheamicin , has resulted in marrow CR rates of 55 % and a median survival of 6 to 7 months when given to patients with refractory - relapsed ALL . DB09052 , a biallelic T cell engaging the CD3 - P15391 monoclonal antibody , also resulted in overall response rates of 40 % to 50 % and a median survival of 6 . 5 months in a similar refractory - relapsed population . Other promising monoclonal antibodies targeting P11836 ( ofatumumab and obinutuzumab ) or P15391 or P11836 and bound to different cytotoxins or immunotoxins are under development . Combined modalities of chemotherapy and the novel monoclonal antibodies are under investigation .",
"Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK99___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .",
"The P04035 inhibitor pravastatin stimulates insulin secretion through organic anion transporter polypeptides . The 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor pravastatin has been reported to have a beneficial effect on reducing the new onset of diabetes as well as lowering plasma lipids . Because pravastatin is a water - soluble organic anion , it can not easily penetrate the lipid bilayer of the cell membrane . As the precise mechanisms of the effect of pravastatin on glucose metabolism and diabetes have not been clarified , we examined the roles of the organic anion transporter family on pravastatin - treated islet and adipocyte functions . Rat oatp1 / slco1a1 , oatp2 / slco1a4 and oatp3 / slco1a5 were expressed in the pancreas , and rat oatp3 / slco1a5 was also detected in rat insulinoma cell line P01308 - 1e . ___MASK18___ was transported not only by oatp1 / slco1a1 and oatp2 / slco1a4 , but also by rat oatp3 / slco1a5 . ___MASK18___ uptake into P01308 - 1e cells was detected and this transport was inhibited by sulfobromophthalein and rifampicin , both of which are known to inhibit oatp family - mediated uptake . In addition , pravastatin enhanced the glucose - stimulated insulin secretion from P01308 - 1e cells . When fat - loaded db / db mice were treated with pravastatin , glucose intolerance and insulin resistance were prevented . In addition , insulin secretion from isolated islets was enhanced by pravastatin . These data suggest that pravastatin has pleiotropic effects on islets through membrane transport under high fat / glucose conditions .",
"The biological features and prognosis of breast cancer diagnosed during pregnancy : a case - control study . BACKGROUND : Breast cancer during pregnancy ( P03999 ) is relatively rare and is associated with controversies about its biology and prognosis . Hence , we designed a case - control study to examine tumor features and outcome in a series of P03999 patients diagnosed and treated in a single institution . MATERIAL AND METHODS : We identified 65 patients diagnosed with P03999 and for each ; we selected two non - pregnant breast cancer patients , who were matched for age , year of surgery , stage , and neoadjuvant chemotherapy . We then compared the differences in pathology , immunohistochemical features ( ER , PR , P04626 and ki - 67 ) , disease - free ( DFS ) and overall survival ( OS ) . RESULTS : We did not find any significant differences in tumor characteristics between the two groups . However , at a median follow - up of four years , P03999 patients had an inferior DFS ( HR 2 . 3 ; 95 % CI 1 . 3 - 4 . 2 ) , after adjustment for possible confounding covariates . No difference in OS was observed . However , upon restricting the analysis to patients who did not receive neoadjuvant chemotherapy , patients with P03999 had inferior OS as well ( HR 2 . 6 ; 95 % CI 1 . 0 - 6 . 5 ) . No association between induction of abortion and prognosis was observed . CONCLUSIONS : While we did not observe any differences in tumor features , P03999 patients have poorer prognosis compared to age and stage - matched control . Further studies should try to elucidate reasons for such poor outcome .",
"Irritable bowel syndrome : methods , mechanisms , and pathophysiology . Genetic epidemiology and pharmacogenetics in irritable bowel syndrome . The objectives of this review are twofold . Our first objective is to evaluate the evidence supporting a role for genetics in irritable bowel syndrome ( IBS ) . Specific examples of the associations of genetic variation and symptoms , syndromes , and intermediate phenotypes , including neurotransmitter ( serotonergic , α ( 2 )- adrenergic , and cannabinoid ) mechanisms , inflammatory pathways ( P22301 , TNFα , GNβ3 , and susceptibility loci involved in Crohn ' s disease ) , and bile acid metabolism , are explored . The second objective is to review pharmacogenetics in IBS , with the focus on cytochrome P - 450 metabolism of drugs used in IBS , modulation of motor and sensory responses to serotonergic agents based on the 5 - hydroxytryptamine ( 5 - HT ) transporter - linked polymorphic region ( 5 - HTTLPR ) and 5 - HT ( 3 ) genetic variants , responses to a nonselective cannabinoid agonist ( dronabinol ) based on cannabinoid receptor ( P21554 ) and fatty acid amide hydrolase ( FAAH ) variation , and responses to a bile acid ( sodium chenodeoxycholate ) and bile acid binding ( colesevelam ) based on klothoβ ( Q86Z14 ) and fibroblast growth factor receptor 4 ( P22455 ) variation . Overall , there is limited evidence of a genetic association with IBS ; the most frequently studied association is with 5 - HTTLPR , and the most replicated association is with P01375 superfamily member 15 . Most of the pharmacogenetic associations are reported with intermediate phenotypes in relatively small trials , and confirmation in large clinical trials using validated clinical end points is still required . No published genome - wide association studies in functional gastrointestinal or motility disorders have been published .",
"The role of aquaporin - 1 ( P29972 ) expression in a murine model of lipopolysaccharide - induced acute lung injury . A murine model of lipopolysaccharide ( LPS ) - induced acute lung injury ( ALI ) was used to evaluate whether aquaporin - 1 ( P29972 ) is involved in lung inflammation and lung edema formation . Swiss strain mice ( n = 122 ) had LPS ( 5 mg / kg ) instilled intratracheally ( IT ) , and were then treated with either 0 . 9 % saline or dexamethasone ( 5 mg / kg / day ) . Mice were euthanized at 2 days and 7 days after treatment . Inflammatory cytokines ( P01375 , P05231 ) , protein concentration in bronchoalveolar lavage ( BAL ) fluid , lung wet - to - dry weight ratio , histology , immunohistochemistry , and P29972 Western blot were performed . Lung wet - to - dry weight ratio and lung vascular permeability were also measured in the P29972 knockout mice ( n = 9 ) that received IT LPS ( 5 mg / kg ) at 2 days . Intratracheal instillation of LPS produced a severe lung injury at 2 days , characterized by elevation of P01375 , P05231 in the BAL fluid , and by histological changes consistent with increased lung vascular permeability and neutrophil infiltration . P29972 - immunoreactivity in the pulmonary capillary endothelium was reduced at 2 days and 7 days . Administration of dexamethasone improved LPS - induced ALI and retained expression of P29972 . However , depletion of P29972 did not affect lung edema formation , lung vascular permeability , or lung histology . The results suggest that although P29972 expression is decreased after lung injury , depletion of P29972 does not alter lung inflammation and lung edema induced by LPS .",
"[ ___MASK12___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .",
"Amplification of human B cell activation by a monoclonal antibody to the B cell - specific antigen P20273 , Bp 130 / 140 . The B cell - specific antigen P20273 is a 130 / 140 - Kd complex and is unique among human B cell antigens , since its surface expression is restricted to a subpopulation of Ig + B cells . Here the function of the P20273 antigen was evaluated by using the mAb Q9UBN7 , directed against one of the epitopes on the molecule . The Q9UBN7 antibody was constimulatory with anti - Ig in inducing small , dense tonsillar cells to proliferate ; however , the antibody by itself was devoid of stimulatory activity . Anti - P20273 antibody also induced more anti - Ig - treated B cells to leave G0 and enter the P55008 phase of the cell cycle . It also was constimulatory with low - m . w . BCGF and with an antibody to a 50 - Kd polypeptide , P25942 , which mediates a BCGF - like activity . Results of kinetic experiments and analysis of different B cell fractions suggested that anti - P20273 acts during an early phase of B cell activation , probably by amplifying the anti - Ig signal . F ( ab ') 2 fragments of anti - P20273 Q9UBN7 were as effective as the whole antibody in inducing augmentation of B cell proliferation , showing that the Fc portion of the molecule was not required for the activity . The results of these experiments , together with the intriguing distribution of the Bp 130 / 140 antigen in B cell ontogeny , suggest that this molecule plays an important role in the process that leads to B cell activation and proliferation .",
"The endocannabinoid 2 - AG protects the blood - brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines . Endocannabinoids are involved in neuroprotection through numerous biochemical pathways . We have shown that the endocannabinoid 2 - arachidonoyl glycerol ( 2 - AG ) is released in mouse brain after closed head injury ( CHI ) , and treatment with exogenous 2 - AG exerts neuroprotection via the central cannabinoid receptor P21554 . This process involves inhibition of inflammatory signals that are mediated by activation of the transcription factor NF - kB . The present study was designed to examine the effect of 2 - AG on the blood - brain barrier ( BBB ) and the possible inhibition of the early expression of proinflammatory cytokines , which are implicated in BBB disruption . We found that 2 - AG decreased BBB permeability and inhibited the acute expression of the main proinflammatory cytokines : P01375 , IL - 1beta and P05231 . It also augmented the levels of endogenous antioxidants . We suggest that 2 - AG exerts neuroprotection in part by inhibition of the early ( 1 - 4 h ) inflammatory response and augmentation of the brain reducing power .",
"Q9UBN7 inhibition impairs effector CD8 T - cell functions during skin inflammation . BACKGROUND : Broad - spectrum histone deacetylase ( HDAC ) inhibitors are useful in the treatment of allergic and autoimmune diseases and malignancy . However , use of more specific HDAC inhibitors might limit the toxicities caused by HDAC inhibition . Q9UBN7 , a member of the HDAC family , is highly expressed on CD8 T cells and has been shown to regulate immune responses through interactions between T cells and antigen - presenting cells . However , the mechanism by which Q9UBN7 inhibition affects the activation and functions of CD8 T cells is unclear . OBJECTIVES : We investigated the role or roles of Q9UBN7 in CD8 T - cell activation and functions during skin inflammation in vitro and in vivo and examined the mechanism by which Q9UBN7 inhibition modifies T - cell receptor signaling in vitro . METHODS : We assessed the clinical and biological effects of ACY - 1215 , an Q9UBN7 - specific inhibitor , by using murine CD8 T cell - related skin disease models , including contact hypersensitivity ( Q99698 ) and experimental graft - versus - host disease ( GVHD ) - like disease . RESULTS : ACY - 1215 , an Q9UBN7 inhibitor , prevented the development of Q99698 and GVHD - like disease in vivo by modulating CD8 T - cell activation and functions ; abrogated the induction of effector T cells from naive CD8 T cells by means of anti - CD3 / P10747 antibody - or antigen - specific stimulation in vitro ; and enhanced the binding of acetylated heat shock protein 90 to lymphocyte - specific protein tyrosine kinase in vitro , disrupting lymphocyte - specific protein tyrosine kinase phosphorylation and leading to impairment of the mitogen - activated protein kinase pathway . CONCLUSION : Q9UBN7 , a key modifier of T - cell receptor signaling , might represent a novel target for the treatment of CD8 T cell - related skin diseases , including Q99698 and GVHD .",
"P00797 - angiotensin system expression in rat bone marrow haematopoietic and stromal cells . The existence of a bone marrow renin - angiotensin system ( DB01367 ) is evidenced by the association of renin , angiotensin converting enzyme ( P12821 ) , and angiotensin ( Ang ) II and its AT ( 1 ) and AT ( 2 ) receptors with both normal and disturbed haematopoiesis . The expression of DB01367 components by rat unfractionated bone marrow cells ( BMC ) , haematopoietic - lineage BMC and cultured marrow stromal cells ( O60682 ) was investigated to determine which specific cell types may contribute to a local bone marrow DB01367 . The mRNAs for angiotensinogen , renin , P12821 , and AT ( 1a ) and AT ( 2 ) receptors were present in BMC and in cultured O60682 ; Q9BYF1 mRNA was detected only in BMC . Two - colour flow fluorocytometry analysis showed immunodetectable angiotensinogen , P12821 , AT ( 1 ) and AT ( 2 ) receptors , and Ang II , as well as binding of Ang II to AT ( 1 ) and AT ( 2 ) receptors , in P01730 (+) , CD11b / c (+) , CD45R (+) and CD90 (+) BMC and cultured O60682 ; renin was found in all cell types with the exception of P01730 (+) BMC . Furthermore , Ang II was detected by radioimmunoassay in O60682 homogenates as well as conditioned culture medium . The presence of Ang II receptors in both haematopoietic - lineage BMC and O60682 , and the de novo synthesis of Ang II by O60682 suggest a potential autocrine - paracrine mechanism for local DB01367 - mediated regulation of haematopoiesis .",
"Stereotactic biopsy diagnosis of primary non - Hodgkin ' s lymphoma of the central nervous system . A histological and immunohistochemical study . We report 29 cases of primary non - Hodgkin lymphomas ( Q9NZ71 ) of the Central Nervous System ( CNS ) , 26 of which were diagnosed by stereotactic biopsy and 3 by autopsy . In seven cases the patients were affected by AIDS . Histological examination of this series revealed 15 cases of immunoblastic lymphoma , 12 cases of centroblastic lymphoma , 1 case of lymphoplasmacytic immunocytoma and 1 case of unclassified high grade lymphoma . By immunohistochemistry the B - cell origin of lymphoma cells was demonstrated in 28 / 29 cases . Eight cases were assigned to the B - cell lineage by demonstration of monotypic surface or cytoplasmic immunoglobulin or of the B - cell phenotype P20273 + , P06729 - , CD3 - , P06127 - . In twenty cases the B - cell nature of lymphoma was identified by positivity with two or more anti - B monoclonal antibodies ( LN1LN2MB2 ) and negativity by the anti - T monoclonal antibody P09936 . The histologically unclassified case was a peripheral T - Q9NZ71 ( CD1 - , P06729 + , CD3 - , P06127 + , P20273 - ) . We conclude that histological and immunohistological evaluation of stereotactic biopsy specimens provides sufficient information for diagnosis and phenotypic characterization of primary Q9NZ71 of the CNS . These lymphomas exhibit important predominance of high - grade malignancy histological types and are nearly always B - cell derived . In addition , we provide further evidence that the panel of monoclonal antibodies LN1 , LN2 , MB2 , and P09936 is useful for immunophenotypic characterization of brain lymphomas when only paraffin embedded stereotactic biopsy tissue is available .",
"New antibody conjugates in cancer therapy . Targeting of radiation , drugs , and protein toxins to cancers selectively with monoclonal antibodies ( MAbs ) has been a topic of considerable interest and an area of continued development . Radioimmunotherapy ( RAIT ) of lymphoma using directly labeled MAbs is of current interest after approval of two radiolabeled anti - P11836 MAbs , as illustrated with the near 100 % overall response rate obtained in a recent clinical trial using an investigational radiolabeled anti - P20273 MAb , 90Y - epratuzumab . The advantage of pretargeted RAIT over directly labeled MAbs is continuing to be validated in preclinical models of lymphoma and solid tumors . Importantly , the advantages of combining RAIT with radiation sensitizers , with immunotherapy , or a drug conjugate targeting a different antigen are being studied clinically and preclinically . The area of drug - conjugated antibodies is progressing with encouraging data published for the trastuzumab - DM1 conjugate in a phase I clinical trial in P04626 - positive breast cancer . The Dock - and - Lock platform technology has contributed to the design and the evaluation of complex antibody - cytokine and antibody - toxin conjugates . This review describes the advances made in these areas , with illustrations taken from advances made in the authors ' institutions .",
"___MASK74___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .",
"___MASK82___ : An orally active renin inhibitor . P00797 inhibitors are antihypertensive drugs that block the first step in the renin - angiotensin system . Their mechanism of action differs from that of the angiotensin - converting enzyme inhibitors and angiotensin - receptor antagonists , but like these drugs , renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion . The renin - angiotensin - aldosterone system ( RAAS ) has long been recognized to play a significant role in hypertension pathophysiology . Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes . Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug . ___MASK82___ is the first of a new class of antihypertensive agents . ___MASK82___ is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once - daily oral dosing . In short - term studies , it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide , and had a low incidence of serious adverse effects . It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives . Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin - receptor blocker . The most common adverse effects reported in clinical trials were headache , fatigue , dizziness , diarrhea , and nasopharyngitis . ___MASK82___ has not been studied in patients with moderate renal dysfunction ; as an RAAS - acting drug , it should be prescribed for such patients only with caution .",
"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK46___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK12___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK52___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .",
"Kinetic method for the large - scale analysis of the binding mechanism of histone deacetylase inhibitors . Performing kinetic studies on protein ligand interactions provides important information on complex formation and dissociation . Beside kinetic parameters such as association rates and residence times , kinetic experiments also reveal insights into reaction mechanisms . Exploiting intrinsic tryptophan fluorescence a parallelized high - throughput Förster resonance energy transfer ( FRET ) - based reporter displacement assay with very low protein consumption was developed to enable the large - scale kinetic characterization of the binding of ligands to recombinant human histone deacetylases ( HDACs ) and a bacterial histone deacetylase - like amidohydrolase ( HDAH ) from Bordetella / Alcaligenes . For the binding of trichostatin A ( P32119 ) , suberoylanilide hydroxamic acid ( ___MASK99___ ) , and two other ___MASK99___ derivatives to HDAH , two different modes of action , simple one - step binding and a two - step mechanism comprising initial binding and induced fit , were verified . In contrast to HDAH , all compounds bound to human Q13547 , Q9UBN7 , and Q9BY41 through a two - step mechanism . A quantitative view on the inhibitor - HDAC systems revealed two types of interaction , fast binding and slow dissociation . We provide arguments for the thesis that the relationship between quantitative kinetic and mechanistic information and chemical structures of compounds will serve as a valuable tool for drug optimization .",
"Transcriptomic biomarkers of the response of hospitalized geriatric patients with infectious diseases . BACKGROUND : Infectious diseases are significant causes of morbidity and mortality among elderly populations . However , the relationship between oxidative stress , immune function and inflammatory response in acute phase of the infectious disease is poorly understood . RESULTS : Herein the abundance of a selection of 148 transcripts involved in immunosenescence and stress response was compared in total RNA of PBMC of 28 healthy aged probands and 39 aged patients in acute phase of infectious disease ( day 2 - 4 after hospitalization ) or in convalescence phase ( day 7 - 10 ) . This study provides a list of 24 differentially abundant transcript species in the acute phase versus healthy aged . For instance , transcripts associated with inflammatory and anti - inflammatory reactions ( P19438 , P14778 , P27930 , Q08334 ) and with oxidative stress ( P09601 , P07203 , P04179 , P30041 ) were more abundant while those associated with T - cell functions ( P10747 , Q07108 , P06239 ) were less abundant in acute phase . The abundance of seven of these transcripts ( P10747 , Q07108 , P06239 , P07339 , P09601 , P19438 and P30041 ) was already known to be altered in healthy aged probands compared to healthy young ones and was further affected in aged patients in acute phase , compromising an efficient response . CONCLUSION : This work provides insights of the state of acute phase response to infections in elderly patients and could explain further the lack of appropriate response in the elderly compared to younger persons .",
"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK52___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .",
"In vitro culture of B - lymphocytes derived from Epstein - Barr - virus - associated posttransplant lymphoproliferative disease : cytokine production and effect of interferon - alpha . Epstein - Barr - virus - associated posttransplant lymphoproliferative disease ranges from transient lymphadenitis to aggressive lymphoma . This study characterizes an in vitro model to study the pathogenesis of this disease with a cell culture system . Five B - cell lines derived from posttransplant lymphoproliferative disease tissue were characterized with regard to immunophenotype , karyotype , molecular genetics , cytokine production , and growth regulation . All cell lines expressed P15391 , CD21 , P20273 , P16150 , and CD77 , but not CD10 antigens . Immunoglobulin light chain restriction was seen in four of five cell lines , and cytogenetic abnormalities were demonstrable in three of the five . Cells proliferating in culture contained multiple Epstein - Barr virus episomes and showed lytic viral replication . All cell lines produced tumor necrosis factor - beta and interleukin - 10 without evidence of autocrine growth regulatory loops involving these cytokines . No evidence of P01583 , P60568 , P05112 , P05113 or P05231 production was found by reverse transcriptase polymerase chain reaction . Adding 500 U IFN - alpha / ml to the culture medium resulted in 30 % inhibition of [ 3H ] thymidine incorporation .",
"Structural and functional similarities between osmotin from Nicotiana tabacum seeds and human adiponectin . Osmotin , a plant protein , specifically binds a seven transmembrane domain receptor - like protein to exert its biological activity via a RAS2 / DB02527 signaling pathway . The receptor protein is encoded in the gene ORE20 / PHO36 and the mammalian homolog of PHO36 is a receptor for the human hormone adiponectin ( Q96A54 ) . Moreover it is known that the osmotin domain I can be overlapped to the β - barrel domain of adiponectin . Therefore , these observations and some already existing structural and biological data open a window on a possible use of the osmotin or of its derivative as adiponectin agonist . We have modelled the three - dimensional structure of the adiponectin trimer ( Q15848 ) , and two Q96A54 and PHO36 receptors . Moreover , we have also modelled the following complexes : Q15848 / Q96A54 , osmotin / PHO36 and osmotin / Q96A54 . We have then shown the structural determinants of these interactions and their physico - chemical features and analyzed the related interaction residues involved in the formation of the complexes . The stability of the modelled structures and their complexes was always evaluated and controlled by molecular dynamics . On the basis of these results a 9 residues osmotin peptide was selected and its interaction with Q96A54 and PHO36 was modelled and analysed in term of energetic stability by molecular dynamics . To confirm in vivo the molecular modelling data , osmotin has been purified from nicotiana tabacum seeds and its nine residues peptide synthesized . We have used cultured human synovial fibroblasts that respond to adiponectin by increasing the expression of P05231 , P01375 and IL - 1beta via Q96A54 . The biological effect on fibroblasts of osmotin and its peptide derivative has been found similar to that of adiponectin confirming the results found in silico .",
"Effects of insulin - like growth factor - 1 on B - cell precursor acute lymphoblastic leukemia . P01308 - like growth factor - 1 ( DB01277 ) is known to be a major growth factor with effects on various cell types , including hematopoietic cells , as well as neoplasms , and is regulated by IGF - binding proteins ( IGFBPs ) . In this study , we investigated the effects of DB01277 on B - cell precursor acute lymphoblastic leukemia ( P03999 - ALL ) cells . When the expression of IGF - 1R in clinical samples of P03999 - ALL was examined , five of thirty - two cases showed IGF - 1R expression , whereas IGF - 1R was expressed in most P03999 - ALL cell lines . We observed that DB01277 enhanced the proliferation of P03999 - ALL cell lines that can be partially inhibited by P08833 , - 3 , and - 4 , but not other IGFBPs . DB01277 also partially inhibited dexamethasone - induced apoptosis , but not apoptosis mediated by DB00773 and irradiation . Interestingly , the proliferative effect of DB01277 was partially blocked by inhibitors of MAPK and AKT , whereas the inhibition of dexamethasone - induced apoptosis was completely blocked by both inhibitors . Our data indicate that DB01277 is involved in cell proliferation and apoptosis regulation in P03999 - ALL cells . Since some P03999 - ALL cases express IGF - 1R , it appears to be a plausible target for prognostic evaluation and may represent a new therapeutic strategy .",
"Physiologically Based Pharmacokinetic Model to Assess the Influence of DB09052 - Mediated Cytokine Elevations on Cytochrome P450 Enzyme Activity . DB09052 is a P15391 / CD3 bispecific T - cell engager ( BiTE ® ) antibody construct for treatment of leukemia . Transient elevation of cytokines ( interleukin ( IL ) - 6 , P22301 , interferon - gamma ( IFN - γ ) ) has been observed within the first 48 hours of continuous intravenous blinatumomab infusion . In human hepatocytes , blinatumomab showed no effect on cytochrome P450 ( CYP450 ) activities , whereas a cytokine cocktail showed suppression of P08684 , P05177 , and P11712 activities . We developed a physiologically based pharmacokinetic ( PBPK ) model to evaluate the effect of transient elevation of cytokines , particularly P05231 , on CYP450 suppression . The predicted suppression of hepatic CYP450 activities was < 30 % , and P05231 - mediated changes in exposure to sensitive substrates of P08684 , P05177 , and P11712 were < twofold and lasted < 1 week . Model verification indicated that P05231 was the key cytokine suppressing CYP450 activities ; the duration of cytokine elevation was a major determinant of magnitude of suppression . This study shows the utility of PBPK modeling for risk assessment of cytokine - mediated drug interactions .",
"Nearly Complete Response of Brain Metastases from P04626 Overexpressing Breast Cancer with ___MASK27___ and DB01101 after Whole Brain Irradiation . DB00072 treatment does not prevent intracranial seeding and is largely ineffective for established central nervous system metastasis in P04626 overexpressing breast cancer patients . Combination therapy of lapatinib and capecitabine may be an effective treatment option for brain metastasis of P04626 - positive breast cancer . We report a patient with breast cancer overexpressing HER - 2 where brain metastases were successfully treated with radiation and a combination of lapatinib and capecitabine .",
"P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV - associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . ___MASK82___ , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV - induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R .",
"The macrophage mannose receptor induces Q16552 in response to Candida albicans . The cytokine Q16552 controls neutrophil - mediated inflammatory responses . The pattern recognition receptor ( s ) that induce Th17 responses during infection , in the absence of artificial mitogenic stimulation with anti - CD3 / anti - P10747 antibodies , remain obscure . We investigated the innate immune receptors and pathogen - associated molecular patterns involved in triggering Th17 responses during pathogen - specific host defense . The prototypic fungal pathogen Candida albicans was found to induce Q16552 more potently than Gram - negative bacteria . Candida mannan , but not zymosan , beta - glucans , Toll - like receptor ( TLR ) agonists , or the Q9HC29 ligand P16444 , induced Q16552 production in the absence of anti - CD3 / anti - P10747 antibodies . Candida - induced Q16552 response was dependent on antigen - presenting cells and the macrophage mannose receptor ( MR ) , demonstrating that Candida mannan is not simply a mitogenic stimulus . The O60603 / dectin - 1 pathway , but not O00206 or Q9HC29 , amplified MR - induced Q16552 production . This study identifies the specific pattern recognition receptors that trigger the Th17 response induced by a human pathogen in the absence of mitogenic stimulation .",
"Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine - directed therapy . DB09052 is a P15391 / CD3 - bispecific T - cell receptor - engaging ( BiTE ) antibody with efficacy in refractory B - precursor acute lymphoblastic leukemia . Some patients treated with blinatumomab and other T cell - activating therapies develop cytokine release syndrome ( CRS ) . We hypothesized that patients with more severe toxicity may experience abnormal macrophage activation triggered by the release of cytokines by T - cell receptor - activated cytotoxic T cells engaged by BiTE antibodies and leading to hemophagocytic lymphohistiocytosis ( HLH ) . We prospectively monitored a patient during blinatumomab treatment and observed that he developed HLH . He became ill 36 hours into the infusion with fever , respiratory failure , and circulatory collapse . He developed hyperferritinemia , cytopenias , hypofibrinogenemia , and a cytokine profile diagnostic for HLH . The HLH continued to progress after discontinuation of blinatumomab ; however , he had rapid improvement after P05231 receptor - directed therapy with tocilizumab . Patients treated with T cell - activating therapies , including blinatumomab , should be monitored for HLH , and cytokine - directed therapy may be considered in cases of life - threatening CRS . This trial was registered at www . clinicaltrials . gov as # NCT00103285 .",
"___MASK18___ improves renal ischemia - reperfusion injury by inhibiting the mevalonate pathway . Statins are known to lessen the severity of renal ischemia - reperfusion injury . The present study was undertaken to define the mechanism of renoprotective actions of statins using a mouse kidney injury model . Treatment of mice with pravastatin , a widely used statin , improved renal function after renal ischemia - reperfusion without lowering the plasma cholesterol level . Administration of pravastatin with mevalonate , a product of P04035 , eliminated renal protection suggesting an effect of pravastatin on mevalonate or its metabolism . In hypercholestrolemic apolipoprotein E knockout mice with reduced P04035 activity ; the degree of injury was less severe than in control mice , however , there was no protective action of pravastatin on renal injury in the knockout mice . Treatment with a farnesyltransferase inhibitor ( L - 744832 ) mimicked pravastatin ' s protective effect but co - administration with the statin provided no additional protection . Both pravastatin and L - 744832 inhibited the injury - induced increase in plasma P05231 concentration to a similar extent . Our results suggest the protective effect of pravastatin on renal ischemia - reperfusion injury is mediated by inhibition of the mevalonate - isoprenoid pathway independent of its lipid lowering action .",
"Chemical coding of the human gastrointestinal nervous system : cholinergic , VIPergic , and catecholaminergic phenotypes . The aim of this investigation was to identify the proportional neurochemical codes of enteric neurons and to determine the specific terminal fields of chemically defined nerve fibers in all parts of the human gastrointestinal ( GI ) tract . For this purpose , antibodies against the vesicular monoamine transporters ( P54219 / 2 ) , the vesicular acetylcholine transporter ( Q16572 ) , tyrosine hydroxylase ( TH ) , dopamine beta - hydroxylase ( P09172 ) , serotonin ( 5 - HT ) , vasoactive intestinal peptide ( P01282 ) , and protein gene product 9 . 5 ( P09936 ) were used . For in situ hybridization ( 35 ) S - labeled P54219 , Q05940 , and Q16572 riboprobes were used . In all regions of the human GI tract , 50 - 70 % of the neurons were cholinergic , as judged by staining for Q16572 . The human gut unlike the rodent gut exhibits a cholinergic innervation , which is characterized by an extensive overlap with VIPergic innervation . Neurons containing Q05940 constituted 14 - 20 % of all intrinsic neurons in the upper GI tract , and there was an equal number of TH - positive neurons . In contrast , P09172 was absent from intrinsic neurons . Cholinergic and monoaminergic phenotypes proved to be completely distinct phenotypes . In conclusion , the chemical coding of human enteric neurons reveals some similarities with that of other mammalian species , but also significant differences . P01282 is a cholinergic cotransmitter in the intrinsic innervation of the human gut . The substantial overlap between Q05940 and TH in enteric neurons indicates that the intrinsic catecholaminergic innervation is a stable component of the human GI tract throughout life . The absence of P09172 from intrinsic catecholaminergic neurons indicates that these neurons have a dopaminergic phenotype .",
"P10599 - dependent hydroperoxide peroxidase activity of bacterioferritin comigratory protein ( P03999 ) as a new member of the thiol - specific antioxidant protein ( P32119 ) / Alkyl hydroperoxide peroxidase C ( AhpC ) family . Escherichia coli bacterioferritin comigratory protein ( P03999 ) , a putative bacterial member of the P32119 / AhpC family , was characterized as a thiol peroxidase . P03999 showed a thioredoxin - dependent thiol peroxidase activity . P03999 preferentially reduced linoleic acid hydroperoxide rather than H ( 2 ) O ( 2 ) and t - butyl hydroperoxide with the use of thioredoxin as an in vivo immediate electron donor . The value of V ( max )/ K ( m ) of P03999 for linoleic acid hydroperoxide was calculated to be 5 - fold higher than that for H ( 2 ) O ( 2 ) , implying that P03999 has a selective capability to reduce linoleic acid hydroperoxide . Replacement of DB00151 - 45 with serine resulted in the complete loss of thiol peroxidase activity , suggesting that P03999 is a new bacterial member of P32119 / AhpC family having a conserved cysteine as the primary site of catalysis . P03999 exists as a monomer , and its functional DB00151 - 45 appeared to exist as cysteine sulfenic acid . The expression level of P03999 gradually elevated during exponential growth until mid - log phase growth , beyond which the expression level was decreased . P03999 was induced 3 - fold by the oxidative stress given by changing the growth conditions from the anaerobic to aerobic culture . Bcp null mutant grew more slowly than its wild type in aerobic culture and showed the hypersensitivity toward various oxidants such as H ( 2 ) O ( 2 ) , t - butyl hydroperoxide , and linoleic acid hydroperoxide . The peroxide hypersensitivity of the null mutant could be complemented by the expression of bcp gene . Taken together , these data suggest that P03999 is a new member of thioredoxin - dependent P32119 / AhpC family , acting as a general hydroperoxide peroxidase .",
"Hypoxic / normoxic preconditioning increases endothelial differentiation potential of human bone marrow CD133 + cells . CD133 + cells are hemangioblasts that have capacity to generate into both hematopoietic and endothelial cells ( ECs ) . Hypoxia / normoxia has shown to be the regulator of the balance between stemness and differentiation . In this study we performed Agilent ' s whole human genome oligo microarray analysis and examined the differentiation potential of the bone - marrow - derived CD133 + cells after hypoxic / normoxic preconditioning of CD133 + cells . Results showed that there was no significant increase in erythroid colony forming unit ( CFU - E ) and CFU - granulocyte , erythrocyte , monocyte , and megakaryocyte formation with cells treated under hypoxia / normoxia . However , a significant increment of EC forming unit at 24 h ( 143 . 2 +/- 8 . 0 % ) compared to 0 h ( 100 +/- 11 . 4 % ) was observed in CFU - EC analysis . Reverse transcription - polymerase chain reaction and immunostaining analysis showed that the differentiated cells diminished hematopoietic stem cell surface markers and acquired the gene markers and functional phenotype of ECs . The transcriptome profile revealed a cluster of 232 downregulated and 498 upregulated genes in cells treated for 24 h under hypoxia . The upregulated genes include angiogenic genes , angiogenic growth factor genes , angiogenic cytokine and chemokine genes , as well as angiogenic - positive regulatory genes , including Q14512 , PDGFB , Q16663 , P48061 , P80162 , P05231 , P21246 , O14944 , P04626 , O95136 , P11487 , Q92913 , Q99988 , P05412 , L1CAM , Q02297 , P08138 , and PDGFB . On the other hand , angiogenesis inhibitors and related genes , including P29459 , P98177 , Q9NY15 , and P16035 , are downregulated . Taken together , hypoxic / normoxic preconditioning may lead to the differentiation of CD133 + cells toward endothelial lineage , which may improve the current clinical trial studies .",
"P00797 inhibition reduces atherosclerotic plaque neovessel formation and regresses advanced atherosclerotic plaques . OBJECTIVE : The interaction between the renin - angiotensin system and toll - like receptors ( TLRs ) in the pathogenesis of advanced atherosclerotic plaques is not well understood . We studied the effects of the renin inhibitor aliskiren on the progression of advanced atherosclerotic plaque in apolipoprotein E - deficient ( ApoE (-/-) ) mice with a special focus on plaque neovessel formation . METHODS AND RESULTS : Four - wk - old ApoE (-/-) mice were fed a high - fat diet for 8 wks , and the mice were randomly assigned to one of three groups and administered a vehicle , hydralazine , or aliskiren for an additional 12 wks . ___MASK82___ reduced the atherosclerotic plaque area and plaque neovessel density . It increased the plaque collagen and elastin contents , and reduced plasma angiotensin II levels and plaque macrophage infiltration and cathepsin S ( CatS ) protein . ___MASK82___ also decreased the levels of AT1R , gp91phox , O60603 , monocyte chemotactic protein - 1 , and CatS mRNAs in the aortic roots . DB01275 had no beneficial vascular effects , although its administration resulted in the same degree of blood pressure reduction as aliskiren . CatS deficiency mimicked the aliskiren - mediated vasculoprotective effect in the ApoE (-/-) mice , but aliskiren showed no further benefits in ApoE (-/-) CatS (-/-) mice . In vitro , O60603 silencing reduced CatS expression induced by angiotensin II . Moreover , aliskiren or the inhibition of CatS impaired the endothelial cell angiogenic action in vitro or / and ex vivo . CONCLUSION : P00797 inhibition appears to inhibit advanced plaque neovessel formation in ApoE (-/-) mice and to decrease the vascular inflammatory action and extracellular matrix degradation , partly by reducing AT1R / O60603 - mediated CatS activation and activity , thus regressing advanced atherosclerosis .",
"Monoclonal antibody therapy in haematological malignancies . This review focuses on the development of monoclonal antibodies that have been or are being introduced in the treatment of both lymphoid and myeloid haematological malignancies in adults . After a general introduction on the principles of antibody selection for therapy , this review summarizes the results of the clinical trials that led to the approval of antibodies by the FDA ( Food and Drug administration , USA ) and / or the EMEA ( European Medicines Agency ) , e . g . different anti - P11836 , anti - P31358 and anti - P20138 antibodies . Furthermore , several antibodies that seem promising in phase I / II studies ( like anti - P20273 , anti - CD23 , anti - P01730 , anti - P28908 , anti - P33681 , anti - P15692 , anti HLA - DR and anti - P01375 ) are highlighted . The application of monoclonal antibodies has nowadays become indispensable in the treatment of lymphoma and leukaemia ' s and the number of new indications is still growing . Therefore , also some interesting phase III studies that are recruiting patients at this moment , and some new technical developments are discussed .",
"P15391 : A multifunctional immunological target molecule and its implications for Blineage acute lymphoblastic leukemia . Over the last 20 - 30 years P15391 has gained attention as a potential target in the therapy of B - cell malignancies . In particular , targeting P15391 with the bispecific T - cell engager ( BiTE ) antibody DB09052 and T - cells modified by chimeric antigen receptors ( CAR ) has shown promising efficacy in early phase clinical trials for adults and children with precursor B - cell ALL ( P03999 - ALL ) . This review will discuss the rationale behind targeting P15391 in P03999 - ALL and its potential importance in P03999 - ALL signaling pathways .",
"Expression profile of genes associated with the dopamine pathway in vitiligo skin biopsies and blood sera . BACKGROUND : Dopamine has been proven to be toxic for melanocytes . In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed . METHODS : With the use of quantitative real - time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway ( PAH , P61457 , TH , DDC , P09172 , PNMT , P07203 , P21397 , P27338 , P21964 , P21728 - P21918 , P54219 and Q05940 ) was observed in vitiligo patients ' and control subjects ' skin and blood . RESULTS : The mRNA expression of P07203 , DDC , P21397 , P21728 and P21918 differs in vitiligo skin and the protein level of DDC , P21397 , P27338 , P21728 and P21918 is changed in vitiligo patients ' skin and / or blood sera . CONCLUSIONS : The dopamine pathway probably influences melanogenesis directly or through the melanocortin pathway . We provide new data about changes of expression profile of the dopamine - synthesizing enzyme DDC , the dopamine - degrading enzymes P21397 and P27338 and the D1 - like family dopamine receptors in vitiligo skin and blood sera .",
"Immunophenotypic characterization of normal peripheral blood B lymphocyte by flow cytometry : reference for diagnosis of chronic B cell leukemia / lymphoma . To establish reference values of various immunophenotypic markers in B lymphocyte population in healthy Chinese adults and build background information for accurate interpretation of B cell immunophenotyping data in clinical practice , peripheral blood from 41 healthy adults were collected separately into test tubes containing DB00974 - K ( 2 ) and stored in room temperature no more than 24 hours before analysis . Whole blood lysis technique and multiparameter flow cytometry were applied to immunophenotype B cells gated on P15391 / SSC dot - plot . The results showed that P20273 , P11836 , CD62L , P25942 , P25063 , CD79b , CD79a , and FMC - 7 were almost positive in the circulating B cell population , whereas CD11a , P33681 , CD103 , CD10 , P29965 , CD54 , P48023 , P42081 , and CD95 were almost negative in the peripheral blood B lymphocytes . P05107 , P16070 , CD23 , P06127 , CD11c and P16150 were positive in different B cell subpopulations . 78 % of B cells were IgD positive and ratio kappa / lambda was 1 . 26 . The significance of all these markers in the differential diagnosis of lymphoproliferative diseases was discussed . The conclusion is that it is necessary to consider the qualitative and quantitative levels of expression of various markers in normal B cell population in order to accurately interpret the pathological immunophenotypic data in clinical practice . It is also important to note the immunotypic differences of B cells between Chinese and Western populations .",
"T cells redirected to EphA2 for the immunotherapy of glioblastoma . Outcomes for patients with glioblastoma ( GBM ) remain poor despite aggressive multimodal therapy . Immunotherapy with genetically modified T cells expressing chimeric antigen receptors ( CARs ) targeting interleukin ( IL ) - 13Rα2 , epidermal growth factor receptor variant III ( EGFRvIII ) , or human epidermal growth factor receptor 2 ( P04626 ) has shown promise for the treatment of gliomas in preclinical models and in a clinical study ( IL - 13Rα2 ) . However , targeting IL - 13Rα2 and EGFRvIII is associated with the development of antigen loss variants , and there are safety concerns with targeting P04626 . Erythropoietin - producing hepatocellular carcinoma A2 ( EphA2 ) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype . To generate EphA2 - specific T cells , we constructed an EphA2 - specific CAR with a P10747 - ζ endodomain . EphA2 - specific T cells recognized EphA2 - positive glioma cells as judged by interferon - γ ( IFN - γ ) and P60568 production and tumor cell killing . In addition , EphA2 - specific T cells had potent activity against human glioma - initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays . Adoptive transfer of EphA2 - specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency ( SCID ) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells . Thus , EphA2 - specific T - cell immunotherapy may be a promising approach for the treatment of EphA2 - positive GBM .",
"___MASK74___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK74___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .",
"P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK47___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .",
"___MASK46___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK46___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway .",
"Peroxisome proliferator - activated receptors ( Q07869 ) agonists affect cell viability , apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors . The nuclear receptors PPARs ( peroxisome proliferator - activated receptors ) are transcription factors activated by specific ligands . PPARs play an important role in carcinogenesis , inflammation , atherosclerosis , lipid metabolism and diabetes . There is evidence that activation of PPARs by specific ligands is able to suppress the growth of different types of human cancer by mechanisms including the growth arrest , apoptosis and induction of differentiation , although the detailed signalling pathways have not been completely elucidated to date . The aim of our study was to determine whether synthetic ligands of PPARalpha and PPARgamma could affect the viability , proliferation , differentiation , apoptosis and expression of some cell cycle related proteins in glial tumor cell lines . The study was performed on human glioblastoma cell lines U - 87 MG , T98G , A172 and U - 118 MG . Cell lines were treated by ligands of PPARalpha ( bezafibrate , gemfibrozil ) and PPARgamma ( ciglitazone ) . MTT , flow cytometry , TUNEL assay and immunoblotting were used for detection of changes in cell viability , proliferation , differentiation and apoptosis . ___MASK46___ , ciglitazone and gemfibrozil inhibited viability of glioblastoma cell lines . The synthetic ligands significantly reduced or induced the expression of cyclins , P46527 , p21Waf1 / Cip1 , MDM - 2 , Bcl - 2 , Bax , PARP , Caspase 3 , androgen receptors , etc . and did not affect the expression of the differentiation marker P14136 . Flow cytometry confirmed arrest of the cell cycle although the detection of apoptosis was controversial . Apart from hypolipidemic and hypoglycaemic effects , Q07869 ligands may also have significant cytostatic effects of potential use in anticancer treatment .",
"Effect of acetazolamide on aquaporin - 1 and fluid flow in cultured choroid plexus . ___MASK74___ ( AZA ) , used in treatment of early or infantile hydrocephalus , is effective in some cases , while its effect on the choroid plexus ( CP ) remains ill - defined . The drug reversibly inhibits aquaporin - 4 ( P55087 ) , the most ubiquitous \" water pore \" in the brain , and perhaps modulation of P29972 ( located apically on CP cells ) by AZA may reduce cerebrospinal fluid ( P04141 ) production . We sought to elucidate the effect of AZA on P29972 and fluid flow in CP cell cultures . CP tissue culture from 10 - day Sprague - Dawley rats and a TRCSF - B cell line were grown on Transwell permeable supports and treated with 100 μM AZA . Fluid assays to assess direction and extent of fluid flow , and P29972 expression patterns by immunoblot , Immuncytochemistry ( ICC ) , and quantitative reverse transcriptase polymerase chain reaction ( qRT - PCR ) were performed . Immunoblots and ICC analyses showed a decrease in P29972 protein shortly after AZA treatment ( lowest at 12 h ) , with transient P29972 reduction mediated by mRNA expression ( lowest at 6 h ) . Transwell fluid assays indicated a fluid shift at 2 h , before significant changes in P29972 mRNA or protein levels . Timing of AZA effect on P29972 suggests the drug alters protein transcription , while affecting fluid flow by a concomitant method . It is plausible that other mechanisms account for these phenomena , as the processes may occur independently .",
"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK82___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .",
"Enhanced delayed - type hypersensitivity and diminished immediate - type hypersensitivity in mice lacking the inducible VPAC ( 2 ) receptor for vasoactive intestinal peptide . Vasoactive intestinal peptide ( P01282 ) and its G protein - coupled receptors , VPAC ( 1 ) R and VPAC ( 2 ) R , are prominent in the immune system and regulate many aspects of T cell - dependent immunity . In mouse T cells , VPAC ( 1 ) R is expressed constitutively , whereas VPAC ( 2 ) R is induced by immune stimuli . VPAC ( 2 ) R - null ( VPAC ( 2 ) R (-/-) ) mice on a C57BL / 6 background are shown here to have normal basic immune characteristics , including serum Ig concentrations , blood levels of all leukocytes , and spleen number of total T cells ( CD3 (+) ) and T cells bearing P01730 , CD8 , and P10747 . Hapten - evoked cutaneous delayed - type hypersensitivity ( DTH ) was significantly enhanced in VPAC ( 2 ) R - null mice compared with age - and sex - matched wild - type mice . In contrast , generation of IgE anti - hapten antibodies and active cutaneous anaphylaxis were > or = 70 % lower in VPAC ( 2 ) R - null mice than in wild - type controls . Cytokine production by splenic P01730 (+) T cells , stimulated with adherent anti - CD3 plus anti - P10747 antibodies , revealed higher levels of P60568 ( mean = 3 - fold ) and P01579 ( mean = 3 - fold ) , and lower levels of P05112 ( mean = one - fifth ) in VPAC ( 2 ) R - null mice than wild - type controls . Loss of P01282 - VPAC ( 2 ) R maintenance of the normal ratio of Th2 / Th1 cytokines thus leads to a state of enhanced DTH and depressed immediate - type hypersensitivity , which may alter both host defense and susceptibility to immune - mediated diseases .",
"The complex of FK506 - binding protein 12 and FK506 inhibits calcineurin phosphatase activity and IgE activation - induced cytokine transcripts , but not exocytosis , in mouse mast cells . FK506 and cyclosporin A ( DB00091 ) are immunosuppressive agents that inhibit P60568 production by activated T cells , but only DB00091 inhibits IgE activation - induced cytokine transcripts in mouse P08700 - dependent , bone marrow - derived mast cells ( BMMC ) . We previously associated the resistance of BMMC to FK506 with a deficiency in the expression of FK506 binding protein ( FKBP ) 12 , a molecule that forms a complex with FK506 capable of inhibiting calcineurin phosphatase activity in vitro . In this report , we establish that P62942 mediates FK506 inhibition of both calcineurin phosphatase activity and IgE activation - induced cytokine transcripts in a Kirsten murine sarcoma virus - immortalized mast cell line that is P62942 deficient . Overexpression of P62942 by transfection enhanced the ability of FK506 to inhibit calcineurin phosphatase activity ( IC50 = 2 nM ) , compared with cells transfected with the expression vector alone ( IC50 > 30 nM ) . The IC50 value for FK506 inhibition of IgE activation - induced transcripts for P01375 decreased from 40 nM in vector control cells to 10 nM in P62942 transfectants . Similarly , the IC50 value for inhibition of P05231 transcripts decreased from > 1000 nM in vector control cells to 35 nM in P62942 transfectants . In contrast , activation - elicited release of the secretory granule mediator beta - hexosaminidase was only partially inhibited by FK506 at 1000 nM , regardless of the levels of P62942 expressed by the cells . Thus , P62942 is the dominant cytosolic protein that mediates FK506 inhibition of P01375 and P05231 transcripts .",
"Current status of antibody therapy in ALL . Despite the significant advances in modern chemotherapy , it remains challenging to treat adult patients with acute lymphoblastic leukaemia ( ALL ) . The relapse rate remains high , and the outcome at the time of relapse is dismal . Antibody - based therapies have demonstrated promising results in this patient group . Variable mechanisms have been applied to target surface antigens ( P11836 [ also termed P11836 ] , P20273 , P31358 and P15391 ) that are commonly expressed on malignant leukaemia cells . In this review , we will focus on the clinical application of such therapies in adult ALL , including the naked antibodies : DB00073 , Ofatumumab , DB04958 and DB00087 ; the immunotoxins : BL22 and Combotox ; the immunoconjugates : inotuzumab and SAR 3419 ; as well as the Bi - specific T cell engaging ( BiTE ) - specific antibody , DB09052 ."
] |
[
"___MASK12___",
"___MASK18___",
"___MASK27___",
"___MASK46___",
"___MASK47___",
"___MASK52___",
"___MASK74___",
"___MASK82___",
"___MASK99___"
] |
___MASK52___
|
MH_train_439
|
interacts_with DB08864?
|
[
"Regulation of P12931 family coactivators by post - translational modifications . Initially identified as a group of auxiliary protein factors involved in transcriptional regulation by steroid hormone receptors as well as by other members of the nuclear receptor superfamily , the steroid receptor coactivators ( SRCs ) have since then been implicated in the transcriptional regulation of other transcription factors which are important components of very different signaling pathways . Members of the P12931 family have been shown to interact with myogenin , Q9P2K5 , transcriptional enhancer factor ( Q10587 ) , NF - kappaB , AP - 1 , P35610 , p53 , and Q01094 , suggesting that P12931 coactivators participate in diverse cellular processes . Recent evidence indicates that various post - translational modifications play critical roles in determining the final transcriptional output and specificity of P12931 coactivators . In this review , we summarized the current knowledge concerning post - translational modifications , dynamic interplay between different modifications , and patho - physiological relevance of the modifications of P12931 proteins .",
"Mind the gap ; regulation of gap junctional , intercellular communication by the P12931 oncogene product and its effectors . Gap junctions are channels that connect the interiors of neighboring cells and are formed by the connexin ( Cx ) proteins . A reduction in gap junctional , intercellular communication ( GJIC ) often correlates with increased growth and neoplastic transformation . P17302 is a widely expressed connexin which can be phosphorylated by the Src oncoprotein tyrosine kinase on tyr247 and - 265 , and this reduces communication . However , Src activates multiple signalling pathways such as the Ras / Raf / Erk and PLCγ / protein kinase C , which can also phosphorylate P17302 and interrupt communication . In addition , the Src effector Cas , which has an adaptor function , binds P17302 to suppress gap junctional communication . In sharp contrast , activation of a different Src effector , the cytoplasmic transcription factor Signal transducer and activator of transcription - 3 ( Stat3 ) is not required for the Src - mediated , GJIC suppression . In fact , Stat3 is actually required for the maintenance of gap junctional communication in normal cells with high GJIC .",
"Connexin36 knockout mice display increased sensitivity to pentylenetetrazol - induced seizure - like behaviors . OBJECTIVE : Large - scale synchronous firing of neurons during seizures is modulated by electrotonic coupling between neurons via gap junctions . To explore roles for connexin36 ( Q9UKL4 ) gap junctions in seizures , we examined the seizure threshold of connexin36 knockout ( Cx36KO ) mice using a pentylenetetrazol ( PTZ ) model . METHODS : Mice ( 2 - 3months old ) with Q9UKL4 wildtype ( WT ) or Cx36KO genotype were treated with vehicle or 10 - 40mg / kg of the convulsant PTZ by intraperitoneal injection . Seizure and seizure - like behaviors were scored by examination of video collected for 20min . Quantitative real - time PCR ( QPCR ) was performed to measure potential compensatory neuronal connexin ( Q8NFK1 , P35212 , P17302 and P36383 ) , pannexin ( Q96RD7 and Q96RD6 ) and gamma - aminobutyric acid type A ( GABA ( A ) ) receptor α1 subunit gene expression . RESULTS : Cx36KO animals exhibited considerably more severe seizures ; 40mg / kg of PTZ caused severe generalized ( ≥ grade III ) seizures in 78 % of KO , but just 5 % of WT mice . A lower dose of PTZ ( 20mg / kg ) induced grade II seizure - like behaviors in 40 % KO vs . 0 % of WT animals . There was no significant difference in either connexin , pannexin or GABA ( A ) α1 gene expression between WT and KO animals . CONCLUSION : Increased sensitivity of Cx36KO animals to PTZ - induced seizure suggests that Q9UKL4 gap junctional communication functions as a physiological anti - convulsant mechanism , and identifies the Q9UKL4 gap junction as a potential therapeutic target in epilepsy .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK99___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"A novel 5 - HT1 - like receptor subtype mediates DB02527 synthesis in porcine pial vein . The 5 - hydroxytryptamine ( 5 - HT ) receptor subtype mediating 5 - HT inhibition of spontaneous rhythmic contractions ( P12931 ) in the porcine pial vein was characterized . Results from pharmacological studies using in vitro tissue bath techniques indicated that the inhibitory effects of 5 - HT on P12931 were qualitatively and quantitatively mimicked by 5 - HT1 - like agonists 5 - methoxytryptamine ( 5 - MT ) and 5 - carboxamidotryptamine ( 5 - CT ) . 5 - HT - , 5 - MT - , and 5 - CT - induced inhibitions of P12931 were attenuated in a concentration - dependent manner by methysergide , which yielded similar pA2 values against these three agonists , suggesting that 5 - HT , 5 - MT , and 5 - CT act on the same 5 - HT1 - like receptors . 5 - MT inhibition of P12931 was not affected by blocking 5 - HT2 ( with ketanserin and spiperone ) , 5 - Q9H205 ( with MDL - 72222 and ICS - 205 - 930 ) , or Q13639 ( with ICS - 205 - 930 ) receptors . Neither was 5 - MT inhibition of P12931 affected by blocking P08908 ( with propranolol and spiperone ) , P28222 ( with propranolol ) , or P28335 ( with ketanserin ) receptors . Furthermore , 5 - HT and 5 - MT inhibitions of P12931 were enhanced by cilostazol [ a selective adenosine 3 ', 5 '- cyclic monophosphate ( DB02527 ) phosphodiesterase inhibitor ] and were diminished by KT - 5720 ( a DB02527 - dependent protein kinase inhibitor ) but were not affected by M & B - 22948 [ a selective guanosine 3 ', 5 '- cyclic monophosphate ( cGMP ) phosphodiesterase inhibitor ] or KT - 5823 ( a cGMP - dependent protein kinase inhibitor ) . Biochemical studies further demonstrated that 5 - HT inhibition of P12931 in porcine pial veins was accompanied by an increase in DB02527 , but not cGMP , synthesis . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Combination of virtual screening and high throughput gene profiling for identification of novel liver X receptor modulators . We conducted virtual docking studies using GLIDE with modified LXRbeta ligand - binding domain ( LBD ) on internal compound collection followed by the gene profiling with ArrayPlate mRNA assay . A total of 69 compounds were found to upregulate LXRalpha and certain LXR regulated genes from 1308 compounds selected by virtual screen ( hit rate : 5 . 3 % ) . Compound 4 was shown to significantly induce the expression of LXR target genes such as O95477 , P45844 , P02649 , O00767 - 1 , and SREBP - 1c in THP - 1 differentiated macrophages . In vitro binding assay confirmed that 4 binds to both LXRalpha and LXRbeta directly and recruits coactivator peptide Q15788 . It functions as a full LXR agonist in stimulating cholesterol efflux in THP - 1 differentiated macrophages and induces lipogenesis in HepG2 cells . This study demonstrates that the combination of virtual screen and high throughput gene profiling is an efficient approach for rapid identification of novel LXR modulators .",
"___MASK45___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .",
"Candidate tumor suppressor LUCA - 15 / P52756 / P52756 modulates expression of apoptosis and cell cycle genes . P52756 ( P52756 / LUCA - 15 / P52756 ) is encoded at the lung cancer tumor suppressor locus 3p21 . 3 and itself has several important characteristics of a tumor suppressor , including both potentiation of apoptosis and inhibition of the cell cycle . Here , we report the effects of both upregulation and downregulation of LUCA - 15 / P52756 on gene expression monitored using cDNA microarrays . Many of the genes modulated by LUCA - 15 / P52756 are involved in the control of apoptosis , the cell cycle , or both . These effects were confirmed for the most significant genes using real - time RT - PCR and / or Western blotting . In particular , LUCA - 15 / P52756 increased the expression of Stat5b and P22003 and decreased the expression of Q9Y6Q9 ( Amplified In Breast Cancer 1 ) , proto - oncogene Pim - 1 , caspase antagonist Q13489 ( cIAP - 2 , MIHC ) , and P24941 ( cyclin - dependent kinase 2 ) . These effects on multiple genes controlling both apoptosis and proliferation are in line with the functional effects of LUCA - 15 / P52756 and indicate that it plays a central role in regulating cell fate consistent with its tumor suppressor activity .",
"Identification of a transcriptionally active peroxisome proliferator - activated receptor alpha - interacting cofactor complex in rat liver and characterization of Q9BYK8 as a coactivator . Q07869 ( Q07869 alpha ) plays a central role in the cell - specific pleiotropic responses induced by structurally diverse synthetic chemicals designated as peroxisome proliferators . Transcriptional regulation by liganded nuclear receptors involves the participation of cofactors that form multiprotein complexes to achieve cell - and gene - specific transcription . Here we report the identification of such a transcriptionally active Q07869 alpha - interacting cofactor ( PRIC ) complex from rat liver nuclear extracts that interacts with full - length Q07869 alpha in the presence of ciprofibrate , a synthetic ligand , and leukotriene B ( 4 ) , a natural ligand . The liganded Q07869 alpha - PRIC complex enhanced transcription from a peroxisomal enoyl - DB01992 hydratase / l - 3 - hydroxyacyl - DB01992 dehydrogenase bifunctional enzyme gene promoter template that contains peroxisome proliferator response elements . Rat liver PRIC complex comprises some 25 polypeptides , and their identities were established by mass spectrometry and limited sequence analysis . Eighteen of these peptides contain one or more LXXLL motifs necessary for interacting with nuclear receptors . PRIC complex includes known coactivators or coactivator - binding proteins ( CBP , Q15788 , PBP , PRIP , PIMT , O75448 , Q09428 - 2 , and P20142 - 1 ) , other proteins that have not previously been described in association with transcription complexes ( CHD5 , TOG , and Q8WYB5 ) , and a few novel polypeptides designated PRIC300 , - 285 , - 215 , - 177 , and - 145 . We describe the cDNA for Q9BYK8 , which contains five LXXLL motifs . It interacts with Q07869 alpha and acts as a coactivator by moderately stimulating Q07869 alpha - mediated transcription in transfected cells . We conclude that liganded Q07869 alpha recruits a distinctive multiprotein complex from rat liver nuclear extracts . The composition of this complex may provide insight into the basis of tissue and species sensitivity to peroxisome proliferators .",
"Rapid effect of P01148 on follicle - stimulating hormone beta gene expression in LbetaT2 mouse pituitary cells requires the progesterone receptor . DB00644 ( P01148 ) activates the progesterone receptor ( P06401 ) in pituitary cells and accentuates gonadotropin expression . We show that P01148 increases Fshb mRNA levels in LbetaT2 mouse pituitary cells within 8 h and is three times more effective than O43555 . By contrast , P01148 and O43555 do not affect Lhb gene expression in these cells . Within the same time frame , small interfering RNA ( siRNA ) knockdown of the P06401 in LbetaT2 cells reduced P01148 activation of a P06401 response element ( PRE ) - driven luciferase reporter gene and Fshb mRNA levels by > 50 % . Chromatin immunoprecipitation ( ChIP ) assays also demonstrated that P06401 loading on the PRE within the Fshb gene promoter in LbetaT2 cells occurred within 8 h after P01148 treatment and was lost by 24 h . While the P01148 - induced upregulation of the PRE reporter gene and Fshb mRNA levels was attenuated by cotreatment with protein kinase A ( H - 89 ) and protein kinase C ( GF109203X ) inhibitors , only GF109203X inhibited P06401 phosphorylation at Ser249 in LbetaT2 cells . Immunoprecipitation assays also showed a progressive increase in the interaction between the P06401 and its coactivator Q9Y6Q9 that peaked at 8 h coincident with the increase in Fshb mRNA after P01148 treatment . The siRNA - mediated knockdown of Q9Y6Q9 in LbetaT2 cells also reduced Fshb mRNA levels after P01148 treatment and loading of Q9Y6Q9 on the Fshb promoter PRE in a ChIP assay . We conclude that the rapid effect of P01148 on Fshb expression in LbetaT2 cells is mediated by P06401 phosphorylation and loading at the PRE within the Fshb promoter together with Q9Y6Q9 .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"___MASK39___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"17 ___MASK94___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK69___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK69___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"P00747 activator inhibitor - 1 is increased in colonic epithelial cells from patients with colitis - associated cancer . BACKGROUND : Patients with long - term ulcerative colitis are at risk for developing colorectal cancer . METHODS : Archival formalin - fixed paraffin - embedded tissue from ulcerative colitis patients who underwent a colectomy for high - grade dysplasia or carcinoma was examined for changes in expression of plasminogen activator inhibitor - 1 ( P05121 ) as well as other mediators of inflammation - associated cancer . Epithelia from areas of colons that showed histologic evidence of carcinoma , high - grade dysplasia , and epithelia that were not dysplastic or malignant but did contain evidence of prior inflammation ( quiescent colitis ) was microdissected using laser capture microscopy . mRNA was extracted from the microdissected tissue and PCR array analysis was performed . To extend our findings , P05121 protein levels were determined using immunohistochemistry . RESULTS : The mRNA expression of P05121 is increased 6 - fold ( p = 0 . 02 ) when comparing the carcinoma group to the quiescent colitis group ; increases were also observed in Q00653 , Q04864 , P12931 , and P15692 . The protein levels of P05121 are increased by 50 % ( p < 0 . 001 ) in high - grade dysplasia and by 60 % ( p < 0 . 001 ) in carcinoma when compared to the quiescent colitis group . CONCLUSIONS : The increase in P05121 in high - grade dysplasia and carcinoma suggests a functional role for P05121 in malignant transformation in colitis - associated cancer . P05121 could also prove a useful diagnostic marker to identify patients at risk for neoplasia and it may be a useful therapeutic target to treat colitis - associated cancer .",
"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK10___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK97___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Identification of new candidate therapeutic target genes in triple - negative breast cancer . Triple - negative breast cancer ( TNBC ) is a subgroup of breast cancer that is negative for estrogen and progesterone receptor and P04626 protein expression . It is characterized by its aggressive behavior and by the lack of targeted therapies . To identify new therapeutic targets in TNBC , we used real - time quantitative RT - PCR to analyze 63 TNBC samples in terms of their mRNA expression of 26 genes coding for the major proteins currently targeted by drugs used to treat other cancers or undergoing clinical trials in breast cancer . Six of the 26 genes tested ( P15692 , P12931 , P09874 , Q05397 , P04049 , and P22607 ) were significantly upregulated in 13 % to 46 % of the TNBCs . None of the 6 genes was specifically upregulated in the TNBCs compared with 3 other classical breast tumor subtypes . No association was observed between overexpression of these 6 genes ( except for P22607 ) and P42336 mutation status . These results confirm the interest of targeting P15692 and P09874 in ongoing clinical trials in TNBC patients and also identify new target genes ( P12931 , Q05397 , P04049 , and P22607 ) . Clinical trials could be initiated easily with existing drugs . Our results also suggest that these target genes might serve as predictive biomarkers of the TNBC treatment response .",
"Agonism of human pregnane X receptor by rilpivirine and etravirine : comparison with first generation non - nucleoside reverse transcriptase inhibitors . DB08864 and etravirine are second generation non - nucleoside reverse transcriptase inhibitors approved recently by the United States Food and Drug Administration for the treatment of human immunodeficiency virus - 1 infection . O75469 ( O75469 ) is a member of the superfamily of nuclear receptors that regulate the expression of various genes controlling diverse biological functions . The present study investigated the effects of rilpivirine and etravirine on the activity of human O75469 ( hPXR ) , including the mode of activation , and compared them to those of efavirenz , nevirapine , and delavirdine , which are first generation non - nucleoside reverse transcriptase inhibitors . In transiently transfected HepG2 cells , rilpivirine , etravirine , and efavirenz , but not nevirapine or delavirdine , activated human , mouse , and rat O75469 . Results from mechanistic studies indicated that rilpivirine , etravirine , and efavirenz , but not nevirapine or delavirdine , bound to the ligand - binding domain of hPXR , as assessed by a transactivation assay and by a competitive ligand - binding assay using time - resolved fluorescence resonance energy transfer ; triggered nuclear translocation of a green fluorescence protein - tagged hPXR , as visualized by confocal imaging ; and recruited steroid receptor coactivator - 1 ( Q15788 ) , P12931 - 2 , and Q9Y6Q9 to hPXR , as demonstrated by mammalian two - hybrid assays . DB08864 , etravirine , and efavirenz , but not nevirapine or delavirdine , increased hPXR target gene ( P08684 ) expression in primary cultures of human hepatocytes . In summary , select non - nucleoside reverse transcriptase inhibitors activated human and rodent O75469 . DB08864 , etravirine , and efavirenz , but not nevirapine or delavirdine , were identified as agonists of hPXR , as assessed in mechanistic experiments , and inducers of P08684 , as determined in primary cultures of human hepatocytes .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK19___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"___MASK23___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK23___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo ."
] |
[
"___MASK10___",
"___MASK19___",
"___MASK23___",
"___MASK39___",
"___MASK45___",
"___MASK69___",
"___MASK94___",
"___MASK97___",
"___MASK99___"
] |
___MASK19___
|
MH_train_440
|
interacts_with DB08439?
|
[
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK61___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK65___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK65___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"Cyclooxygenase 2 inhibition exacerbates P41181 and pAQP2 downregulation independently of V2 receptor abundance in the postobstructed kidney . Previously we demonstrated that P03950 II receptor ( AT1R ) blockade attenuates V2 receptor ( P30518 ) , P41181 , and pS256 - P41181 downregulation in the postobstructed kidney and partially reverses obstruction - induced inhibition of DB02527 generation and cyclooxygenase 2 ( P35354 ) induction . Therefore , we speculated whether the effects of AT1R blockade on P30518 and the vasopressin - regulated pathway are attributable to attenuated P35354 induction . To examine this , rats were subjected to 24 - h bilateral ureteral obstruction ( BUO ) followed by 48 - h release and treated with the P35354 inhibitor parecoxib or saline . Control rats were sham - operated . DB08439 treatment significantly reduced urine output 24 h after release of BUO whereas urine osmolality and solute - free water reabsorption was comparable between saline - and parecoxib - treated BUO rats . Immunoblotting revealed a significant decrease in P41181 and pS256 - P41181 abundance to 20 and 23 % of sham levels in parecoxib - treated BUO rats compared with 40 and 55 % of sham levels in saline - treated BUO rats . Immunohistochemistry confirmed the exacerbated P41181 and pS256 - P41181 downregulation in parecoxib - treated BUO rats . Finally , parecoxib treatment had no effect on P30518 downregulation and the inhibited , vasopressin - stimulated DB02527 generation in inner medullary membrane fractions from the postobstructed kidney . In conclusion , P35354 inhibition exacerbates P41181 and pS256 - P41181 downregulation 48 h after release of 24 - h BUO independently of P30518 abundance and vasopressin - stimulated DB02527 generation . The results indicate that P35354 inhibition does not mimic AT1R blockade - mediated effects and that AT1R - mediated P41181 regulation in the postobstructed kidney collecting duct is independent of P35354 induction .",
"Altered expression of beta - catenin , P12830 , cycloxygenase - 2 , and p53 protein by ovine intestinal adenocarcinoma cells . Around 1 . 6 % of sheep in New Zealand develop small - intestinal adenocarcinomas . These neoplasms typically develop widespread metastases . The common development of these neoplasms and their subsequent behavior suggests that sheep could be a useful animal model of human colonic cancer . However , for an animal model of human disease to be relevant , similar genetic mutations should be present . Genetic mutations within human colonic cancers frequently result in expression of cycloxygenase - 2 ( P35354 ) , loss of membranous expression of beta - catenin and P12830 , and accumulation of p53 protein within the neoplastic cells . Immunohistochemistry was used to investigate the presence of these 4 proteins within 26 ovine intestinal adenocarcinomas . Loss of membranous beta - catenin reactivity was observed in 14 of 26 ovine intestinal adenocarcinomas ( 54 % ) . The loss of membranous beta - catenin reactivity was accompanied by cytoplasmic and nuclear reactivity in 2 neoplasms . Loss of P12830 was observed within 8 of 26 neoplasms ( 31 % ) . Neoplastic cell expression of P35354 was observed in 12 of 26 neoplasms ( 46 % ) , whereas cells within 3 of 26 neoplasms ( 11 % ) contained visible p53 protein . In conclusion , all 4 proteins that commonly have altered expression in human colonic cancers were also altered in a proportion of the ovine intestinal adenocarcinomas . These results provide additional evidence that sheep could be useful for the study of human colonic cancer .",
"Efficacy and safety of intravenous parecoxib sodium in relieving acute postoperative pain following gynecologic laparotomy surgery . BACKGROUND : This study tested the hypothesis that an injectable cyclooxygenase ( P36551 ) - 2 - specific inhibitor will be at least as effective and well tolerated as a P36551 - nonspecific conventional nonsteroidal antiinflammatory drug ( NSAID ) by comparing the analgesic efficacy and tolerability of one intravenous dose of parecoxib sodium , an injectable prodrug of the novel P35354 - specific inhibitor , valdecoxib , with ketorolac and placebo in postoperative laparotomy surgery patients . Intravenous morphine , 4 mg , was studied as a positive analgesic control . METHODS : In this multicenter , double - blinded , placebo - controlled study , women experiencing moderate - to - severe pain on the first day after abdominal hysterectomy or myomectomy received one intravenous dose of parecoxib sodium , 20 or 40 mg , ketorolac , 30 mg , morphine , 4 mg , or placebo . Analgesic efficacy and tolerability were evaluated for 24 h postdose or until patients , whose pain was not adequately controlled , opted to receive rescue analgesia . RESULTS : Two hundred two patients were enrolled . All treatment groups had comparable demographics and baseline pain status . All active treatments had an equally rapid time to onset of analgesia ( 10 - 23 min ) . Overall , each parecoxib sodium dose and ketorolac were significantly superior to morphine and placebo for most measures of analgesic efficacy at most time points , including a significantly longer ( two - to threefold ) time to rescue analgesia ( P </= 0 . 05 ) . All treatments were well tolerated . CONCLUSIONS : Single intravenous doses of parecoxib sodium , 20 mg and 40 mg , have comparable analgesic effects and are well tolerated after laparotomy surgery . DB08439 sodium appears to be as effective as intravenous ketorolac , 30 mg , and superior to intravenous morphine , 4 mg .",
"[ Anticoagulants of primary haemostasis ] . Inhibition of platelet function plays an important role in the treatment and secondary prevention of cardiovascular or cerebrovascular ischemic diseases . Established antiplatelet agents use different pharmacological targets for this role . Acetyl salicylic acid achieves a reduction of thromboxane A2 formation by inhibition of P23219 . DB00208 or clopidogrel are ADP - Q9H244 receptor antagonists . Tirofiban , abciximab or eptifibatid are used for the inhibition of the glycoprotein IIb / IIIa receptor which is activated at the surface of platelets preceding the final step of their aggregation . The mechanism of dipyridamole is based on the inhibition of adenosine uptake and of phosphodiesterase - 5 . Efforts are made to improve antiplatelet therapy with the aim to find agents with favorable clinical outcome and lower bleeding risk . Current clinical studies focus on a new generation of ADP receptor antagonists ( prasugrel , cangrelor and ticagrelor ) as successors of ticlopidine and clopidogrel after coronary arterial interventions . Developments using platelet targets different from established drugs are thrombin receptor antagonists ( like SCH530348 ) or thromboxane receptor antagonists ( like S18886 / terutroban ) in patients with cerebrovascular events . Results from recent experimental studies could lead to new strategies for antiplatelet therapy ( like inhibition of GP Ib receptor , GP VI receptor , platelet - leukocyte interaction , factor XII and others ) in the future .",
"Delayed administration of parecoxib , a specific P35354 inhibitor , attenuated postischemic neuronal apoptosis by phosphorylation Akt and GSK - 3β . DB08439 is a recently described novel P35354 inhibitor whose functional significance and neuroprotective mechanisms remain elusive . Therefore , in this study , we aimed to investigate whether delayed administration of parecoxib inhibited mitochondria - mediated neuronal apoptosis induced by ischemic reperfusion injury via phosphorylating Akt and its downstream target protein , glycogen synthase kinase 3β ( GSK - 3β ) . Adult male Sprague - Dawley rats were administered parecoxib ( 10 or 30 mg kg (- 1 ) , IP ) or isotonic saline twice a day starting 24 h after middle cerebral artery occlusion ( MCAO ) for three consecutive days . Cerebral infarct volume , apoptotic neuron , caspase - 3 immunoreactivity and the protein expression of p - Akt , p - GSK - 3β and Cytochrome C in cerebral ischemic cortex were evaluated at 96 h after reperfusion . DB08439 significantly diminished infarct volume and attenuated neuron apoptosis in a dose - independent manner , compared with MCAO group alone . Increased p - Akt and p - GSK - 3β was observed in the ischemic penumbra of parecoxib group after stroke . Moreover , parecoxib also reduced the release of Cytochrome C from mitochondrial into cytosol and attenuated the caspase - 3 immunoreactivity in the penumbra . Taken together , these results suggested that parecoxib ameliorated postischemic mitochondria - mediated neuronal apoptosis induced by focal cerebral ischemia in rats and this neuroprotective potential is involved in phosphorylation of Akt and GSK - 3β .",
"DB08439 as an alternative in P35354 hypersensitivity . The group of non - steroidal anti - inflammatory drugs ( NSAIDs ) is commonly involved in hypersensitivity reactions . In clinical practice the physician is often faced with the need to choose an alternative anti - inflammatory agent for a patient who has suffered a hypersensitivity reaction to a NSAID . The most common approach to choosing the safest NSAID is to perform a challenge test . DB08439 is the first injectable P35354 selective inhibitor indicated for the treatment of acute postoperative pain . The authors report the case of a patient with a history of cutaneous adverse reactions to different classes of NSAIDs , including selective P35354 inhibitors , who underwent and tolerated challenge with parecoxib .",
"The selective cyclooxygenase - 2 inhibitor parecoxib markedly improves the ability of the duodenum to regulate luminal hypertonicity in anaesthetized rats . AIM : To examine whether the prevention of post - operative duodenal ileus by treatment with parecoxib , a selective cyclooxygenase - 2 ( P35354 ) inhibitor , affects the ability of the duodenum to respond to luminal hypertonicity . METHODS : The proximal duodenums of anaesthetized rats were perfused with hypertonic NaCl solutions with osmolalities of 400 , 500 , 600 or 700 mOsm kg (- 1 ) , and the effects on mucosal permeability , motility , transepithelial net fluid flux and effluent osmolality were assessed in the absence ( control ) and presence of parecoxib . RESULTS : DB08439 - treated , but not control animals , exhibited duodenal contractions , which were reduced by the nicotinic receptor antagonists mecamylamine and hexamethonium and by perfusion with 700 mOsm kg (- 1 ) . All animals responded to luminal hypertonicity with induction of net fluid secretion , which peaked at an osmolality of 500 mOsm kg (- 1 ) . The hypertonicity - induced increases in fluid secretion were twofold greater in parecoxib - treated than in control rats and attenuated by nicotinic receptor blockade . The decrease in luminal osmolality correlated with the osmolality of the perfusion solution in both control and parecoxib - treated animals but the osmolality - adjusting capability was markedly better in the latter group . Rats exposed to duodenal luminal distension responded to hypertonicity with a greater fluid secretion and a larger decrease in luminal osmolality than control rats . Perfusion with 700 mOsm kg (- 1 ) increased mucosal permeability in parecoxib - treated animals only , an effect abolished by nicotinic receptor blockade . CONCLUSION : DB08439 markedly improved the ability of the duodenum to sense and to decrease luminal hypertonicity by a mechanism most probably involving inhibition of P35354 and stimulation of nicotinic acetylcholine receptors .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"P62158 - sensitive adenylyl cyclases mediate AVP - dependent DB02527 production and Cl - secretion by human autosomal dominant polycystic kidney cells . In autosomal dominant polycystic kidney disease ( ADPKD ) , binding of AVP to the V2 receptor ( P30518 ) increases DB02527 and accelerates cyst growth by stimulating cell proliferation and Cl (-)- dependent fluid secretion . Basal DB02527 is elevated in human ADPKD cells compared with normal human kidney ( NHK ) cells . P30518 mRNA levels are elevated in ADPKD cells ; however , AVP caused a greater increase in global DB02527 in NHK cells , suggesting an intrinsic difference in DB02527 regulation . Expression , regulatory properties , and receptor coupling of specific adenylyl cyclases ( ACs ) provide temporal and spatial regulation of the DB02527 signal . ADPKD and NHK cells express mRNAs for all nine ACs . Ca ( 2 +)- inhibited ACs 5 and 6 are increased in ADPKD cells , while Ca ( 2 +)/ P62158 - stimulated ACs 1 and 3 are downregulated . ACs 1 , 3 , 5 , and 6 were detected in cyst cells in situ , and codistribution with aquaporin - 2 suggests that these cysts were derived from collecting ducts . To determine the contribution of P62158 - sensitive ACs to AVP signaling , cells were treated with W - 7 , a P62158 inhibitor . W - 7 decreased AVP - induced DB02527 production and Cl (-) secretion by ADPKD cells . CaMKII inhibition increased AVP - induced DB02527 , suggesting that DB02527 synthesis is mediated by O60266 . In contrast , P62158 and CaMKII inhibition in NHK cells did not affect AVP - induced DB02527 production . Restriction of intracellular Ca ( 2 +) switched the response in NHK cells , such that P62158 inhibition decreased AVP - induced DB02527 production . We suggest that a compensatory response to decreased Ca ( 2 +) in ADPKD cells switches P30518 coupling from Ca ( 2 +)- inhibited ACs 5 / 6 to Ca ( 2 +)/ P62158 - stimulated O60266 , to mitigate high DB02527 levels in response to continuous AVP stimulation .",
"P35354 inhibition attenuates endotoxin - induced downregulation of organic anion transporters in the rat renal cortex . Renal excretion of organic anions such as DB00345 is reduced during severe sepsis and following ischemia / reperfusion injury . In order to better define the pathophysiology of sepsis - associated renal tubular dysfunction we measured the effect of lipopolysaccharide on renocortical organic anion transporter ( P04181 ) expression in the rat . DB00917 ( DB00917 ) downregulates OATs in vitro , therefore , we also evaluated the effect of the cyclooxygenase ( P36551 ) - 2 inhibitor parecoxib on this process . Endotoxemia caused a time - and dose - dependent decrease of Q4U2R8 and Q8TCC7 expression that paralleled increased renocortical P35354 expression and DB00917 formation . Pretreatment with parecoxib decreased endotoxin - stimulated PGE ( 2 ) formation . DB08439 attenuated Q4U2R8 and Q8TCC7 gene repression in the rat kidney following endotoxin treatment and during ischemia / reperfusion - induced acute renal injury . P35354 inhibition improved the creatinine clearance in lipopolysaccharide - treated rats but not after ischemia / reperfusion - induced acute renal injury . The decreased clearance of DB00345 in rats following endotoxin - or ischemia / reperfusion - induced renal injury was improved by parecoxib . Our findings show that P35354 derived prostanoids downregulate OATs during lipopolysaccharide - induced acute renal injury .",
"Thrombosis is reduced by inhibition of P23219 , but unaffected by inhibition of P35354 , in an acute model of platelet activation in the mouse . BACKGROUND : Clinical use of selective inhibitors of cyclooxygenase ( P36551 ) - 2 appears associated with increased risk of thrombotic events . This is often hypothesised to reflect reduction in anti - thrombotic prostanoids , notably P06744 ( 2 ) , formed by P35354 present within endothelial cells . However , whether P35354 is actually expressed to any significant extent within endothelial cells is controversial . Here we have tested the effects of acute inhibition of P36551 on platelet reactivity using a functional in vivo approach in mice . METHODOLOGY / PRINCIPAL FINDINGS : A non - lethal model of platelet - driven thromboembolism in the mouse was used to assess the effects of aspirin ( 7 days orally as control ) diclofenac ( 1 mg . kg (- 1 ) , i . v . ) and parecoxib ( 0 . 5 mg . kg (- 1 ) , i . v . ) on thrombus formation induced by collagen or the thromboxane ( TX ) A ( 2 )- mimetic , U46619 . The P36551 inhibitory profiles of the drugs were confirmed in mouse tissues ex vivo . Collagen and U46619 caused in vivo thrombus formation with the former , but not latter , sensitive to oral dosing with aspirin . Diclofenac inhibited P23219 and P35354 ex vivo and reduced thrombus formation in response to collagen , but not U46619 . DB08439 inhibited only P35354 and had no effect upon thrombus formation caused by either agonist . CONCLUSIONS / SIGNIFICANCE : Inhibition of P23219 by diclofenac or aspirin reduced thrombus formation induced by collagen , which is partly dependent upon platelet - derived TXA ( 2 ) , but not that induced by U46619 , which is independent of platelet TXA ( 2 ) . These results are consistent with the model demonstrating the effects of P23219 inhibition in platelets , but provide no support for the hypothesis that acute inhibition of P35354 in the circulation increases thrombosis .",
"___MASK70___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK70___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK70___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK70___ inhibits activated T cells . We show that in vitro , ___MASK70___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK70___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK70___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK70___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK70___ to treat chronic inflammatory disease .",
"Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .",
"DB08439 has non - significant long - term effects on bone healing in rats when administered for a short period after fracture . INTRODUCTION : Selective and non - selective cyclo - oxygenase ( P36551 ) inhibitors impair bone healing by inhibiting prostaglandin synthesis . The purpose of this study was to evaluate the long - term effect of parecoxib , a selective P35354 inhibitor , on bone healing in rats , when it is applied in a pattern similar to clinical treatment patterns , that is , in a high dose and for a short period after bone fracture . METHOD : Closed non - displaced mid - diaphyseal fractures in the middle of the left femoral shaft were generated in each animal . In the study group , parecoxib sodium ( 1 . 06 mg / kg ) was administered intra - peritoneally every day for 7 days . In the control group , normal saline was administered intra - peritoneally every day for 7 days . In both groups fracture healing ( bone union and callus formation ) was evaluated with X - rays 28 and 42 days after surgery . RESULTS : Bone healing was lower in the study group ( 60 vs . 80 % in the control group 28 days after fracture and 80 vs . 90 % 42 days after fracture ) but this difference was not statistically significant ( P > 0 . 05 ) . CONCLUSION : DB08439 does not have a significant long - term effect on bone healing in rats , when it is administered in a high dose and for a short period after bone fracture .",
"Role of the JAK - P35610 pathway in protection against myocardial ischemia / reperfusion injury . The Janus kinase ( JAK ) - signal transducers and activators of transcription ( P35610 ) pathway is a stress - responsive mechanism that transduces signals from the cell surface to the nucleus , thereby modulating gene expression . Recent studies have demonstrated that myocardial ischemia and reperfusion induce rapid activation of this pathway . Although the functional consequences of this event remain to be elucidated , there is emerging evidence that JAK - P35610 signaling plays an important role in the development of the cardioprotected phenotype associated with ischemic preconditioning . Specifically , brief episodes of myocardial ischemia / reperfusion activate P23458 and O60674 , followed by recruitment of P42224 and P40763 , resulting in transcriptional upregulation of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) , which then mediate the infarct - sparing effects of the late phase of preconditioning . The present review focuses on this novel cardioprotective role of JAK - P35610 signaling and on its potential exploitation for developing therapeutic strategies aimed at limiting ischemia / reperfusion injury .",
"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK49___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .",
"DB08439 suppresses P35638 and Foxo1 nuclear translocation , but increases P11021 levels in a rat model of focal ischemia . DB08439 , a novel P35354 inhibitor , functions as a neuroprotective agent and rescues neurons from cerebral ischemic reperfusion injury - induced apoptosis . However , the molecular mechanisms underlying parecoxib neuroprotection remain to be elucidated . There is growing evidence that endoplasmic reticulum ( ER ) stress plays an important role in neuronal death caused by brain ischemia . However , very little is known about the role of parecoxib in mediating pathophysiological reactions to ER stress induced by ischemic reperfusion injury . Therefore , in the present study , we investigated whether delayed administration of parecoxib attenuates brain damage via suppressing ER stress - induced cell death . Adult male Sprague - Dawley rats were administered parecoxib ( 10 or 30 mg kg (- 1 ) , IP ) or isotonic saline twice a day starting 24 h after middle cerebral artery occlusion ( MCAO ) for three consecutive days . The expressions of glucose - regulated protein 78 ( P11021 ) and oxygen - regulated protein 150 ( Q9Y4L1 ) and P35638 ( P35638 ) and forkhead box protein O 1 ( Foxo1 ) in cytoplasmic and nuclear fraction were determined by Western blotting . The levels of caspase - 12 expression were checked by immunohistochemistry analysis , served as a marker for ER stress - induced apoptosis . DB08439 significantly suppressed cerebral ischemic injury - induced nuclear translocation of P35638 and Foxo1 and attenuated the immunoreactivity of caspase - 12 in ischemic penumbra . Furthermore , the protective effect of delayed administration of parecoxib was accompanied by an increased P11021 and Q9Y4L1 expression . Therefore , our study suggested that elevation of P11021 and Q9Y4L1 , and suppression of P35638 and Foxo1 nuclear translocation may contribute to parecoxib - mediated neuroprotection during ER stress responses .",
"NSAIDS inhibit in vitro O60682 chondrogenesis but not osteogenesis : implications for mechanism of bone formation inhibition in man . The non - steroidal anti - inflammatory drugs ( NSAIDs ) are widely used for analgesia but may inhibit bone formation . We investigated whether the reported NSAID effect on bone is related to inhibition of bone marrow mesenchymal stem cell ( O60682 ) proliferation and osteogenic and chondrogenic differentiation and evaluated both cyclooxygenase ( P36551 ) - 1 and P35354 specific drugs . The effects of seven P23219 and P35354 inhibitors on O60682 proliferation and osteogenic and chondrogenic differentiation were tested using Vybrant , sodium 3 '- [ 1 -( phenylaminocarbonyl )- 3 , 4 - tetrazolium ] - bis ( 4 - methoxy - 6 - nitro ) benzene sulfonic acid hydrate ( XTT ) , functional and quantitative assays of O60682 differentiation . The O60682 expression of P23219 and P35354 and prostaglandin E2 ( PGE - 2 ) levels were evaluated serially during lineage differentiation by quantitative PCR and ELISA . None of the NSAIDs at broad range of concentration ( range 10 (- 3 ) to 100 μg / ml ) significantly affected O60682 proliferation . Surprisingly , O60682 osteogenic differentiation inhibition was not evident . However , NSAIDs affected chondrogenic potential with a reduction in sulphated glycosaminoglycans ( sGAG ) content by 45 % and 55 % with diclofenac and ketorolac , respectively ( P < 0 . 05 compared to controls ) . DB08439 and meloxicam , more P35354 specific reagents inhibited sGAG to a lesser degree , 22 % and 27 % respectively ( P < 0 . 05 compared to controls ) . Cartilage pellet immunohistochemistry confirmed the above results . Pellet chondrogenesis was associated with increased P23219 expression levels but not P35354 , and P23219 specific drugs suppressed O60682 PGE - 2 more than P35354 specific inhibitors . These findings suggest that NSAIDs may inhibit bone formation via blockage of O60682 chondrogenic differentiation which is an important intermediate phase in normal endochondral bone formation .",
"Single doses of parecoxib sodium intravenously are as effective as ketorolac in reducing pain after oral surgery . PURPOSE : Our goal was to compare the analgesic efficacy and safety of single doses of intravenous parecoxib sodium , a prodrug of the novel cyclooxygenase ( P36551 ) - 2 - selective inhibitor valdecoxib , with intravenous ketorolac and placebo in postoperative oral surgery patients . PATIENTS AND METHODS : Eligible patients experiencing moderate to severe pain within 6 hours of surgery to extract 2 or more impacted third molars were randomized to receive a single dose of parecoxib sodium 1 , 2 , 5 , 10 , 20 , 50 , or 100 mg ; ketorolac 30 mg ; or placebo . Analgesic efficacy was assessed over a 24 - hour treatment period or until rescue analgesia was required . RESULTS : DB08439 sodium doses ( particularly 50 and 100 mg ) had a rapid onset of analgesia ( within 11 minutes ) . The analgesic efficacy of parecoxib sodium 20 to 100 mg was similar to that of ketorolac 30 mg . DB08439 sodium doses below 20 mg had suboptimal analgesic activity compared with placebo and ketorolac . A plateau of efficacy was observed at the parecoxib sodium 50 - mg dose . DB08439 sodium 50 and 100 mg had a significantly longer duration of analgesia than ketorolac 30 mg . All doses of parecoxib sodium were well tolerated . CONCLUSIONS : DB08439 sodium , a novel parenteral prodrug of the P35354 - selective inhibitor valdecoxib , is as effective and longer acting at 50 - and 100 - mg intravenous doses than a standard dose of ketorolac 30 mg intravenously . DB08439 sodium appears to be safe and well tolerated and , therefore , merits further evaluation in other models of postsurgical pain .",
"Multifaceted link between cancer and inflammation . Increasing evidence from epidemiological , preclinical and clinical studies suggests that dysregulated inflammatory response plays a pivotal role in a multitude of chronic ailments including cancer . The molecular mechanism ( s ) by which chronic inflammation drives cancer initiation and promotion include increased production of pro - inflammatory mediators , such as cytokines , chemokines , reactive oxygen intermediates , increased expression of oncogenes , P35354 ( cyclo - oxygenase - 2 ) , 5 - P28300 ( P09917 ) and MMPs ( matrix metalloproteinases ) , and pro - inflammatory transcription factors such as NF - κB ( nuclear factor κB ) , P40763 ( signal transducer and activator of transcription 3 ) , AP - 1 ( activator protein 1 ) and HIF - 1α ( hypoxia - inducible factor 1α ) that mediate tumour cell proliferation , transformation , metastasis , survival , invasion , angiogenesis , chemoresistance and radioresistance . These inflammation - associated molecules are activated by a number of environmental and lifestyle - related factors including infectious agents , tobacco , stress , diet , obesity and alcohol , which together are thought to drive as much as 90 % of all cancers . The present review will focus primarily on the role of various inflammatory intermediates responsible for tumour initiation and progression , and discuss in detail the critical link between inflammation and cancer .",
"Temporal and pharmacological characterization of angiostatin release and generation by human platelets : implications for endothelial cell migration . Platelets play an important role in thrombosis and in neo - vascularisation as they release and produce factors that both promote and suppress angiogenesis . Amongst these factors is the angiogenesis inhibitor angiostatin , which is released during thrombus formation . The impact of anti - thrombotic agents and the kinetics of platelet angiostatin release are unknown . Hence , our objectives were to characterize platelet angiostatin release temporally and pharmacologically and to determine how angiostatin release influences endothelial cell migration , an early stage of angiogenesis . We hypothesized anti - platelet agents would suppress angiostatin release but not generation by platelets . Human platelets were aggregated and temporal angiostatin release was compared to vascular endothelial growth factor ( P15692 ) . Immuno - gold electron microscopy and immunofluorescence microscopy identified α - granules as storage organelles of platelet angiostatin . Acetylsalicylic acid , MRS2395 , P08514 / IIIa blocking peptide , and aprotinin were used to characterize platelet angiostatin release and generation . An endothelial cell migration assay was performed under hypoxic conditions to determine the effects of pharmacological platelet and angiostatin inhibition . Compared to P15692 , angiostatin generation and release from α - granules occurred later temporally during platelet aggregation . Consequently , collagen - activated platelet releasates stimulated endothelial cell migration more potently than maximally - aggregated platelets . Platelet inhibitors prostacyclin , S - nitroso - glutathione , acetylsalicylic acid , and P08514 / IIIa blocking peptide , but not a Q9H244 inhibitor , suppressed angiostatin release but not generation . Suppression of angiostatin generation in the presence of acetylsalicylic acid enhanced platelet - stimulated endothelial migration . Hence , the temporal and pharmacological modulation of platelet angiostatin release may have significant consequences for neo - vascularization following thrombus formation .",
"DB08439 does not suppress thromboxane synthesis in newborn piglets with group B streptococcal sepsis . Group B streptococci ( GBS ) cause fatal sepsis in newborns . Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension . In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP - 3 receptor gene expression . Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP - 3 receptor in infected lung tissue , parecoxib did not suppress urine levels of thromboxane like indometacin . We presume that P35354 inhibition in GBS sepsis is associated with enhanced thrombogenicity .",
"Effects of nitric oxide synthase inhibition with or without cyclooxygenase - 2 inhibition on resting haemodynamics and responses to exendin - 4 . BACKGROUND AND PURPOSE : Interactions between the NO system and the cyclooxygenase systems may be important in cardiovascular regulation . Here we measured the effects of acute cyclooxygenase - 2 inhibition ( with parecoxib ) , alone and in combination with NOS inhibition ( with NG - nitro - L - arginine methyl ester ( L - NAME ) ) , on resting cardiovascular variables and on responses to the glucagon - like peptide 1 agonist , exendin - 4 , which causes regionally - selective vasoconstriction and vasodilatation . EXPERIMENTAL APPROACH : Rats were instrumented with flow probes and intravascular catheters to measure regional haemodynamics in the conscious , freely moving state . L - NAME was administered as a primed infusion 180 min after administration of parecoxib or vehicle , and exendin - 4 was given 60 min after the onset of L - NAME infusion . KEY RESULTS : DB08439 had no effect on resting cardiovascular variables or on responses to L - NAME . Exendin - 4 caused a pressor response accompanied by tachycardia , mesenteric vasoconstriction and hindquarters vasodilatation . DB08439 did not affect haemodynamic responses to exendin - 4 , but L - NAME inhibited its hindquarters vasodilator and tachycardic effects . When combined , L - NAME and parecoxib almost abolished the hindquarters vasodilatation while enhancing the pressor response . CONCLUSIONS AND IMPLICATIONS : P35354 - derived products do not affect basal haemodynamic status in conscious normotensive rats , or influence the NO system acutely . The inhibitory effects of L - NAME on the hindquarters vasodilator and tachycardic effects of exendin - 4 are consistent with a previous study that showed those events to be beta - adrenoceptor mediated . The additional effect of parecoxib on responses to exendin - 4 in the presence of L - NAME , is consistent with other evidence for enhanced involvement of vasodilator prostanoids when NO production is reduced .",
"DB08439 . Pharmacia corp . Pharmacia ( formerly Monsanto ) is developing parecoxib , an injectable P35354 inhibitor , for the management of post - surgical acute pain [ 287279 ] , [ 313957 ] . By January 1999 , the compound was in phase III trials for this indication [ 312280 ] . In October 2000 , Pharmacia submitted an NDA for parecoxib sodium for the management of acute pain to the FDA . The company anticipated a 12 - month review of the NDA [ 387654 ] but received a ' not approvable ' letter in July 2001 , indicating there were deficiencies in the filing ; at this time , Pharmacia anticipated refiling before the end of 2002 [ 415668 ] . Under a license agreement with Pharmacia Corp , parecoxib ( designated YM - 177 ) is being developed in Japan by Yamanouchi [ 392030 ] . Prior to the FDA ruling , in June 2000 , the company anticipated that the compound would be launched by 2001 [ 370466 ] . In March 2000 , Merrill Lynch predicted that parecoxib would be filed in the third quarter of 2000 [ 361969 ] , [ 382577 ] . By May 2001 , the analysts revised their predictions to launch in 2002 [ 411811 ] .",
"Effects of parecoxib on plasma protein extravasation and c - fos expression in the rat . OBJECTIVE : We aimed to investigate the effects of the cyclooxygenases - 2 ( P35354 ) inhibitor parecoxib on meningeal plasma protein extravasation ( PPE ) and on c - fos expression in the nucleus trigeminalis caudalis in an animal model of trigeminovascular activation . Background .- Recent reports about the efficacy of P35354 inhibitors in migraine treatment suggest the involvement of P35354 in migraine pathophysiology . So far , studies on the role of P35354 in animal models of migraine are lacking . METHODS : Unilateral electrical stimulation of the trigeminal ganglion was performed in anesthetized male Sprague Dawley rats . We assessed PPE in the ipsilateral dura mater and expression of c - fos within the ipsilateral trigeminal nucleus caudalis ( P24821 ) under control conditions and after pretreatment with parecoxib . RESULTS : DB08439 significantly attenuated PPE in the rat dura mater . The PPE ratio under control conditions ( 1 . 73 +/- 0 . 19 ( mean +/- SD ) ) was reduced by 58 . 9 +/- 30 % after pretreatment with 10 mg / kg parecoxib and by 78 . 1 +/- 23 % after pretreatment with 50 mg / kg . c - fos experiments : Compared with vehicle , all doses of parecoxib ( 1 mg / kg , 10 mg / kg , 50 mg / kg ) significantly reduced the number of c - fos positive cells in the ipsilateral P24821 ( P < . 05 ) . The number of c - fos positive cells in the ipsilateral P24821 was 50 +/- 2 . 7 ( mean +/- SEM ) under control conditions and 9 . 1 +/- 0 . 6 after pretreatment with 50 mg / kg parecoxib . CONCLUSION : Our study results suggest that P35354 is involved in neurogenic inflammation of the rat dura mater . Moreover , the study points to a role of P35354 inhibitors in trigeminal nociception at the second - order level .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK73___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"The P35354 inhibitor parecoxib is neuroprotective but not antiepileptogenic in the pilocarpine model of temporal lobe epilepsy . The enzyme cyclooxygenase - 2 ( P35354 ) , which catalyzes the production of pro - inflammatory prostaglandins , is induced in the brain after various insults , thus contributing to brain inflammatory processes involved in the long - term consequences of such insults . Mounting evidence supports that inflammation may contribute to epileptogenesis and neuronal injury developing after brain insults . Anti - inflammatory treatments , such as selective P35354 inhibitors , may thus constitute a novel approach for anti - epileptogenesis or disease - modification after brain injuries such as head trauma , cerebral ischemia or status epilepticus ( SE ) . However , recent rat experiments with prophylactic administration of two different P35354 inhibitors after SE resulted in conflicting results . In the present study , we evaluated whether treatment with parecoxib , a pro - drug of the highly potent and selective P35354 inhibitor valdecoxib , alters the long - term consequences of a pilocarpine - induced SE in rats . DB08439 was administered twice daily at 10 mg / kg for 18 days following SE . Five weeks after termination of treatment , spontaneous recurrent seizures were recorded by continuous video / EEG monitoring . Prophylactic treatment with parecoxib prevented the SE - induced increase in prostaglandin E ( 2 ) and reduced neuronal damage in the hippocampus and piriform cortex . However , the incidence , frequency or duration of spontaneous seizures developing after SE or the behavioral and cognitive alterations associated with epilepsy were not affected by parecoxib . Only the severity of spontaneous seizures was reduced , indicating a disease - modifying effect . These results substantiate that P35354 contributes to neuronal injury developing after SE , but inhibition of P35354 is no effective means to modify epileptogenesis .",
"The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .",
"Ovarian hyperstimulation syndrome inhibition by targeting P15692 , P35354 and calcium pathways : a preclinical randomized study . OBJECTIVE : The efficacy of vascular endothelial growth factor ( P15692 ) , P35354 , calcium and aromatase inhibitors in an ovarian hyperstimulation syndrome ( OHSS ) rat model was tested . METHODS : One hundred and eight female Wistar rats were randomly divided in nine groups . The control group received saline , while the OHSS group received rec - DB00094 for 4 consecutive days . The other seven groups received rec - DB00094 ( 4d ) and DB00112 twice , DB08439 daily , Verapamil daily , DB08439 daily and DB00112 twice , Verapamil daily and DB00112 twice , DB08439 and Verapamil daily , Letrozole and Meloxicam daily , respectively . All groups received also hCG at the 5th day . RESULTS : All intervention groups were characterized by reduced vascular permeability compared to the OHSS group , which in the groups of Verapamil ( DB01373 inhibition ) and DB08439 + Verapamil ( P35354 + DB01373 inhibition ) presented significant statistical difference . The Verapamil group showed the lowest corpus luteum formation , while the DB08439 ( P35354 inhibition ) , the DB08439 + Verapamil ( P35354 + DB01373 inhibition ) , the DB00112 + DB08439 ( P15692 + P35354 inhibition ) and the DB00112 + Verapamil ( P15692 + DB01373 inhibition ) groups were also characterized by lower corpus luteum numbers compared to the OHSS group . Furthermore , lower graafian follicle formation was observed in the above groups , while the ovarian weight and the hormonal profile were not significantly affected . CONCLUSIONS : Studying the different check points of the P15692 pathway , we conclude that targeting calcium pathways could be beneficial for the vascular permeability control in an OHSS animal model .",
"___MASK59___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK59___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK59___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK59___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK59___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"The pharmacokinetics and in vitro / ex vivo cyclooxygenase selectivity of parecoxib and its active metabolite valdecoxib in cats . DB08439 ( PX ) is an injectable prodrug of valdecoxib ( VX , which is a selective cyclo - oxyganase - 2 ( P35354 ) ) inhibitor licensed for humans . The aim of the present study was to evaluate pharmacokinetics and in vitro / ex vivo cyclooxygenase selectivity of PX and VX in cats . In a whole blood in vitro study , PX did not affect either P36551 enzymes whereas VX revealed a P35354 selective inhibitory effect in feline whole blood . The IC50 values of VX for P35354 and P23219 were 0 . 45 and 38 . 6 µM , respectively . Six male cats were treated with 2 . 5 mg / kg of PX by intramuscular injection . PX was rapidly converted to VX with a relatively short half - life of 0 . 4 h . VX achieved peak plasma concentration ( 2 . 79 ± 1 . 59 µg / mL ) at 7 h following PX injection . The mean residence times for PX and VX were 0 . 43 ± 0 . 15 and 5 . 94 ± 0 . 88 h , respectively . In the ex vivo study , PX showed a P35354 inhibition rate of about 70 % in samples taken at 1 , 2 , 4 and 10 h after injection , with a significant difference compared to the control . In contrast , P23219 was slightly inhibited , ranging from 0 . 7 % to 9 . 7 % of the control inhibition rate without any significant difference for 24 h after PX administration . The preliminary findings of the present research appear promising and encourage further studies to investigate whether PX can be successfully used in feline medicine .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Genetic mechanism of aspirin - induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin - related hypersensitivity often associated with aspirin - intolerant asthma . Genetic studies on aspirin - intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin - induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin - induced urticaria / angioedema . A polymorphism study that examined nine single - nucleotide polymorphisms of five leukotriene - related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 - activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( - 1708A > G ) and Q9Y271 ( - 634C > T ) were significantly different between aspirin - intolerant asthma and aspirin - induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine - related genes , did not find any significant associations with aspirin - induced urticaria / angioedema for the genes P50135 ( encoding histamine N - methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high - affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin - induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin - induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .",
"Increased risk of cardiovascular events with parecoxib / valdecoxib : a systematic review and meta - analysis . OBJECTIVE : To determine the risk of serious cardiovascular events associated with the use of the P35354 inhibitor valdecoxib and its prodrug parecoxib following major surgery . METHODS : A systematic review and meta - analysis of placebo - controlled randomised double - blind clinical trials of IV parecoxib followed by oral valdecoxib treatment , that presented data on serious cardiovascular events . Studies were identified from six databases including Medline and the FDA website on parecoxib / valdecoxib . The main outcome measure was major cardiovascular events . The pooled fixed effects estimates for the odds ratio for risk of cardiovascular events for the use of parecoxib / valdecoxib were calculated using the inverse variance weighting method . RESULTS : Three studies with a total of 2 , 604 subjects were included in the meta - analysis . DB08439 / valdecoxib was associated with a significantly increased risk of major cardiovascular events , with an odds ratio of 2 . 3 ( 95 % CI : 1 . 1 - 4 . 7 ) . CONCLUSION : There is an increased cardiovascular risk associated with parecoxib / valdecoxib therapy in the post - surgical situation . These findings are consistent with a class effect for P35354 inhibitors increasing the risk of cardiovascular events .",
"Inhibition of JAKs in macrophages increases lipopolysaccharide - induced cytokine production by blocking P22301 - mediated feedback . Macrophages are an important source of cytokines following infection . Stimulation of macrophages with TLR agonists results in the secretion of P01375 - α , P05231 , and IL - 12 , and the production of these cytokines is controlled by multiple feedback pathways . Macrophages also produce P22301 , which acts to inhibit proinflammatory cytokine production by macrophages via a JAK / P40763 - dependent pathway . We show in this paper that , ___MASK55___ , a recently described selective inhibitor of JAKs , increases P01375 , P05231 , and IL - 12 secretion in mouse bone marrow - derived macrophages stimulated with LPS . This effect is largely due to its ability to block P22301 - mediated feedback inhibition on cytokine transcription in macrophages . Similar results were also obtained with a second structurally unrelated Jak inhibitor , DB08895 . In addition , LPS induced the production of IFN - β , which was then able to activate JAKs in macrophages , resulting in the stimulation of P42224 phosphorylation . The initial induction of P22301 was independent of JAK signaling ; however , inhibition of JAKs did reduce P22301 secretion at later time points . This reflected a requirement for the IFN - β feedback loop to sustain P22301 transcription following LPS stimulation . In addition to P22301 , IFN - β also helped sustain P05231 and IL - 12 transcription . Overall , these results suggest that inhibition of JAKs may increase the inflammatory potential of macrophages stimulated with O00206 agonists .",
"Effect of selective inhibition of cyclooxygenase - 2 on lipopolysaccharide - induced hyperalgesia . Lipopolysaccharide ( LPS ) is known to increase the expression and release of various pro - inflammatory mediators , including cyclooxygenase - 2 ( P35354 ) and produce hyperalgesia . It is also well known that prostaglandins ( PGs ) , synthesised both in the periphery and centrally by P36551 isoforms , play a key role in sensitisation of nociceptors and nociceptive processing . To investigate the role of P35354 in LPS - induced hyperalgesia , parecoxib , a selective P35354 - inhibiting pro - drug , was injected intravenously 30 min before assessing hyperalgesia induced by intraperitoneal or subcutaneous administration of LPS ( 50 microg / mouse or 25 microg / paw of rat , respectively ) . DB03166 - induced writhing and tail immersion assay in mice and paw withdrawal response to thermal and mechanical stimuli in rats were used to assess the effect of inhibition of P35354 on LPSinduced hyperalgesia . Animals showed significant hyperalgesic behavior 8 h after LPS injection . DB08439 ( up to 20 mg / kg , i . v . ) had no effect in the two acute nociceptive assays but showed marked antinociceptive activity in writhing and tail immersion assay in LPS - pretreated mice . Similarly , parecoxib reversed the hyperalgesia in the LPS - injected paw but not in the contralateral paw of rats . Pre - treatment with dexamethasone , an inhibitor of P35354 expression before LPS injection significantly affected the development of hyperalgesia in both mice and rats . These findings suggest that inducible P35354 derived PGs are involved in central nociceptive processing , which resulted in hyperalgesic behavior following LPS administration and inhibition of P35354 or its expression attenuated LPS - induced hyperalgesia .",
"Modulation of mucosal permeability by vasoactive intestinal peptide or lidocaine affects the adjustment of luminal hypotonicity in rat duodenum . AIMS : To examine whether modulation of paracellular solute permeability affects the capability of the duodenum to adjust luminal osmolality . METHODS : Proximal duodenum was perfused with a hypotonic NaCl solution and effects on paracellular permeability to ( 51 ) Cr - DB00974 , motility , anion secretion , net fluid flux and perfusate osmolality determined in anaesthetized rats in the absence and presence of the P35354 inhibitor parecoxib . Vasoactive intestinal peptide ( P01282 ) was used to reduce and lidocaine to augment the hypotonicity - induced increase in paracellular permeability . RESULTS : DB01174 hypotonicity slightly increased paracellular permeability in control animals . DB08439 induced motility , increased electrolyte and fluid secretion , potentiated the hypotonicity - induced rise in paracellular permeability and enhanced the capability to adjust luminal osmolality . P01282 , given to control animals stimulated electrolyte and fluid secretion and augmented the capability to adjust luminal osmolality . Administration of P01282 to parecoxib - treated animals increased secretion further , markedly reduced the hypotonicity - induced increase in permeability but did not change the osmolality - adjusting capability . DB01174 lidocaine potentiated the hypotonicity - induced increase in permeability , reduced the hypotonicity - induced net fluid absorption and the osmolality - adjusting capability was 50 % greater than in controls . DB00281 , given to parecoxib - treated animals potentiated the hypotonicity - induced increase in permeability , reduced the hypotonicity - induced net fluid absorption but did not change the osmolality - adjusting capability . CONCLUSIONS : Vasoactive intestinal peptide reduces the osmolality - adjusting capacity of the duodenum by inhibiting paracellular solute permeability but improves this capacity by stimulating active electrolyte and fluid secretion . In contrast , lidocaine improves the osmolality - adjusting capability by augmenting paracellular solute transport but depresses it by reducing the hypotonicity - induced net fluid absorption .",
"Motility - induced but not vasoactive intestinal peptide - induced increase in luminal alkalinization in rat duodenum is dependent on luminal Cl (-) . AIM : to investigate whether the motility - and the vasoactive intestinal peptide ( P01282 ) - induced increase in luminal alkalinization in the duodenum is dependent on luminal Cl (-) . METHODS : experiments were performed in anaesthetized rats in vivo . The proximal duodenum was perfused luminally with an isotonic solution , containing zero or low Cl (-) and the effects on luminal alkalinization , motility , fluid flux and epithelial permeability were determined . DB08439 , a P35354 inhibitor , was used to induce duodenal contractions . RESULTS : control rats lacked duodenal wall contractions while parecoxib - treated ones exhibited contractions throughout the experiment . Most animals had a net fluid absorption during the perfusion with isotonic NaCl . DB01174 alkalinization was about 100 % higher in parecoxib - treated rats than in controls . Cl (-) - free solutions did not affect epithelial permeability or motility but decreased luminal alkalinization by ≥ 50 % and decreased net fluid absorption in both control and parecoxib - treated animals . Reduction in luminal Cl (-) decreased alkalinization in a concentration - dependent manner . The parecoxib - induced increase in alkalinization was markedly reduced in the absence of luminal Cl (-) . P01282 increased luminal alkalinization and induced fluid secretion . The lack of luminal Cl (-) did not affect the P01282 - induced increase in alkalinization but reduced fluid secretion . CONCLUSIONS : the parecoxib - induced increase in luminal alkalinization is highly dependent on luminal Cl (-) and it is proposed that P35354 inhibition , via induction of duodenal motility , enhances HCO ( 3 ) ( - ) efflux through stimulation of apical Cl (-) / HCO ( 3 ) ( - ) exchange in duodenal epithelial cells . Although the P01282 - induced stimulation of fluid secretion is partly dependent on luminal Cl (-) , the P01282 - induced increase in luminal alkalinization is not .",
"DB08439 and indomethacin delay early fracture healing : a study in rats . Nonsteroidal antiinflammatory drugs ( NSAIDs ) are used to reduce inflammatory response and pain . These drugs have been reported to impair bone metabolism . DB08439 , a specific P35354 inhibitor , exerts an inhibitory effect on the mineralization of fracture callus after a tibial fracture in rats . Decreased bone mineral density ( BMD ) at a fracture site may indicate impairment of early healing , casting doubt on the safety of using P35354 inhibitors during the early treatment of diaphyseal fractures . Forty - two female Wistar rats were randomly allocated to three groups . They were given parecoxib , indomethacin , or saline intraperitoneally for 7 days after being subjected to a closed tibial fracture stabilized with an intramedullary nail . Two and 3 weeks after surgery , the bone density at the fracture site was measured using dual energy xray absorptiometry ( DEXA ) . Three weeks after the operation the rats were euthanized and the healing fractures were mechanically tested in three - point cantilever bending . DB08439 decreased BMD at the fracture site for 3 weeks after fracture , indomethacin for 2 weeks . Both parecoxib and indomethacin reduced the ultimate bending moment and the bending stiffness of the healing fractures after 3 weeks . These results suggest P36551 inhibitors should be avoided in the early phase after fractures .",
"Evaluation of intravenous parecoxib for the relief of acute post - surgical pain . DB08439 is a prodrug of valdecoxib , which is a potent and selective inhibitor of P35354 . Intravenous preparation of parecoxib is in Phase III clinical trials for the management of acute and severe post - surgical pain . It is the only P35354 inhibitor that is available in a parenteral formulation . Clinical results compare parecoxib with ketorolac , a NSAID , which is the only non - narcotic analgesic available in parenteral formulation that can be administered for the relief of moderate to severe acute pain . Pharmacokinetic studies have shown that parecoxib is converted to valdecoxib within a short time following administration by im . or iv . injection . In clinical trials , parecoxib compares favourably with ketorolac and produces less gastric or duodenal ulcers , the predominant adverse effect , than ketorolac . DB08439 , thus , fulfils some of the desirable characteristics of an ideal non - narcotic analgesic for severe post - surgical pain and has application in other acutely painful conditions . DB08439 is expected to be filed for approval before the end of 2000 and is expected to be introduced in the market in 2001 . It has favourable prospects for a fair share of the post - surgical pain relief market which is valued at approximately US $ 1 billion for the year 2000 .",
"Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries . BACKGROUND : Atherosclerosis affects aorta , coronary , carotid , and iliac arteries most frequently than any other body vessel . There may be common molecular pathways sustaining this process . Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis . RESULTS : We used DNA microarrays and meta - analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression . We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis . Caveolae and JAK / P35610 pathways , and P06702 / P05109 interacting proteins are certainly involved in the development of vascular disease . We found that the system of caveolae is directly connected with genes that respond to hormone receptors , and indirectly with the apoptosis pathway . Cytokines , chemokines and growth factors released in the blood flux were investigated in parallel . High levels of RANTES , IL - 1ra , MIP - 1 alpha , MIP - 1 beta , P60568 , P05112 , P05113 , P05231 , P13232 , Q16552 , DB00102 , P15692 and P01579 were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels . CONCLUSION : The pattern of cytokine and P06702 / P05109 up - regulation characterizes atherosclerosis as a proinflammatory disorder . Activation of the JAK / P35610 pathway is confirmed by the up - regulation of P05231 , P42224 , Q00978 and Q13651 genes in coronary and carotid plaques . The functional network constructed in our research is an evidence of the central role of P35610 protein and the caveolae system to contribute to preserve the plaque . Moreover , Cav - 1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype .",
"DB08439 vs . lornoxicam in the treatment of postoperative pain after laparoscopic cholecystectomy : a prospective randomized placebo - controlled trial . BACKGROUND AND OBJECTIVE : Non - steroidal anti - inflammatory drugs are considered as an effective treatment of postoperative pain after laparoscopic cholecystectomy . P35354 inhibitors are newer drugs having less adverse effects . Data supporting their efficacy postoperatively in comparison to older non - steroidal anti - inflammatory drugs are scarce . Our study is a prospective , randomized , double - blinded , placebo - controlled trial comparing the efficacy of lornoxicam vs . parecoxib for the management of pain after laparoscopic cholecystectomy . MATERIALS AND METHODS : We enrolled 76 patients , ASA I and II , scheduled for elective laparoscopic cholecystectomy . The patients were randomized to receive before induction parecoxib 40 mg i . v . , lornoxicam 8 mg i . v . or placebo . Pain at rest and on movement was assessed using a visual analogue scale at 0 , 6 , 12 h postoperatively . Total meperidine consumption and adverse effects were also recorded . RESULTS : At 12 h , visual analogue scale scores at rest and on movement were significantly lower with parecoxib and lornoxicam compared with control ( P = 0 . 047 ) . The percentage of patients needing meperidine and the average dose of meperidine administered was significantly lower with parecoxib and lornoxicam compared with control ( P < 0 . 001 and P = 0 . 018 ) . There was no difference between parecoxib and lornoxicam . One patient receiving lornoxicam vomited . CONCLUSIONS : DB08439 40 mg i . v . and lornoxicam 8 mg i . v . were equianalgesic and both were more efficacious than placebo for the management of pain after laparoscopic cholecystectomy .",
"Purinergic P47900 receptor signaling mediates wound stimuli - induced cyclooxygenase - 2 expression in intestinal subepithelial myofibroblasts . Intestinal subepithelial myofibroblasts ( ISMFs ) are crucial for barrier formation against inflammatory stimuli . Physical injury induces cyclooxygenase - 2 ( P35354 ) expression , which accelerates wound healing by ISMFs . However , the mechanism of P35354 induction remains unclear . Physically damaged cells release DB00171 . Here , we investigate the role of DB00171 - purinergic signaling in wound - induced P35354 induction in ISMFs . By 24h post - injury , bovine ISMFs had migrated to and closed the wounded area . A P36551 inhibitor , indomethacin or a purinergic P2 receptor antagonist , suramin , inhibited wound healing . However , additional treatment with indomethacin did not influence wound healing in suramin - treated ISMFs . RT - PCR showed an increase in P35354 mRNA expression 2h post - injury , which was inhibited by suramin . These results suggest that DB00171 mediates wound - induced P35354 elevation . We next assessed the contribution of various purinergic receptors in P35354 induction . An DB00171 analog , ATPγS and a purinergic P47900 , 11 - 13 receptors agonist , ADP , were among the agents tested which increased P35354 expression . ATPγS - induced P35354 mRNA expression was suppressed by suramin or a purinergic P2Xs , P47900 , 4 , 6 , and 13 receptors antagonist , PPADS . These data suggest the involvement of Gq - coupled purinergic P47900 receptor or Gi - coupled purinergic Q9BPV8 receptor in P35354 induction . U73122 , an inhibitor of phospholipase C , which is a downstream signal of Gq protein , showed suppression of P35354 mRNA expression . However , pertussis toxin , a Gi inhibitor , did not show suppression . We also revealed that inhibitors of p38 MAPK and PKC inhibited ATPγS - induced P35354 mRNA expression . Collectively , purinergic P47900 receptor signaling mediates wound - induced P35354 expression through p38 MAPK and PKC pathways in ISMFs .",
"The role of cycloxygenase - 2 in the rodent kidney following ischaemia / reperfusion injury in vivo . The role of cyclooxygenase - 2 ( P35354 ) in the pathophysiology of renal ischaemia / reperfusion injury is still not fully understood . In order to elucidate the role of P35354 in ischaemia / reperfusion injury of the kidney , we have evaluated the effects of ischaemia / reperfusion on renal dysfunction and injury in ( i ) rats treated with either vehicle or the selective P35354 inhibitor parecoxib , and ( ii ) wild - type mice or mice in which the gene for P35354 has been deleted ( P35354 knock - out mice or P35354 (-/-) ) . Rats were subjected to bilateral renal ischaemia ( 45 min ) and reperfusion ( 6 h ) , and received parecoxib ( 20 mg / kg , i . v . ) 30 min prior to ischaemia and 3 h after the commencement of reperfusion . Serum urea , serum creatinine , serum aspartate aminotransferase , creatinine clearance and fractional excretion of sodium were all used as indicators of renal dysfunction and injury . Mice ( wild - type and P35354 (-/-) ) were subjected to bilateral renal ischaemia ( 30 min ) and reperfusion ( 24 h ) after which renal dysfunction ( serum urea and creatinine ) and renal injury was assessed by histological analysis . DB08439 significantly augmented the degree of renal dysfunction and injury caused by ischaemia / reperfusion in the rat . In addition , the degree of renal injury and dysfunction caused by ischaemia / reperfusion was also significantly augmented in P35354 (-/-) mice when compared to their wild - type littermates . These findings support the view that metabolites of P35354 protect the kidney against ischaemia / reperfusion injury , and ( ii ) that selective inhibitors of P35354 may worsen renal dysfunction and injury in conditions associated with renal ischaemia .",
"Synthetic triterpenoid induces P15428 expression and suppresses inflammation - driven colon carcinogenesis . Colitis - associated colon cancer ( CAC ) develops as a result of inflammation - induced epithelial transformation , which occurs in response to inflammatory cytokine - dependent downregulation of 15 - hydroxyprostaglandin dehydrogenase ( P15428 ) and subsequent suppression of prostaglandin metabolism . Agents that both enhance P15428 expression and suppress cyclooxygenase - 2 ( P35354 ) production may more effectively prevent CAC . Synthetic triterpenoids are a class of small molecules that suppress P35354 as well as inflammatory cytokine signaling . Here , we found that administration of the synthetic triterpenoid 2 - cyano - 3 , 12 - dioxooleana - 1 , 9 ( 11 )- dien - C28 - methyl ester ( CDDO - Me ) suppresses CAC in mice . In a spontaneous , inflammation - driven intestinal neoplasia model , deletion of Q13485 specifically in T cells led to progressive production of inflammatory cytokines , including P01375 - α , IFN - γ , P35228 , P05231 , IL - 1β ; as well as activation of P42224 and P40763 ; along with suppression of P15428 expression . Oral administration of CDDO - Me to mice with Q13485 - deficient T cells increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators and increasing expression of P15428 . Induction of P15428 by CDDO - Me was dose dependent in epithelial cells and was abrogated following treatment with TGF - β signaling inhibitors in vitro . Furthermore , CDDO - Me - dependent P15428 induction was not observed in P84022 -/- mice . Similarly , CDDO - Me suppressed azoxymethane plus dextran sodium sulfate - induced carcinogenesis in wild - type animals , highlighting the potential of small molecules of the triterpenoid family as effective agents for the chemoprevention of CAC in humans .",
"Topical glucocorticoids downregulate P23219 positive cells in nasal polyps . BACKGROUND : Influx of inflammatory cells is one of the hallmarks of nasal polyposis . As glucocorticoids ( GC ) are known to exhibit strong anti - inflammatory effects , these drugs are frequently used in the treatment of the disease . Part of the anti - inflammatory effects of GC is attributed to their interference with prostanoid synthesis . As cyclooxygenases ( P36551 ) are key enzymes in the synthesis of both pro - ( P23219 , P35354 ) and anti - inflammatory prostanoids ( P35354 ) , we investigated the role of topical GC on P23219 , P35354 and inflammatory markers in nasal polyps ( NP ) . METHODS : Immunohistochemical analysis of inflammatory markers ( P34810 , CD117 , MBP , elastase , IgE , BB - 1 , P05112 , P05113 and P05231 ) , P23219 and P35354 was performed on normal nasal mucosa ( NM ) ( n = 18 ) , non - GC treated NP ( n = 27 ) and topical GC treated NP ( n = 12 ) . NP groups were matched for allergy , asthma and ASA intolerance . RESULTS : Increased numbers of eosinophils , P05113 + cells and IgE + cells and decreased numbers of mastcells are striking features of NP inflammation ( P < 0 . 05 ) . In addition , increased numbers of P23219 + cells are observed in NP epithelium compared to NM ( P < 0 . 05 ) . CONCLUSION : Topical GC significantly reduce the number of P23219 + NP cells ( P < 0 . 05 ) , but have no significant effect on P35354 + NP cells . No significant reduction in the number of eosinophils is observed for GC treated NP . The number of P05113 + cells is however increased significantly upon GC treatment ( P < 0 . 05 ) .",
"Preconditioning of intravenous parecoxib attenuates focal cerebral ischemia / reperfusion injury in rats . BACKGROUND : Several studies suggest that cyclooxygenase - 2 ( P35354 ) contributes to the delayed progression of ischemic brain damage . This study was designed to investigate whether P35354 inhibition with parecoxib reduces focal cerebral ischemia / reperfusion injury in rats . METHODS : Ninety male Sprague - Dawley rats were randomly assigned to three groups : the sham group , ischemia / reperfusion ( I / R ) group and parecoxib group . The parecoxib group received 4 mg / kg of parecoxib intravenously via the vena dorsalis penis 15 minutes before ischemia and again at 12 hours after ischemia . The neurological deficit scores ( NDSs ) were evaluated at 24 and 72 hours after reperfusion . The rats then were euthanized . Brains were removed and processed for hematoxylin and eosin staining , Nissl staining , and measurements of high mobility group Box 1 protein ( P09429 ) and tumor necrosis factor - α ( P01375 - α ) levels . Infarct volume was assessed with 2 , 3 , 5 - triphenyltetrazolium chloride ( TTC ) staining . RESULTS : The rats in the I / R group had lower NDSs ( P < 0 . 05 ) , larger infarct volume ( P < 0 . 05 ) , lower P09429 levels ( P < 0 . 05 ) , and higher P01375 - α levels ( P < 0 . 05 ) compared with those in the sham group . DB08439 administration significantly improved NDSs , reduced infarct volume , and decreased P09429 and P01375 - α levels ( P < 0 . 05 ) . CONCLUSIONS : Pretreatment with intravenous parecoxib was neuroprotective . Its effects may be associated with the attenuation of inflammatory reaction and the inhibition of inflammatory mediators .",
"[ Clinical pharmacology of the selective P35354 inhibitors ] . The discovery of two isoforms of cyclooxygenases ( P23219 and P35354 ) has provided a new insight into the involvement of prostaglandins in the clinical effectiveness and gastrointestinal toxicity of NSAIDs . Currently , there are four selective P35354 inhibitors available in Germany : celecoxib , rofecoxib , valdecoxib and parecoxib . Orally administered rofecoxib , celecoxib and valdecoxib have been approved for the relief of symptoms of osteoarthritis and rheumatoid arthritis . DB08439 , the first selective P35354 inhibitor for parenteral administration , has been approved for the short - term treatment of post - operative pain . The clinical efficacy of the marketed P35354 inhibitors has been proved in large phase III clinical trials in comparison to both placebo and classical NSAIDs ( e . g . diclofenac , naproxen ) . The incidence of gastrointestinal complications was significantly lower than that with the non - selective NSAIDs . However , the clinical relevance of these effects was , at least in some populations of patients ( e . g . patients on low dose aspirin ) , not as high as initially expected . While not replacing less expensive classical NSAIDs , selective P35354 inhibitors provide a marked enrichment of the spectrum of anti - inflammatory and analgesic therapeutics .",
"Selective inhibition of P23458 and O60674 is efficacious in rodent models of arthritis : preclinical characterization of INCB028050 . Inhibiting signal transduction induced by inflammatory cytokines offers a new approach for the treatment of autoimmune diseases such as rheumatoid arthritis . Kinase inhibitors have shown promising oral disease - modifying antirheumatic drug potential with efficacy similar to anti - P01375 biologics . Direct and indirect inhibition of the JAKs , with small molecule inhibitors like CP - 690 , 550 and ___MASK55___ or neutralizing Abs , such as the anti - P05231 receptor Ab tocilizumab , have demonstrated rapid and sustained improvement in clinical measures of disease , consistent with their respective preclinical experiments . Therefore , it is of interest to identify optimized JAK inhibitors with unique profiles to maximize therapeutic opportunities . INCB028050 is a selective orally bioavailable P23458 / O60674 inhibitor with nanomolar potency against P23458 ( 5 . 9 nM ) and O60674 ( 5 . 7 nM ) . INCB028050 inhibits intracellular signaling of multiple proinflammatory cytokines including P05231 and IL - 23 at concentrations < 50 nM . Significant efficacy , as assessed by improvements in clinical , histologic and radiographic signs of disease , was achieved in the rat adjuvant arthritis model with doses of INCB028050 providing partial and / or periodic inhibition of P23458 / O60674 and no inhibition of P52333 . Diminution of inflammatory Th1 and Th17 associated cytokine mRNA levels was observed in the draining lymph nodes of treated rats . INCB028050 was also effective in multiple murine models of arthritis , with no evidence of suppression of humoral immunity or adverse hematologic effects . These data suggest that fractional inhibition of P23458 and O60674 is sufficient for significant activity in autoimmune disease models . Clinical evaluation of INCB028050 in RA is ongoing .",
"DB08439 impairs early tendon repair but improves later remodeling . BACKGROUND : P35354 inhibitors inhibit bone repair . HYPOTHESIS : Cyclooxygenase inhibitors might also have a negative effect on early tendon repair , although a positive effect on late tendon repair previously has been shown . STUDY DESIGN : Controlled laboratory study . METHODS : Achilles tendon transection was performed on 80 rats . Sixty rats were given daily intramuscular injections of either parecoxib ( 6 . 4 mg / kg body weight ) or saline for the first 5 days after surgery and sacrificed either at 8 or 14 days . The remaining 20 rats were given intramuscular parecoxib or saline injections from day 6 until sacrifice at 14 days . RESULTS : At 8 days , early parecoxib treatment caused a 27 % decrease in force at failure ( P = . 007 ) , a 25 % decrease in maximum stress ( P = . 01 ) , and a 31 % decrease in energy uptake ( P = . 05 ) . Stiffness and transverse area were not significantly affected . At 14 days , early parecoxib treatment caused a decrease in stiffness ( P = . 004 ) . In contrast to early treatment , late parecoxib treatment caused a 16 % decrease in cross - sectional area ( P = . 03 ) and a 29 % increase in maximum stress ( P = . 04 ) . CONCLUSIONS : During early tendon repair , a cyclooxygenase - 2 inhibitor had a detrimental effect . During remodelling , however , inflammation appears to have a negative influence , and cyclooxygenase - 2 inhibitors might be of value . CLINICAL RELEVANCE : The results suggest that cyclooxygenase - 2 inhibitors should be used with care in the early period after tendon injury .",
"Efficacy and safety of the first parenteral selective P35354 inhibitor , parecoxib sodium , in adult patients with postoperative pain . DB08439 , a prodrug of valdecoxib , a selective P35354 inhibitor , has been recently introduced for the treatment of moderate to severe postoperative pain . This prospective , open , multicentric study enrolled 260 patients undergoing orthopaedic , gynaecological , dental and general surgery . Postoperatively , patients were treated with parecoxib , 40 mg IM / IV . There was a statistically significant decrease in the mean pain intensity score ( p < 0 . 05 ) . At the end of 24 hours , 89 . 6 % of total cases had a very good to total relief of pain . The mean duration of analgesia was 19 . 26 hours and mean time of onset of analgesia was 16 . 25 minutes ranging from 11 - 20 minutes . The laboratory values were within normal limits . The drug was well tolerated . There was no report of any hypersensitivity reaction . This study suggests that parecoxib , in a dose of 40 mg IM / IV , is an effective and safe option for the management of postoperative pain .",
"___MASK55___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK55___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK55___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK55___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"Amelioration of meconium - induced acute lung injury by parecoxib in a rabbit model . P35354 ( P35354 ) plays important roles in various inflammatory conditions and is significantly increased in meconium - induced lung injury . We investigated the effects of parecoxib on meconium - induced acute lung injury ( ALI ) in rabbits . Twenty - four rabbits were randomized into sham , control , and parecoxib groups . Rabbits in the control and parecoxib groups underwent tracheal instillation of meconium , followed by intravenous injection of saline or parecoxib and 4 h of ventilation . The airway pressure , dynamic compliance , and ratio of partial pressure of oxygen in arterial blood to fraction of inspired oxygen ( PaO2 / FiO2 ratio ) were recorded at baseline ( T0 ) and 4 h after instillation ( T1 - DB00451 ) . The lung tissue wet - to - dry weight ratio ; neutrophil percentage ; and total protein , tumor necrosis factor - α ( P01375 - α ) , interleukin ( IL ) - 1β , P10145 , prostaglandin E2 , and malondialdehyde levels in bronchoalveolar lavage fluid ( BALF ) were evaluated . The myeloperoxidase activity , P35354 expression , and degree of histopathologic injury in lung tissue were also analyzed . The airway pressure , compliance , and PaO2 / FiO2 ratio were significantly improved by parecoxib after meconium instillation . The lung wet - to - dry weight ratio , total protein level , and neutrophil percentage in BALF were lowest in the parecoxib group . The P01375 - α , IL - 1β , P10145 , prostaglandin E2 , and malondialdehyde levels in the BALF were lowest in the parecoxib group . The P35354 expression and myeloperoxidase activity in lung tissue were significantly reduced by parecoxib . The degree of lung injury was also reduced . In conclusions : DB08439 effectively ameliorates respiratory function and attenuates meconium - induced ALI . These effects are correlated with prostaglandin E2 and P35354 inhibition .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK94___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"Constitutive cyclo - oxygenase - 2 does not contribute to the development of human visceral pain hypersensitivity . BACKGROUND AND AIMS : Central sensitisation ( CS ) , contributes to the development and maintenance of gastrointestinal pain hypersensitivity . Constitutive cyclo - oxygenase - 2 ( P35354 ) contributes to central sensitisation in somatic pain hypersensitivity but its role in mediating visceral pain hypersensitivity is unknown . We therefore conducted a study to determine if P35354 inhibition with DB00580 attenuates the development or early maintenance of CS in a validated human oesophageal pain hypersensitivity model . METHODS : Healthy volunteers were studied in two randomised , double blind , crossover studies in which pain thresholds ( PT ) to electrical stimulation were assessed in the proximal oesophagus , chest wall and foot , prior to and following a distal oesophageal acid infusion . Protocol 1 : DB00580 , ( 40 mg ) or matching placebo was given orally for 4 days prior to oesophageal acid infusion . Protocol 2 : IV DB08439 ( 40 mg ) or saline was given 120 min after oesophageal acid infusion . RESULTS : DB00580 did not prevent the induction of secondary allodynia in the proximal oesophagus nor did it attenuate it following its establishment . Chest wall PT fell following oesophageal acid but foot PT remained unchanged ; highlighting the development viscero - somatic convergence due to CS . DB00580 had no analgesic or anti - hyperalgesic effect on chest wall or foot PT . CONCLUSIONS : Neither the induction nor initial maintenance of acid induced oesophageal pain hypersensitivity is prevented by DB00580 , suggesting that constitutive spinal P35354 does not contribute to the development or early maintenance of acute visceral central sensitisation .",
"DB08439 inhibits apoptosis in acute myocardial infarction due to permanent coronary ligation but not due to ischemia - reperfusion . PURPOSE : Myocardial ischemia induces cyclooxygenase 2 ( P35354 ) expression . We evaluated the effects of parecoxib , a P35354 inhibitor , in 2 different mouse models of myocardial ischemia : permanent left coronary artery ligation ( PI ) and transient ligation ( 30 minutes ischemia ) followed by reperfusion ( I / R ) . METHODS : Forty adult male Institute of Cancer Research mice underwent PI ( n = 24 ) or I / R ( n = 16 ) , followed by randomization to parecoxib ( 0 . 75 mg / kg intraperitoneal daily ) or normal saline for 7 days . RESULTS : DB08439 significantly reduced apoptosis [ 0 . 8 % vs . 3 . 4 % ( saline ) , P < 0 . 001 ] and 7 - day mortality [ 0 % vs . 57 % ( saline ) , P = 0 . 040 ] in the PI group but showed no benefit in the I / R group . DB08439 - treated mice also exhibited greater fractional shortening in the PI group [ 22 % vs . 14 % ( saline ) , P = 0 . 045 ) but not in the I / R group . DB08439 did not affect infarct size in either group . CONCLUSIONS : P35354 may play a pivotal role in mediating apoptosis in the ischemic peri - infarct myocardium that is not reperfused after infarct .",
"Ca2 +/ calmodulin effects on DB02527 response in cultured chick ciliary epithelial cells . The authors investigated the influence of the elevation of intracellular Ca2 + concentration on the production of cyclic adenosine 3 ', 5 '- monophosphate ( DB02527 ) using cultured chick embryo ciliary epithelium ( CE ) . We examined the effects of calcium ionophore ( A23187 ) on DB02527 production after incubation with vasoactive intestinal peptide ( P01282 ) , isoproterenol ( ISO ) , sodium fluoride ( NaF ) or forskolin ( FSK ) . A23187 had no effect on the basal DB02527 level , or the NaF - and FSK - stimulated responses for DB02527 level ; but A23187 potentiated P01282 - and ISO - stimulated DB02527 responses . P62158 antagonist ( W - 7 ) was very effective in inhibiting the potentiating effects of A23187 on P01282 and ISO - stimulated production of DB02527 . Our present findings suggested that Ca2 +/ calmodulin may potentiate the receptor - mediated DB02527 pathway through Ca2 +/ calmodulin - dependent protein kinase in the CE .",
"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK11___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .",
"P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK49___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK49___ is in clinical development as an orally active agent .",
"Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity ."
] |
[
"___MASK11___",
"___MASK49___",
"___MASK55___",
"___MASK59___",
"___MASK61___",
"___MASK65___",
"___MASK70___",
"___MASK73___",
"___MASK94___"
] |
___MASK94___
|
MH_train_441
|
interacts_with DB06698?
|
[
"[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK53___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"Phosphodiesterase - 4 influences the PKA phosphorylation status and membrane translocation of G - protein receptor kinase 2 ( P25098 ) in P29320 - 293beta2 cells and cardiac myocytes . Membrane - recruitment of P25098 ( G - protein receptor kinase 2 ) provides a fundamental step in the desensitization process controlling GPCRs ( G - protein - coupled receptors ) , such as the beta2AR ( beta2 - adrenergic receptor ) . In the present paper , we show that challenge of P29320 - 293beta2 [ human embryonic kidney cells stably overexpressing the FLAG - tagged beta2AR - GFP ( green fluorescent protein ) ] cells with the beta - adrenoceptor agonist , isoprenaline , causes P25098 to become phosphorylated by PKA ( DB02527 - dependent protein kinase ) . This action is facilitated when DB02527 - specific DB05876 ( phosphodiesterase - 4 ) activity is selectively inactivated , either chemically with rolipram or by siRNA ( small interfering RNA ) - mediated knockdown of Q07343 and Q08499 . DB05876 - selective inhibition by rolipram facilitates the isoprenaline - induced membrane translocation of P25098 , phosphorylation of the beta2AR by P25098 , membrane translocation of beta - arrestin and internalization of beta2ARs . DB05876 - selective inhibition also enhances the ability of isoprenaline to trigger the PKA phosphorylation of P25098 in cardiac myocytes . In the absence of isoprenaline , rolipram - induced inhibition of DB05876 activity in P29320 - 293beta2 cells acts to stimulate PKA phosphorylation of P25098 , with consequential effects on P25098 membrane recruitment and P25098 - mediated phosphorylation of the beta2AR . We propose that a key role for DB05876 enzymes is : ( i ) to gate the action of PKA on P25098 , influencing the rate of P25098 phosphorylation of the beta2AR and consequential recruitment of beta - arrestin subsequent to beta - adrenoceptor agonist challenge , and ( ii ) to protect P25098 from inappropriate membrane recruitment in unstimulated cells through its phosphorylation by PKA in response to fluctuations in basal levels of DB02527 .",
"Proopiomelanocortin but not vasopressin or renin - angiotensin system induces resuscitative effects of central P08908 activation in haemorrhagic shock in rats . The aim of this study was to determine the effectory mechanisms : vasopressin , renin - angiotensin system and proopiomelanocortin - derived peptides ( P01189 ) , partaking in the effects of serotonin through central serotonin 1A receptor ( P08908 ) receptors in haemorrhagic shock in rats . The study was conducted on male Wistar rats . All experimental procedures were carried out under full anaesthesia . The principal experiment included a 2 hour observation period in haemorrhagic shock . Drugs used - a selective P08908 agonist 8 - OH - DPAT ( 5 μg / 5 μl ) ; V1a receptor antagonist [ β - mercapto - β , β - cyclo - pentamethylenepropionyl ( 1 ), O - me - DB00135 ( 2 ), DB00125 ( 8 ) ] AVP ( 10 μg / kg ) ; angiotensin type I receptor antagonist ( AT1 ) ZD7155 ( 0 . 5 mg / kg , i . v . ) ; angiotensin - converting - enzyme inhibitor captopril ( 30 mg / kg , i . v . ) ; melanocortin type 4 ( MC4 ) receptor antagonist HS014 ( 5 μg , i . c . v . ) . There was no influence of ZD715 , captopril or blocking of the V1a receptors on changes in the heart rate ( HR ) , mean arterial pressure ( Q96HU1 ) , peripheral blood flow or resistance caused by the central stimulation of P08908 receptors ( P ≥ 0 . 05 ) . However , selective blocking of central MC4 receptors caused a slight , but significant decrease in HR and Q96HU1 ( P < 0 . 05 ) . P01189 derivatives acting via the central MC4 receptor participate in the resuscitative effects of 8 - OH - DPAT . The angiotensin and vasopressin systems do not participate in these actions .",
"Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease - related and genetic factors contribute to inter - individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four - point categorical scales . In stratified regression models including demographical and disease - related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid - or nausea / vomiting signalling pathways ( P08183 , P35372 , P41145 , P32121 , P42226 , P21964 , P20309 , P08912 , P35367 , P14416 , P35462 , P25103 , P46098 , O95264 , Q8WXA8 , P21554 ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter - individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0 . 01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 ; rs165722 , rs4680 and rs4633 in P21964 ; rs10802789 and rs685550 in P20309 . Only the SNP rs1672717 in O95264 passed the Benjamini - Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 , P21964 and P20309 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain .",
"Neuropeptide expression in the airways of P48444 patients and smokers with normal lung function . Neurogenic mechanisms seem to play a role in the pathogenesis of chronic obstructive pulmonary disease ( P48444 ) , as suggested by a number of in vitro data . However , few studies have investigated the presence of neuropeptides in the airways of patients with P48444 , and they have yielded conflicting results . The aim of this study is to compare the expression of the neuropeptide DB05875 ( SP ) , vasoactive intestinal peptide ( P01282 ) , and neuropeptide Y ( P01303 ) in the airways of smokers with and without P48444 . Surgical lung samples were obtained from 15 smokers with P48444 and 16 smokers with normal lung function , who underwent lobectomy for a solitary lung carcinoma . Airway expression and distribution of SP , P01282 , and P01303 were identified by immunohistochemistry and analyzed by a computerized image analysis system . Compared to smokers with normal lung function , P48444 patients exhibited an increased immunoreactivity for SP and P01282 , paralleled by a decreased P01303 expression in the epithelium and glands , and a decreased expression of all these three neuropeptides in the smooth muscle layer . Therefore , in the present study we have documented a different expression and distribution of the neuropeptides SP , P01282 , and P01303 in the airways of smokers with and without P48444 . These findings suggest a possible involvement of such neuropeptides in the pathogenesis of some changes occurring in P48444 .",
"Pharmacologic attenuation of pelvic pain in a murine model of interstitial cystitis . BACKGROUND : Interstitial cystitis / painful bladder syndrome ( IC / PBS ) is a bladder disease that causes debilitating pelvic pain of unknown origin , and IC / PBS symptoms correlate with elevated bladder lamina propria mast cell counts . Similar to IC / PBS patients , pseudorabies virus ( PRV ) infection in mice induces a neurogenic cystitis associated with bladder lamina propria mast cell accumulation and pelvic pain . We evaluated several drugs to determine the effectiveness of reducing PRV - induced pelvic pain . METHODS : Neurogenic cystitis was induced by the injection of Bartha ' s strain of PRV into the abductor caudalis dorsalis tail base muscle of female C57BL / 6 mice . Therapeutic modulation of pelvic pain was assessed daily for five days using von Frey filament stimulation to the pelvic region to quantify tactile allodynia . RESULTS : Significant reduction of PRV - induced pelvic pain was observed for animals treated with antagonists of neurokinin receptor 1 ( P25103 ) and histamine receptors . In contrast , the P35367 antagonist hydroxyzine , proton pump inhibitors , a histamine receptor 3 agonist , and gabapentin had little or no effect on PRV - induced pelvic pain . CONCLUSION : These data demonstrate that bladder - associated pelvic pain is attenuated by antagonists of P25103 and P25021 . Therefore , P25103 and P25021 represent direct therapeutic targets for pain in IC / PBS and potentially other chronic pain conditions .",
"DB06698 treatment in managing vertigo and improving vestibular compensation : clarification . DB06698 dihydrochloride ( betahistine ) is currently used in the management of vertigo and vestibular pathologies with different aetiologies . The main goal of this review is to clarify the mechanisms of action of this drug , responsible for the symptomatic relief of vertigo and the improvement of vestibular compensation . The review starts with a brief summary recalling the role of histamine as a neuromodulator / neurotransmitter in the control of the vestibular functions , and the role of the histaminergic system in vestibular compensation . Then are presented data recorded in animal models demonstrating that betahistine efficacy can be explained by mechanisms targeting the histamine receptors ( HRs ) at three different levels : the vascular tree , with an increase of cochlear and vestibular blood flow involving the P35367 ; the central nervous system , with an increase of histamine turnover implicating the Q9Y5N1 , and the peripheral labyrinth , with a decrease of vestibular input implying the Q9Y5N1 / Q9H3N8 . Clinical data from vestibular loss patients show the impact of betahistine treatment for the long - term control of vertigo , improvement of balance and quality of life that can be explained by these mechanisms of action . However , two conditions , at least , are required for reaching the betahistine therapeutic effect : the dose and the duration of treatment . Experimental and clinical data supporting these requirements are exposed in the last part of this review .",
"Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine - treated schizophrenic patients . RATIONALE : ___MASK62___ , a classical antipsychotic drug , has the potential to induce extrapyramidal side effects ( EPS ) . Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug . OBJECTIVES : To evaluate the impact of polymorphisms in the dopamine D ( 2 ) and D ( 3 ) and serotonin 2A and 2C receptor genes ( P14416 , P35462 , P28223 , and P28335 ) on short - term effects of perphenazine monotherapy in schizophrenic patients . MATERIALS AND METHODS : Forty - seven Estonian inpatients were evaluated before and after 4 - 6 weeks of treatment by Simpson - Angus rating scale , Barnes scale , and Positive and Negative Symptom Scale . Genotyping was performed for common P14416 , P35462 , P28223 , and P28335 gene polymorphisms , previously reported to influence receptor expression and / or function . RESULTS : Most of the patients ( n = 37 ) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response . The 102C allele of P28223 and the - 697C and 23Ser alleles of P28335 were more frequent among patients with EPS ( n = 25 ) compared to patients without EPS ( n = 22 ) ( p = 0 . 02 , 0 . 01 , and 0 . 02 , respectively ) . The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age , gender , and duration of antipsychotic treatment as covariants . There was no significant association between EPS occurrence and polymorphisms in the P14416 and P35462 genes . CONCLUSIONS : An association was observed between polymorphisms in P28223 and P28335 genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy . Larger study populations are needed to confirm our findings .",
"Stimulation of the histamine 4 receptor with 4 - methylhistamine modulates the effects of chronic stress on the Th1 / Th2 cytokine balance . Alterations to the immune system caused by stress have been considered to markedly increase the risk for immune - related diseases such as cancer and autoimmune disorders . We investigated the potential anti - stress effects of the histamine 4 receptor ( Q9H3N8 ) agonist , 4 - methylhistamine ( 4 - MeH ) , in a murine stress model . Mice were placed in 50ml conical centrifuge tubes for 12h followed by a 12h rest . The effects of treatment with 4 - MeH ( 30mg / kg , i . p . , twice daily ) for 2 days were assessed . At 2 days after physical restraint , mice were sacrificed and tissues harvested . We evaluated the effects of 4 - MeH treatment on P01730 (+) T cell production , and intracellular IFN - γ and P05112 expression in these cells . We also assessed IL - 1β , IFN - γ , P01375 - α , and P05112 mRNA expression as well as IFN - γ , P01375 - α , Q9Y5U5 , Ox40 and P05112 protein expression in the spleen . The results showed that 4 - MeH treatment of stressed mice results in a substantial increase in the P01730 (+) T cells as well as in IFN - γ production by these cells . Compared to both untreated and stressed controls . In contrast , P05112 expression decreased significantly following 4 - MeH treatment of mice . Moreover , stimulation of the Q9H3N8 resulted in up - regulated expression of IL - 1β , IFN - γ and P01375 - α mRNAs and decreased the expression of P05112 . Western blot analysis confirmed decreased protein expression of IFN - γ , P01375 - α , Q9Y5U5 , Ox40 and increased P05112 in the SC group and treatment of mice with 4 - MeH reversed these effects . Our results confirm the significant impact of chronic stress on T cell function and production of Th1 / Th2 mediators Q9H3N8 .",
"P35367 promotes atherosclerotic lesion formation by increasing vascular permeability for low - density lipoproteins . OBJECTIVE : Enhanced endothelial permeability leading to intimal accumulation of low - density lipoproteins ( LDL ) stimulates the formation of atherosclerotic lesions . DB11320 is known to increase vascular permeability . Whether this affects the formation of atherosclerotic lesions , however , remains elusive . METHODS AND RESULTS : P02649 - null ( ApoE (-/-) ) mice treated with a histamine H1 receptor but not an H2 receptor antagonist developed 40 % fewer atherosclerotic lesions in the aorta than placebo - treated controls . Similarly , genetic deletion of the H1 but not the H2 receptor resulted in a 60 % reduction of lesions compared with ApoE (-/-) controls . The H1 receptor enhanced LDL permeability and lipid accumulation in the aorta , whereas plasma lipoprotein levels remained unaltered . In contrast , the H1 receptor did not affect proliferation and migration of vascular smooth muscle cells . Bone marrow transplantation confirmed that the formation of atherosclerotic lesions depended on the H1 receptor in vascular cells , whereas its presence in bone marrow - derived cells was irrelevant for plaque development . Mice expressing the H1 receptor exhibited higher levels of the chemokine ( C - C motif ) ligand 5 and higher numbers of macrophages and T - helper lymphocytes in plaques , higher numbers of circulating lymphocytes , and larger spleens . CONCLUSION : These data indicate that H1 but not H2 receptor activation drives the formation of atherosclerotic lesions through an increased vascular permeability for LDL , which is associated with an enhanced secondary aortic and systemic inflammation . These data open novel perspectives for the prevention and treatment of atherosclerotic vascular disease .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK62___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .",
"Polymorphisms of stress - related genes and the risk of nonsyndromic cleft lip with or without cleft palate . BACKGROUND : Nonsyndromic cleft lip with or without cleft palate ( P19338 / P ) is a common structural malformation with a complex and multifactorial etiology . It has been shown that maternal psychological stress in the periconceptional period can contribute to an increase in the risk of P19338 / P affecting pregnancy . METHODS : Twenty - four single nucleotide polymorphisms of 11 stress - related genes ( P21964 , P34998 , Q13451 , Q16445 , HSD11β2 , P21397 , P01303 , P04150 , P08185 , P31645 , and Q8IWU9 ) were investigated in 220 healthy mothers of children with facial clefts and 210 matched controls using restriction fragment - length polymorphism and high - resolution melting analysis . RESULTS : We found that polymorphisms in P31645 , Q8IWU9 , and P08185 appear to be maternal factors increasing the risk of having a child with facial clefts . The closest correlations with P19338 / P were found for the P31645 rs2020942 and Q8IWU9 rs10879357 gene variants ( odds ratio [ OR ] , 1 . 720 ; 95 % confidence interval [ CI ] , 1 . 158 - 2 . 553 ; p = 0 . 0069 ; p ( trend ) = 0 . 0036 ; and OR , 1 . 837 ; 95 % CI , 1 . 226 - 2 . 753 , p = 0 . 0030 , p ( trend ) = 0 . 0057 ; respectively ) . Moreover , haplotype analysis revealed that several combinations of markers in P31645 , Q8IWU9 , and P08185 might be significantly associated with the risk of P19338 / P affected pregnancies . However , these associations were not statistically significant after correction for multiple testing . CONCLUSION : This study suggests that nucleotide variants of genes encoding components of the hypothalamus - pituitary - adrenal axis and serotoninergic system have a role in the etiology of P19338 / P in the Polish population . P31645 , Q8IWU9 , and P08185 might be novel candidate genes for this common congenital anomaly .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK80___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"Ectopic DB01285 syndrome caused by bronchial carcinoid tumor indistinguishable from Cushing ' s disease . A 75 - year - old woman was admitted to our hospital because of a poor glycemic control . She was found to have Cushingoid feature and dynamic endocrine tests showed elevated plasma DB01285 and cortisol levels , lack of their circadian rhythm , non - suppressibility to high - dose dexamethasone , responsiveness to P06850 , but not to ___MASK59___ , and suppression to octreotide . Pituitary Q9BWK5 showed an equivocal small lesion . CT scan of the chest showed two nodular lesions in the right lung ( S5 , S7 ) , while a mild uptake was noted only in S5 lesion by DB09150 - PET , but positive uptake was only in S7 lesion by somatostatin receptor scintigraphy ( SRS ) . Inferior petrosal sinus sampling revealed a gradient of plasma DB01285 after P06850 stimulation , consistent with the diagnosis of Cushing ' s disease . She underwent middle and inferior lobectomy of the right lung . The resected tumor in S7 was consistent with the diagnosis of a bronchial carcinoid tumor with positive DB01285 immunoreactivity , while that of S5 was cryptococcal granuloma . RT - PCR revealed abundant expressions of P01189 and SSTR ( - 1 , - 2 , - 5 ) , but not of P34998 and P47901 . Postoperatively , abnormal endocrine data were normalized along with improvement of hypertension and diabetes . This was a diagnostic challenging case with ectopic DB01285 syndrome indistinguishable from Cushing ' s disease by various endocrine and imaging tests , among which SRS successfully localized the tumor responsible for ectopic DB01285 secretion .",
"DB11320 stimulates hydrogen peroxide production by bronchial epithelial cells via histamine H1 receptor and dual oxidase . Oxidative stress has been implicated in the pathogenesis of bronchial asthma . Besides granulocytes , the airway epithelium can produce large amounts of reactive oxygen species and can contribute to asthma - related oxidative stress . DB11320 is a major inflammatory mediator present in large quantities in asthmatic airways . Whether histamine triggers epithelium - derived oxidative stress is unknown . We therefore aimed at characterizing human airway epithelial H2O2 production stimulated by histamine . We found that air - liquid interface cultures of primary human bronchial epithelial cells ( BECs ) and an immortalized BEC model ( Cdk4 / hTERT HBEC ) produce H2O2 in response to histamine . The main source of airway epithelial H2O2 is an NADPH dual oxidase , Duox1 . Out of the four histamine receptors ( P35367 - Q9H3N8 ) , P35367 has the highest expression in BECs and mediates the H2O2 - producing effects of histamine . P05112 induces Duox1 gene and protein expression levels and enhances histamine - induced H2O2 production by epithelial cells . Using P29320 - 293 cells expressing Duox1 or Duox2 and endogenous P35367 , histamine triggers an immediate intracellular calcium signal and H2O2 release . Overexpression of P35367 further increases the oxidative output of Duox - expressing P29320 - 293 cells . Our observations show that BECs respond to histamine with Duox - mediated H2O2 production . These findings reveal a mechanism that could be an important contributor to oxidative stress characteristic of asthmatic airways , suggesting novel therapeutic targets for treating asthmatic airway disease .",
"___MASK68___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK68___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK68___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK36___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK36___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK36___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK36___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK36___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK36___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK36___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK36___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK36___ in the treatment of changes in hypervigilance following severe stress .",
"___MASK68___ for joints and bones . ___MASK68___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK68___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK68___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"DB06698 ameliorates olanzapine - induced weight gain through modulation of histaminergic , P01303 and AMPK pathways . Olanzapine is widely used to treat schizophrenia and other disorders , but causes adverse obesity and other metabolic side - effects . Both animal and clinical studies have shown that co - treatment with betahistine ( a histaminergic H1 receptor agonist and H3 receptor antagonist ) is effective for ameliorating olanzapine - induced weight gain / obesity . To reveal the mechanisms underlying these effects , this study investigated the effects of co - treatment of olanzapine and betahistine ( O + B ) on expressions of histaminergic H1 receptor ( P35367 ) , AMP - activated protein kinase ( AMPK ) , neuropeptide Y ( P01303 ) , and proopiomelanocortin ( P01189 ) in the hypothalamus associated with reducing olanzapine - induced weight gain . Olanzapine significantly upregulated the mRNA and protein expressions of P35367 , while O + B co - treatment significantly downregulated the P35367 levels , compared to the olanzapine - only treatment group . The P01303 mRNA expression was significantly enhanced by olanzapine , but it was significantly reversed by O + B co - treatment . The hypothalamic P35367 expression was positively correlated with total food intake , and P01303 expression . Olanzapine also increased AMPKα activation measured by the AMPKα phosphorylation ( pAMPKα ) / AMPKα ratio compared with controls , whereas O + B co - treatment decreased the pAMPKα / AMPKα ratio , compared with olanzapine only treatment . The pAMPKα / AMPKα ratio was positively correlated with total food intake and P35367 expression . Although olanzapine administration decreased the P01189 mRNA level , this level was not affected by O + B co - treatment . Therefore , these results suggested that co - treatment with betahistine may reverse olanzapine - induced body weight gain via the P35367 - P01303 and P35367 - pAMPKα pathways .",
"Inhibitory effect of P01303 on isoprenaline - induced osteoclastogenesis in mouse bone marrow cells . The effect of neuropeptide Y ( P01303 ) , a co - transmitter with noradrenaline in peripheral sympathetic nerve fibers , on the osteoclastogenesis in mouse bone marrow cell cultures treated with isoprenaline , a beta - adrenergic receptor ( beta - AR ) agonist , was examined . The mouse bone marrow cells constitutively expressed mRNAs for the P01303 - Q03519 receptor and beta2 - AR . P01303 inhibited the formation of osteoclast - like cells induced by isoprenaline but not that by 1alpha , 25 - dihydroxyvitamin D3 ( DB00136 ) or soluble receptor activator of nuclear factor - kappaB ligand ( O14788 ) ; and it suppressed the production of O14788 and cyclic AMP ( DB02527 ) increased by isoprenaline but not those increased by DB00136 . P01303 also inhibited osteoclastogenesis induced by forskolin , an activator of adenylate cyclase ; however , it did not inhibit that induced by exogenously supplied dibutyryl DB02527 , a cell - permeable DB02527 analog that activates DB02527 - dependent protein kinase . These results demonstrate that P01303 inhibited the isoprenaline - induced osteoclastogenesis by blocking the agonist - elicited increases in the production of DB02527 and O14788 in mouse bone marrow cells , suggesting an interaction between P01303 and beta - AR agonist in bone resorption .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK55___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"Neuropeptide Y induces cardiomyocyte hypertrophy via calcineurin signaling in rats . Neuropeptide Y ( P01303 ) has been shown to participate in cardiac hypertrophy . However , the mechanisms by which P01303 induces cardiomyocyte hypertrophy are poorly understood . This study tested the hypothesis that P01303 induces cardiomyocyte hypertrophy through Ca2 +/ P62158 - dependent calcineurin ( CaN ) pathway in cultured neonatal rat cardiomyocytes . After 24 - h treatment , P01303 ( 100 nM ) significantly increased 3H - leucine incorporation and c - Jun mRNA expression , concomitant with augment of CaN activity and protein level in cardiomyocytes compared to those cells without P01303 treatment . The enhancement of 3H - leucine incorporation and c - Jun mRNA expression in cardiomyocytes treated with P01303 were markedly inhibited by cyclosporine A ( DB00091 ) , a selective inhibitor of CaN . We also investigated the effect of P01303 on intracellular Ca2 + level in cardiomyocytes . There were no obvious changes in intracellular Ca2 + level of cytoplasm and nucleus in cardiomyocytes treated with P01303 ( 100 nM ) for 10 min . However , P01303 significantly increased intracellular Ca2 + level of cytoplasm and nucleus in cardiomyocytes after 24 - h treatment . The result suggested that P01303 could induce hypertrophy of cardiomyocytes via Ca2 +/ P62158 - dependent CaN signal pathway . The enhancement of [ Ca2 +] i caused by P01303 may activate CaN signal pathways to mediate cardiac hypertrophy .",
"___MASK1___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK1___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK5___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"DB01184 treatment for gastroparesis : demographic and pharmacogenetic characterization of clinical efficacy and side - effects . BACKGROUND : DB01184 is a useful alternative to metoclopramide for treatment of gastroparesis due to better tolerability . Effectiveness and side - effects from domperidone may be influenced by patient - related factors including polymorphisms in genes encoding drug - metabolizing enzymes , drug transporters , and domperidone targets . AIMS : The aim of this study was to determine if demographic and pharmacogenetic parameters of patients receiving domperidone are associated with response to treatment or side - effects . METHODS : Patients treated with domperidone for gastroparesis provided saliva samples from which DNA was extracted . Fourteen single - nucleotide polymorphisms ( SNPs ) in seven candidate genes ( P08183 , P10635 , P14416 , P15382 , Q9Y6J6 , Q12809 , P51787 ) were used for genotyping . SNP microarrays were used to assess single - nucleotide polymorphisms in the ADRA1A , P35368 , and P25100 loci . RESULTS : Forty - eight patients treated with domperidone participated in the study . DNA was successfully obtained from each patient . Age was associated with effectiveness of domperidone ( p = 0 . 0088 ) . Genetic polymorphism in Q12809 was associated with effectiveness of domperidone ( p = 0 . 041 ) . The efficacious dose was associated with polymorphism in P08183 gene ( p = 0 . 0277 ) . The side - effects of domperidone were significantly associated with the SNPs in the promoter region of P25100 gene . CONCLUSIONS : Genetic characteristics associated with response to domperidone therapy included polymorphisms in the drug transporter gene P08183 , the potassium channel Q12809 gene , and α1D -- adrenoceptor P25100 gene . Age was associated with a beneficial response to domperidone . If verified in a larger population , this information might be used to help determine which patients with gastroparesis might respond to domperidone and avoid treatment in those who might develop side - effects .",
"[ Level of neuropeptide Y in serum of patients with chronic congestive heart failure ] . The purpose of the study was to measure plasma concentrations of neuropeptide Y ( P01303 ) , endothelin - 1 , 2 ( ET - 1 , 2 ) , alpha atrial natriuretic polypeptide ( P01160 ) and noradrenaline ( NA ) in relation to cardiac index ( CI ) and left ventricular ejection fraction ( LVEF ) in patients with congestive heart failure ( CHF ) . There were significant increases in venous blood concentrations of P01303 , Na , ET - 1 , 2 , P01160 in the patients with CHF . Plasma concentrations of P01303 correlated with plasma NA concentrations but plasma noradrenaline concentrations alone correlated with CI and LVEF . In patients with CHF plasma NA concentrations seems to be more sensitive index of cardiac dysfunction then the concentrations of neuropeptide Y .",
"Further characterization of a somatic cell hybrid panel : ten new assignments to the bovine genome . Thirty - six partially characterized hamster - bovine hybrid cell lines were used for the determination of synteny groups . Sixteen additional reference loci , selected for their coverage of the bovine genome , were analysed on these hybrid cells . This increases to 25 the number of synteny groups detected . This panel was then used to make synteny assignments for 10 additional loci , eight by Southern blotting ( P02452 , P08123 , FAS , P07858 , P07711 , P07510 , P07686 and P08908 ) and two by polymerase chain reaction ( PCR ) amplification ( P35367 and ETH1112 ) . These loci were assigned to international synteny groups U12 ( P35367 ) , U13 ( P08123 ) , U17 ( P07510 ) , U21 ( P02452 , FAS ) , U29 ( ETH1112 ) , to chromosome 20 ( U14 or U25 ) for P07686 and P08908 , and to the same local synteny group ( A ) , which is probably U18 , for P07858 and P07711 . For three loci already mapped in humans ( P02452 , P08123 and P07510 ) , the present results are in accordance with the predictions based on comparative mapping between the human and bovine species ."
] |
[
"___MASK1___",
"___MASK36___",
"___MASK53___",
"___MASK55___",
"___MASK59___",
"___MASK5___",
"___MASK62___",
"___MASK68___",
"___MASK80___"
] |
___MASK1___
|
MH_train_442
|
interacts_with DB05773?
|
[
"Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . ___MASK24___ , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol - treated group ( p less than 0 . 05 ) . This effect was lost after 17 days of treatment . P03372 binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0 . 05 ) and the testosterone ( p less than 0 . 01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone .",
"Characterization of heparanase - induced phosphatidylinositol 3 - kinase - AKT activation and its integrin dependence . Q9Y251 functions as a heparan sulfate - degrading enzyme and as a ligand for an unidentified signaling receptor ( s ) . Here , several reactions involved in the activation of the PI3K - AKT pathway by latent heparanase were characterized . Protein suppression using specific siRNAs revealed that heparanase - induced phosphorylation of AKT at DB00133 - 473 was Q6R327 - P42345 - dependent , whereas Q13418 and PAK1 / 2 were dispensable . p110α was the PI3K catalytic isoform preferred by heparanase for AKT activation and cell proliferation because the p110α inhibitor YM024 blocked these processes . Q9Y251 - induced AKT phosphorylation was low in mouse embryonic fibroblast cells expressing a DB01367 interaction - defective p110α compared with wild type cells , indicating that DB01367 has an important role in the PI3K - AKT activation . The response to heparanase was also inefficient in suspension cultures of several cell lines , suggesting a requirement of integrins in this pathway . Adhesion via either αVβ3 or α5β1 promoted heparanase - induced AKT phosphorylation , and a stronger effect was seen when both integrins were engaged . Simultaneous inhibition of Q05397 and Q14289 using a chemical inhibitor , or suppression of their expression , inhibited heparanase - induced AKT activation and cell proliferation . Stimulation of cells with heparanase enhanced their resistance against oxidative stress - or growth factor starvation - induced apoptosis . These results demonstrate that there is an intimate cross - talk between the heparanase receptor ( s ) and integrins during induction of the prosurvival PI3K - AKT pathway by heparanase .",
"DB00072 emtansine : a novel antibody - drug conjugate for P04626 - positive breast cancer . DB00072 emtansine ( DB05773 ) is a novel P04626 - directed antibody - drug conjugate . DB05773 consists of the potent antimicrotubule agent DM1 , linked via a noncleavable linker to the P04626 - specific monoclonal antibody trastuzumab . Preclinical studies demonstrate that DB05773 has dual mechanisms of action : selective delivery of DM1 to the P04626 - positive ( P04626 (+) ) tumor cell combined with trastuzumab ' s activation of antibody - dependent cell - mediated cytotoxicity and inhibition of P04626 - mediated signal transduction . In phase II studies , DB05773 was active in patients with trastuzumab - and lapatinib - refractory metastatic breast cancer and led to improved progression - free survival compared with the combination of trastuzumab and docetaxel in the first - line setting . In a recent phase III trial in patients with metastatic breast cancer who previously received trastuzumab and a taxane , DB05773 resulted in improved progression - free and overall survival compared with capecitabine and lapatinib . DB05773 is associated with a favorable toxicity profile ; reversible thrombocytopenia and hepatic transaminase elevations are the only grade ≥ 3 adverse event present in 5 % or more of patients . Alopecia , peripheral neuropathy , and neutropenia are distinctly uncommon . On the basis of its improved efficacy and toxicity compared with capecitabine / lapatinib , DB05773 should be considered the standard for patients with P04626 (+) metastatic breast cancer who have previously progressed on trastuzumab and a taxane . Results from additional randomized studies in metastatic breast cancer are pending , and trials in the ( neo ) adjuvant setting are being initiated .",
"Semi - mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer . DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate ( ADC ) composed of multiple molecules of the antimicrotubule agent DM1 linked to trastuzumab , a humanized anti - human epidermal growth factor receptor 2 ( P04626 ) monoclonal antibody . Pharmacokinetics data from phase I ( n = 52 ) and phase II ( n = 111 ) studies in P04626 - positive metastatic breast cancer patients show a shorter terminal half - life for DB05773 than for total trastuzumab ( TTmAb ) . In this work , we translated prior preclinical modeling in monkeys to develop a semi - mechanistic population pharmacokinetics model to characterize DB05773 and TTmAb concentration profiles . A series of transit compartments with the same disposition parameters was used to describe the deconjugation process from higher to lower drug - to - antibody ratios ( DARs ) . The structure could explain the shorter terminal half - life of DB05773 relative to TTmab . The final model integrates prior knowledge of DB05773 DARs from preclinical studies and could provide a platform for understanding and characterizing the pharmacokinetics of other ADC systems .",
"The identification and characterization of breast cancer CTCs competent for brain metastasis . Brain metastatic breast cancer ( BMBC ) is uniformly fatal and increasing in frequency . Despite its devastating outcome , mechanisms causing BMBC remain largely unknown . The mechanisms that implicate circulating tumor cells ( CTCs ) in metastatic disease , notably in BMBC , remain elusive . We characterize CTCs isolated from peripheral blood mononuclear cells of patients with breast cancer and also develop CTC lines from three of these patients . In epithelial cell adhesion molecule ( EpCAM ) - negative CTCs , we identified a potential signature of brain metastasis comprising \" brain metastasis selected markers ( BMSMs ) \" P04626 + / P00533 + / Q9Y251 + / Notch1 + . These CTCs , which are not captured by the CellSearch platform because of their EpCAM negativity , were analyzed for cell invasiveness and metastatic competency in vivo . CTC lines expressing the BMSM signature were highly invasive and capable of generating brain and lung metastases when xenografted in nude mice . Notably , increased brain metastatic capabilities , frequency , and quantitation were detected in EpCAM - CTCs overexpressing the BMSM signature . The presence of proteins of the BMSM CTC signature was also detected in the metastatic lesions of animals . Collectively , we provide evidence of isolation , characterization , and long - term culture of human breast cancer CTCs , leading to the description of a BMSM protein signature that is suggestive of CTC metastatic competency to the brain .",
"Smith - Magenis syndrome resulting from a de novo direct insertion of proximal 17q into 17p11 . 2 . We report on a de novo intrachromosomal rearrangement of chromosome 17 in a patient with Smith - Magenis syndrome ( P52788 ) . This 11 - year - old boy had short stature , midfacial hypoplasia , and behavioral problems characteristic of this syndrome . Cytogenetic analysis showed that the proximal long arm of a chromosome 17 ( q11 . 2 - q21 . 3 ) was inserted into its short arm at p11 . 2 , resulting in an apparent deletion of the P52788 critical region [ ins ( 17 )( p11 . 2q11 . 2q21 . 3 ) ] . Fluorescence in situ hybridization studies ( Q5TCZ1 ) demonstrated that the inserted segment included both the P04626 and P10276 loci , and dual color hybridizations defined the insertion as direct , with P04626 located more proximally on the short arm of the der ( 17 ) . The resulting deletion of the short arm included loci c130G3 , D17S258 , FLI , and D17S29 , while the more proximal loci , D17S446 and D17S58 , remained apparently unaffected and in their native locations . The CMT1A locus also remained in its native location on the short arm of the metacentric der ( 17 ) chromosome . A de novo intrachromosomal insertional rearrangement of chromosome 17 in a case of P52788 has not been reported previously and further illustrates the instability of this chromosomal region .",
"[ Chemotherapy for breast cancer refractory to anthracycline , taxane or trastuzumab ] . Anthracycline , taxane or trastuzumab play a central role in systemic chemotherapy for breast cancer . The standard of subsequent treatment is capecitabine , S - 1 , vinorelbine , irinotecan or gemcitabine . DB04845 or nanoparticle paclitaxel is effective for taxane - resistant breast cancer . DB01259 proves effective for trastuzumab - resistant P04626 - overexpressing breast cancer and also for brain metastasis . DB05773 , pertuzumab and neratinib are promising drugs . In terms of antiangiogenic agents , bevacizumab in combination with taxane demonstrates efficacy . DB06626 , sunitinib or pazopanib is under investigation . It is necessary to study the best manner of sequence and combination in these drugs .",
"A mechanistic pharmacokinetic model elucidating the disposition of trastuzumab emtansine ( DB05773 ) , an antibody - drug conjugate ( ADC ) for treatment of metastatic breast cancer . DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate ( ADC ) therapeutic for treatment of human epidermal growth factor receptor 2 ( P04626 ) - positive cancers . The DB05773 dose product contains a mixture of drug - to - antibody ratio ( DAR ) moieties whereby the small molecule DM1 is chemically conjugated to trastuzumab antibody . The pharmacokinetics ( PK ) underlying this system and other ADCs are complex and have not been elucidated . Accordingly , we have developed two PK modeling approaches from preclinical data to conceptualize and understand DB05773 PK , to quantify rates of DM1 deconjugation , and to elucidate the link between trastuzumab , DB05773 , and DAR measurements . Preclinical data included PK studies in rats ( n = 34 ) and cynomolgus monkeys ( n = 18 ) at doses ranging from 0 . 3 to 30 mg / kg and in vitro plasma stability . DB05773 and total trastuzumab ( TT ) plasma concentrations were measured by enzyme - linked immunosorbent assay . Individual DAR moieties were measured by affinity capture liquid chromatography - mass spectrophotometry . Two PK modeling approaches were developed for DB05773 using NONMEM 7 . 2 software : a mechanistic model fit simultaneously to TT and DAR concentrations and a reduced model fit simultaneously to TT and DB05773 concentrations . DAR moieties were well described with a three - compartmental model and DM1 deconjugation in the central compartment . DM1 deconjugated fastest from the more highly loaded trastuzumab molecules ( i . e . , DAR moieties that are ≥ 3 DM1 per trastuzumab ) . DB05773 clearance ( CL ) was 2 - fold faster than TT CL due to deconjugation . The two modeling approaches provide flexibility based on available analytical measurements for DB05773 and a framework for designing ADC studies and PK - pharmacodynamic modeling of ADC efficacy - and toxicity - related endpoints .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK64___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"DB00072 emtansine : a unique antibody - drug conjugate in development for human epidermal growth factor receptor 2 - positive cancer . DB00072 emtansine ( DB05773 ) is a human epidermal growth factor receptor ( P04626 ) - targeted antibody - drug conjugate , composed of trastuzumab , a stable thioether linker , and the potent cytotoxic agent DM1 ( derivative of maytansine ) , in phase III development for P04626 - positive cancer . Extensive analysis of DB05773 in preclinical studies has shown that DB05773 combines the distinct mechanisms of action of both DM1 and trastuzumab , and has antitumor activity in trastuzumab - and lapatinib - refractory experimental models . Clinically , DB05773 has a consistent pharmacokinetics profile and minimal systemic exposure to free DM1 , with no evidence of DM1 accumulation following repeated DB05773 doses . Although a few covariates were shown to affect interindividual variability in DB05773 exposure and clearance in population - pharmacokinetics analyses , the magnitude of their effect on DB05773 exposure was not clinically relevant . Phase I and phase II clinical trials of DB05773 as a single agent and in combination with paclitaxel , docetaxel , and pertuzumab have shown clinical activity and a favorable safety profile in patients with P04626 - positive metastatic breast cancer . Two randomized phase III trials of DB05773 are recruiting patients : EMILIA ( NCT00829166 ) is evaluating DB05773 compared with lapatinib plus capecitabine , and MARIANNE ( NCT01120184 ) is evaluating DB05773 plus placebo versus DB05773 plus pertuzumab versus trastuzumab plus a taxane . Additional combinations of DB05773 ( for example , with P16260 - 0941 ) and additional disease settings ( early - stage P04626 - positive breast cancer ) are also under investigation . Data from the phase III trials and other studies of DB05773 - containing agents are eagerly awaited .",
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK43___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK43___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .",
"Is the Improved Efficacy of DB00072 and DB01259 Combination Worth the Added Toxicity ? A Discussion of Current Evidence , Recommendations , and Ethical Issues Regarding Dual P04626 - Targeted Therapy . Following FDA approval of trastuzumab in 1998 and lapatinib in 2007 , several clinical studies have addressed the question of whether trastuzumab and lapatinib combination therapy is better than trastuzumab alone in the metastatic breast cancer and neoadjuvant setting . In this review , updated to September 2012 , we focus on the relevant clinical trials that address this question and , based on the available data , reach conclusions regarding a rational and reasonably individualized approach to the management of P04626 + breast cancer . With the FDA approval of pertuzumab in June 2012 and the likely approval of DB05773 approaching , several ethical issues overshadow the excitement oncologists have for these new treatment options . We discuss the potential evolution of highly active anti - P04626 therapy ( HAAHT ) as an optimal treatment paradigm for P04626 + breast cancer . Additionally , we review lessons learned from the evolution of HAART for HIV treatment .",
"Population pharmacokinetics of trastuzumab emtansine ( DB05773 ) , a P04626 - targeted antibody - drug conjugate , in patients with P04626 - positive metastatic breast cancer : clinical implications of the effect of covariates . PURPOSE : DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate comprising the humanized monoclonal antibody trastuzumab linked to DM1 , a highly potent cytotoxic agent . A population pharmacokinetic ( PK ) analysis was performed to estimate typical values and interindividual variability of DB05773 PK parameters and the effects of clinically relevant covariates . METHODS : Serum samples were collected from 671 patients with human epidermal growth factor receptor 2 - positive locally advanced or metastatic breast cancer ( MBC ) who received single - agent DB05773 in five phase I to phase III studies . Nonlinear mixed - effects modeling with the first - order conditional estimation method was used . RESULTS : A linear two - compartment model with first - order elimination from the central compartment described DB05773 PKs in the clinical dose range . DB05773 elimination clearance was 0 . 676 L / day , volume of distribution in the central compartment ( V c ) was 3 . 127 L , and terminal elimination half - life was 3 . 94 days . Age , race , region , and renal function did not influence DB05773 PK . Given the low - to - moderate effect of all statistically significant covariates on DB05773 exposure , none of these covariates is expected to result in a clinically meaningful change in DB05773 exposure . CONCLUSIONS : DB05773 PK properties are consistent and predictable in patients . A further refinement of dose based on baseline covariates other than body weight for the current 3 . 6 mg / kg regimen would not yield clinically meaningful reductions in interindividual PK variability in patients with MBC .",
"DB00072 emtansine in human epidermal growth factor receptor 2 - positive breast cancer : a review . PURPOSE OF REVIEW : In this review , we aim to update the clinical data of trastuzumab - DM1 ( DB05773 ) in terms of safety and efficacy , and describe ongoing and future trials evaluating its potential role in the management of patients with human epidermal growth factor receptor 2 ( P04626 ) - positive breast cancer . RECENT FINDINGS : DB00072 emtansine ( DB05773 ) is an antibody drug conjugate that optimizes delivery of chemotherapy with an anti - P04626 monoclonal antibody . As a conjugate , DB05773 ' s systemic side effects are significantly minimized due to its targeted delivery by trastuzumab to P04626 - positive cells . Phase I and II studies show that the maximum tolerated dose , and thus the recommended dose for DB05773 , is 3 . 6 mg / kg given intravenously every 3 weeks . Single arm phase Ib / II , II and a randomized phase II first - line study of DB05773 versus the combination of trastuzumab + docetaxel all showed improved tolerability , and at least equivalent efficacy , compared with our current standard of care . Two randomized phase III registration studies are now active , evaluating this agent in the refractory and first - line P04626 - positive settings . SUMMARY : DB05773 has been shown to be a very promising agent for the targeted delivery of chemotherapy and anti - P04626 monoclonal antibody therapy for patients with metastatic , P04626 - positive breast cancer . DB05773 will likely play a role in the management of patients with advanced and early stage P04626 - positive breast cancer , but this awaits further study .",
"DB05773 ( Kadcyla ) for P04626 - positive metastatic breast cancer .",
"Genome - wide analysis of DNA copy number alterations and gene expression in gastric cancer . Genomic copy number aberrations ( CNAs ) are believed to play a major role in the development and progression of human cancers . Although many CNAs have been reported in gastric cancer , their genome - wide transcriptional consequences are poorly understood . In this study , to reveal the impact of CNAs on genome - wide expression in gastric cancer , we analysed 30 cases of gastric cancers for their CNAs by array comparative genomic hybridization ( array CGH ) and 24 of these 30 cases for their expression profiles by oligonucleotide - expression microarray . We found that with the application of laser microdissection , most CNAs were detected at higher frequency than in previous studies . Notably , gain at 20q13 was detected in almost all cases ( 97 % ) , suggesting that this may play an important role in the pathogenesis of gastric cancer . By comparing the array CGH data with expression profiles of the same samples , we showed that both genomic amplification and deletion strongly influence the expression of genes in altered genomic regions . Furthermore , we identified 125 candidate genes , consisting of 114 up - regulated genes located in recurrent regions ( > 10 % ) of amplification and 11 down - regulated genes located in recurrent regions of deletion . Up - regulation of several candidate genes , such as Q99741 , P60059 , Q9BTT0 , Q13895 and P37268 , was confirmed by immunohistochemistry . Interestingly , some candidate genes were localized at genomic loci adjacent to well - known genes such as P00533 , P04626 and Q13485 , and concordantly deregulated by genomic alterations . Based on these results , we propose that our list of candidate genes may contain novel genes involved in the pathogenesis of advanced gastric cancer .",
"Therapeutic targeting of P04626 in breast cancer : understanding resistance in the laboratory and combating it in the clinic . P04626 gene amplification occurs in about one quarter of breast carcinomas ( BCs ) and identifies a distinct clinical subset of BC . The introduction in the clinic of DB00072 , a humanized monoclonal antibody ( mAb ) directed to the P04626 extracellular domain , has had a great impact on the therapeutic management of P04626 + BC . Yet , not all patients respond to DB00072 and resistance develops also among patients that initially benefit from DB00072 - based regimens . Pre - clinical studies have discovered several mechanisms through which tumor cells may escape from DB00072 - mediated P04626 inhibition . These include rewiring of the ErbB signaling network , loss of P04626 expression , expression of P04626 isoforms refractory to DB00072 inhibition , vicarious signaling by non - ErbB tyrosine kinases and constitutive activation of downstream signaling routes , such as the PI3K pathway . While the relative contribution of each of these mechanisms to establishing DB00072 resistance in the clinical setting is not fully understood , much attention has been focused on abating resistance by achieving complete blockade of P04626 - containing dimers . This approach , propelled by the development of novel anti - P04626 therapeutics , has led to the recent approval of DB01259 , DB06366 and DB05773 as additional anti - P04626 therapeutics in BC . However , full success is far from being achieved and resistance to P04626 targeting remains a relevant problem in the clinical management of BC . Herein , we provide an overview of biological and molecular bases underpinning resistance to P04626 therapeutics in BC , discuss outstanding issues in the field of P04626 therapeutic targeting and elaborate on future directions of translational research on P04626 + breast cancer .",
"Exposure - response relationship of DB05773 : insight into dose optimization for patients with P04626 - positive metastatic breast cancer . Exposure - response ( E - R ) analyses for ado - trastuzumab emtansine ( DB05773 , Kadcyla ) were performed using data from a randomized , active control ( lapatinib plus capecitabine ) trial in patients with human epidermal growth factor 2 - positive metastatic breast cancer . Kaplan - Meier survival analyses stratified by DB05773 trough concentration on day 21 of cycle 1 ( Cmin , C1D21 ) were performed for overall survival ( OS ) and progression - free survival ( PFS ) . E - R analyses indicated that after adjusting for baseline risk factors , higher DB05773 exposure is associated with improved efficacy . DB05773 - treated patients with Cmin , C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm . The percentage of patients who received DB05773 dose adjustments was similar across the exposure range and was lower than that of the active control arm . Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low DB05773 exposure for improved efficacy with acceptable tolerability .",
"P01308 - like growth factor - 1 receptor as a novel prognostic marker and its implication as a cotarget in the treatment of human adenocarcinoma of the esophagus . P01308 - like growth factor - 1 receptor ( IGF - 1R ) and human epidermal growth factor receptor - 2 ( P04626 ) receptor expression has been found to be a key regulator of tumorigenesis . The purpose of our study was to establish the prognostic significance of IGF - 1R in esophageal cancer and to determine the effect of IGF - 1R and P04626 targeting with alpha - IR3 and Herceptin antibodies on the proliferation of esophageal cancer cells in vitro . IGF - 1R expression and clinicopathological correlations were analyzed with a tissue microarray containing 234 esophageal cancer specimens ( 133 adenocarcinomas and 101 squamous cell carcinomas ) . Proliferation changes associated with Herceptin and alpha - IR3 blockage were evaluated with the unique human esophageal cancer cell lines Pt1590 and LN1590 . IGF - 1R and P04626 expression levels , activation and phosphorylation status of downstream signaling proteins involved in the activation pathways were analyzed by Western blotting . IGF - 1R overexpression was detected in 121 ( 52 % ) of the 234 esophageal tumors examined . In the subgroup of 87 P04626 - positive tumors , 93 . 1 % showed concordant overexpression for IGF - 1R . IGF - 1R was identified as a variable associated with reduced overall survival for adenocarcinoma ( p = 0 . 05 ) , but not for squamous cell carcinoma . The combination of Herceptin and alpha - IR3 was more effective in inhibiting in vitro proliferation than treatment with either agent alone ( p < 0 . 01 ) . This was associated with a decrease in P04626 and IGF - 1R protein levels and suppression of Akt - and Q96HU1 kinase phosphorylation . IGF - 1R expression can be used as a novel prognostic marker for adenocarcinomas of the esophagus . Cotreatment with IGF - 1R and P04626 antibodies might become a valuable and effective treatment option in esophageal adenocarcinoma .",
"DB00072 emtansine ( DB05773 ) : a novel agent for targeting P04626 + breast cancer . Increased understanding of the molecular mechanisms of tumorigenesis has led to the development of novel agents that target tumor cells with minimal effects on normal cells . The success of this approach is exemplified by the development of monoclonal antibodies directed toward antigens expressed selectively by tumor cells . The conjugation of these monoclonal antibodies with potent cytotoxic drugs has the potential to further improve efficacy while retaining a favorable safety profile . DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate ( ADC ) currently in clinical development . It combines the humanized antibody trastuzumab , which targets the human epidermal growth factor receptor 2 ( P04626 ) receptor on cancer cells , and the potent antimicrotubule agent DM1 using a unique highly stable linker . When DB05773 binds to P04626 , a proportion of the receptors are thought to be internalized by the process of receptor endocytosis , followed by the intracellular release of an active form of DM1 , which in turn kills the tumor cell . This review presents the rationale for the development of DB05773 and summarizes the preclinical and clinical data for this novel agent for the treatment of breast cancer .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK37___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"1 -( 3 - Trifluoromethylphenyl ) piperazine ( TFMPP ) in the ventral tegmental area reduces the effect of desipramine in the forced swimming test in rats : possible role of serotonin receptors . 1 -( 3 - Trifluoromethylphenyl ) piperazine ( TFMPP ) , a serotonin1 ( 5 - HT1 ) receptor agonist , injected i . p . in doses of 0 . 1 and 0 . 6 mg / kg , did not modify the immobility time of rats in the forced swimming test but significantly antagonized the effect of a 7 days treatment with 10 mg / kg per day desipramine ( ___MASK43___ ) . A similar effect was found on infusing 1 and 5 micrograms / microliters TFMPP bilaterally into the ventral tegmental area ( VTA ) . Infusion of 5 micrograms / microliters TFMPP into the nucleus accumbens or into the globus pallidus did not modify the effect of ___MASK43___ . The effect of 5 micrograms TFMPP infused into the VTA was prevented by the i . p . administration of 5 mg / kg metergoline , a non - selective serotonin receptor antagonist . Infusion of 5 micrograms / microliters 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , a specific P08908 receptor agonist , into the VTA did not modify the effect of ___MASK43___ . Besides acting as a P28222 receptor agonist , TFMPP may also act on other 5 - HT receptor types , but available evidence suggests that its former action is more important . It thus appears that 5 - HT1 receptors in the VTA , presumably of the P28222 type , act by preventing the anti - immobility effect of ___MASK43___ . The role of VTA dopamine and non - dopamine cells in the effect of TFMPP is discussed .",
"Treatment of P04626 - overexpressing breast cancer . The HER family of receptors consists of four closely related type 1 transmembrane TK receptors : P00533 ( P00533 ) , P04626 , P21860 and Q15303 . Signalling via the HER family of receptors underpins the majority of the intricate array of cellular activities on which cell survival and functionality depend . Aberrant P04626 expression and / or functionality have been implicated in the evolution of breast cancer and this receptor has proved to be a potent target for anticancer therapies , including antibody - based therapies to prevent ligand binding , dimer formation or the recruitment of antibody - dependent cell - mediated cytotoxicity , and direct kinase inhibition to prevent molecular activation and recruitment of downstream signalling partners . Novel strategies against P04626 include HER tyrosine kinase inhibitors , HSP90 inhibitors and antibody - chemotherapy conjugates . This latter approach is exemplified by DB05773 , a potent antibody that has a good safety profile and that has shown remarkable activity in patients with advanced disease . In addition , pertuzumab , an mAb that directly inhibits the formation of P04626 dimers including the P04626 : P21860 dimer , offers a unique mechanism of P21860 inhibition . All these approaches have shown substantial clinical activity in patients refractory to trastuzumab . It is anticipated that with the increased availability of novel anti - P04626 agents together with a better understanding of the mechanisms of resistance to anti - P04626 agents we should be able to further improve the outcome of patients with P04626 breast cancer . There will also be an increasing tendency towards moving the study of these agents to earlier stages of the disease , namely in the adjuvant and neoadjuvant setting .",
"[ Endometrial cancer in young women -- clinical and molecular aspects ] . OBJECTIVES : The aim the study was to compare two groups of endometrial cancer patients ( below and above 45 years of age ) in the aspect of clinicopathological and molecular data . MATERIAL AND METHODS : The study encompassed 456 primary tumour samples retrospectively collected from a cohort of endometrial cancer patients , primarily treated by surgery Molecular analysis covered : copy number variations of 10 genes ( P11388 , P00533 , P04626 , P21860 , Q15303 , MYC , P24385 , P03372 , P42336 , O60216 ) analyzed by quantitative PCR ; mRNA expression of 6 genes ( Q13296 , RAD27 , Q01196 , O95863 , O43623 , O43490 ) analyzed with the use of reverse transcription quantitative PCR ; protein expression analysis of 8 markers ( P06401 , P03372 ; P00533 , P04626 , P21860 , Q15303 , P11388 , pAKT1 ) performed with the use of immunohistochemistry . RESULTS : The younger group of patients was characterized by less frequent hypertension ( p < 0 . 00007 ) , less frequent myometrial infiltration ( p = 0 . 002 ) and longer overall survival ( p = 0 . 003 ) . Apart from O60216 gene aberrations , which were more frequent in younger patients ( p = 0 . 02 ) , the study revealed no statistically significant differences between the groups . CONCLUSIONS : The study showed no molecular differences in the profile of younger and older endometrial cancer patients . Data on both the prognostic and predictive significance of O60216 in endometrial cancer are still insufficient . The clinical profile of younger patients with endometrial carcinoma was slightly better when compared to elderly patients . Younger patients were characterized by longer overall survival .",
"DB05773 , a novel antibody - drug conjugate , is highly effective against primary P04626 overexpressing uterine serous carcinoma in vitro and in vivo . Amplification of c - erbB2 has been reported in over 30 % of uterine serous carcinoma ( USC ) and found to confer poor survival because of high proliferation and increased resistance to therapy . In this study , we evaluated for the first time DB00072 emtansine ( DB05773 ) , a novel antibody - drug conjugate , against multiple epidermal growth factor receptor - 2 ( P04626 ) - positive USC cells in vitro followed by developing a supportive in vivo model . Fifteen primary USC cell lines were assessed by immunohistochemistry ( IHC ) and flow cytometry for P04626 protein expression . C - erbB2 gene amplification was evaluated using fluorescent in situ hybridization . Sensitivity to DB05773 and trastuzumab ( T ) - induced antibody - dependent cell - mediated cytotoxicity was evaluated in 5 - h chromium release assays . DB05773 and T cytostatic and apoptotic activities were evaluated using flow - cytometry - based proliferation assays . In vivo activity of DB05773 versus T in USC xenografts in SCID mice was also evaluated . High levels of P04626 protein overexpression and P04626 gene amplification were detected in 33 % of USC cell lines . DB05773 was considerably more effective than trastuzumab in inhibiting cell proliferation and in causing apoptosis ( P = 0 . 004 ) of USC showing P04626 overexpression . Importantly , DB05773 was highly active at reducing tumor formation in vivo in USC xenografts overexpressing P04626 ( P = 0 . 04 ) and mice treated with TDM - 1 had significantly longer survival when compared to T - treated mice and control mice ( P ≤ 0 . 0001 ) . DB05773 shows promising antitumor effect in P04626 - positive USC cell lines and USC xenografts and its activity is significantly higher when compared to T . DB05773 may represent a novel treatment option for P04626 - positive USC patients with disease refractory to trastuzumab and traditional chemotherapy .",
"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .",
"P04626 - family signalling mechanisms , clinical implications and targeting in breast cancer . Approximately 20 % of human breast cancers ( BC ) overexpress P04626 protein , and P04626 - positivity is associated with a worse prognosis . Although P04626 - targeted therapies have significantly improved outcomes for P04626 - positive BC patients , resistance to trastuzumab - based therapy remains a clinical problem . In order to better understand resistance to P04626 - targeted therapies in P04626 - positive BC , it is necessary to examine HER family signalling as a whole . An extensive literature search was carried out to critically assess the current knowledge of HER family signalling in P04626 - positive BC and response to P04626 - targeted therapy . Known mechanisms of trastuzumab resistance include reduced receptor - antibody binding ( Q99102 , p95HER2 ) , increased signalling through alternative HER family receptor tyrosine kinases ( RTK ) , altered intracellular signalling involving loss of P60484 , reduced p27kip1 , or increased PI3K / AKT activity and altered signalling via non - HER family RTKs such as P08069 . Emerging strategies to circumvent resistance to P04626 - targeted therapies in P04626 - positive BC include co - targeting P04626 / PI3K , pan - HER family inhibition , and novel therapies such as DB05773 . There is evidence that immunity plays a key role in the efficacy of HER - targeted therapy , and efforts are being made to exploit the immune system in order to improve the efficacy of current anti - HER therapies . With our rapidly expanding understanding of P04626 signalling mechanisms along with the repertoire of HER family and other targeted therapies , it is likely that the near future holds further dramatic improvements to the prognosis of women with P04626 - positive BC .",
"New therapies in P04626 - positive breast cancer : a major step towards a cure of the disease ? Overexpression of the human epidermal growth factor receptor 2 ( P04626 ) predicts a poor prognosis in metastatic breast cancer . While the introduction of P04626 - targeted therapies , such as the monoclonal antibody trastuzumab and the small - molecule tyrosine kinase inhibitor lapatinib , has significantly improved outcomes in P04626 + breast cancer compared with previously available therapies , use of these targeted therapies is often limited by the development of drug resistance and tolerability issues . These limitations create the need for further development and investigation of new targeted therapies that show potent and selective inhibition of these targets or closely connected molecular pathways . Recently , several agents have demonstrated promising activity in P04626 + metastatic breast cancer , either as monotherapy or in combination therapy , including the tyrosine - kinase inhibitors neratinib ( HKI - 272 ) and afatinib ( BIBW - 2992 ) and the anti - P04626 monoclonal antibodies pertuzumab and trastuzumab - DM1 ( DB05773 ) . Agents that target other molecular pathways , such as the vascular endothelial growth factor receptor , mammalian target of rapamycin , P19957 - kinases , insulin - like growth factor ( IGFR ) , HSP - 90 , and other kinases also have potential , in combination with anti - P04626 and / or other systemic therapies , to be active in this subtype of breast cancer . Innovative clinical studies are required in well - characterized patient populations to define the true clinical value of these emerging new approaches .",
"P04626 - positive breast cancer : beyond trastuzumab . The outlook for patients with P04626 - positive breast cancer was revolutionized by the development of trastuzumab ( Herceptin ) , a humanized murine monoclonal antibody . Use of this agent led to improved overall survival when it was added to chemotherapy for the treatment of metastatic breast cancer . Improved understanding of mechanisms of resistance to trastuzumab has facilitated the development of novel agents for P04626 - positive breast cancer , and also resulted in superior outcomes when added to chemotherapy in the adjuvant setting . This review explores the use of several such agents , including lapatinib ( DB01259 ) , HSP90 inhibitors , DB05773 , and other tyrosine kinase inhibitors . Emerging data from trials of these agents indicate that the P04626 pathway remains a valid therapeutic target following disease progression on trastuzumab , and suggest a promising role for combined P04626 blockade with two or more agents .",
"Transforming growth factor - alpha directly augments histidine decarboxylase and vesicular monoamine transporter 2 production in rat enterochromaffin - like cells . For the production and vesicle storage of histamine , Enterochromaffin - like ( ECL ) cells express histidine decarboxylase ( HDC ) and vesicular monoamine transporter 2 ( Q05940 ) . Although HDC and Q05940 show dynamic changes during gastric ulcer healing , the control system of their expression has not been fully investigated . In the present study , we investigated the effect of transforming growth factor - alpha ( TGF - alpha ) and proinflammatory cytokines on HDC and Q05940 expression in rat ECL cells . Time course changes in the expression of TGF - alpha during the healing of acetic acid - induced ulcers were studied . P01133 receptor ( P00533 ) expression was also examined in ECL cells , whereas the direct effects of TGF - alpha and proinflammatory cytokines on HDC and Q05940 expression in ECL cells were investigated using in vivo and in vitro models . During the process of ulcer healing , expression of TGF - alpha mRNA was markedly augmented . Furthermore , P00533 was identified in isolated ECL cells . TGF - alpha stimulated HDC and Q05940 mRNA expression and protein production and also increased histamine release from ECL cells . Selective P00533 tyrosine kinase inhibitor tyrphostin AG1478 almost completely inhibited HDC and Q05940 gene expression induced by TGF - alpha in vivo and in vitro . During gastric mucosal injury , TGF - alpha was found to stimulate ECL cell functions by increasing HDC and Q05940 expression .",
"Overcoming treatment resistance in P04626 - positive breast cancer : potential strategies . Human epidermal growth factor receptor ( HER ) - 2 overexpression or amplification occurs in about 20 % of all breast cancers and results in a worse prognosis . Nevertheless , anti - P04626 treatments have recently been developed , resulting in dramatic improvements in the clinical outcome of patients with P04626 - positive breast cancer . DB00072 has shown efficacy in early and advanced breast cancer treatment and lapatinib is currently approved for the treatment of advanced disease . Other anti - P04626 agents are being investigated . Mechanisms of resistance to trastuzumab treatment include crosstalk with heterologous receptors and amplification of P04626 signalling ; amplification of the phosphoinositide 3 - kinase ( PI3K ) / AKT pathway ; alteration in binding of trastuzumab to P04626 ; and loss of P04626 expression . Proposed mechanisms of resistance to lapatinib involve derepression and / or activation of compensatory survival pathways through increased PI3K / AKT or estrogen receptor ( ER ) signalling . Several strategies to overcome resistance to anti - P04626 treatment are in different phases of development and include treatment with pertuzumab , DB05773 and mammalian target of rapamycin ( P42345 ) inhibitors .",
"DB05773 : a P04626 - positive targeted antibody - drug conjugate . OBJECTIVE : To review the pharmacology , pharmacokinetics , efficacy , adverse effects , drug - drug interactions , dosage and administration , and formulary considerations for ado - trastuzumab emtansine . DATA SOURCES : Sources of information were identified through a PubMed search ( 1966 to June 2014 ) using the key terms ado - trastuzumab emtansine , trastuzumab - DM1 , trastuzumab - MCC - DM1 , and DB05773 . Other information was obtained from clinicaltrials . gov , product labeling , and press releases . STUDY SELECTION AND DATA EXTRACTION : All English - language clinical trials and abstracts evaluating ado - trastuzumab emtansine in humans were reviewed for inclusion . DATA SYNTHESIS : Overexpression or amplification of human epidermal growth factor receptor 2 ( P04626 ) occurs in approximately 20 % of breast cancers and is associated with more aggressive tumors and poorer prognosis in the absence of treatment . Although effective therapies for the initial management of P04626 - positive metastatic breast cancer ( MBC ) exist , many patients will experience disease progression . Most second - line therapies are associated with either significant toxicities or limited improvements in overall survival ( OS ) . DB05773 is a P04626 - positive directed antibody drug conjugate ( ADC ) approved in February 2013 . In phase III clinical trials comparing the efficacy and safety of ado - trastuzumab emtansine with lapatinib - capecitabine or physician ' s choice , ado - trastuzumab emtansine had a better tolerability profile and improved progression - free survival compared with lapatinib - capecitabine or physician ' s choice and increased OS compared with lapatinib - capecitabine . CONCLUSION : DB05773 is a novel ADC effective for P04626 - positive MBC in patients previously treated with trastuzumab , lapatinib , and a taxane . Further studies will determine its use in the adjuvant and neoadjuvant setting and in combination with pertuzumab .",
"New perspectives of vesicular monoamine transporter 2 chemical characteristics in mammals and its constant expression in type 1 diabetes rat models . Vesicular monoamine transporter 2 ( Q05940 ) has been exploited as a biomarker of β - cell mass in human islets . However , a current report suggested no immunoreactivity of Q05940 in the β cells of rat islets . To investigate the cellular localization of Q05940 in islets further , the pancreatic tissues from monkeys and humans were compared with those of rats and mice . The study was performed using among - species comparisons and a type 1 diabetes model ( T1DM ) for rats by Western blotting , double - label immunofluorescence , and confocal laser scanning microscopy . We found that Q05940 - immunoreactivity ( IR ) was distributed peripherally in the islets of rodents , but was widely scattered throughout the islets of primates . Consistent with rodent islets , Q05940 - IR did not exist in insulin ( P01308 ) - IR cells but was abundantly present in glucagon ( GLU ) - IR and pancreatic polypeptide ( PP ) - IR cells in monkey and human islets . Q05940 - IR had no colocalization with P01308 - IR in any part of the rat pancreas ( head , body , and tail ) . P01308 - IR cells were reduced dramatically in T1DM rat islets , but no significant alteration in the proportion of Q05940 - IR cells and GLU - IR cells was observed . Furthermore , a strong colocalization of Q05940 - IR with GLU - IR was distributed in the peripheral regions of diabetic islets . For the first time , the current study demonstrates the presence of Q05940 in α cells and PP cells but not in β cells in the islets of monkeys and humans . This study provides convinced morphologic evidence that Q05940 is not present in β cells . There needs to be studies for new markers for β cell mass .",
"[ DB05773 and pertuzumab : emerging anti - P04626 therapeutics ] . P04626 - targeted therapy for P04626 - positive breast cancer is one of the success stories in medical oncology . DB00072 , a humanized monoclonal antibody , was the first approved P04626 - targeted agent . Subsequent developments include agents with different mechanisms , such as lapatinib , a tyrosine kinase inhibitor . We describe here the results of late - phase clinical trials of two newly - available anti - P04626 agents , DB05773 and pertuzumab .",
"[ Antibody - drug conjugates in oncology : from the concept to trastuzumab emtansine ( DB05773 ) ] . DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate ( ADC ) which associates the selective intracellular targeting of the cytotoxic agent , DM1 ( maytansine derivative ) to the antitumor activity of trastuzumab . DB05773 targets the epidermal growth factor receptor 2 ( P04626 ) , highly expressed in the most aggressive forms of breast cancer . Current standard of care in P04626 - positive advanced or metastatic breast cancers has its limitations , particularly after progression on P04626 - targeted approved therapies . DB05773 showed a significant antitumor activity in vitro and in vivo , and in experimental models resistant to P04626 - targeted agents . Phase I and II studies showed that the maximum tolerated dose for DB05773 is 3 . 6 mg / kg given intravenously every three weeks . At this recommended dose , DB05773 provided objective tumor responses and favourable safety profile . A phase II randomised study , evaluating DB05773 in first line vs trastuzumab plus docetaxel , the current standard of care in advanced or metastatic breast cancers , showed improved tolerability and efficacy . Recently , the results of EMILIA , a phase III randomised study assessing , after prior treatment with trastuzumab and a taxane , the efficacy and the safety of DB05773 vs lapatinib plus capecitabine , confirmed the therapeutic benefit . DB05773 appears to be an effective therapeutic option to treat patients with P04626 - positive metastatic breast cancer .",
"Advanced P04626 - positive gastric cancer : current and future targeted therapies . The prognostic value of human epidermal growth factor receptor 2 ( P04626 ) in gastric cancer is controversial . Consensus guidelines have standardized the testing of P04626 status in gastric cancer . Overexpression of this receptor occurs in approximately 20 % of gastric and gastro - esophageal junction adenocarcinomas , predominantly those of the intestinal type . Recently , trastuzumab has emerged as the first targeted drug to improve overall survival when combined with chemotherapy in advanced P04626 - positive gastric cancer . Primary and secondary resistance to trastuzumab has become a major problem and new strategies to overcome this resistance are needed . A high percentage of advanced P04626 - positive gastric cancer patients who progress on trastuzumab therapy are candidates for second - line therapy . New families of targeted drugs , including tyrosine kinase inhibitors ( TKIs ) such as lapatinib and PF - 00299804 , mammalian target of rapamycin ( P42345 ) pathway inhibitors such as everolimus , heat - shock protein 90 ( HSP90 ) inhibitors such as AUY922 , HER dimerization inhibitors such as pertuzumab , and antibody - chemotherapy conjugates such as trastuzumab - emtansine ( DB05773 ) , could offer alternative second - line treatments when trastuzumab - based first - line therapy fails .",
"A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro . Statins and nitrogenous bisphosphonates ( NBP ) inhibit 3 - hydroxy - 3 - methylglutaryl - coenzyme - A reductase ( P04035 ) and farnesyl diphosphate synthase ( P14324 ) , respectively , leading to depletion of farnesyl diphosphate ( FPP ) and disruption of protein prenylation . P37268 ( P37268 ) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis . Herein , we have identified novel bisphosphonates as potent and specific inhibitors of P37268 , including the tetrasodium salt of 9 - biphenyl - 4 , 8 - dimethyl - nona - 3 , 7 - dienyl - 1 , 1 - bisphosphonic acid ( compound 5 ) . Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells . At high concentrations , lovastatin and zoledronate impaired protein prenylation and decreased cell viability , which limits their potential use for cholesterol depletion . When combined with lovastatin , compound 5 prevented lovastatin - induced FPP depletion and impairment of protein farnesylation . Compound 5 in combination with the NBP zoledronate completely prevented zoledronate - induced impairment of both protein farnesylation and geranylgeranylation . Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone . The combination of an P37268 inhibitor with an P04035 or P14324 inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion .",
"Breast cancer brain metastases responding to lapatinib plus capecitabine as second - line primary systemic therapy . Brain metastases ( BM ) are diagnosed in up to 40 % of P04626 - positive breast cancer patients . Standard treatment includes local approaches such as whole - brain radiotherapy ( WBRT ) , radiosurgery , and neurosurgery . The landscape trial established primary systemic therapy as an effective and safe alternative to WBRT in selected patients with Her2 - positive BM . We aim to further focus on the role of systemic therapy in oligosymptomatic patients by presenting this case report . We report on a 50 - year - old patient diagnosed with multiple BM 5 years after early breast cancer diagnosis . As the patient was asymptomatic and had a favorable diagnosis - specific P02724 score , she received primary systemic treatment with DB05773 . She achieved partial remission within the brain for eight treatment cycles and then progressed despite stable extracranial disease . As the patient remained asymptomatic and refused WBRT , we decided upon trastuzumab , lapatinib plus capecitabine as second - line therapy . Another partial remission of BM was observed ; to date , she has received 11 treatment cycles without any sign of disease progression . In this case , WBRT was delayed by at least 14 months , again indicating the activity of systemic treatment in BM . Apparently , in selected patients , BM can be controlled with multiple lines of systemic therapy similar to extracranial disease . Further investigation of systemic treatment approaches is therefore warranted .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK54___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"DB05773 for the treatment of human epidermal growth factor receptor 2 - positive metastatic breast cancer . PURPOSE : An update on completed and ongoing clinical trials of ado - trastuzumab emtansine for the treatment of metastatic breast cancer ( MBC ) is presented . SUMMARY : DB05773 ( Kadcyla , Genentech ) , the first U . S .- approved antibody - drug conjugate for MBC , is indicated for use as a single - agent therapy in patients with human epidermal growth factor receptor 2 ( P04626 ) - positive MBC who have received prior treatment with unconjugated trastuzumab and a taxane - based regimen . The standard dosage of ado - trastuzumab is 3 . 6 mg / kg i . v . every three weeks . In completed Phase II or III clinical trials , ado - trastuzumab was found to confer significant survival and quality - of - life benefits . The largest of those trials ( the EMILIA study , n = 991 ) showed that ado - trastuzumab was superior to a regimen of lapatinib plus capecitabine in terms of progression - free survival ( 9 . 6 months versus 6 . 4 months , p < 0 . 001 ) and overall survival ( 30 . 9 months versus 25 . 1 months , p < 0 . 001 ) ; it also had a more favorable tolerability profile , with lower rates of treatment - limiting adverse effects . The most common adverse effects of ado - trastuzumab are thrombocytopenia ( reported in about 12 % of clinical trial participants overall ) and increased transaminase levels . Two ongoing Phase III trials - the TH3RESA study ( slated for completion in June 2015 ) and the MARIANNE study ( estimated completion in 2016 ) - may help determine the optimal role of ado - trastuzumab relative to other P04626 - targeted agents and its potential use as a front - line therapy for both heavily pretreated and treatment - naive patients with MBC . CONCLUSION : With a novel targeted mechanism of action , ado - trastuzumab is an effective treatment option for P04626 - positive MBC in previously treated patient populations .",
"P04626 - directed therapy for metastatic breast cancer . Human epidermal growth factor receptor 2 ( P04626 ) overexpression drives the biology of 20 % of breast cancers , and predicts a poor prognosis for patients . P04626 - targeted therapies significantly improve outcomes for P04626 - positive patients with both early and metastatic breast cancer . Currently three P04626 - targeted agents , trastuzumab ( Herceptin ) , lapatinib ( DB01259 ) , and pertuzumab ( Perjeta ) , are available for the treatment of P04626 - positive metastatic breast cancer ( MBC ) . Numerous studies have attempted to optimize their use by combining them with each other , or with endocrine and cytotoxic therapies . Most recently , the FDA approved the combination of trastuzumab , pertuzumab , and docetaxel as first - line treatment for MBC , and in late February 2013 approved a fourth P04626 - targeted agent , trastuzumab emtansine ( DB05773 , Kadcyla ) , for accelerated approval . These advances create a number of clinical dilemmas , including identification of the optimal sequence of P04626 - targeted agents and the best drug combinations to use , as well as the recognition of primary and acquired drug resistance . In this article , we review clinical data informing the effective management of P04626 - positive MBC .",
"___MASK40___ ( PD 0332991 ) : targeting the cell cycle machinery in breast cancer . INTRODUCTION : The cyclin D - cyclin - dependent kinases 4 and 6 ( P11802 / 6 ) - retinoblastoma ( P06400 ) pathway , governing the cell cycle restriction point , is frequently altered in breast cancer and is a potentially relevant target for anticancer therapy . ___MASK40___ ( PD 0332991 ) , a potent and selective inhibitor of P11802 and Q00534 , inhibits proliferation of several P06400 - positive cancer cell lines and xenograft models . AREAS COVERED : The basic features and abnormalities of the cell cycle in breast cancer are described , along with their involvement in estrogen signaling and endocrine resistance . The pharmacological features of palbociclib , its activity in preclinical models of breast cancer and the potential determinants of response are then illustrated , and its clinical development in breast cancer described . A literature search on the topic was conducted through PubMed and the proceedings of the main cancer congresses of recent years . EXPERT OPINION : The combination of palbociclib with endocrine agents is a very promising treatment and Phase III clinical trials are ongoing to confirm its efficacy . Further , potentially useful combinations are those with drugs targeting mitogenic signaling pathways , such as P04626 - and PI3K - inhibitors . Combination with chemotherapy seems more problematic , as antagonism has been reported in preclinical models . The identification of predictive factors , already explored in preclinical studies , must be further refined and validated in clinical trials .",
"Preclinical safety profile of trastuzumab emtansine ( DB05773 ) : mechanism of action of its cytotoxic component retained with improved tolerability . DB00072 emtansine ( DB05773 ) is the first antibody - drug conjugate ( ADC ) approved for patients with human epidermal growth factor receptor 2 ( P04626 ) - positive metastatic breast cancer . The therapeutic premise of ADCs is based on the hypothesis that targeted delivery of potent cytotoxic drugs to tumors will provide better tolerability and efficacy compared with non - targeted delivery , where poor tolerability can limit efficacious doses . Here , we present results from preclinical studies characterizing the toxicity profile of DB05773 , including limited assessment of unconjugated DM1 . DB05773 binds primate ErbB2 and human P04626 but not the rodent homolog c - neu . Therefore , antigen - dependent and non - antigen - dependent toxicity was evaluated in monkeys and rats , respectively , in both single - and repeat - dose studies ; toxicity of DM1 was assessed in rats only . DB05773 was well tolerated at doses up to 40 mg / kg ( ~ 4400 μg DM1 / m ( 2 ) ) and 30 mg / kg ( ~ 6000 μg DM1 / m ( 2 ) ) in rats and monkeys , respectively . In contrast , DM1 was only tolerated up to 0 . 2mg / kg ( 1600 μg DM1 / m ( 2 ) ) . This suggests that at least two - fold higher doses of the cytotoxic agent are tolerated in DB05773 , supporting the premise of ADCs to improve the therapeutic index . In addition , DB05773 and DM1 safety profiles were similar and consistent with the mechanism of action of DM1 ( i . e . , microtubule disruption ) . Findings included hepatic , bone marrow / hematologic ( primarily platelet ) , lymphoid organ , and neuronal toxicities , and increased numbers of cells of epithelial and phagocytic origin in metaphase arrest . These adverse effects did not worsen with chronic dosing in monkeys and are consistent with those reported in DB05773 - treated patients to date .",
"A phase 1 study of weekly dosing of trastuzumab emtansine ( DB05773 ) in patients with advanced human epidermal growth factor 2 - positive breast cancer . BACKGROUND : We conducted a phase 1 , multicenter , open - label , dose - escalation study ( TDM3569g ) to assess the safety , tolerability , and pharmacokinetics of single - agent trastuzumab emtansine ( DB05773 ) administered weekly and once every 3 weeks in patients with P04626 - positive metastatic breast cancer previously treated with trastuzumab . The weekly dose results are described here . METHODS : Patients were administered escalating doses of DB05773 weekly , starting at 1 . 2 mg / kg . Additional patients were enrolled at the maximum tolerated dose ( MTD ) to better characterize tolerability and pharmacokinetics . RESULTS : Twenty - eight patients received weekly DB05773 , and the MTD was determined to be 2 . 4 mg / kg . In general , DB05773 was well tolerated , requiring few dose modifications or discontinuations because of adverse events ( AEs ) . Grade ≥ 3 AEs were reported in 19 patients ( 67 . 9 % ) ; treatment - related AEs occurred in 25 ( 89 . 3 % ) patients . Exposure to weekly DB05773 was dose - proportional at ≥ 1 . 2 mg / kg , and accumulation of DB05773 and total trastuzumab was observed . Objective partial tumor responses were reported in 13 ( 46 . 4 % ) patients ; the median duration of response was 18 . 6 months , and the 6 - month clinical benefit rate was 57 . 1 % . CONCLUSION : The results suggest that a weekly dose of DB05773 2 . 4 mg / kg has antitumor activity and is well tolerated in patients with P04626 - positive metastatic breast cancer .",
"Beyond trastuzumab and lapatinib : new options for P04626 - positive breast cancer . P04626 - positive breast cancer ( BC ) constitutes a molecular subtype of the disease with an aggressive biologic behavior . DB00072 revolutionized the treatment of this disease , changing its natural history . DB01259 is active in the metastatic setting , approved for patients who were pretreated with trastuzumab . However , resistance to anti - P04626 agents is a major clinical issue , occurring in both early - stage and advanced disease , and new treatment options are clearly needed . An abundance of P04626 - targeted agents are being clinically developed : monoclonal antibodies , small molecule inhibitors , and antibody drug conjugates ( ADC ) . Combining P04626 - targeted agents in regimens of dual P04626 blockade has already reached clinical practice in the metastatic setting , confirming the preclinical efficacy of enhanced P04626 inhibition . Promising results have been generated in the neoadjuvant setting , and large randomized trials are seeking evidence for dual P04626 blockade in the adjuvant setting . ADC represent another hope for improved treatment outcomes of P04626 - positive BC , as exemplified by the positive results of clinical trials employing trastuzumab - DM1 ( trastuzumab emtansine , DB05773 ) . Moreover , an understanding of the molecular mechanisms mediating resistance to P04626 blockade has opened new therapeutic avenues , with several targeted agents entering clinical trials . This paper presents the clinical data of the P04626 - targeted agents under development , as well as an overview of the biologic rationale for the development of agents aimed at circumventing anti - P04626 resistance .",
"Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine ( DB05773 ) : an emphasis on preclinical and clinical catabolism . DB00072 emtansine ( DB05773 ) is an antibody - drug conjugate in clinical development for the treatment of human epidermal growth factor receptor 2 ( P04626 ) - positive cancers . Herein , we describe a series of studies to assess DB05773 absorption , distribution , metabolism , and excretion ( ADME ) in rats as well as to assess human exposure to DB05773 catabolites . Following administration of unlabeled and radiolabeled DB05773 in female Sprague Dawley rats as a single dose , plasma , urine , bile and feces were assessed for mass balance , profiling and identification of catabolites . In rats , the major circulating species in plasma was DB05773 , while DM1 concentrations were low ( 1 . 08 to 15 . 6 ng / mL ) . The major catabolites found circulating in rat plasma were DM1 , [ N - maleimidomethyl ] cyclohexane - 1 - carboxylate - DM1 ( MCC - DM1 ) , and DB00123 - MCC - DM1 . These catabolites identified in rats were also detected in plasma samples from patients with P04626 - positive metastatic breast cancer who received single - agent DB05773 ( 3 . 6 mg / kg every 3 weeks ) in a phase 2 clinical study . There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing . In rats , DB05773 was distributed nonspecifically to the organs without accumulation . The major pathway of DM1 - containing catabolite elimination in rats was the fecal / biliary route , with up to 80 % of radioactivity recovered in the feces and 50 % in the bile . The rat DB05773 ADME profile is likely similar to the human profile , although there may be differences since trastuzumab does not bind the rat P04626 - like receptor . Further research is necessary to more fully understand the DB05773 ADME profile in humans .",
"P35354 expression in prognosis and in prediction to endocrine therapy in early breast cancer patients . In breast cancer , the prognostic impact of P35354 expression varies widely between studies . We examined the prognostic value of P35354 expression in a large cohort of breast cancer patients treated with primary surgery between 1985 and 1994 and explained the variable results of P35354 expression found in the literature . A tissue microarray was constructed of available tumour material , and ER , PgR , P04626 , Ki67 and P35354 were examined by immunohistochemistry . Median follow - up was 19 years . Fifty - five percent ( n = 369 / 677 ) of patients received no systemic treatment . P35354 was scored using a weighted histoscore . Analysis of P35354 expression in two groups based on the median ( 148 ; below vs . above ) showed an increased hazard ratio ( HR ) of 1 . 35 ( 95 % CI 1 . 05 - 1 . 75 , P = 0 . 021 ) for disease - free survival ( DFS ) and of 1 . 39 ( 95 % CI 1 . 03 - 1 . 82 , P = 0 . 016 ) for overall survival ( OS ) . However , P35354 did not remain independent in multivariate analysis . In patients with hormone receptor positive tumours , P35354 expression had a negative influence on outcome ( low vs . high : DFS : HR 1 . 37 , 95 % CI 1 . 07 - 1 . 76 , P = 0 . 013 ) . This effect disappeared when endocrine therapy was administered ( low vs . high : DFS : HR 0 . 93 , 95 % CI 0 . 51 - 1 . 70 , P = 0 . 811 ) while it remained statistically significant when endocrine therapy was omitted ( low vs . high : DFS : HR 1 . 48 , 95 % CI 1 . 12 - 1 . 94 , P = 0 . 005 ) . Our results show that P35354 plays a role in hormonal pathways . Our results can explain the results found in previously published studies .",
"Letter to the editor concerning ' DB00072 emtansine ( DB05773 ) versus lapatinib plus capecitabine in patients with P04626 - positive metastatic breast cancer and central nervous system metastases : a retrospective , exploratory analysis in EMILIA ' .",
"The adjuvant treatment of P04626 - positive breast cancer . About 15 - 20 % of patients with early stage breast cancer present with tumors that have overexpression or amplification of the human epidermal growth factor receptor 2 ( P04626 ) gene . Before 2005 , these individuals had an increased risk of recurrence and death , but since then their outcomes have substantially improved with the adoption in most countries of adjuvant trastuzumab as a standard component of therapy for P04626 - positive early - stage breast cancer . Consequently , access to high - quality and accurate P04626 testing methods is critical to accurately determine P04626 status , guide treatment decisions , and ultimately improve clinical outcomes . In 2012 , the humanized monoclonal anti - HER antibody trastuzumab was the only approved P04626 - targeted therapy in the adjuvant setting . Data from the first generation of trials combining it with various chemotherapy regimens showed significant improvements in disease - free and overall survival ( DFS / OS ) . Based on results from five randomized clinical trials , a trastuzumab - containing regimen for up to 1 year is now considered standard for all patients with P04626 - positive tumors larger than 1 cm in size who would have fulfilled eligibility to those studies , and this recommendation is sometimes extended to patients with stage I tumors greater than 0 . 5 cm ( T1b ) . Second generation adjuvant studies with other P04626 - targeted agents like lapatinib and pertuzumab are ongoing , and newer drugs like DB05773 and neratinib are being actively tested in the metastatic setting .",
"Dual targeting of P04626 - positive cancer with trastuzumab emtansine and pertuzumab : critical role for neuregulin blockade in antitumor response to combination therapy . PURPOSE : Targeting P04626 with multiple P04626 - directed therapies represents a promising area of treatment for P04626 - positive cancers . We investigated combining the P04626 - directed antibody - drug conjugate trastuzumab emtansine ( DB05773 ) with the P04626 dimerization inhibitor pertuzumab ( Perjeta ) . EXPERIMENTAL DESIGN : Drug combination studies with DB05773 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of P04626 - amplified cancer . In patients with P04626 - positive locally advanced or metastatic breast cancer ( mBC ) , DB05773 was dose - escalated with a fixed standard pertuzumab dose in a 3 + 3 phase Ib / II study design . RESULTS : Treatment of P04626 - overexpressing tumor cells in vitro with DB05773 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death . The presence of the P21860 ligand , heregulin ( Q99988 β ) , reduced the cytotoxic activity of DB05773 in a subset of breast cancer lines ; this effect was reversed by the addition of pertuzumab . Results from mouse xenograft models showed enhanced antitumor efficacy with DB05773 and pertuzumab resulting from the unique antitumor activities of each agent . In patients with mBC previously treated with trastuzumab , lapatinib , and chemotherapy , DB05773 could be dosed at the maximum tolerated dose ( MTD ; 3 . 6 mg / kg every 3 weeks ) with standard dose pertuzumab . Adverse events were mostly grade 1 and 2 , with indications of clinical activity . CONCLUSIONS : Dual targeting of P04626 with the combination of DB05773 and pertuzumab in cell culture and mouse xenograft models resulted in enhanced antitumor activity . In patients , this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy .",
"DB05773 ( DB05773 ) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer . DB00072 ( Herceptin (®) ) is currently used as a treatment for patients whose breast tumors overexpress P04626 / ErbB2 . DB05773 ( DB05773 , trastuzumab emtansine ) is designed to combine the clinical benefits of trastuzumab with a potent microtubule - disrupting drug , DM1 ( a maytansine derivative ) . Currently DB05773 is being tested in multiple clinical trials . The mechanisms of action for trastuzumab include inhibition of PI3K / AKT signaling pathway , inhibition of HER - 2 shedding and Fcγ receptor mediated engagement of immune cells , which may result in antibody - dependent cellular cytotoxicity ( ADCC ) . Here we report that DB05773 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors .",
"Expression Enhancement in DB00072 Therapeutic Monoclonal Antibody Production using Genomic Amplification with ___MASK78___ . BACKGROUND : DB00072 ( Herceptin ) is a humanized monoclonal antibody ( mAb ) which is used for specific treatment of metastatic breast cancer in patients with overexpression of P04626 / neu receptor . In this study , we have attempted to develop a biosimilar version of trastuzumab mAb . METHODS : According to in silico studies , the heavy and light chains of trastuzumab mAb were designed and constructed . The recombinant constructs were co - transfected in CHO DG44 cell line . Stable transformants were selected on a semi solid medium . Genomic amplification with methotrexate was achieved for heavy chain gene amplification . Biological activity of produced antibody in comparison with Herceptin was tested by flow cytometry method . RESULTS : Three folds of amplification were obtained after seven rounds of methotrexate treatments . The results indicated the equal expression level of heavy and light chains . The yield of purified mAb was between 50 to 60 mg / l / day . According to the results , the produced mAb had similar affinity to P04626 (+) tumor cells to that of Herceptin . CONCLUSION : High - level recombinant protein expression can be achieved by amplification of the recombinant gene with a selectable marker , such as Dihydrofolate Reductase ( P00374 ) . It is usually accepted that P00374 gene can be amplified in P00374 (－) CHO cells , which consequently leads to amplification of the co - linked target gene , and finally amplification of recombinant protein . In this research , with the aim of producing a biosimilar version of herceptin , the effect of genomic amplification was investigated on the increasing the gene copy number using quantitative real - time PCR .",
"Clinical implications of pathophysiological and demographic covariates on the population pharmacokinetics of trastuzumab emtansine , a P04626 - targeted antibody - drug conjugate , in patients with P04626 - positive metastatic breast cancer . DB00072 emtansine ( DB05773 ) is a P04626 - targeted antibody - drug conjugate in development for treatment of P04626 - positive cancers . DB05773 has been tested as a single agent in a phase I and 2 phase II studies of patients with heavily pretreated metastatic breast cancer ( MBC ) , with the maximum tolerated dose established at 3 . 6 mg / kg intravenously for every - 3 - week dosing . The authors present results from the population pharmacokinetics analysis for DB05773 . Population pharmacokinetics for DB05773 were characterized using a clinical database of 273 patients from the 3 studies . Pharmacokinetics was best described by a linear 2 - compartment model . Population estimates ( interindividual variability [ IIV ] ) for pharmacokinetic parameters were clearance , 0 . 7 L / d ( 21 . 0 % ) ; central compartment volume ( V ( c ) ) , 3 . 33 L ( 13 . 2 % ) ; peripheral compartment volume ( V ( p ) ) , 0 . 89 L ( 50 . 4 % ) ; and intercompartmental clearance , 0 . 78 L / d . Body weight , albumin , tumor burden , and aspartate aminotransferase levels were identified as statistically significant covariates accounting for interindividual variability in DB05773 pharmacokinetics , with body weight having a greater effect on IIV of clearance and V ( c ) than other covariates . DB05773 exposure was relatively consistent across the weight range following body weight - based dosing . This analysis suggests no further DB05773 dose adjustments are necessary in heavily pretreated patients with MBC .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK81___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"Human epidermal growth factor receptor 2 positive ( P04626 + ) metastatic breast cancer : how the latest results are improving therapeutic options . Human epidermal growth factor receptor 2 positive ( P04626 + ) metastatic breast cancer ( MBC ) remains an incurable disease , and approximately 25 % of patients with P04626 + early breast cancer still relapse after adjuvant trastuzumab - based treatment . P04626 is a validated therapeutic target that remains relevant throughout the disease process . Recently , a number of novel P04626 targeted agents have become available , including lapatinib ( a small molecule tyrosine kinase inhibitor of both P04626 and the epidermal growth factor receptor ) , pertuzumab ( a new anti - P04626 monoclonal antibody ) and ado - trastuzumab emtansine ( DB05773 , a novel antibody - drug conjugate ) , which provide additional treatment options for patients with P04626 + MBC . The latest clinical trials have demonstrated improved outcome with treatment including pertuzumab or DB05773 compared with standard P04626 targeted therapy . Here we review the clinical development of approved and investigational targeted agents for the treatment of P04626 + MBC , summarize the latest results of important clinical trials supporting use of these agents in the treatment of P04626 + MBC , and discuss how these results impact therapeutic options in clinical practice .",
"DB05773 ( DB05773 ) in human epidermal growth factor receptor 2 ( P04626 ) - positive metastatic breast cancer : latest evidence and clinical potential . In February 2013 , ado - trastuzumab emtansine ( DB05773 , Kadcyla ® ) received regulatory approval in the United States for treatment - refractory human epidermal growth factor receptor 2 ( P04626 ) positive metastatic or locally advanced breast cancer based on results from EMILIA , a large phase III trial that compared standard of care lapatinib plus capecitabine to DB05773 . Several other studies have been reported in the metastatic setting and multiple trials are ongoing or planned in the neoadjuvant , adjuvant and advanced disease settings . Here we provide an updated and comprehensive review of clinical trials evaluating DB05773 , discuss management of toxicity associated with this drug , propose potential mechanisms of resistance and offer practical considerations for the treating oncologist .",
"Updates on the treatment of human epidermal growth factor receptor type 2 - positive breast cancer . PURPOSE OF REVIEW : To review the most recent developments in the treatment of human epidermal growth factor receptor type 2 ( P04626 ) - positive breast cancer with novel P04626 - targeting agents and combinations that have significantly improved clinical outcomes . RECENT FINDINGS : Since the approval of trastuzumab 15 years ago , the natural history of P04626 - positive breast cancer has been altered with improvements in survival for both early and advanced disease with the addition of this agent to standard chemotherapy . The P04626 receptor pathway drives breast cancer growth and aggressiveness , and P04626 - targeted agents can improve survival in early and advanced disease . In the advanced setting , two new drugs have been approved since 2012 , pertuzumab and ado - trastuzumab emtansine ( DB05773 ) , both of which improve survival without any reciprocal increase in toxicity . However , resistance almost always ensues , pointing to the need to understand the driving mechanisms and to biomarkers that will help individualize therapy and point to newer signal transduction and other modulators . SUMMARY : P04626 - positive breast cancer represents a distinct subtype with more aggressive clinical characteristics . P04626 - targeted therapies , usually in combination with chemotherapy , are the standard of care , improving the cure rate in early - stage breast cancer and lengthening survival in the advanced setting .",
"Interactome mapping of the phosphatidylinositol 3 - kinase - mammalian target of rapamycin pathway identifies deformed epidermal autoregulatory factor - 1 as a new glycogen synthase kinase - 3 interactor . The phosphatidylinositol 3 - kinase - mammalian target of rapamycin ( PI3K - P42345 ) pathway plays pivotal roles in cell survival , growth , and proliferation downstream of growth factors . Its perturbations are associated with cancer progression , type 2 diabetes , and neurological disorders . To better understand the mechanisms of action and regulation of this pathway , we initiated a large scale yeast two - hybrid screen for 33 components of the PI3K - P42345 pathway . Identification of 67 new interactions was followed by validation by co - affinity purification and exhaustive literature curation of existing information . We provide a nearly complete , functionally annotated interactome of 802 interactions for the PI3K - P42345 pathway . Our screen revealed a predominant place for glycogen synthase kinase - 3 ( GSK3 ) A and B and the AMP - activated protein kinase . In particular , we identified the deformed epidermal autoregulatory factor - 1 ( O75398 ) transcription factor as an interactor and in vitro substrate of P49840 and P49841 . Moreover , GSK3 inhibitors increased O75398 transcriptional activity on the P08908 serotonin receptor promoter . We propose that O75398 may represent a therapeutic target of lithium and other GSK3 inhibitors used in bipolar disease and depression .",
"DB05773 is highly effective in preclinical models of P04626 - positive gastric cancer . BACKGROUND : A novel antibody - drug conjugate ( trastuzumab - DM1 , DB05773 ) is currently in clinical trials for patients with trastuzumab resistant P04626 - positive breast cancer . Since no clinical data is available from gastric cancer , we studied DB05773 on P04626 - positive human gastric cancer cells and xenograft tumors . METHODS : Effects of DB05773 were studied in four P04626 - positive gastric cancer cell lines ( N - 87 , OE - 19 , SNU - 216 and MKN - 7 ) in vitro . Xenograft tumors from N - 87 and OE - 19 were studied to determine the effect of DB05773 in vivo . RESULTS : DB05773 was found more effective than trastuzumab in N - 87 and OE - 19 , and moderately effective in MKN - 7 cells . On SNU - 216 cells both trastuzumab and DB05773 showed limited efficacy . In xenograft tumor experiments , complete pathological response was observed in all OE - 19 xenografted mice and in half of the N - 87 xenografted mice . The results were equally good irrespective of the tumor burden at therapy initiation , or preceding trastuzumab treatment . DB05773 treatment showed direct effects ( apoptotic cell death and aberrant mitosis ) as well as it mediated antibody - dependent cellular cytotoxicity ( ADCC ) . CONCLUSIONS : DB05773 showed a promising anti - tumor effect in P04626 - positive gastric cancer cell lines in vitro and in vivo , even in tumors which had developed resistance to trastuzumab . DB05773 therapy may warrant clinical trials for P04626 - positive gastric cancer patients .",
"Potential mechanisms for thrombocytopenia development with trastuzumab emtansine ( DB05773 ) . PURPOSE : DB00072 - emtansine ( DB05773 ) is an antibody - drug conjugate ( ADC ) comprising the cytotoxic agent DM1 conjugated to trastuzumab with a stable linker . Thrombocytopenia was the dose - limiting toxicity in the phase I study , and grade ≥ 3 thrombocytopenia occurred in up to 13 % of patients receiving DB05773 in phase III studies . We investigated the mechanism of DB05773 - induced thrombocytopenia . EXPERIMENTAL DESIGN : The effect of DB05773 on platelet function was measured by aggregometry , and by flow cytometry to detect the markers of activation . The effect of DB05773 on differentiation and maturation of megakaryocytes ( MK ) from human hematopoietic stem cells was assessed by flow cytometry and microscopy . Binding , uptake , and catabolism of DB05773 in MKs , were assessed by various techniques including fluorescence microscopy , scintigraphy to detect T -[ H ( 3 )]- DM1 and ( 125 ) I - DB05773 , and mass spectrometry . The role of FcγRIIa was assessed using blocking antibodies and mutant constructs of trastuzumab that do not bind FcγR . RESULTS : DB05773 had no direct effect on platelet activation and aggregation , but it did markedly inhibit MK differentiation via a cytotoxic effect . Inhibition occurred with DM1 - containing ADCs but not with trastuzumab demonstrating a role for DM1 . MKs internalized these ADCs in a P04626 - independent , FcγRIIa - dependent manner , resulting in intracellular release of DM1 . Binding and internalization of DB05773 diminished as MKs matured ; however , prolonged exposure of mature MKs to DB05773 resulted in a disrupted cytoskeletal structure . CONCLUSIONS : These data support the hypothesis that DB05773 - induced thrombocytopenia is mediated in large part by DM1 - induced impairment of MK differentiation , with a less pronounced effect on mature MKs .",
"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK72___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK72___ .",
"Emerging therapeutic targets in bladder cancer . Treatment of muscle invasive urothelial bladder carcinoma ( BCa ) remains a major challenge . Comprehensive genomic profiling of tumors and identification of driver mutations may reveal new therapeutic targets . This manuscript discusses relevant molecular drivers of the malignant phenotype and agents with therapeutic potential in BCa . Small molecule pan - FGFR inhibitors have shown encouraging efficacy and safety results especially among patients with activating FGFR mutations or translocations . P42345 inhibitors for patients with Q92574 mutations and concomitant targeting of PI3K and MEK represent strategies to block PI3K / AKT / P42345 pathway . Encouraging preclinical results with ado - trastuzumab emtansine ( DB05773 ) exemplifies a new potential treatment for P04626 - positive BCa along with innovative bispecific antibodies . Inhibitors of cell cycle regulators ( aurora kinase , polo - like kinase 1 , and cyclin - dependent kinase 4 ) are being investigated in combination with chemotherapy . Early results of clinical studies with anti - P16410 and anti - Q9NZQ7 are propelling immune modulating drugs to the forefront of emerging treatments for BCa . Collectively , these novel therapeutic targets and treatment strategies hold promise to improve the outcome of patients afflicted with this malignancy ."
] |
[
"___MASK24___",
"___MASK37___",
"___MASK40___",
"___MASK43___",
"___MASK54___",
"___MASK64___",
"___MASK72___",
"___MASK78___",
"___MASK81___"
] |
___MASK40___
|
MH_train_443
|
interacts_with DB01022?
|
[
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK8___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"Titration of KATP channel expression in mammalian cells utilizing recombinant baculovirus transduction . A variety of transfection approaches have been used to deliver plasmids encoding ion channel genes into cells . We have used the baculovirus transduction system , BacMam , to demonstrate transient expression of multi - subunit KATP channels in CHO - P04264 and P29320 - 293 EBNA cells using sulfonylurea receptor 1 ( Q09428 ) , SUR2A , SUR2B , and P55040 6 . 2 genes . [ 3H ] - glyburide binding , patch clamp , and DiBAC4 ( 3 ) measurements of membrane potential changes were used to monitor channel expression . BacMam delivery of each Q09428 isoform with KIR6 . 2 was demonstrated based on its pharmacological profiles . Expression levels of Q09428 and KIR6 . 2 were titrated by varying the viral concentration or time of virus addition , with functional activity measured in as little as 4 - 6 hours posttransduction . Further increases in BacMam virus induced sufficient KATP expression to dominate membrane potential without pharmacological opening of the channel . Independently altering treatment with virus containing either the Q09428 or KIR6 . 2 gene revealed interactions among subunits during formation of functional channels in the plasma membrane . This study demonstrates the utility and versatility of BacMam as a valuable gene delivery tool for the study of ion channel function .",
"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK85___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .",
"Serial changes in serum vitamin P04264 , triglyceride , cholesterol , osteocalcin and 25 - hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis . Serum vitamin P04264 concentrations were measured at presentation ( just before surgery ) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur ( FON , n = 13 ) or total hip replacement for osteoarthritis of the hip ( OA , n = 16 ) . In comparison with healthy elderly volunteers ( n = 25 ) , serum vitamin P04264 concentrations were significantly lower in both groups at presentation , and fell significantly within 24 h after surgery to concentrations approaching non - detectable , subsequently returning to pre - operative values within 3 weeks . Serum vitamin P04264 tended to be lower in the fracture group both before and after operation , although calculation of a vitamin P04264 - triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group . P02818 concentrations were similar and fell significantly after operation in both groups , returning to pre - operative levels within 7 days . No differences in the two forms of osteocalcin ( carboxylated and undercarboxylated ) were observed either before or after operation in either group . DB00146 concentrations were not significantly different between the two groups at any time . DB01022 status may be lower than desirable in certain groups of the elderly population , and supplementation should be considered as prophylactic therapy .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Lessons learned from the irinotecan metabolic pathway . ___MASK36___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK36___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK36___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .",
"Novel biologically active bibenzyls from Bauhinia saccocalyx Pierre . Four new bibenzyls , bauhinols A - D ( 1 - 4 ) , together with the two known bibenzyls 5 and 6 , were isolated from the roots of Bauhinia saccocalyx , and their structures were elucidated by analyses of spectroscopic data . Bauhinol A ( 1 ) exhibits significant cytotoxicity towards NCI - H187 ( small - cell lung cancer ) , BC ( breast cancer ) , and KB ( oral - cavity cancer ) cell lines , with IC50 values of 2 . 7 - 4 . 5 microg / ml . Bauhinol B ( 2 ) is cytotoxic against NCI - H187 ( IC50 = 1 . 1 microg / ml ) and BC ( IC50 = 9 . 7 microg / ml ) cell lines , but inactive toward the KB cell line ( at 20 microg / ml ) . Compound 2 also is mildly antifungal towards Candia albicans ( IC50 = 28 . 9 microg / ml ) . Bibenzyl 6 is active against NCI - H187 ( IC50 = 14 . 1 microg / ml ) and BC ( IC50 = 4 . 0 microg / ml ) cells , but inactive ( at 20 microg / ml ) toward the KB cell line . Compounds 1 , 2 , and 6 show mild antimycobacterial activities , with MIC values of 25 - 50 microg / ml , but are inactive at 20 microg / ml against the P04264 malarial parasite strain ( Plasmodium falciparum ) . While bauhinol A ( 1 ) is inactive against cyclooxygenase 1 ( P23219 ) and cyclooxygenase 2 ( P35354 ) , compounds 2 and 6 inhibit both P23219 and P35354 , with IC50 values comparable to those of the standard drug , aspirin ( Table 3 ) .",
"Paradoxical effects of resveratrol on the two prostaglandin H synthases . Prostaglandin H synthase ( PGHS ) is the primary enzyme responsible for the biosynthesis of prostaglandins and thromboxanes . Of the two isoenzymes of PGHS , P23219 is constitutively expressed and P35354 is inducible by mitogens or other inflammatory stimuli . Constitutive expression of P35354 in neoplastic tissues has been implicated in carcinogenesis . DB02709 , a lignan , was recently shown to be an anticarcinogen that selectively inhibits P23219 . In vitro experiments to resolve these seemingly paradoxical observations revealed that resveratrol is not only an inhibitor of P23219 but also is an activator of P35354 . DB02709 non - competitively inhibited P23219 with a P04264 of 26 +/- 2 microM but enhanced the P35354 activity nearly twofold . Additionally , resveratrol did not serve as a reducing co - substrate for the peroxidase activities of either enzyme despite being an easily oxidizable phenolic compound . DB02709 inhibited the peroxidase activity of P23219 ( IC50 = 15 microM ) better than that of P35354 ( IC50 = > 200 microM ) . Inhibition of the perxidase activity but not the cyclooxygenase activity of P35354 resulted in the production of PGG2 from arachidonic acid . A plausible relationship between these observation and the anticarcinogenic activity of resveratrol is discussed .",
"Genomic comparison of Escherichia coli P04264 strains isolated from the cerebrospinal fluid of patients with meningitis . Escherichia coli is a major cause of enteric / diarrheal diseases , urinary tract infections , and sepsis . E . coli P04264 is the leading gram - negative organism causing neonatal meningitis , but the microbial basis of E . coli P04264 meningitis is incompletely understood . Here we employed comparative genomic hybridization to investigate 11 strains of E . coli P04264 isolated from the cerebrospinal fluid ( P04141 ) of patients with meningitis . These 11 strains cover the majority of common O serotypes in E . coli P04264 isolates from P04141 . Our data demonstrated that these 11 strains of E . coli P04264 can be categorized into two groups based on their profile for putative virulence factors , lipoproteins , proteases , and outer membrane proteins . Of interest , we showed that some open reading frames ( ORFs ) encoding the type III secretion system apparatus were found in group 2 strains but not in group 1 strains , while ORFs encoding the general secretory pathway are predominant in group 1 strains . These findings suggest that E . coli P04264 strains isolated from P04141 can be divided into two groups and these two groups of E . coli P04264 may utilize different mechanisms to induce meningitis .",
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK56___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK56___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"The testis anion transporter TAT1 ( Q96RN1 ) physically and functionally interacts with the cystic fibrosis transmembrane conductance regulator channel : a potential role during sperm capacitation . The Slc26 gene family encodes several conserved anion transporters implicated in human genetic disorders , including Pendred syndrome , diastrophic dysplasia and congenital chloride diarrhea . We previously characterized the TAT1 ( testis anion transporter 1 ; Q96RN1 ) protein specifically expressed in male germ cells and mature sperm and showed that in the mouse , deletion of Tat1 caused male sterility due to a lack of sperm motility , impaired sperm capacitation and structural defects of the flagella . Ca ( 2 +) , Cl (-) and HCO ( 3 )(-) influxes trigger sperm capacitation events required for oocyte fertilization ; these events include the intracellular rise of cyclic adenosine monophosphate ( DB02527 ) and protein kinase A ( PKA ) - dependent protein phosphorylation . The cystic fibrosis transmembrane conductance regulator ( P13569 ) is expressed in mature sperm and has been shown to contribute to Cl (-) and HCO ( 3 )(-) movements during capacitation . Furthermore , several members of the SLC26 family have been described to form complexes with P13569 , resulting in the reciprocal regulation of their activities . We show here that TAT1 and P13569 physically interact and that in Xenopus laevis oocytes and in CHO - P04264 cells , TAT1 expression strongly stimulates P13569 activity . Consistent with this , we show that Tat1 inactivation in mouse sperm results in deregulation of the intracellular DB02527 content , preventing the activation of PKA - dependent downstream phosphorylation cascades essential for sperm activation . These various results suggest that TAT1 and P13569 may form a molecular complex involved in the regulation of Cl (-) and HCO ( 3 )(-) fluxes during sperm capacitation . In humans , mutations in P13569 and / or TAT1 may therefore be causes of asthenozoospermia and low fertilizing capacity of sperm .",
"Human P01730 + CD25low adaptive T regulatory cells suppress delayed - type hypersensitivity during transplant tolerance . Adaptive T regulatory ( T ( R ) ) cells mediate the suppression of donor - specific , delayed - type hypersensitivity ( DTH ) in tolerant organ transplant recipients . We hypothesized that cells belonging to the P01730 (+) CD25 (+) T cell subset but distinct from natural T ( R ) cells may fulfill this role . To test this hypothesis , PBMC and biopsy samples from two tolerant kidney transplant recipients ( P04264 and K2 ) were analyzed . When transferred with recipient P25054 into a SCID mouse footpad , P01730 (+) T cells were hyporesponsive in DTH to donor type HLA - B Ags and derivative allopeptides . However , anti - human TGF - beta1 Ab revealed a response to immunodominant allopeptides in both patients , suggesting that P01730 (+) T effector ( T ( E ) ) cells coexisted with suppressive , TGF - beta1 - producing P01730 (+) T ( R ) cells . During in vitro culture , allopeptide stimulation induced both P01579 - producing and surface TGF - beta1 (+) T cells . The relative strength of the latter response in patient P04264 was inversely correlated with the level of systemic anti - donor DTH , which varied over a 6 - year interval . Allopeptide - induced surface TGF - beta1 expression was found primarily in Forkhead box P09131 ( FoxP3 ) - negative P01730 (+) CD25 ( low ) T cells , which could adoptively transfer suppression of donor - specific DTH . Biopsy samples contained numerous surface TGF - beta1 (+) mononuclear cells that costained for P01730 and , less frequently CD25 , but were negative for FoxP3 . The P01730 (+) TGF - beta1 (+) T cells were localized primarily to the tubulointerstitium , whereas TGF - beta1 (-) FoxP3 (+) CD25 (+) cells were found mainly in lymphoid aggregates . Thus , adaptive T ( R ) cells suppressing T ( E ) cell responses to donor allopeptides in two tolerant patients appear to be functionally and phenotypically distinct from P01730 (+) CD25 ( high ) FoxP3 (+) T cells .",
"Synaptic vesicular monoamine transporter expression : distribution and pharmacologic profile . The human vesicular monoamine transporter ( hSVMT ) cDNA predicts a protein of 515 amino acids that shares 92 % amino acid identity with the rat cDNA . Northern analyses reveal expression of 4 . 3 kb Q05940 mRNAs in rat hypothalamus , midbrain and brainstem , a 3 kb hSVMT mRNA in human brainstem and a 4 . 8 kb hSVMT mRNA in human hypothalamus . In situ hybridization documents significant Q05940 expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers . COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine , micromolar affinities for haloperidol , GBR12909 , serotonin , mazindol , nomifensin and ___MASK38___ , while dopamine , epinephrine , norepinephrine and histamine each displayed millimolar affinities . These observations extend the pharmacological characterization of hSVMT and studies of its distribution , and indicate likely physiological roles for Q05940 in packaging monoamine transmitters including histamine .",
"Presynaptic monoaminergic vesicles in Parkinson ' s disease and normal aging . We present development and human application of a method for determining the regional cerebral density of the type 2 vesicular monoamine transporter ( Q05940 ) using positron emission tomography ( PET ) and [ 11C ] dihydrotetrabenazine ( DTBZ ) . Previous animal studies indicate striatal Q05940 density is linearly related to the integrity of substantia nigra dopamine neurons and is not subject to drug - or lesion - compensatory regulation . In the present studies , kinetic compartmental modeling was employed to estimate blood - brain [ 11C ] DTBZ transport ( P04264 ) and Q05940 binding site density ( tissue - to - plasma DTBZ distribution volume , DV ) from the cerebral and plasma DTBZ time courses after intravenous tracer injection . In controls , we found reductions of putamen DTBZ DVwith advancing age , corresponding to losses of 0 . 77 % per year in specific Q05940 binding . Parkinson ' s disease ( PD ) patients had reduction in specific DTBZ DV in the putamen ( - 61 % ) and in the caudate nucleus ( - 43 % ) . There was no overlap of lowest specific putamen DTBZ DV between individual elderly controls and PD patients . The present results indicate the suitability of [ 11C ] DTBZ PET for objective quantification of nigrostriatal integrity , including evaluation of PD progression and its possible therapeutic modification .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK23___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK23___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK23___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK23___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK23___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK23___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK23___ .",
"DB09280 - ___MASK92___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"___MASK42___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"Transcriptional regulation of the P04264 gene product of Kaposi ' s sarcoma - associated herpesvirus . The P04264 protein of Kaposi ' s sarcoma - associated herpesvirus ( KSHV ) has been shown to be a transforming protein capable of inducing morphological changes and focus formation in rodent fibroblasts . P04264 can activate B - cell receptor ( P11274 ) signaling and upregulate activity of the NFAT and NF - kappaB transcription factors . In order to understand the regulation of P04264 gene expression , we have analyzed sequences upstream of the P04264 gene to identify the P04264 promoter element . We have performed 5 ' rapid amplification of cDNA ends as well as a nuclease protection assay to map the transcriptional start site of the KSHV P04264 transcript . The P04264 transcriptional start site lies 75 bp upstream of the translation start site . Sequences upstream of the P04264 gene were characterized for their ability to activate a luciferase reporter gene in 293 epithelial cells , KSHV - negative B cells ( BJAB ) , KSHV - positive B cells ( BCBL - 1 ) , and KS tumor - derived endothelial cells ( SLK - KS (-) ) . We found that a 125 - bp sequence upstream of the P04264 transcript start site was sufficient to fully activate the luciferase reporter gene in all cell types tested . In addition , the viral transcription factor KSHV Orf50 / Rta was capable of further activating this promoter element in 293 , BJAB , and BCBL - 1 cells but not in SLK - KS (-) cells . Promoter constructs containing additional sequences upstream of the 125 - bp element did not show further augmentation of transcription in the presence or absence of KSHV Orf50 .",
"Activity of retinoic acid receptor - gamma selectively binding retinoids alone and in combination with interferon - gamma in breast cancer cell lines . Retinoids modulate several cell functions and especially inhibit the growth of a wide variety of cells including breast cancer . Retinoic acid receptor - gamma ( P13631 ) has been shown to mediate the antiproliferative activity of retinoids . To further test this hypothesis we examined the effects of different P13631 selectively binding retinoids ( CD2325 , CD2247 , CD666 and CD437 ) on breast cancer cell lines . With exception of CD2247 , all retinoids inhibited proliferation of MCF - 7 , SKBR - 3 , T47D and ZR - 75 - 1 breast cancer cell lines , similar to the natural compound all - trans retinoic acid ( ___MASK57___ ) . In addition , all 4 compounds were able to act synergistically with interferon - gamma ( P01579 ) in all breast cancer cell lines including the retinoid - resistant BT - 20 and 734 - B lines . In functional transactivation assays we demonstrated that only in the MCF - 7 cell line , TPA - mediated AP - 1 activity was suppressed only by ___MASK57___ and CD2325 , whereas in SKBR - 3 , another RA - sensitive breast cancer cell line , it was not . The synergistic antiproliferative activity involving retinoids and P01579 could not be explained by an enhanced anti - AP - 1 activity . No correlation was found between expression of RARs and cellular retinoic acid binding proteins ( CRABPs ) and antiproliferative effects of the retinoids . P13631 selectively binding retinoids are potent inhibitors of breast cancer cell proliferation , alone and in combination with P01579 . For this reason and because of a possible low toxicity , as compared with retinoic acid , we speculate that these P13631 selective binding retinoids might be of clinical importance .",
"RNAi suppression of Bax and Bak enhances viability in fed - batch cultures of CHO cells . Bcl - 2 family proteins play a crucial role in the regulation of the mitochondrial pathway that leads to apoptosis . Members of the Bcl - 2 family can be divided into the anti - apoptotic proteins such as Bcl - 2 and Bcl - X ( L ) , and the pro - apoptotic proteins such as Bax and Bak and the BH3 - only proteins . In this study , siRNA constructs to silence the Bax and Bak genes in Chinese hamster ovary ( CHO ) cells were generated . Stable CHO cell lines in which the expression of Bax and Bak were significantly knocked down were screened by Western blot analysis and confirmed by RT - PCR . CHO cells with both Bax and Bak knocked down showed a clear resistance against cytotoxic lectins and UV irradiation - induced apoptosis . Compared to original CHO - P04264 cells , these cells also survived longer when cultured under extreme conditions such as complete nutrient depletion or in high - osmolality medium . CHO cells with both Bax and Bak genes knocked down displayed an extended lifespan as well as higher viable cell densities in fed - batch cultures , both in adherent form on microcarrier beads and in suspension . The P01579 productivity by a rCHO P01579 cell line in which both Bak and Bax were knocked down increased by 35 % compared to the control cells . These results indicate that the genetic inactivation of Bax and Bak in recombinant CHO cells can be an effective strategy in delaying the onset of apoptosis in batch and fed - batch cultures ."
] |
[
"___MASK23___",
"___MASK36___",
"___MASK38___",
"___MASK42___",
"___MASK56___",
"___MASK57___",
"___MASK85___",
"___MASK8___",
"___MASK92___"
] |
___MASK57___
|
MH_train_444
|
interacts_with DB00279?
|
[
"PIP3 pathway in regulatory T cells and autoimmunity . Regulatory T cells ( Tregs ) play an important role in preventing both autoimmune and inflammatory diseases . Many recent studies have focused on defining the signal transduction pathways essential for the development and the function of Tregs . Increasing evidence suggest that T - cell receptor ( TCR ) , interleukin - 2 ( P60568 ) receptor ( IL - 2R ) , and co - stimulatory receptor signaling are important in the early development , peripheral homeostasis , and function of Tregs . The phosphoinositide - 3 kinase ( PI3K ) - regulated pathway ( PIP3 pathway ) is one of the major signaling pathways activated upon TCR , IL - 2R , and P10747 stimulation , leading to T - cell activation , proliferation , and cell survival . Activation of the PIP3 pathway is also negatively regulated by two phosphatidylinositol phosphatases Q92835 and P60484 . Several mouse models deficient for the molecules involved in PIP3 pathway suggest that impairment of PIP3 signaling leads to dysregulation of immune responses and , in some cases , autoimmunity . This review will summarize the current understanding of the importance of the PIP3 pathway in T - cell signaling and the possible roles this pathway performs in the development and the function of Tregs .",
"The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .",
"P10828 is essential for development of auditory function . Congenital thyroid disorders are often associated with profound deafness , indicating a requirement for thyroid hormone ( DB00279 ) and its receptors in the development of hearing . Two DB00279 receptor genes , Tr alpha and Tr beta are differentially expressed , although in overlapping patterns , during development . Thus , the extent to which they mediate unique or redundant functions is unclear . We demonstrate that Tr beta - deficient ( Thrb -/- ) mice exhibit a permanent deficit in auditory function across a wide range of frequencies , although they show no other overt neurological defects . The auditory - evoked brainstem response ( Q12979 ) in Thrb -/- mice , although greatly diminished , displayed normal waveforms , which suggested that the primary defect resides in the cochlea . Although hypothyroidism causes cochlear malformation , there was no evidence of this in Thrb -/- mice . These findings suggest that Tr beta controls the maturation of auditory function but not morphogenesis of the cochlea . Thrb -/- mice provide a model for the human endocrine disorder of resistance to thyroid hormone ( RTH ) , which is typically associated with dominant mutations in Tr beta . However , deafness is generally absent in RTH , indicating that dominant and recessive mutations in Tr beta have different consequences on the auditory system . Our results identify Tr beta as an essential transcription factor for auditory development and indicate that distinct Tr genes serve certain unique functions .",
"GpIIb / IIIa + subpopulation of rat megakaryocyte progenitor cells exhibits high responsiveness to human thrombopoietin . The recently cloned factor thrombopoietin ( P07202 ) has been shown to exhibit megakaryocyte colony - stimulating activity in vitro . In this investigation , to further evaluate the action of P07202 on megakaryocyte progenitor cells ( colony - forming units - megakaryocyte [ CFU - MK ] ) , GpIIb / IIIa + and GpIIb / IIIa - populations of CFU - MK were prepared from rat bone marrow cells based on their reactivity with P55 antibody , a monoclonal antibody against rat GpIIb / IIIa , and their responsiveness to recombinant human P07202 ( rhTPO ) and recombinant rat interleukin - 3 ( rrIL - 3 ) was examined using a megakaryocyte colony - forming assay ( Meg - Q13216 ). rhTPO supported only megakaryocyte colony growth from both fractions in a dose - dependent fashion . The mean colony size observed with the GpIIb / IIIa + population was smaller than that seen with the GpIIb / IIIa - population . With the optimal concentration of either rhTPO or rrIL - 3 , similar numbers of megakaryocyte colonies were formed from the GpIIb / IIIa + population previously shown to be highly enriched for CFU - MK . In contrast , the maximum number of megakaryocyte colonies from the GpIIb / IIIa - population stimulated by rhTPO was only 24 . 2 % of that achieved with rrIL - 3 . Morphologic analysis of rhTPO - promoted megakaryocyte colonies from the GpIIb / IIIa + population showed that the average colony size was smaller but that the mean diameter of individual megakaryocytes was larger than in megakaryocyte colonies promoted with rrIL - 3 . rhTPO plus rrIL - 3 , each at suboptimal concentrations , had an additive effect on proliferation of CFU - MK in the GpIIb / IIIa + fraction , whereas rhTPO plus murine P05231 or murine granulocyte - macrophage colony - stimulating factor ( mG - P09603 ) modestly but significantly reduced megakaryocyte colony growth . These results indicate that P07202 preferentially acts on GpIIb / IIIa + late CFU - MK with lower proliferative capacity and interacts with some other cytokines in CFU - MK development .",
"Differential expression of an orphan receptor COUP - Q07654 and corepressors in adrenal tumors . Recently , it has been shown that P05093 gene transcription is activated by Q13285 ( Steroidogenic Factor - 1 ) binding to a cyclic AMP - responsive sequence within the promoter region of the gene , whereas it is inhibited by COUP - TF ( Chicken Ovalbumin Upstream Promoter - Transcription Factor ) binding to the sequence . We have shown that transcriptional repression by COUP - Q07654 is mediated by corepressors , O75376 ( nuclear receptor corepressor ) and Q9Y618 ( silencing mediator for retinoid and thyroid hormone - receptor ) . Therefore , we compared the expression of COUP - Q07654 , O75376 and Q9Y618 in non - hyperfunctioning adrenocortical adenomas and normal adrenal glands . We found significantly higher expression of COUP - Q07654 mRNA in non - hyperfunctioning adenomas ( n = 5 , 227 +/- 18 % ) than in normal adrenals ( n = 5 , 96 +/- 4 % ) . Interestingly , the pattern of O75376 and Q9Y618 expression was different compared with COUP - Q07654 expression . These data suggest that COUP - Q07654 , O75376 , and Q9Y618 may play a differential role in steroid biosynthesis of non - hyperfunctioning adenomas .",
"The thyroid hormone receptor β induces DNA damage and premature senescence . There is increasing evidence that the thyroid hormone ( TH ) receptors ( THRs ) can play a role in aging , cancer and degenerative diseases . In this paper , we demonstrate that binding of TH DB00279 ( triiodothyronine ) to P10828 induces senescence and deoxyribonucleic acid ( DNA ) damage in cultured cells and in tissues of young hyperthyroid mice . DB00279 induces a rapid activation of Q13315 ( ataxia telangiectasia mutated ) / PRKAA ( adenosine monophosphate - activated protein kinase ) signal transduction and recruitment of the NRF1 ( nuclear respiratory factor 1 ) and P10828 to the promoters of genes with a key role on mitochondrial respiration . Increased respiration leads to production of mitochondrial reactive oxygen species , which in turn causes oxidative stress and DNA double - strand breaks and triggers a DNA damage response that ultimately leads to premature senescence of susceptible cells . Our findings provide a mechanism for integrating metabolic effects of THs with the tumor suppressor activity of P10828 , the effect of thyroidal status on longevity , and the occurrence of tissue damage in hyperthyroidism .",
"Allelic combinations of immune - response genes associated with glatiramer acetate treatment response in Russian multiple sclerosis patients . BACKGROUND : Glatiramer acetate ( GA ) is widely used as a first - line disease - modifying treatment for multiple sclerosis ( MS ) . However , a significant proportion of MS patient appears to experience modest benefit from GA - treatment . Genetic variants affecting the clinical response to GA are believed to be relevant as biomarkers of GA - treatment efficiency . PATIENTS & METHODS : Nine polymorphisms in candidate genes were analyzed as possible determinants of GA response in 285 Russian MS patients . Special attention was given to identification of response - associated allelic combinations by means of the APSampler algorithm . RESULTS : No significant associations were found for individual polymorphisms . Alleles Q8IUH3 * 15 , P01137 * T , P51681 * d and P17181 * G were the components of the combinations , of which carriage was significantly higher in nonresponders than in responders . Carriers of the most significant combinations : Q8IUH3 * 15 + P01137 * T + P51681 * d + P17181 * G and Q8IUH3 * 15 + P01137 * T + P51681 * d ( permutation p - values : 0 . 0056 and 0 . 013 , respectively ) had a 14 to 15 - times increased risk of ineffective response to GA therapy . DISCUSSION : The results suggest that the influence of immune - response genes on GA - induced response has a polygenic nature . The data are interpreted as evidence of additive and epistatic influences of the genes on GA efficiency for MS treatment .",
"Q13315 - dependent nuclear accumulation of O15111 plays an important role in the regulation of p73 - mediated apoptosis in response to cisplatin . I kappa B kinase ( IKK ) complex plays an important role in the regulation of signaling pathway that activates nuclear factor - kappa - B ( NF - kappaB ) . Recently , we reported that cisplatin ( DB00515 ) treatment causes a remarkable nuclear accumulation of O15111 in association with stabilization and activation of p73 . However , underlying mechanisms of DB00515 - induced nuclear accumulation of O15111 are elusive . Here , we found that ataxia - telangiectasia mutated ( Q13315 ) is one of upstream mediators of O15111 during DB00515 - induced apoptosis . In response to DB00515 , Q13315 was phosphorylated at DB00133 - 1981 , which was accompanied with nuclear accumulation of O15111 in HepG2 cells , whereas DB00515 treatment had undetectable effects on O15111 in Q13315 - deficient cells . Indirect immunofluorescence experiments demonstrated that phosphorylated form of Q13315 colocalizes with nuclear O15111 in response to DB00515 . In vitro kinase assay indicated that Q13315 phosphorylates O15111 at DB00133 - 473 . Moreover , O15111 - deficient MEFs displayed DB00515 - resistant phenotype as compared with wild - type MEFs . Taken together , our present results suggest that Q13315 - mediated phosphorylation of nuclear O15111 , which stabilizes p73 , is one of the main apoptotic pathways in response to DB00515 .",
"Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .",
"Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF - B ) is a peptide ( s ) isolated from bovine hypothalamic extracts by Sephadex G - 100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( ___MASK89___ ) in vitro and in vivo . It is similar in molecular size to the 41 - residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF - B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti - oCRF and anti - rCRF antibodies . CRF - B cross - reacted well with anti - oCRF antibodies but poorly with anti - rCRF antibodies . Purification of CRF - B with preparative isoelectric focusing yielded four CRF peaks , B - 1 ( pH 4 . 7 ) , B - 2 ( pH 5 . 5 ) , B - 3 ( pH 6 . 3 ) , and B - 4 ( pH 7 . 0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B - 2 , B - 3 , and B - 4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B - 1 showed only immunoreactivity . Their relative bioactivity / immunoreactivity ratios were 0 ( B - 1 ) , 1 ( B - 2 ) , 1 ( B - 3 ) , and 3 ( B - 4 ) . All of these CRF - B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G - 100 chromatography , which suggests that their molecular modifications are relatively minor .",
"Changes of thyroid hormone levels and related gene expression in zebrafish on early life stage exposure to triadimefon . In this study , zebrafish was exposed to triadimefon . Thyroid hormones levels and the expression of related genes in the hypothalamic - pituitary - thyroid ( Q9HD23 ) axis , including thyroid - stimulating hormone ( P01222 ) , deiodinases ( dio1 and dio2 ) and the thyroid hormone receptor ( thraa and thrb ) were evaluated . After triadimefon exposure , increased DB00451 can be explained by increased thyroid - stimulating hormone ( P01222 ) . The conversion of DB00451 to DB00279 ( deiodinase type I - dio1 ) was decreased , which reduced the DB00279 level . P10828 ( thrb ) mRNA levels were significantly down - regulated , possibly as a response to the decreased DB00279 levels . The overall results indicated that triadimefon exposure could alter gene expression in the Q9HD23 axis and that mechanisms of disruption of thyroid status by triadimefon could occur at several steps in the synthesis , regulation , and action of thyroid hormones .",
"On the relevance of glycolysis process on brain gliomas . The proposed analysis considers aspects of both statistical and biological validation of the glycolysis effect on brain gliomas , at both genomic and metabolic level . In particular , two independent datasets are analyzed in parallel , one engaging genomic ( Microarray Expression ) data and the other metabolomic ( Magnetic Resonance Spectroscopy Imaging ) data . The aim of this study is twofold . First to show that , apart from the already studied genes ( markers ) , other genes such as those involved in the human cell glycolysis significantly contribute in gliomas discrimination . Second , to demonstrate how the glycolysis process can open new ways towards the design of patient - specific therapeutic protocols . The results of our analysis demonstrate that the combination of genes participating in the glycolytic process ( P04075 , P09972 , P09104 , P04406 , P52789 , P00338 , P07195 , P40925 , P11177 , P08237 , P06744 , P00558 , P36871 and P30613 ) with the already known tumor suppressors ( P60484 , Rb , P04637 ) , oncogenes ( P11802 , P00533 , PDGF ) and Q9BYW2 , enhance the discrimination of low versus high - grade gliomas providing high prediction ability in a cross - validated framework . Following these results and supported by the biological effect of glycolytic genes on cancer cells , we address the study of glycolysis for the development of new treatment protocols .",
"[ The interconnections of molecular mechanisms of hormone actions and their role in pathogenesis of obesity , insulin resistance , and diabetes mellitus ] . The various hormones , proteins and other compounds related to developing obesity , insulin resistance and type 2 diabetes are analyzed in the paper . 1 ) Leptin , ciliary neurutrophic factor , adiponectin , glucagon - like peptide 1 , peptide YY , neuromedin S , as well as the protein receptors of these hormones decrease the food consumption , increase the energy turnover , and prevent obesity , insulin resistance , and type 2 diabetes development . The mediators of these hormone and receptor actions are melanocyte stimulating hormone ( MSH ) , corticotropin - releasing hormone ( P06850 ) , and the others . 2 ) Ghrelin , endogenose cannabinoides , galanin - like peptide and the mediators of their actions : neuropeptide Y ( P01303 ) and Agouti gene related protein ( O00253 ) increase the appetite and food consumption . Peroxisome proliferation - activated receptor ( Q07869 ) performs the similar action on food intake . The activation of the first group compound functioning decreases the obesity , increases the energy turnover , facilitates the insulin action and prevents the insulin resistance and type 2 diabetes . Increasing the activities of the second group , as well as , decreasing the actions of the first one of substances induce the opposite effects and facilitate obesity , insulin resistance , and type 2 diabetes developments . The interconnections of the molecular mechanisms of so many hormone actions make the very complicated tusk to study the various endocrine disorders including diabetes mellitus as well .",
"The v - ErbA oncoprotein quenches the activity of an erythroid - specific enhancer . v - ErbA is a mutated variant of thyroid hormone receptor ( TRalpha / P10827 ) borne by the Avian Erythroblastosis virus causing erythroleukemia . TRalpha is known to activate transcription of specific genes in the presence of its cognate ligand , DB00279 hormone , while in its absence it represses it . v - ErbA is unable to bind ligand , and hence is thought to contribute to leukemogenesis by actively repressing erythroid - specific genes such as the carbonic anhydrase II gene ( CA II ) . In the prevailing model , v - ErbA occludes liganded TR from binding to its cognate elements and constitutively interacts with the corepressors NCoR / Q9Y618 . We previously identified a v - ErbA responsive element ( VRE ) within a P24855 hypersensitive region ( Q5VYS8 ) located in the second intron of the CA II gene . We now show that Q5VYS8 fulfils all the requirements for a genuine enhancer that functions independent of its orientation and position with a profound erythroid - specific activity in normal erythroid progenitors ( T2ECs ) and in leukemic erythroid cell lines . We find that the Q5VYS8 enhancer activity is governed by two adjacent GATA - factor binding sites . v - ErbA as well as unliganded TR prevent Q5VYS8 activity by nullifying the positive function of factors bound to GATA - sites . However , v - ErbA , in contrast to TR , does not convey active repression to silence the transcriptional activity intrinsic to a heterologous tk promoter . We propose that depending on the sequence and context of the binding site , v - ErbA contributes to leukemogenesis by occluding liganded TR as well as unliganded TR thereby preventing activation or repression , respectively .",
"Characterization of rat P23510 by monoclonal antibody . OX40 ( CD134 ) is a member of the tumor necrosis factor ( P01375 ) receptor superfamily first identified as a rat T cell activation marker . We previously identified the rat ligand for OX40 ( P23510 ) by molecular cloning . In the present study , we newly generated an anti - rat P23510 mAb ( Q13315 - 2 ) that can inhibit the binding of OX40 to rat P23510 and thus efficiently inhibits the T cell costimulatory activity of rat P23510 . Flow cytometric analyses using Q13315 - 2 and an anti - rat OX40 mAb ( MRC OX40 ) indicated that OX40 was inducible on splenic P01730 (+) T cells by stimulation with immobilized anti - CD3 mAb , while P23510 was not expressed on resting or activated T cells . P23510 was expressed on splenic B cells after stimulation with lipopolysaccharide ( LPS ) , but not on peritoneal macrophages . Interestingly , splenic dendritic cells ( DC ) expressed P23510 constitutively , which was further upregulated by LPS stimulation . The potent costimulatory activities of splenic DC for anti - CD3 - stimulated rat P01730 (+) T cell proliferation and cytokine ( P60568 , P01579 , P22301 , and P35225 ) production were substantially inhibited by Q13315 - 2 . These results indicated that P23510 is expressed on professional antigen - presenting cells ( P25054 ) , and may be involved in humoral immune responses via T - B interaction and in cellular immune responses via T - DC interaction in the rat system .",
"___MASK62___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK95___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"Murine autoimmune hearing loss mediated by P01730 + T cells specific for inner ear peptides . Autoimmune sensorineural hearing loss ( ASNHL ) is characterized typically by bilateral , rapidly progressive hearing loss that responds therapeutically to corticosteroid treatment . Despite its name , data implicating autoimmunity in the etiopathogenesis of ASNHL have been limited , and targeted self - antigens have not been identified . In the current study we show that the inner ear - specific proteins cochlin and beta - tectorin are capable of targeting experimental autoimmune hearing loss ( EAHL ) in mice . Five weeks after immunization of SWXJ mice with either Coch 131 - 150 or beta - tectorin 71 - 90 , auditory brainstem responses ( Q12979 ) showed significant hearing loss at all frequencies tested . Flow cytometry analysis showed that each peptide selectively activated P01730 (+) T cells with a proinflammatory Th1 - like phenotype . T cell mediation of EAHL was determined by showing significantly increased Q12979 thresholds 6 weeks after adoptive transfer of peptide - activated P01730 (+) T cells into naive SWXJ recipients . Immunocytochemical analysis showed that leukocytic infiltration of inner ear tissues coincided with onset of hearing loss . Our study provides a contemporary mouse model for clarifying our understanding of ASNHL and facilitating the development of novel effective treatments for this clinical entity . Moreover , our data provide experimental confirmation that ASNHL may be a T cell - mediated organ - specific autoimmune disorder of the inner ear .",
"P25963 and p65 regulate the cytoplasmic shuttling of nuclear corepressors : cross - talk between Notch and NFkappaB pathways . Notch and NFkappaB pathways are key regulators of numerous cellular events such as proliferation , differentiation , or apoptosis . In both pathways , association of effector proteins with nuclear corepressors is responsible for their negative regulation . We have previously described that expression of a p65 - NFkappaB mutant that lacks the transactivation domain ( p65DeltaTA ) induces cytoplasmic translocation of O75376 leading to a positive regulation of different promoters . Now , we show that cytoplasmic sequestration of p65 by P25963 is sufficient to both translocate nuclear corepressors Q9Y618 / O75376 to the cytoplasm and upregulate transcription of Notch - dependent genes . Moreover , p65 and P25963 are able to directly bind Q9Y618 , and this interaction can be inhibited in a dose - dependent manner by the CREB binding protein ( CBP ) coactivator and after P01375 treatment , suggesting that p65 acetylation is modulating this interaction . In agreement with this , P01375 treatment results in downregulation of the Hes1 gene . Finally , we present evidence on how this mechanism may influence cell differentiation in the 32D myeloid progenitor system .",
"[ Moclobemide ( ___MASK24___ ) , the first P21397 - inhibitor : really something new ? ] .",
"Polymorphisms in the phosphate and tensin homolog gene are not associated with late - onset Alzheimer ' s disease . The varepsilon4 allele of the P02649 locus is the only confirmed risk factor for late - onset Alzheimer ' s disease ( LOAD ) . The phosphate and tensin homolog ( P60484 ) gene is both a biological and positional candidate gene for LOAD . Eight polymorphisms spanning this gene were selected from dbSNP and genotyped in pooled DNA samples of both cases and controls . No evidence for association with LOAD was obtained in this study although further investigation revealed low levels of linkage disequlibrium ( LD ) between the genotyped SNPs . Our results suggest that it is unlikely that genetic variation within the P60484 gene contributes to risk of LOAD .",
"Novel non - genomic signaling of thyroid hormone receptors in thyroid carcinogenesis . The thyroid hormone receptors ( TRs ) are transcription factors that mediate the pleiotropic activities of the thyroid hormone , DB00279 . Four DB00279 - binding isoforms , TRalpha1 , TRbeta1 , TRbeta2 , and TRbeta3 , are encoded by two genes , P10827 and P10828 . Mutations and altered expression of TRs have been reported in human cancers . A targeted germ - line mutation of the Thrbeta gene in the mouse leads to spontaneous development of follicular thyroid carcinoma ( TRbeta ( PV / PV ) mouse ) . The TRbetaPV mutant has lost DB00279 - binding activity and displays potent dominant negative activity . The striking phenotype of thyroid cancer exhibited by TRbeta ( PV / PV ) mice has recently led to the discovery of novel non - genomic actions of TRbetaPV that contribute to thyroid carcinogenesis . These actions involve direct physical interaction of TRbetaPV with cellular proteins , namely the regulatory subunit of the phosphatidylinositol 3 - kinase ( p85alpha ) , the pituitary tumor transforming gene ( O95997 ) and beta - catenin , that are critically involved in cell proliferation , motility , migration , and metastasis . Thus , a TRbeta mutant ( TRbetaPV ) , via a novel mode of non - genomic action , acts as an oncogene in thyroid carcinogenesis .",
"Hepatocyte proliferation during liver regeneration is impaired in mice with liver - specific IGF - 1R knockout . Recent evidence indicates that growth hormone ( GH ) is involved in liver regeneration . To test whether insulin - like growth factor I ( P05019 ) mediates this effect , we studied liver regeneration induced by partial hepatectomy in liver - specific IGF type 1 receptor knockout ( LIGFREKO ) mice . The absence of IGF - 1R caused a significant decrease in hepatocyte proliferation in males ( - 52 % ) , but not in females , as assessed by Ki67 immunohistochemistry . P12004 D1 and cyclin A protein levels in the livers of LIGFREKO males were only half those in controls , indicating that cyclin induction during liver regeneration is dependent on IGF - 1R signaling . Analyzing the signaling cascade initiated by IGF - 1R , we observed a lack of P35568 induction in LIGFREKO livers . In contrast , the induction of Q9Y4H2 synthesis was similar in LIGFREKO and control groups , suggesting the existence of differential regulation of P41252 synthesis during liver regeneration . Regenerating livers from LIGFREKO animals also showed significantly less activated ERKs than controls . Our findings demonstrate that IGF - 1R makes a significant contribution to liver regeneration . Using the LIGFREKO model , we provide new evidence that IGF - 1R / P35568 / P29323 signaling may be the intracellular pathway controlling the cell cycle via cyclin D1 and cyclin A in the regenerating liver .",
"Delirium and the functional recovery of older medical inpatients after acute illness : the significance of biological factors . Previous studies have not clarified the relationship of delirium to functional capacity during acute illness . We have investigated this relationship , incorporating the potential roles of P02649 genotype and circulating cytokines in a longitudinal study of acutely admitted patients aged 70 + years . In all participants was measured the : Barthel Index ( BI ) , mini - mental state examination ( MMSE ) , confusion assessment method ( P62158 ) , delirium rating scale ( Q9H307 ) , APACHE II , P02649 genotype . In a sub - sample : serum interferon - γ ( IFN - γ ) , interleukin - 1 ( Levels of IL - 1α , IL - 1β and IL - 1 receptor antagonist activity IL - 1RA ) , interleukin - 6 ( P05231 ) , leukemia inhibitory factor ( P15018 ) , tumor necrosis factor - α ( P01375 - α ) and insulin - like growth factor - I ( P05019 ) . Of 164 participants , mean age 84 . 6 ± 6 . 57 years ( ± S . D . ) , 67 . 1 % were women . On first assessment , mean BI was 14 . 13 ± 4 . 46 and delirium prevalence was 25 . 6 % . At discharge , the mean BI of survivors ( n = 150 ) was 15 . 61 ± 4 . 22 . By discharge , survivors who had recovered from prevalent delirium had significant improvement in BI ( n = 38 , p = 0 . 005 ) , but non - recovers did not ( n = 14 , p = 0 . 512 ) . On , multivariate analysis , BI was significantly affected by MMSE , P02649 , IL - 1α , P05231 , P15018 and P01375 - α levels ( p < 0 . 05 ) but not by delirium . Delirium in acutely admitted patients is associated with functional decline only in those who do not recover . Biological factors , rather that delirium itself , may be responsible for this .",
"Effects of perfluorooctane sulfonate on rat thyroid hormone biosynthesis and metabolism . The potential toxicity of perfluorooctane sulfonate ( PFOS ) , an environmentally persistent organic pollutant , is of great concern . The present study examines the ability of PFOS to disturb thyroid function and the possible mechanisms involved in PFOS - induced thyroid hormone alteration . Male Sprague - Dawley rats were exposed to 1 . 7 , 5 . 0 , and 15 . 0 mg / L of PFOS in drinking water for 91 consecutive days . Serum was collected for analysis of total and free thyroxine ( DB00451 ) , total triiodothyronine ( DB00279 ) , and thyrotrophin ( DB00024 ) . Thyroid and liver were removed for the measurement of endpoints closely related to thyroid hormone biosynthesis and metabolism following PFOS exposure . Determined endpoints were the messenger RNA ( mRNA ) levels for two isoforms of uridine diphosphoglucuronosyl transferases ( P19224 and P22309 ) and type 1 deiodinase ( P49895 ) in liver , sodium iodide symporter ( Q92911 ) , DB00024 receptor ( P16473 ) , and P49895 in thyroid as well as the activity of thyroid peroxidase ( P07202 ) . Serum total DB00451 level decreased significantly at all applied dosages , whereas total DB00279 level increased markedly only at 1 . 7 mg / L of PFOS . No statistically significant toxic effects of PFOS on serum DB00024 were observed . Hepatic UGTIA1 , but not P19224 , mRNA was up - regulated at 5 . 0 and 15 . 0 mg / L of PFOS . Treatment with PFOS lowered hepatic P49895 mRNA at 15 . 0 mg / L but increased thyroidal P49895 mRNA dose dependently . The activity of P07202 , Q92911 , and P16473 mRNA in thyroid were unaffected by PFOS treatment . These results indicate that increased hepatic DB00451 glucuronidation via P22309 and increased thyroidal conversion of DB00451 to DB00279 via P49895 were responsible in part for PFOS - induced hypothyroxinemia in rats .",
"Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK89___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK89___ peptide content within the pituitary , and plasma ___MASK89___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK89___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK89___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK89___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .",
"cDNA microarray reveals signaling pathways involved in hormones expression of human pituitary . Pituitary , a master gland of neuroendocrine system , secretes hormones that orchestrate many physiological processes , under the regulation of multiple signaling pathways . To investigate the genes involved in hormones expression of human pituitary , homemade cDNA microarray containing 14 , 800 human genes / ESTs were used to profile the gene expression in both fetal and adult pituitaries . Seven hundred and twelve known genes changed over 2 - fold between the both tissues . Of which , 23 genes were changed with hormones expression in aging were confirmed by RT - PCR , not only the known regulators such as Pit1 , P43694 , P11474 , GABA - A , and EMK , but also LOC55884 , P51452 , Q9H307 , and O43598 , which had not been reported to be involved in the hormones expression . Correspondingly , the mRNAs of GH , PRL , P01189 , P01222 , DB00094 - beta , and LH - beta , was increased as much as 6 - to 20 - fold in adult pituitary than those in fetal pituitary , by real - time quantitative RT - PCR assay . In addition , the mRNAs of signaling pathways , such as DB02527 - PKA - CREB , PI3K - Akt , and PKA - P29323 were further investigated . Of them , it was only DB02527 - PKA - CREB pathway , but not PI3K - Akt and PKA - P29323 have the same expressing pattern as hormones . It suggested that cDNA microarray is highly advantages to profile the differential expressed genes that were involved in hormones expression of human pituitary , but it might ignore some responding proteins regulated posttranscriptionally .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK6___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"Targeting mitochondrial 18 kDa translocator protein ( TSPO ) regulates macrophage cholesterol efflux and lipid phenotype . The aim of the present study was to establish mitochondrial cholesterol trafficking 18 kDa translocator protein ( TSPO ) as a potential therapeutic target , capable of increasing macrophage cholesterol efflux to ( apo ) lipoprotein acceptors . Expression and activity of TSPO in human ( THP - 1 ) macrophages were manipulated genetically and by the use of selective TSPO ligands . Cellular responses were analysed by quantitative PCR ( Q - PCR ) , immunoblotting and radiolabelling , including [ 3H ] cholesterol efflux to ( apo ) lipoprotein A - I ( apoA - I ) , high - density lipoprotein ( HDL ) and human serum . Induction of macrophage cholesterol deposition by acetylated low - density lipoprotein ( AcLDL ) increased expression of TSPO mRNA and protein , reflecting findings in human carotid atherosclerosis . Transient overexpression of TSPO enhanced efflux ( E % ) of [ 3H ] cholesterol to apoA - I , HDL and human serum compared with empty vector ( EV ) controls , whereas gene knockdown of TSPO achieved the converse . Ligation of TSPO ( using PK11195 , FGIN - 1 - 27 and flunitrazepam ) triggered increases in [ 3H ] cholesterol efflux , an effect that was amplified in TSPO - overexpressing macrophages . Overexpression of TSPO induced the expression of genes [ Q07869 ( peroxisome - proliferator - activated receptor α ) , Q13133 ( nuclear receptor 1H3 / liver X receptor α ) , O95477 ( DB00171 - binding cassette A1 ) , Q9H172 ( DB00171 - binding cassette G4 ) and P02649 ( apolipoprotein E ) ] and proteins ( O95477 and PPARα ) involved in cholesterol efflux , reduced macrophage neutral lipid mass and lipogenesis and limited cholesterol esterification following exposure to AcLDL . Thus , targeting TSPO reduces macrophage lipid content and prevents macrophage foam cell formation , via enhanced cholesterol efflux to ( apo ) lipoprotein acceptors .",
"Evidence for cooperative transforming activity of the human pituitary tumor transforming gene and human T - cell leukemia virus type 1 Tax . Aneuploidy is frequent in cancers . Recently it was found that pituitary tumor transforming gene ( O95997 ; also called Pds1p or securin ) is overexpressed in many different tumors . Human T - cell leukemia virus type 1 ( HTLV - 1 ) is a retrovirus that primarily infects P01730 + T lymphocytes and causes adult T - cell leukemia . Here , we report that overexpression of human O95997 cooperated with the HTLV - I Tax oncoprotein in cellular transformation . Coexpression of Tax and O95997 enhanced chromosomal instability and neoplastic changes to levels greater than overexpression of either factor singularly . Cells that overexpressed both O95997 and Tax induced tumors more robustly in nude mice than cells that expressed either O95997 alone or Tax alone .",
"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK52___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK52___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK52___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .",
"The genetics of psoriasis and psoriatic arthritis . Genetic epidemiological studies have demonstrated a significant genetic basis to both psoriasis and psoriatic arthritis ( PsA ) . Although candidate gene association studies had identified genes for disease susceptibility , recent genome - wide association studies have demonstrated robust associations both within and outside the major histocompatibility region on chromosome 6p . The susceptibility genes identified include HLA - C , P35225 , P05112 , P21580 , Q9NPF7 , Q5VWK5 , Q8IU57 , Q04864 , Q9BYX4 , ERAP , O43734 , P25963 , P29597 , Q9Y508 , NOS2 , Q6PCT2 and P25963 in subjects of European ethnicity and HLA - C , P29460 , Q9BYE3 , Q9NZ08 , Q15025 , O95997 , Q96PZ7 , P29033 , P50452 and Q0VGE8 in subjects of Chinese ethnicity . These associations provide us with a model for the pathogenesis of psoriasis involving skin barrier function , innate and adaptive immunity . Gene - gene and gene - environmental interaction effects have also been demonstrated . However , loci identified to date do not fully account for the high heritability of psoriasis and PsA , and therefore many genetic as well as environmental factors and interaction effects remain to be determined . This article reviews the current status of genetic studies in psoriasis and PsA .",
"AP - 1 transrepressing retinoic acid does not deplete coactivators or AP - 1 monomers but may target specific Jun or Fos containing dimers . Retinoic acid ( RA ) inhibits tumor promotion in many models in vivo and in vitro , among them mouse epidermal JB6 cells . RA treatment suppresses 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) induced AP - 1 activity , an activity that is required for transformation of JB6 P + cells . The molecular mechanism of AP - 1 transrepression by retinoids is unclear , especially as related to inhibition of transformation . Overexpression of AP - 1 components did not rescue TPA induced AP - 1 activation nor did a Q86UG4 pull down experiment implicate direct binding , thus rendering unlikely both a Jun / Fos - RA - RAR direct interaction and a Jun / Fos sequestration mechanism . Overexpression of p300 , Q15788 or pCAF did not abrogate AP - 1 suppression by RA , thus arguing against coactivator competition . Overexpression of the corepressor silencing mediator for retinoic acid and thyroid hormone receptors ( Q9Y618 ) suppressed AP - 1 activity . However , Q9Y618 but not RA inhibited cJun transactivation , suggesting Q9Y618 does not mediate RA transrepression . RA treatment also did not block TPA induced P29323 phosphorylation , Jun / Fos family protein expression except for cFos , or DNA binding of the AP - 1 complex . The transcriptional activities of full - length JunB and full - length Fra - 1 , but not the transactivation domain fusions , were increased by TPA treatment and suppressed by RA . Since these full - length fusions have bzip domains , the results suggest that JunB and / or Fra - 1 - containing dimers may constitute one target of RA for transrepression of AP - 1 .",
"Nuclear translocation of Q02750 triggers a complex T cell response through the corepressor silencing mediator of retinoid and thyroid hormone receptor . Q02750 phosphorylates P27361 / 2 and regulates T cell generation , differentiation , and function . Q02750 has recently been shown to translocate to the nucleus . Its nuclear function is largely unknown . By studying human P01730 T cells , we demonstrate that a low level of Q02750 is present in the nucleus of P01730 T cells under basal conditions . T cell activation further increases the nuclear translocation of Q02750 . Q02750 interacts with the nuclear receptor corepressor silencing mediator of retinoid and thyroid hormone receptor ( Q9Y618 ) . Q02750 reduces the nuclear level of Q9Y618 in an activation - dependent manner . Q02750 is recruited to the promoter of c - Fos upon TCR stimulation . Conversely , Q9Y618 is bound to the c - Fos promoter under basal conditions and is removed upon TCR stimulation . We examined the role of Q9Y618 in regulation of T cell function . Small interfering RNA - mediated knockdown of Q9Y618 results in a biphasic effect on cytokine production . The production of the cytokines P60568 , P05112 , P22301 , and IFN - γ increases in the early phase ( 8 h ) and then decreases in the late phase ( 48 h ) . The late - phase decrease is associated with inhibition of T cell proliferation . The late - phase inhibition of T cell activation is , in part , mediated by P22301 that is produced in the early phase and , in part , by β - catenin signaling . Thus , we have identified a novel nuclear function of Q02750 . Q02750 triggers a complex pattern of early T cell activation , followed by a late inhibition through its interaction with Q9Y618 . This biphasic dual effect most likely reflects a homeostatic regulation of T cell function by Q02750 .",
"A phase II study of a Q13641 oncofoetal antigen tumour - targeted superantigen ( Q12979 - 214936 ) therapy in patients with advanced renal cell carcinoma . In a phase II study , 43 renal cell carcinoma patients were treated with individualised doses of Q12979 - 214936 ; a fusion of a Fab recognising the antigen Q13641 , and Staphylococcal enterotoxin A . Drug was given intravenously on 4 consecutive days , treatment was repeated 1 month later . Treatment was associated with moderate fever and nausea , but well tolerated . Of 40 evaluable patients , 28 had disease control at 2 months , and at 4 months , one patient showed partial response ( PR ) and 16 patients stable disease . Median survival , with minimum follow - up of 26 months was 19 . 7 months with 13 patients alive to date . Stratification by the Motzer ' s prognostic criteria highlights prolonged survival compared to published expectation . Patients receiving higher drug exposure had greater disease control and lived almost twice as long as expected , whereas the low - exposure patients survived as expected . Sustained interleukin - 2 ( P60568 ) production after a repeated injection appears to be a biomarker for clinical effect , as the induced - P60568 level on the day 2 of treatment correlated with survival . The high degree of disease control and the prolonged survival suggest that this treatment can be effective . These findings will be used in the trial design for the next generation of drug , with reduced antigenicity and toxicity .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK14___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"Focal brain inflammation and autism . Increasing evidence indicates that brain inflammation is involved in the pathogenesis of neuropsychiatric diseases . Autism spectrum disorders ( P51689 ) are characterized by social and learning disabilities that affect as many as 1 / 80 children in the USA . There is still no definitive pathogenesis or reliable biomarkers for P51689 , thus significantly curtailing the development of effective therapies . Many children with P51689 regress at about age 3 years , often after a specific event such as reaction to vaccination , infection , stress or trauma implying some epigenetic triggers , and may constitute a distinct phenotype . P51689 children respond disproportionally to stress and are also affected by food and skin allergies . P06850 ( P06850 ) is secreted under stress and together with neurotensin ( NT ) stimulates mast cells and microglia resulting in focal brain inflammation and neurotoxicity . NT is significantly increased in serum of P51689 children along with mitochondrial DNA ( mtDNA ) . NT stimulates mast cell secretion of mtDNA that is misconstrued as an innate pathogen triggering an auto - inflammatory response . The phosphatase and tensin homolog ( P60484 ) gene mutation , associated with the higher risk of P51689 , which leads to hyper - active mammalian target of rapamycin ( P42345 ) signalling that is crucial for cellular homeostasis . P06850 , NT and environmental triggers could hyperstimulate the already activated P42345 , as well as stimulate mast cell and microglia activation and proliferation . The natural flavonoid luteolin inhibits P42345 , mast cells and microglia and could have a significant benefit in P51689 .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"P10828 mutants : Dominant negative regulators of peroxisome proliferator - activated receptor gamma action . Thyroid hormone ( DB00279 ) and peroxisome proliferators have overlapping metabolic effects in the maintenance of lipid homeostasis . Their actions are mediated by their respective receptors : thyroid hormone receptors ( TR ) and peroxisome proliferator - activated receptors ( Q07869 ) . We recently found that a dominantly negative TRbeta mutant ( PV ) that causes a genetic disease , resistance to thyroid hormone , acts to repress the ligand ( troglitazone )- mediated transcriptional activity of PPARgamma in cultured thyroid cells . This finding suggests that TRbeta mutants could crosstalk with PPARgamma - signaling pathways . The present study explored the molecular mechanisms by which PV represses the PPARgamma transcriptional activity . Gel - shift assays show that the PV , similar to wild - type TRbeta , bound to the peroxisome proliferator response element ( PPRE ) as homodimers and heterodimers with PPARgamma or the retinoid X receptor ( RXR ) , thereby competing with PPARgamma for binding to PPRE and for sequestering RXR . Association of PPRE - bound PV with corepressors [ e . g . , nuclear receptor corepressor ( NCoR ) ] that led to transcriptional repression was independent of DB00279 and troglitazone . Chromatin immunoprecipitation assay further demonstrated that , despite the presence of ligands , NCoR was recruited to PPRE - bound PV on a PPARgamma - target gene , the lipoprotein lipase , in vivo , suggesting the dominant action of PV on PPARgamma - mediated transcriptional activity . Thus , the dominant negative action of PV is not limited on the wild - type TRs . The findings that TRbeta mutants affect PPARgamma functions through dominant negative action provide insights into the molecular mechanisms by which TR regulates the PPARgamma - target genes involved in metabolic pathways , lipid homeostasis , and carcinogenesis .",
"Pituitary tumor transforming gene 1 induces tumor necrosis factor - α production from keratinocytes : implication for involvement in the pathophysiology of psoriasis . Proliferation and differentiation in the epidermis must be tightly regulated . This regulation is known to involve a range of transcription factors , including pituitary tumor transforming gene 1 ( O95997 ) , a ubiquitously distributed transcription factor that regulates keratinocyte proliferation and differentiation . Psoriasis is a common but refractory skin disorder , the pathophysiology of which is characterized by hyperproliferation and impaired differentiation in the epidermis . The present study was conducted to clarify the less well - known roles of O95997 in the pathophysiology of psoriasis , focusing on its relationship with tumor necrosis factor - α ( P01375 - α ) , which is a critical mediator of the disease . The levels of O95997 expression were increased in the psoriatic epidermis . Overexpression of O95997 resulted in the overproduction of P01375 - α , and P01375 - α itself had an inductive effect on O95997 expression , suggesting that their expression may involve autoinduction . Moreover , overexpression of O95997 involved augmented the expression of cyclin A and B1 proteins in both cultured keratinocytes and the psoriatic epidermis . Therefore , enhanced expression of O95997 in the psoriatic epidermis may result in aberrant regulation of the cell cycle and impaired differentiation via the interplay between O95997 and P01375 - α .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK39___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK39___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK39___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK39___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK39___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK39___ increased the protein expression of hepatic P05181 and ___MASK39___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK39___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK39___ and RFP - induced hepatotoxicity .",
"Induction of platelet - derived growth factor B / DB00102 by the v - erbA oncogene in glial cells . The v - erbA oncogene codes for a mutated form of the thyroid hormone receptor TR / P10827 . Thyroid hormone ( triiodothyronine , DB00279 ) regulates glial functions such as myelination and both astrocytes and oligodendrocytes have been shown to express thyroid hormone receptors ( TRs ) . To study putative effects of v - erbA on glial precursors , we have expressed it in a glial clonal cell line established from early embryonal mouse brain . We have found that v - erbA increases cell survival in serum - free conditions . Moreover , v - erbA - expressing cells show a substantial growth in the presence of insulin or P05019 , whereas normal and TR / c - erbA - over - expressing cells progressively degenerate . By Northern blotting , immunofluorescence , immunoprecipitation , and neutralization experiments , we show that v - erbA actions are mediated by an increase in the levels of PDGF B / DB00102 mRNA and protein . We used anti - PDGF receptor and anti - phosphotyrosine antibodies to show the constitutive activation of PDGF receptors in B3 . 1 + v - erbA cells , and neutralizing anti - PDGF antibodies to demonstrate that v - erbA enhances the secretion of active PDGF into the culture medium . Our data indicate that v - erbA induces PDGF B / DB00102 , a factor involved in the generation of gliomas , the most common central nervous system tumor in humans .",
"Nuclear IKK activity leads to dysregulated notch - dependent gene expression in colorectal cancer . Nuclear functions for O15111 ( IKK ) , including phosphorylation of histone H3 and nuclear corepressors , have been recently described . Here , we show that IKK is activated in colorectal tumors concomitant with the presence of phosphorylated Q9Y618 ( silencing mediator of retinoic acid and thyroid hormone receptor ) corepressor that is aberrantly localized in the cytoplasm . In these tumors , IKKalpha associates to the chromatin of specific Notch targets , leading to the release of Q9Y618 . Abrogation of IKK activity by BAY11 - 7082 or by expressing dominant negative IKKalpha restores the association of Q9Y618 with Notch target genes , resulting in specific gene repression . Finally , BAY11 - 7082 significantly reduces tumor size in colorectal cancer xenografts ( CRC - Xs ) implanted in nude mice .",
"Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP3A ) , a phase II enzyme ( P22309 / 6 / 9 ) , two drug transporters ( P - gp and Q9Y6L6 ) and a component of the renal function ( Videau et al . 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat . The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC - MS / MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated . The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1 / 2 with omeprazole / omeprazole - sulfone , midazolam / 1 '- hydroxymidazolam or 4 - hydroxymidazolam and / or dextromethorphan / 3 - methoxymorphinan , CYP2C6 / 11 with tolbutamide / 4 - hydroxytolbutamide , CYP2D1 / 2 with omeprazole / 5 - hydroxyomeprazole or dextromethorphan / dextrorphan , and P19224 / 7 with acetaminophen / acetaminophen - glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP2C11 and CYP2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors .",
"Early diagnosis of ataxia - telangiectasia using radiosensitivity testing . OBJECTIVES : To utilize radiosensitivity testing to improve early diagnosis of patients with ataxia - telangiectasia ( A - T ) . STUDY DESIGN : We established normal ranges for the colony survival assay ( Q13216 ) by testing cells from 104 patients with typical A - T , 29 phenotypic normal patients , and 19 A - T heterozygotes . We also analyzed 61 samples from patients suspected of having A - T and 25 patients with related disorders to compare the Q13216 with other criteria in the diagnosis of A - T . RESULTS : When cells were irradiated with 1 . 0 Gy , the mean survival fraction ( microSF +/- 1 SD ) for patients with A - T was 13 . 1 % +/- 7 . 2 % compared with 50 . 1 % +/- 13 . 5 % for healthy control patients . These data served to define a diagnostic range for the Q13216 ( ie , < 21 % ) , a normal range ( > 36 % ) , and a nondiagnostic intermediate range of 21 % to 36 % . The mutations of patients with A - T with intermediate radiosensitivity tended to cluster around the functional domains of the Q13315 gene . CONCLUSIONS : The Q13216 is a useful adjunctive test for confirming an early clinical diagnosis of A - T . However , Q13216 is also abnormal in other chromosomal instability and immunodeficiency disorders .",
"Modulation of the P22301 / IL - 12 cytokine circuit by interferon - beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis . IFN - beta has been shown to be effective in the treatment of multiple sclerosis ( MS ) . However , the primary mechanism by which IFN - beta mediates its therapeutic effect remains unclear . Recent studies indicate that under defined conditions , IFN - beta may downregulate DC expression of IL - 12 . We and others have shown that IFN - beta may also downregulate P22301 . In light of the recently proposed paradigm that an P22301 / IL - 12 immunoregulatory circuit controls susceptibility to autoimmune disease , we examined the effect of IFN - beta on the development and behavior of the autoreactive T cell repertoire during experimental autoimmune encephalomyelitis ( EAE ) , an animal model sharing many features with MS . SWXJ mice were immunized with the immunodominant p139 - 151 determinant of myelin proteolipid protein ( PLP ) , and at onset of EAE were treated every other day with IFN - beta . After eight weeks of treatment , we assessed autoreactivity and observed no significant IFN - beta effect on splenocyte proliferation or splenocyte production of P01579 , P60568 , P05112 , or P05113 in response to the priming determinant used to initiate disease . However , in IFN - beta treated mice , the cytokine profile in response to the priming immunogen was significantly skewed toward an increased production of P22301 and a concurrent decreased production of IL - 12 . Moreover , the in vivo modulation of the P22301 / IL - 12 immunoregulatory circuit in response to the priming immunogen was accompanied by an aborted development of epitope spreading . Our results indicate that IFN - beta induces a reciprocal modulation of the P22301 / IL - 12 cytokine circuit in vivo . This skewed autoreactivity establishes an inflammatory microenvironment that effectively prevents endogenous self - priming thereby inhibiting the progression of disease associated with epitope spreading .",
"Tracing the conversion process from primordial germ cells to pluripotent stem cells in mice . To understand mechanisms underlying acquisition of pluripotency , it is critical to identify cells that can be converted to pluripotent stem cells . For this purpose , we focused on unipotent primordial germ cells ( PGCs ) , which can be reprogrammed into pluripotent embryonic germ ( EG ) cells under defined conditions . Treatment of PGCs with combinations of signaling inhibitors , including inhibitors of MAP2K ( MEK ) , P49841 ( GSK - 3beta ) , and P01137 ( TGFbeta ) type 1 receptors , induced cells to enter a pluripotent state at a high frequency ( 12 . 1 % ) by Day 10 of culture . When we employed fluorescence - activated cell sorting to monitor conversion of candidate cells to a pluripotent state , we observed a cell cycle shift to S phase , indicating enrichment of pluripotent cells , during the early phase of EG formation . Transcriptome analysis revealed that PGCs retained expression of some pluripotent stem cell - associated genes , such as Pou5f1 and Sox2 , during EG cell formation . On the other hand , PGCs lost their germ lineage characteristics and acquired expression of pluripotent stem cell markers , such as Klf4 and Eras . The overall gene expression profiles revealed by this system provide novel insight into how pluripotency is acquired in germ - committed cells .",
"Mechanisms for epigallocatechin gallate induced inhibition of drug metabolizing enzymes in rat liver microsomes . DB03823 gallate ( EGCG ) inhibits drug metabolizing enzymes by unknown mechanisms . Here we examined if the inhibition is due to covalent - binding of EGCG to the enzymes or formation of protein aggregates . EGCG was incubated with rat liver microsomes at 1 - 100μM for 30min . The EGCG - binding proteins were affinity purified using m - aminophenylboronic acid agarose and probed with antibodies against glyceraldehyde - 3 - phosphate dehydrogenase ( P04406 ) , actin , cytochrome P450 ( CYP ) 1A1 , P05177 , CYP2B1 / 2 , P05181 , CYP3A , catechol - O - methyltransferase ( P21964 ) and microsomal glutathione transferase 1 ( P10620 ) . All but actin and soluble P21964 were positively detected at ≥ 1μM EGCG , indicating EGCG selectively bound to a subset of proteins including membrane - bound P21964 . The binding correlated well with inhibition of CYP activities , except for P05181 whose activity was unaffected despite evident binding . The antioxidant enzyme P10620 , but not cytosolic GSTs , was remarkably inhibited , providing novel evidence supporting the pro - oxidative effects of EGCG . When microsomes incubated with EGCG were probed on Western blots , all but the actin and P05181 antibodies showed a significant reduction in binding at ≥ 1μM EGCG , suggesting that a fraction of the indicated proteins formed aggregates that likely contributed to the inhibitory effects of EGCG but were not recognizable by antibodies against the intact proteins . This raised the possibility that previous reports on EGCG regulating protein expression using P04406 as a reference should be revisited for accuracy . Remarkable protein aggregate formation in EGCG - treated microsomes was also observed by analyzing Coomassie Blue - stained SDS - PAGE gels . EGCG effects were partially abolished in the presence of 1mM glutathione , suggesting they are particularly relevant to the in vivo conditions when glutathione is depleted by toxicant insults .",
"MicroRNAs in thyroid cancer . CONTEXT : Traditionally , factors predisposing to diseases are either genetic ( \" nature \" ) or environmental , also known as lifestyle - related ( \" nurture \" ) . Papillary thyroid cancer is an example of a disease where the respective roles of these factors are surprisingly unclear . EVIDENCE ACQUISITION : Original articles and reviews summarizing our current understanding of the role of microRNA in thyroid tumorigenesis are reviewed and evaluated . CONCLUSION : The genetic predisposition to papillary thyroid cancer appears to consist of a variety of gene mutations that are mostly either of low penetrance and common or of high penetrance but rare . Moreover , they likely interact with each other and with environmental factors . The culpable genes may not be of the traditional , protein - coding type . A limited number of noncoding candidate genes have indeed been described , and we propose here that the failure to find mutations in traditional protein - coding genes is not coincidental . Instead , a more likely hypothesis is that changes in the expression of multiple regulatory RNA genes , e . g . microRNAs , may be a major mechanism . Our review of the literature strongly supports this notion in that a polymorphism in one microRNAs ( miR - 146a ) predisposes to thyroid carcinoma , whereas numerous other microRNAs are involved in signaling ( mainly P60484 / PI3K / AKT and DB00279 / P10828 ) that is central to thyroid carcinogenesis .",
"___MASK52___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .",
"P51681 : A novel player in the adipose tissue inflammation and insulin resistance ? Adipose tissue macrophage ( Q13315 ) accumulation through C - C motif chemokine receptor 2 ( P41597 ) and its ligand monocyte chemoattractant protein - 1 ( P13500 ) is considered pivotal in the development of insulin resistance . However , our new study has demonstrated that P51681 , a different CC chemokine receptor , plays an important role in the Q13315 recruitment and activation and subsequent development of insulin resistance ( see the recent article in Diabetes ) . Although recent human studies have shown upregulation of the expression of not only P13500 - P41597 but also other CC chemokines and their receptors in the visceral fat of obese individuals , it is not known if P51681 is involved in Q13315 recruitment and insulin resistance . This article has shown several new important observations . First , expression of P51681 and its ligands is significantly increased and is equal to that of P41597 and its ligands in the white adipose tissue ( WAT ) of obese mice , particularly in the macrophage fraction . Second , fluorescence - activated cell sorter analysis clearly demonstrates a robust increase in accumulation of P51681 (+) ATMs in response to a high fat ( HF ) diet . Third , and most important , two distinct models , both Ccr5 ( -/- ) mice and chimeric mice lacking P51681 only in myeloid cells , are protected from insulin resistance and diabetes through reduction in Q13315 accumulation . Finally , it is interesting that an alternatively activated , M2 - dominant shift in Q13315 is induced in obese Ccr5 ( -/- ) mice . Taken together , these data indicate that P51681 is a novel link between obesity , adipose tissue inflammation , and insulin resistance .",
"Impact of α - lipoic acid on liver peroxisome proliferator - activated receptor - α , vascular remodeling , and oxidative stress in insulin - resistant rats . This study sought to determine the impact of α - lipoic acid ( LA ) on superoxide anion ( O ( 2 )(•-) ) production and peroxisome proliferator - activated receptor - α ( PPARα ) expression in liver tissue , plasma free fatty acids ( FFA ) , and aortic remodeling in a rat model of insulin resistance . Sprague - Dawley rats ( 50 - 75 g ) were given either tap water or a drinking solution containing 10 % D - glucose for 14 weeks , combined with a diet with or without LA supplement . O ( 2 )(•-) production was measured by lucigenin chemiluminescence , and Q07869 - α expression by Western blotting . Cross - sectional area ( Q13216 ) of the aortic media and lumen and number of smooth muscle cells ( SMC ) were determined histologically . DB09341 increased systolic blood pressure ( SBP ) , plasma levels of glucose and insulin , and insulin resistance ( HOMA index ) . All of these effects were attenuated by LA . Whereas glucose had no effect on liver Q07869 - α protein level , it decreased plasma FFA . LA decreased the aortic and liver O ( 2 )(•-) production , body weight , and plasma FFA levels in control and glucose - treated rats . Liver Q07869 - α protein levels were increased by LA , and negatively correlated with plasma FFA . Medial Q13216 was reduced in all glucose - treated rats , and positively correlated with plasma FFA but not with SBP or aortic O ( 2 )(•-) production . DB09341 also reduced aortic lumen area , so that the media - to - lumen ratio remained unchanged . The ability of LA to lower plasma FFA appears to be mediated , in part , by increased hepatic Q07869 - α expression , which may positively affect insulin resistance . DB09341 - fed rats may serve as a unique model of aortic atrophic remodeling in hypertension and early metabolic syndrome .",
"TGF - β1 - ROS - Q13315 - CREB signaling axis in macrophage mediated migration of human breast cancer MCF7 cells . Macrophages in the tumor microenvironment play an important role in tumor cell survival . They influence the tumor cell to proliferate , invade into surrounding normal tissues and metastasize to local and distant sites . In this study , we evaluated the effect of conditioned medium from monocytes and macrophages on growth and migration of breast cancer cells . Macrophage conditioned medium ( MϕCM ) containing elevated levels of cytokines P01375 - α , IL - 1β and P05231 had a differential effect on non - invasive ( MCF7 ) and highly invasive ( MDA - MB - 231 ) breast cancer cell lines . MϕCM induced the secretion of TGF - β1 in MCF7 cells . This was associated with apoptosis in a fraction of cells and generation of reactive oxygen and nitrogen species ( ROS and RNS ) and DNA damage in the remaining cells . This , in turn , increased expression of DB02527 response element binding protein ( CREB ) and vimentin resulting in migration of cells . These effects were inhibited by neutralization of P01375 - α , IL - 1β and P05231 , inhibition of ROS and RNS , DNA damage and siRNA mediated knockdown of Q13315 . In contrast , MDA - MB - 231 cells which had higher basal levels of pCREB were not affected by MϕCM . In summary , we have found that pro - inflammatory cytokines secreted by macrophages induce TGF - β1 in tumor cells , which activate pCREB signaling , epithelial - mesenchymal - transition ( EMT ) responses and enhanced migration .",
"___MASK89___ - releasing hormone inhibits insulin - like growth factor - I release from primary cultures of rat granulosa cells . ___MASK89___ - releasing hormone ( P06850 ) , a neuropeptide which modulates gonadal function during stress , is expressed by several cell types of the rat ovary and is able to suppress oestrogen release from rat granulosa cells . The mechanism of this effect is , however , not known . Since insulin - like growth factor ( IGF ) - I is produced by rat granulosa cells and exerts a synergistic role with DB00094 on granulosa cell steroidogenesis , we hypothesised that P06850 may suppress oestrogen release from granulosa cells by inhibiting P05019 release and / or stimulating the release of its binding protein ( P17936 ) . To test this hypothesis , granulosa cells were obtained from immature female Sprague - Dawley rats primed with diethylstilboestrol , and hormone concentrations were measured in the conditioned medium by radioimmunoassay . P06850 suppressed oestrogen and P05019 release stimulated by DB00094 used at a concentration of 1 IU / l , whereas it did not have any statistically significant effect on oestrogen and P05019 release in basal conditions or in response to 5 IU / l DB00094 . The suppressive effects of P06850 on oestrogen and P05019 release were antagonised by a selective P06850 receptor antagonist . P06850 had no effects on P17936 release . P06850 did not have any effect on oestrogen release stimulated by increasing concentrations of P05019 and its suppressive effect on DB00094 - stimulated oestrogen release was overcome by the addition of low doses of exogenous P05019 . In conclusion , P06850 suppressed the release of oestrogen and P05019 , but not of P17936 . Thus , the inhibitory effects of P06850 on oestrogen release could be mediated , partly , by a suppression of the autocrine / paracrine action of P05019 .",
"Q16696 enhances the sensitivity of human bronchial epithelial cells to aflatoxin B1 - induced DNA damage . Q16696 ( Q16696 ) mainly expresses in human respiratory system and mediates the metabolic activation of aflatoxin B1 ( AFB1 ) . Our previous study suggested that Q16696 could increase the cytotoxic and apoptotic effects of AFB1 in immortalized human bronchial epithelial cells ( BEAS - 2B ) . However , the role of Q16696 in AFB1 - induced DNA damage is unclear . Using BEAS - 2B cells that stably express Q16696 ( B - 2A13 ) , P05177 ( B - 1A2 ) , and P11509 ( B - 2A6 ) , we compared their effects in AFB1 - induced DNA adducts , DNA damage , and cell cycle changes . BEAS - 2B cells that were transfected with vector ( B - vector ) were used as a control . The results showed that AFB1 ( 5 - 80 nM ) dose - and time - dependently induced DNA damage in B - 2A13 cells . AFB1 at 10 and 80nM significantly augmented this effect in B - 2A13 and B - 1A2 cells , respectively . B - 2A6 cells showed no obvious DNA damage , similar to B - vector cells and the vehicle control . Similarly , compared with B - vector , B - 1A2 or B - 2A6 cells , B - 2A13 cells showed more sensitivity in AFB1 - induced γ P16104 expression , DNA adduct 8 - hydroxy - deoxyguanosine formation , and S - phase cell - cycle arrest . Furthermore , AFB1 activated the proteins related to DNA damage responses , such as Q13315 , ATR , Chk2 , p53 , P38398 , and P16104 , rather than the proteins related to DNA repair . These effects could be almost completely inhibited by 100 μM nicotine ( a substrate of Q16696 ) or 1 μM 8 - methoxypsoralen ( DB00553 ; an inhibitor of CYP enzyme ) . Collectively , these findings suggest that Q16696 plays an important role in low - concentration AFB1 - induced DNA damage , possibly linking environmental airborne AFB1 to genetic injury in human respiratory system .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK67___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"Down - regulation of the oncogene O95997 via the Q99612 tumor suppressor during induction of myeloid differentiation . The aberrant expression of proto - oncogenes is involved in processes that are responsible for cellular proliferation and the inhibition of myeloid differentiation in acute myeloid leukemia ( AML ) . Pituitary Tumor - Transforming gene 1 ( O95997 ) , an oncogenic transcription factor , is abundantly expressed in various human cancers and hematopoietic malignancies . However , its expression in normal leukocytes and most normal tissues is very low or undetectable . The mechanism by which O95997 overexpression modifies myeloid cell development and promotes leukemogenesis remain unclear . To investigate the mechanistic links between O95997 overexpression and leukemia cell differentiation , we utilized phorbol 12 - myristate 13 - acetate ( PMA ) , a well - known agent that triggers monocyte / macrophage differentiation , to analyze the expression patterns of O95997 in PMA - induced myeloid differentiation . We found that O95997 is down - regulated at the transcriptional level in PMA - treated HL - 60 and THP1 cells . In addition , we identified a binding site for a tumor suppressor protein , Kruppel - like factor 6 ( Q99612 ) , in the O95997 promoter . We found that Q99612 could directly bind and repress O95997 expression . In HL - 60 and THP1 cells , Q99612 mRNA and protein levels are up - regulated with a concordant reduction of O95997 expression upon treatment with PMA . Furthermore , Q99612 knockdown by shRNA abolished the suppression of O95997 and reduced the activation of the differentiation marker CD11b in PMA - primed cells . The protein kinase C ( PKC ) inhibitor and the MAPK / P29323 kinase ( MEK ) inhibitor significantly blocked the potentiation of PMA - mediated Q99612 induction and the down - regulation of O95997 , indicating that O95997 is suppressed via the activation of PKC / P29323 / Q99612 pathway . Our findings suggest that drugs that increase the Q99612 inhibition of O95997 may have a therapeutic application in AML treatment strategies .",
"Suppression of experimental autoimmune neuritis by Q12979 - 215062 is associated with altered Th1 / Th2 balance and inhibited migration of inflammatory cells into the peripheral nerve tissue . The therapeutic effects of Q12979 - 215062 , which is a new immunoregulator derived from DB11366 , have been evaluated in experimental autoimmune neuritis ( EAN ) , a P01730 (+) T cell - mediated animal model of Guillain - Barré syndrome in man . In previous studies , we reported that DB11366 suppressed the clinical EAN and myelin antigen - reactive T and B cell responses . Here EAN induced in Lewis rats by inoculation with peripheral nerve myelin P0 protein peptide 180 - 199 and Freund ' s complete adjuvant was strongly suppressed by Q12979 - 215062 administered daily subcutaneously from the day of inoculation . Q12979 - 215062 dose - dependently reduced the incidence of EAN , ameliorated clinical signs and inhibited P0 peptide 180 - 199 - specific T cell responses as well as also the decreased inflammation and demyelination in the peripheral nerves . The suppression of clinical EAN was associated with inhibition of the inflammatory cytokines P01579 and P01375 , as well as the enhancement of anti - inflammatory cytokine P05112 in lymph node cells and periphery nerve tissues , respectively , in a dose - dependent manner . These effects indicate that Q12979 - 215062 may mediate its effects by regulation of Th1 / Th2 cytokine balance and suggest that Q12979 - 215062 is potentially a new chemical entity for effective treatment of autoimmune diseases .",
"Reverse crosstalk of TGFβ and PPARβ / δ signaling identified by transcriptional profiling . Previous work has provided strong evidence for a role of peroxisome proliferator - activated receptor β / δ ( PPARβ / δ ) and transforming growth factor - β ( TGFβ ) in inflammation and tumor stroma function , raising the possibility that both signaling pathways are interconnected . We have addressed this hypothesis by microarray analyses of human diploid fibroblasts induced to myofibroblastic differentiation , which revealed a substantial , mostly reverse crosstalk of both pathways and identified distinct classes of genes . A major class encompasses classical Q07869 target genes , including Q9BY76 , P50416 , Q99541 and Q16654 . These genes are repressed by TGFβ , which is counteracted by PPARβ / δ activation . This is mediated , at least in part , by the TGFβ - induced recruitment of the corepressor Q9Y618 to Q07869 response elements , and its release by PPARβ / δ ligands , indicating that TGFβ and PPARβ / δ signals are integrated by chromatin - associated complexes . A second class represents TGFβ - induced genes that are downregulated by PPARβ / δ agonists , exemplified by Q9NZQ7 and P05231 , which is consistent with the anti - inflammatory properties of PPARβ / δ ligands . Finally , cooperative regulation by both ligands was observed for a minor group of genes , including several regulators of cell proliferation . These observations indicate that PPARβ / δ is able to influence the expression of distinct sets of both TGFβ - repressed and TGFβ - activated genes in both directions .",
"Thyroid hormone status interferes with estrogen target gene expression in breast cancer samples in menopausal women . We investigated thyroid hormone levels in menopausal BrC patients and verified the action of triiodothyronine on genes regulated by estrogen and by triiodothyronine itself in BrC tissues . We selected 15 postmenopausal BrC patients and a control group of 18 postmenopausal women without BrC . We measured serum P07202 - AB , DB00024 , FT4 , and estradiol , before and after surgery , and used immunohistochemistry to examine estrogen and progesterone receptors . BrC primary tissue cultures received the following treatments : ethanol , triiodothyronine , triiodothyronine plus 4 - hydroxytamoxifen , 4 - hydroxytamoxifen , estrogen , or estrogen plus 4 - hydroxytamoxifen . Genes regulated by estrogen ( P01135 , P01137 , and P06401 ) and by triiodothyronine ( Q07011 , P22004 , and P10827 ) in vitro were evaluated . DB00024 levels in BrC patients did not differ from those of the control group ( 1 . 34 ± 0 . 60 versus 2 . 41 ± 1 . 10 μ U / mL ) , but FT4 levels of BrC patients were statistically higher than controls ( 1 . 78 ± 0 . 20 versus 0 . 95 ± 0 . 16 ng / dL ) . P01135 was upregulated and downregulated after estrogen and triiodothyronine treatment , respectively . DB00279 increased P06401 expression ; however 4 - hydroxytamoxifen did not block triiodothyronine action on P06401 expression . DB04468 , alone or associated with triiodothyronine , modulated gene expression of Q07011 , P22004 , and P10827 , similar to triiodothyronine treatment . Thus , our work highlights the importance of thyroid hormone status evaluation and its ability to interfere with estrogen target gene expression in BrC samples in menopausal women ."
] |
[
"___MASK14___",
"___MASK24___",
"___MASK39___",
"___MASK52___",
"___MASK62___",
"___MASK67___",
"___MASK6___",
"___MASK89___",
"___MASK95___"
] |
___MASK95___
|
MH_train_445
|
interacts_with DB06825?
|
[
"Effect of ethanol on androgen receptors in the anterior pituitary , hypothalamus and brain cortex in rats . The purpose of this study was to investigate ethanol - induced changes in androgen receptor sites in the anterior pituitary , hypothalamus , and brain cortex . Young adult male King - Holtzman rats were fed for 5 months a nutritionally complete liquid diet , with ethanol or isocaloric sucrose constituting 36 % of the total calories . P10275 sites were measured by sucrose density gradient and charcoal assay using tritiated dihydrotestosterone ( ___MASK91___ ) . Scatchard plot analysis of the data revealed that apparent dissociation constants of ___MASK91___ - receptor complex for the anterior pituitary , hypothalamus , and brain cortex from alcohol - fed animals were estimated to be 0 . 7 +/- 0 . 13 , 0 . 6 +/- 0 . 16 and 0 . 9 +/- 0 . 15 nM , respectively . These values are identical to those of their isocaloric controls . The concentrations of cytosol androgen receptors of the pituitary , hypothalamus , and brain cortex from alcohol - fed rats were 8 . 0 +/- 1 . 2 , 6 . 2 +/- 1 . 0 and 4 . 9 +/- 0 . 7 fmol / mg protein , respectively . This represents about a 34 , 24 , and 22 % reduction when compared to the values of the isocaloric control animals . In contrast to control rats , neither castration nor androgen or P01148 replacement to castrated alcohol - fed rats altered an alcohol - induced reduction of androgen receptor contents . Serum LH and testosterone levels were significantly decreased in alcohol - fed rats but these hormone levels were increased by administration of P01148 or norepinephrine . Such reduction of androgen receptors , serum LH and testosterone , but enhancement of these hormone levels by treatment with neurohormone and neurotransmitter in these animals suggests that ethanol exerts an adverse effect on the hypothalamic - pituitary unit and the neurotransmitter - hypothalamic hormone relationship , resulting in impairment of the androgen - induced sexual events and a suppression of the pituitary gonadotropin secretion .",
"DB00644 induction of extracellular - signal regulated kinase is blocked by inhibition of calmodulin . Our previous studies demonstrate that DB00644 - induced P29323 activation required influx of extracellular Ca2 + in alphaT3 - 1 and rat pituitary cells . In the present studies , we examined the hypothesis that calmodulin ( Cam ) plays a fundamental role in mediating the effects of Ca2 + on P29323 activation . Cam inhibition using W7 was sufficient to block DB00644 - induced reporter gene activity for the c - Fos , murine glycoprotein hormone alpha - subunit , and MAPK phosphatase ( MKP ) - 2 promoters , all shown to require P29323 activation . Inhibition of Cam ( using a dominant negative ) was sufficient to block DB00644 - induced P29323 but not c - Jun N - terminal kinase activity activation . The Cam - dependent protein kinase ( CamK ) II inhibitor KN62 did not recapitulate these findings . DB00644 - induced phosphorylation of Q02750 and c - Raf kinase was blocked by Cam inhibition , whereas activity of phospholipase C was unaffected , suggesting that Ca2 +/ Cam modulation of the P29323 cascade potentially at the level of c - Raf kinase . Enrichment of Cam - interacting proteins using a Cam agarose column revealed that c - Raf kinase forms a complex with Cam . Reconstitution studies reveal that recombinant c - Raf kinase can associate directly with Cam in a Ca2 +- dependent manner and this interaction is reduced in vitro by addition of W7 . Cam was localized in lipid rafts consistent with the formation of a Ca2 +- sensitive signaling platform including the P30968 and c - Raf kinase . These data support the conclusion that Cam may have a critical role as a Ca2 + sensor in specifically linking Ca2 + flux with P29323 activation within the DB00644 signaling pathway .",
"Thirteen type I loci from HSA4q , HSA6p , HSA7q and HSA12q were comparatively Q5TCZ1 - mapped in four river buffalo and sheep chromosomes . Thirteen goat BAC clones containing coding sequences from HSA7 , HSA12q , HSA4 and HSA6p were fluorescence in situ mapped to river buffalo ( Bubalus bubalis , BBU ) and sheep ( Ovis aries , OAR ) R - banded chromosomes . The following type I loci were mapped : P03999 to BBU8q32 and OAR4q32 , P35523 to BBU8q34 and OAR4q34 , P17936 to BBU8q24 and OAR4q27 , KRT to BBU4q21 and OAR 3q21 , P01579 to BBU4q23 and OAR3q23 , IGF1 to BBU4q31 and OAR3q31 , P30968 to BBU7q32 and OAR6q32 , P55157 to BBU7q21 and OAR6q15 , P35913 to BBU7q36 and OAR6q36 , BF to BBU2p22 and OAR20q22 , P05305 to BBU2p24 and OAR20q24 , P08263 to BBU2p22 and OAR20q22 , OLADRB ( MHC ) to BBU2p22 and OAR20q22 . All mapped loci appeared to be located on homologous chromosomes and chromosome bands in both bovids . Comparison between gene orders in bovid ( BBU and OAR ) and human ( HSA ) chromosomes revealed complex rearrangements , especially between BBU7 / OAR6 and HSA4 , as well as between BBU2p / OAR20 and HSA6p .",
"Effects of gonadoliberin analogue triptorelin on the pituitary - testicular complex in neonatal rats . DB06825 , a synthetic analogue of neurohormone gonadoliberin ( gonadotropin - releasing hormone , DB00644 ) administered daily to rats on postnatal days 5 - 7 suppressed the expression of P30968 in the pituitary gland , but did not change functioning of the pituitary - testicular complex . Administration of triptorelin on postnatal days 12 - 14 ( i . e . during the formation of pulsatile pattern of DB00644 secretion and increasing levels of its mRNA receptor in the pituitary gland ) had no effect on receptor expression , but increased the levels of luteinizing hormone mRNA in the pituitary gland and the weight of testes . At that time , blood levels of testosterone were lowered , which indicated disturbed pulsatile pattern of DB00644 secretion .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK30___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"Modulation of diabetes with gonadotropin - releasing hormone antagonists in the nonobese mouse model of autoimmune diabetes . The nonobese mouse model of autoimmune diabetes ( NOD mouse ) exhibits a strain - dependent preponderance of disease in females . Castration of male NOD mice leads to an increased incidence of diabetes , suggesting that testosterone directly modulates the expression of diabetes in the NOD mouse . However , castration also modulates hypothalamic and pituitary hormone production via removal of the negative feedback effects of testosterone . One hypothalamic hormone with immunomodulatory properties whose expression is increased by castration is DB00644 . To test whether the increased incidence of diabetes in castrated male NOD mice is related to an increase in DB00644 activity , we treated castrated male NOD mice with Antide , a P30968 antagonist , to determine the effect on the incidence and timing of onset of diabetes . The prevalence of diabetes at 40 wk of age in male NOD mice was 50 % in sham - operated mice , compared with an 83 % prevalence in castrated males . Antide administration prevented the increased incidence of diabetes in the castrated male mice . Antide reduced total serum IgG levels , P05231 cytokine expression in cultured splenocytes , and the lymphocytic infiltration of islets . DB00644 administration exerted reciprocal effects , leading to earlier timing of onset of diabetes and increases in serum total IgG levels . We conclude that DB00644 modulates the expression of diabetes in the NOD mouse independently of gonadal steroids .",
"Transcript and protein profiling identifies signaling , growth arrest , apoptosis , and NF - κB survival signatures following P01148 receptor activation . P01148 significantly inhibits proliferation of a proportion of cancer cell lines by activating P01148 receptor ( P30968 ) - G protein signaling . Therefore , manipulation of P30968 signaling may have an under - utilized role in treating certain breast and ovarian cancers . However , the precise signaling pathways necessary for the effect and the features of cellular responses remain poorly defined . We used transcriptomic and proteomic profiling approaches to characterize the effects of P30968 activation in sensitive cells ( HEK293 - P30968 , SCL60 ) in vitro and in vivo , compared to unresponsive HEK293 . Analyses of gene expression demonstrated a dynamic response to the P01148 superagonist DB06825 . Early and mid - phase changes ( 0 . 5 - 1 . 0 h ) comprised mainly transcription factors . Later changes ( 8 - 24 h ) included a P01148 target gene , P01215 , and up - or downregulation of transcripts encoding signaling and cell division machinery . Pathway analysis identified altered MAPK and cell cycle pathways , consistent with occurrence of G ( 2 )/ M arrest and apoptosis . Nuclear factor kappa B ( NF - κB ) pathway gene transcripts were differentially expressed between control and DB06825 - treated SCL60 cultures . Reverse - phase protein and phospho - proteomic array analyses profiled responses in cultured cells and SCL60 xenografts in vivo during DB06825 anti - proliferation . Increased phosphorylated NF - κB ( p65 ) occurred in SCL60 in vitro , and p - NF - κB and IκBε were higher in treated xenografts than controls after 4 days DB06825 . NF - κB inhibition enhanced the anti - proliferative effect of DB06825 in SCL60 cultures . This study reveals details of pathways interacting with intense P30968 signaling , identifies potential anti - proliferative target genes , and implicates the NF - κB survival pathway as a node for enhancing P01148 agonist - induced anti - proliferation .",
"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .",
"DB00163 prevents ethanol - induced inflammatory , hormonal , and cytotoxic changes in reproductive tissues . DB00898 causes decreased function of the hypothalamic - pituitary - gonadal ( HPG ) axis . DB00898 resulted in inflammatory changes in HPG manifested by increased concentrations of pro - inflammatory cytokines . Since , such cytokines have deleterious effects on functions of HPG , it seemed possible that ethanol ' s suppressive action could be due , at least in part , to this inflammation . Since oxidative stress can cause inflammation , we have used the antioxidant vitamin E to test , whether reducing inflammation might protect reproductive functions from ethanol . Rats were fed an ethanol diet or pair fed identically without ethanol for a 3 - week period . For the last 10 days , animals were given 30 IU / kg or 90 IU / kg or vehicle . DB00898 significantly increased hypothalamic , pituitary and testicular P01375 and P05231 , all changes prevented by the higher dose of vitamin E . Also , ethanol induced changes in P01148 , LH , testosterone , and testicular germ cell apoptosis were similarly prevented by vitamin E . These data strikingly show that vitamin E protects the HPG from deleterious effects of ethanol and suggests that the mechanism of this protection might be both anti - inflammatory and antioxidant .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK4___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK9___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"Hypothalamic regulation of the adenohypophyseal - testicular axis in the male chick embryo . An antibody against luteinizing hormone - releasing hormone ( P01148 ) as well as naloxone , an opioid antagonist , were added to the chorioallantoic membrane ( P62158 ) of 11 . 5 - and 14 . 5 - day - old male chick embryos and plasma testosterone ( T ) concentrations were determined . This protocol was designed to demonstrate : ( 1 ) Whether P01148 is essential in the regulation of the adenohypophyseal - testicular axis in the male embryo and ( 2 ) if P01148 is operative in this unit ' s function , are opiatergic pathways involved in the secretion of P01148 by the hypothalamus . Both anti - P01148 and naloxone lowered plasma T levels in 14 . 5 - day - old embryos , but not 11 . 5 - day - old embryos . This indicates that the hypothalamus , via P01148 , begins to regulate the pituitary - testicular unit at some time between Days 11 . 5 and 14 . 5 , i . e . , the hypothalamo - adenohypophyseal - testicular axis is established . The results also strongly suggest that the normal secretory pattern of P01148 is dependent upon opiatergic innervation of the hypothalamus at the same embryonic time .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK40___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"DB00644 - II increases membrane type I metalloproteinase production via beta - catenin signaling in ovarian cancer cells . DB00644 - II is produced by ovarian cancer cells and enhances their invasiveness in vitro . In our studies of OVCAR - 3 and CaOV - 3 ovarian cancer cell lines , DB00644 - II treatment induced phosphorylation of Akt and glycogen synthase kinase ( GSK ) 3β , as well as β - catenin accumulation in the nucleus , and the latter was reduced by small interfering RNA ( siRNA ) - mediated depletion of the P30968 . The phosphatidylinositol 3 kinase ( PI3K ) / Akt pathway is involved in β - catenin - dependent signaling , and pretreatment of these human ovarian cancer cells with a PI3K / Akt inhibitor , LY294002 , attenuated DB00644 - II - stimulated phosphorylation of GSK3β and inhibited DB00644 - II - induced invasion . It also attenuated DB00644 - II induced trans - activation of a β - catenin - dependent reporter gene , most likely because GSK3β phosphorylation promotes translocation of β - catenin to the nucleus . Membrane type I matrix metalloproteinase ( P50281 ) contributes to tumor progression directly , or by processing the latent P08253 zymogen , and is a known target of β - catenin signaling . When OVCAR - 3 and CaOV - 3 cells were treated with DB00644 - II , P50281 levels increased approximately 3 - fold , whereas siRNA - mediated depletion of P30968 or pretreatment with LY294002 abrogated this . In addition , lithium chloride , which increases GSK3β phosphorylation and the nuclear translocation of β - catenin , increased P50281 levels in these ovarian cancer cells . By contrast , depletion of β - catenin by siRNA treatment abolished DB00644 - II - induced P50281 synthesis and reduced their invasive potential . Furthermore , siRNA - mediated reduction of P50281 levels reduced DB00644 - II - induced invasion in ovarian cancer cells . We therefore conclude that DB00644 - II stimulates the PI3K / Akt pathway , and the phosphorylation of GSK3β , thereby enhancing the β - catenin - dependent up - regulation of P50281 production , which contributes to ovarian cancer metastasis .",
"Elevated retinol binding protein 4 induces apolipoprotein B production and associates with hypertriglyceridemia . CONTEXT AND OBJECTIVE : A high level of retinol binding protein 4 ( P02753 ) is reported to be associated with insulin resistance in humans . However , evidence from large - scale populations about the relationship between serum P02753 and metabolic phenotypes is scarce . In the present study , we aimed to evaluate serum P02753 distribution and its association with metabolic phenotypes among middle - aged and elderly Chinese . DESIGN AND PARTICIPANTS : Serum concentrations of P02753 in a cross - sectional sample of 2780 Chinese population aged 50 - 70 years old in Guangzhou were measured by ELISA . RESULTS : The mean of serum P02753 concentration was 28 . 04 μg / mL for male and 37 . 76 μg / mL for female ( P < . 01 ) , respectively . Circulating P02753 was positively correlated with serum triglyceride and apolipoprotein B ( apoB ) concentrations . The odds ratio ( OR ) was substantially higher for hypertriglyceridemia ( OR , 3 . 26 ; 95 % confidence interval , 2 . 36 - 4 . 51 ) in the highest P02753 quartile compared with those in the lowest quartile after multiple adjustment for confounders . Furthermore , serum P02753 was significantly associated with fasting glucose , insulin levels , and homeostasis model assessment index - insulin resistance ( HOMA - IR ) . Moreover , we showed that P02753 enhanced microsomal triglyceride transfer protein ( P55157 ) expression and activity via up - regulation of protein disulfide isomerase ( P07237 ) , suppressed low - density lipoprotein receptor ( P01130 ) expression , and impaired insulin - signaling pathway , leading to inductions in apoB secretion both in vitro and in vivo . CONCLUSIONS : Elevated circulating P02753 concentrations were associated with higher risk of hypertriglyceridemia by inducing the secretion of triglyceride - rich apoB - containing lipoproteins .",
"Dependence of gonadotropin - releasing hormone - induced neuronal MAPK signaling on epidermal growth factor receptor transactivation . The hypothalamic decapeptide , gonadotropin - releasing hormone ( DB00644 ) , utilizes multiple signaling pathways to activate extracellularly regulated mitogen - activated protein kinases ( P27361 / 2 ) in normal and immortalized pituitary gonadotrophs and transfected cells expressing the P30968 . In immortalized hypothalamic DB00644 neurons ( GT1 - 7 cells ) , which also express DB00644 receptors , DB00644 , epidermal growth factor ( P01133 ) , and phorbol 12 - myristate 13 - acetate ( PMA ) caused marked phosphorylation of P27361 / 2 . This action of DB00644 and PMA , but not that of P01133 , was primarily dependent on activation of protein kinase C ( PKC ) , and the P27361 / 2 responses to all three agents were abolished by the selective P01133 receptor kinase inhibitor , AG1478 . Consistent with this , both DB00644 and P01133 increased tyrosine phosphorylation of the P01133 receptor . DB00644 and PMA , but not P01133 , caused rapid phosphorylation of the proline - rich tyrosine kinase , Pyk2 , at DB00135 ( 402 ) . This was reduced by Ca ( 2 +) chelation and inhibition of PKC , but not by AG1478 . DB00644 stimulation caused translocation of PKC alpha and - epsilon to the cell membrane and enhanced the association of Src with PKC alpha and PKC epsilon , Pyk2 , and the P01133 receptor . The Src inhibitor , Q99463 , the C - terminal Src kinase ( Csk ) , and dominant - negative Pyk2 attenuated P27361 / 2 activation by DB00644 and PMA but not by P01133 . These findings indicate that Src and Pyk2 act upstream of the P01133 receptor to mediate its transactivation , which is essential for DB00644 - induced P27361 / 2 phosphorylation in hypothalamic DB00644 neurons .",
"Estrogen - astrocyte - luteinizing hormone - releasing hormone signaling : a role for transforming growth factor - beta ( 1 ) . The purpose of this study was to identify factors from astrocytes that can regulate P01148 neurosecretion . Exposure of P01148 - secreting ( GT1 - 7 ) cells to conditioned media ( CM ) from P13671 glial cells and hypothalamic astrocytes ( HA ) stimulated P01148 release . Assays of P13671 and HA CM revealed that transforming growth factor - beta ( 1 ) ( TGF - beta ( 1 ) ) and 3alpha - hydroxy - 5alpha - pregnane - 20 - one ( 3alpha , 5alpha - THP ) , both known P01148 secretagogues , were present in CM and their levels increased in parallel to the P01148 - releasing activity of CM . In contrast , TGF - alpha was undetectable in P13671 or HA CM . Ultrafiltration to remove peptides with molecular weights > 10 kDa virtually abolished the P01148 - releasing ability of the HA CM . Furthermore , immunoneutralization with a panspecific DB00116 - beta antibody dose - dependently attenuated the P01148 - releasing activity of the CM . Rat hypothalamus and GT1 - 7 cells were demonstrated to express TGF - beta receptors as well as furin , an enzyme that converts latent TGF - beta ( 1 ) to active TGF - beta ( 1 ) . P03372 - alpha and Q92731 mRNA and protein were also demonstrated in HAs by reverse transcription - polymerase chain reaction and double immunofluorescence , and treatment with 17beta - estradiol ( 17beta - E ( 2 ) ) increased both active and latent TGF - beta ( 1 ) levels in HA CM . The effect of 17beta - E ( 2 ) was completely blocked by the ER antagonist ICI8280 . As a whole , these studies provide evidence of a previously undescribed 17beta - E ( 2 )- TGF - beta ( 1 )- P01148 signaling pathway .",
"Characterization of the human gonadotropin - releasing hormone receptor heterologously produced using the baculovirus / insect cell and the Semliki Forest virus systems . 1 . Two eukaryotic viral systems , the baculovirus / insect cell and the Semliki Forest virus systems , were tested for heterologous expression of human gonadotropin - releasing hormone receptor ( GnRHR ) cDNA . 2 . An unmodified as well as a c - myc epitope - tagged human P30968 was produced in two insect cell lines ( Spodoptera frugiperda , Trichoplusia ni ) after infection with the respective recombinant baculoviruses . In both insect cell lines , the receptor was identified by immunoblot analysis as a triplet of bands between 35 and 40 kDa . After deglycosylation of the receptor the molecular mass decreased to 35 kDa . The P30968 was localized in membrane compartments within the infected insect cells . However , only in membranes of infected Trichoplusia ni insect cells could approximately 2000 receptors per cell be detected . 3 . Production of the P30968 in BHK cells using the Semliki Forest virus system resulted in approximately 50 , 000 receptors per cell . A maximal yield of 0 . 42 pmol / mg membrane protein was obtained 24 hr after electroporation of BHK cells with in vitro synthesized RNA . Binding of the antagonist [ 125I ] DB00050 was saturable with a KD of 1 . 3 nM . The receptor produced in the BHK cells was further characterized by ligand displacement studies . The rank order of agonist and antagonist affinities was DB00050 > DB06825 > Antide > DB00644 .",
"Modulation of the P22301 / IL - 12 cytokine circuit by interferon - beta inhibits the development of epitope spreading and disease progression in murine autoimmune encephalomyelitis . IFN - beta has been shown to be effective in the treatment of multiple sclerosis ( MS ) . However , the primary mechanism by which IFN - beta mediates its therapeutic effect remains unclear . Recent studies indicate that under defined conditions , IFN - beta may downregulate DC expression of IL - 12 . We and others have shown that IFN - beta may also downregulate P22301 . In light of the recently proposed paradigm that an P22301 / IL - 12 immunoregulatory circuit controls susceptibility to autoimmune disease , we examined the effect of IFN - beta on the development and behavior of the autoreactive T cell repertoire during experimental autoimmune encephalomyelitis ( EAE ) , an animal model sharing many features with MS . SWXJ mice were immunized with the immunodominant p139 - 151 determinant of myelin proteolipid protein ( PLP ) , and at onset of EAE were treated every other day with IFN - beta . After eight weeks of treatment , we assessed autoreactivity and observed no significant IFN - beta effect on splenocyte proliferation or splenocyte production of P01579 , P60568 , P05112 , or P05113 in response to the priming determinant used to initiate disease . However , in IFN - beta treated mice , the cytokine profile in response to the priming immunogen was significantly skewed toward an increased production of P22301 and a concurrent decreased production of IL - 12 . Moreover , the in vivo modulation of the P22301 / IL - 12 immunoregulatory circuit in response to the priming immunogen was accompanied by an aborted development of epitope spreading . Our results indicate that IFN - beta induces a reciprocal modulation of the P22301 / IL - 12 cytokine circuit in vivo . This skewed autoreactivity establishes an inflammatory microenvironment that effectively prevents endogenous self - priming thereby inhibiting the progression of disease associated with epitope spreading .",
"Genetic structure of candidate genes for litter size in Italian Large White pigs . The aim of this work was to verify whether polymorphisms in candidate genes for litter size segregate in Italian Large White ( ITLW ) pigs . We genotyped 120 sows that belonged to six different farms for 10 single nucleotide polymorphisms ( SNPs ) of 10 different genes . Polymorphisms in the chosen genes had already been associated with litter - size traits in other pig populations and were candidates for function and / or chromosomal location . The results indicated that the O14967 , pDAZL , and RFN4 SNPs were not segregating in the genotyped samples . The remaining seven markers were polymorphic with minor allele frequencies ranging from 0 . 10 ( AFP ) to 0 . 48 ( P02753 ) . Because of the observed genetic variabilities in the investigated loci , the polymorphisms in the AFP , O00238 , P02778 , Q92731 , P30968 , Q9Y2E5 , and P02753 genes can be considered suitable markers for association studies with litter - size traits in ITLW pigs .",
"Effect of luteinizing hormone - releasing hormone ( P01148 ) analogue treatment on a cytokine profile in prostate cancer patients . The aim of the study was to test serum concentrations of the chosen cytokines in patients with prostate cancer ( PCa ) treated with an luteinizing hormone - releasing hormone ( P01148 ) analogue . We tested interleukin ( IL ) - 2 , P22301 , tumor necrosis factor ( P01375 ) - alpha , interferon ( P27352 ) - gamma in blood at three time points ; I - before the injection , II - 10 days and III - 20 days after the injection in 14 men with PCa . Patients had one depot injection of the P01148 analogue monthly . The cytokine concentrations in serum samples were determined by ELISA method . Prostate specific antigen ( PSA ) level was examined before and after six months of the P01148 analogue treatment . After six months of the therapy , we observed normalization of serum PSA value from 16 . 48 ng / ml to 1 . 45 ng / ml . P01148 analogue injection resulted in a significant drop of the P60568 concentration , and the value gradually returned to normal in the next 20 days . P22301 concentration transiently increased and then was down - regulated . Serum P01375 and P27352 - gamma concentrations in PCa patients were significantly lower compared to controls and were not affected by the treatment . P01148 analogue treatment in PCa patients modulates concentrations of the chosen cytokines which may result both in antitumor and a transient immunosuppressive effect .",
"Impact of aromatic residues within transmembrane helix 6 of the human gonadotropin - releasing hormone receptor upon agonist and antagonist binding . To investigate the impact of aromatic residues within transmembrane helix 6 ( TMH6 ) of the human gonadotropin - releasing hormone receptor ( P30968 ) on agonist and antagonist binding , residues Y ( 283 ) , Y ( 284 ) , W ( 289 ) , Y ( 290 ) , W ( 291 ) , and F ( 292 ) were exchanged to alanine and analyzed comprehensively in functional reporter gene and ligand binding assays . Whereas receptor mutants Y ( 283 ) A , Y ( 284 ) A , and W ( 291 ) A were capable of neither ligand binding nor signal transduction , mutants W ( 289 ) A , Y ( 290 ) A , and F ( 292 ) A were functional : the F ( 292 ) A mutant behaved like wild - type receptor , while mutants W ( 289 ) A and Y ( 290 ) A differentiated between agonistic and antagonistic ligands . On the basis of the high - resolution X - ray structure of bovine rhodopsin as well as available data on P30968 mutants , models for ligand - receptor interactions are proposed . The model for D - DB00150 ( 6 )- DB00644 ( DB06825 ) binding , representing a superagonistic ligand , is in full accordance to available data . Furthermore , new interactions are proposed : pGlu ( 1 ) interacts with N ( 212 ) in transmembrane helix 5 , DB00135 ( 5 ) with Y ( 290 ) , and D - DB00150 ( 6 ) with W ( 289 ) . The binding behavior of mutants W ( 289 ) A and Y ( 290 ) A corresponds to the proposed binding model for the antagonist DB00050 . In summary , our data as presented indicate that Y ( 290 ) plays a key function in agonist but not antagonist binding .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK33___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"Association of germline p53 mutation with Q03164 segmental jumping translocation in treatment - related leukemia . Segmental jumping translocations are chromosomal abnormalities in treatment - related leukemias characterized by multiple copies of the P00519 and / or Q03164 oncogenes dispersed throughout the genome and extrachromosomally . Because gene amplification potential accompanies loss of wild - type p53 , we examined the p53 gene in a case of treatment - related acute myeloid leukemia ( t - AML ) with Q03164 segmental jumping translocation . The child was diagnosed with ganglioneuroma and embryonal rhabdomyosarcoma ( ERMS ) at 2 years of age . Therapy for ERMS included alkylating agents , P11387 and DNA topoisomerase II inhibitors , and local radiation . t - AML was diagnosed at 4 years of age . The complex karyotype of the t - AML showed structural and numerical abnormalities . Fluorescence in situ hybridization analysis showed multiple copies of the Q03164 gene , consistent with segmental jumping translocation . A genomic region including CD3 , Q03164 , and a segment of band 11q24 was unrearranged and amplified by Southern blot analysis . There was no family history of a cancer predisposing syndrome , but single - strand conformation polymorphism ( SSCP ) analysis detected identical band shifts in the leukemia , ganglioneuroma , ERMS , and normal tissues , consistent with a germline p53 mutation , and there was loss of heterozygosity in the ERMS and the t - AML . Sequencing showed a P01215 --> TGA nonsense mutation at codon 306 in exon 8 . The results of this analysis indicate that loss of wild - type p53 may be associated with genomic instability after DNA - damaging chemotherapy and radiation , manifest as a complex karyotype and gene amplification in some cases of t - AML .",
"Amelioration of scopolamine induced cognitive dysfunction and oxidative stress by Inonotus obliquus - a medicinal mushroom . The present study was aimed to investigate the cognitive enhancing and anti - oxidant activities of Inonotus obliquus ( Chaga ) against scopolamine - induced experimental amnesia . Methanolic extract of Chaga ( Q9NRJ3 ) at 50 and 100 mg kg (- 1 ) doses were administered orally for 7 days to amnesic mice . Learning and memory was assessed by passive avoidance task ( PAT ) and Morris water maze ( MWM ) test . Tacrine ( ___MASK63___ , 10 mg kg ( - 1 ) , orally ( p . o ) ) used as a reference drug . To elucidate the mechanism of the cognitive enhancing activity of Q9NRJ3 , the activities of acetylcholinesterase ( P22303 ) , anti - oxidant enzymes , the levels of acetylcholine ( ACh ) and nitrite of mice brain homogenates were evaluated . Q9NRJ3 treatment for 7 days significantly improved the learning and memory as measured by PAT and MWM paradigms . Further , Q9NRJ3 significantly reduced the oxidative - nitritive stress , as evidenced by a decrease in malondialdehyde and nitrite levels and restored the glutathione and superoxide dismutase levels in a dose dependent manner . In addition , Q9NRJ3 treatment significantly decreased the P22303 activity in both the salt and detergent - soluble fraction of brain homogenates . Further , treatment with Q9NRJ3 restored the levels of ACh as did ___MASK63___ . Thus , the significant cognitive enhancement observed in mice after Q9NRJ3 administration is closely related to higher brain anti - oxidant properties and inhibition of P22303 activity . These findings stress the critical impact of Chaga , a medicinal mushroom , on the higher brain functions like learning and memory .",
"Genetic polymorphisms of the P01148 and P30968 genes and risk of breast cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium ( BPC3 ) . BACKGROUND : Gonadotropin releasing hormone ( P01148 ) triggers the release of follicle stimulating hormone and luteinizing hormone from the pituitary . Genetic variants in the gene encoding P01148 or its receptor may influence breast cancer risk by modulating production of ovarian steroid hormones . We studied the association between breast cancer risk and polymorphisms in genes that code for P01148 and its receptor ( P30968 ) in the large National Cancer Institute Breast and Prostate Cancer Cohort Consortium ( NCI - BPC3 ) . METHODS : We sequenced exons of P01148 and P30968 in 95 invasive breast cancer cases . Resulting single nucleotide polymorphisms ( SNPs ) were genotyped and used to identify haplotype - tagging SNPs ( htSNPS ) in a panel of 349 healthy women . The htSNPs were genotyped in 5 , 603 invasive breast cancer cases and 7 , 480 controls from the Cancer Prevention Study - II ( CPS - II ) , European Prospective Investigation on Cancer and Nutrition ( EPIC ) , Multiethnic Cohort ( Q9NRJ3 ) , Nurses ' Health Study ( Q6T4R5 ) , and Women ' s Health Study ( WHS ) . Circulating levels of sex steroids ( androstenedione , estradiol , estrone and testosterone ) were also measured in 4713 study subjects . RESULTS : Breast cancer risk was not associated with any polymorphism or haplotype in the P01148 and P30968 genes , nor were there any statistically significant interactions with known breast cancer risk factors . Polymorphisms in these two genes were not strongly associated with circulating hormone levels . CONCLUSION : Common variants of the P01148 and P30968 genes are not associated with risk of invasive breast cancer in Caucasians .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK21___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK63___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK63___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK63___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK63___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK63___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( ___MASK91___ ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .",
"___MASK49___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK49___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK49___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK49___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK49___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK49___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .",
"Targeting hormonal signaling pathways in castration resistant prostate cancer . It is now well established that hormonal pathways are involved in the development of prostate cancer towards the castration resistant ( CRPC ) stage and can be effective molecular targets for novel treatment strategies . Most CRPC are sensitive to androgens and this can be due to the intratumoral production of androgens , androgen receptor ( AR ) amplification / mutations and epigenetic modifications of AR expression / signaling . Based on these observations , potent agents targeting the AR axis were developed : 1 ) inhibitors of P05093 ( a key enzyme in the production of androgens ) , such as abiraterone and orteronel ; 2 ) AR antagonists that bind to AR and impair AR activation , such as enzalutamide and ARN - 509 . Moreover , gonadotropin - releasing hormone receptors ( P30968 ) , associated with a strong antitumor activity , are expressed in CRPC cells , indicating that they might represent an important target for DB00644 analog - based therapeutic strategies . In addition to DB00644 agonists and antagonists ( i . e . , degarelix ) , cytotoxic DB00644 - based bioconjugates , delivering chemotherapeutic drugs to cancer cells expressing the P30968 , were developed and reported to exert antitumor effects on CRPC cells ; some of them ( i . e . , AN - 152 ) have already entered clinical trials . This review discusses the most relevant patents and recent observations on the anti - cancer efficacy of novel drugs targeting the AR and the P30968 pathways in CRPC .",
"Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 ."
] |
[
"___MASK21___",
"___MASK30___",
"___MASK33___",
"___MASK40___",
"___MASK49___",
"___MASK4___",
"___MASK63___",
"___MASK91___",
"___MASK9___"
] |
___MASK33___
|
MH_train_446
|
interacts_with DB06273?
|
[
"Influence of cystic fibrosis transmembrane conductance regulator on gene expression in response to Pseudomonas aeruginosa infection of human bronchial epithelial cells . Chronic lung infection by Pseudomonas aeruginosa causes significant morbidity in cystic fibrosis patients initiated by the failure of innate immune responses . We used microarray analysis and real - time PCR to detect transcriptional changes associated with cytokine production in isogenic bronchial epithelial cell lines with either wild - type ( WT ) or mutant cystic fibrosis transmembrane conductance regulator ( P13569 ) in response to P . aeruginosa infection . The transcription of four NF - kappaB - regulated cytokine genes was maximal in the presence of WT P13569 : the interleukin - 8 ( P10145 ) , P05231 , P09341 , and intracellular adhesion molecule 1 ( P05362 ) genes . Analysis of protein expression in two cell lines paired for wild - type and mutant P13569 with three P . aeruginosa strains showed P05231 and P10145 expressions were consistently enhanced by the presence of WT P13569 in both cell lines with all three strains of P . aeruginosa , although some strains gave small P10145 increases in cells with mutant P13569 . P09341 production showed consistent enhancement in cells with WT P13569 using all three bacterial strains in one cell line , whereas in the other cell line , P09341 showed a significant increase in cells with either WT or mutant P13569 . P05362 was unchanged at the protein level in one of the cell lines but did show mild enhancement with WT P13569 in the other cell pair . Inhibitions of NF - kappaB prior to infection indicated differing degrees of dependence on NF - kappaB for production of the cytokines , contingent on the cell line . Cytokine effectors of innate immunity to P . aeruginosa were found to be positively influenced by the presence of WT P13569 , indicating a role in resistance to P . aeruginosa infection .",
"[ ___MASK80___ sodium ( Photofrin - II ) ] . ___MASK80___ sodium ( ___MASK80___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK80___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"Modulation of Q8IVT5 activity in Caenorhabditis elegans by Zn ions , P25116 kinase and PP2A phosphatase . Vulval differentiation in Caenorhabditis elegans is controlled by a conserved signal transduction pathway mediated by Ras and a kinase cascade that includes Raf , Mek and MAPK . Activation of this cascade is positively regulated by a number of proteins such as Q8IVT5 ( kinase suppressor of Ras ) , Q09428 - 8 / Q5T124 - 2 , Q09428 - 6 / PP2A - B and P05231 - 1 . We describe the functional characterization of sur - 7 and several genes that regulate signaling downstream of ras . We identified sur - 7 by isolating a mutation that suppresses an activated ras allele , and showed that Q09428 - 7 is a divergent member of the cation diffusion facilitator family of heavy metal ion transporters that is probably localized to the endoplosmic recticulum membrane and regulates cellular Zn ( 2 +) concentrations . Genetic double mutant analyses suggest that the Q09428 - 7 - mediated effect is not a general toxic response . Instead , Zn ( 2 +) ions target a specific step of the pathway , probably regulation of the scaffolding protein Q8IVT5 . Biochemical analysis in mammalian cells indicates that high Zn ( 2 +) concentration causes a dramatic increase of Q8IVT5 phosphorylation . Genetic analysis also indicates that PP2A phosphatase and P25116 kinase act downstream of Raf to positively and negatively regulate Q8IVT5 activity , respectively .",
"___MASK5___ triggers cytokine release by macrophages : rationale for stents eluting everolimus and a glucocorticoid . OBJECTIVE : Stent - based delivery of the mammalian target of rapamycin ( P42345 ) inhibitor everolimus is a promising strategy for the treatment of coronary artery disease . We studied potential adverse effects associated with P42345 inhibition . METHODS AND RESULTS : Macrophages in culture were either treated with everolimus or starved to inhibit P42345 . ___MASK5___ led to inhibition of protein translation , activation of p38 MAPK , and the release of proinflammatory cytokines ( eg , P05231 , TNFα ) and chemokines ( eg , MCP1 , Rantes ) before induction of autophagic death . These effects were also observed with rapamycin , but not after starvation . ___MASK5___ - induced cytokine release was similar in macrophages lacking the essential autophagy gene Atg7 but was inhibited when macrophages were cotreated with p38 MAPK inhibitor SB202190 or the glucocorticoid clobetasol . Combined stent - based delivery of clobetasol and everolimus in rabbit plaques downregulated TNFα expression as compared with everolimus - treated plaques but did not affect the ability of everolimus to induce macrophage clearance . CONCLUSIONS : P42345 inhibition by everolimus triggers cytokine release in macrophages through inhibition of protein translation and p38 activation . These findings provide a rationale for combined local treatment of atherosclerotic plaques with everolimus and an anti - inflammatory agent .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK79___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"P25116 - mediated synovial proliferation in patients with rheumatoid arthritis . Synovial cell proliferation is one of the pathological bases of rheumatoid arthritis ( RA ) . Several cytokines including IL - 1 and P05231 and growth factors have been shown to be involved in the synovial cell proliferation in RA . Thrombin is a multifunctional protease and acts as a mitogen for several cell types through its specific receptor . To assess whether thrombin is involved in overproliferation of rheumatoid synovial cells , we measured the concentration of thrombin - anti - thrombin III ( P01008 ) complex ( TAT ) in synovial fluid obtained from patients with RA or osteoarthritis ( OA ) . We also examined the effect of thrombin or thrombin receptor agonist peptide ( TRAP ) on cell growth of synovial cell clones ( SCCs ) established from an RA patient . The concentrations of TAT in the synovial fluid from patients with RA were significantly higher than in those with OA . Moreover , both thrombin and TRAP enhanced proliferation of synovial cells in vitro . We also characterized the expression of thrombin receptor mRNA by reverse transcription - PCR . The expression of mRNA for thrombin receptor was up - regulated by thrombin or TRAP stimulation . P25116 antigen was also detected on both SCCs and synovial tissue from RA patients by immunostaining using a monoclonal antibody against thrombin receptor . These findings indicate that thrombin may act as a mitogen for synovial cells through thrombin receptor and may play some role in synovial overproliferation and remodeling in RA .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK94___ and Tissue P00747 Activator in Occluded Arteries .",
"___MASK61___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .",
"DB06273 in pediatric rheumatology : the clinical experience . During the last two decades , clinical use of novel biological therapy has led to increased mechanistic understanding of complex rheumatological diseases . Conversely , basic and translational studies have led to development of new and varied therapeutic agents . These new medications which \" target \" specific steps in one or more immune pathways have the potential to control disease symptoms , improve quality of life and long - term prognosis , and perhaps in some , restore immunological tolerance . Use of these agents in clinical trials , combined with post - marketing surveillance , has revealed both the benefits and the undesirable side - effects of biological disease - modifying anti - rheumatic drugs ( DMARDs ) . In this review we focus on the use of tocilizumab , a monoclonal antibody directed against the P05231 receptor ( P08887 ) , which potently inhibits P05231 / P08887 signaling .",
"Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .",
"Dopamine agonists upregulate P05231 and P10145 production in human keratinocytes . AIM : Catecholamines regulate functions of the nervous , neuroendocrine and immune systems . Dopamine may modulate the activity of keratinocytes , which play a role in secreting cytokines and chemokines . The aim of this study was to evaluate the effect of dopaminergic agonists on the production of P05231 and P10145 by a non - tumoral human keratinocyte cell line ( HaCaT ) . METHODS : Cells were stimulated with dopamine and the P14416 agonist cabergoline . Levels of P05231 and P10145 in culture supernatants were then determined . Cell proliferation was also assessed . Assays were carried out in the presence or absence of the dopaminergic and β - adrenergic receptor antagonists ( sulpiride and propranolol , respectively ) and ascorbic acid . RESULTS : Dopamine stimulated the production of P05231 and P10145 in a concentration - dependent manner . The effects observed on the secretion of P05231 were more potent than those corresponding to P10145 and were reduced by ascorbic acid . The dopamine - induced P05231 secretion was partially reduced by sulpiride and abrogated by propranolol . The latter drug was able to block the effect of dopamine on the secretion of P10145 . The cabergoline - induced P05231 release was reduced by sulpiride . Cell viability was not affected by any of the drugs . CONCLUSIONS : Dopaminergic agonists can stimulate keratinocytes to produce P05231 and P10145 which are related to inflammatory cutaneous processes . These effects are mediated by dopaminergic and β - adrenergic receptors and by receptor - independent oxidative mechanisms .",
"Glioma cell activation by Alzheimer ' s peptide Abeta1 - 42 , alpha1 - antichymotrypsin , and their mixture . We compared the effects ofAlzheimer ' s peptide ( Abeta1 - 42 ) , a ,- antichymotrypsin ( ACT ) and an ACT / Abeta1 - 42 mixture on human glioma DK - MG cells . The solution of Abeta ( 5 microM ) formed by 2 - h incubation at room temperature induced tumour necrosis factor - alpha ( P01375 ) and interleukin ( IL ) - 6 levels by 55 and 45 % , respectively , and increased gelatinase B activity by 67 % , while exposure of cells to the ACT / Abeta1 - 42 mixture ( 1 : 10 molar ratio ACT : Abeta1 - 42 ) under the same experimental conditions showed no effect on P05231 levels or gelatinase B activity , but strongly induced P01375 ( by 190 % ) , compared to the controls . Stimulation of the cells with Abeta1 - 42 alone , but not with ACT , increased by about 20 % low - density lipoprotein ( LDL ) uptake and mRNA levels for P01130 and P04035 , while the ACT / Abeta1 - 42 mixture significantly increased LDL uptake ( by 50 % ) , up - regulated mRNA levels for P01130 and P04035 by 48 and 63 % , respectively , and increased lipid accumulation by about 20 - fold . These data suggest a possible new role for Abeta in Alzheimer ' s disease through its interaction with the inflammatory reactant , ACT .",
"Anti - interleukin 6 receptor antibody treatment in rheumatic disease . Interleukin 6 ( P05231 ) is a pleiotropic cytokine with a wide range of biological activities . P05231 transgene into mice gives rise to the abnormalities such as hypergammaglobulinaemia , thrombocytosis , infiltration of inflammatory cells into the tissues , mesangial cell proliferation of the kidney as well as splenomegaly and lymphadenopathy , which are predictable by the biological functions of P05231 shown in vitro . Continuous overproduction of P05231 is observed in patients with some immune - inflammatory diseases such as Castleman ' s disease and rheumatoid arthritis that are frequently associated with similar abnormalities to those of P05231 transgenic mice , strongly suggesting the involvement of P05231 in the human diseases . Successful treatment of the model animals for immune - inflammatory diseases with anti - P05231 receptor ( P08887 ) antibody thus indicates the possible application of P05231 blocking agents to treat the P05231 related immune - inflammatory diseases of humans . In this review , the new therapeutic strategy for Castleman ' s disease and RA using humanized antibody to human P05231 receptor , DB06273 , is discussed .",
"Anti - P05231 - receptor - alpha ( tocilizumab ) does not inhibit human monocyte - derived dendritic cell maturation or alloreactive T - cell responses . Significant comorbidites and lethality complicate GVHD and its treatment . Targeting the cytokine milieu may improve GVHD control ; and P05231 is an attractive candidate , given its role in dendritic cell activation and T - cell differentiation . DB06273 is a humanized mAb to P05231 - receptor - α ( P08887 - α ) , which is Food and Drug Administration - approved for treatment of rheumatoid arthritis . Mouse transplant models have demonstrated that P05231 blockade also improves GVHD scores and survival . Definitive immunologic effects of P05231 inhibition have not emerged given inconsistent alterations in regulatory T cells ( Tregs ) and suppression of T - cell proliferation . Despite on - target suppression of P08887 - α signaling in human monocyte - derived dendritic cells ( moDCs ) and T cells , our data show no effect on moDC maturation / activation , alloreactive T - cell proliferation , Treg expansion , or allogeneic Th1 / Th17 responses in vitro . These findings merit attention in any clinical trials of tocilizumab for GVHD prevention or treatment and provide a rationale for evaluating more specific inhibitors of downstream O60674 / P40763 signaling as well .",
"P05231 - receptor polymorphisms rs12083537 , rs2228145 , and rs4329505 as predictors of response to tocilizumab in rheumatoid arthritis . DB06273 ( TCZ ) , a monoclonal antibody targeting the human interleukin - 6 - receptor ( IL - 6R ) , is indicated for the treatment of rheumatoid arthritis ( RA ) . We examined whether three P08887 single - nucleotide polymorphisms rs12083537 , rs2228145 ( formerly rs8192284 ) , and rs4329505 with previously reported functional effects were associated with clinical response to TCZ in a retrospective study cohort consisting of 79 RA patients . Three months after initiation of TCZ therapy , changes in swollen joint count ( SJC ) and , subordinately , tender joint count ( TJC ) , serum - CRP , DAS28 - CRP , and EULAR - response were tested for association with the P08887 - haplotype or genotype . The major allele ( A ) of rs12083537 and the minor allele ( C ) of rs4329505 were associated with a poor SJC response ( P = 0 . 02 and 0 . 02 , respectively ) . Moreover , the AAC - haplotype ( for rs12083537 , rs2228145 , and rs4329505 , respectively ) was associated with a poor SJC response ( P = 0 . 00004 ) and , with borderline significance , EULAR - response ( P = 0 . 05 ) . These data suggest that genetic variation in P08887 may aid in predicting TCZ therapy outcome in RA patients .",
"Effect of endothelin receptor antagonist ___MASK12___ on chronic hypoxia - induced inflammation and chemoafferent neuron adaptation in rat carotid body . Chronic hypoxia ( CH ) induces an inflammatory response in rat carotid body that is characterized by immune cell invasion and the expression of pro - inflammatory cytokines . In the present study , we have investigated the role of type - A endothelin ( P25101 ) receptors in the development of CH - induced inflammation . After 7 days of CH ( 380 Torr ) , double - label immunofluorescence studies demonstrated elevated levels of P25101 receptor and tyrosine hydroxylase ( TH ) in O ( 2 )- sensitive type I cells . Following CH , P25101 receptors were also expressed on resident and invasive P08575 + immune cells distributed in tissue surrounding chemosensory cell lobules . Immnofluorescence and quantitative PCR studies showed that concurrent treatment with the P25101 / B receptor antagonist , ___MASK12___ ( 200 mg / kg / day ) , blocked CH - induced ED - 1 + macrophage invasion and the upregulation of cytokines , including interleukin - 1β ( IL - 1β ) , interleukin - 6 ( P05231 ) , tumor necrosis factor α ( TNFα ) , and monocyte chemoattractant protein - 1 ( P13500 ) . Moreover , ___MASK12___ treatment blocked the CH - induced increases in expression of acid - sensitive ion channels ( ASICs ) in chemoafferent neurons in the petrosal ganglion ( PG ) . Our findings are consistent with the hypothesis that CH - induced inflammation involves the upregulation and release of ET - 1 from type I cells . ET - 1 may act in an autocrine / paracrine mechanism via P25101 receptors on chemosensory type I cells and immune cells to promote an inflammatory response .",
"[ ___MASK60___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK60___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"Drosophila Answers to Q13148 Proteinopathies . Initially implicated in the pathogenesis of P13569 and HIV - 1 transcription , nuclear factor Q13148 was subsequently found to be involved in the origin and development of several neurodegenerative diseases . In 2006 , in fact , it was reported for the first time the cytoplasmic accumulation of Q13148 in ubiquitin - positive inclusions of P35858 and FTLD patients , suggesting the presence of a shared underlying mechanism for these diseases . Today , different animal models of Q13148 proteinopathies are available in rodents , nematodes , fishes , and flies . Although these models recapitulate several of the pathological features found in patients , the mechanisms underpinning the progressive neuronal loss observed in Q13148 proteinopathies remain to be characterized . Compared to other models , Drosophila are appealing because they combine the presence of a sophisticated brain with the possibility to investigate quickly and massively phenotypic genetic modifiers as well as possible therapeutic strategies . At present , the development of Q13148 - related Drosophila models has further strengthened the hypothesis that both Q13148 \" loss - of - function \" and \" gain - of - function \" mechanisms can contribute to disease . The aim of this paper is to describe and compare the results obtained in a series of transgenic and knockout flies , along with the information they have generated , towards a better understanding of the mechanisms underlying Q13148 proteinopathies .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK14___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"DB06273 infusion therapy normalizes inflammation in sporadic P35858 patients . Patients with sporadic amyotrophic lateral sclerosis ( sALS ) show inflammation in the spinal cord and peripheral blood . The inflammation is driven by stimulation of macrophages by aggregated superoxide dismutase 1 ( P00441 ) through caspase1 , interleukin 1 ( IL1 ) , P05231 and chemokine signaling . Inflammatory gene activation is inhibited in vitro by tocilizumab , a humanized antibody to P05231 receptor ( P08887 ) . DB06273 inhibits global interleukin - 6 ( P05231 ) signaling , a key mechanism in chronic rheumatoid disorders . Here we studied in vivo baseline inflammatory gene transcription in peripheral blood mononuclear cells ( PBMCs ) of 10 sALS patients , and the effects of tocilizumab ( Actemra ( R ) ) infusions . At baseline , one half of P35858 subjects had strong inflammatory activation ( Group 1 ) ( 8 genes up regulated > 4 - fold , P < 0 . 05 vs . controls ) and the other half ( Group 2 ) had weak activation . All patients showed greater than four - fold up regulation of P03956 , P80098 , Q99616 and O00175 . DB06273 infusions in the Group 1 patients resulted in down regulation of inflammatory genes ( in particular IL1β ) , whereas in the Group 2 patients in up regulation of inflammatory genes . Post - infusion serum and P04141 concentrations of tocilizumab inhibited caspase1 activation in vitro . Three of 5 patients receiving tocilizumab infusions showed time - limited attenuation of clinical progression . In conclusion , inflammation of sALS patients at baseline is up - or down - regulated in comparison to controls , but is partially normalized by tocilizumab infusions .",
"Prevention of atherosclerosis by the P42345 inhibitor everolimus in P01130 -/- mice despite severe hypercholesterolemia . ___MASK5___ inhibits the mammalian target of rapamycin ( P42345 ) in proliferating cells . It is widely used in transplant patients and has also been exploited by drug - eluting stents for the treatment of cardiovascular disease . However , there is only limited data on the pathophysiological effects of P42345 - inhibitors on the vascular wall . We aimed to unravel the effects of everolimus on cholesterol - induced atherosclerosis and on circulating cell mediators in LDL - receptor - deficient ( P01130 (-/-) ) mice . Male hypercholesterolemic P01130 (-/-) mice received either solvent ( group A ; n = 28 ) or everolimus at 0 . 05 mg / kg ( group B , n = 22 ) and 1 . 5 mg / kg ( group C , n = 29 ) per body weight per day by subcutaneously implanted osmotic minipumps for the study period of 12 weeks . Group B showed 44 % reduction of atherosclerotic lesions at the brachiocephalic artery ( BCA ) . In group C atherosclerotic lesions were reduced by 85 % in the BCA and by 60 % at the aortic root . This was associated with a significantly lower complexity of lesions in both treated groups ( p < 0 . 001 ) and despite a 40 % increase of plasma cholesterol . ___MASK5___ caused a significant reduction of circulating cell mediators such as interleukin - 1alpha , interleukin - 5 , GM - P04141 and interleukin - 12p40 . ___MASK5___ increased the plasma levels of KC but had no effect on eighteen other circulating cell mediators studied . ___MASK5___ strongly inhibits atherosclerosis development in LDL - receptor (-/-) mice despite severe hypercholesterolemia . ___MASK5___ application had only small effects on circulating cell mediators . The significant reduction of atherosclerotic lesions was associated with a delayed transition from early macrophages enriched lesions to advanced atherosclerotic plaques .",
"P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .",
"___MASK5___ - induced human keratinocytes toxicity is mediated by P40763 inhibition . BACKGROUND : P42345 ( P42345 ) inhibitors are associated with dermatological adverse events . The chief aim of this study was to examine the relation between the signal transducer and activator of transcription 3 ( P40763 ) protein and the dermatological adverse events associated with the P42345 inhibitor everolimus . METHODS : We evaluated the effects of P40763 activity and related signal transduction activities on everolimus - induced cell growth inhibition in the human keratinocyte HaCaT cell line via a WST - 8 assay , and on signal transduction mechanisms involved in everolimus treatments via a western blot analysis . Apoptosis was evaluated using an imaging cytometric assay . RESULTS : The cell growth inhibitory effects of everolimus were enhanced by stattic or P50402 - 21 , which are selective inhibitors of P40763 , treatment in HaCaT cells , although such effects were not observed in Caki - 1 and HepG2 cells . Phosphorylation at tyrosine 705 of P40763 was decreased by treatment with everolimus in a dose - dependent manner in HaCaT cells ; in contrast , phosphorylation at serine 727 was not decreased by everolimus , but slightly increased . Furthermore , we found that pretreatment of p38 MAPK inhibitor and transfection with constitutively active form of P40763 in HaCaT cells resisted the cytostatic activity of everolimus . CONCLUSIONS : These findings suggest that P40763 activity may be a biomarker of everolimus - induced dermatological toxicity .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK77___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"The endocannabinoid 2 - AG protects the blood - brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines . Endocannabinoids are involved in neuroprotection through numerous biochemical pathways . We have shown that the endocannabinoid 2 - arachidonoyl glycerol ( 2 - AG ) is released in mouse brain after closed head injury ( CHI ) , and treatment with exogenous 2 - AG exerts neuroprotection via the central cannabinoid receptor P21554 . This process involves inhibition of inflammatory signals that are mediated by activation of the transcription factor NF - kB . The present study was designed to examine the effect of 2 - AG on the blood - brain barrier ( BBB ) and the possible inhibition of the early expression of proinflammatory cytokines , which are implicated in BBB disruption . We found that 2 - AG decreased BBB permeability and inhibited the acute expression of the main proinflammatory cytokines : P01375 , IL - 1beta and P05231 . It also augmented the levels of endogenous antioxidants . We suggest that 2 - AG exerts neuroprotection in part by inhibition of the early ( 1 - 4 h ) inflammatory response and augmentation of the brain reducing power .",
"Differential regulation of cystic fibrosis transmembrane conductance regulator by interferon gamma in mast cells and epithelial cells . P13569 ( P13569 ) is a P13569 in epithelial cells ; recently , we identified it in mast cells . Previous work that we confirmed showed that interferon gamma ( IFNgamma ) down - regulated P13569 expression in epithelial cells ( T84 ) , but by contrast , we found that IFNgamma up - regulated P13569 mRNA and protein expression in rat and human mast cells . IFNgamma up - regulation of P13569 in mast cells was inhibited by p38 and extracellular signal - regulated kinase ( P29323 ) kinase inhibitors but not a Janus tyrosine kinase ( JAK ) 2 inhibitor , whereas in T84 cells IFNgamma - mediated down - regulation of P13569 was O60674 - dependent and P29323 - and p38 - independent . Furthermore , IFNgamma down - regulation of P13569 in T84 epithelial cells was P42224 - dependent , but up - regulation of P13569 in mast cells was P42224 - independent . Thus , differential regulatory pathways of P13569 expression in mast cells and epithelial cells exist that depend upon either p38 / P29323 or JAK / P35610 pathways , respectively . Surprisingly , IFNgamma treatment of mast cells inhibited Cl (-) efflux , in contrast to up - regulation of P13569 / mRNA and protein expression . However , down - regulation of Cl (-) flux correlated with IFNgamma - mediated inhibition of mediator secretion . This and other work suggests that the effect of IFNgamma on P13569 expression in mast cells is important for their function ."
] |
[
"___MASK12___",
"___MASK14___",
"___MASK5___",
"___MASK60___",
"___MASK61___",
"___MASK77___",
"___MASK79___",
"___MASK80___",
"___MASK94___"
] |
___MASK5___
|
MH_train_447
|
interacts_with DB01101?
|
[
"___MASK77___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK77___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK77___ is a promising pharmacological tool in the treatment of renal edema .",
"Fucoxanthin enhances cisplatin - induced cytotoxicity via NFκB - mediated pathway and downregulates DNA repair gene expression in human hepatoma HepG2 cells . Cisplain , a platinum - containing anticancer drug , has been shown to enhance DNA repair and to inhibit cell apoptosis , leading to drug resistance . Thus , the combination of anticancer drugs with nutritional factors is a potential strategy for improving the efficacy of cisplatin chemotherapy . In this study , we investigated the anti - proliferative effects of a combination of fucoxanthin , the major non - provitamin A carotenoid found in Undaria Pinnatifida , and cisplatin in human hepatoma HepG2 cells . We found that fucoxanthin ( 1 - 10 μΜ ) pretreatment for 24 h followed by cisplatin ( 10 μΜ ) for 24 h significantly decreased cell proliferation , as compared with cisplatin treatment alone . Mechanistically , we showed that fucoxanthin attenuated cisplatin - induced NFκB expression and enhanced the NFκB - regulated Bax / Bcl - 2 mRNA ratio . DB00515 alone induced mRNA expression of excision repair cross complementation 1 ( P07992 ) and thymidine phosphorylase ( TP ) through phosphorylation of P29323 , p38 and PI3K / AKT pathways . However , fucoxanthin pretreatment significantly attenuated cisplatin - induced P07992 and TP mRNA expression , leading to improvement of chemotherapeutic efficacy of cisplatin . The results suggest that a combined treatment with fucoxanthin and cisplatin could lead to a potentially important new therapeutic strategy against human hepatoma cells .",
"Pharmacogenomic strategies for developing customized chemotherapy in non - small cell lung cancer . In this review , we deal with six groups of cytotoxic drugs commonly used in the treatment of non - small cell lung cancer ( NSCLC ) . Although there are many reviews of thymidylate synthase ( TS ) and antifolate inhibitors , in this article , we have tried to highlight aspects that are more important for medical oncologists to consider when treating NSCLC patients . There is compelling evidence that TS gene transcripts and TS polymorphisms could be used to decide which patients can best benefit from adjuvant chemotherapy approaches , especially in colorectal cancer , and not less importantly , to tailor chemotherapy in metastatic NSCLC when using drugs akin to fluorouracil , such as pemetrexed . Secondly , cisplatin is central to chemotherapy combinations and evidence indicates that DNA repair capacity influences response to cisplatin - based regimens . P07992 gene transcript stands out as a predictive marker of cisplatin sensitivity . Thirdly , preliminary studies indicate that upregulation of beta - tubulin III correlates with response to paclitaxel and vinorelbine . Fourthly , overexpression of ribonucleotide reductase can influence response to gemcitabine . Fifthly , we describe mechanisms of resistance to topoisomerase I inhibitors , although this subject has not yet been completely elucidated . Finally , to understand the mechanisms of resistance to P01133 - R inhibitors , which have been shown to be useful in many different types of cancer , the Src - P35610 signaling pathways are described here in detail . Hopefully , the assessment of Src and of P35610 - 3 can be implemented as predictive markers .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK97___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"miR - 17 - 5p targets the p300 / CBP - associated factor and modulates androgen receptor transcriptional activity in cultured prostate cancer cells . BACKGROUND : P10275 ( AR ) signalling is critical to the initiation and progression of prostate cancer ( PCa ) . Transcriptional activity of AR involves chromatin recruitment of co - activators , including the p300 / CBP - associated factor ( Q92831 ) . Distinct miRNA expression profiles have been identified in PCa cells during the development and progression of the disease . Whether miRNAs regulate Q92831 expression in PCa cells to regulate AR transcriptional activity is still unclear . METHODS : Expression of Q92831 was investigated in several PCa cell lines by qRT - PCR , Western blot , and immunocytochemistry . The effects of Q92831 expression on AR - regulated transcriptional activity and cell growth in PCa cells were determined by chromatin immunoprecipitation , reporter gene construct analysis , and MTS assay . Targeting of Q92831 by miR - 17 - 5p was evaluated using the luciferase reporter assay . RESULTS : Q92831 was upregulated in several PCa cell lines . Upregulation of Q92831 promoted AR transcriptional activation and cell growth in cultured PCa cells . Expression of Q92831 in PCa cells was associated with the downregulation of miR - 17 - 5p . Targeting of the 3 '- untranslated region of Q92831 mRNA by miR - 17 - 5p caused translational suppression and RNA degradation , and , consequently , modulation of AR transcriptional activity in PCa cells . CONCLUSIONS : Q92831 is upregulated in cultured PCa cells , and upregulation of Q92831 is associated with the downregulation of miR - 17 - 5p . Targeting of Q92831 by miR - 17 - 5p modulates AR transcriptional activity and cell growth in cultured PCa cells .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Specific Biomarkers Are Associated with Docetaxeland Gemcitabine - Resistant NSCLC Cell Lines . Five - year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non - small cell lung cancer cell lines . Therefore , we checked - in the control condition as well as after short - term pharmacological treatment with either docetaxel or gemcitabine - the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness - related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug - related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness - related genes were downregulated in the control condition but became upregulated in docetaxel - resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK73___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK71___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK35___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"___MASK94___ : kinetic and dynamic profile in the treatment of pain . ___MASK94___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK94___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK94___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK94___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"Expression profiling of cancer - related genes in human keratinocytes following non - lethal ultraviolet B irradiation . Ultraviolet B irradiation initiates and promotes skin cancers , photo - aging , and immune suppression . In order to elucidate the effect of these processes at the level of gene expression , we used cDNA microarray technology to examine the effect of ultraviolet B irradiation on 588 cancer - related genes in human keratinocytes at 1 , 6 , and 24 h post - irradiation with a mildly cytotoxic dose of ultraviolet B ( 170 mJ / cm ( 2 ) ) . The viability of the irradiated keratinocytes was 75 % at 24 h post - irradiation . Various cytokeratins and transcription factors were up - regulated within 1 h post - irradiation . After 6 h , expression of a variety of genes related to growth regulation ( e . g . P38936 ( P38936 ) , notch 4 , and smoothened ) , apoptosis ( e . g . caspase 10 , hTRIP , and Q13114 ) , DNA repair ( P07992 , P18887 ) , cytokines ( e . g . P05231 , P35225 , TGF - beta , and endothelin 2 ) , and cell adhesion ( e . g . RhoE , and RhoGDI ) were altered in human keratinocytes . These data suggest the changes in a cascade of gene expression in human keratinocytes occurring within 24 h after UVB exposure . Although the roles of these cellular genes after UVB - irradiation remain to be elucidated , microarray analysis may provide a new view of gene expression in epidermal keratinocytes following UVB exposure .",
"Synergistic effect of curcumin and cisplatin via down - regulation of thymidine phosphorylase and excision repair cross - complementary 1 ( P07992 ) . Curcumin ( diferuloylmethane ) , a phenolic compound obtained from the rhizome of Curcuma longa , is known to have antiproliferative and antitumor properties . P19971 ( TP ) , an enzyme of the pyrimidine salvage pathway , is considered an attractive therapeutic target , and its expression could suppress cancer cell death induced by DNA damage agents . Excision repair cross - complementary 1 ( P07992 ) is a protein involved the process of nucleotide excision repair . The P07992 gene is expressed at high levels in cancers and has been associated with resistance to platinum - based chemotherapy . In this study , the effects of curcumin on TP and P07992 expression induced by cisplatin in non - small - cell lung cancer ( NSCLC ) cell lines was investigated . Exposure of the NSCLC cells to various concentrations of curcumin ( 5 - 40 μM ) down - regulates the mRNA and protein levels of TP and P07992 through destabilization of the mRNA and proteins via a mechanism involving inactivation of Q02750 / 2 - extracellular signal - regulated kinase ( P27361 / 2 ) . Depletion of endogenous TP or P07992 expression by transfection with specific small interfering RNAs significantly decreases cell viability in curcumin - exposed NSCLC cells . Curcumin enhances the sensitivity of cisplatin treatment for NSCLC through inactivation of P27361 / 2 and by decreasing the TP and P07992 protein levels . Enhancement of P27361 / 2 signaling by constitutively active Q02750 / 2 causes an increase in TP and P07992 protein levels and promotes cell viability after cotreatment with curcumin and cisplatin . Enhancement of the cytotoxicity to cisplatin by administration of curcumin is mediated by down - regulation of the expression levels of TP and P07992 and by inactivation of P27361 / 2 .",
"Dual inhibition of P00533 and VEGFR pathways in combination with irradiation : antitumour supra - additive effects on human head and neck cancer xenografts . The aim of this study was to investigate the effects of combining antiangiogenic treatment , epidermal growth factor receptor ( P00533 ) targeting and irradiation ( RT ) . We evaluated DB04849 , a highly potent , orally active , vascular endothelial growth factor ( P15692 ) signalling inhibitor , gefitinib , an P00533 tyrosine kinase inhibitor and RT . The antitumour efficacy of these treatments , administered alone and in combination for 2 weeks , was assessed in a P15692 - secreting human head and neck tumour cell line , CAL33 that highly expresses P00533 , established as xenografts ( 250 mm ( 3 ) ) in nude mice . The median time to reach a tumour volume of 1000 mm ( 3 ) was significantly increased for DB04849 or gefitinib alone compared with the control . Greater inhibition of tumour growth was seen with the combination of DB04849 + gefitinib compared with either drug alone , and the triple combination compared with either DB04849 + gefitinib or RT alone . The intensity of endothelial cell staining was slightly reduced by each agent given alone , and markedly diminished by the double or triple combination . The triple combination almost completely abolished cell proliferation . The marked RT - induced enhancement in the DNA - repair enzyme P07992 expression was totally abolished by the triple combination . This observation could help to explain the supra - additive antitumour effect produced by this combination and could provide a basis for future innovative clinical trials .",
"Phase II study of weekly intravenous oxaliplatin combined with oral daily capecitabine and radiotherapy with biologic correlates in neoadjuvant treatment of rectal adenocarcinoma . PURPOSE : To evaluate the efficacy of a combination of capecitabine , oxaliplatin , and radiotherapy ( RT ) in the neoadjuvant treatment of Stage II and III rectal cancers . METHODS : DB01101 was given at 725 mg / m ( 2 ) orally twice daily Monday through Friday concurrently with RT . DB00526 was given intravenously at 50 mg / m ( 2 ) once weekly five times starting the first day of RT . The radiation dose was 50 . 4 Gy in 28 fractions ( 1 . 8 Gy / fraction ) , five fractions weekly . Endorectal tumor biopsies were obtained before treatment and on the third day of treatment to explore the effects of treatment on thymidine phosphorylase , thymidylate synthase , excision repair cross - complementing rodent repair deficiency complementation group 1 ( P07992 ) , and apoptosis . RESULTS : A total of 25 patients were enrolled in this study ; 6 patients ( 24 % ) had a complete pathologic response . T - downstaging occurred in 52 % of patients , and N - downstaging occurred in 53 % . Grade 3 diarrhea was the most common Grade 3 - 4 toxicity , occurring in 20 % of patients . Only 2 patients experienced disease recurrence , with a median of 20 months of follow - up . P04818 , thymidine phosphorylase , P07992 , and apoptosis did not vary significantly between the pretreatment and Day 3 tumor biopsies , nor did they predict for T - downstaging or a complete pathologic response . CONCLUSION : DB01101 at 725 mg / m ( 2 ) orally twice daily , oxaliplatin 50 mg / m ( 2 )/ wk , and RT at 50 . 4 Gy is an effective neoadjuvant combination for Stage II and III rectal cancer and results in a greater rate of complete pathologic responses than historically shown in fluoropyrimidine plus RT controls .",
"___MASK32___ improves hippocampal neurogenesis and depression - like behaviors via P08908 receptor stimulation in olfactory bulbectomized mice . ___MASK32___ is a non - competitive inhibitor of both acetylcholinesterase ( P22303 ) and butylcholinesterase ( BuChE ) used to treat mild to moderate dementia in Alzheimer ' s disease ( AD ) patients . Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients , its ability to improve Behavioral and Psychological Symptoms of Dementia ( BPSD ) remains unclear . To determine whether rivastigmine treatment antagonizes depression - like behaviors , we chronically administered rivastigmine ( 0 . 1 - 1 . 0mg / kg ) to olfactory bulbectomized ( OBX ) mice once a day for 2weeks , starting 2weeks after bulbectomy . Chronic treatment at 0 . 3 or 1 . 0mg / kg dose dependently and significantly improved depression - like behaviors , as assessed by tail suspension ( Q16762 ) , forced swim ( P19883 ) , locomotion and novelty - suppressed feeding ( NSFT ) tests . Importantly , co - administration with WAY - 100635 ( 1 . 0mg / kg ) , a P08908 receptor antagonist , but not ketanserin ( 1 . 0mg / kg , ) , a 5 - Q13049 receptor antagonist , completely blocked rivastigmine - induced anti - depressive effects , suggesting that P08908 receptor stimulation mediates this activity . Consistent with this observation , rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a P08908 receptor - dependent manner . Furthermore , enhanced protein kinase B ( Akt ) and extracellular signal - regulated kinase ( P29323 ) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis . These effects were blocked by WAY - 100635 but not ketanserin treatment . Finally , we confirmed that P08908 but not 5 - Q13049 receptor stimulation by specific agonists mimicked rivastigmine - induced anti - depression activity and promoted hippocampal neurogenesis . We conclude that , in addition to enhancing the cholinergic system , rivastigmine treatment restores normal function of the hippocampal serotonergic system , an activity that likely ameliorates depressive behaviors in AD patients .",
"___MASK75___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK75___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"Stress - related gene expression in mice treated with inorganic arsenicals . Arsenic ( As ) is an environmental chemical of high concern for human health . Acute toxicity of arsenic is dependent on its chemical forms and proximity to high local arsenic concentrations is one of the mechanisms for cell death . This study was designed to define acute arsenic - induced stress - related gene expression in vivo . Mice were injected sc with either sodium arsenite [ As ( III ) , 100 micromol / kg ] , sodium arsenate [ As ( V ) , 300 micromol / kg ] , or saline . To examine stress - related gene expression , livers were removed 3 h after arsenic injection for RNA and protein extraction . The Atlas Mouse Stress / Toxicology array revealed that the expression of genes related to stress , DNA damage , and metabolism was altered by acute arsenic treatments . Expression of heme oxygenase 1 ( P09601 ) , a hallmark for arsenic - induced stress , was increased 10 - fold , along with increases in heat shock protein - 60 ( HSP60 ) , DNA damage inducible protein P24522 , and the DNA excision repair protein P07992 . Downregulation of certain cytochrome P450 enzymes occurred with arsenic treatment . Multiprobe RNase protection assay revealed the activation of the c - Jun / AP - 1 transcription complex after arsenic treatments . Western blot analysis further confirmed the enhanced production of arsenic - induced stress proteins such as P09601 , HSP70 , HSP90 , metallothionein , the metal - responsive transcription factor MTF - 1 , nuclear factor kappa B and c - Jun / AP - 1 . Increases in caspase - 1 and cytokines such as tumor necrosis factor - alpha ( P01375 ) and macrophage inflammatory protein - 2 were also evident . In summary , this study profiled the gene expression pattern in mice treated with inorganic arsenicals , which adds to our understanding of acute arsenic poisoning and toxicity .",
"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .",
"Activation of a Q92993 / Q01094 / P07992 network in human lung adenocarcinoma cells exposed to cisplatin . The Q92993 and Q01094 proteins are key players of the cellular response induced by genotoxic stresses . Here , new insights into the involvement of both proteins during the DNA damage response are provided . We show that Q92993 interacts with Q01094 and promotes its acetylation . We identify the lysine residues 120 / 125 of the Q01094 protein as the prime target sites of Q92993 and show that acetylation at these sites promotes the accumulation of Q01094 . Importantly , we demonstrate that cisplatin induces the accumulation of Q01094 in a Q92993 - dependent manner . However , and in contrast to Q92831 and p300 , Q92993 is not required for the induction of apoptosis in cisplatin - treated cells . Instead , Q92993 and Q01094 are involved in the upregulation of the excision repair cross - complementation group 1 protein expression , an enzyme involved in the repair of cisplatin - induced DNA lesions . These findings identify Q92993 as a direct regulator of Q01094 and support their cooperative role in DNA repair .",
"The V2 vasopressin receptor stimulates P27361 / 2 activity independently of heterotrimeric G protein signalling . The V2 vasopressin receptor ( P30518 ) activates the mitogen activated protein kinases ( MAPK ) P27361 / 2 through a mechanism involving the scaffolding protein beta arrestin . Here we report that this activating pathway is independent of G alpha s , G alpha i , G alpha q or G betagamma and that the P30518 - mediated activation of G alpha s inhibits P27361 / 2 activity in a DB02527 / PKA - dependent manner . In the HEK293 cells studied , the beta arrestin - promoted activation was found to dominate over the PKA - mediated inhibition of the pathway , leading to a strong vasopressin - stimulated P27361 / 2 activation . Despite the strong MAPK activation and in contrast with other GPCR , P30518 did not induce any significant increase in DNA synthesis , consistent with the notion that the stable interaction between P30518 and beta arrestin prevents signal propagation to the nucleus . Beta arrestin was found to be essential for the P27361 / 2 activation , indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues . Based on the use of selective pharmacological inhibitors , dominant negative mutants and siRNA , we conclude that the beta arrestin - dependent activation of P27361 / 2 by the P30518 involves c - Src and a metalloproteinase - dependent trans - activation event . These findings demonstrate that beta arrestin is a genuine signalling initiator that can , on its own , engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK92___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK92___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders ."
] |
[
"___MASK32___",
"___MASK35___",
"___MASK71___",
"___MASK73___",
"___MASK75___",
"___MASK77___",
"___MASK92___",
"___MASK94___",
"___MASK97___"
] |
___MASK71___
|
MH_train_448
|
interacts_with DB00642?
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[
"Transmitter neurochemistry of the efferent neuron system innervating the labyrinth . It is likely that several mechanisms contribute to the efferent control of cochlear and vestibular function . Different effects are probably mediated by different neuronal transmitters . In spite of a number of transmitter candidates , it is still widely assumed that the entire efferent system can be globally characterized as cholinergic . We attempted to label retrogradely identified efferent neurons in the brainstem with a monoclonal antibody against choline acetyltransferase ( P28329 ) , the acetylcholine ( ACh ) synthesizing enzyme . Only a portion of the vestibular efferents could thus be shown to be cholinergic in the rat . Medial cochlear efferents , terminating under outer hair cells , may also be cholinergic since they stain intensely for acetylcholine esterase ( P22303 ) after pre - treatment with the P22303 inhibitor diisopropylfluorophosphate ( ___MASK53___ ) . The lateral cochlear efferents terminating under inner hair cells , as well as more than half of the vestibular efferent neuron population , reacted negatively with either method designed to identify cholinergic neurons . Half of the lateral olivo - cochlear neuron population filled retrogradely with tritiated gamma - amino butyric acid [ ( 3H ] - GABA ) . These cells were similar in size and distribution to neurons staining for the GABA synthesizing enzyme glutamic acid decarboxylase ( Q99259 ) . Retrograde transport of [ 3H ] - aspartate from the inner ear to the brainstem was seen in half of the lateral olivocochlear population , as well as in part of the efferent vestibular population in group E and in the caudal pontine reticular nucleus ( P16435 ) . Since various peptides have also been located in efferent neurons , this system is chemically diversified . Several distinct mechanisms of efferent control with presumably differing functions must , therefore , exist .",
"Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK53___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK53___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .",
"Effects of pemetrexed , gefitinib , and their combination on human colorectal cancer cells . PURPOSE : The study investigated the effects of pemetrexed , gefitinib , and their combination on human colorectal cancer cells . METHODS : Six human colorectal cancer cells were exposed to pemetrexed , gefitinib , and their combination . Antitumor effects were measured by 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide assay . P04818 ( TS ) mRNA expression and P00533 mutation were studied by real - time RT - PCR and DNA sequence determination . Pharmacological interaction was studied using the combination index method . Cell cycle distribution and apoptosis were determined by flow cytometry . Activity assay was performed to assess the effects of drugs on TS activity , and Western blot was performed to assess the protein expression of pEGFR , pAKT , and pERK 1 / 2 . RESULTS : Six colorectal cancer cells are all sensitive to pemetrexed , and TS gene expression of cells was negatively related to pemetrexed sensitivity . The cytotoxic synergism was observed in concurrent pemetrexed combined with gefitinib and sequential pemetrexed followed by gefitinib . The combination of pemetrexed and gefitinib modulated cell cycle and induced apoptosis . DB00642 combined with gefitinib decreased TS mRNA expression and in situ activity . DB00642 induced an P00533 - mediated activation of the phosphatidylinositol 3 - kinase / AKT and P29323 pathway , which was inhibited by gefitinib . CONCLUSIONS : DB00642 is a promising agent , and pemetrexed combined with gefitinib has a significantly synergistic effect on colorectal cancer cells , which seems to present a strategy of pemetrexed combined with P00533 - TKIs in colorectal cancer treatment .",
"Menadione reduction by pharmacological doses of ascorbate induces an oxidative stress that kills breast cancer cells . Oxidative stress generated by ascorbate - driven menadione redox cycling kills MCF7 cells by a concerted mechanism including glycolysis inhibition , loss of calcium homeostasis , DNA damage and changes in mitogen activated protein kinases ( MAPK ) activities . Cell death is mediated by necrosis rather than apoptosis or macroautophagy . Neither 3 - methyladenine nor Z - VAD affects cytotoxicity by ascorbate / menadione ( Asc / Men ) . BAPTA - AM , by restoring cellular capacity to reduce MTT , underlines the role of calcium in the necrotic process . Oxidative stress - mediated cell death is shown by the opposite effects of DB06151 and 3 - aminotriazole . Moreover , oxidative stress induces DNA damage ( protein poly - ADP - ribosylation and gamma - P16104 phosphorylation ) and inhibits glycolysis . Asc / Men deactivates extracellular signal - regulated kinase ( P29323 ) while activating p38 , suggesting an additional mechanism to kill MCF7 cells . Since ascorbate is taken up by cancer cells and , due to their antioxidant enzyme deficiency , oxidative stress should affect cancer cells to a greater extent than normal cells . This differential sensitivity may have clinical applications .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"Benign mixed tumor of the skin , hypercellular variant : a case report . A 71 - year - old man presented with a slowly growing 2 . 0x2 . 0x1 . 0 cm scalp lesion that was surgically removed . Microscopic examination showed a well - circumscribed dermally located tumor composed of ductal elements lined by double to multiple cell layers of bland cuboidal inner cells and elongated spindled outer cells with areas showing cribriform and solid growth patterns . Some cells showed prominent cytoplasmic clearing . A few mitotic figures are noted ranging from 1 - 2 mitotic figure / 10 hpf . There are also foci of squamous differentiation as well as occasional mature adipocytes . The background stroma was predominantly sclerotic with only small area of myxoid background ( confirmed by Hale ' s colloidal iron ) . Immunohistochemical studies revealed positive immunoreactivity for P15941 , P06731 , CD117 , HWMK , LWMK , CK7 , P10275 and S100 in the ductal ( epithelial ) cells and positive immunereactivity for calponin , SMA , CK 5 / 6 and p63 in the myoepithelial component . No immunoreactivity for Brst - 2 , ER , PR and CK20 was noted . MIB - 1 showed mildly increased proliferrative index highlighting 5 % of the nuclei . The overall morphology and immunohistochemical profile are that of a benign cutanoues mixed tumor ( chondroid syringoma ) . Given the unusual striking celluarlity , we suggest to subclassify this as a hyper - cellular variant .",
"Biochemical and Hematologic Manifestations of Gastric Intrinsic Factor ( GIF ) Deficiency : A Treatable Cause of B12 Deficiency in the Old Order Mennonite Population of Southwestern Ontario . Intrinsic factor deficiency ( OMIM # 261000 , IFD ) is a rare inherited disorder of vitamin B12 metabolism due to mutations in the gastric intrinsic factor ( GIF ) gene . We report three individuals from an Old Order Mennonite community who presented with B12 deficiency . Two cases are siblings born to consanguineous parents and the third case is not known to be closely related . The older male sib presented at 4 years with gastrointestinal symptoms , listlessness , and pallor . He had pancytopenia with megaloblastic anemia . Serum B12 was 61 ( 198 - 615 pmol / L ) . Methylmalonic aciduria was present . P01024 was elevated on acylcarnitine profile . Homocysteine was high at 16 . 7 ( 5 . 0 - 12 . 0 umol / L ) . DB00117 asymptomatic female sibling was also found to have B12 deficiency . Genetic testing for methylmalonic aciduria ( MMAA ) , transcobalamin deficiency ( P20062 ) , and Imerslund - Gräsbeck syndrome ( Q9BXJ7 ) showed no mutation in both siblings . The third patient , a 34 - year - old woman , had presented in infancy with a diagnosis of pernicious anemia . Mutation analysis of GIF revealed compound heterozygosity for a c . 79 + 1G > A substitution and a c . 973delG deletion in all three individuals . Oral or parenteral vitamin B12 has led to complete recovery of clinical parameters and vitamin B12 levels . Newborn screening samples on the siblings revealed normal methylcitrate , P01024 , and P01024 / P06681 ratios thus indicating no disruption of propionic or methylmalonic acid metabolism . A high index of suspicion should be maintained if children present with megaloblastic anemia since GIF deficiency is a treatable disorder and newborn screening may not be able to detect this condition .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK12___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK12___ who were treated with a single dose of mifepristone .",
"APRIL and Q9Y275 proteins increase proliferation of human adipose - derived stem cells through activation of Erk1 / 2 Q96HU1 kinase . Human adipose - derived stem cells ( Q9ULZ3 ) are DB05914 with reduced immunogenicity and the ability to modulate immune responses . APRIL and Q9Y275 proteins are overexpressed in inflammatory and autoimmune diseases for which allogeneic Q9ULZ3 therapy is currently under clinical investigation . Modification of Q9ULZ3 properties by the tissue microenvironment could be a critical factor in patient outcome and is still not well understood . Our aim was to characterize the APRIL / Q9Y275 system in Q9ULZ3 by analyzing the ligand and receptor expression patterns , the effects mediated by APRIL and Q9Y275 on Q9ULZ3 , and the underlying signaling . We found that Q9ULZ3 express the tumor necrosis factor proteins APRIL ( a proliferation - inducing ligand ) and Q9Y275 ( B cell - activator factor ) as well as their receptors O14836 ( transmembrane activator and calcium - modulator and cyclophilin ligand interactor ) , Q02223 ( B cell maturation antigen ) and the Q9Y275 - specific receptor ( Q96RJ3 ) . APRIL and Q9Y275 secretion was differentially enhanced by P48061 and interferon ( IFN ) - γ , implicated in Q9ULZ3 - mediated migration and immunosuppression , respectively . In addition , APRIL and Q9Y275 induced rapid phosphorylation of extracellular signal - regulated kinases 1 / 2 ( P27361 / 2 ) and Akt kinases and promoted an increase in Q9ULZ3 proliferation , without affecting the immunosuppressive capacity of these cells . The use of specific chemical inhibitors indicated that the PI3K transduction pathway is involved in Q9ULZ3 basal growth and that APRIL - and Q9Y275 - mediated effects are P29323 - dependent . These results provide new information about the molecular mechanisms that underlie APRIL and Q9Y275 secretion and signaling in Q9ULZ3 , and are of special relevance for the use of allogeneic Q9ULZ3 as therapeutic tools .",
"Rapid increase in resistance of Plasmodium falciparum to chloroquine - Fansidar in Uganda and the potential of amodiaquine - Fansidar as a better alternative . Combinations of chloroquine ( CQ ) and sulfadoxine - pyrimethamine ( SP ) [ CQSP ] as the first line agents in Uganda have replaced CQ monotherapy . The idea of the combination is to delay the development of malaria resistance to either drug when used alone . We compared the clinical , parasitological and molecular findings of two studies with treatment arms of CQSP , amodiaquine ( AQ ) plus SP ( AQSP ) both done in 2003 with a study done 1 year earlier ( 2002 ) using SP alone . There was a notable decrease in adequate clinical response ( P10323 ) by day 14 from 92 . 7 % with SP to 80 % with the combination CQSP , a year later . AQSP combination was found to have the best effect ( 94 . 3 % P10323 ) . There were no early treatment failures in the AQSP group . However , treatment failures were recorded at 20 % on day 14 and 43 % on day 28 for CQSP treatment and 5 . 7 % by day 14 and 28 . 8 % by day 28 in the AQSP group . The number of mutations that are associated with SP resistance increased from 2002 to 2003 at all loci monitored , from 83 . 8 to 100 % at codon 108 , 58 . 7 to 76 % at codon 59 in the P00374 gene , and from 58 . 8 to 86 % at codon 437 and 33 to 43 % at codon 540 in the P49366 gene . We conclude that there has been a rapid development of resistance since the introduction of the new policy guidelines . AQSP was found to be a superior drug combination compared to CQSP and could be used as a low cost alternative at the moment .",
"Establishment of pemetrexed - resistant non - small cell lung cancer cell lines . DB00642 ( P15941 ) , a multitargeted antifolate with manageable toxicity , is active against non - squamous non - small cell lung cancer ; however , most patients eventually acquire resistance to P15941 . To elucidate the resistant mechanism , we established P15941 - resistant lung adenocarcinoma cell lines . Two parental cell lines , PC - 9 and A549 , were treated with step - wise increasing concentrations of P15941 . Growth inhibition was determined by the 3 -[ 4 , 5 - dimethyl - thizol - 2 - yl ]- 2 , 5 - diphenyltetrazolium bromide assay . Expression of the genes encoding thymidylate synthase ( TS ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyltransferase ( GARFT ) was analyzed by quantitative real - time reverse transcriptase polymerase chain reaction . The four PC - 9 sublines were more resistant than the PC - 9 cell line to P15941 ( 2 . 2 - , 2 . 9 - , 8 . 4 - , and 14 . 3 - fold , respectively ) . The four A549 sublines also showed more resistance to P15941 ( 7 . 8 - , 9 . 6 - , 42 . 3 - , and 42 . 4 - fold , respectively ) than the parent cell line . All resistant sublines showed cross - resistance to cisplatin , but not to docetaxel , vinorelbine , 5 - fluorouracil , or the active metabolite of irinotecan , SN - 38 . All P15941 - resistant sublines expressed more TS than the parental cells , by polymerase chain reaction and Western blotting . P00374 was significantly increased in the four P15941 - resistant A549 sublines . GARFT did not correlate with resistance to P15941 . In summary , P15941 - resistant cells remained sensitive to docetaxel , vinorelbine , 5 - fluorouracil , and irinotecan . TS expression appeared to be associated with resistance to P15941 .",
"___MASK14___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK14___ , in the USA in 2003 .",
"DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . DB00563 ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .",
"Increased interleukin 21 and follicular helper T - like cells and reduced interleukin 10 + B cells in patients with new - onset systemic lupus erythematosus . OBJECTIVE : To elucidate the potential role of follicular helper T cells ( TFH ) and interleukin 10 ( P22301 )+ B cells in the development of systemic lupus erythematosus ( SLE ) . METHODS : The numbers of peripheral blood P26842 + , P28907 + , P42081 + , CD95 + , P22301 + B cells , and inducible T cell costimulator ( Q9Y6W8 )+ , programmed death - 1 ( P18621 )+ , Q9HBE4 + , P32302 + P01730 + TFH - like cells were examined in 23 patients with new onset SLE and 20 healthy controls ( HC ) . RESULTS : In comparison with HC , significantly reduced numbers of P15391 + and P22301 + B cells , but increased numbers of P26842 ( high ) , P42081 + , CD95 + B cells , P32302 + P01730 + , Q9Y6W8 + , P18621 + , and Q9HBE4 + TFH - like cells were detected , which were accompanied by higher levels of serum Q9HBE4 , but lower levels of P22301 in the patients . Treatment with anti - SLE therapy modulated the imbalance of different subsets of B and TFH - like cells . The levels of serum Q9HBE4 and P22301 were positively correlated with the numbers of P01730 + P32302 + TFH - like and P15391 + P06127 + CD1d + B cells in the patients , respectively . The numbers of P26842 ( high ) B cells were correlated positively with Q9HBE4 + TFH - like cells , but negatively with P22301 + B cells . The values of SLE Disease Activity Index , P01024 , and erythrocyte sedimentation rate were correlated positively with serum Q9HBE4 , but negatively with P22301 in those patients . CONCLUSION : Our data indicate that the imbalance of Q9HBE4 + TFH - like , P26842 ( high ) , and P22301 + B cells may be associated with the pathogenesis of SLE , and levels of serum Q9HBE4 and P22301 may be valuable for evaluating disease activity in SLE .",
"New data integrating multitargeted antifolates into treatment of first - line and relapsed non - small - cell lung cancer . Non - small - cell lung cancer ( NSCLC ) represents approximately 80 % of all lung cancers . With modern platinum - based combination regimens , overall median survival has reached 9 - 12 months . Antifolates are active against several solid tumors and hematologic malignancies . The cytotoxic action of antifolates is mainly related to their ability to inhibit several different folate - dependent enzymes involved in DNA synthesis . DB00642 is a novel multitargeted antifolate that inhibits at least 3 of the enzymes involved in purine and pyrimidine synthesis : thymidylate synthase ( TS ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyltransferase ( GARFT ) . DB00642 was approved for the treatment of relapsed NSCLC as it produced equivalent response and survival rates and less toxicity compared with docetaxel . DB00642 in combination with platinum analogues or with gemcitabine showed equivalent clinical impact compared with standard combinations of platinum plus third - generation agents . We analyze the potential implications of pemetrexed ' s role in first - line chemotherapy of NSCLC as well as hints of differential cytotoxic action according to histology , new schedules of vitamin supplementation , and target enzymes expression levels . Issues of pharmacogenomics are becoming relevant in defining pemetrexed efficacy . Chemosensitivity was significantly linked to low levels of TS , GARFT , and P00374 in preclinical models . Consequently , the differential expression of TS according to histology might explain the different activity of pemetrexed according to histology , as recently postulated .",
"Implants of encapsulated human P26441 - producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington ' s disease . Delivery of neurotrophic molecules to the CNS has gained considerable attention as a potential treatment strategy for neurological disorders . In the present study , a P00374 - based expression vector containing the human ciliary neurotrophic factor ( hCNTF ) was transfected into a baby hamster kidney fibroblast cell line ( BHK ) . Using a polymeric device , encapsulated BHK - control cells and those secreting hCNTF ( BHK - hCNTF ) were transplanted unilaterally into the rat lateral ventricle . Twelve days later , the same animals received unilateral injections of quinolinic acid ( QA ; 225 nmol ) into the ipsilateral striatum . After surgery , animals were behaviorally tested for apomorphine - induced rotation behavior and for skilled forelimb function using the staircase test . Rats receiving BHK - hCNTF cells rotated significantly less than animals receiving BHK - control cells . No behavioral effects of hCNTF were observed on the staircase test . Nissl - stained sections demonstrated that BHK - hCNTF cells significantly reduced the extent of striatal damage produced by QA . Quantitative analysis of striatal neurons further demonstrated that both choline acetyltransferase - and Q99259 - immunoreactive neurons were protected by BHK - hCNTF implants . In contrast , a similar loss of NADPH - diaphorase - positive cells was observed in the striatum of both implant groups . Analysis of retrieved capsules revealed numerous viable and mitotically active BHK cells that continued to secrete hCNTF . These results support the concepts that implants of polymer - encapsulated hCNTF - releasing cells can be used to protect striatal neurons from excitotoxic damage and that this strategy may ultimately prove relevant for the treatment of Huntington ' s disease .",
"DB00642 : its promise in treating non - small - cell lung cancer . The use of chemotherapy in the treatment of early and advanced non - small - cell lung cancer ( NSCLC ) has increased during the past decade . One of the main reasons for the increased acceptance of chemotherapy is the development of several new cytotoxic agents with a unique mechanism ( s ) of action and high single - agent activity , combined with a favorable toxicity profile . DB00642 ( Alimta ) is a novel antifolate that inhibits several enzymes involved in DNA synthesis ( thymidylate synthase [ TS ] , dihydrofolate reductase [ P00374 ] , and glycinamide ribonucleotideformyltransferase [ GARFT ] ) . DB00642 ' s toxicity is markedly reduced by folic acid and vitamin B12 supplementation . The compound has been studied extensively in various tumor types , including NSCLC . In NSCLC , pemetrexed at 500 mg / m2 , every 3 weeks , given i . v . over 10 minutes , has shown promising activity , and can safely be administrated with vitamin supplementation . After registration , single - agent pemetrexed will certainly add to the chemotherapeutic options available for pretreated patients and will most likely change significantly chemotherapy prescriptions in second - line chemotherapy . In first - line chemotherapy , the role of platinum - based and - free combination doublet chemotherapy with pemetrexed still needs to be defined . Phase II data indicate high efficacy combined with favorable toxicity for pemetrexed in combination with cisplatin , carboplatin ( DB00958 ) , oxaliplatin ( Eloxatin ) , gemcitabine ( Gemzar ) , and vinorelbine ( Navelbine ) . This review summarizes the clinical experience obtained thus far during the early clinical development of pemetrexed in NSCLC .",
"Telomerase - immortalized human fibroblasts retain UV - induced mutagenesis and p53 - mediated DNA damage responses . Immortalized cells frequently have disruptions of p53 activity and lack p53 - dependent nucleotide excision repair ( P55055 ) . We hypothesized that telomerase immortalization would not alter p53 - mediated ultraviolet light ( UV ) - induced DNA damage responses . DNA repair proficient primary diploid human fibroblasts ( GM00024 ) were immortalized by transduction with a telomerase expressing retrovirus . Empty retrovirus transduced cells senesced after a few doublings . Telomerase transduced GM00024 cells ( tGM24 ) were cultured continuously for 6 months ( > 60 doublings ) . Colony forming ability after UV irradiation was dose - dependent between 0 and 20J / m2 UVC ( LD50 = 5 . 6J / m2 ). p53 accumulation was UV dose - and time - dependent as was induction of p48 ( XPE / Q92466 ) , P38936 ( CIP1 / P38936 ) , and phosphorylation on p53 - S15 . UV dose - dependent apoptosis was measured by nuclear condensation . UV exposure induced UV - damaged DNA binding as monitored by electrophoretic mobility shift assays using UV irradiated radiolabeled DNA probe was inhibited by p53 - specific siRNA transfection . p53 - Specific siRNA transfection also prevented UV induction of p48 and improved UV survival measured by colony forming ability . Strand - specific P55055 of cyclobutane pyrimidine dimers ( O75976 ) within P00374 was identical in tGM24 and GM00024 cells . O75976 removal from the transcribed strand was nearly complete in 6h and from the non - transcribed strand was 73 % complete in 24h . UV - induced P00492 mutagenesis in tGM24 was indistinguishable from primary human fibroblasts . These wide - ranging findings indicate that the UV - induced DNA damage response remains intact in telomerase - immortalized cells . Furthermore , telomerase immortalization provides permanent cell lines for testing the immediate impact on P55055 and mutagenesis of selective genetic manipulation without propagation to establish mutant lines .",
"DB00642 : mRNA expression of the target genes TS , GARFT and P00374 correlates with the in vitro chemosensitivity of human solid tumors .",
"Counteraction between angiotensin II and angiotensin -( 1 - 7 ) via activating angiotensin type I and Mas receptor on rat renal mesangial cells . In the updated concept of renin - angiotensin system ( DB01367 ) , it contains the angiotensin converting enzyme ( P12821 ) - angiotensin ( Ang ) II - angtiogensin type 1 receptor ( AT1 ) axis and the angiotensin - converting enzyme - related carboxypeptidase ( Q9BYF1 ) - Ang -( 1 - 7 )- Mas axis . The former axis has been well demonstrated performing the vasoconstrictive , proliferative and pro - inflammatory functions by activation of AT1 receptors , while the later new identified axis is considered counterbalancing the effects of the former . The present study is aimed at observing the interaction between Ang -( 1 - 7 ) and Ang II on cultured rat renal mesangial cells ( MCs ) . RT - PCR , Western blot and immunofluorescent staining and confocal microscopy results showed that both AT1 and Mas receptor were co - distributed in rat renal MCs . Ang -( 1 - 7 ) showed similar effects on Ang II in cultured MCs that stimulated phosphorylated extracellular signal - regulated kinase ( P29323 ) 1 / 2 phosphorylation and transforms growth factor - β1 synthesis , and cell proliferation and extracellular matrix synthesis . Co - treatment of the cell with Ang -( 1 - 7 ) and Ang II , Ang -( 1 - 7 ) counteracted AngII - induced effects in a concentration dependent manner , but failed to alter the changes induced by endothelin - 1 . The stimulating effect of Ang II was mediated by AT1 receptor while all the effects of Ang -( 1 - 7 ) were blocked by Mas receptor antagonist A - 779 , but not by AT1 receptor antagonist losartan or P50052 receptor antagonist PD123319 . These results suggest that Ang -( 1 - 7 ) and Ang II specifically interact with each other on rat renal MCs via activation of their specific receptors , Mas and AT1 receptor respectively .",
"___MASK97___ is the favorable alternative for cisplatin resistance reversal of ovarian cancer in vitro and in nude mice in vivo . This study aimed to observe the effects of octreotide ( O75051 ) on cisplatin resistance reversal of cancer cells in vitro and in nude mice in vivo . MTT method and flow cytometry were used to investigate the effect of cisplatin , O75051 or the combination of these two compounds on the proliferation and apoptosis of SKOV3 - O60220 cells . The size and weight of xenograft tumors from the nude mice model were measured . Real - time PCR was used to detect the mRNA expression of P30874 , P08183 , Q92887 , Q86UG4 - pi and P00533 in SKOV3 / O60220 cells following the different treatment . At the concentration of 2 . 5 - 20 g / ml , O75051 significantly reduced IC50 ( p < 0 . 05 ) and promoted apoptosis ( p < 0 . 05 ) of SKOV3 - O60220 cells ' response to cisplatin . Unchanged expression was found in P30874 on the SKOV3 / O60220 cell in vitro after O75051 treatment , but increased expression in vivo ( p < 0 . 05 ) . O75051 increased Q86UG4 - pi expression ( p < 0 . 05 ) and reduced Q92887 and P00533 expression ( p < 0 . 05 ) in a dose - dependent manner . The similar results were obtained in mice in vivo experiment , except the reduced expression of Q86UG4 - pi . It is suggested that O75051 could inhibit ovarian cancer proliferation and promote apoptosis , via the cell surface P30874 , and reverse cisplatin resistance through inhibition of Q92887 , P00533 , and even Q86UG4 - pi expressions .",
"The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK52___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .",
"An improved effect size for single - case research : nonoverlap of all pairs . Nonoverlap of All Pairs ( Q8WYA6 ) , an index of data overlap between phases in single - case research , is demonstrated and field tested with 200 published AB contrasts . Q8WYA6 is a novel application of an established effect size known in various forms as Area Under the Curve ( AUC ) , the Common Language Effect Size ( CL ) , the Probability of Superiority ( PS ) , the Dominance Statistic ( DS ) , Mann - Whitney ' s U , and Sommers D , among others . Q8WYA6 was compared with 3 other non - overlap - based indices : P01160 ( percent of nonoverlapping data ) , P15941 ( percent of data points exceeding the median ) , and PAND ( percent of all nonoverlapping data ) , as well as Pearson ' s R ( 2 ) . Five questions were addressed about Q8WYA6 : ( a ) typical Q8WYA6 values , ( b ) its ability to discriminate among typical single - case research results , ( c ) its power and precision ( confidence interval width ) , ( d ) its correlation with the established effect size index , R ( 2 ) , and ( e ) its relationship with visual judgments . Results were positive , the new index equaling or outperforming the other overlap indices on most criteria .",
"Protection of lung epithelial cells from protease - mediated injury by trappin - 2 A62L , an engineered inhibitor of neutrophil serine proteases . Neutrophil serine proteases ( NSPs ) , including elastase , proteinase 3 and cathepsin G , play critical roles in the pathogenesis of chronic inflammatory lung diseases . The release of excess NSPs leads to the destruction of lung tissue and an overexuberant , sustained inflammatory response . Antiproteases could be valuable tools for controlling these NSP - mediated inflammatory events . We have examined the capacity of trappin - 2 A62L , a potent engineered inhibitor of all three NSPs , to protect human lung A549 epithelial cells from the deleterious effects of NSPs . Trappin - 2 A62L , significantly inhibited the detachment of A549 cells and the degradation of the tight - junction proteins , P12830 , β - catenin and ZO - 1 , induced by each individual NSP and by activated neutrophils . Trappin - 2 A62L also decreased the release of the pro - inflammatory cytokines P05231 and P10145 from A549 cells that had been stimulated with elastase or LPS . Trappin - 2 A62D / M63L , a trappin - 2 variant that has no antiprotease activity , has similar properties , suggesting that the anti - inflammatory action of trappin - 2 is independent of its antiprotease activity . Interestingly , we present evidence that trappin - 2 A62L , as well as wild - type trappin - 2 , enter A549 cells and move rapidly to the cytoplasm and nucleus , where they are likely to exert their anti - inflammatory effects . We have also demonstrated that trappin - 2 A62L inhibits the early apoptosis of A549 cells mediated by NSPs . Thus , our data indicate that trappin - 2 A62L is a powerful anti - protease and anti - inflammatory agent that could be used to develop a treatment for patients with inflammatory lung diseases .",
"Impact of stress and mast cells on brain metastases . Metastases continue to be the chief cause of morbidity and mortality for many tumors , including brain metastases of lung and mammary adenocarcinoma . Stress appears to increase metastases , but the mechanism is not understood . Recent evidence suggests that local inflammation is conducive for cancer growth and a unique immune cell , the mast cell , accumulates in the stroma surrounding tumors and is critically located at the blood - brain - barrier ( BBB ) . Mast cells express receptors for and can be stimulated by corticotropin - releasing hormone ( P06850 ) , secreted under stress , to release mediators such as histamine , P10145 , tryptase and vascular endothelial growth factor ( P15692 ) , which disrupt the BBB permitting metastases . Stress and mast cells could serve as new targets for drug development to prevent brain metastases , especially since P06850 receptor antagonists and brain mast cell inhibitors have recently been developed .",
"___MASK41___ : kinetic and dynamic profile in the treatment of pain . ___MASK41___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK41___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK41___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK41___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"Expression patterns of the implantation - associated genes in the uterus during the estrous cycle in mice . The mRNA expression patterns of P01133 , HB - P01133 , P15514 , P01133 receptor , DB01277 , P09603 , P01583 , P01584 , IL - 1 receptor type 1 , IL - 1 receptor antagonist , P15018 , P23219 , P35354 , P15941 , calcitonin , and rat Q6X4U4 mouse homologue , all of which are involved in the process of conceptus implantation to the endometrium , were examined during the estrous cycle by means of real - time quantitative PCR . P35354 , HB - P01133 , P15018 , P15941 , P09603 , P01583 , P01584 , and IL - 1 receptor antagonist were temporally regulated during the estrous cycle and highly expressed during the estrous stage . In the case of P23219 , P01133 , DB01277 , and P01133 receptor , the highest mRNA expression was during the diestrous stage . In contrast , the rat Q6X4U4 mouse homologue mRNA expression did not change during the estrous cycle . These results indicate that rat Q6X4U4 mouse homologue expression at implantation might be specifically regulated by embryonic factors rather than the maternal environment .",
"Increased serum concentration of Q9Y275 / APRIL and IgA2 subclass in patients with mixed connective tissue disease complicated by interstitial lung disease . B cell activating factor ( Q9Y275 ) and a proliferation - inducing ligand ( APRIL ) are known to be crucial for B cell maturation and survival , and increased expression of these factors in various autoimmune diseases has been reported . Human B cells produce two IgA subclasses : IgA1 and IgA2 , the latter being abundant in the distal intestine , saliva , colostrum and bronchial fluid . We investigated these parameters in patients with mixed connective tissue disease ( MCTD ) complicated by interstitial lung disease ( ILD + ) , and compared them with those in MCTD patients without ILD ( ILD - ) . Sixty - three MCTD patients were divided into two groups : 21 ILD + patients and 42 ILD - patients . In each patient group we analyzed soluble Q9Y275 / APRIL using ELISA , and IgA1 and IgA2 using double immunodiffusion . Furthermore , we analyzed Q9Y275 - APRIL receptors , Q02223 , Q96RJ3 and O14836 , using flow cytometry . The ILD + patients had significantly higher levels of Q9Y275 / APRIL than the ILD - patients . There were significant correlations between Q9Y275 / APRIL , Q9Y275 / P15941 and APRIL / P15941 . Although there was no significant inter - group difference in the serum IgA1 level , ILD + patients had a significantly elevated IgA2 level in comparison with ILD - patients . Moreover , although there were no significant inter - group differences in the expression of Q02223 , Q96RJ3 and O14836 on B cells , the expression of Q96RJ3 was significantly decreased in the ILD + patients . In recent years , relationships between Q9Y275 / APRIL and IgA subclass have been reported . Our results suggest that an elevated level of Q9Y275 / APRIL drives the maturation of B cells , subsequently leading to IgA2 class switching , and possibly to the development of ILD in patients with MCTD .",
"Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with ___MASK21___ , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20 - week - old Zucker obese and 16 - week - old ZDF rats were treated with ___MASK21___ ( 25 mg / kg / day ) or Enalapril ( 20 mg / kg / day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75 - 175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with ___MASK21___ or Enalapril .",
"Down - regulation of P15941 in cancer cells inhibits cell migration by promoting P12830 / catenin complex formation . P15941 , a tumor associated glycoprotein , is over - expressed in most cancers and can promote proliferation and metastasis . The objective of this research was to study the role of P15941 in cancer metastasis and its potential mechanism . Pancreatic ( PANC1 ) and breast ( MCF - 7 ) cancer cells with stable ' knockdown ' of P15941 expression were created using RNA interference . beta - Catenin and P12830 protein expression were upregulated in PANC1 and MCF - 7 cells with decreased P15941 expression . Downregulation of P15941 expression also induced beta - catenin relocation from the nucleus to the cytoplasm , increased P12830 / beta - catenin complex formation and P12830 membrane localization in PANC1 cells . PANC1 cells with ' knockdown ' P15941 expression had decreased in vitro cell invasion . This study suggested that P15941 may affect cancer cell migration by increasing P12830 / beta - catenin complex formation and restoring P12830 membrane localization .",
"Recent advances in classical and non - classical antifolates as antitumor and antiopportunistic infection agents : Part II . Antifolates that inhibit the key enzymes thymidylate synthase ( TS ) and dihydrofolate reductase ( P00374 ) have found clinical utility as antitumor and antiopportunistic agents . DB00563 { MTX , ( 1 ) } and 5 - fluorouracil ( DB00544 ) were among the first clinically useful P00374 and TS inhibitors , respectively . The development of resistance to DB00544 , its occasional unpredictable activity and toxicity resulted in the search of novel antifolates . DB00642 ( 4 ) and raltitrexed ( 5 ) are newer antifolates that specifically inhibit TS , and are clinically useful as antitumor agents . A major mechanism of tumor resistance to clinically useful antifolates is based on their need for polyglutamylation via the enzyme folylpoly - gamma - glutamate synthetase ( Q05932 ) . Recently , classical antifolates that do not need to be polyglutamylated have also been developed and include plevitrexed ( 6 ) and GW1843 ( 7 ) . Nolatrexed ( 8 ) , trimethoprim { P54849 , ( 11 ) } and piritrexim { PTX , ( 12 ) } are nonclassical antifolates for antitumor and parasitic chemotherapy that passively diffuse into cells and hence do not have to depend on Q05932 or the reduced folate carrier ( P41440 ) . Structural requirements for inhibition with antifolates have been studied extensively and novel agents that exploit key interactions in the active site of TS , P00374 , Q05932 , and P41440 have been proposed . This two - part review discusses the design , synthesis and structural requirements for TS and P00374 inhibition and their relevance to antitumor and parasitic chemotherapy , since 1996 . Monocyclic and 6 - 5 fused bicyclic antifolates were discussed in Part I . The 6 - 6 bicyclic and tricyclic antifolates will be discussed here in Part II .",
"Release of mediators of systemic inflammatory response syndrome in the course of a severe delayed hemolytic transfusion reaction caused by anti - D . BACKGROUND : In vitro studies suggest that mediators of systemic inflammatory response syndrome are generated in the course of hemolytic transfusion reactions . Evidence for the in vivo significance of these findings is given by the present clinical and laboratory analysis of a severe delayed hemolytic transfusion reaction ( P10275 ) . CASE REPORT : A 67 - year - old patient ( blood group O , D - negative ) with a negative pretransfusion antibody screen received a massive transfusion because of arterial bleeding ( Day 1 ) . The transfusion of group O , D - positive red cell concentrates was unavoidable because of limited supplies . At Day 10 , the patient developed a P10275 with symptoms of septic - toxic syndrome and signs of hemolysis ; he received an exchange transfusion . Serologic markers , as well as proinflammatory and anti - inflammatory mediators , were monitored at the onset of the P10275 and during the exchange transfusion . RESULTS : At Day 10 , the direct antiglobulin test was positive ; anti - D was present , most likely as the result of an anamnestic immune response . Interleukin ( IL ) - 1 was not detectable ; all other mediators monitored were elevated : IL - 1 receptor antagonist , tumor necrosis factor , P05231 , P10145 , P22301 , neopterin , elastase , C3a - desArg , P02741 , and fibrinogen . Most of the values declined during the exchange transfusion , which was followed by an improvement of the clinical presentation . CONCLUSIONS : Mediators of systemic inflammatory response syndrome were released in the course of a P10275 caused by anti - D . Severe clinical symptoms could be treated successfully by exchange transfusion .",
"B7h triggering inhibits umbilical vascular endothelial cell adhesiveness to tumor cell lines and polymorphonuclear cells . Vascular endothelial cells ( ECs ) are key players in leukocyte recruitment into tissues and metastatic dissemination of tumor cells . ECs express B7h , which is the ligand of the Q9Y6W8 T cell costimulatory molecule . The aim of this work was to assess the effect of B7h triggering by a soluble form of Q9Y6W8 ( Q9Y6W8 - Fc ) on the adhesion of colon carcinoma cell lines to HUVECs . We found that B7h triggering inhibited HUVEC adhesiveness to HT29 and DLD1 cells ( by 50 and 35 % , respectively ) but not to HCT116 cells . The effect was dependent on the Q9Y6W8 - Fc dose and was detectable as early as 30 min after treatment and was still present after 24 h . It was inhibited by soluble anti - Q9Y6W8 reagents ( mAb and B7h - Fc ) and silencing of B7h on HUVECs , and it was not displayed by an F119S mutated form of Q9Y6W8 - Fc that does not bind B7h . HUVEC treatment with Q9Y6W8 - Fc did not modulate expression of adhesion molecules and cytokines , but it substantially downmodulated P29323 phosphorylation induced by P16581 triggering or osteopontin , which may influence HUVEC adhesiveness . Moreover , HUVEC treatment with Q9Y6W8 - Fc also inhibited adhesion of polymorphonuclear cells and several tumor cell lines from different origins . Therefore , the B7h - Q9Y6W8 interaction may modulate spreading of cancer metastases and recruitment of polymorphonuclear cells in inflammatory sites , which opens a view on the use of Q9Y6W8 - Fc as an immunomodulatory drug .",
"High contrast ultrasound images of defects in food package seals . Previous work to detect defects in food packaging seals using pulse - echo ultrasound inspired the backscattered amplitude integral ( BAI ) imaging technique , which could reliably identify channels with diameters 38 microm or larger at a center frequency of 17 . 3 MHz ( lambda = 86 microm ) . The current study presents two new processing techniques that more reliably reveal smaller channels ( approximately 6 microm in diameter ) . The RF sampling technique ( RFS ) displays a single , time - gated , pressure value from the received ( not envelope - detected ) RF waveform at each transducer position . The RF correlation technique ( P41440 ) calculates the correlation coefficients of the RF signals with a reference signal that does not pass through a channel . The correlation coefficient can be calculated for the entire RF signal ( RFCE ) or over a short segment of the RF signal ( RFCS ) . The performance of these imaging methods for detecting channel defects is investigated for plastic and aluminum foil trilaminate films with 6 , 10 , 15 , 38 , and 50 microm channels filled with water or air . Data are collected with a focused ultrasound transducer ( 17 . 3 MHz , 6 . 35 mm in diameter , f / 2 , 173 microm - 6 dB pulse - echo lateral beamwidth at the focus ) scanned over a rectangular grid , keeping the package in the focus . Performance is measured using detection rates , image contrast , and contrast - to - noise ratio ( P21554 ) . Both RFS and RFCS have improved detection rates relative to BAI for channels 15 microm or smaller . The RFCS technique is the most effective at smoothing the background , leading to the greatest P21554 improvements .",
"Translational research with pemetrexed in breast cancer . DB00642 ( Alimta ) is a novel folate antimetabolite that primarily inhibits the enzymes thymidylate synthase ( TS ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyl transferase ( GARFT ) , all of which are involved in pyrimidine and purine synthesis . In a phase II trial of patients with DB00279 / 4 , N0 - 2 breast cancer , expression of thymidylate synthase ( TS ) , dihydrofolate reductase ( P00374 ) , glycinamide ribonucleotide formyltransferase ( GARFT ) , p53 , and c - erb - B2 ( at the mRNA or protein level ) was examined in tumor biopsy specimens before and 24 hours after the first dose of pemetrexed and after three cycles of single - agent treatment to establish correlations of biomarker levels and changes with clinical outcome and toxicity . Although final data are not available , initial indications are that clinical response may correlate with decreased or low TS expression . The results obtained from clinical data are supported by laboratory results in three cell lines ( MDA - 231 , MCF - 7 , and ZR - 75 ) . These results suggest that in vitro transcript profiling to identify which genes are important predictors of successful cytotoxic chemotherapy , followed by a focused clinical trial to confirm the in vitro results , may be the best approach for translational research .",
"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK73___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .",
"Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK53___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK53___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK53___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Insights into antifolate resistance from malarial P00374 - TS structures . Plasmodium falciparum dihydrofolate reductase - thymidylate synthase ( PfDHFR - TS ) is an important target of antimalarial drugs . The efficacy of this class of P00374 - inhibitor drugs is now compromised because of mutations that prevent drug binding yet retain enzyme activity . The crystal structures of PfDHFR - TS from the wild type ( TM4 / 8 . 2 ) and the quadruple drug - resistant mutant ( V1 / S ) strains , in complex with a potent inhibitor WR99210 , as well as the resistant double mutant ( P04264 P21554 ) with the antimalarial pyrimethamine , reveal features for overcoming resistance . In contrast to pyrimethamine , the flexible side chain of WR99210 can adopt a conformation that fits well in the active site , thereby contributing to binding . The single - chain bifunctional PfDHFR - TS has a helical insert between the P00374 and TS domains that is involved in dimerization and domain organization . Moreover , positively charged grooves on the surface of the dimer suggest a function in channeling of substrate from TS to P00374 active sites . These features provide possible approaches for the design of new drugs to overcome antifolate resistance .",
"___MASK97___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .",
"Exposure to an organophosphate ( ___MASK53___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK53___ ( ___MASK53___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK53___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK53___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK53___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .",
"___MASK73___ ( ___MASK73___ ) : from concept to care , a programme in rational drug discovery . DB00158 - based anticancer drugs with specificity for thymidylate synthase ( TS ) have come of age . Ideas nurtured in the early 1970s led to the first - generation of antifolates with TS and dihydrofolate reductase ( P00374 ) inhibitory activities . Compounds with increased selectivity for TS followed with the highly specific inhibitor , CB3717 being synthesised in 1979 at the Institute of Cancer Research ( ICR ) . CB3717 had significant clinical activity but its development had to be abandoned because its low aqueous solubility led to occasional nephrotoxicity . Collaborative laboratory studies between the ICR and ICI Pharmaceuticals ( later to become Zeneca Pharmaceuticals ) led to the discovery of ___MASK73___ ( ___MASK73___ ) , the first antifolate to be licensed for the treatment of cancer ( UK 1995 ) in nearly 40 years and the first new drug for colorectal cancer in about 35 years . ___MASK73___ belongs to a class of compounds that use the reduced - folate carrier ( P41440 ) for uptake into cells and which are excellent substrates for folylpolyglutamate synthetase ( Q05932 ) . This paper reviews the underlying philosophies , and the milestones reached during the development of ___MASK73___ .",
"___MASK97___ - targeted liposomes loaded with CPT - 11 enhanced cytotoxicity for the treatment of medullary thyroid carcinoma . Medullary thyroid carcinoma ( P04629 ) is a rare endocrine tumor that frequently metastasizes , but treatment with irinotecan ( CPT - 11 ) is limited because of side effects . P04629 is known to overexpress the somatostatin receptor subtype 2 ( P30874 ) . ___MASK97___ ( Oct ) is a somatostatin analogue that has a high binding affinity for SSTR and can be used as a tumor - targeting ligand . We prepared Oct - targeted liposomes loaded with CPT - 11 using Oct - poly ( ethylene glycol ) ( PEG ) - lipid and evaluated Oct - mediated association and cytotoxicity of the liposomes with an P04629 cell line TT . The association of higher concentrations of modified Oct - targeted liposomes with TT cells was significantly higher than PEGylated liposomes and was significantly inhibited by empty Oct - targeted liposomes but not by free Oct . With exposure for 96 h , the cytotoxicity of Oct - targeted liposomal CPT - 11 ( IC50 : 1 . 05 ± 0 . 47 μM ) was higher than free CPT - 11 ( IC50 : 3 . 76 ± 0 . 61 μM ) or PEGylated liposomal CPT - 11 ( IC50 : 3 . 05 ± 0 . 28 μM ) . In addition , empty Oct - targeted liposomes showed significantly higher cytotoxicity than empty nontargeted liposomes at a concentration where free Oct did not show cytotoxicity , suggesting that Oct as a ligand showed cytotoxicity . Moreover , Oct - targeted liposomal CPT - 11 led to significantly higher antitumor activity and prolonged the survival time compared with nontargeted liposomal and free CPT - 11 at a one - third dose and lower administration times with free CPT - 11 . These findings indicated that Oct - targeted liposomes loaded with CPT - 11 may offer considerable potential for P04629 chemotherapy because cytotoxicity of both CPT - 11 and Oct was enhanced by effective cellular uptake via P30874 .",
"P01308 / P05019 signaling pathways enhances tumor cell invasion through bisecting GlcNAc N - glycans modulation . an interplay with P12830 . Changes in glycosylation are considered a hallmark of cancer , and one of the key targets of glycosylation modifications is P12830 . We and others have previously demonstrated that P12830 has a role in the regulation of bisecting GlcNAc N - glycans expression , remaining to be determined the P12830 - dependent signaling pathway involved in this N - glycans expression regulation . In this study , we analysed the impact of P12830 expression in the activation profile of receptor tyrosine kinases such as insulin receptor ( IR ) and P08069 ( IGF - IR ) . We demonstrated that exogenous P12830 expression inhibits IR , IGF - IR and P29323 1 / 2 phosphorylation . Stimulation with insulin and P05019 in MDA - MD - 435 cancer cells overexpressing P12830 induces a decrease of bisecting GlcNAc N - glycans that was accompanied with alterations on P12830 cellular localization . Concomitantly , IR / IGF - IR signaling activation induced a mesenchymal - like phenotype of cancer cells together with an increased tumor cell invasion capability . Altogether , these results demonstrate an interplay between P12830 and IR / IGF - IR signaling as major networking players in the regulation of bisecting N - glycans expression , with important effects in the modulation of epithelial characteristics and tumor cell invasion . Here we provide new insights into the role that P01308 / P05019 signaling play during cancer progression through glycosylation modifications .",
"Quinazoline thymidylate synthase inhibitors : methods for assessing the contribution of polyglutamation to their in vitro activity . Many quinazoline thymidylate synthase ( TS ) inhibitors undergo intracellular metabolism to polyglutamate forms which can significantly alter their activity and pharmacodynamics through improved TS inhibition and drug retention . When a series of quinazolines was tested for inhibitory activity towards TS ( IC50 0 . 001 - 2 microM ) and the growth of L1210 cells ( IC50 0 . 005 - 10 microM ) , no direct correlation was observed . However , a very good correlation was apparent if a L1210 variant cell line ( L1210 : RD1694 ) was used . This line is deficient in its ability to form antifolate polyglutamates . A number of other intact cell methods have also been developed which estimate the contribution that intracellular polyglutamation makes to a compound ' s activity . These assays were validated using a series of quinazoline - based TS inhibitors with well - defined activity for TS , folypolyglutamate synthetase ( Q05932 ) and the reduced - folate cell membrane carrier ( P41440 ) . Short - exposure growth - inhibition assays or the measurement of TS activity in situ after various incubation times , followed by different lengths of time in drug - free medium , can indicate both the speed and extent of appearance of retentive forms ( usually polyglutamates ) . Continuous - exposure growth - inhibition assays , in the presence of leucovorin ( LV ) , are also useful , since only the growth - inhibitory potency of polyglutamated analogues is significantly decreased by LV . Highly polyglutamated compounds , e . g . ___MASK73___ , are virtually inactive in the presence of a high concentration of LV . It is proposed that these methods , when considered together , provide a greater degree of information concerning the rate and extent of polyglutamation of a particular compound than isolated Q05932 assays alone .",
"Evaluating gene expression profiling by quantitative polymerase chain reaction to develop a clinically feasible test for outcome prediction in multiple myeloma . The gene expression profiles ( GEPs ) of 96 selected genes were analysed by real - time quantitative polymerase chain reaction ( qPCR ) with a TaqMan low - density array card in isolated tumour plasma cells ( PCs ) from 157 newly diagnosed multiple myeloma ( MM ) patients . This qPCR - based GEP correctly classified cases following the Translocation - cyclin D classification . Classic prognostic parameters and qPCR - based GEP predicted MM patient outcome and , although multivariate analyses revealed that cytogenetic risk ( standard vs . high risk ) was the variable that most strongly predicted prognosis , GEP added significant information for risk stratification . Considering only the standard risk cytogenetic patients , multivariate analyses revealed that high β2 - microglobulin , low P38936 and high P41440 gene expression levels independently predicted a short time - to - progression ( TTP ) , while high International Staging System stage , low P42772 and high Q969Z0 gene expression predicted poor overall survival ( OS ) . A gene expression risk score enabled the division of standard risk patients into two groups with different TTPs ( 83 % vs . 38 % at 3 years , P < 0 · 0001 ) and OS rates ( 88 % vs . 61 % at 5 years ; P = 0 · 003 ) . This study demonstrates that quantitative PCR is a robust , accurate and feasible technique for implementing in the daily routine as a surrogate for GEP - arrays .",
"___MASK52___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK52___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK52___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"An unusual presentation of medullary thyroid carcinoma . Medullary thyroid carcinoma ( P04629 ) is extremely uncommon having varied presentations & their prognosis is not exactly known ; but as P04629 is an aggressive tumor hence it needs to be documented in literature to help to know the behaviour of this variant . We report a rare presentation of medullary carcinoma of thyroid in a 48 years old man who presented with huge swelling at left side of neck extending from parotid to supraclavicular region with normal - sized thyroid gland of long duration . FNAC & incision HPE of this swelling was inconclusive so we had operated this swelling . Immunohistochemistry reported it as metastatic Medullary carcinoma of thyroid ; tumor cells express Cytokeratin , P01258 , P15941 , P08247 , P10645 . The stroma shows deposits of Amyloid , which have been confirmed by Congo red staining . Post - operatively FNAC from thyroid gland supported the diagnosis of Medullary carcinoma . Post - operatively the residual mass was regressed with chemotherapy & radiotherapy . The calcitonin level also decreased following this treatment . There was no recurrence at 11 months but ultimately patient died with metastasis .",
"The elmiric acids : biologically active anandamide analogs . As chemical entities , lipoamino acids have been known for some time . However , more recently their occurrence and importance in mammalian species has been discovered . They appear to have close relationships with the endocannabinoids not only structurally but also in terms of biological actions . The latter include analgesia , anti - inflammatory effects , inhibition of cell proliferation and calcium ion mobilization . To date about 40 naturally occurring members of this family have been identified and , additionally , several synthetic analogs have been prepared and studied . To facilitate their identity , a nomenclature system has been suggested based on the name elmiric acid ( P15941 ) . The prototypic example , N - arachidonoyl glycine , does not bind to P21554 , however it does inhibit the glycine transporter GLYT2a and also appears to be a ligand for the orphan G - protein - coupled receptor Q14330 . It may also have a role in regulating tissue levels of anandamide by virtue of its inhibitory effect on FAAH the enzyme that mediates inactivation of anandamide . Its concentration in rat brain is several - fold higher than anandamide supporting its possible role as a physiological mediator . Future studies should be aimed at elucidating the actions of all of the members of this interesting family of molecules .",
"Levels of NT - proBNP , markers of low - grade inflammation , and endothelial dysfunction during spironolactone treatment in patients with diabetic kidney disease . P00797 - angiotensin - aldosterone system ( RAAS ) blockade may reduce levels of biomarkers of chronic low - grade inflammation and endothelial dysfunction . We investigated the effect of spironolactone added to standard RAAS blockade on these biomarkers in an analysis of four original studies . MATERIALS AND METHODS : The studies were double - blind , randomised , placebo - controlled studies in 46 type 1 and 23 type 2 diabetic patients with micro - or macroalbuminuria treated with angiotensin - converting enzyme inhibitor ( P12821 inhibitor ) or angiotensin receptor blocker ( ARB ) , and randomised to additional treatment with spironolactone 25 mg and placebo daily for 60 days . OUTCOME MEASURES : Changes in inflammatory ( hsCRP , s - ICAM , P01375 α , P05231 , P10145 , Serum amyloid A , IL1β ) , endothelial dysfunction ( sE - selectin , s - P05362 , s - P19320 , P04275 , p - selectin , s - thrombomodulin ) and NT - proBNP after each treatment period . RESULTS : During spironolactone treatment , u - albumin excretion rate was reduced from 605 ( 411 - 890 ) to 433 ( 295 - 636 ) mg / 24 h , as previously reported . Markers of inflammation and endothelial dysfunction did not change ; only changes in NT - proBNP ( reduced by 14 % , p = 0 . 05 ) and serum amyloid A ( reduced by 62 % , p = 0 . 10 ) were borderline significant . DISCUSSIONS : Our results indicate that the renoprotective effect of spironolactone when added to RAAS blockade is not mediated through anti - inflammatory pathways since markers of inflammation and endothelial dysfunction are not affected during treatment .",
"P00374 protects endothelial nitric oxide synthase from uncoupling in tetrahydrobiopterin deficiency . DB00360 ( BH4 ) is a required cofactor for the synthesis of NO by endothelial nitric oxide synthase ( P29474 ) , and endothelial BH4 bioavailability is a critical factor in regulating the balance between NO and superoxide production ( P29474 coupling ) . Biosynthesis of BH4 is determined by the activity of GTP - cyclohydrolase I ( GTPCH ) . However , BH4 levels may also be influenced by oxidation , forming 7 , 8 - dihydrobiopterin ( BH2 ) , which promotes P29474 uncoupling . Conversely , dihydrofolate reductase ( P00374 ) can regenerate BH4 from BH2 , but whether P00374 is functionally important in maintaining P29474 coupling remains unclear . To investigate the mechanism by which P00374 might regulate P29474 coupling in vivo , we treated wild - type , BH4 - deficient ( hph - 1 ) , and GTPCH - overexpressing ( P30793 - Tg ) mice with methotrexate ( MTX ) , to inhibit BH4 recycling by P00374 . MTX treatment resulted in a striking elevation in BH2 and a decreased BH4 : BH2 ratio in the aortas of wild - type mice . These effects were magnified in hph - 1 but diminished in P30793 - Tg mice . Attenuated P29474 activity was observed in MTX - treated hph - 1 but not wild - type or P30793 - Tg mouse lung , suggesting that inhibition of P00374 in BH4 - deficient states leads to P29474 uncoupling . Taken together , these data reveal a key role for P00374 in regulating the BH4 vs BH2 ratio and P29474 coupling under conditions of low total biopterin availability in vivo .",
"B - cell maturation antigen ( Q02223 ) activation exerts specific proinflammatory effects in normal human keratinocytes and is preferentially expressed in inflammatory skin pathologies . TNFα is known to be expressed in human skin , regulating immune - related responses . Here we report that human normal skin keratinocytes express the members of the P01375 superfamily members O75888 ( APRIL ; O75888 ) , B cell - activating factor ( Q9Y275 ; Q9Y275 ) , and their receptors , B cell maturation antigen ( Q02223 ; Q02223 ) and transmembrane activator , calcium - modulator , and cyclophilin ligand interactor ( O14836 ; O14836 ) , in a distinct spatial pattern . Our data show a differential expression of these molecules within epidermal layers and skin appendages , whereas the Q9Y275 - specific receptor Q96RJ3 ( Q96RJ3 ) is absent . Importantly , APRIL and Q02223 but not Q9Y275 or O14836 are up - regulated in inflammatory skin lesions of psoriasis and squamous cell carcinomas . To explore the functional significance of this system in the skin , we assayed these receptors and ligands in cultured primary keratinocytes and HaCaT cells . We show that both cell types express Q9Y275 , APRIL , Q02223 , and O14836 . Furthermore , APRIL and / or Q9Y275 trigger nuclear factor - κB activation and P05231 and granulocyte macrophage colony - stimulating factor ( GM - P04141 ) expression through functional Q02223 receptors , an activation inhibited by anti - Q02223 short hairpin RNA . However , Q9Y275 and / or APRIL do not induce P10145 or TNFα production . Our data advance Q02223 as an inflammation - related TNFSFR member in keratinocytes , of potential importance in the management of inflammatory skin conditions .",
"Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK32___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .",
"The role of pemetrexed in advanced non small - cell lung cancer : special focus on pharmacology and mechanism of action . DB00642 is a newer antifolate drug that has been approved as first - line treatment for patients with advanced non - squamous , non - small cell lung cancer ( NSCLC ) in combination with cisplatin , and as single agent for relapsed or chemotherapy refractory NSCLC after platinum - containing chemotherapy , at a dose of 500 mg / m ( 2 ) . DB00642 undergoes intracellular activation by poly - gamma - glutamylation , that is essential for its antiproliferative activity . Polyglutamate derivatives mainly inhibit three key enzymes of intracellular folate metabolism , i . e . thymidylates synthase ( P04818 ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyltransferase ( GARFT ) , with P04818 being the most relevant target . DB00642 undergoes rapid renal elimination as unchanged parent compound , with a terminal half - life of between two to five hours . In later clinical development , the usefulness of supplementation with folic acid and vitamin B ( 12 ) became evident , to control pemetrexed - related toxicity . The results from the phase III upfront registration study , a retrospective observational data , and a recent maintenance study of pemetrexed in NSCLC suggest histological subtype to be the most important predictive marker for clinical outcome in patients receiving pemetrexed , DB00642 is active in patients with non - squamous cell NSCLC while no benefit is seen in patients with squamous - cell histology , possibly as a result of different expression of intratumoral P04818 . These are important steps towards individualisation of anticancer treatment in patients with advanced NSCLC .",
"Epidermal growth factor enhances androgen receptor ‑ mediated bladder cancer progression and invasion via potentiation of AR transactivation . P10275 ( AR ) plays a critical role in bladder cancer ( BCa ) development . Our early studies found AR knock - out mice ( with few androgens and deleted AR ) failed to develop BCa , yet 50 % of castrated mice ( with few androgens and existing AR ) still developed BCa in an N - butyl - N -( 4 - hydroxybutyl ) nitrosamine ( BBN ) carcinogen - induced BCa mouse model , suggesting the existing AR in BCa of castrated mice may still play important roles in promoting BCa development at the castration level of androgens . The mechanism underlying this and / or which factors potentiate AR function at the castration level of androgen remains unclear . Epidermal growth factor ( P01133 ) , a key player in BCa progression , has been demonstrated to be able to potentiate AR transactivation in prostate cancer . In the present study , we found that P01133 could increase BCa cell growth , migration and invasion in the presence of AR under the low amount of androgen and P01133 was able to potentiate AR transactivation through P00533 by activating PI3K / AKT and MAPK pathway at castration androgen level . The increased suppression effects by P00533 inhibitor of PD168393 on AR function after addition of anti - androgen , ___MASK32___ , further suggested AR might play a key role in the effects of P01133 on BCa progression and metastasis . Collectively , our results indicate that P01133 may be able to potentiate AR transactivation that leads to enhancing BCa progression , which may help us to develop a better therapeutic approach to treat BCa via targeting both P01133 and AR signaling .",
"Chronic daily tadalafil prevents the corporal fibrosis and veno - occlusive dysfunction that occurs after cavernosal nerve resection . OBJECTIVES : To determine whether a long - term single daily oral dose of a longer half - life phosphodiesterase - 5 ( O76074 ) inhibitor , tadalafil , has a similar effect to that of the shorter half - life O76074 inhibitors sildenafil and vardenafil , and can prevent the fibrosis and resultant corporal veno - occlusive dysfunction ( CVOD ) occurring after cavernosal nerve ( CN ) injury . MATERIALS AND METHODS : Male rats ( 10 per group ) had either a sham operation , unilateral CN resection ( P21554 ) or bilateral P21554 , and were left untreated or given retrolingually 5 mg / kg per day of tadalafil . After 45 days , CVOD was assessed via cavernosometry , and the underlying corporal tissue changes were examined by immunohistochemistry and histochemistry ( followed by quantitative image analysis ) , Western blots , and ad hoc methods . RESULTS : ___MASK14___ treatment normalized the low response to papaverine and high drop rate in the intracavernosal pressure measured by cavernosometry after P21554 compared with sham - operated rats . ___MASK14___ also normalized the increase in penile shaft collagen content , and the reduction in corporal smooth muscle cell ( SMC ) content , SMC / collagen , and replication index , and improved the lower collagen III / I ratio and the increase in apoptotic index , caused by P21554 , compared with sham operation . There were no effects of tadalafil on increased transforming growth factor beta1 , inducible nitric oxide synthase and xanthine oxidoreductase levels . CONCLUSIONS : A long - term single daily dose of tadalafil prevented CVOD and the underlying corporal fibrosis in the rat caused by CN damage , as effectively as the previously reported continuous treatment with vardenafil or sildenafil , through a cGMP - related mechanism that appears to be independent of inducible nitric oxide synthase induction .",
"DB00563 induces apoptosis through p53 / P38936 - dependent pathway and increases P12830 expression through downregulation of HDAC / Q15910 . DB00563 ( MTX ) is a dihydrofolate reductase ( P00374 ) inhibitor widely used as an anticancer drug in different kinds of human cancers . Here we investigated the anti - tumor mechanism of MTX against non - small cell lung cancer ( NSCLC ) A549 cells . MTX not only inhibited in vitro cell growth via induction of apoptosis , but also inhibited tumor formation in animal xenograft model . RNase protection assay ( RPA ) and RT - PCR demonstrated its induction of p53 target genes including DR5 , P38936 , Puma and Noxa . Moreover , MTX promoted p53 phosphorylation at Ser15 and acetylaion at Lys373 / 382 , which increase its stability and expression . The apoptosis and inhibition of cell viability induced by MTX were dependent on p53 and , partially , on P38936 . In addition , MTX also increased P12830 expression through inhibition of histone deacetylase ( HDAC ) activity and downregulation of polycomb group protein enhancer of zeste homologue 2 ( Q15910 ) . Therefore , the anticancer mechanism of MTX acts through initiation of p53 - dependent apoptosis and restoration of P12830 expression by downregulation of HDAC / Q15910 .",
"___MASK21___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK21___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .",
"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK32___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .",
"Tetrandrine inhibits proinflammatory cytokines , P35228 and P35354 expression in human monocytic cells . Tetrandrine ( TET ) , a bis - benzylisoquinoline alkaloid isolated from the dried root of hang - fang - chi ( Stephania tetrandra S . Moore ) , is traditionally used in China for treating inflammation , hypertension and silicosis . In this study , our aim was to examine the anti - inflammatory mechanism of TET through measuring the inducible nitric oxide synthase ( P35228 ) , cyclooxygenase - 1 , and - 2 ( P23219 and P35354 ) expression , cytokines ( P01375 , P05112 and P10145 ) formation , nitric oxide ( NO ) release and prostaglandin E2 ( DB00917 ) generation in lipopolysaccharide ( LPS ) - induced human monocytic ( THP - 1 ) cells . Results showed that TET remarkably suppressed the LPS ( 1 microg / ml ) induction of NO release and DB00917 generation . It also significantly attenuated the LPS - induced transcription of proinflammatory cytokines ( P01375 , P05112 and P10145 ) in a dose - dependent manner . Furthermore , TET at 100 microM significantly blocked the LPS induction of P35228 and P35354 expression , but not the P23219 . Taken together , these results suggest that TET exerts anti - inflammatory effects probably through the suppression of P35354 and P35228 expression .",
"DB00642 alters folate phenotype and inflammatory profile in EA . hy 926 cells grown under low - folate conditions . Elevated homocysteine is a risk marker for several major human pathologies . Emerging evidence suggests that perturbations of folate / homocysteine metabolism can directly modify production of inflammatory mediators . DB00642 acts by inhibiting thymidylate synthetase ( P04818 ) , dihydrofolate reductase ( P00374 ) , and glycinamide ribonucleotide formyltransferase ( GARFT ) . EA . hy 926 cells grown under low ( \" Lo \" ) and high ( \" Hi \" ) folate conditions were treated with pemetrexed . The concentrations of several intracellular folate derivatives were measured using LC - MRM / MS . Lo cells had lower total folate concentrations and a different distribution of the intracellular folate derivatives than Hi cells . Treatment with pemetrexed caused a decrease in individual folate analytes . Microarray analysis showed that several genes were significantly up or down - regulated in pemetrexed treated Lo cells . Several of the significantly up - regulated transcripts were inflammatory . Changes in transcript levels of selected targets , including P01024 , P10145 , and P00374 , were confirmed by quantitative RT - PCR . P01024 and P10145 transcript levels were increased in pemetrexed - treated Lo cells relative to Lo controls ; P00374 transcript levels were decreased . In Lo cells , P10145 and P01024 protein concentrations were increased following pemetrexed treatment . DB00642 drug treatment was shown in this study to have effects that lead to an increase in pro - inflammatory mediators in Lo cells . No such changes were observed in Hi cells , suggesting that pemetrexed could not modify the inflammatory profile in the context of cellular folate sufficiency .",
"Design , synthesis , and X - ray crystal structures of 2 , 4 - diaminofuro [ 2 , 3 - d ] pyrimidines as multireceptor tyrosine kinase and dihydrofolate reductase inhibitors . To optimize dual receptor tyrosine kinase ( RTK ) and dihydrofolate reductase ( P00374 ) inhibition , the E - and Z - isomers of 5 -[ 2 -( 2 - methoxyphenyl ) prop - 1 - en - 1 - yl ] furo [ 2 , 3 - d ] pyrimidine - 2 , 4 - diamines ( 1a and 1b ) were separated by HPLC and the X - ray crystal structures ( 2 . 0 and 1 . 4A , respectively ) with mouse P00374 and NADPH as well as 1b with human P00374 ( 1 . 5A ) were determined . The E - and Z - isomers adopt different binding modes when bound to mouse P00374 . A series of 2 , 4 - diaminofuro [ 2 , 3 - d ] pyrimidines 2 - 13 were designed and synthesized using the X - ray crystal structures of 1a and 1b with P00374 to increase their P00374 inhibitory activity . Wittig reactions of appropriate 2 - methoxyphenyl ketones with 2 , 4 - diamino - 6 - chloromethyl furo [ 2 , 3 - d ] pyrimidine afforded the Q99618 - P02748 unsaturated compounds 2 - 7 and catalytic reduction gave the saturated 8 - 13 . Homologation of the P02748 - methyl analog maintains P00374 inhibitory activity . In addition , inhibition of P00533 and P09619 were discovered for saturated P02748 - homologated analogs 9 and 10 that were absent in the saturated P02748 - methyl analogs ."
] |
[
"___MASK12___",
"___MASK14___",
"___MASK21___",
"___MASK32___",
"___MASK41___",
"___MASK52___",
"___MASK53___",
"___MASK73___",
"___MASK97___"
] |
___MASK41___
|
MH_train_449
|
interacts_with DB00013?
|
[
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK11___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"[ Pulmonary artery thromboembolism on the background of hyperhomocysteinemia ] . The article provides a detailed description of a clinical case report of acute massive pulmonary artery thromboembolism ( Q8WXA2 ) in an elderly female patient . She was diagnosed with a carrier state of polymorphism of genes associated with impairment in the folate cycle P42898 : 677 - TT , Q9UBK8 : 66 - AG and polymorphisms associated with disordered blood coagulation system F13 - GT ; P05106 : 1565 - TC ; P05121 ( P05121 ): 675 - 4G4G . She was also found to have hyperhomocysteinemia - 67 . 1 μmol / l and hyperaggregation syndrome . Timely prescribed antithrombotic therapy and an agent containing in its base folic acid , vitamins B6 and B12 after surgical intervention in the scope of endovascular recanalization of pulmonary arteries and additional thromboembolic therapy resulted in a favourable outcome .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"The plasminogen - activating system in hepatic stellate cells . DB00013 plasminogen activator ( uPA ) generates plasmin , a process inhibited by plasminogen - activator inhibitor ( P05121 ) - 1 and localized to the cell surface by binding of uPA to a specific receptor . Plasmin degrades extracellular matrix ( Q13201 ) both directly and by activation of matrix metalloproteinases ( MMPs ) . Because stellate cells play a central role in the pathogenesis of liver fibrosis both via production of Q13201 proteins and through secretion of MMPs , their contribution to plasmin generation was assessed . Stellate cells were prepared from rat liver and cultured on plastic . Northern analysis showed cellular expression of messenger RNA ( mRNA ) for P05121 , uPA , and uPA receptor . Zymography / reverse zymography identified cell - surface - associated uPA activity and uPA and P05121 in culture media . Net uPA activity in culture media was maximal after 7 days in culture and then declined , whereas P05121 antigen levels remained consistently elevated between 7 and 21 days in culture . Stellate cell - mediated plasmin generation was also seen in in vitro cultures supplemented with plasminogen . Because hepatic stellate cells ( HSCs ) contain retinoids and release them on activation , the effect of retinoic acid on the plasminogen - activating system was also assessed . Treatment of cultured HSCs with retinoic acid ( 1 micromol / L ) increased uPA secretion 2 . 6 - fold but did not alter P05121 . We conclude that stellate cells synthesize key components of the plasminogen - activating system and generate plasmin and therefore have the ability to regulate MMP activation . Upregulation of uPA synthesis by retinoic acid may have implications in matrix remodeling in sites of stellate cell activation in which high concentrations of retinoids may be achieved .",
"The effect of antisense inhibition of urokinase receptor in human squamous cell carcinoma on malignancy . Concomitant expression of urokinase type plasminogen activator ( uPA ) and its surface receptor ( Q03405 ) has been shown to correlate strongly with a more invasive tumor cell phenotype . A highly malignant human epidermoid carcinoma cell line ( HEp3 ) was transfected with a vector capable of expressing an antisense transcript complementary to 300 bases of the 5 ' end of Q03405 , including the ATG codon . Six stably transfected antisense ( AS - 2 , 3 , 5 , 9 , 10 , 12 ) and eight control clones were characterized . All clones produced high levels of uPA activity . Examination of collagenase production and doubling time showed that all of the clones tested produced similar activities . The antisense clones showed a 20 - 74 % reduction in the Q03405 sites ; the Q03405 mRNA level was also reduced . A test of the invasive ability of all clones in a modified chorioallantoic membrane ( P62158 ) showed that invasiveness of the antisense - inhibited clones was directly proportional to the density of surface Q03405 . The AS - 2 clone , which expressed the lowest number of uPARs showed a significantly reduced level of invasion . The invasiveness of additional AS - inhibited clones was also reduced . Seven control and four AS - inhibited clones were tested for tumorigenicity on CAMs of chick embryos . Inoculation of control cells produced large tumors , while the As clones were non - tumorigenic . AS - 2 did not produce tumors even if kept in vivo for up to 10 weeks . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Gene expression analysis of 1 , 25 ( OH ) 2D3 - dependent differentiation of HL - 60 cells : a cDNA array study . The alterations in gene expression associated with 1 , 25 ( OH ) 2D3 - induced differentiation of HL - 60 cells were studied in order to identify potential targets for further investigation of the genetic basis of acute myeloid leukaemia . Atlas human haematology filters , including 406 genes ( Clontech ) , were used to study gene expression in response to 1 , 25 ( OH ) 2D3 ( concentration , 5 x 10 - 8 mol / l ) for 24 and 72 h . Compared with untreated cells , expression differences were found in 43 genes . Downregulated genes at both time - points were : P01589 , CMYC , P06748 , P35659 , P51825 , Q01543 , htlf , P41218 , P11274 , Q13422 , P17213 and Q12968 . Upregulated genes at both time - points were P01584 , P08571 and Q07820 . P08174 , P19256 , P14316 , P16220 , P18848 , P63000 , TIAR , P42331 , P48634 , Q06187 , RCK , EV12B and P10153 were downregulated at 24 h , while P17947 , P46734 , P62324 and P10145 were upregulated . At 72 h the upregulated genes were IL1RA , P31785 , P61073 , P22362 , P10147 , P13236 , P13501 , O00626 , P07355 , Q01151 and Q03405 . cDNA array results were confirmed on randomly selected genes using quantitative real - time polymerase chain reaction for three upregulated ( P61073 , P01584 and P08571 ) and three downregulated ( P35659 , P51825 and Q01543 ) genes . Gene expression analysis after differentiation induction may provide a tool to study the roles of P35659 , P51825 and Q01543 in cell proliferation and differentiation . To demonstrate the genes that initiate differentiation , sequential gene expression analysis has to be performed during the first 24 h of the differentiation process .",
"___MASK22___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK69___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK69___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK69___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK69___ among adults with ADHD .",
"Development of peptidomimetic ligands of Pro - DB00149 - DB00145 - NH ( 2 ) as allosteric modulators of the dopamine D ( 2 ) receptor . A variety of stable , small - molecule peptidomimetic ligands have been developed to elucidate the mechanism by which the neuropeptide Pro - DB00149 - DB00145 - NH ( 2 ) ( P00747 ) modulates dopaminergic neurotransmission . Photoaffinity labeling ligands based upon P00747 peptidomimetics have been used to establish that P00747 binds to the P14416 at a site that is different from the orthosteric site , thus making P00747 and its peptidomimetics allosteric modulators of the dopamine receptor . Through the design , synthesis and pharmacological evaluation of conformationally constrained peptidomimetics containing lactam , bicyclic , and spiro - bicyclic scaffolds , support was provided for the hypothesis that the bioactive conformation of P00747 is a type II β - turn . In addition , studies with peptidomimetics designed to mimic either a type VI β - turn or polyproline II helix conformation yielded molecules that were able to modulate dopamine receptors because of their ability to place the carboxamide NH ( 2 ) pharmacophore in the same topological space as that seen in the type II β - turn . Extensive studies with the spiro - bicyclic P00747 peptidomimetics also established that both positive and negative modes of modulation were possible for the same series of peptidomimetics simply as a result of minor differences in the stereochemistry about the bridgehead carbon within the scaffold . This information was used to transform existing positive modulators into negative modulators , which demonstrated that small structural changes in the spiro - bicyclic dopamine receptor modulators are capable of causing major changes in the modulatory activity of P00747 peptidomimetics .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK1___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"DB00013 stimulates human vascular smooth muscle cell migration via a phosphatidylinositol 3 - kinase - Tyk2 interaction . Janus kinases Jak1 and Tyk2 play an important role in urokinase - type plasminogen activator ( uPA ) - dependent signaling . We have recently demonstrated that both kinases are associated with the uPA receptor ( Q03405 ) and mediate uPA - induced activation of signal transducers and activators of transcription ( Stat1 , Stat2 , and Stat4 ) in human vascular smooth muscle cells ( VSMC ) . Janus kinases are not only required for Stat activation but may also interfere with other intracellular signaling pathways . Here we report that in VSMC , Tyk2 interacts with a downstream signaling cascade involving phosphatidylinositol 3 - kinase ( P19957 - K ) . We demonstrate that uPA induces P19957 - K activation , which is abolished in VSMC expressing the dominant negative form of Tyk2 . The regulatory subunit p85 of P19957 - K co - immunoprecipitates with Tyk2 but not with Jak1 , Jak2 , or Jak3 , and uPA stimulation increases the P19957 - K activity in Tyk2 immunoprecipitates . Tyk2 directly binds to either of the two Src homology 2 ( SH2 ) p85 domains in a uPA - dependent fashion . We provide evidence that the Tyk2 - mediated P19957 - K activation in response to uPA is required for VSMC migration . Thus , two unrelated structurally distinct specific inhibitors of P19957 - K , wortmannin and LY294002 , prevent VSMC migration induced by uPA . No migratory effect of uPA was observed in VSMC expressing the dominant negative form of Tyk2 . Our results underscore the versatile function of Tyk2 in uPA - related intracellular signaling and indicate that P19957 - K plays a selective role in the regulation of VSMC migration .",
"Targeting of tumor cells by cell surface urokinase plasminogen activator - dependent anthrax toxin . DB00013 plasminogen activator receptor ( Q03405 ) binds pro - urokinase plasminogen activator ( pro - uPA ) and thereby localizes it near plasminogen , causing the generation of active uPA and plasmin on the cell surface . Q03405 and uPA are overexpressed in a variety of human tumors and tumor cell lines , and expression of Q03405 and uPA is highly correlated to tumor invasion and metastasis . To exploit these characteristics in the design of tumor cell - selective cytotoxins , we constructed mutated anthrax toxin - protective antigen ( PrAg ) proteins in which the furin cleavage site is replaced by sequences cleaved specifically by uPA . These uPA - targeted PrAg proteins were activated selectively on the surface of Q03405 - expressing tumor cells in the presence of pro - uPA and plasminogen . The activated PrAg proteins caused internalization of a recombinant cytotoxin , FP59 , consisting of anthrax toxin lethal factor residues 1 - 254 fused to the ADP - ribosylation domain of Pseudomonas exotoxin A , thereby killing the Q03405 - expressing tumor cells . The activation and cytotoxicity of these uPA - targeted PrAg proteins were strictly dependent on the integrity of the tumor cell surface - associated plasminogen activation system . We also constructed a mutated PrAg protein that selectively killed tissue plasminogen activator - expressing cells . These mutated PrAg proteins may be useful as new therapeutic agents for cancer treatment .",
"DB00013 binding and catabolism by Hep G2 cells is plasminogen activator inhibitor - 1 dependent , analogous to interactions of tissue - type plasminogen activator with these cells . The adherent human hepatoma cell line Hep G2 exhibits receptor mediated endocytosis and catabolism of tissue - type plasminogen activator . plasminogen activator inhibitor type - 1 ( t - PA . P05121 ) complexes formed when exogenous t - PA combines with endogenous P05121 in the extracellular matrix . To determine whether the other major PA , urokinase ( u - PA ) , which also complexes with P05121 , is metabolised via the same mechanism , 125I - labelled high ( hmw ) and low ( lmw ) molecular weight forms of u - PA were incubated with Hep G2 cells at 4 degrees C for 2 hr in the absence and presence of a 100 - fold excess of unlabelled ligand in order to detect specific binding . Both hmw and lmw 125I - u - PA formed complexes with P05121 and these bound specifically and with high affinity ( apparent Kd 3 . 9 and 4 . 1 nM , with Bmax 78 x 10 ( 3 ) and 83 x 10 ( 3 ) binding sites / cell respectively ) . Binding by each form of radiolabelled u - PA was inhibited in a dose - dependent fashion by unlabelled t - PA , hmw - u - PA , lmw - u - PA , and by monoclonal anti - P05121 antibody . At 37 degrees C , bound hmw and lmw 125I - u - PA . P05121 complexes were internalised and degraded rapidly . These findings indicate that the specificity of the previously described receptor which mediates P05121 dependent catabolism of t - PA by Hep G2 cells extends to complexes of u - PA with this inhibitor .",
"[ Measuring the concentration of various plasma and placenta extract proteolytic and vascular factors in pregnant patients with HELLP syndrome , pre -/ eclampsia and highly pathologic Doppler flow values ] . OBJECTIVE : Impaired trophoblast invasion plays a major role in the development of preeclampsia . Therefore various factors that are involved in invasion were investigated in gestational disease . METHODS : In pregnant women with HELLP - syndrome ( n = 18 ) , pre -/ eclampsia ( n = 21 ) and highly pathological Doppler flow measurements ( hpD ) ( n = 13 ) , plasma and placental tissue extract concentrations of uPA , uPA - receptor , tPA , P05121 , P22894 , P14780 , P01033 , thrombomodulin , and angiogenin were measured using ELISA . RESULTS : In all three collectives , P05121 plasma concentrations were significantly higher ( p < 0 , 05 ) than in normal pregnancies , in patients with HELLP - syndrome , tPA and P01033 plasma levels were also elevated . P14780 concentrations in placental tissue extracts were lower in pre -/ eclampsia than in normal pregnancies . CONCLUSIONS : Impaired placental implantation and remodelling in gestational disease is reflected by changes in plasma and placental tissue extract concentrations of various factors that are involved in these processes .",
"Inhibition of c - kit receptor tyrosine kinase activity by ___MASK15___ , a selective tyrosine kinase inhibitor . ___MASK15___ ( formerly known as CGP 57148B ) is a known inhibitor of the c - abl , bcr - abl , and platelet - derived growth - factor receptor ( P09619 ) tyrosine kinases . This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia . We sought to extend the activity profile of ___MASK15___ by testing its ability to inhibit the tyrosine kinase activity of c - kit , a receptor structurally similar to P09619 . We treated a c - kit expressing a human myeloid leukemia cell line , M - 07e , with ___MASK15___ before stimulation with Steel factor ( SLF ) . ___MASK15___ inhibited c - kit autophosphorylation , activation of mitogen - activated protein ( Q96HU1 ) kinase , and activation of Akt without altering total protein levels of c - kit , Q96HU1 kinase , or Akt . The concentration that produced 50 % inhibition for these effects was approximately 100 nmol / L . ___MASK15___ also significantly decreased SLF - dependent growth of M - 07e cells in a dose - dependent manner and blocked the antiapoptotic activity of SLF . In contrast , the compound had no effect on Q96HU1 kinase activation or cellular proliferation in response to granulocyte - macrophage colony - stimulating factor . We also tested the activity of ___MASK15___ in a human mast cell leukemia cell line ( HMC - 1 ) , which has an activated mutant form of c - kit . ___MASK15___ had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand - dependent activation of the wild - type receptor . These findings show that ___MASK15___ selectively inhibits c - kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival . This compound may be useful in treating cancers associated with increased c - kit kinase activity .",
"Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain . The perinatal brain requires a tightly regulated iron transport system . DB01592 regulatory proteins ( IRPs ) 1 and 2 are cytosolic proteins that regulate the stability of mRNA for the two major cellular iron transporters , transferrin receptor ( P02786 ) and divalent metal transporter - 1 ( P49281 ) . We studied the localization of IRPs , their change in expression during perinatal development , and their relationship to P02786 and P49281 in rat brain between postnatal days ( P01160 ) 5 and 15 . Twelve - micron frozen coronal sections of fixed brain tissue were obtained from iron - sufficient Sprague - Dawley rat pups on P01160 5 , 10 , and 15 , and were visualized at 20 to 1 , 000x light microscopy for diaminobenzidine activity after incubation with specific primary P09544 - 1 , P09544 - 2 , P49281 , and P02786 antibodies and a universal biotinylated secondary and tertiary antibody system . P09544 and transport protein expression increased in parallel over time . P21399 , P48200 , and P49281 were partially expressed in the choroid plexus epithelial cells at P01160 5 and 10 , and fully expressed at P01160 15 . The cerebral blood vessels and ependymal cells strongly expressed P21399 , P48200 , and P49281 as early as P01160 5 . Substantive P02786 staining was not seen in the choroid plexus or ependyma until P01160 15 . Glial and neuronal expression of P21399 , P48200 , P49281 , and P02786 in cortex , hippocampal subareas and striatum increased over time , but showed variability in cell number and intensity of expression based on brain region , cell type , and age . These developmental changes in P09544 and transporter expression suggest potentially different time periods of brain structure vulnerability to iron deficiency or iron overload .",
"DB00013 plasminogen activator induces angiogenesis and tumor vessel invasion in breast cancer . DB00013 plasminogen activator ( uPA ) is a proteolytic enzyme implicated in cancer invasion and tumor progression . DB00013 PA and its inhibitor ( P05121 ) appear to be new and independent prognostic markers in breast cancer . To investigate how uPA - and P05121 - levels correlate with angiogenesis and tumor vessel invasion , we counted microvessels and their tumor invasion and determined the uPA - and P05121 levels in 42 primary invasive breast carcinomas . 20 Patients had no lymph node metastasis at the time of surgery , while 22 patients had positive nodes . Using light microscopy , we highlighted the vessels by staining their endothelial cells immunocytochemically for CD31 and Factor VIII . After gaining tumor tissue extracts , we determined the uPA - and P05121 - levels by ELISA . A positive correlation between microvessel density , angioinvasion and uPA - and P05121 - levels was found . We speculate that high uPA levels may induce tumor neovascularisation , angioinvasion and may cause tumor progression and metastasis . The degradation of the vessel wall by uPA causes a leak . This wall defect may , on the one hand , be the stimulus for endothelial cell proliferation and formation of new blood vessels and , on the other hand , it may be the place of tumor cell entry .",
"Immunological and molecular characterization of plasminogen activator inhibitors 1 and 2 in baboon ( Papio anubis ) placental tissues . Two major plasminogen activator inhibitors ( P05121 and P05120 ) increase in the peripheral circulation during pregnancy in humans . P05121 is of vascular endothelial origin whereas P05120 is produced primarily by human placental tissues . This study was undertaken to determine a ) if P05121 and P05120 are also present in the baboon and b ) their association with pregnancy . Citrated plasma was obtained from pregnant baboons sequentially at 15 +/- 3 - day intervals between Days 30 and 140 of pregnancy . P05121 activity increased significantly ( p less than 0 . 05 ) at Day 120 ( 15 . 3 IU / ml ) and 140 ( 21 . 8 IU / ml ) of gestation and returned to baseline ( 2 . 6 IU / ml ) 48 h post cesarean section . Placental tissues obtained at cesarean section during the third trimester were either placed in explant culture , fixed for immunocytochemistry , or frozen for RNA extraction . Western blot analysis of tissue culture media ( TCM ) indicated that the polyclonal antibody to P05121 reacted with a major band ( Mr 47 000 ) in TCM from placental tissues while the P05120 antibody reacted primarily with a doublet ( Mr 67 000 and 69 000 ) in these same media . P05121 was immunocytochemically localized primarily in the chorioamniotic tissue ( P62158 - D ) and P05120 was found predominantly in placental villi . Slot blot hybridization with cDNAs to P05121 and P05120 indicated that the mRNA for P05120 was found primarily in placental villi , whereas the mRNA for P05121 was present in all three tissue compartments . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Role of steroid receptor coactivators in glucocorticoid and transforming growth factor beta regulation of plasminogen activator inhibitor gene expression . TGFbeta is a major regulator of extracellular matrix deposition and a potent inducer of type - 1 plasminogen activator inhibitor ( P05121 ) gene expression . We have reported that liganded glucocorticoid receptor ( GR ) represses TGFbeta transactivation of P05121 in Hep3B human hepatoma cells and that it interacts functionally and physically with the C - terminal activation domain of P84022 , a mediator of TGFbeta signaling . The ligand binding domain of GR is required for GR - mediated transrepression , but the GR DNA binding domain and activation function 1 domains are not . We report here that overexpression of steroid receptor coactivator - 1 ( Q15788 ) and GR - interacting protein - 1 ( Q9Y3R0 ) enhanced repression by liganded GR , and by a GR mutant defective in repression . Surprisingly , Q15788 and Q9Y3R0 also enhanced TGFbeta - induced activation from the TGFbeta - responsive sequence of the P05121 gene by a GR - independent mechanism . Coimmunoprecipitation and mammalian one - hybrid experiments demonstrated that Q15788 and Q9Y3R0 interact physically with endogenous P84022 and functionally with the C - terminal domain of P84022 to directly enhance transcription . Thus , the GR coactivators , Q15788 and Q9Y3R0 , act as both corepressors of the glucocorticoid repression of P05121 gene transcription , and coactivators of TGFbeta - induced activation of the P05121 promoter .",
"[ Expressions of receptor tyrosine kinases mRNA and protein in carcinoma of bladder ] . OBJECTIVE : To detect the expressions of receptor tyrosine kinases ( RTKs ) mRNA and protein and to explore potentially promising tumor markers and conceivable drug target in bladder cancer . METHODS : The expressions of RTKs mRNA and protein in tissue from invasive urothelial carcinoma of the bladder were examined by real - time quantitative PCR array and cytokine antibody array , with normal bladder tissue as control . The Results were analyzed using bioinformatic approaches . RESULTS : The expressions of P01135 , Q9NY15 , P05121 , O15123 , Q9NQ38 , O95841 , P58294 , P21741 , Q07325 , P28799 , Q01196 , P15692 , and P01137 were obviously upregulated in bladder cancer tissue , while those of O43854 , P21246 , P13500 , Q9GZP0 , Q92913 , P21583 , P09038 , P36955 , and P01375 were downregulated . Q9UM73 , Btk , EphB2 , ErbB4 , P09619 - α , ROS , Tie - 2 , Tyk2 , and P35916 were over - expressed in bladder cancer , while P42685 , Fyn , IGF - IR , P01308 R , Itk , P23458 , P52333 , and P06239 were low - expressed . CONCLUSION : Vascular endothelial growth factor / platelet - derived growth factor - targeted therapies may play an active role in treating carcinoma of bladder .",
"Restoration of flow following haemodialysis catheter thrombus . Analysis of rt - PA infusion in tunnelled dialysis catheters . PROBLEM : DB00013 and streptokinase are commonly used thrombolytic agents for obstructed central venous catheters . Although proven to be efficacious , these agents have the potential to induce fibrin breakdown and streptokinase can not be used repeatedly because of its allergenic nature . Published evidence suggests that DB00013 is safe and effective ( > 70 % efficacy for catheter installation ) and that P00750 ( rt - PA ) can achieve as much as 98 % success . OBJECTIVE : To describe our experience with and our protocol for the use of rt - PA as an alternative agent for catheter thrombolysis . DESIGN : Investigation of a cohort of haemodialysis patients with tunnelled central venous catheter ( SPCVC ) placed between December 2001 to August 2003 and who developed catheter thrombus ( female , n = 8 : male , n = 12 ) . Each patient was given an infusion of between 1 and 2 mg rt - PA / h for 4 h . The dose was dependent on partial or total line obstruction . The technical success of rt - PA is defined as returning catheter blood flow to > 250 mL / min for a 4 - h period . FINDINGS : Twenty patients required 57 infusions in 38 lumens between 01 / 01 / 02 to 01 / 09 / 03 . For completely blocked lines rt - PA was infused at 2 mg / h for 4 h achieving 85 % success rate . For inadequate flow ( < 250 mL / min ) rt - PA was infused at 1 mg / h for 4 h achieving an 88 % success rate . CONCLUSION : Rt - PA administered at 2 mg / h for blocked lines effectively restores haemodialysis catheter patency , and at 1 mg / h for sluggish lines is also effective in restoring blood flow through catheters .",
"The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice . P00747 activation to plasmin protects from lung fibrosis , but the mechanism underlying this antifibrotic effect remains unclear . We found that mice lacking plasminogen activation inhibitor - 1 ( P05121 ) , which are protected from bleomycin - induced pulmonary fibrosis , exhibit lung overproduction of the antifibrotic lipid mediator prostaglandin E2 ( DB00917 ) . P00747 activation upregulated DB00917 synthesis in alveolar epithelial cells , lung fibroblasts , and lung fibrocytes from saline - and bleomycin - treated mice , as well as in normal fetal and adult primary human lung fibroblasts . This response was exaggerated in cells from Pai1 -/- mice . Although enhanced DB00917 formation required the generation of plasmin , it was independent of proteinase - activated receptor 1 ( P25116 ) and instead reflected proteolytic activation and release of P14210 with subsequent induction of P35354 . That the P14210 / P35354 / DB00917 axis mediates in vivo protection from fibrosis in Pai1 -/- mice was demonstrated by experiments showing that a selective inhibitor of the P08581 c - DB00134 increased lung collagen to WT levels while reducing P35354 protein and DB00917 levels . Of clinical interest , fibroblasts from patients with idiopathic pulmonary fibrosis were found to be defective in their ability to induce P35354 and , therefore , unable to upregulate DB00917 synthesis in response to plasmin or P14210 . These studies demonstrate crosstalk between plasminogen activation and DB00917 generation in the lung and provide a mechanism for the well - known antifibrotic actions of the fibrinolytic pathway .",
"P04035 inhibitors up - regulate anti - aging klotho mRNA via RhoA inactivation in IMCD3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age - related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age - suppressor gene , klotho in mIMCD3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real - time RT - PCR . ___MASK24___ and pitavastatin increased the expression of klotho mRNA in a dose - dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho - kinase by Y27632 up - regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down - regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II - induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over - expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection .",
"DB00013 plasminogen activator receptor is expressed in invasive cells in gastric carcinomas from high - and low - risk countries . Gastric cancer is the second cancer causing death worldwide . Both incidence and mortality rates vary according to geographical regions . The receptor for urokinase plasminogen activator ( Q03405 ) is involved in extracellular matrix degradation by mediating cell surface associated plasminogen activation , and its presence on gastric cancer cells is linked to micro - metastasis and poor prognosis . Immunohistochemical analyses of a set of 44 gastric cancer lesions from Costa Rica showed expression of Q03405 in cancer cells in both intestinal subtype ( 14 of 27 ) and diffuse subtype ( 10 of 17 ) . We compared the expression pattern of Q03405 in gastric cancers from a high - risk country ( Costa Rica ) with a low - risk country ( Norway ) . We found Q03405 on gastric cancer cells in 24 of 44 cases ( 54 % ) from Costa Rica and in 13 of 23 cases ( 56 % ) from Norway . Q03405 was seen in macrophages and neutrophils in all cases . We also examined the nonneoplastic mucosa and found that Q03405 was more frequently seen in epithelial cells located at the luminal edge of the crypts in cases with Helicobacter pylori infection than in similar epithelial cells in noninfected mucosa ( p = 0 . 033 ; chi ( 2 ) = 4 . 54 ) . In conclusion , the expression of Q03405 in cancer cells in more than half of the gastric cancer cases suggests that their Q03405 - positivity do not contribute to explain the different mortality rates between the 2 countries , however , the actual prevalence of Q03405 - positive cancer cells in the gastric cancers may still provide prognostic information .",
"P00747 activator inhibitor type - 1 inhibits insulin signaling by competing with alphavbeta3 integrin for vitronectin binding . Functional cooperation between integrins and growth factor receptors has been reported for several systems , one of which is the modulation of insulin signaling by alphavbeta3 integrin . P00747 activator inhibitor type - 1 ( P05121 ) , competes with alphavbeta3 integrin for vitronectin ( VN ) binding . Here we report that P05121 , in a VN - dependent manner , prevents the cooperation of alphavbeta3 integrin with insulin signaling in NIH3T3 fibroblasts , resulting in a decrease in insulin - induced protein kinase B ( P31749 ) phosphorylation , vascular endothelial growth factor ( P15692 ) expression and cell migration . P01308 - induced HUVEC migration and angiotube formation was also enhanced in the presence of VN and this enhancement is inhibited by P05121 . By using specific P05121 mutants with either VN binding or plasminogen activator ( PA ) inhibiting activities ablated , we have shown that the P05121 - mediated interference with insulin signaling occurs through its direct interaction with VN , and not through its PA neutralizing activity . Moreover , using cells deficient for uPA receptor ( Q03405 ) we have demonstrated that the inhibition of P05121 on insulin signaling is independent of Q03405 - VN binding . These results constitute the first demonstration of the interaction of P05121 with the insulin response .",
"Erratum to : Improved Pharmacokinetic and Biodistribution Properties of the Selective DB00013 Inhibitor P05120 ( SerpinB2 ) by Site - Specific PEGylation : Implications for Drug Delivery .",
"DB00013 and tissue plasminogen activators and their P05121 inhibitor in tumors of patients with oral mucosal cancer : relationship with the main clinical morphological factors . Enhanced activation of plasminogen by the urokinase pathway ( uPA elevation ) in patients with cancer of the oral mucosa paralleled by an increase of P05121 level in the tumor compared to the adjacent mucosa was shown by enzyme immunoassay . No statistically significant associations of the level of the studied proteins in the tumor with such prognostic factors as location , growth form , histological structure , differentiation degree , size , and dissemination of the primary tumor , involvement of the regional lymph nodes , and stage of the disease were detected .",
"Comparison of expression profiles induced by dust mite in airway epithelia reveals a common pathway . BACKGROUND : Airway epithelial cells have shown to be active participants in the defense against pathogens by producing signaling and other regulatory molecules in response to the encounter . METHODS : In previous manuscripts , we have studied the effect of house dust mite ( HDM ) extract on both an epithelial cell - line ( H292 ) and primary nasal epithelial cell . When we compare these responses we conclude that the H292 cells more closely resemble nasal epithelium of healthy controls ( share 107 probe - sets ) than of allergic individuals ( share 17 probe - sets ) . RESULTS : Interestingly , probably because of an absent intraindividual variation between samples , more probe - sets ( 8280 ) change expression significantly in H292 than in either healthy ( 555 ) or allergic ( 401 ) epithelium . CONCLUSIONS : A direct comparison of all the responses in these epithelial cells reveals a core - response to HDM of just 29 genes . These genes ( P78556 , P10145 , P19875 , P09341 , IL - 1B , P15514 , P21580 , Q99075 , P35354 , P12643 , P01130 , Q03405 , P00749 , Q00653 , P19838 , P05412 , P18847 , P18146 , O15118 , Q8IUC6 , P29317 , P29279 , P28562 , O43609 , TLR - 3 , complement factor P01024 , Q9Y6Y0 , SerpinB3 , and Q9Y617 ) have described links with allergy or inflammation and may even describe the well - established relationship between viral infections and allergic exacerbations or allergy development .",
"Prognostic significance of urokinase plasminogen activator receptor and its cleaved forms in blood from patients with non - small cell lung cancer . DB00013 plasminogen activator ( uPA ) cleaves its three - domain cell surface receptor , Q03405 , liberating domain I [ Q03405 ( I ) ] and leaving the cleaved Q03405 ( II - III ) on the cell surface . Both intact and cleaved Q03405 can be shed from the cell surface . Q03405 ( I ) was previously shown to be a prognostic factor in lung tumour extracts . Here we analyse Q03405 forms in blood from patients with non - small cell lung cancer ( NSCLC ) . Preoperatively sampled plasma / serum from 32 patients with NSCLC was analysed . Three time - resolved fluoroimmunoassays ( TR - FIAs ) measuring intact Q03405 ( I - III ) ( TR - FIA 1 ) , Q03405 ( I - III ) + Q03405 ( II - III ) ( TR - FIA 2 ) and Q03405 ( I ) ( TR - FIA 3 ) were applied . The Spearman rank correlations between plasma and serum levels of Q03405 ( I - III ) , Q03405 ( I - III ) + Q03405 ( II - III ) , and Q03405 ( I ) were 0 . 89 , 0 . 94 and 0 . 68 respectively . Survival analysis demonstrated that high levels of all Q03405 forms were associated with shorter survival . Adjusted for histological subtype high plasma Q03405 ( I - III ) and Q03405 ( I ) levels as well as serum Q03405 ( I ) levels were significantly associated with shorter OS ( hazards ratios = 4 . 3 , 2 . 8 and 3 . 8 respectively ) . High blood levels of intact Q03405 and its cleaved forms are associated with poor prognosis in NSCLC .",
"Enhanced expression of urokinase plasminogen activator and its receptor in pancreatic carcinoma . DB00013 plasminogen activator ( uPA ) is a serine proteinase that has been suggested to play an important role in cancer invasion and metastasis . It binds to a specific membrane receptor denominated uPA receptor ( Q03405 ). uPA activates plasminogen to form plasmin , which participates in tissue degradation and proteolysis . Binding of uPA to its receptor accelerates Q96NZ9 ' s own activation from pro - uPA , enhancing the activity of the uPA / Q03405 cascade . Using immunohistochemistry and Northern blot analysis , we analysed the role of uPA and Q03405 in 30 human pancreatic cancers . Immunohistochemical analysis demonstrated moderate to strong immunostaining of both factors in most pancreatic cancers . Cancer lesions with signs of invasion exhibited the strongest immunohistochemical signals for both factors . In addition , in desmoplastic areas adjacent to the cancer cells , moderate uPA and Q03405 immunoreactivity was detectable . Northern blot analysis revealed a sixfold and a fourfold increase in uPA and Q03405 mRNA levels in pancreatic cancer , respectively , in comparison with normal controls ( P < 0 . 01 ) . Correlation of the Northern blot data with the clinical parameters of the patients indicated that patients with concomitant overexpression of uPA and Q03405 had a shorter post - operative survival ( median 9 months ; mean +/- s . d . 10 . 2 +/- 3 . 6 months ) than patients in whom only one or none of these factors were overexpressed ( median 18 months ; mean +/- s . d . 20 . 3 +/- 8 . 7 months ) ( P < 0 . 002 ) . Our data suggest that uPA and Q03405 may serve as prognostic markers in human pancreatic cancer and that the marked overexpression of both factors may create an environment that enables pancreatic cancer cells to invade surrounding tissues .",
"Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44 . 1 ± 72 . 1 days ) were genetically analyzed for P51787 , Q12809 , P15382 - 5 , P63252 , Q14524 , P36382 , and P62158 by using denaturing high - performance liquid chromatography and direct sequencing . Whole - cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 and Q12809 cDNA . In 5 of 7 patients , we identified 4 mutations ( p . N1774D , p . T290fsX53 , p . F1486del and p . N406K ) in Q14524 , and 1 mutation ( p . G628D ) in Q12809 . N1774D , F1486del , and N406K in Q14524 displayed tetrodotoxin - sensitive persistent late Na (+) currents . By contrast , Q14524 - T290fsX53 was nonfunctional . Q12809 - G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 mutations , as well as loss of function associated with the Q12809 mutation .",
"DB00013 receptor ( CD87 ) clustering in detergent - insoluble adhesion patches leads to cell adhesion independently of integrins . The urokinase - type plasminogen activator receptor ( Q03405 ) is a glycosylphosphatidyl inositol - anchored protein that mediates cell adhesion to the extracellular matrix protein vitronectin ( VN ) . We demonstrate here that this cell adhesion process is accompanied by the formation of an adhesion patch characterized by an accumulation of Q03405 into areas of direct contact between the cell and the matrix . The adhesion patch requires the glycolipid anchor and develops only on a VN - coated substrate , but not on fibronectin . It consists of detergent - insoluble microdomains that accumulate F - actin and tyrosine - phosphorylated proteins , but not beta ( 1 ) integrins . Lack of inhibition of adhesion in the presence of integrin - blocking reagents and adhesion on a VN fragment without the RGD sequence indicated that the adhesion of Q03405 - bearing cells on VN could occur independently of integrins . Hence , Q03405 - mediated cell adhesion on VN relies on the formation of a unique cellular structure that we have termed \" detergent - insoluble adhesion patch \" ( DIAP ) .",
"DB00013 gene expression indicates early invasive growth in squamous cell lesions of the uterine cervix . The plasminogen activating system plays a key role in the cascade of tumour - associated proteolysis leading to extracellular matrix degradation and stromal invasion . Changes in the expression of this system , consisting of urokinase - and tissue - type plasminogen activators ( uPA and tPA , respectively ) , plasminogen activator inhibitors ( P05121 , P05120 ) and uPA receptor , have been associated with tumour aggressiveness in a variety of solid malignant tumours . This paper describes a study of squamous intraepithelial lesions ( SILs , n = 36 ) , squamous cell carcinomas ( SCCs , n = 42 ) , and normal mucosa ( n = 5 ) of the uterine cervix by in situ hybridization with ( 35 ) S - labelled RNA probes . uPA transcripts were absent from normal mucosa and non - invasive lesions , but present in atypical epithelial cells of all microinvasive carcinomas ( n = 19 ) and in some of the more advanced invasive carcinomas ( n = 11 ) . P05121 transcripts were found in stromal cells of most tissue samples with , however , significantly increased levels in invasive SCC compared with Q15468 , microinvasive SCC , and normal mucosa . uPA - positive invasive carcinomas often displayed additional P05121 expression by tumour cells . At variance with uPA , tPA transcripts were found in atypical epithelial cells of low - and high - grade SILs . In the majority of SCCs tested ( 27 / 29 cases ) , the HPV 16 E6 / E7 oncogene and uPA transcription were correlated . uPA and P05121 expression indicates invasive growth when expressed by atypical epithelial cells of squamous cervical lesions . Moreover , the presence of uPA transcripts is indicative of early invasive growth . uPA and tPA seem to have different functions in the development of invasive properties in uterine cervical squamous epithelium .",
"Effect of atorvastatin on endothelial function and inflammation in long - duration type 1 diabetic patients without coronary heart disease and arterial hypertension . AIM : We evaluated the ability of atorvastatin , an P04035 inhibitor , to affect endothelial function and inflammation in long - duration ( > 10 years ) type 1 diabetes mellitus ( T1DM ) patients without coronary heart disease ( Q8NE62 ) and arterial hypertension ( AH ) . METHODS AND RESULTS : We randomized 204 Caucasians with long - duration T1DM into either the atorvastatin 40 mg / day plus hypolipaemic diet group ( n = 154 ) or the placebo plus hypolipaemic diet group ( n = 50 ) for 6 months . Endothelium - dependent flow - mediated ( FMD ) and endothelium - independent flow - mediated vasodilatation , serum levels of plasminogen activator inhibitor - 1 ( P05121 ) , P04275 ( P04275 ) and high sensitivity P02741 ( hs - CRP ) were estimated before and after treatment . After 6 months of therapy , FMD was increased by 44 % in the atorvastatin plus diet group compared with the placebo plus diet group . Treatment with atorvastatin led to a significant reduction in levels of P05121 and hs - CRP ; however , the elevation of P04275 level was observed . In the placebo plus diet group , we observed a significant reduction in levels of hs - CRP but not of P04275 and P05121 . CONCLUSIONS : ___MASK24___ improves endothelial function and reduces some proinflammatory and prothrombotic markers of atherosclerosis in T1DM patients without Q8NE62 and AH . The surprising effect of atorvastatin on serum P04275 levels in T1DM requires further study .",
"A cleavage - resistant urokinase plasminogen activator receptor exhibits dysregulated cell - surface clearance . DB00013 plasminogen activator receptor ( u - PAR ) binds urokinase plasminogen activator ( u - PA ) and participates in plasminogen activation in addition to modulating several cellular processes such as adhesion , proliferation , and migration . u - PAR is susceptible to proteolysis by its cognate ligand and several other proteases . To elucidate the biological significance of receptor cleavage by u - PA , we engineered and expressed a two - chain urokinase plasminogen activator ( tcu - PA ) cleavage - resistant u - PAR ( cr - u - PAR ) . This mutated receptor was similar to wild - type u - PAR in binding u - PA and initiating plasminogen activation . However , cr - u - PAR exhibited accelerated internalization and resurfacing due to direct association with the endocytic receptor alpha ( 2 )- macroglobulin receptor / low density lipoprotein receptor - related protein in the absence of the enzyme x inhibitor complex of tcu - PA and plasminogen activator inhibitor - 1 ( tcu - PA . P05121 ) . cr - u - PAR - expressing cells had enhanced migration compared with wild - type u - PAR - expressing cells , and cr - u - PAR was less sensitive to chymotrypsin cleavage as compared with wt u - PAR . Our studies suggest that these mutations in the linker region result in a rearrangement within the cr - u - PAR structure that makes it resemble its ligand - bound form . This constitutively active variant may mimic highly glycosylated cleavage - resistant u - PAR expressed in certain highly malignant cancer - cells .",
"Tissue plasminogen activator and urokinase mediate the binding of DB00142 - plasminogen to plasma fibrin I . Evidence for new binding sites in plasmin - degraded fibrin I . The effect of tissue plasminogen activator ( TPA ) or urokinase on the specific binding of human DB00142 - plasminogen to fibrin I formed in plasma by clotting with Reptilase was studied using 125I - plasminogen and 131I - fibrinogen . In the absence of TPA , small amounts of plasminogen were bound to fibrin I . TPA induced binding of plasminogen to plasma fibrin I that was dependent upon the concentrations of TPA and plasminogen as well as upon the time of incubation . P00747 binding occurred in association with fibrin clot lysis and the formation in the clot supernatant of alpha 2 - plasmin inhibitor - plasmin complexes . DB00013 also induced binding of plasminogen to plasma fibrin I that was concentration - and time - dependent . The molecular form of plasminogen bound to the fibrin I plasma clot was identified as DB00142 - plasminogen by dodecyl sulfate - polyacrylamide gel electrophoresis and by fast performance liquid chromatography . Further studies demonstrated that fibrin I formed from fibrinogen that had been progressively degraded by plasmin - bound DB00142 - plasminogen . The mole ratio of plasminogen bound increased with the time of plasmin digestion . DB00142 - plasminogen did not bind to fibrin I formed from fibrinogen progressively digested by human leukocyte elastase , thereby demonstrating the specificity of plasmin . These studies demonstrate that plasminogen activators regulate the binding of DB00142 - plasminogen to fibrin I by catalyzing plasmin - mediated modifications in the fibrin substrate .",
"DB00013 receptor , P03956 and P14780 are markers to differentiate prognosis , adenoma and carcinoma in thyroid malignancies . The identification of high - risk patients with thyroid cancer and the preoperative differentiation between follicular adenoma and carcinoma remain clinically challenging . Our study was conducted to analyze whether the quantification of matrix metalloproteinases ( MMPs ) and urokinase - type plasminogen activator receptor ( u - PAR ) and transcription factor binding to the u - PAR promoter improve prognostic predictability and differential diagnosis of thyroid tumors . Tumor / normal tissue was collected from 69 prospectively followed patients with thyroid carcinomas ( papillary , medullary , follicular and anaplastic , PTC , P04629 , FTC and ATC ) or follicular adenomas . Q03405 , P03956 , P09237 and P14780 amounts were determined by ELISA , and transcription factor binding was determined by electrophoretic mobility shift assay . Binding of transcription factors to the u - PAR promoter was observed , but not associated with u - PAR expression . Carcinomas except P04629 expressed significantly more u - PAR / MMPs than adenomas / normal tissues , this being associated with advanced pT - or M - stages . P03956 and P14780 were significantly higher in follicular carcinomas than in adenomas . In carcinomas , high u - PAR - gene expression correlated significantly with high P14780 , the latter being associated with P09237 in normal tissues . Poor survival in differentiated tumors was associated in trend ( p = 0 . 07 ) ; poor survival of all patients ( p = 0 . 043 ) and especially of patients with carcinomas of follicular origin ( including ATC ) , but not medullary carcinomas , were significantly associated with high u - PAR - protein ( p = 0 . 015 ) . Quantification of u - PAR is of prognostic relevance in thyroid carcinomas of non - c - cell origin , and u - PAR in part may be regulated nontranscriptionally in thyroid cancers . This is the first study to suggest P03956 /- 9 as significant differentiation markers between follicular adenoma and follicular carcinoma .",
"Characterization of the 5 ' flanking region of the rat P35462 gene . The P35462 has a restricted regional distribution in brain and is regulated by dopaminergic agents . Additionally , the D ( 3 ) gene is implicated in the pathogenesis of several neuropsychiatric disorders or in their response to pharmacological agents . Elucidating its transcription control mechanisms is therefore of interest in order to explain these biological features of the D ( 3 ) gene . In this study , the 5 ' flanking region of the rat D ( 3 ) gene was characterized by isolating the 5 ' end of its cDNA as well as 4 . 6 kb of genomic sequence . Analysis of this region revealed the presence of two new exons 196 - bp and 120 - bp long , separated by an 855 - bp intron , located several kilobases upstream of the previously published coding exons . Thus , current evidence indicates that the rat D ( 3 ) gene is organized into eight exons . Transcription initiation site was determined by primer extension analysis and repeated rounds of 5 ' RACE and was found to localize at a pyrimidine - rich consensus ' initiator ' sequence , similar to the rat D ( 2 ) gene . The D ( 3 ) promoter lacks TATA or CAAT boxes but unlike that of other dopamine receptor genes has only 52 % GC content . Functional analysis of D ( 3 ) promoter deletion mutants fused to a reporter gene in TE671 cells , which endogenously express this gene , revealed strong transcriptional activity localized within 36 nucleotides upstream of transcription start site , and a potent silencer between bases -- 37 and -- 537 . The D ( 3 ) promoter is inactive in P13671 and COS7 cells . We conclude that the D ( 3 ) gene , similar to the closely related D ( 2 ) gene , is transcribed from a tissue specific promoter which is under intense negative control .",
"[ P00747 activator system and its clinical significance in patients with a malignant disease ] . DB00013 ( uPA ) plays an essential role in the activation of plasminogen to plasmin , a serine protease participating in the activation of matrixmetaloproteinases , latent elastases , growth factors and cytokines involved in the degradation of extracellular matrix elements . Together with its receptor ( Q03405 ) , tissue activator ( tPA ) and urokinase inhibitors ( P05121 , P05120 , P05154 and protease nexin ) , it forms the plasminogen activator system ( DB00233 ) , a component of metastatic cascade importantly contributing to the invasive growth and angiogenesis of malignant tumours . P05121 inhibits uPA - dependent invasiveness of some cancer cell lines . The vitronectin - P05121 complex inhibits migration of smooth muscle cells by binding alpha ( v ) beta3 integrin to vitronectin . P05121 or its deficiency interferes with signalling pathways such as PI3K / Akt and JAK / P35610 and it is included in the processes of maintaining the integrity of the endothelial cells and thereby regulation of cell death . P05121 affects apoptosis by reducing cell adhesion and functioning of intracellular signalling pathways . The individual components of DB00233 undoubtedly play an important role in angiogenesis and metastasising of malignant tumours . In the near future , results of published studies with various types of cancer could be reflected in diagnostic and therapeutic algorithms and , at the same time , could serve as the goal for targeted therapies .",
"DB00013 - dependent human vascular smooth muscle cell adhesion requires selective vitronectin phosphorylation by ectoprotein kinase CK2 . DB00013 ( uPA ) - and urokinase receptor ( Q03405 ) - dependent cell adhesion to the extracellular matrix protein vitronectin ( Vn ) is an important event in wound healing , tissue remodeling , immune response , and cancer . We recently demonstrated that in human vascular smooth muscle cells ( VSMC ) uPA / Q03405 are functionally associated with the ectoprotein kinase casein kinase - 2 ( CK2 ) . We now asked whether CK2 regulates uPA - dependent cell adhesion to Vn , since the latter is a natural CK2 substrate . We found that Vn is indeed selectively phosphorylated by CK2 and that this phosphorylation is uPA - regulated in VSMC . Vn induces release of ecto - CK2 from the cell surface via a process termed as \" shedding . \" CK2 - mediated Vn phosphorylation was decisive for the uPA - dependent VSMC adhesion . Specific inhibition of CK2 completely abolished the uPA - induced cell adhesion to Vn . This effect was specific for cell adhesion to Vn and required participation of both Q03405 and alpha ( v ) beta ( 3 ) integrins as adhesion receptors . CK2 localization at the cell surface was highly dynamic ; Vn induced formation of clusters where CK2 colocalized with Q03405 and alpha ( v ) beta ( 3 ) integrins . These results indicate that the uPA - dependent VSMC adhesion is a function of selective Vn phosphorylation by the ectoprotein kinase CK2 and suggest a regulatory role for Vn phosphorylation in the uPA - directed adhesive process .",
"Signaling cascade that mediates endothelial nitric oxide synthase activation induced by atrial natriuretic peptide . Atrial natriuretic peptide ( P01160 ) induces activation of nitric oxide - synthase ( NOS ) . AIMS : to identify the isoform of NOS involved in P01160 effects , to study whether P01160 modifies NOS expression and to investigate the signaling pathways and receptors involved in NOS stimulation . NOS activation induced by P01160 would be mediated by endothelial NOS ( P29474 ) since neuronal or inducible NOS inhibition did not alter P01160 effect . The peptide induced no changes in P29474 protein expression . NOS activity stimulated by P01160 , in the kidney , aorta and left ventricle , was partially abolished by the P16066 / B antagonist , as well as PKG inhibition , but no difference in atria was observed . 8 - Br - cGMP partially mimicked the effect of P01160 on NOS in all tissues . NOS stimulation by P01160 in atria disappeared when G protein was inhibited , but this effect was partial in the other tissues . P62158 antagonist abolished NOS stimulation via P01160 . Inhibition of the P98160 , PKC or P19957 kinase / Akt pathway failed to alter NOS activation induced by P01160 . P01160 would activate P29474 in the aorta , heart and kidney without modifying the expression of the enzyme . P01160 would interact with P17342 coupled via G proteins leading to the activation of Ca ( 2 +)- calmodulin - dependent NOS in atria ; while in ventricle , aorta and kidney , P01160 could also interact with P16066 / B , increasing cGMP , which in turns activates PKG to stimulate P29474 .",
"DB00013 receptor genotypes in colorectal cancer . A previous study has reported a high frequency of rare alleles of the urokinase - type plasminogen activator receptor ( Q03405 ) in a set of 15 colorectal cancer ( CRC ) cell lines . Our study investigated Q03405 gene variation in 92 CRC patients and in tumour DNA from a subset of 69 patients using the Q03405 - IVS3 marker located in an intron of this gene . The overall distribution of the marker alleles in the patients did not differ significantly from a set of 105 controls . A pairwise analysis of individual allele frequencies showed , however , that the common allele 147 was significantly decreased ( P = 0 . 027 ) and allele 149 was significantly increased ( P = 0 . 033 ) in the patients . These results may indicate an effect of Q03405 gene variation in CRC carcinogenesis and encourages further examination of this marker in an independent series of patients .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK96___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"[ Results of in situ arterial thrombolysis by the combination of urokinase and lysyl plasminogen in acute arterial occlusive diseases of the lower limbs ] . 35 patients with acute arterial occlusions [ 27 ] and graft thromboses [ 8 ] , responsible for severe and recent ischemia , were treated by fibrinolytic therapy ( DB00013 : 1 000 units / kg / hour , and Lys P00747 ) . These drugs were delivered at the site of occlusions using a 5 French catheter . Angiographically , initial success was obtained in 30 patients ( 85 % ) and a significant clinical benefit persisted 5 months later , in 20 patients ( 57 % ) . 4 distal embolisms during the treatment were noted , and one woman died a few hours after the withdrawal of an axillary catheter of a cerebellar infarction . Only two minor ( 6 % ) and one severe ( 3 % ) groin hematoma were encountered . No patient had at any moment a fibrinogen concentration lower than 1 g / l . Thus , the thrombolytic treatment used in the study appears as effective as locally administered DB00086 but better tolerated .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK27___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK27___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK27___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK27___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"P02786 and P60709 as the best reference genes to quantify DB00013 P00747 Activator in breast cancer . BACKGROUND : Biomedical researchers have long looked for ways to diagnose and treat cancer patients at the early stages through biomarkers . Although conventional techniques are routinely applied in the detection of biomarkers , attitudes towards using Real - Time PCR techniques in detection of many biomarkers are increasing . Normalization of quantitative Real - Time PCR is necessary to validate non - biological alteration occurring during the steps of RNA quantification . Selection of variably expressed housekeeping genes ( HKs ) will affect the validity of the data . The aim of the present study was to identify uniformly expressed housekeeping genes in order to use in the breast cancer gene expression studies . DB00013 P00747 Activator was used as a gene of interest . FINDINGS : The expression of six HKs ( P02786 , P08236 , P04406 , P60709 , P00492 and P05388 ) was investigated using geNorm and NormFinder softwares in forty breast tumor , four normal and eight adjacent tissues . P05388 and P04406 revealed maximum M value , while P02786 demonstrated lowest M value . CONCLUSIONS : In the present study the most and the least stable genes were P02786 and P05388 respectively . P02786 and P60709 were verified as the best combination of two genes for breast cancer quantification . The result of this study shows that in each gene expression analysis HKs selection should be done based on experiment conditions .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK15___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK15___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"Regulation by nitric oxide of endotoxin - induced tissue factor and plasminogen activator inhibitor - 1 in endothelial cells . The increase in nitric oxide ( NO ) production in lipopolysaccharide ( LPS ) - induced sepsis is thought to contribute to the development of shock . However , NO could also play an antithrombotic role . Little is known about the modulating effect of NO on the endothelial overexpression and production of tissue factor ( TF ) and plasminogen activator inhibitor - 1 ( P05121 ) occurring in endotoxemia . We analyzed the effect of N ( G )- nitro - L - arginine - methyl - ester ( L - NAME ) , an inhibitor of NO synthases , and S - nitroso - N - acetyl - D , L - penicillamine ( P60880 ) , a NO donor , on the expression and synthesis of TF and P05121 by LPS - challenged human umbilical vein endothelial cells ( HUVEC ) : L - NAME enhanced the increase in TF mRNA and antigen levels ( P < 0 . 05 ) observed in LPS - treated HUVEC ; P60880 down - regulated the LPS - induced TF increment ( p < 0 . 05 ) . However , no effects of NO on regulation of the LPS - dependent increase in P05121 could be seen . Thus , NO could play an antithrombotic role in sepsis by down - regulating the endothelial overexpression and production of TF .",
"DB00013 receptor counteracts vascular smooth muscle cell functional changes induced by surface topography . Current treatments for human coronary artery disease necessitate the development of the next generations of vascular bioimplants . Recent reports provide evidence that controlling cell orientation and morphology through topographical patterning might be beneficial for bioimplants and tissue engineering scaffolds . However , a concise understanding of cellular events underlying cell - biomaterial interaction remains missing . In this study , applying methods of laser material processing , we aimed to obtain useful markers to guide in the choice of better vascular biomaterials . Our data show that topographically treated human primary vascular smooth muscle cells ( VSMC ) have a distinct differentiation profile . In particular , cultivation of VSMC on the microgrooved biocompatible polymer E - shell induces VSMC modulation from synthetic to contractile phenotype and directs formation and maintaining of cell - cell communication and adhesion structures . We show that the urokinase receptor ( Q03405 ) interferes with VSMC behavior on microstructured surfaces and serves as a critical regulator of VSMC functional fate . Our findings suggest that microtopography of the E - shell polymer could be important in determining VSMC phenotype and cytoskeleton organization . They further suggest Q03405 as a useful target in the development of predictive models for clinical VSMC phenotyping on functional advanced biomaterials .",
"Binding of urokinase to low density lipoprotein - related receptor ( Q14764 ) regulates vascular smooth muscle cell contraction . DB00013 plasminogen activator ( uPA ) is a multifunctional protein that has been implicated in several physiological and pathological processes involving cell adhesion and migration in addition to fibrinolysis . In a previous study we found that two - chain urokinase plasminogen activator ( tcuPA ) stimulates phenylephrine - induced vasoconstriction of isolated rat aortic rings . In the present paper we report that uPA (-/-) mice have a significantly lower mean arterial blood pressure than do wild type mice and that aortic rings from uPA (-/-) mice show an attenuated contractile response to phenylephrine . In contrast , the blood pressure of urokinase receptor knockout ( Q03405 (-/-) ) mice and the response of their isolated aortic rings to phenylephrine were normal , indicating that the effect of uPA on vascular contraction is independent of Q03405 . Addition of mouse and human uPA almost completely reversed both the impaired vascular contractility and the lower arterial blood pressure in vivo . The in vitro and in vivo effects of infused uPA on aortic contractility and the restoration of normal blood pressure in uPA (-/-) mice were prevented by antibody to low - density lipoprotein receptor - related protein / alpha ( 2 )- macroglobulin receptor ( Q14764 ) . A modified form of uPA that lacks the kringle failed to restore the blood pressure in uPA (-/-) mice , notwithstanding having a longer half - life in the circulation . Ligands that regulate the interaction of uPA with Q14764 , such as P05121 or the P05121 - derived peptide ( EEIIMD ) , abolished the vasoactivity of tcuPA in vitro and in vivo . These studies identify a novel signal transducing cellular receptor pathway involved in the regulation of vascular contractility .",
"Leukocyte urokinase plasminogen activator receptor and PSGL1 play a role in endogenous arterial fibrinolysis . Fibrin is an integral component of arterial thrombi . Using a mouse model of arteriolar thrombosis , high - speed fluorescence microscopy reveals that , within minutes , the fibrin content of thrombi rapidly increases and then decreases . The decrease in fibrin coincides with leukocyte binding to the thrombi , a process mediated by the interaction of leukocyte P16109 glycoprotein ligand - 1 ( Q14242 ) with P16109 on the surface of activated platelets . Because leukocytes possess urokinase - type plasminogen activator ( uPA ) activity , we used mice deficient in uPA or the uPA receptor ( Q03405 ) to explore the contribution of leukocyte - associated uPA to the loss of fibrin from these thrombi . Fibrin loss in both uPA - deficient mice and Q03405 - deficient mice was reduced compared with that in wild - type controls . Transfusion of leukocytes from wild - type mice into Q03405 - deficient mice restored fibrin loss to levels similar to that in wild - type mice . In contrast , transfusion of leukocytes from mice deficient in Q03405 or Q14242 did not enhance fibrin loss . Thus , fibrin loss from microarteriolar thrombi is mediated , at least in part , by leukocyte - associated uPA in a process that requires leukocyte Q03405 and Q14242 .",
"Functions of the fibrinolytic system in human Ito cells and its control by basic fibroblast and platelet - derived growth factor . During liver fibrogenesis , hepatic stellate cells ( P19526 ) proliferate and migrate under the influence of growth factors , including platelet - derived growth factor ( PDGF ) and basic - fibroblast growth factor ( b - FGF ) . The plasminogen activation system regulates extracellular matrix ( Q13201 ) catabolism and cell movement . We evaluated the expression and biological functions of the plasminogen activation system in human P19526 and its interaction with PDGF and b - FGF . DB00013 - plasminogen activator receptors ( u - PAR ) were measured by radioligand binding , cell cross - linking , immunoassay , and RNAse protection assay . u - PA and plasminogen activator inhibitors ( PAIs ) expression and activities were analyzed by zymography , immunoassay , and RNase protection assay . Cell migration and proliferation , studied in Boyden chambers and by microscopic counting , were evaluated after the addition of PDGF , b - FGF , and blockade with anti - u - PA , anti - u - PAR antibodies , and antisense oligodeoxynucleotides ( aODN ) against u - PAR mRNA . We have shown that P19526 produce u - PAR , u - PA , and P05121 . PDGF and b - FGF up - regulate u - PA and u - PAR , but not P05121 , and exogenous addition of u - PA stimulates P19526 proliferation , chemotaxis , and chemoinvasion . Inhibition of u - PA / u - PAR with antibodies against u - PA or u - PAR and with u - PAR aODN inhibit the proliferative , chemotactic , and chemoinvasive activity of PDGF and b - FGF . These findings indicate that u - PA and u - PAR are required for the mitogenic and chemoinvasive activity of PDGF and b - FGF on P19526 .",
"DB00013 plasminogen activator expression by primary and HPV 16 - transformed keratinocytes . The molecular events underlying progression of human papillomavirus ( HPV ) 16 - associated intraepithelial neoplasia to invasive cancer have not been studied in detail . Penetration of the basement membrane is an early , but poorly understood step in this process and probably involves the action of one or more metallo - and serine proteinases . P00749 ( uPA ) is a serine proteinase that has been implicated in the pathogenesis of several epithelial tumors , but its role in HPV - associated tumors is not known . To examine uPA expression by HPV 16 - transformed keratinocytes in vitro , primary foreskin keratinocyte cultures were transfected by HPV 16 DNA . The primary parental cells and the HPV 16 - transformed keratinocytes were studied using substrate gel zymography , Western blot analysis and an in vitro assay measuring penetration of a Matrigel artificial basement membrane . Both uPA and its inhibitor , plasminogen activator inhibitor - 1 ( P05121 ) , were overexpressed in the HPV 16 - transformed cells relative to the parental cell line . The transformed cells , but not the parental cells , were able to degrade and penetrate the Matrigel membrane and penetration was blocked by both P05121 and by antibodies to uPA . Our data suggest that HPV 16 - induced transformation of keratinocytes is associated with upregulation of uPA expression . In conjunction with other proteinases , uPA plays an important role in the ability of HPV 16 - transformed keratinocytes to penetrate artificial basement membranes .",
"The anti - aging and tumor suppressor protein Q9UEF7 enhances differentiation of a human oligodendrocytic hybrid cell line . Q9UEF7 functions as an aging suppressor , which , in mice , extends lifespan when overexpressed and accelerates development of aging - like phenotypes when disrupted . Q9UEF7 is mainly expressed in brain and kidney and is secreted into the serum and P04141 . We have previously shown that Q9UEF7 is reduced in brains of old monkeys , rats , and mice . We further reported the ability of Q9UEF7 to enhance oligodendrocyte differentiation and myelination . Here , we examined the signaling pathways induced by Q9UEF7 in Q03405 . 13 , a human oligodendrocytic hybrid cell line . We show that exogenous Q9UEF7 affects the P29323 and Akt signaling pathways , decreases the proliferative abilities and enhances differentiation of Q03405 . 13 cells . Furthermore , microarray analysis of Q9UEF7 - treated Q03405 . 13 cells reveals a massive change in gene expression with 80 % of the differentially expressed genes being downregulated . Using gene set enrichment analysis , we predicted potential transcription factors involved in regulating Q9UEF7 - treated Q03405 . 13 cells and found that these cells are highly enriched in the gene sets , that are similarly observed in cancer , cardiovascular disease , stress , aging , and hormone - related chemical and genetic perturbations . Since Q9UEF7 is downregulated in all brain tumors tested to date , enhancing Q9UEF7 has therapeutic potential for treating brain and other malignancies .",
"P00747 activator dependent pathways in the dissemination of human tumor cells in the chick embryo . We have previously shown that inhibition of uPA activity of a human tumor - HEp3 - results in a drastic reduction of its metastasis in the chick embryo . Using 125IUdR - labeled tumor cells , we have now studied the role of uPA in individual steps of tumor metastasis . We found that , 48 hr after inoculation of tumor cells on the P62158 , the organs of the embryos , inoculated with cells in which uPA was inhibited , contained 4 - fold less cells than the controls . Neither the initial advance of the tumor mass into the P62158 nor the process of extravasation was affected by the inhibition of tumor uPA . However , the infiltration of the P62158 mesenchyme by individual tumor cells was blocked when tumor uPA activity or production was inhibited . In addition , indirect evidence implicated uPA as an essential factor in the tumor cell intravasation .",
"A pleiotropic antiatherogenic action of ibuprofen . Ibuprofen is a cyclooxygenase ( P23219 and P35354 ) inhibitor known to reduce the production of prostaglandins that play prominent role in inflammation . Other properties of the drug , aside from its anti - inflammatory effects , have been recently studied . In this paper we shall discuss several properties of ibuprofen that making the drug interesting for treatment of conditions associated with atherosclerosis . Ibuprofen exerts pleiotropic effects such as inhibition of adhesion and transendothelial migration of leukocytes , suppressing intracellular production of reactive oxygen species and oxidative modification of LDL . Interestingly , ibuprofen increased HDL cholesterol levels and reduced the level of triglicerides . Ibuprofen can also modulate efficiency of fibrynolisis by inhibiting production of plasminogen activator inhibitor ( P05121 ) . This properties of ibuprofen may be due to changing the activity of transcription factors . Ibuprofen inhibits the activation of NF - kB and activates PPARa and PPARg .",
"DB00013 plasminogen activator , Q03405 , P08253 , and P14780 in the P13671 - glioblastoma rat model . BACKGROUND : In glioblastoma multiforme ( GBM ) , the serine protease urokinase plasminogen activator ( uPA ) , and matrix metalloproteases ( P08253 / P14780 ) contribute to its invasive growth pattern , which is the major obstacle to successful surgical treatment . MATERIALS AND METHODS : The expression of uPA was determined in monolayers and spheroids of the rodent GBM cell line P13671 by immunohistochemistry and polymerase chain reaction ( PCR ) . The longitudinal expression of proteases was studied in orthotopically implanted spheroids by semi - quantitative immunohistochemistry ( IHC ) in Sprague Dawley rats ( n = 40 ) . The tumor volume was monitored by magnetic resonance imaging ( Q9BWK5 ) . RESULTS : In vitro , the GBM cell line P13671 expresses high levels of uPA . In vivo , a continuous increase of uPA , uPA - receptor ( Q03405 ) , P08253 , and P14780 expression was found in the infiltration zone . uPA was located exclusively in the infiltration zone and in the vascular basal layers . The mean tumor volume 23 days after implantation was 3 . 2 mm3 . CONCLUSION : uPA , Q03405 , P08253 and P14780 play an important role in GBM growth . Blockade of uPA and interruption of the proteolytic cascade could become a useful tool in the therapy of GBM .",
"[ Dynamic observation of alpha - granule membrane protein 140 during the treatment of thrombolytic and anticoagulant therapy in patients with acute myocardial infarction ] . The degree of platelet activation and damage in 15 cases with acute myocardial infarction ( AMI ) receiving thrombolytic therapy and 15 cases with AMI receiving anticoagulant therapy were studied in vivo and in vitro by using specific monoclonal antibodies ( SZ - 51 & P28222 ) against alpha - granule membrane protein 140 ( P16109 ) . Clinical indexes and myocardial enzyme changes in the two groups of patients were also observed . The results showed that the number of P16109 molecules on platelet surface and the concentration of P16109 in plasma were increased before treatment . The number of P16109 molecules on platelet surface began to decrease on the 1st day and returned to baseline on the 7th day after treatment . The concentration of P16109 in plasma reached a peak on the 1st day , began to fall on the 2nd day and returned to baseline on the 3rd day after treatment . There were no significant differences in the dynamic changes of number of P16109 molecules on platelet surface and the concentration of P16109 in plasma between groups of thrombolytic therapy and anticoagulant therapy . In vitro experiment showed that the thrombolytic medicine urokinase neither activated platelets nor inhibited platelet activation induced by thrombin . Significantly greater reperfusion rate and earlier appearance of CK and CK - MB peaks were found in the thrombolytic than in the anticoagulant group . LVEF determined by echocardiography , rate of return of ST segments to baseline and alleviation rate of chest pain were significantly greater and complications of AMI ( ventricular fibrillation , left ventricular failure and angina ) were less in the group receiving thrombolytic therapy . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Steroid hormone receptors and coregulators in endocrine - resistant and estrogen - independent breast cancer cells . Resistance to hormonal therapy is often a problem in the treatment of breast cancer patients . It has been suggested that resistance could be explained by altered nuclear hormone receptor or coregulator levels or inappropriately increased agonist activity of selective estrogen receptor modulator ( SERM ) . To test these hypotheses , we have established novel MCF - 7 cell line - derived in vitro models of anti - estrogen - and progestin - resistant and estrogen - independent breast cancer by long - term culture in the presence of toremifene and medroxyprogesterone acetate ( ___MASK27___ ) and in the absence of estradiol , respectively . Using cell growth and multiprobe ribonuclease protection assays , the expression of 5 nuclear hormone receptors and 9 coregulators as well as the alterations in the cell proliferation and target gene transcription in response to hormonal treatments were studied . P06401 ( PR ) expression was decreased and silencing mediator for retinoid acid and thyroid hormone receptors ( Q9Y618 ) and amplified in breast cancer - 1 ( Q9Y6Q9 ) expression increased in anti - estrogen - resistant cells . Estrogen caused PR and ERbeta upregulation in all cell lines , but we did not observe increased agonist activity of anti - estrogen measured by regulation of these estrogen target genes . Basal ERalpha levels and estrogenic growth response were decreased and p300 / CBP - associated factor ( pCAF ) and Q9Y6Q9 upregulated by estrogen in progestin - resistant cells , but coregulator levels were unchanged . Estrogen - independent cells were still estrogen - responsive and PR , nuclear receptor corepressor ( O75376 ) and Q9Y618 expression was increased whereas steroid receptor coactivator - 1 ( P12931 - 1a ) and CBP - related protein p300 ( p300 ) expression decreased . Their growth was inhibited by toremifene , but estradiol was able to abrogate this effect , which might have interesting clinical implications concerning the use of postmenopausal hormone replacement therapy .",
"Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .",
"DB00013 plasminogen activator and its inhibitor , P05121 , as prognostic markers in breast cancer : from pilot to level 1 evidence studies . BACKGROUND : For optimum management of patients with cancer , accurate assessment of prognosis is essential . The primary determinant of outcome in malignancy is the formation of distant metastases . DB00013 plasminogen activator ( uPA ) is a serine protease causally involved in invasion and metastasis . CONTENT : Data from model systems show that uPA is unequivocally involved in cancer dissemination . Consistent with its role in metastasis , multiple independent groups have shown that high uPA concentrations in primary breast cancers correlate with poor prognosis . For determining outcome , the prognostic impact of uPA was both independent of traditionally used factors and prognostic in patients with axillary node - negative disease . Paradoxically , high concentrations of plasminogen activator inhibitor ( P05121 ) , an endogenous inhibitor of uPA , also correlate with poor prognosis in patients with breast cancer , including the subgroup with node - negative disease . The prognostic value of uPA / P05121 in axillary node - negative breast cancer patients was recently confirmed in both a prospective randomized trial and a pooled analysis , i . e . , two different level 1 evidence ( LOE - 1 ) studies . CONCLUSIONS : uPA and P05121 are among the first biological prognostic factors to have their clinical value validated using LOE - 1 evidence studies . Determination of these analytes may help identify low - risk node - negative breast cancer patients for whom adjuvant chemotherapy is unnecessary .",
"Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment : insights into the development of Alzheimer ' s disease . Mild cognitive impairment ( D6RGH6 ) is generally referred to the transitional zone between normal cognitive function and early dementia or clinically probable Alzheimer ' s disease ( AD ) . Oxidative stress plays a significant role in AD and is increased in the superior / middle temporal gyri of D6RGH6 subjects . Because AD involves hippocampal - resident memory dysfunction , we determined protein oxidation and identified the oxidized proteins in the hippocampi of D6RGH6 subjects . We found that protein oxidation is significantly increased in the hippocampi of D6RGH6 subjects when compared to age - and sex - matched controls . By using redox proteomics , we determined the oxidatively modified proteins in D6RGH6 hippocampus to be alpha - enolase ( P06733 ) , glutamine synthetase ( P15104 ) , pyruvate kinase M2 ( P14618 ) and peptidyl - prolyl cis / trans isomerase 1 ( Q13526 ) . The interacteome of these proteins revealed that these proteins functionally interact with P12931 , hypoxia - inducible factor 1 , plasminogen ( P00747 ) , MYC , tissue plasminogen activator ( P00750 ) and Q07817 . Moreover , the interacteome indicates the functional involvement of energy metabolism , synaptic plasticity and mitogenesis / proliferation . Therefore , oxidative inactivation of P06733 , P15104 and Q13526 may alter these cellular processes and lead to the development of AD from D6RGH6 . We conclude that protein oxidation plays a significant role in the development of AD from D6RGH6 and that the oxidative inactivation of P06733 , P15104 , P14618 and Q13526 is involved in the progression of AD from D6RGH6 . The current study provides a framework for future studies on the development of AD from D6RGH6 relevant to oxidative stress .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK34___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK34___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK34___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) ."
] |
[
"___MASK11___",
"___MASK15___",
"___MASK1___",
"___MASK22___",
"___MASK24___",
"___MASK27___",
"___MASK34___",
"___MASK69___",
"___MASK96___"
] |
___MASK1___
|
MH_train_450
|
interacts_with DB00073?
|
[
"___MASK68___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK68___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"___MASK15___ binding to human and rat dopamine and 5 - HT receptors . ___MASK15___ ( ___MASK15___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK15___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK15___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK15___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"DB00073 - dependent cytotoxicity by natural killer cells : influence of P08637 polymorphism on the concentration - effect relationship . The P08637 gene dimorphism generates two allotypes : FcgammaRIIIa - 158V and FcgammaRIIIa - 158F . The genotype homozygous for FcgammaRIIIa - 158V ( VV ) is associated with higher clinical response to rituximab , a chimeric anti - P11836 IgG1 used in the treatment of B lymphoproliferative malignancies . Our objective was to determine whether this genetic association relates to rituximab - dependent cytotoxicity mediated by FcgammaRIIIa / CD16a + cells . The number of CD16 + circulating monocytes , T cells , and natural killer ( NK ) cells in 54 donors was first shown to be unrelated to P08637 polymorphism . We then demonstrated that FcgammaRIIIa - 158V displays higher affinity for rituximab than FcgammaRIIIa - 158F by comparing rituximab concentrations inhibiting the binding of 3G8 mAb ( anti - CD16 ) with VV NK cells and NK cells homozygous for FcgammaRIIIa - 158F ( FF ) . VV and FF NK cells killed Daudi cells similarly after FcgammaRIIIa engagement by saturating concentrations of rituximab or 3G8 . However , the rituximab concentration resulting in 50 % lysis ( EC ( 50 ) ) observed with NK cells from VV donors was 4 . 2 times lower than that observed with NK cells from FF donors ( on average 0 . 00096 and 0 . 00402 microg / ml , respectively , P = 0 . 0043 ) . Finally , the functional difference between VV and FF NK cells was restricted to rituximab concentrations weakly sensitizing P11836 . This study supports the conclusion that P08637 genotype is associated with response to rituximab because it affects the relationship between rituximab concentration and NK cell - mediated lysis of P11836 + cells . DB00073 administration could therefore be adjusted according to P08637 genotype .",
"Platelet - associated antibodies , cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia . DB00073 is widely used in autoimmune diseases including immune thrombocytopenia ( ITP ) , although the mechanism of effect remains unclear . This study describes the effects of rituximab on platelet - associated antibodies ( PA - APAs ) , B and T cell counts and clonality ( IGHV and TRG @ gene rearrangements ) , P08637 ( FcγRIIIa ) and P12318 ( FcγRIIa ) polymorphisms and correlation to anti - P29965 ( P29965 ) response . PA - APA levels fell more frequently in responders ( 6 / 8 ) than in non - responders ( 2 / 10 : P = 0 · 08 - 0 · 15 ) . Two responders had no PA - APAs . Two non - responders with a fall in PA - APAs had very high CD8 levels . One non - responder had a B cell clone , one responder and one non - responder had a T cell clone . 15 / 16 patients had the same responses to rituximab and antiCD40L . Patients with P08637 V / V polymorphisms were more likely to respond to rituximab ( P = 0 · 03 ) . In summary , the fall in PA - APAs in responders confirms the humoural effect of rituximab . Failure to respond in patients with very high CD8 levels , despite PA - APA fall indicates a role for T cell - mediated platelet / megakaryocyte destruction . Concordance of response to anti - P29965 suggests autoantibody - producing cells are under T cell control . Finally , the effect of FCGR polymorphisms on response confirms the importance of FCGR - mediated depletion of B cells in autoimmunity . This has implications on the pathology of ITP as well as the immunological effect of B cell depletion .",
"M2 macrophages phagocytose rituximab - opsonized leukemic targets more efficiently than m1 cells in vitro . Because macrophages have been implicated as major players in the mechanism of action of rituximab , we have investigated the factors that modulate their tumor cell killing potential . Human macrophages , differentiated in vitro from peripheral blood monocytes , were used in binding and phagocytosis assays using B - chronic lymphocytic leukemia or lymphoma target cells opsonized with rituximab . Phagocytosis was maximal at 0 . 1 microg / ml rituximab and was not significantly affected by P11836 expression levels or by P08637 polymorphism at position 158 ( DB00161 / DB00120 ) . The role of FcgammaRs was demonstrated by complete inhibition of phagocytosis by excess human Igs . Because macrophages can be differentiated to M1 - or M2 - type cells with either GM - P04141 or P09603 , respectively , and can be classically activated by proinflammatory stimuli ( P01579 / LPS ) or undergo alternative activation with cytokines such as P05112 or P22301 , we have analyzed the effect of these different polarization programs on the phagocytosis mediated by rituximab . Macrophages differentiated in presence of P09603 showed a 2 - to 3 - fold greater phagocytic capacity compared with GM - P04141 - induced cells . Furthermore , addition of P22301 significantly increased , whereas P05112 decreased phagocytosis by both P09603 - and GM - P04141 - differentiated macrophages . LPS / P01579 had little effect . Expression of CD16 , CD32 , and CD64 in different macrophage populations correlated with phagocytic activity . Interestingly , several B lymphoma cell lines were observed to secrete 400 - 1300 pg / ml P22301 in vitro , and coculture of human macrophages with lymphoma conditioned medium increased significantly their phagocytic capacity . Our data suggest that cytokines secreted by lymphoma cells can favor alternate activation of macrophages with a high phagocytic capacity toward rituximab - opsonized targets .",
"___MASK11___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK11___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK33___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"P12318 polymorphism is correlated with clinical outcome after immunotherapy of neuroblastoma with anti - GD2 antibody and granulocyte macrophage colony - stimulating factor . PURPOSE : Anti - GD2 murine IgG3 antibody 3F8 kills neuroblastoma cells by antibody - dependent cell - mediated cytotoxicity ( ADCC ) . Granulocyte macrophage colony - stimulating factor ( GM - P04141 ) enhances phagocyte - mediated ADCC . The differential affinity of the human FCGR polymorphic alleles for 3F8 may influence the effectiveness of antibody immunotherapy . PATIENTS AND METHODS : The entire cohort of high risk neuroblastoma patients ( N = 136 ) treated on protocol using 3F8 and GM - P04141 were the subjects of this analysis . Tumor response was measured by standard clinical tools plus sensitive molecular monitoring using quantitative reverse transcription - polymerase chain reaction ( qRT - PCR ) . Polymorphic alleles of P12318 and P08637 were determined by PCR plus direct sequencing using genomic DNA samples obtained from marrow or blood of patients . RESULTS : P12318 ( R / R ) genotype correlated with progression - free survival for the entire cohort ( P = . 049 ) and for the subset of patients with no history of prior relapse ( P = . 023 ) . P12318 ( R / R ) also correlated with marrow remission 2 . 5 months after treatment initiation : by histology ( P = . 021 and P = . 036 , for the entire cohort and the subset , respectively ) and by qRT - PCR ( P = . 052 and P = . 033 , respectively ) . CONCLUSION : The favorable outcome associated with P12318 ( R / R ) genotype is consistent with the proposed role of P12318 and phagocyte - mediated ADCC in 3F8 plus GM - P04141 immunotherapy .",
"Human bone marrow megakaryocytes and platelets express PPARgamma , and PPARgamma agonists blunt platelet release of P29965 and thromboxanes . P37231 ( PPARgamma ) is a ligand - activated transcription factor important in lipid metabolism , diabetes , and inflammation . We evaluated whether human platelets and megakaryocytes express PPARgamma and whether PPARgamma agonists influence platelet release of bioactive mediators . Although PPARgamma is mainly considered a nuclear receptor , we show that enucleate platelets highly express PPARgamma protein as shown by Western blotting , flow cytometry , and immunocytochemistry . Meg - 01 megakaryocyte cells and human bone marrow megakaryocytes also express PPARgamma . Platelet and Meg - 01 PPARgamma bound the PPARgamma DNA consensus sequence , and this was enhanced by PPARgamma agonists . Platelets are essential not only for clotting , but have an emerging role in inflammation in part due to their release or production of the proinflammatory and proatherogenic mediators P29965 ( P29965 ) and thromboxanes ( TXs ) . Platelet incubation with a natural PPARgamma agonist , 15d - PGJ ( 2 ) , or with a potent synthetic PPARgamma ligand , rosiglitazone , prevented thrombin - induced P29965 surface expression and release of P29965 and thromboxane B ( 2 ) ( TXB ( 2 ) ) . 15d - PGJ ( 2 ) also inhibited platelet aggregation and adenosine triphosphate ( DB00171 ) release . Our results show that human platelets express PPARgamma and that PPARgamma agonists such as the thiazolidinedione class of antidiabetic drugs have a new target cell , the platelet . This may represent a novel mechanism for treatment of inflammation , thrombosis , and vascular disease in high - risk patients .",
"Synthesis and biological evaluation of novel pyrrolidine - 2 , 5 - dione derivatives as potential antidepressant agents . Part 1 . A series of 3 -( 1H - indol - 3 - yl ) pyrrolidine - 2 , 5 - dione derivatives was synthesized and their biological activity was evaluated . The chemical structures of the newly prepared compounds were confirmed by ( 1 ) H NMR , ( 13 ) C NMR and P19957 - HRMS spectra data . All tested compounds proved to be potent P08908 receptor and serotonin transporter protein ( P31645 ) ligands . Among them , compounds 15 , 18 , 19 and 30 showed significant affinity for P08908 and P31645 . Computer docking simulations carried out for compounds 15 , 31 and 32 to models of P08908 receptor and P31645 confirm the results of biological tests . Due to high affinity for the P08908 receptor and moderate affinity for P31645 , compounds 31 , 32 , 35 , and 37 were evaluated for their affinity for D2L , P50406 , P34969 and 5 - Q13049 receptors . In vivo tests , in turn , resulted in determining the functional activity of compounds 15 , 18 , 19 and 30 to the P08908 receptor . The results of these tests indicate that all of the ligands possess properties characteristic of P08908 receptor agonists .",
"Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1 - polarizing capacity . Inhibitors of DB02527 - specific phosphodiesterase ( PDE ) 4 have been shown to inhibit inflammatory mediator release and T cell proliferation , and are considered candidate therapies for T ( h ) 1 - mediated diseases . However , little is known about how DB05876 inhibitors influence dendritic cells ( DC ) , the cells responsible for the priming of naive T ( h ) cells . Therefore , we investigated the PDE profile of monocyte - derived DC , and whether DB05876 inhibitors modulate DC cytokine production and T cell - polarizing capacity . We mainly found DB02527 - specific DB05876 enzymatic activity in both immature and mature DC . In contrast to monocytes that mainly express Q07343 , we found that P27815 is the predominant DB05876 subtype present in DC . Immature DC showed reduced ability to produce IL - 12p70 and tumor necrosis factor ( P01375 ) - alpha upon lipopolysaccharide or P29965 ( P29965 ) stimulation in the presence of DB05876 inhibitors , whereas cytokine production upon P29965 stimulation of fully mature DC in the presence of DB05876 inhibitors was not affected . Exposure to DB05876 inhibitors for 2 days during DC maturation did not influence T cell - stimulatory capacity or acquisition of a mature phenotype , but increased the expression of the chemokine receptor P61073 . Furthermore , DC matured in the presence of DB05876 inhibitors showed reduced capacity to produce IL - 12p70 and P01375 upon subsequent P29965 stimulation . Using these DB05876 inhibitor - matured DC to stimulate naive T cells resulted in a reduction of P01579 - producing ( T ( h ) 1 ) cells . These findings indicate that DB05876 inhibitors can affect T cell responses by acting at the DC level and may increase our understanding of the therapeutic implication of DB05876 inhibitors for T ( h ) 1 - mediated disorders .",
"___MASK26___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK26___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"P08637 - 158 polymorphism influences the biological response to infliximab in Crohn ' s disease through affecting the ADCC activity . An association between P08637 - 158 V / F polymorphism and biological responses to infliximab has been reported in Crohn ' s disease ( CD ) in Western countries . However , little is known about the mechanism by which gene polymorphism affects the responses to infliximab . The aims of this study were to confirm the association in Japanese CD patients and to reveal the effect of gene polymorphism on biological responses to infliximab . Japanese CD patients were examined retrospectively at weeks 8 and 30 . Clinical and biological responses were assessed by the Crohn ' s disease activity index and P02741 levels , respectively . The infliximab - binding affinity of natural killer ( NK ) cells from P08637 - 158 V / V , V / F and F / F donors was examined . DB00065 - mediated antibody - dependent cell - mediated cytotoxicity ( ADCC ) activities were also determined using transmembrane P01375 - α - expressing Jurkat T cells as target cells and peripheral blood mononuclear cells ( PBMCs ) from V / V , V / F and F / F donors as effector cells . Biological responses at week 8 were statistically higher in V / V patients , whereas no significant differences were observed in either clinical responses at weeks 8 and 30 or biological responses at week 30 among the three genotypes . NK cells and PBMCs from V / V patients also showed higher infliximab - binding affinity and infliximab - mediated ADCC activity , respectively . Our results suggest that P08637 - 158 polymorphism is a predicting factor of biological responses to infliximab in the early phases . P08637 - 158 polymorphism was also found to affect the infliximab - binding affinity of NK cells and infliximab - mediated ADCC activity in vitro , suggesting that an effect on ADCC activity influences biological responses to infliximab in CD patients .",
"Screening of 134 single nucleotide polymorphisms ( SNPs ) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes . More than 120 published reports have described associations between single nucleotide polymorphisms ( SNPs ) and type 2 diabetes . However , multiple studies of the same variant have often been discordant . From a literature search , we identified previously reported type 2 diabetes - associated SNPs . We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium ( r ( 2 ) > 0 . 8 ) with another typed SNP . Of the 114 SNPs examined , we followed up the 20 most significant SNPs ( P < 0 . 10 ) on an additional 384 case subjects and 366 control subjects from a population - based study in Finland . In the combined data , we replicated association ( P < 0 . 05 ) for 12 SNPs : P37231 Pro12Ala and His447 , Q14654 Glu23Lys and rs5210 , P01375 - 857 , P11168 Ile110Thr , P20823 / TCF1 rs2701175 and GE117881_360 , P35558 - 232 , Q13562 Thr45Ala , P05231 - 598 , and P22413 Lys121Gln . The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association ( P = 0 . 012 ) . We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample ( P = 0 . 03 ) , although we also replicated 4 of 58 SNPs from genes that had only one previous report of association .",
"Association of the P08637 - 158F / V gene polymorphism with the response to rituximab treatment in Spanish systemic autoimmune disease patients . DB00073 is being used as treatment for systemic autoimmune diseases . The objective of this study was to determine whether the genetic variant in the Fc gamma - receptor III a ( P08637 ) gene , 158F / V , contributes to the observed variation in response to rituximab in patients with systemic autoimmune diseases . DNA samples from 132 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for P08637 - 158F / V ( rs396991 ) gene polymorphism using the TaqMan (®) allelic discrimination technology . Six months after infusion with rituximab we evaluated the response to the drug : 61 % of the patients showed a complete response , partial 27 % and 12 % did not respond to the treatment . A statistically significant difference was observed in V allele frequency between responder ( 38 % ) and nonresponder ( 16 % ) patients ( p = 0 . 01 ; odds ratio [ OR ]= 3 . 24 , 95 % confidence interval [ CI ] 1 . 17 - 11 . 1 ) . DB00073 was also more effective in V allele carriers ( 94 % ) than in homozygous FF patients ( 81 % ) : p = 0 . 02 ; OR = 3 . 96 , 95 % CI 1 . 10 - 17 . 68 . These results suggest that P08637 - 158F / V ( rs396991 ) gene polymorphism play a role in the response to rituximab in autoimmune diseases . Validation of these findings in independent cohorts is warranted .",
"___MASK72___ block of cloned human T - type voltage - gated calcium channels . ___MASK72___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"Activation of tumor - promoting type 2 macrophages by P00533 - targeting antibody cetuximab . PURPOSE : In a recent randomized phase III clinical trial in metastatic colorectal cancer patients , the addition of the anti - epidermal growth factor receptor ( P00533 ) monoclonal antibody ( mAb ) cetuximab to bevacizumab and chemotherapy resulted in decreased progression - free survival , in particular for patients with the high - affinity FcγRIIIA . EXPERIMENTAL DESIGN : The presence of natural killer ( NK ) cells and type 2 ( M2 ) macrophages in colorectal cancer was determined by immunohistochemistry , using antibodies to lineage - specific markers O76036 and P34810 with Q86VB7 , respectively . Influence of tumor - bound cetuximab on M2 macrophages was carried out in vitro with P00533 - expressing tumor cells and short - term differentiated monocytes from blood donors , who were typed for the FcγRIIIA polymorphism ( CD16 ) . RESULTS : Antibody - dependent cellular cytotoxicity by NK cells is generally proposed as one of the antitumor mechanisms of mAbs . We found that Q86VB7 - positive M2 macrophages are much more abundant in colorectal carcinomas . In vitro analysis of M2 macrophages revealed high levels of Fc - gamma receptors ( FcγR ) and Q9NZQ7 and production of P22301 and P15692 but not IL - 12 . These anti - inflammatory and tumor - promoting mediators were released upon coculture with P00533 - positive tumor cells loaded with low concentrations of cetuximab . Macrophage activation depended on P00533 expression on the tumor cells , FcγRs , target specificity of the mAb and mobility of antibody complexes . Cetuximab - induced macrophage responses were more pronounced for P08637 158 - DB00161 ( high - affinity ) carriers . CONCLUSION : These results suggest that tumor - promoting M2 macrophages are activated by the therapeutic mAb cetuximab in the local tumor microenvironment and argue that this immune mechanism should be taken into account for the application of therapeutic antibodies .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK31___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"Polymorphisms in inflammatory cytokines and Fcgamma receptors in childhood chronic immune thrombocytopenic purpura : a pilot study . Inflammatory cytokines and low - affinity Fcgamma receptor ( FcgammaR ) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura ( cITP ) and 218 controls . Genotype analysis included common variants in the regulatory regions of cytokines , P01375 , P01374 , P18510 , P01583 , P01584 , P05112 , P05231 and P22301 , and structural variants of the low affinity FcgammaRs , P12318 , P08637 and O75015 . Associations were observed for P01375 ( P = 0 . 0032 ) , P01374 ( P = 0 . 019 ) , P08637 ( P = 0 . 038 ) and O75015 ( P = 0 . 0034 ) . Two combinations of genotypes ( P01375 and P08637 ; P = 0 . 0003 , and P01374 and O75015 ; P = 0 . 011 ) were significantly associated with cITP . These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK95___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"DB11320 stimulates hydrogen peroxide production by bronchial epithelial cells via histamine H1 receptor and dual oxidase . Oxidative stress has been implicated in the pathogenesis of bronchial asthma . Besides granulocytes , the airway epithelium can produce large amounts of reactive oxygen species and can contribute to asthma - related oxidative stress . DB11320 is a major inflammatory mediator present in large quantities in asthmatic airways . Whether histamine triggers epithelium - derived oxidative stress is unknown . We therefore aimed at characterizing human airway epithelial H2O2 production stimulated by histamine . We found that air - liquid interface cultures of primary human bronchial epithelial cells ( BECs ) and an immortalized BEC model ( Cdk4 / hTERT HBEC ) produce H2O2 in response to histamine . The main source of airway epithelial H2O2 is an NADPH dual oxidase , Duox1 . Out of the four histamine receptors ( P35367 - Q9H3N8 ) , P35367 has the highest expression in BECs and mediates the H2O2 - producing effects of histamine . P05112 induces Duox1 gene and protein expression levels and enhances histamine - induced H2O2 production by epithelial cells . Using P29320 - 293 cells expressing Duox1 or Duox2 and endogenous P35367 , histamine triggers an immediate intracellular calcium signal and H2O2 release . Overexpression of P35367 further increases the oxidative output of Duox - expressing P29320 - 293 cells . Our observations show that BECs respond to histamine with Duox - mediated H2O2 production . These findings reveal a mechanism that could be an important contributor to oxidative stress characteristic of asthmatic airways , suggesting novel therapeutic targets for treating asthmatic airway disease .",
"T lymphocytes expressing a CD16 signaling receptor exert antibody - dependent cancer cell killing . To expand applications for T - cell - based immunotherapy in cancer , we designed a receptor that binds the Fc portion of human immunoglobulins and delivers activation signals . The construct included the high - affinity CD16 ( P08637 ) V158 variant , CD8α hinge , and transmembrane domains , along with signaling domains from CD3ζ and 4 - 1BB ( Q07011 ) , forming a chimeric receptor termed CD16V - BB - ζ . After retrovirus - mediated expression in human T cells , CD16V - BB - ζ bound humanized antibodies with higher affinity than a control receptor containing the more common F158 variant . Engagement of CD16V - BB - ζ provoked T - cell activation , exocytosis of lytic granules , and sustained proliferation , with a mean cell recovery after 4 - week coculture with Daudi lymphoma cells and rituximab of nearly 70 - fold relative to input cells . In contrast , unbound antibody alone produced no effect . CD16V - BB - ζ T cells specifically killed lymphoma cells and primary chronic lymphocytic leukemia cells in combination with rituximab at a low effector : target ratio , even when assayed on mesenchymal cells . DB00072 triggered CD16V - BB - ζ - mediated killing of P04626 ( P04626 ) (+) breast and gastric cancer cells ; similar results were obtained with an anti - GD2 antibody in neuroblastoma and osteosarcoma cells . Furthermore , coadministration of CD16V - BB - ζ T cells with immunotherapeutic antibodies exerted considerable antitumor activity in vivo . Signaling mediated by 4 - 1BB - CD3ζ induced higher T - cell activation , proliferation , and cytotoxicity than CD3ζ or FcεRIγ , and the receptor was expressed effectively after mRNA electroporation without viral vectors , facilitating clinical translation . Our results offer preclinical proof of concept for CD16V - BB - ζ as a universal , next - generation chimeric receptor with the potential to augment the efficacy of antibody therapies for cancer .",
"Maturation of dendritic cells by recombinant human P29965 - trimer leads to a homogeneous cell population with enhanced surface marker expression and increased cytokine production . Dendritic cells ( DC ) have been shown to be potent inducers of specific cytotoxic T - cell responses both in vivo and in vitro . Furthermore , exposure to cytokines such as tumour necrosis factor ( P01375 ) - alpha or P25942 triggering changes DC phenotype and cytokine production and may enhance the T - cell activating capacity of the DC . We studied DC phenotype and cytokine production as well as the T - cell proliferation and cytotoxic T lympocyte ( CTL ) activation induced by DC generated in vitro . In addition , the effect of exposure to recombinant human P29965 - trimer ( huCD40LT ) on these parameters was investigated . Effective differentiation of monocytes derived from freshly isolated peripheral blood mononuclear cells ( PBMC ) was obtained with granulocyte macrophage - colony stimulating factor ( GM - P04141 ) and interleukin ( IL ) - 4 . The DC expression of human leucocyte antigen ( HLA ) molecules , P33681 , Q01151 , and P42081 was markedly enhanced by exposure to huCD40LT even compared to P01375 exposure . Only a moderate cytokine production was observed initially , while P01375 addition or P25942 triggering , especially , induced enhanced production of P05231 and IL - 12 p40 . Surprisingly , comparable induction of T - cell proliferation by a DC allostimulus or through the presentation of PPD , and influenza M1 - peptide specific CTL activity was obtained with nonmaturated ( Q01151 - ) and maturated ( Q01151 + ) DC . In conclusion , a final maturation of monocyte - derived DC through huCD40LT resulted in a highly homogeneous cell population with enhanced surface marker expression and high production of pro - inflammatory cytokines . In addition , the induction of responses to allo or recall antigens presented by huCD40LT maturated DC was comparable to the responses obtained with the DC maturated through P01375 exposure .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"Identification of the fused bicyclic 4 - amino - 2 - phenylpyrimidine derivatives as novel and potent DB05876 inhibitors . 2 - Phenyl - 4 - piperidinyl - 6 , 7 - dihydrothieno [ 3 , 4 - d ] pyrimidine derivative ( 2 ) was found to be a new DB05876 inhibitor with moderate Q07343 activity ( IC50 = 150 nM ) . A number of derivatives with a variety of 4 - amino substituents and fused bicyclic pyrimidines were synthesized . Among these , 5 , 5 - dioxo - 7 , 8 - dihydro - 6H - thiopyrano [ 3 , 2 - d ] pyrimidine derivative ( 18 ) showed potent Q07343 inhibitory activity ( IC50 = 25 nM ) . Finally , N - propylacetamide derivative ( 31b ) was determined as a potent inhibitor for both Q07343 ( IC50 = 7 . 5 nM ) and P01375 - α production in mouse splenocytes ( IC50 = 9 . 8 nM ) and showed good in vivo anti - inflammatory activity in the LPS - induced lung inflammation model in mice ( ID50 = 18 mg / kg ) . The binding mode of the new inhibitor ( 31e ) in the catalytic site of Q07343 is presented based on an X - ray crystal structure of the ligand - enzyme complex .",
"Involvement of P50406 receptors in nigro - striatal function in rodents . 4 - Amino - N - ( 2 , 4 bis - methylamino - pyrimidin - 4 - yl ) benzene sulphonamide ( Ro 04 - 6790 ) is a potent , selective and competitive antagonist for the P50406 receptor which can be detected in the cerebro - spinal fluid ( P04141 ) of rats following intraperitoneal administration . Since P50406 receptor mRNA and P50406 receptor - like immunoreactivity have been shown to be present in the striatum , the purpose of the present study was to evaluate the effect of P50406 receptor antagonism on haloperidol - and P35240 23390 - induced catalepsy in mice and on the turning behaviour of rats with unilateral 6 - hydroxydopamine ( 6 - OHDA ) lesions of the medial forebrain bundle . Ro 04 - 6790 ( 3 , 10 and 30 mg kg (- 1 ) i . p . ) did not induce catalepsy and had no effect on catalepsy induced by either haloperidol or P35240 23390 . Ro 04 - 6790 ( 3 , 10 and 30 mg kg (- 1 ) i . p . ) did not itself induce rotational behaviour in rats with unilateral 6 - hydroxydopamine ( 6 - OHDA ) lesions of the medial forebrain bundle nor did it affect the rotational behaviour induced by either L - Dopa or amphetamine . P50406 receptor antagonism inhibited the rotational behaviour of 6 - OHDA lesioned rats induced by treatment with the muscarinic antagonists scopolamine and atropine . The data support earlier conclusions from experiments with antisense oligonucleotides that the P50406 receptor is involved in the control of acetylcholine neurotransmission in the rat brain .",
"P25942 / P29965 interaction induces Abeta production and increases gamma - secretase activity independently of tumor necrosis factor receptor associated factor ( TRAF ) signaling . P25942 , a member of tumor necrosis factor receptor superfamily , and its cognate ligand P29965 are both elevated in the brain of Alzheimer ' s disease ( AD ) patients compared to controls . We have shown that pharmacological or genetic interruption of P25942 / P29965 interaction results in mitigation of AD - like pathology in vivo in transgenic AD mouse models , and in vitro . Recently , we showed that P29965 stimulation could increase Abeta levels via NFkappaB signaling , presumably through TRAFs . In the present work , using P25942 mutants , we show that P29965 can increase levels of Abeta ( 1 - 40 ) , Abeta ( 1 - 42 ) , sAPPbeta , sAPPalpha and CTFbeta independently of TRAF signaling . We report an increase in mature / immature P05067 ratio after P29965 treatment of CD40wt and P25942 - mutant cells , reflecting alterations in P05067 trafficking . In addition , results from P29965 treatment of a neuroblastoma cell line over - expressing the C - 99 P05067 fragment suggest that P29965 has an effect on gamma - secretase . Furthermore , inhibition of gamma - secretase activity significantly reduces sAPPbeta levels in the P29965 treated P29320 / APPsw CD40wt and the P25942 - mutant cells . The latter suggests P25942 / P29965 interaction primarily acts on gamma - secretase and affects beta - secretase via a positive feedback mechanism . Taken together , our data suggest that P25942 / P29965 interaction modulates P05067 processing independently of TRAF signaling .",
"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK63___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK63___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .",
"Rapid and coordinated switch in chemokine receptor expression during dendritic cell maturation . Dendritic cells ( DC ) migrate into inflamed peripheral tissues where they capture antigens and , following maturation , to lymph nodes where they stimulate T cells . To gain insight into this process we compared chemokine receptor expression in immature and mature DC . Immature DC expressed P32246 , P41597 , P51681 and P25024 and responded to their respective ligands , which are chemokines produced at inflammatory sites . Following stimulation with LPS or P01375 maturing DC expressed high levels of P32248 mRNA and acquired responsiveness to the P32248 ligand Q99731 ( Q99731 ) , a chemokine produced in lymphoid organs . Maturation also resulted in up - regulation of P61073 and down - regulation of P25024 mRNA , while P32246 and P51681 mRNA were only marginally affected for up to 40 h . However , P32246 and P51681 were lost from the cell surface within 3 h , due to receptor down - regulation mediated by chemokines produced by maturing DC . A complete down - regulation of P32246 and P51681 mRNA was observed only after stimulation with P29965 of DC induced to mature by LPS treatment . These different patterns of chemokine receptors are consistent with \" inflammatory \" and \" primary response \" phases of DC function .",
"P25942 engagement on synovial fibroblast up - regulates production of vascular endothelial growth factor . We tested the impact of P25942 engagement on the production of vascular endothelial growth factor ( P15692 ) from rheumatoid synovial fibroblasts . Fibroblast - like synovial cells ( FLS ) were prepared from the synovial tissues of rheumatoid arthritis patients and cultured in the presence of P29965 - transfected ( P29965 + ) L cells . P15692 levels were determined in the culture supernatants by ELISA . Stimulation of FLS by P29965 + L cells increased the production of P15692 by 4 . 1 - fold over the constitutive levels of unstimulated FLS . The P29965 on activated T cells from rheumatoid synovial fluid also up - regulated P15692 production from FLS . Neither indomethacin nor Abs to IL - 1beta , P01375 , and TGF - beta did affect P29965 - induced P15692 production . Stimulation of FLS with P01375 , IL - 1beta , and TGF - beta increased P15692 production by 1 . 6 - , 2 . 0 - , and 5 . 2 - fold , respectively , and displayed an additive effect on the production of P15692 by P29965 . P15692 mRNA expression was also up - regulated by the stimulation of FLS with membranes from the P29965 + L cells . Dexamethasone completely abrogated P29965 - induced P15692 production . In addition , pyrrolidine dithiocarbamate partially down - regulated P29965 - induced P15692 production , showing that the NF - kappaB pathway was partly involved in the signaling of P29965 leading to P15692 production . Collectively , these results suggest that the interaction between P25942 on synovial fibroblasts and P29965 expressed on activated T lymphocytes may be directly involved in the neovascularization in rheumatoid synovitis by enhancing the production of P15692 .",
"P29965 ( P29965 ) does not stimulate proliferation of vascular smooth muscle cells . The present study investigates the effects of P29965 ( P29965 ) on mitogenic signalling , proliferation , and migration of cultured bovine coronary artery smooth muscle cells ( SMC ) . A time - and concentration - dependent phosphorylation of the extracellular signal - regulated kinases - 1 / 2 ( P27361 / 2 ) and the mitogen - activated protein kinase p38 ( p38 - MAPK ) was observed upon stimulation with soluble P29965 ( sCD40L ) . This phosphorylation was inhibited by neutralizing antibodies against the P25942 and P29965 , respectively . Activation of the phosphatidylinositol - 3 - phosphate ( P19957 ) kinase pathway by sCD40L , as determined by the measurement of Akt phosphorylation , was not detected . However , there was evidence for direct activation of the NFkappaB system ( degradation of P25963 and nuclear translocation of the p65 NFkappaB subunit ) by sCD40L . Accordingly , sCD40L caused a small but significant increase in DNA synthesis . However , sCD40L - induced DNA synthesis was not followed by proliferation ( increase in cell number ) . Furthermore , sCD40L did not potentiate SMC mitogenesis induced by known mitogens such as platelet - derived growth factor - BB , thrombin or serum . The lack of cell proliferation was not caused by a concomitant induction of SMC apoptosis by sCD40L . The possible role of membrane - bound P29965 in SMC mitogenesis was also studied using different membrane preparations ( platelets , lymphocytes ) . However , no mitogenic effects of membrane - bound P29965 were detected . Finally , sCD40L did not induce SMC migration . From these data it is concluded that P29965 activates mitogenic signalling and DNA synthesis but does not contribute to proliferation or migration of vascular SMC ."
] |
[
"___MASK11___",
"___MASK15___",
"___MASK26___",
"___MASK31___",
"___MASK33___",
"___MASK63___",
"___MASK68___",
"___MASK72___",
"___MASK95___"
] |
___MASK31___
|
MH_train_451
|
interacts_with DB01276?
|
[
"Glucagon - like peptide - 1 inhibits adipose tissue macrophage infiltration and inflammation in an obese mouse model of diabetes . AIMS / HYPOTHESIS : Obesity and insulin resistance are associated with low - grade chronic inflammation . Glucagon - like peptide - 1 ( P0C6A0 ) is known to reduce insulin resistance . We investigated whether P0C6A0 has anti - inflammatory effects on adipose tissue , including adipocytes and adipose tissue macrophages ( Q13315 ) . METHODS : We administered a recombinant adenovirus ( rAd ) producing P0C6A0 ( rAd - P0C6A0 ) to an ob / ob mouse model of diabetes . We examined insulin sensitivity , body fat mass , the infiltration of Q13315 and metabolic profiles . We analysed the mRNA expression of inflammatory cytokines , lipogenic genes , and M1 and M2 macrophage - specific genes in adipose tissue by real - time quantitative PCR . We also examined the activation of nuclear factor κB ( NF - κB ) , extracellular signal - regulated kinase 1 / 2 and Jun N - terminal kinase ( JNK ) in vivo and in vitro . RESULTS : Fat mass , adipocyte size and mRNA expression of lipogenic genes were significantly reduced in adipose tissue of rAd - P0C6A0 - treated ob / ob mice . Macrophage populations ( F4 / 80 (+) and F4 / 80 (+) CD11b (+) CD11c (+) cells ) , as well as the expression and production of P05231 , P01375 - α and monocyte chemoattractant protein - 1 , were significantly reduced in adipose tissue of rAd - P0C6A0 - treated ob / ob mice . Expression of M1 - specific mRNAs was significantly reduced , but that of M2 - specific mRNAs was unchanged in rAd - P0C6A0 - treated ob / ob mice . NF - κB and JNK activation was significantly reduced in adipose tissue of rAd - P0C6A0 - treated ob / ob mice . Lipopolysaccharide - induced inflammation was reduced by the P43220 agonist , exendin - 4 , in 3T3 - Q9NUQ9 adipocytes and Q13315 . CONCLUSIONS / INTERPRETATION : We suggest that P0C6A0 reduces macrophage infiltration and directly inhibits inflammatory pathways in adipocytes and Q13315 , possibly contributing to the improvement of insulin sensitivity .",
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK40___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"P01308 and local growth factor PDGF induce intimal hyperplasia in bypass graft culture models of saphenous vein and internal mammary artery . OBJECTIVE : In arteriosclerosis and bypass graft stenosis , intimal proliferation is controlled by local and systemic growth factors , such as platelet derived growth factor ( PDGF ) or insulin . Intimal hyperplasia can be produced in organ culture models . Our aim was to compare neointima formation in two organ culture models of internal mammary artery ( IMA ) and saphenous vein ( SV ) , with special reference to the influence of systemic and local growth stimuli . METHODS : Rings of freshly isolated human SV and IMA were cultured over a 3 - , 6 - or 8 - day period . They were distributed into five groups of incubation protocols : incubation with 10 % serum ; insulin 50 ng / ml and 100 ng / ml ; DB00102 5 ng / ml and 10 ng / ml . Frozen sections of cultured rings and pre - culture segments were subjected to elastic stain and immunohistochemistry . Antibodies directed against beta - actin and smooth muscle alpha - actin were used to characterize smooth muscle cell phenotype and against proliferating cell nuclear antigen ( P12004 ) to demonstrate proliferating cells . RESULTS : Growth factor incubation caused massive intimal hyperplasia with increased elastic fibers in SV and intimal smooth muscle cell as well as matrix accumulation in IMA . Intimal thickening , P12004 and beta - actin expression reached their maximum on day 6 of culture . In both culture models , serum , insulin and PDGF caused increasing intimal thickening , with more pronounced effects in SV . CONCLUSIONS : These organ culture models demonstrate the effects of insulin and PDGF on intimal hyperplasia in IMA and SV representing models for arteriosclerosis and bypass graft stenosis and stressing the role of insulin and growth factors for neointima development .",
"Neuroprotective effect of the glucagon - like peptide - 1 receptor agonist , synthetic exendin - 4 , in streptozotocin - induced diabetic rats . BACKGROUND AND PURPOSE : Glucagon - like peptide - 1 ( P0C6A0 ) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation . The aim of this study was to investigate the effect of the P0C6A0 pathway on peripheral nerves in streptozotocin - induced diabetic rats . EXPERIMENTAL APPROACH : Diabetic and nondiabetic rats were treated with the P43220 agonist , synthetic exendin - 4 ( i . p . , 1 nmol · kg (- 1 )· day (- 1 ) ) or placebo for 24 weeks , and current perception threshold values , DB02527 levels and nerve fibre size in the sciatic nerve were measured . We also investigated P43220 expression , quantitative changes in P09936 - positive intraepidermal nerve fibres and cleaved caspase 3 - stained Schwann cells by immunohistochemistry . KEY RESULTS : P43220 expression was detected in the sciatic nerve and skin . After exendin - 4 treatment , the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced . Also , the decrease in myelinated fibre size or axon / fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated . These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the DB02527 level in exendin - 4 - treated diabetic rats , compared with placebo - treated animals . CONCLUSION AND IMPLICATIONS : DB01276 may prevent peripheral nerve degeneration induced by diabetes in an animal model , supporting the hypothesis that P0C6A0 may be useful in peripheral neuropathy . The neuroprotection is probably attributable to P43220 activation , antiapoptotic effects and restoration of DB02527 content .",
"Effects of statins on regeneration of olfactory epithelium . BACKGROUND : This study was performed to investigate whether statins can enhance the recovery of the olfactory epithelium ( OE ) damaged by 3 - methylindole ( 3MI ) , an olfactotoxicant , and to compare the effects with those of steroids . METHODS : Randomized placebo - controlled trial was performed . Fifty - four healthy female Sprague - Dawley rats ( aged 9 - 10 weeks and weighing 160 - 180 g each ) were randomly allocated to the statin - treated , steroid - treated , or control groups . Olfactory loss was induced using i . p . injection of 3MI in adult rats . DB01076 ( 10 mg / kg for 4 weeks ) , prednisolone ( 1 mg / kg for 2 weeks ) , or normal saline ( 1 cc for 4 weeks ) was then administered per os with a gastric tube . Hematoxylin and eosin ( H & E ) staining and immunohistochemical staining were performed to evaluate the change of thickness and the arrangement of the OE , and immunoreactivity to protein gene product ( A6NDG6 ) 9 . 5 and proliferating cell nuclear antigen ( P12004 ) . RESULTS : The statin - treated group showed the earliest increase of the thickness of the OE ( p = 0 . 002 at 7 days after 3MI injection ) and the immunoreactivity to P12004 ( p = 0 . 032 at 7 days after 3MI injection ) among the three groups . The immunoreactivity to P09936 showed significantly better improvement at the 7th and 28th days after 3MI injection compared with the steroid - treated or control groups ( p = 0 . 002 and p < 0 . 001 , respectively ) . CONCLUSION : Statins might enhance the proliferation and neuroregenesis of the OE after 3MI injection .",
"P38398 , Q9BXW9 and Chk1 are potential molecular targets for the modulation of a radiation - induced DNA damage response in bystander cells . Radiotherapy is an important treatment option for many human cancers . Current research is investigating the use of molecular targeted drugs in order to improve responses to radiotherapy in various cancers . The cellular response to irradiation is driven by both direct DNA damage in the targeted cell and intercellular signalling leading to a broad range of bystander effects . This study aims to elucidate radiation - induced DNA damage response signalling in bystander cells and to identify potential molecular targets to modulate the radiation induced bystander response in a therapeutic setting . Stalled replication forks in T98G bystander cells were visualised via bromodeoxyuridine ( BrdU ) nuclear foci detection at sites of single stranded DNA . γ P16104 co - localised with these BrdU foci . P38398 and Q9BXW9 foci formed in T98G bystander cells . Using ATR mutant F02 - 98 hTERT and Q13315 deficient GM05849 fibroblasts it could be shown that ATR but not Q13315 was required for the recruitment of Q9BXW9 to sites of replication associated DNA damage in bystander cells whereas P38398 bystander foci were Q13315 - dependent . Phospho - Chk1 foci formation was observed in T98G bystander cells . Clonogenic survival assays showed moderate radiosensitisation of directly irradiated cells by the Chk1 inhibitor P55089 - 01 but increased radioresistance of bystander cells . This study identifies P38398 , Q9BXW9 and Chk1 as potential targets for the modulation of radiation response in bystander cells . It adds to our understanding of the key molecular events propagating out - of - field effects of radiation and provides a rationale for the development of novel molecular targeted drugs for radiotherapy optimisation .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK15___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .",
"P01308 growth factor - receptor ( IGF - 1R ) antibody cixutumumab combined with the P42345 inhibitor temsirolimus in patients with refractory Ewing ' s sarcoma family tumors . PURPOSE : ___MASK100___ was combined with cixutumumab , a fully human IgG1 monoclonal antibody directed at the insulin growth factor - 1 receptor ( IGF - 1R ) . EXPERIMENTAL DESIGN : Patients received cixutumumab , 6 mg / kg i . v . weekly , and temsirolimus , 25 to 37 . 5 mg i . v . weekly ( 4 - week cycles ) , with restaging after 8 weeks . Median follow - up was 8 . 9 months . RESULTS : Twenty patients [ 17 with Ewing ' s sarcoma ( Q01844 ) , 3 with desmoplastic small - round cell tumor ( DSRCT ) ] were enrolled . Twelve patients ( 60 % ) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting . The most frequent toxicities were thrombocytopenia ( 85 % ) , mucositis ( 80 % ) , hypercholesterolemia ( 75 % ) , hypertriglyceridemia ( 70 % ) , and hyperglycemia ( 65 % ; mostly grade I - II ) . Seven of 20 patients ( 35 % ) achieved stable disease ( SD ) for more than 5 months or complete / partial ( CR / PR ) responses . Tumor regression of more than 20 % ( 23 % , 23 % , 27 % , 100 % , 100 % ) occurred in five of 17 ( 29 % ) patients with Q01844 , and they remained on study for 8 to 27 months . One of six patients with Q01844 who previously developed resistance to a different IGF - 1R inhibitor antibody achieved a CR . Four of the seven best responders developed grade III mucositis , myelosuppression , or hyperglycemia , which were controlled while maintaining drug dose . CONCLUSION : Cixutumumab combined with temsirolimus was well - tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated Q01844 family tumors .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK96___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"Multidisciplinary approach in diagnosis of lung carcinoma . AIM : To employ multidisciplinary approach in order to make the correct diagnosis of lung carcinoma clinically and morphologically mimicking lymphoma . METHODS : Immunostaining was performed by incubating tissue sections with appropriate antibodies , using the streptavidin - biotin technique . Antigen - antibody complexes were visualized with 3 - amino - 9 - ethylcarbasole or diaminobenzidine hydrochloride substrate solution . We have investigated p53 gene mutations by polymerase chain reaction and DNA sequence analysis of exons 5 , 6 , 7 , 8 and 9 . RESULTS : Tumor cells expressed cytokeratin P02730 / P48751 , epithelial membrane antigen ( P15941 ) and thyroid transcription factor - 1 ( Q15669 - 1 ) without thyreoglobulin positivity . Further , tumor cells expressed neuroendocrine mar kers : synaptophysin , chromogranin A , neuron - specific enolase ( P09104 ) , CD56 / P13591 , CD57 / DB00149 - 7 and protein gene product 9 . 5 ( P09936 ) . P04637 was also expressed . Diffuse large cell lymphomas of B and T cell origin were excluded . Direct sequencing analysis of exon 6 of the p53 gene revealed ATC to ACC mutation at codon 195 . Final diagnosis of large cell lung neuroendocrine carcinoma ( LCNEC ) was established . CONCLUSIONS : Morphological pattern of tumor complied with large cell non - Hodgkin ' s lymphoma , but large cell lung carcinoma with neuroendocrine differentiation was proved immunohistochemically and confirmed by genetic analysis of p53 mutations in tumor tissue sample . Multidisciplinary approach in diagnosis of lung carcinoma is useful for its final diagnosis .",
"[ DB01276 : first once weekly P43220 agonist ( exenatide P10586 ) ] . DB01276 is a new galenic formulation ( long - acting release ) of exenatide , the first agonist of Glucagon - Like Peptide - 1 ( P0C6A0 ) receptors having been commercialized for the management of type 2 diabetes . The microsphere technology permits a prolonged absorption of exenatide from the subcutaneous depot , which allows one injection per week instead of two injections per day with the initial formulation of exenatide ( DB01276 ) . The clinical development programme DURATION showed that exenatide 2 mg once weekly more markedly reduces glycated haemoglobin ( HbA ( 1c ) ) , with a similar weight loss but a better digestive tolerance profile ( less nausea and vomiting after treatment initiation ) , compared with the twice daily 10 microg exenatide . When compared to other glucose - lowering agents , once weekly exenatide is more efficacious than sitagliptin , pioglitazone or basal insulin ( glargine or detemir ) , with the advantage of producing weight loss and lowering arterial blood pressure . It does not induce hypoglycaemia and does not necessarily require home blood glucose monitoring , two advantages compared with insulin therapy . DB01276 is currently only reimbursed in Belgium after failure of and in addition to metformin - sulfonylurea combination .",
"' Neuron - specific ' protein gene product 9 . 5 ( P09936 ) is also expressed in glioma cell lines and its expression depends on cellular growth state . Protein gene product 9 . 5 ( P09936 ) , which in the normal nervous system is restricted to certain neurons , has been detected in two glioma cell lines , rat P13671 and human GL15 , by immunoblotting and immunocytochemistry . Its expression in these cells depends on the cellular growth state , being maximal between the first and second post - plating day . Only a faint P09936 immunoreactivity can be observed in glioma cells after the eleventh post - plating day , i . e . about one week after confluency has been reached . The present results suggest that P09936 in cultured glial cells is maximally expressed during the growth phase and that the protein could play a role during brain development in glial cells , in reactive gliosis , or in tumorigenesis of the glial lineage .",
"Different expression of ubiquitin C - terminal hydrolase - Q9NUQ9 and αII - spectrin in ischemic and hemorrhagic stroke : Potential biomarkers in diagnosis . The two primary categories of stroke , ischemic and hemorrhagic , both have fundamentally different mechanisms and thus different treatment options . These two stroke categories were applied to rat models to identify potential biomarkers that can distinguish between them . Ischemic stroke was induced by middle cerebral artery occlusion ( MCAO ) without reperfusion while hemorrhagic stroke was induced by injecting collagenase IV into the striatum . Brain hemispheres and biofluids were collected at two time points : 3 and 6h after stroke . Known molecules were tested on the rat samples via quantitative immunoblotting ( injured brain , P04141 ) and Banyan ' s proprietary ELISA assays ( P04141 , serum ) . The injured brain quantitative analyses revealed that αII - spectrin breakdown products ( SBDP150 , SBDP145 ) were strongly increased after 6h ischemia . In P04141 , SBDP145 and ubiquitin C - terminal hydrolase - Q9NUQ9 ( P09936 ) levels were elevated after 6h ischemic stroke detected by Western blot and ELISA . In serum P09936 levels were increased after 3 and 6h of ischemia detected by ELISA . However , levels of those proteins in hemorrhagic stroke remain normal . In summary , in both the brain and the biofluids , SBDPs and P09936 were elevated after ischemic but not hemorrhagic stroke . These molecules behaved differently in the two stroke models and thus may be capable of being differentiated .",
"Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK45___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK45___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .",
"Aging and age - related diseases -- from endocrine therapy to target therapy . Aging represents an important health issue not only for the individual , but also for society in general . Burdens associated with aging are expanding as longevity increases . This has led to an enhanced focus on issues related to aging and age - related diseases . Until recently , anti - aging endocrine - therapy has been largely limited to hormone - replacement therapy ( HRT ) that is associated with multiple side effects , including an increased risk of cancer . This has greatly limited the application of HRT in anti - aging therapy . Recently , the focus of anti - aging research has expanded from endocrine signaling pathways to effects on regulatory gene networks . In this regard , the P01286 - GH - DB01277 / P01308 , TOR - P23443 , NAD (+)- Sirtuin , P04637 , Q9UEF7 and P02649 pathways have been linked to processes associated with age - related diseases , including cancer , cardiovascular disease , diabetes , osteoporosis , and neurodegenerative diseases , all of which directly influence health in aging , and represent key targets in anti - aging therapy .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"P0C6A0 treatment reduces endogenous insulin resistance via activation of central P0C6A0 receptors in mice fed a high - fat diet . Glucagon - like peptide - 1 ( P0C6A0 ) improves insulin sensitivity in humans and rodents . It is currently unknown to what extent the ( metabolic ) effects of P0C6A0 treatment are mediated by central P0C6A0 receptors . We studied the impact of central P43220 ( P43220 ) antagonism on the metabolic effects of peripheral P0C6A0 administration in mice . High - fat - fed insulin - resistant C57Bl / 6 mice were treated with continuous subcutaneous infusion of P0C6A0 or saline ( PBS ) for 2 wk , whereas the P43220 antagonist exendin - 9 ( EX - 9 ) and cerebrospinal fluid ( P04141 ) were simultaneously infused in the left lateral cerebral ventricle ( icv ) . DB09341 and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp . VLDL - triglyceride ( VLDL - TG ) production was determined in hyperinsulinemic conditions . Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by P0C6A0 . Simultaneous icv infusion of EX - 9 diminished this effect by 62 % . The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by P0C6A0 . Simultaneous icv infusion of EX - 9 significantly diminished the latter effect . Central P43220 antagonism alone did not affect glucose metabolism . Also , P0C6A0 treatment reinforced the inhibitory action of insulin on VLDL - TG production . In conclusion , peripheral administration of P0C6A0 reinforces the ability of insulin to suppress endogenous glucose and VLDL - TG production ( but not lipolysis ) and boosts its capacity to stimulate glucose disposal in high - fat - fed C57Bl / 6 mice . Activation of central GLP - 1Rs contributes substantially to the inhibition of endogenous glucose production by P0C6A0 treatment in this animal model .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK3___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"The development of DB01276 ( exenatide ) from the venom of the Gila monster as an anti - diabetic agent . The development of DB01276 ( synthetic exendin - 4 ; exenatide ) as a treatment of diabetes arose from two , parallel lines of investigation . The development of the ' incretin concept ' which hypothesised that hormones from the gut contributed to the insulin secretion in response to meals , led to the identification of glucagon - like peptide 1 ( P0C6A0 ) as an important ' incretin ' hormone . P0C6A0 not only increases insulin secretion but increases β - cell proliferation and survival , suppresses glucagon secretion , delays gastric emptying and suppresses appetite , all of these actions contributing to a potential anti - diabetic effect . However , P0C6A0 has a very short half due to its rapid breakdown by dipeptidyl peptidase IV and ectopeptidases . A systematic investigation of the composition and activity of venom from the Gila monster , Heloderma suspectum , led to the isolation of a 39 - amino acid peptide , designated exendin - 4 , showing 53 % structural homology with P0C6A0 ( 7 - 36 ) . Exendin - 4 mimicked P0C6A0 through stimulating the P43220 . The much greater stability of exendin - 4 led to its experimental and clinical evaluation as an anti - diabetic agent and its introduction to the market in 2005 .",
"Skeletal muscle insulin resistance induced by adipocyte - conditioned medium : underlying mechanisms and reversibility . P01308 resistance in skeletal muscle is an early event in the development of diabetes , with obesity being one of the major contributing factors . In vitro , conditioned medium ( CM ) from differentiated human adipocytes impairs insulin signaling in human skeletal muscle cells , but it is not known whether insulin resistance is reversible and which mechanisms may underlie this process . CM induced insulin resistance in human myotubes at the level of insulin - stimulated Akt and GSK - 3 phosphorylation . In addition , insulin - resistant skeletal muscle cells exhibit enhanced production of reactive oxygen species and ceramide as well as a downregulation of myogenic transcription factors such as myogenin and MyoD . However , insulin resistance was not paralleled by increased apopotosis . Regeneration of myotubes for 24 or 48 h after induction of insulin resistance restored normal insulin signaling . However , the expression level of myogenin could not be reestablished . In addition to decreasing myogenin expression , CM also decreased the release of P05231 and P10145 and increased monocyte chemotactic protein - 1 ( P13500 ) secretion from skeletal muscle cells . Although regeneration of myotubes reestablished normal secretion of P05231 , the release of P10145 and P13500 remained impaired for 48 h after withdrawal of CM . In conclusion , our data show that insulin resistance in skeletal muscle cells is only partially reversible . Although some characteristic features of insulin - resistant myotubes normalize in parallel to insulin signaling after withdrawal of CM , others such as P10145 and P13500 secretion and myogenin expression remain impaired over a longer period . Thus , we propose that the induction of insulin resistance may cause irreversible changes of protein expression and secretion in skeletal muscle cells .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK54___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"___MASK100___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK100___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK100___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK100___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .",
"Role of - 675 4G / 5G in the plasminogen activator inhibitor - 1 gene and - 308G / A tumor necrosis factor - α gene polymorphisms in obese Argentinean patients . AIM : P00747 activator inhibitor - 1 ( P05121 ) and tumor necrosis factor - α ( P01375 - α ) are increased in the circulation of obese persons . Because a direct link between P05121 and P01375 - α in obesity has been observed , they are candidate genes for the development of obesity . We sought to evaluate the relation between the genotypic and allelic frequencies of the - 675 4G / 5G P05121 and - 308 G / A P01375 - α polymorphisms and their association with the risk for obesity in an Argentinean population . METHODS : A group of 110 consecutive obese persons and a group of 111 lean controls were recruited . Polymerase chain reaction was used to determine the frequency of P05121 and P01375 - α polymorphisms ; serum fasting glucose , insulin , and lipid levels were measured by standard methods . P01308 sensitivity was evaluated by using homeostasis model assessment . RESULTS : The - 308 P01375 - α and - 675 4G / 5G P05121 genotype distribution did not significantly differ between the groups ( p = 0 . 544 and p = 0 . 327 , respectively ) . Homeostasis model assessment was the only positive independent determinant of body mass index ( R ( 2 )= 0 . 493 ; p < 0 . 001 ) . CONCLUSION : The - 675 4G / 5G P05121 and the - 308 P01375 - α polymorphism variants tested in this study , individually or combined , were not associated with obesity in an Argentinean population .",
"___MASK47___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK47___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"Signaling and biological effects of glucagon - like peptide 1 on the differentiation of DB05914 from human bone marrow . Glucagon - like peptide 1 ( P0C6A0 ) functions as an incretin hormone with antidiabetogenic properties . However , the role of P0C6A0 in human bone marrow - derived DB05914 ( hMSCs ) , if any , remains unknown . The effects of P0C6A0 on hMSCs were tested with regard to cell proliferation , cytoprotection , and cell differentiation into adipocytes . The signaling pathways involved in these processes were also analyzed . Cells were characterized with biochemical and morphological approaches before and after being induced to differentiate into adipocytes . P12004 protein levels were used as a proliferation index , whereas cell apoptosis was studied by deprivation of fetal bovine serum . Isolated hMSCs expressed stem cell markers as well as mRNA and P43220 protein . P0C6A0 increased the proliferation of hMSCs , which decreased when they were induced to differentiate into adipocytes . This process produced biochemical and morphological changes in cells expressing PPARgamma , C / EBPbeta , AP2 , and P06858 in a time - dependent pattern . Notably , P0C6A0 significantly reduced the expression of PPARgamma , C / EBPbeta , and P06858 . These effects were exerted at least through the MEK and PKC signaling pathways . In addition , P0C6A0 significantly reduced cell apoptosis . Our data indicate that , in hMSCs , P0C6A0 promotes cellular proliferation and cytoprotection and prevents cell differentiation into adipocytes . These latter findings underscore the potential therapeutic role of P0C6A0 in preventing the adipocyte hyperplasia associated with obesity and , additionally , could bolster the maintenance of hMSC stores by promoting the proliferation and cytoprotection of undifferentiated hMSC .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Exendin - 4 stimulates islet cell replication via the IGF1 receptor activation of mTORC1 / P23443 . P43220 ( P43220 ) agonists , such as exendin - 4 , potentiate glucose - stimulated insulin secretion and are currently used in the management of type 2 diabetes . Interestingly , P43220 agonists also have the ability to augment β - cell mass . In this report , we provide evidence that in the presence of glucose , exendin - 4 stimulates rodent islet cell DNA replication via the activation of ribosomal protein S6 kinase 1 ( P23443 ) and that this is mediated by the protein kinase B ( P31749 ) - dependent activation of P42345 complex 1 ( mTORC1 ) . We show that activation of this pathway is caused by the autocrine or paracrine activation of the IGF1 receptor ( P08069 ) , as siRNA - mediated knockdown of the P08069 effectively blocked exendin - 4 - stimulated P31749 and mTORC1 activation . In contrast , pharmacological inactivation of the epidermal growth factor receptor has no discernible effect on exendin - 4 - stimulated P31749 or mTORC1 activation . Therefore , we conclude that P43220 agonists stimulate β - cell proliferation via the P31749 - dependent stimulation of mTORC1 / P23443 whose activation is mediated through the autocrine / paracrine activation of the P08069 . This work provides a better understanding of the molecular basis of GLP1 agonist - induced β - cell proliferation which could potentially be exploited in the identification of novel drug targets that increase β - cell mass .",
"P00747 activator inhibitor - 1 is a downstream mediator of the P09936 - related oncogenic pathway in esophageal squamous cell carcinoma . BACKGROUND & MATERIALS AND METHODS : Recently , it has been proved that P09936 is an oncogene candidate for squamous cell carcinomas . To examine the P09936 - related oncogenic pathway , we tested for global patterns of gene expression in cancer cells following P09936 gene introduction using an oligonucleotide microarray approach . RESULTS : P00747 activator inhibitor - 1 ( P05121 ) was identified as an overexpressed gene in a P09936 - expressed esophageal squamous cancer cell line . To confirm the data obtained , we performed Northern analysis using a P09936 or a P05121 cDNA probe and found that P05121 mRNA was induced by P09936 expression in NUEC1 cells . We further examined endogenous P09936 and P05121 expression in 6 esophageal cancer cell lines . One cell line ( NUEC2 ) with P09936 expression exhibited P05121 expression , suggesting the possibility that P09936 might induce P05121 directly or indirectly . CONCLUSION : These results suggested that P05121 might be a novel downstream mediator of P09936 in esophageal squamous cell carcinomas .",
"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK45___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .",
"T - lymphocyte activation pathways in alcoholic liver disease . Immune system derangement in cirrhotic patients with evidence of malnutrition is a well - recognized characteristic of chronic alcohol abuse . However , in vitro studies on cellular immune function performed with lectin mitogens have produced conflicting results . The recent development of more accurate immunological techniques for studying lymphocyte transformation , that use monoclonal antibodies directed against surface structures ( CD3 and P06729 ) involved in antigen recognition , as well in adhesion functions , prompted us to study discrete in vitro T - cell hypo - responsiveness in a series of alcoholic liver disease ( P33897 ) patients with no evidence of malnutrition or hepatic cirrhosis . The results indicated that the P06729 pathway is markedly defective in P33897 T lymphocytes , accompanied by reduced interleukin - 2 ( P60568 ) receptor expression upon in vitro activation . This defect can not be reversed by the addition of recombinant P60568 ( rIL - 2 ) or rIL - 1 . Faulty intracellular signal transduction by protein kinase C ( PKC ) and defective intracellular Ca2 + mobilization may be responsible for the P06729 pathway impairment . The addition of small amounts of phorbol 12 - myristate , 13 - acetate , but not Ca2 + ionophore A23187 , is able to overcome the defect , thereby suggesting a direct PKC involvement . The hypothesis of a direct ethanol effect on transmembrane signal transduction systems is suggested by the demonstration of an expansion of circulating virgin ( naive ) T cells ( CD3 +/ P09936 - low ) that binds tyrosine phosphatase ( CD45RA antigen ) on their surface .",
"Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents . The risk of developing pancreatitis is elevated in type 2 diabetes and obesity . Cases of pancreatitis have been reported in type 2 diabetes patients treated with P0C6A0 ( P43220 ) receptor agonists . To examine whether the P43220 agonist exenatide potentially induces or modulates pancreatitis , the effect of exenatide was evaluated in normal or diabetic rodents . Normal and diabetic rats received a single exenatide dose ( 0 . 072 , 0 . 24 , and 0 . 72 nmol / kg ) or vehicle . Diabetic ob / ob or HF - Q11206 mice were infused with exenatide ( 1 . 2 and 7 . 2 nmol · kg (- 1 )· day (- 1 ) ) or vehicle for 4 wk . Post - exenatide treatment , pancreatitis was induced with caerulein ( CRN ) or sodium taurocholate ( ST ) , and changes in plasma amylase and lipase were measured . In ob / ob mice , plasma cytokines ( IL - 1β , P60568 , P05231 , P13500 , IFNγ , and TNFα ) and pancreatitis - associated genes were assessed . Pancreata were weighed and examined histologically . Exenatide treatment alone did not modify plasma amylase or lipase in any models tested . Exenatide attenuated CRN - induced release of amylase and lipase in normal rats and ob / ob mice but did not modify the response to ST infusion . Plasma cytokines and pancreatic weight were unaffected by exenatide . Exenatide upregulated Reg3b but not Il6 , Ccl2 , Nfkb1 , or Vamp8 expression . Histological analysis revealed that the highest doses of exenatide decreased CRN - or ST - induced acute inflammation , vacuolation , and acinar single cell necrosis in mice and rats , respectively . Ductal cell proliferation rates were low and similar across all groups of ob / ob mice . In conclusion , exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis in normal and diabetic rodents .",
"Novel P0C6A0 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain . One of the symptoms of diabetes is the progressive development of neuropathies . One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells . We have tested the effects of the novel P0C6A0 mimetics exenatide ( exendin - 4 ; DB01276 ) and liraglutide ( DB06655 ; DB06655 ) , which are already on the market as treatments for type 2 diabetes , on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes . P0C6A0 analogues were injected subcutaneously for 4 , 6 , or 10 weeks once daily in three mouse models of diabetes : ob / ob mice , db / db mice , or high - fat - diet - fed mice . Twenty - four hours before perfusion , animals were injected with 5 '- bromo - 2 '- deoxyuridine ( BrdU ) to mark dividing progenitor cells . By using immunohistochemistry and stereological methods , the number of progenitor cells or doublecortin - positive young neurons in the dentate gyrus was estimated . We found that , in all three mouse models , progenitor cell division was enhanced compared with nondiabetic controls after chronic i . p . injection of either liraglutide or exendin - 4 by 100 - 150 % ( P < 0 . 001 ) . We also found an increase in young neurons in the DG of high - fat - diet - fed mice after drug treatment ( P < 0 . 001 ) . The P43220 antagonist exendin ( 9 - 36 ) reduced progenitor cell proliferation in these mice . The results demonstrate that P0C6A0 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer ' s disease , because these novel drugs cross the blood - brain barrier and increase neuroneogenesis .",
"Suppressive effects of glucagon - like peptide - 1 on interferon - gamma - induced nitric oxide production in insulin - producing cells is mediated by inhibition of tumor necrosis factor - alpha production . During the development of Type 1 diabetes , inflammatory cytokines are known to induce the expression of inducible nitric oxide synthase ( P35228 ) in pancreatic islets , and subsequent production of nitric oxide ( NO ) contributes to beta cell destruction . Glucagon - like peptide - 1 ( P0C6A0 ) has been shown to reduce cytokine - induced apoptosis of beta cells . In this study , we investigated whether P0C6A0 affects cytokine - induced NO production , resulting in the inhibition of beta - cell apoptosis . We treated MIN6N8a mouse beta cells with interferon ( IFN ) - gamma in the presence or absence of P0C6A0 and found that P01579 treatment induced P35228 mRNA expression and NO production , which was significantly inhibited by treatment with P0C6A0 . Blocking of P43220 signaling via the cyclic AMP and phosphatidylinositol 3 - kinase pathway did not directly affect the suppressive effect of P0C6A0 on IFN - gamma - induced P35228 mRNA expression . Further studies revealed that P01579 induced the expression of P01375 mRNA and protein , which synergistically induced NO production , and P0C6A0 treatment inhibited this induction of P01375 . To examine whether the reduction of P01375 by P0C6A0 treatment plays a role in suppressing NO production , we treated MIN6N8a cells with P01579 in the presence of anti - P01375 neutralizing antibody and found that NO production was reduced . In addition , treatment of mouse islets with P0C6A0 inhibited the expression of P35228 and TNFmRNA . These results suggest that P0C6A0 inhibits P01579 - induced NO production by suppression of P01375 production .",
"Diabetes mellitus in cancer patients treated with combination interleukin 2 and alpha - interferon . Diabetes mellitus is thought to be an autoimmune disease caused by destruction of beta cells in pancreatic islets . P01308 resistance in the peripheral tissues may also play a role . Both interleukin 2 ( P60568 ) and alpha interferon can enhance immune function by stimulating formation of cytolytic T cells and / or antigen expression on both normal and tumor cells . This report describes three patients with advanced malignancy who were treated with combination P60568 and alpha interferon who had the onset or worsening of diabetes mellitus . One patient died as a result . There is evidence that interferon can increase insulin resistance and it is likely that both agents can initiate or enhance an ongoing autoimmune process . Physicians using this combination of drugs should be aware of this potential serious toxicity .",
"Molecular physiology of glucagon - like peptide - 1 insulin secretagogue action in pancreatic β cells . P01308 secretion from pancreatic β cells is stimulated by glucagon - like peptide - 1 ( P0C6A0 ) , a blood glucose - lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e . g . , DB01276 ) and P0C6A0 analogs ( e . g . , DB06655 ) activate the β cell P43220 ( P43220 ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase - IV ( DPP - IV ) inhibitors ( e . g . , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post - prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e . g . , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac2 - mediated actions of P0C6A0 to regulate DB00171 - sensitive K ⁺ channels , voltage - dependent K ⁺ channels , O94759 cation channels , intracellular Ca ⁺ release channels , and Ca ⁺- dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM .",
"[ ___MASK98___ : A new drug of B - cell malignancies ] . ___MASK98___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK98___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK98___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .",
"P01308 - like growth factor - 1 attenuates cisplatin - induced gammaH2AX formation and DNA double - strand breaks repair pathway in non - small cell lung cancer . Because insulin - like growth factor - 1 ( DB01277 ) counteracts the anti - neoplastic effect of cisplatin that induces DNA damage and cell death through the formation of platinum - DNA adducts , we investigated the effects of DB01277 on the DNA double - strand breaks ( DSBs ) repair system induced by cisplatin . NCI - H1299 and H460 non - small cell lung cancer ( NSCLC ) cells treated with DB01277 recovered from cisplatin - derived inhibited proliferation and apoptosis . Decreased tail length in comet assay and suppressed phosphorylation of histone P16104 at Ser139 with DB01277 cotreatment indicates that DB01277 attenuates cisplatin - induced DNA damage . Cotreatment with DB01277 attenuates phosphorylation of ataxia - telangiectasia mutated ( Q13315 ) at Ser1981 , and Q13315 - Rad3 - related ( ATR ) at Ser428 and subsequent phosphorylation of Chk2 , Chk1 , and p53 also dwindled by DB01277 . On the other hand , suppression of the IGF system with AG1024 or siRNA of insulin receptor substrate - 1 ( P35568 ) , a major adaptor molecule of the IGF system , augmented cisplatin - induced gammaH2AX , Ser1981 - pATM , and Ser428 - pATR generation . Q13315 , which plays an important role in the phosphorylation of histone P16104 and Chk2 at Thr68 , strongly binds with P35568 under the influence of cisplatin , and the interaction was partially inhibited by DB01277 . Immunocytochemistry revealed that cisplatin induces nuclear translocation of P35568 with Ser1981 - pATM , which is suppressed by cotreatment with DB01277 . In conclusion , cisplatin - induced gammaH2AX formation , DNA DSBs repair , and damage checkpoint pathway is inhibited by DB01277 . DB00515 derives interaction between Q13315 and P35568 , which is suppressed by DB01277 . Modulation of biologic activity of the DB01277 system could be a promising modality that raises the response rate of conventional chemotherapy .",
"Serum concentrations of growth factors in women with and without endometriosis : the action of anti - endometriosis medicines . Endometriosis is a common gynecologic syndrome of unknown etiology and pathogenesis . Growth factors and inflammatory mediators produced by peritoneal leukocytes have recently been postulated to participate in the pathogenesis of endometriosis . Angiogenic factors released from peritoneal macrophages may also play a role in the development of this disease . In the present study , we investigate the soluble levels of vascular endothelial growth factor ( P15692 ) , epidermal growth factor - receptor ( P01133 - R ) , granulocyte / macrophage - colony stimulating factor ( GM - P04141 ) , P01308 - like growth factor - 1 ( DB01277 ) and interferon - gamma ( P01579 ) in the serum of 28 women with and 20 without endometriosis . We also compared these levels before , during and after treatment with danazol and leuprorelin acetate depot , the two therapeutic regiments of choice concerning this disease . We found that only sVEGF levels were higher in women with endometriosis in comparison to controls ( P < 0 . 001 ) while sEGF - R is not present . GM - P04141 , DB01277 and P01579 soluble levels are not affected in either healthy or endometriotic subjects . The 6 - month treatment with danazol decreased sVEGF levels ( P < 0 . 02 ) and increased sEGF - R levels ( P < 0 . 001 ) . These observations support the view that P15692 may be associated with the disease process and that danazol may bring sVEGF levels to a normal threshold . However , future studies will be focused on the anti - angiogenic control of the action of P15692 in patients with endometriosis .",
"New insights into the role of DB02527 in the production and function of the incretin hormone glucagon - like peptide - 1 ( P0C6A0 ) . The proglucagon gene ( gcg ) encodes both glucagon and glucagon - like peptide - 1 ( P0C6A0 ) , produced in pancreatic alpha cells and intestinal endocrine L cells , respectively . The incretin hormone P0C6A0 stimulates insulin secretion and pro - insulin gene transcription . P0C6A0 also enhances pancreatic beta - cell proliferation , inhibits cell apoptosis , and has been utilized in the trans - differentiation of insulin producing cells . A long - term effective P43220 agonist , DB01276 , has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders . The expression of gcg and the production of P0C6A0 can be activated by the elevation of the second messenger cyclic AMP ( DB02527 ) . Recent studies suggest that in addition to protein kinase A ( PKA ) , exchange protein activated by DB02527 ( Epac ) , another effector of DB02527 , and the crosstalk between PKA and the Wnt signaling pathway , are involved in DB02527 - stimulated gcg transcription and P0C6A0 production as well . Finally , functions of P0C6A0 in pancreatic beta cells are also mediated by PKA , Epac , as well as the effector of the Wnt signaling pathway . Together , these novel findings bring us a new insight into the role of DB02527 in the production and function of the incretin hormone P0C6A0 .",
"Exenatide twice daily : a review of its use in the management of patients with type 2 diabetes mellitus . Exenatide , administered subcutaneously twice daily ( DB01276 (®) ) , is a synthetic version of the natural peptide exendin - 4 , which is a glucagon - like peptide - 1 ( P0C6A0 ) receptor agonist ( incretin mimetic ) . Exenatide binds to the P43220 with the same affinity as P0C6A0 , but has a much longer half - life , since it is not degraded by the enzyme dipeptidyl peptidase - 4 . Exenatide twice daily enhances glucose - dependent insulin secretion , suppresses inappropriately elevated glucagon secretion , slows gastric emptying and reduces caloric intake . In well - designed clinical trials , adjunctive subcutaneous exenatide 5 or 10 μg twice daily for 16 - 52 weeks significantly and dose - dependently improved glycaemic control and reduced mean body weight compared with placebo in patients with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs ( OADs ) and / or basal insulin . The improvements in glycaemic control and reductions in body weight were stably maintained during long - term therapy ( up to 3 . 5 years ) . The efficacy of adjunctive exenatide twice daily was generally similar to that of basal , prandial or biphasic insulin , sulfonylureas , rosiglitazone and lixisenatide , and less than that of liraglutide , taspoglutide or exenatide once weekly with respect to reductions in glycated haemoglobin . Exenatide twice daily was generally well tolerated ; mild to moderate nausea and vomiting , which decreased with time on therapy , were the most common adverse events . In patients not receiving concomitant sulfonylureas or insulin , the incidence of hypoglycaemia was low ; when it did occur , it was generally mild in severity . Thus , adjunctive exenatide twice daily is a valuable option in the treatment of type 2 diabetes inadequately controlled with OADs and / or basal insulin .",
"Geniposide inhibits CoCl2 - induced PC12 cells death via the mitochondrial pathway . BACKGROUND : A number of studies have shown that oxidative stress and mitochondrial involvement are major triggering factors in the development of neurodegenerative diseases . Cobalt chloride ( CoCl ( 2 ) ) - induced cell death in PC12 cells may serve a simple and convenient in vitro model of hypoxia - induced neuronal cytotoxicity . To explore the effect of geniposide on CoCl ( 2 ) which induced cytotoxicity and mitochondrial function in rat pheochromocytoma PC12 cells , we analyzed the influence of geniposide on the expression of apoptosis - related proteins . METHODS : PC12 cells and RNAi PC12 cells were treated with 0 , 12 . 5 , 25 , 50 , 100 micromol / L geniposide for 12 hours and then exposure to 400 micromol / L CoCl ( 2 ) for 12 hours . Cell viability , cell morphology , and expression of Bcl - 2 , Bax , P04637 and caspase - 9 were determined using Western blotting . RESULTS : Pretreatment with geniposide markedly improved the cells viability and morphology , decreased the expression of Bax , P04637 and caspase - 9 , and increased the expression of Bcl - 2 in PC12 cells challenged by CoCl ( 2 ) 2 . However , in the RNAi PC12 cells , geniposide had no significant effect on the expression of these proteins . CONCLUSION : Geniposide protects PC12 cells from CoCl ( 2 ) involved in mitochondrial mediated apoptosis , and P43220 might play a critical role in the neuroprotection of geniposide in PC12 cells .",
"Improvement of psoriasis during exenatide treatment in a patient with diabetes . CONTEXT AND AIM : Psoriasis is an immune - mediated skin disorder frequently associated with obesity and type 2 diabetes ( T2D ) . This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a P43220 agonist ( exenatide ) . OBSERVATION : A 61 - year - old male patient ( BMI : 25 . 5 kg / m ( 2 ) ) with T2D treated with metformin and sulphonylureas had also complained , since 1980 , of extensive psoriasis that required multiple steroid - based treatments [ Psoriasis Area and Sensitivity Index ( PASI ) score : 11 ] . In September 2008 , his diabetes treatment was intensified with exenatide ( DB01276 (®) ) to improve poor glycaemic control . The patient , as expected , lost weight and reduced HbA ( 1c ) levels from 65 mmol / mol to 56 mmol / mol . However , after just 1 month of treatment with exenatide , the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 - year follow - up ( PASI : estimated at 3 - 4 ) . Withdrawal of exenatide was associated with weight gain , deterioration of glycaemic control and deterioration of psoriasis ( PASI : > 10 ) . After reinstating exenatide treatment , the patient again reported a prompt improvement in psoriasis ( PASI : 3 . 1 ) . CONCLUSION : There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide . A possible mechanism might be through direct modulation of the immune system by P43220 agonists ."
] |
[
"___MASK100___",
"___MASK15___",
"___MASK3___",
"___MASK40___",
"___MASK45___",
"___MASK47___",
"___MASK54___",
"___MASK96___",
"___MASK98___"
] |
___MASK96___
|
MH_train_452
|
interacts_with DB06480?
|
[
"Discovery and optimization of sulfonyl acrylonitriles as selective , covalent inhibitors of protein phosphatase methylesterase - 1 . The serine hydrolase protein phosphatase methylesterase - 1 ( Q9Y570 ) regulates the methylesterification state of protein phosphatase 2A ( PP2A ) and has been implicated in cancer and Alzheimer ' s disease . We recently reported a fluorescence polarization - activity - based protein profiling ( fluopol - P05067 ) high - throughput screen for Q9Y570 that uncovered a remarkably potent and selective class of aza - β - lactam ( P00519 ) Q9Y570 inhibitors . Here , we describe a distinct set of sulfonyl acrylonitrile inhibitors that also emerged from this screen . The optimized compound , 28 ( AMZ30 ) , selectively inactivates Q9Y570 and reduces the demethylated form of PP2A in living cells . Considering that 28 is structurally unrelated to P00519 inhibitors of Q9Y570 , these agents , together , provide a valuable set of pharmacological probes to study the role of methylation in regulating PP2A function . We furthermore observed that several serine hydrolases were sensitive to analogues of 28 , suggesting that more extensive structural exploration of the sulfonyl acrylonitrile chemotype may result in useful inhibitors for other members of this large enzyme class .",
"[ Some practical questions on chronic stipsis treatment with prucalopride ] . Chronic constipation is a frequent pathological condition bearing relevant socioeconomic burdens , mainly due to uncertain management and unsatisfactory response to traditional laxatives . DB06480 is a novel enterokinetic drug , that has been demonstrated to improve bowel functions and relieve a broad spectrum of digestive symptoms in patients with severe chronic constipation who had failed to respond to various traditional laxatives . In this paper we discussed the practical aspects of chronic constipation treatment , in particular focusing on some questions about the practical use of prucalopride . DB06480 is a potent , selective , high - affinity agonist of the Q13639 receptors widely expressed in the gastrointestinal tract . Unlike other Q13639 agonists , such as cisapride and tegaserod , it is devoid of adverse cardiovascular effects . Furthermore , it is characterized by a low potential for interactions with other drugs , due to its pharmacokinetic characteristics . DB06480 was approved , in 2009 , by the European Medicines Agency for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief , however , there are ongoing studies to extend the use of the drug even to males .",
"Endogenous serotonin excites striatal cholinergic interneurons via the activation of 5 - HT 2C , P50406 , and P34969 serotonin receptors : implications for extrapyramidal side effects of serotonin reuptake inhibitors . The striatum is richly innervated by serotonergic afferents from the raphe nucleus . We explored the effects of this input on striatal cholinergic interneurons from rat brain slices , by means of both conventional intracellular and whole - cell patch - clamp recordings . Bath - applied serotonin ( 5 - HT , 3 - 300 microM ) , induced a dose - dependent membrane depolarization and increased the rate of spiking . This effect was mimicked by the 5 - HT reuptake blockers citalopram and fluvoxamine . In voltage - clamped neurons , 5 - HT induced an inward current , whose reversal potential was close to the K (+) equilibrium potential . Accordingly , the involvement of K (+) channels was confirmed either by increasing extracellular K (+) concentration and by blockade of K (+) channels with barium . Single - cell reverse transcriptase - polymerase chain reaction ( RT - PCR ) profiling demonstrated the presence of P28335 , P50406 , and P34969 receptor mRNAs in identified cholinergic interneurons . The depolarization / inward current induced by 5 - HT was partially mimicked by the 5 - HT2 receptor agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine and antagonized by both ketanserin and the selective P28335 antagonist RS102221 , whereas the selective 5 - Q9H205 and Q13639 receptor antagonists tropisetron and RS23597 - 190 had no effect . The depolarizing response to 5 - HT was also reduced by the selective P50406 and P34969 receptor antagonists SB258585 and SB269970 , respectively , and mimicked by the P34969 agonist , 5 - CT . Accordingly , activation of either P50406 or P34969 receptor induced an inward current . The 5 - HT response was attenuated by U73122 , blocker of phospholipase C , and by SQ22 , 536 , an inhibitor of adenylyl cyclase . These results suggest that 5 - HT released by serotonergic fibers originating in the raphe nuclei has a potent excitatory effect on striatal cholinergic interneurons .",
"Molecular genetics of bipolar disorder . Bipolar disorder ( BPD ) is an often devastating illness characterized by extreme mood dysregulation . Although family , twin and adoption studies consistently indicate a strong genetic component , specific genes that contribute to the illness remain unclear . This study gives an overview of linkage studies of BPD , concluding that the regions with the best evidence for linkage include areas on chromosomes 2p , 4p , 4q , 6q , 8q , 11p , 12q , 13q , 16p , 16q , 18p , 18q , 21q , 22q and Xq . Association studies are summarized , which support a possible role for numerous candidate genes in BPD including P21964 , Q01959 , Q13639 , P21917 , P14416 , P28223 , 5 - HTT , the P59103 / G30 complex , Q9NRI5 , Q99572 , P21397 and P23560 . Animal models related to bipolar illness are also reviewed , with special attention paid to those with clear genetic implications . We conclude with suggestions for strategies that may help clarify the genetic bases of this complex illness .",
"Activation of P42345 : a culprit of Alzheimer ' s disease ? Alzheimer ' s disease ( AD ) is characterized by cognitive impairment in clinical presentation , and by β - amyloid ( Aβ ) production and the hyper - phosphorylation of tau in basic research . More highlights demonstrate that the activation of the mammalian target of rapamycin ( P42345 ) enhances Aβ generation and deposition by modulating amyloid precursor protein ( P05067 ) metabolism and upregulating β - and γ - secretases . P42345 , an inhibitor of autophagy , decreases Aβ clearance by scissoring autophagy function . P42345 regulates Aβ generation or Aβ clearance by regulating several key signaling pathways , including phosphoinositide 3 - kinase ( P19957 - K ) / protein kinase B ( Akt ) , glycogen synthase kinase 3 [ GSK - 3 ] , AMP - activated protein kinase ( AMPK ) , and insulin / insulin - like growth factor 1 ( DB01277 ) . The activation of P42345 is also a contributor to aberrant hyperphosphorylated tau . DB00877 , the inhibitor of P42345 , may mitigate cognitive impairment and inhibit the pathologies associated with amyloid plaques and neurofibrillary tangles by promoting autophagy . Furthermore , the upstream and downstream components of P42345 signaling are involved in the pathogenesis and progression of AD . Hence , inhibiting the activation of P42345 may be an important therapeutic target for AD .",
"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK9___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK9___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .",
"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK70___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .",
"Ras - dependent P29323 activation by the human G ( s )- coupled serotonin receptors Q13639 ( b ) and P34969 ( a ) . Receptor tyrosine kinases activate mitogen - activated protein ( Q96HU1 ) kinases through Ras , P04049 , and MEK . Receptor tyrosine kinases can be transactivated by G protein - coupled receptors coupling to G ( i ) and G ( q ) . The human G protein - coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) couple to G ( s ) and elevate intracellular DB02527 . Certain G ( s )- coupled receptors have been shown to activate Q96HU1 kinases through a protein kinase A - and Rap1 - dependent pathway . We report the activation of the extracellular signal - regulated kinases ( ERKs ) 1 and 2 ( Q8TCB0 and Q8NFH3 Q96HU1 kinase ) through the human serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in COS - 7 and human embryonic kidney HEK293 cells . In transfected HEK293 cells , 5 - HT - induced activation of P27361 / 2 is sensitive to H89 , which indicates a role for protein kinase A . The observed activation of P27361 / 2 does not require transactivation of epidermal growth factor receptors . Furthermore , 5 - HT induced activation of both Ras and Rap1 . Whereas the presence of P47736 did not influence the 5 - HT - mediated activation of P27361 / 2 , the activation of P27361 / 2 was abolished in the presence of dominant negative Ras ( RasN17 ) . P27361 / 2 activation was reduced in the presence of \" dominant negative \" Raf1 ( RafS621A ) and slightly reduced by dominant negative B - Raf , indicating the involvement of one or more Raf isoforms . These findings suggest that activation of P27361 / 2 through the human G ( s )- coupled serotonin receptors 5 - HT ( 4 ( b )) and 5 - HT ( 7 ( a )) in HEK293 cells is dependent on Ras , but independent of Rap1 .",
"Effect of prucalopride on symptoms of chronic constipation . BACKGROUND : DB06480 is a Q13639 receptor agonist with gastrointestinal prokinetic activities . This integrated analysis of data from three 12 - week , double - blind trials evaluated the effect of prucalopride 2 mg q . d . on common constipation symptoms in women in whom laxatives had failed to provide adequate relief . The effect of prucalopride on bowel function was outside the scope of the analysis and has been described elsewhere . METHODS : Women with self - reported inadequate relief from laxatives and included in the prucalopride 2 mg or placebo arm of the trials were selected for analysis . Symptom severity was determined with the Patient Assessment of Constipation Symptoms ( PAC - SYM ) questionnaire . Observed changes from baseline in individual item scores were also evaluated by calculating Cohen ' s D effect sizes using baseline standard deviation ( SD ) ( > 0 . 2 - 0 . 5 , > 0 . 5 - 0 . 8 and > 0 . 8 for small , moderate and large effects , respectively ) . KEY RESULTS : Data were analyzed for 936 women . The proportion of women with a PAC - SYM severity score > 2 at baseline was 50 . 0 % for abdominal symptoms , 71 . 4 % for stool symptoms , and 15 . 5 % for rectal symptoms . Excluding the women without presence of a symptom at baseline from the effect size calculations showed that prucalopride 2 mg had a large effect ( > 0 . 8 ) on all PAC - SYM items , including abdominal pain , abdominal discomfort , bloating , straining , and painful bowel movements . For abdominal symptoms and stool symptoms , effect sizes with prucalopride 2 mg were 1 . 3 - 2 . 3 times larger than those with placebo . CONCLUSIONS & INFERENCES : DB06480 2 mg q . d . for 12 weeks alleviates common constipation symptoms in women in whom laxatives had failed to provide adequate relief .",
"DB06480 reduces the number of reflux episodes and improves subjective symptoms in gastroesophageal reflux disease : a case series . INTRODUCTION : Treatment of persistence to proton pump inhibitors or non - acid reflux episodes in patients with gastroesophageal reflux disease is challenging . DB06480 , a selective high affinity serotonin ( Q13639 ) receptor agonist , might offer a possible new therapeutic alterative . CASE PRESENTATIONS : We report four chronically constipated female gastroesophageal reflux disease - patients with reflux symptoms and an increased number of reflux episodes in combined esophageal pH and multichannel impedance monitoring treated with prucalopride ( 2mg per day ) . Symptoms were persistent to proton pump inhibitors and ranitidine . Gastroesophageal reflux was detected by pH or multichannel impedance ( MII ) monitoring . Numbers of all reflux episodes as well as non - acid reflux episodes were reduced in all of our patients . The objective findings were concordant with subjective reports of symptom relief . There were no major adverse events in any patient during therapy with prucalopride . CONCLUSION : Administration of prucalopride showed promising results in the treatment of persisting or weakly and / or non - acid reflux episodes in our case series in four constipated patients . Therefore , prucalopride can be regarded as a possible therapeutic option in the treatment of standard proton pump inhibitor - persistent reflux in the chronically constipated patient . However , further prospective trials are needed to prove our findings .",
"___MASK3___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK3___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"Synergism between bosutinib ( ___MASK56___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"The serotonin Q13639 receptor and the amyloid precursor protein processing . A large body of evidence supports a major role for the serotonin 5 - HT ( 4 ) receptor in learning and memory and it is suggested that 5 - HT ( 4 ) agonists may be beneficial for memory disorders such as Alzheimer ' s disease ( AD ) . The 5 - HT ( 4 ) receptors are members of the G protein - coupled receptor superfamily and are positively coupled to adenylyl cyclase . In this communication we show that a neuronal isoform of the human 5 - HT ( 4 ) receptor , h5 - HT ( 4 ( g )) regulates the metabolism of the amyloid precursor protein ( APP695 ) . This process is observed in Chinese hamster ovary ( CHO ) cells stably coexpressing the neuronal h5 - HT ( 4 ( g )) receptor isoform as well as the human APP695 . The 5 - HT ( 4 ) agonists strongly stimulate the release of the non - amyloidogenic soluble amyloid precursor protein sAPPalpha as detected by immunoblot . DB06480 was more potent than serotonin ( 5 - HT ) with regard to enhanced of sAPPalpha secretion . This process was blocked by a selective 5 - HT ( 4 ) antagonist , GR113808 . Furthermore , 5 - HT ( 4 ) ligands enhance sAPPalpha secretion via DB02527 - dependent and PKA - independent signalling pathways indicating there are alternative pathways by which the h5 - HT ( 4 ) receptor via DB02527 regulates P05067 metabolism . Because the alpha - cleavage event may preclude the formation of amyloidogenic peptides , and secreted sAPPalpha has putative neuroprotective and enhancing - memory properties , our present data suggest the 5 - HT ( 4 ) receptor as a novel target for the treatment of AD .",
"Granulocyte - colony stimulating factor attenuates oligomeric amyloid β neurotoxicity by activation of neprilysin . Soluble oligomeric amyloid β ( oAβ ) causes synaptic dysfunction and neuronal cell death , which are involved in the pathogenesis of Alzheimer ' s disease ( AD ) . The hematopoietic growth factor granulocyte - colony stimulating factor ( DB00099 ) is expressed in the central nervous system ( CNS ) and drives neurogenesis . Here we show that G - P04141 attenuated oAβ neurotoxicity through the enhancement of the enzymatic activity of Aβ - degrading enzyme neprilysin ( NEP ) in neurons , while the NEP inhibitor thiorphan abolished the neuroprotection . Inhibition of Q13163 / Q13164 , a major downstream effector of G - P04141 signaling , also ablated neuroprotective effect of DB00099 . Furthermore , intracerebroventricular administration of G - P04141 enhanced NEP enzymatic activity and clearance of Aβ in P05067 / P49768 transgenic mice . Thus , we propose that G - P04141 may be a possible therapeutic strategy against AD .",
"Efficacy and safety of prucalopride in adults and children with chronic constipation . INTRODUCTION : Chronic constipation ( CC ) is a debilitating condition with high prevalence rates both in children and adults . Despite the broad range of medical and pharmaceutical treatments , the bowel function does not restore in a fair amount of patients . DB06480 is a first - in - class selective , high affinity serotonin 5 - hydroxytryptamine type 4 ( Q13639 ) receptor agonist promoting gastro - intestinal prokinetic activity and has been evaluated for the treatment of CC . AREAS COVERED : A PubMed search ( 1965 - 2014 ) using the following terms alone or in combination : prucalopride , Q13639 , R093877 , safety , toxicity , pharmacokinetics , pharmacodynamics , transit , cardiac , human ether - a - go - go related gene ( hERG ) , arrhythmia , potassium current , elderly , children . EXPERT OPINION : DB06480 , a highly selective Q13639 receptor agonist , stimulates gastrointestinal motility and has been proven to be effective in the treatment of CC in adults by increasing stool frequency , reducing constipation - related symptoms and improving quality of life ( QoL ) . The safety and tolerability have been proven to be excellent . More research would be preferable on the effect of prucalopride on men , children and in other gastrointestinal motility disorders .",
"Chronic Q13639 receptor activation decreases Aβ production and deposition in hAPP / P49768 mice . Lowering the production and accumulation of Aβ has been explored as treatment for Alzheimer ' s disease ( AD ) , because Aβ is postulated to play an important role in the pathogenesis of AD . Q13639 receptors are an interesting drug target in this regard , as their activation might stimulate α - secretase processing , which increases sAPPα and reduces Aβ , at least according to the central dogma in P05067 processing . Here we describe a novel high - affinity Q13639 receptor agonist SSP - 002392 that , in cultured human neuroblastoma cells , potently increases the levels of DB02527 and sAPPα at 100 - fold lower concentrations than the effective concentrations of prucalopride , a known selective Q13639 receptor agonist . Chronic administration of this compound in a hAPP / P49768 mouse model of Alzheimer ' s disease decreased soluble and insoluble Aβ in hippocampus , but the potential mechanisms underlying these observations seem to be complex . We found no evidence for direct α - secretase stimulation in the brain in vivo , but observed decreased P05067 and P56817 - 1 expression and elevated astroglia and microglia responses . Taken together these results provide support for a potential disease - modifying aspect when stimulating central Q13639 receptors ; however , the complexity of the phenomena warrants further research .",
"Dual P00533 and P42345 targeting in squamous cell carcinoma models , and development of early markers of efficacy . The epidermal growth factor receptor ( P00533 ) is a validated target in squamous cell carcinoma ( SCC ) of the head and neck . Most patients , however , do not respond or develop resistance to this agent . P42345 ( P42345 ) is involved in the pathogenesis of SCC of the head and neck ( SCCHN ) . This study aimed to determine if targeting P42345 in combination with P00533 is effective in SCC , and to develop early pharmacodynamic markers of efficacy . Two SCC cell lines , one resistant ( HEP2 ) and one of intermediate susceptibility ( Detroit 562 ) to P00533 inhibitors , were xenografted in vivo and treated with an P42345 inhibitor ( temsirolimus ) , an P00533 inhibitor ( erlotinib ) or a combination of both . ___MASK39___ exerted superior growth arrest in both cell lines than erlotinib . The combined treatment resulted in synergistic antitumor effects in the Detroit 562 cell line . Immunohistochemical assessment of pharmacodynamic effects in fine - needle aspiration ( FNA ) biopsies early after treatment using phospho MAPK , Phospho - P70 and Ki67 as end points demonstrated pathway abrogation in the Detroit 562 tumours treated with the combination , the only group where regressions were seen . In conclusion , an P42345 inhibitor showed antitumor activity in P00533 - resistant SCC cell lines . Marked antitumor effects were associated with dual pathway inhibition , which were detected by early FNA biopsies .",
"Emerging pharmacologic therapies for irritable bowel syndrome . New therapies are being developed for irritable bowel syndrome ( IBS ) . These advances are based on understanding pathophysiology or the development of medications with greater selectivity in classes of agents with known efficacy . DB06480 , the newest European Medicines Agency - approved Q13639 ( 5 - HT ( 4 ) ) agonist , is effective in the treatment of chronic constipation with improved cardiovascular safety relative to older 5 - HT ( 4 ) drugs ; similarly , ramosetron , the P46098 ( 5 - HT ( 3 ) ) antagonist , appears efficacious in diarrhea - predominant IBS . Secretagogues with different mechanisms of action target apical domains in enterocytes that are involved in chloride secretion , such as chloride channels , the cystic fibrosis transmembrane regulator , and guanylate cyclase C . As a class , such secretagogues have high efficacy and safety for constipation . With more data obtained from phase 2 and 3 trials , we expect other classes of medications , including bile acid modulators , anti - inflammatory agents , visceral analgesics , and newer centrally acting agents to be efficacious and enter the armamentarium for the treatment of IBS in the future .",
"Role of prucalopride , a serotonin ( 5 - HT ( 4 ) ) receptor agonist , for the treatment of chronic constipation . Constipation affects up to a quarter of the population in developed countries and is associated with poor quality of life and significant economic burden . Many patients with chronic constipation are dissatisfied with current therapy due to lack of long - term efficacy or side effects . Previous nonselective Q13639 ( 5 - HT ( 4 ) ) agonists have been associated with significant interactions with other receptors ( 5 - HT ( 1B ) , 5 - HT ( 1D ) , and 5 - HT ( 2B ) for tegaserod ; hERG for cisapride ) , leading to adverse cardiovascular events resulting in withdrawal of these drugs from the market . DB06480 is a novel gastrointestinal prokinetic agent . It acts as a high affinity , highly - selective 5 - HT ( 4 ) agonist . Its efficacy in patients with chronic constipation has been demonstrated in several phase II and phase III clinical trials showing significant improvements in bowel transit , bowel function , gastrointestinal symptoms , and quality of life , with benefit maintained for up to 24 months in open label , multicenter , follow - up studies . DB06480 ' s high selectivity for the 5 - HT ( 4 ) receptor may explain its favorable safety and tolerability profiles , even in elderly subjects with stable cardiovascular disease . DB06480 is a well tolerated and efficacious prokinetic medication that should enhance the treatment of chronic constipation unresponsive to first - line treatments .",
"___MASK39___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK39___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK39___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK39___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"Q13639 receptors located on cholinergic nerves in human colon circular muscle . 5 - Hydroxytryptamine 4 ( Q13639 ) receptor agonists promote colonic propulsion . The alteration of circular muscle ( CM ) motility underlying this involves inhibition of contractility via smooth muscle Q13639 receptors and proximal colonic motility stimulation , the mechanism of the latter not having been characterized . Our aim was to identify and characterize a Q13639 receptor - mediated stimulation of human colon CM contractile activity . Q13639 receptor ligands were tested on electrical field stimulation ( O43281 ) - induced contractions of human colonic muscle strips cut in the circular direction ( called ' whole tissue ' strips ) . Additionally , after incubation of tissues with [ 3H ] - choline these compounds were tested on O43281 - induced release of tritium in whole tissue strips and in ' isolated ' CM strips , obtained by superficial cutting in the CM layer . DB05232 and atropine blocked O43281 - induced contractions of whole tissue CM strips . DB06480 ( 0 . 3 micromol L - 1 ) evoked a heterogenous response on O43281 - induced contraction , ranging from inhibition ( most frequently observed ) to enhancement . In the release experiments , O43281 - induced tritium efflux was blocked by tetrodotoxin . DB06480 increased O43281 - induced tritium and [ 3H ] - acetylcholine efflux in whole tissue and in isolated CM strips . All effects of prucalopride were antagonized by the selective Q13639 receptor antagonist GR113808 . The results obtained indicate the presence of excitatory Q13639 receptors on cholinergic nerves within the CM of human colon .",
"Q13639 receptor agonists increase sAPPalpha levels in the cortex and hippocampus of male C57BL / 6j mice . BACKGROUND AND PURPOSE : A strategy to treat Alzheimer ' s disease ( AD ) is to increase the soluble form of amyloid precursor protein ( sAPPalpha ) , a promnesic protein , in the brain . Because strong evidence supports beneficial effects of 5 - hydroxytryptamine 5 - HT ( 4 ) receptor agonists in memory and learning , we investigated the role of 5 - HT ( 4 ) receptors on P05067 processing in 8 weeks - old male C57BL / 6j mice . EXPERIMENTAL APPROACH : Mice were given , subcutaneously , prucalopride or ML 10302 ( s . c . ) , two highly selective 5 - HT ( 4 ) receptor agonists and , up to 240 min later , the hippocampus and cortex were analysed by Western blot for sAPPalpha determination . KEY RESULTS : DB06480 ( 5 or 10 mg kg (- 1 ) ) significantly increased sAPPalpha levels in the hippocampus and cortex , but did not modify the expression level of P05067 mRNA as detected by quantitative RT - PCR . A selective 5 - HT ( 4 ) receptor antagonist , GR125487 ( 1 mg kg (- 1 ) , s . c . ) inhibited prucalopride induced - increase in sAPPalpha levels . In addition , levels of sAPPalpha were increased by ML10302 only at 20 mg kg (- 1 ) and was limited to the cortex . Also , prucalopride increased sAPPalpha levels in the cortex of a transgenic mouse model of AD , expressing the London mutation of P05067 . Furthermore , the combined injection of a selective acetylcholinesterase inhibitor , donepezil and prucalopride induced a synergic increase in sAPPalpha levels in the cortex and hippocampus . CONCLUSIONS AND IMPLICATIONS : Our results demonstrate that the 5 - HT ( 4 ) receptor plays a key role in the non - amyloidogenic pathway of P05067 metabolism in vivo and give support to the beneficial use of 5 - HT ( 4 ) agonists for AD treatment .",
"P35968 - 5169 , a new gastrointestinal prokinetic agent , enhances gastric contractile and emptying activities in dogs and rats . P35968 - 5169 , 4 - amino - 5 - chloro - N -[ 1 -( 3 - fluoro - 4 - methoxybenzyl ) piperidin - 4 - yl ]- 2 -( 2 - hydroxyethoxy ) benzamide hydrochloride dihydrate , is a new prokinetic with a dual action , i . e . , stimulation of the Q13639 receptor and antagonism of the dopamine D2 receptor . In this study , we determined in vitro activities of P35968 - 5169 towards both receptors and demonstrated the effect of the compound on gastrointestinal motor activity in conscious dogs and rats . In dogs , intravenous P35968 - 5169 stimulated upper gastrointestinal motility in the fasting state and also eliminated the depressive effect of 3 , 4 - dihydroxyphenylalanine ( DB01235 ) on this motility in the postprandial state . The effect of P35968 - 5169 on gastric emptying was further characterized by the use of three rat gastroparesis models ( dopamine D2 receptor agonist ( quinpirol )- , abdominal surgery - , or combined - situation - induced ) . DB01184 ( a dopamine D2 receptor antagonist ) was effective in the quinpirol - delay and combination - delay models , and cisapride and mosapride ( Q13639 receptor agonists ) were effective in the surgery - delay model . Only P35968 - 5169 eliminated the delay of gastric emptying in all three models . In addition , P35968 - 5169 accelerated emptying to above the normal level in the combination - delay model . These results suggest that P35968 - 5169 would be effective in various types of gastric ileus caused by different mechanisms .",
"Beta - amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin - proteasome system . Increasing evidence links intraneuronal beta - amyloid ( Abeta42 ) accumulation with the pathogenesis of Alzheimer ' s disease ( AD ) . In Abeta precursor protein ( P05067 ) mutant transgenic mice and in human AD brain , progressive intraneuronal accumulation of Abeta42 occurs especially in multivesicular bodies ( MVBs ) . We hypothesized that this impairs the MVB sorting pathway . We used the trafficking of the epidermal growth factor receptor ( P00533 ) and TrkB receptor to investigate the MVB sorting pathway in cultured neurons . We report that , during P01133 stimulation , P05067 mutant neurons demonstrated impaired inactivation , degradation , and ubiquitination of P00533 . P00533 degradation is dependent on translocation from MVB outer to inner membranes , which is regulated by the ubiquitin - proteasome system ( P08397 ) . We provide evidence that Abeta accumulation in P05067 mutant neurons inhibits the activities of the proteasome and deubiquitinating enzymes . These data suggest a mechanism whereby Abeta accumulation in neurons impairs the MVB sorting pathway via the P08397 in AD .",
"DB06480 : safety , efficacy and potential applications . Chronic constipation is a very common functional gastrointestinal disorder which can be associated with significant impairments in quality of life for some people with the condition . Its management has , traditionally , been based on dietary and lifestyle changes and the use of a variety of laxative agents . The evidence base for the efficacy of the latter is , in many cases , slim . Not surprisingly , many patients remain dissatisfied with laxatives thus leading to the development of more pharmacological approaches . Among these approaches is the use of prokinetic agents ; while prior molecules have been troubled by lack of selectivity and cardiac side effects , the new agent , prucalopride , appears to be highly selective for the serotonin Q13639 receptor and is , therefore , a potent stimulator of gut motility . In three large pivotal randomized controlled trials , prucalopride has been effective in relieving the cardinal symptoms of chronic constipation ; these effects have been sustained in open - label follow up for as long as 18 months . The safety profile has been encouraging and , especially so , the absence of arrhythmogenic potential . Studies in men , in constipation - predominant irritable bowel syndrome and in other motor disorders are eagerly awaited .",
"Dissociation of Akt / P31749 and ribosomal S6 kinase signaling markers in a transgenic mouse model of Alzheimer ' s disease . Previous studies demonstrated that the P19525 ( double - stranded RNA - activated protein kinase ) pathway was activated while the P42345 ( mammalian target of rapamycin ) pathway was inhibited in Alzheimer ' s disease ( AD ) . Here , we analysed upstream and downstream factors of P42345 in brain of P05067 ( SL )/ P49768 KI mice displaying a massive neuronal loss in hippocampus . While P42345 levels were not modified , we found a great activation of Akt with a robust accumulation of P - Akt ( ( T308 ) ) in non - apoptotic neurons at 6 months of age . At the opposite , a significant decrease of the P08133 / 85S6K activation was observed in brain of P49768 KI and P05067 ( SL )/ P49768 KI mice with a very weak or no nucleocytoplasmic P - P08133 / 85S6K ( ( T389 ) ) staining in apoptotic neurons of P05067 ( SL )/ P49768 KI mice . Furthermore , the activation of Erk1 / 2 , Q13541 and p70S6K ( ( T421 / S424 ) ) ( substrate of Erk1 / 2 ) , except P06730 , was not modified . These findings demonstrate a clear dissociation between Akt and ribosomal S6K signaling markers in these mice which could be involved in the AD pathological process .",
"Abnormal sensitivity of cortisol - producing adrenocortical adenomas to serotonin : in vivo and in vitro studies . Two patients with incidentally discovered adrenocortical adenomas underwent a series of pharmacological and physiological tests after pretreatment with dexamethasone . Illicit plasma cortisol responses to the serotonin ( 5 - HT ) 4 receptor agonist cisapride were observed in the two patients . Significant increases in plasma cortisol levels were also noticed after glucagon and combined TRH / DB00644 / P01286 stimulation tests in patient 1 and after administration of the lysine vasopressin precursor terlipressin in patient 2 . After adrenalectomy , in vitro studies were conducted to investigate the cortisol responses of cultured tumor cells to serotonergic ligands and peptide hormones . In the two cases , 5 - HT stimulated cortisol secretion from tumor cells with increased efficacy and / or potency to activate steroidogenesis by comparison with normal adrenocortical cells . The corticotropic effect of 5 - HT was inhibited by the specific Q13639 receptor antagonist GR 113808 and more potently by methiothepin , a nonspecific serotonergic antagonist having no affinity for the Q13639 receptor . These results show that the hypersensitivity of the tumors to 5 - HT was related to tissue expression of an ectopic serotonergic receptor in addition to the eutopic Q13639 receptor . In the two adenoma tissues , immunohistochemical studies revealed the presence of 5 - HT - like immunoreactivity within clusters of steroidogenic cells , suggesting that 5 - HT acted through an autocrine / paracrine mechanism to stimulate steroidogenesis . Glucagon and DB00644 but not TRH , P01286 , and human chorionic gonadotropin stimulated cortisol secretion from tumor 1 cells . In conclusion , this study provides the first observation of adrenocortical cortisol - producing adenomas hypersensitive in vivo and in vitro to serotonergic agonists . Our results also show that cortisol - producing adenomas can express simultaneously several illegitimate receptors .",
"Neto1 associates with the DB01221 receptor / amyloid precursor protein complex . Neuropilin tolloid - like 1 ( Neto1 ) , is a CUB domain - containing transmembrane protein that was recently identified as a novel component of the DB01221 receptor complex . Here , we have investigated the possible association of Neto1 with the amyloid precursor protein ( P05067 ) 695 / Q05586 / Q12879 and APP695 / Q05586 / Q13224 DB01221 receptor trafficking complexes that we have previously identified . Neto1 ( HA ) was shown to co - immunoprecipitate with assembled DB01221 receptors via Q12879 or Q13224 subunits ; Neto1 ( HA ) did not co - immunoprecipitate APP695 ( FLAG ) . Co - immunoprecipitations from mammalian cells co - transfected with APP695 ( FLAG ) , Neto1 ( HA ) and Q05586 / Q12879 or Q05586 / Q13224 revealed that all four proteins co - exist within one macromolecular complex . Immunoprecipitations from native brain tissue similarly revealed the existence of a Q05586 / Q12879 or Q13224 / P05067 / Neto1 complex . Neto1 ( HA ) caused a reduction in the surface expression of both DB01221 receptor subtypes , but had no effect on APP695 ( FLAG ) - or A5PKW4 - 95α ( c - Myc ) enhanced surface receptor expression . The Neto1 binding domain of Q12879 was mapped using Q05586 / Q12879 chimeras and Q12879 truncation constructs . The extracellular Q12879 domain does not contribute to association with Neto1 ( HA ) but deletion of the intracellular tail resulted in a loss of Neto - 1 ( HA ) co - immunoprecipitation which was paralleled by a loss of association between Q12879 and Q92796 . Thus , Neto1 is concluded to be a component of P05067 / DB01221 receptor trafficking complexes .",
"Identification of novel genetic alterations in samples of malignant glioma patients . Glioblastoma is the most frequent and malignant human brain tumor . High level of genomic instability detected in glioma cells implies that numerous genetic alterations accumulate during glioma pathogenesis . We investigated alterations in AP - PCR DNA profiles of 30 glioma patients , and detected specific changes in 11 genes not previously associated with this disease : Q86UP9 , Q13326 , Q13639 , P05556 , P31327 , P07225 , P55259 , Q9UJ96 , Q08499 , Q8N743 , and Q14642 . Further correlations revealed that 8 genes might play important role in pathogenesis of glial tumors , while changes in P55259 , Q9UJ96 and Q8N743 should be considered as passenger mutations , consequence of high level of genomic instability . Identified genes have a significant role in signal transduction or cell adhesion , which are important processes for cancer development and progression . According to our results , Q86UP9 might be characteristic of primary glioblastoma , Q13326 , Q13639 , P05556 , P31327 , P07225 and Q14642 were detected predominantly in anaplastic astrocytoma , suggesting their role in progression of secondary glioblastoma , while alterations of Q08499 seem to have important role in development of both glioblastoma subtypes . Some of the identified genes showed significant association with p53 , p16 , and P00533 , but there was no significant correlation between loss of P60484 and any of identified genes . In conclusion our study revealed genetic alterations that were not previously associated with glioma pathogenesis and could be potentially used as molecular markers of different glioblastoma subtypes .",
"Modulation of hippocampal excitability by Q13639 receptor agonists persists in a transgenic model of Alzheimer ' s disease . 5 - HT ( 4 ) receptors are widely distributed in both peripheral and central nervous systems where they couple , via a G - protein , to the activation of adenylate cyclase . In the brain , the highest 5 - HT ( 4 ) receptor densities are found in the limbic system , including the hippocampus and frontal cortex . It has been suggested that activation of these receptors may be of therapeutic benefit in diseases that produce cognitive deficits such as Alzheimer ' s disease ( AD ) . Previous electrophysiological studies have shown that the 5 - HT ( 4 ) agonist , Zacopride , can increase population spike amplitude recorded in region P00915 of rat hippocampal slices in a cyclic AMP ( DB02527 ) / DB02527 - dependent protein kinase A - dependent manner . We report here that the 5 - HT ( 4 ) agonist , DB06480 , and the 5 - HT ( 4 ) partial agonist , SL65 . 0155 , produce a similar effect in rat hippocampal slices and that the specific 5 - HT ( 4 ) antagonist , GR113808 , blocks these effects . To investigate the potential use of 5 - HT ( 4 ) agonists in the treatment of AD , DB06480 was applied to hippocampal slices from a transgenic mouse line that overexpresses the Abeta peptide . Despite the deficit in synaptic transmission present in these mice , the percentage increase of the P00915 population spike induced by DB06480 was the same as that observed in wild - type mice . These data support 5 - HT ( 4 ) receptors as a target for cognitive enhancement and suggest that a partial agonist would be sufficient to produce benefits , while reducing potential peripheral side effects . In addition , we show that 5 - HT ( 4 ) receptors remain functional in the presence of excess Abeta peptide and may therefore be a useful target in AD .",
"Targeted treatment of advanced and metastaticbreast cancer with lapatinib . Improved molecular understanding of breast cancer in recent years has led to the discovery of important drug targets such as HER - 2 and P00533 . ___MASK79___ is a potent dual inhibitor of HER - 2 and P00533 . Preclinical and phase I studies have shown activity with lapatinib in a number of cancers , including breast cancer , and the drug is well tolerated . The main known drug interactions are with paclitaxel and irinotecan . The most significant side - effects of lapatinib are diarrhea and adverse skin events . Rates of cardiotoxicity compare favorably with trastuzumab , a monoclonal antibody against HER - 2 . This paper focuses on lapatinib in advanced and metastatic breast cancer , which remains an important therapeutic challenge . Phase II and III studies show activity as monotherapy , and in combination with chemotherapy or hormonal agents . Results from these studies suggest that the main benefit from lapatinib is in the HER - 2 positive breast cancer population . Combinations of lapatinib and trastuzumab are also being studied and show encouraging results , particularly in trastuzumab - refractory metastatic breast cancer . ___MASK79___ may have a specific role in treating HER - 2 positive CNS metastases . The role of lapatinib as neoadjuvant therapy and in early breast cancer is also being evaluated .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"A whole genome Bayesian scan for adaptive genetic divergence in West African cattle . BACKGROUND : The recent settlement of cattle in West Africa after several waves of migration from remote centres of domestication has imposed dramatic changes in their environmental conditions , in particular through exposure to new pathogens . West African cattle populations thus represent an appealing model to unravel the genome response to adaptation to tropical conditions . The purpose of this study was to identify footprints of adaptive selection at the whole genome level in a newly collected data set comprising 36 , 320 SNPs genotyped in 9 West African cattle populations . RESULTS : After a detailed analysis of population structure , we performed a scan for SNP differentiation via a previously proposed Bayesian procedure including extensions to improve the detection of loci under selection . Based on these results we identified 53 genomic regions and 42 strong candidate genes . Their physiological functions were mainly related to immune response ( MHC region which was found under strong balancing selection , P11912 , P61073 , P80370 , P48380 , Q9H3S1 , Q8IUC6 and P19474 ) , nervous system ( Q96NK8 , O95897 , MAGI1 , Q9H3S1 and Q13639 ) and skin and hair properties ( P24530 , TRSP1 and Q8IUC2 ) . CONCLUSION : The main possible underlying selective pressures may be related to climatic conditions but also to the host response to pathogens such as Trypanosoma ( sp ) . Overall , these results might open the way towards the identification of important variants involved in adaptation to tropical conditions and in particular to resistance to tropical infectious diseases .",
"Phosphodiesterase - 5 inhibitor sildenafil prevents neuroinflammation , lowers beta - amyloid levels and improves cognitive performance in P05067 / P49768 transgenic mice . Memory deficit is a marker of Alzheimer ' s disease ( AD ) that has been highly associated with the dysfunction of cyclic GMP ( cGMP ) signaling and an ongoing inflammatory process . Phosphodiesterase - 5 ( O76074 ) inhibitors prevent the breakdown of cGMP and are currently studied as a possible target for cognitive enhancement . However , it is still unknown whether inhibition of O76074 reversed β - amyloid peptide ( Aβ ) - induced neuroinflammation in P05067 / P49768 transgenic ( Tg P05067 / P49768 ) mice . The present study evaluated the cognitive behaviors , inflammatory mediators , and cGMP / PKG / pCREB signaling in 15 - month - old Tg P05067 / P49768 mice and age - matched wild - type ( WT ) mice that were treated with O76074 inhibitor sildenafil and the inhibitor of cGMP - dependent protein kinase Rp - 8 - Br - PET - cGMPS . In comparison with WT mice , Tg P05067 / P49768 mice were characterized by impaired cognitive ability , neuroinflammatory response , and down - regulated cGMP signaling . ___MASK8___ reversed these memory deficits and cGMP / PKG / pCREB signaling dysfunction ; it also reduced both the soluble Aβ1 - 40 and Aβ1 - 42 levels in the hippocampus . These effects of sildenafil were prevented by intra - hippocampal infusion of the Rp - 8 - Br - PET - cGMPS . These results suggest that sildenafil could restore cognitive deficits in Tg P05067 / P49768 mice by the regulation of PKG / pCREB signaling , anti - inflammatory response and reduction of Aβ levels .",
"DB06480 : a review of its use in the management of chronic constipation . The highly selective serotonin Q13639 receptor agonist prucalopride ( Resolor (®) , Resotran (®) , Resotrans (®) ) is indicated for the treatment of chronic constipation . In four randomized , double - blind , multicentre , 12 - week trials in patients ( predominantly women ) with chronic constipation , oral prucalopride 2 mg once daily improved bowel function to a significantly greater extent than placebo , with a significantly greater proportion of prucalopride than placebo recipients achieving an average of ≥ 3 spontaneous , complete bowel movements per week ( primary endpoint ) . Significantly greater improvements in health - related quality of life , patient satisfaction with treatment and bowel habit , and a range of constipation - related symptoms were also seen with prucalopride than with placebo . Satisfaction with treatment and bowel habit was maintained with prucalopride in the longer term . DB06480 was generally well tolerated in patients with chronic constipation , with the most commonly reported adverse events ( headache , nausea , abdominal pain , diarrhoea ) primarily occurring on the first day of treatment . During the clinical trials , no cardiovascular safety issues have arisen in patients with chronic constipation receiving prucalopride . In conclusion , prucalopride is an important option for use in patients with chronic constipation who have not experienced adequate relief with laxatives .",
"DB06480 for chronic constipation . Chronic constipation is a frequently reported medical disorder that reduces patients ' quality of life and imposes a significant economic burden on the health care system . Symptoms of constipation are diverse and include infrequent bowel movements , hard stool , straining at stool , sensations of anorectal obstruction and feelings of incomplete evacuation . Patients with chronic constipation can be categorized into one of three main groups based on their underlying pathophysiology : normal transit constipation ; colonic inertia ; and pelvic floor dyssynergia . Specialized tests ( i . e . , anorectal manometry , radio - opaque marker study ) may be required in some patients to help distinguish the different subtypes of constipation and to guide appropriate therapy . Although the underlying mechanism of constipation differs among patients , serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) appears to have an important role in colonic motility in some patients . Previous research has demonstrated that stimulation of Q13639 receptors improves symptoms of chronic constipation in some patients . DB06480 , a selective Q13639 agonist , relieved symptoms of constipation in phase II and phase III clinical trials . In this monograph , we review the pharmacology , mechanism of action , efficacy and safety of the selective Q13639 agonist prucalopride in patients with chronic constipation .",
"___MASK78___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK78___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"Effects of the enterokinetic prucalopride ( R093877 ) on colonic motility in fasted dogs . The novel enterokinetic drug prucalopride was tested at various intravenous and oral doses in fasted dogs to assess : ( i ) the effects on colonic contractile motility patterns ; and ( ii ) the mediation of these effects by 5 - hydroxytryptamine ( Q13639 ) receptors . Colonic motility patterns were assessed in conscious dogs with four chronically implanted strain - gauge force transducers that were sutured on the serosal side of the colon . DB06480 altered colonic contractile motility patterns in a dose - dependent fashion by stimulating high - amplitude clustered contractions in the proximal colon and by inhibiting contractile activity in the distal colon . DB06480 was equipotent after oral and intravenous administration , as reflected by the values for the effective dose that induced 50 % of maximum effect ( 95 % confidence limits ) : 0 . 04 mg kg (- 1 ) p . o . ( 0 . 01 - 0 . 1 mg kg (- 1 ) ) and 0 . 01 mg kg (- 1 ) i . v . ( 0 . 006 - 0 . 04 mg kg (- 1 ) ) . DB06480 also caused a dose - dependent decrease in the time to the first giant migrating contraction ( GMC ) ; at higher doses of prucalopride , the first GMC generally occurred within the first half - hour after treatment . Subcutaneous pretreatment with the Q13639 receptor antagonist GR125487 ( 40 microg kg (- 1 ) bodyweight ) completely prevented the effects of orally administered prucalopride ( 0 . 31 mg kg (- 1 ) bodyweight ) . DB06480 , given orally or intravenously , alters colonic motility in the fasted conscious dog in a dose - dependent fashion . It induces GMCs and causes proximal colon stimulation and distal colon inhibition of contractile motility patterns by stimulating Q13639 receptors .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"New - generation Q13639 receptor agonists : potential for treatment of gastrointestinal motility disorders . IMPORTANCE OF THE FIELD : Gastrointestinal ( GI ) dysmotility is an important mechanism in functional GI disorders ( FGIDs ) including constipation , irritable bowel syndrome , functional dyspepsia , and gastroparesis . 5 - hydroxytryptamine ( 4 ) ( 5 - HT ( 4 ) ) receptors are targets for the treatment of GI motility disorders . However , older 5 - HT ( 4 ) receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac Q12809 potassium channel . AREAS COVERED IN THIS REVIEW : We conducted a PubMed search using the following key words alone or in combination : 5 - HT ( 4 ) , safety , toxicity , pharmacokinetics , pharmacodynamics , clinical trial , cardiac , hERG , arrhythmia , potassium current , elderly , prucalopride , ATI - 7505 , and velusetrag ( DB05655 ) , to review mechanisms of action , clinical efficacy , safety and tolerability of three new - generation 5 - HT ( 4 ) receptor agonists . WHAT THE READER WILL GAIN : DB06480 , ATI - 7505 , and velusetrag ( DB05655 ) are highly selective , high - affinity 5 - HT ( 4 ) receptor agonists that are devoid of action on other receptors within their therapeutic range . Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and , to a variable degree , in clinical trials that significantly relieve chronic constipation . Currently available evidence shows that the new 5 - HT ( 4 ) receptor agonists have safe cardiac profiles . TAKE HOME MESSAGE : New - generation 5 - HT ( 4 ) receptor agonists and future drugs targeting organ - specific splice variants are promising approaches to treat GI dysmotility , particularly colonic diseases .",
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK80___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK80___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm ."
] |
[
"___MASK39___",
"___MASK3___",
"___MASK56___",
"___MASK70___",
"___MASK78___",
"___MASK79___",
"___MASK80___",
"___MASK8___",
"___MASK9___"
] |
___MASK79___
|
MH_train_453
|
interacts_with DB00887?
|
[
"Dedifferentiated chondrosarcoma mimicking a giant cell tumor . Is this low grade dedifferentiated chondrosarcoma ? We report a very rare case of a dedifferentiated chondrosarcoma mimicking a benign giant cell tumor . A 22 - year - old male was admitted to our hospital with a history of mild left wrist pain after a skiing trauma . Radiology revealed an extensive meta - epiphyseal osteolytic lesion in the distal ulna , which appeared to be a giant cell tumor . Histological examination showed a biphasic tumor comprising chondroid and non - chondroid areas with a giant cell - rich lesion resembling a conventional giant cell tumor of the bone . Immunohistochemistry showed no expression of p16 ( INK4a ) , P17948 , P35968 ( P35968 ) , P35916 , cKIT , Q00987 or P11802 . However , high expression of the tyrosine kinases P16234 and P09619 was observed . Molecular analysis showed no amplification of the cMYC gene and no activating mutations in the cKIT ( exons 9 and 11 ) or P16234 ( exon 18 ) genes . He has been on follow - up for ten months , with no evidence of local recurrence or metastatic disease . In summary , this report highlights a very rare case of a dedifferentiated chondrosarcoma in which the dedifferentiated component of the tumor bears histologic resemblance to a conventional giant cell tumor of bone . We suggest that this tumor might be categorized in the group of low - grade dedifferentiated chondrosarcomas .",
"Effect of allergy and inflammation on eicosanoid gene expression in P13569 deficiency . BACKGROUND : Allergic bronchopulmonary aspergillosis ( ABPA ) is a complicating factor in cystic fibrosis ( CF ) , affecting 2 - 15 % of patients . We hypothesized that sensitization / challenge of P13569 (-/-) mice with an Aspergillus fumigatus ( Af ) extract will affect eicosanoid pathway gene expression , impacting ABPA and CF . METHODS : FABP - hCFTR (+/-)- P13569 (-/-) mice were sensitized / challenged with an Af extract and gene expression of lung mRNA was evaluated for > 40 genes , with correlative data in human CF ( IB3 . 1 ) and P13569 - corrected ( S9 ) bronchoepithelial cell lines . RESULTS : Pla2g4c , Pla2g2c , Pla2g2d and Pla2g5 were induced in response to Af in P13569 (-/-) mice . Interestingly , Q9UNK4 was induced by LPS , P60568 , P05231 , P35225 , and Af only in P13569 - deficient human IB3 . 1 cells . Prostanoid gene expression was relatively constant , however , several P16050 genes were induced in response to Af . Numerous cytokines also caused differential expression of P16050 only in IB3 . 1 cells . CONCLUSIONS : The distinct regulation of Q9UP65 , Q9UNK4 and P16050 genes in Aspergillus sensitization and / or cystic fibrosis could provide new insights into diagnosis and treatment of ABPA and CF .",
"Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK97___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation .",
"DB09280 - ___MASK81___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK89___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"DB02527 inhibition of murine intestinal Na / H exchange requires P13569 - mediated cell shrinkage of villus epithelium . BACKGROUND AND AIMS : Unlike the intestine of normal subjects , small - intestinal epithelia of cystic fibrosis patients and cystic fibrosis transmembrane conductance regulator protein - null ( P13569 (-) ) mice do not respond to stimulation of intracellular cyclic adenosine monophosphate with inhibition of electroneutral NaCl absorption . Because P13569 - mediated anion secretion has been associated with changes in crypt cell volume , we hypothesized that P13569 - mediated cell volume reduction in villus epithelium is required for intracellular cyclic adenosine monophosphate inhibition of Na (+)/ H (+) exchanger ( primarily P48764 ) activity in the proximal small intestine . METHODS : Transepithelial ( 22 ) Na flux across the jejuna of P13569 (+) , P13569 (-) , the basolateral membrane Na (+)/ K (+)/ 2Cl (-) co - transporter protein P55011 (+) , and P55011 (-) mice were correlated with changes in epithelial cell volume of the midvillus region . RESULTS : Stimulation of intracellular cyclic adenosine monophosphate resulted in cessation of Na (+)/ H (+) exchanger - mediated Na (+) absorption ( J ( ms )( NHE ) ) in P13569 (+) jejunum but had no effect on J ( ms )( NHE ) across P13569 (-) jejunum . Cell volume indices indicated an approximately 30 % volume reduction of villus epithelial cells in P13569 (+) jejunum but no changes in P13569 (-) epithelium after intracellular cyclic adenosine monophosphate stimulation . In contrast , cell shrinkage induced by hypertonic medium inhibited J ( ms )( NHE ) in both P13569 (+) and P13569 (-) mice . DB00887 treatment to inhibit Cl (-) secretion by blockade of the Na (+)/ K (+)/ 2Cl (-) co - transporter , P55011 , of stimulated P13569 (+) jejunum prevented maximal volume reduction of villus epithelium and recovered approximately 40 % of J ( ms )( NHE ) . Likewise , J ( ms )( NHE ) and cell volume were unaffected by intracellular cyclic adenosine monophosphate stimulation in P55011 (-) jejuna . CONCLUSIONS : These findings show a previously unrecognized role of functional P13569 expressed in villus epithelium : regulation of P48764 - mediated Na (+) absorption by alteration of epithelial cell volume .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK91___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"DB00887 blocks P13569 GCl in the native sweat duct . DB00887 is well known for its ability to inhibit the nonconductive Na +- K +- 2Cl - cotransporter . We were surprised in preliminary studies to find that bumetanide in the contraluminal bath also inhibited NaCl absorption in the human sweat duct , which is apparently poor in cotransporter activity . Inhibition was accompanied by a marked decrease in the transepithelial electrical conductance . Because the cystic fibrosis transmembrane conductance regulator ( P13569 ) Cl - channel is richly expressed in the sweat duct , we asked whether bumetanide acts by blocking this anion channel . We found that bumetanide 1 ) significantly increased whole cell input impedance , 2 ) hyperpolarized transepithelial and basolateral membrane potentials , 3 ) depolarized apical membrane potential , 4 ) increased the ratio of apical - to - basolateral membrane resistance , and 5 ) decreased transepithelial Cl - conductance ( GCl ) . These results indicate that bumetanide inhibits P13569 GCl in both cell membranes of this epithelium . We excluded bumetanide interference with the protein kinase A phosphorylation activation process by \" irreversibly \" phosphorylating P13569 [ by using adenosine 5 '- O -( 3 - thiotriphosphate ) in the presence of a phosphatase inhibition cocktail ] before bumetanide application . We then activated P13569 GCl by adding 5 mM DB00171 . DB00887 in the cytoplasmic bath ( 10 (- 3 ) M ) inhibited approximately 71 % of this DB00171 - activated P13569 GCl , indicating possible direct inhibition of P13569 GCl . We conclude that bumetanide inhibits P13569 GCl in apical and basolateral membranes independent of phosphorylation . The results also suggest that > 10 (- 5 ) M bumetanide can not be used to specifically block the Na +- K +- 2Cl - cotransporter .",
"Fluid secretion caused by aerolysin - like hemolysin of Aeromonas sobria in the intestines is due to stimulation of production of prostaglandin E2 via cyclooxygenase 2 by intestinal cells . To clarify the mechanisms of diarrheal disease induced by Aeromonas sobria , we examined whether prostaglandin E2 ( DB00917 ) was involved in the intestinal secretory action of A . sobria hemolysin by use of a mouse intestinal loop model . The amount of DB00917 in jejunal fluid and the fluid accumulation ratio were directly related to the dose of hemolysin . The increase over time in the level of DB00917 was similar to that of the accumulated fluid . In addition , hemolysin - induced fluid secretion and DB00917 synthesis were inhibited by the selective cyclooxygenase 2 ( P35354 ) inhibitor NS - 398 but not the P23219 inhibitor SC - 560 . Western blot analysis revealed that hemolysin increased the P35354 protein levels but reduced the P23219 protein levels in mouse intestinal mucosa in vivo . These results suggest that DB00917 functions as an important mediator of diarrhea caused by hemolysin and that DB00917 is produced primarily through a P35354 - dependent mechanism . Subsequently , we examined the relationship between DB00917 , cyclic AMP ( DB02527 ) , and cystic fibrosis transmembrane conductance regulator ( P13569 ) Cl - channels in mouse intestinal mucosa exposed to hemolysin . Hemolysin increased the levels of DB02527 in the intestinal mucosa . NS - 398 inhibited the increase in DB02527 production , but SC - 560 did not . In addition , H - 89 , a DB02527 - dependent protein kinase A ( PKA ) inhibitor , and glibenclamide , a P13569 inhibitor , inhibited fluid accumulation . Taken together , these results indicate that hemolysin activates DB00917 production via P35354 and that DB00917 stimulates DB02527 production . DB02527 then activates PKA , which in turn stimulates P13569 Cl - channels and finally leads to fluid accumulation in the intestines .",
"Role of chloride transport proteins in the vasorelaxant action of nitroprusside in isolated rat aorta . Chloride ions play a key role in smooth muscle contraction , but little is known concerning their role in smooth muscle relaxation . Here we investigated the effect of chloride transport inhibitors on the vasorelaxant responses to nitroprusside in isolated and endothelium - denuded rat aorta , precontracted with phenylephrine 1 muM . Incubation of aortic rings in NO ( 3 )(-) media strongly potentiated the vasorelaxant responses to nitroprusside . DB00887 , DIDS ( 4 , 4 '- diisothiocyanatostilbene - 2 , 2 '- disulfonic acid ) and acetazolamide strongly potentiated the vasorelaxant responses to nitroprusside ( by 70 - 100 % ) . EC ( 50 ) were 2 . 3 +/- 0 . 5 microM for bumetanide , 26 +/- 15 microM for DIDS and 510 +/- 118 microM for acetazolamide ( n = 6 for condition ) . Niflumic acid , a selective inhibitor of ClCa ( calcium - activated chloride channels ) , potentiated nitroprusside relaxation to a similar extent as chloride transport inhibitors , in a non - additive manner . Zinc and nickel ions , both modestly potentiated nitroprusside vasorelaxation ( by 20 - 30 % ) . Cobaltum had negligible effect on nitroprusside vasorelaxation . P15085 ( p - chlorophenoxy - acetic acid ) , an inhibitor of volume - sensitive chloride channels ( ClC ) , slightly potentiated nitroprusside vasorelaxation ( by 15 % ) , and the cystic fibrosis transmembrane conductance regulator ( P13569 ) chloride channel inhibitors P13569 ( inh ) 172 ( 5 -[( 4 - Carboxyphenyl ) methylene ]- 2 - thioxo - 3 - [ ( 3 - trifluoromethyl ) phenyl - 4 - thiazolidinone ) , DPC ( diphenylamine - 2 , 2 '- dicarboxylic acid ) and glibenclamide were without significant effect . In conclusion , inhibition of chloride transport proteins strongly potentiates the vasorelaxant responses to nitroprusside in isolated rat aorta . This effect seems mediated by chloride depletion and inhibition of a chloride channel activated by both , calcium and cyclic GMP ( cGMP ) .",
"The potential role of PD0332991 ( ___MASK82___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK82___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .",
"DCEBIO stimulates Cl - secretion in the mouse jejunum . We investigated the effects of 5 , 6 - dichloro - 1 - ethyl - 1 , 3 - dihydro - 2H - benzimidazol - 2 - one ( DCEBIO ) on the Cl - secretory response of the mouse jejunum using the Ussing short - circuit current ( Isc ) technique . DCEBIO stimulated a concentration - dependent , sustained increase in Isc ( EC50 41 +/- 1 microM ) . Pretreating tissues with 0 . 25 microM forskolin reduced the concentration - dependent increase in Isc by DCEBIO and increased the EC50 ( 53 +/- 5 microM ) . DB00887 blocked ( 82 +/- 5 % ) the DCEBIO - stimulated Isc consistent with Cl - secretion . DCEBIO was a more potent stimulator of Cl - secretion than its parent molecule , 1 - ethyl - 2 - benzimidazolinone . DB01016 or P16860 reduced the DCEBIO - stimulated Isc by > 80 % indicating the participation of P13569 in the DCEBIO - stimulated Isc response . Clotrimazole reduced DCEBIO - stimulated Isc by 67 +/- 15 % , suggesting the participation of the intermediate conductance Ca2 +- activated K + channel ( IKCa ) in the DCEBIO - activated Isc response . In the presence of maximum forskolin ( 10 microM ) , the DCEBIO response was reduced and biphasic , reaching a peak response of the change in Isc of 43 +/- 5 microA / cm2 and then falling to a steady - state response of 17 +/- 10 microA / cm2 compared with DCEBIO control tissues ( 61 +/- 6 microA / cm2 ) . The forskolin - stimulated Isc in the presence of DCEBIO was reduced compared with forskolin control tissues . Similar results were observed with DCEBIO and 8 - BrcAMP where adenylate cyclase was bypassed . H89 , a PKA inhibitor , reduced the DCEBIO - activated Isc , providing evidence that DCEBIO increased Cl - secretion via a DB02527 / PKA - dependent manner . These data suggest that DCEBIO stimulates Cl - secretion of the mouse jejunum and that DCEBIO targets components of the Cl - secretory mechanism .",
"DB01645 stimulates electrogenic Cl (-) secretion in mouse jejunum . We used the short - circuit current ( I ( sc ) ) technique to investigate the effects of the isoflavone genistein on the electrogenic Cl (-) secretion of the mouse jejunum . DB01645 stimulated a sustained increase in I ( sc ) that was dose dependent . DB00887 inhibited 76 +/- 5 % of the genistein - stimulated I ( sc ) consistent with activation of Cl (-) secretion . DB01645 failed to stimulate I ( sc ) following maximal activation of the DB02527 pathway by forskolin . In addition , forskolin had a reduced effect on I ( sc ) of the mouse jejunum in the presence of genistein . DB01016 , a blocker of P13569 , eliminated the genistein - stimulated increase of I ( sc ) and reduced the forskolin - activated I ( sc ) . Clotrimazole , a Ca ( 2 +)- activated K (+) channel blocker , failed to reduce the genistein - stimulated I ( sc ) . Vanadate , a blocker of tyrosine - dependent phosphatases , reduced the genistein - activated I ( sc ) . Tyrphostin A23 , a tyrosine kinase inhibitor , reduced basal I ( sc ) , after which genistein failed to stimulate I ( sc ) . These data suggest that genistein activated a sustained Cl (-) secretory response of the mouse jejunum and that the effect of genistein was via a tyrosine - dependent phosphorylation pathway .",
"P13569 mediated chloride secretion in the avian renal proximal tubule . In primary cell cultures of the avian ( Gallus gallus ) renal proximal tubule parathyroid hormone and DB02527 activation generate a Cl (-)- dependent short circuit current ( I ( SC ) ) response , consistent with net transepithelial Cl (-) secretion . In this study we investigated the expression and physiological function of the Na - K - 2Cl ( NKCC ) transporter and P13569 chloride channel , both associated with Cl (-) secretion in a variety of tissues , in these proximal tubule cells . Using both RT - PCR and immunoblotting approaches , we showed that NKCC and P13569 are expressed , both in proximal tubule primary cultures and in a proximal tubule fraction of non - cultured ( native tissue ) fragments . We also used electrophysiological methods to assess the functional contribution of NKCC and P13569 to forskolin - activated I ( SC ) responses in filter grown cultured monolayers . DB00887 ( 10 μM ) , a specific blocker of NKCC , inhibited forskolin activated I ( SC ) by about 40 % , suggesting that basolateral uptake of Cl (-) is partially mediated by NKCC transport . In monolayers permeabilized on the basolateral side with nystatin , forskolin activated an apical Cl (-) conductance , manifested as bidirectional diffusion currents in the presence of oppositely directed Cl (-) gradients . Under these conditions the apical conductance appeared to show some bias towards apical - to - basolateral Cl (-) current . Two selective P13569 blockers , P13569 Inhibitor 172 and GlyH - 101 ( both at 20 μM ) inhibited the forskolin activated diffusion currents by 38 - 68 % , with GlyH - 101 having a greater effect . These data support the conclusion that avian renal proximal tubules utilize an apical P13569 Cl (-) channel to mediate DB02527 - activated Cl (-) secretion .",
"Crystal structure of the PDZ1 domain of human Na (+)/ H (+) exchanger regulatory factor provides insights into the mechanism of carboxyl - terminal leucine recognition by class I PDZ domains . The Na (+)/ H (+) exchanger regulatory factor ( O14745 ; also known as O14745 ) contains two PDZ domains that mediate the assembly of transmembrane and cytosolic proteins into functional signal transduction complexes . The O14745 PDZ1 domain interacts specifically with the motifs DSLL , DSFL , and DTRL present at the carboxyl termini of the beta ( 2 ) adrenergic receptor ( beta ( 2 ) AR ) , the platelet - derived growth factor receptor ( P09619 ) , and the cystic fibrosis transmembrane conductance regulator ( P13569 ) , respectively , and plays a central role in the physiological regulation of these proteins . The crystal structure of the human O14745 PDZ1 has been determined at 1 . 5 A resolution using multiwavelength anomalous diffraction phasing . The overall structure is similar to known PDZ structures , with notable differences in the O14745 PDZ1 carboxylate - binding loop that contains the GYGF motif , and the variable loop between the beta2 and beta3 strands . In the crystalline state , the carboxyl - terminal sequence DEQL of PDZ1 occupies the peptide - binding pocket of a neighboring PDZ1 molecule related by 2 - fold crystallographic symmetry . This structure reveals the molecular mechanism of carboxyl - terminal leucine recognition by class I PDZ domains , and provides insights into the specificity of O14745 interaction with the carboxyl termini of several membrane receptors and ion channels , including the beta ( 2 ) AR , P09619 , and P13569 .",
"Reduction of neuronal and inducible nitric oxide synthase gene expression in patients with cystic fibrosis . As a consequence of diminished nitric oxide synthase ( NOS ) protein concentration , the airway concentration of nitric oxide ( NO ) is reduced in patients with cystic fibrosis ( CF ) . This appears to lead to a reduced elimination of such microorganisms as Pseudomonas aeruginosa . The objective of this study was to analyze whether inducible ( P35228 ) , endothelial ( P29474 ) and neuronal ( P29475 ) NOS are reduced at mRNA level and if so whether this is caused directly by the defective CF transmembrane conductance regulator ( P13569 ) . Nasal polyps from three patients with CF and four otherwise healthy patients were obtained . The expression of the three NOS isoenzymes was quantified using real - time PCR . The P35228 expression was assessed in colon carcinoma cells ( CaCo ) transfected with a normal and a mutated ( DeltaF508 ) P13569 . In CF patients , P35228 mRNA expression was 10 - to 20 - fold and P29475 gene expression was one - fifth to one - tenth that in control patients ( P < 0 . 001 ) . In CaCo cells , P35228 gene expression under basal and endotoxin - stimulated conditions did not differ between cells transfected with a mutated P13569 and those transfected with an intact P13569 . This observation suggests that cystic fibrosis is associated with reduced P35228 and P29475 gene expression in nasopharyngeal tissue , possibly disturbing the barrier against infective agents already at the site of entrance .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK65___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Methoxsalen stimulates electrogenic Cl - secretion in the mouse jejunum . We used the short - circuit current ( I ( sc ) ) and patch - clamp techniques to investigate the effects of methoxsalen ( MTX ) on the electrogenic Cl - secretion of the mouse jejunum . MTX stimulated a sustained increase in Isc that was dose dependent . DB00887 inhibited MTX - stimulated Isc in a dose - dependent manner consistent with activation of Cl - secretion . MTX failed to stimulate I ( sc ) following maximal activation of the DB02527 pathway by forskolin , but did increase Isc after a submaximal dose of forskolin . DB01016 , a blocker of the cystic fibrosis transmembrane conductance regulator ( P13569 ) , reduced the MTX - stimulated increase of Isc by 59 +/- 6 % . The DB02527 - dependent K + channel blocker 293B did not alter the MTX - activated I ( sc ) ; however , clotrimazole , an intermediate Ca2 (+)- activated K + channel ( IK ( Ca ) ) blocker , reduced the MTX - stimulated I ( sc ) . MTX did not alter Na (+)- glucose cotransport across the mouse jejunum . In cell - attached membrane patches , MTX increased the open probability of the basolateral IK ( Ca ) channel of isolated crypts . These data suggest that the P13569 and IK ( Ca ) channels participate in the MTX - activated , sustained Cl - secretory response of the mouse jejunum .",
"Microelectrode measurements of the effects of basolateral adenosine in polarized human intestinal epithelial cells in culture . Activation of the basolateral receptor for adenosine in HT - 29cl . 19A cells , by 100 microM adenosine , increased the equivalent short - circuit current ( DeltaIsc = 24 +/- 2 microA / cm2 ) , depolarized the intracellular potential ( DeltaVa = 26 +/- 2 mV ) and decreased the fractional apical membrane resistance ( DeltafRa =- 0 . 48 ) . The changes in all parameters reached their peak values simultaneously . This suggests that the primary action of the adenosine - activated pathway is on only one membrane . DB00887 inhibited the transepithelial response and repolarized the cell potential . After preincubation with 100 microM forskolin , application of 300 microM adenosine caused a significant further change in Va , Isc , the transepithelial potential ( Vt ) and fRa . Together with the results from ion - replacement studies , the observations indicate that adenosine activates channels other than the cystic fibrosis transmembrane conductance regulator ( P13569 ) . The rank order of potencies of adenosine and adenosine analogues implies that the receptor is of the A2 subtype . Preincubation with 4 - bromophenacyl bromide ( 4 - BPB ) inhibited the effect of an adenosine analogue by 50 % , indicating that activation of phospholipase A2 may be involved in the adenosine - induced response .",
"Refined localization and yeast artificial chromosome ( YAC ) contig -- mapping of genes and DNA segments in the 7q21 - q32 region . The chromosome localizations for 159 gene and DNA segments have been refined to one of five intervals in the 7q21 - 132 region through hybridization analysis with a panel of somatic cell hybrid lines . Seventy - two of these chromosome 7 markers are also mapped on common or overlapping yeast artificial chromosome ( YAC ) clones . In addition , the breakpoints of chromosome rearrangement contained in five of the somatic cell hybrid lines have been defined by flanking probes within YAC contigs . To provide a framework for further mapping of the 7q21 - q32 region , we have established the physical order of a set of reference markers : cen -( P08123 - D7S15 - P08684 - P27169 )- D7S456 - ( brea kpoint contained in cell hybrid 1EF2 / 3 / K017 ) - P08236 - D7S186 - ASL - ( P08183 - P21439 - P62879 - EPO - P22303 ) - D7S238 - ( proximal breakpoint in GM1059 - Rag5 ) - D7S240 -( CUTL1 - P05121 )- ( breakp oints in 1CF2 / 5 / K016 and 2068Rag22 - 2 ) -( P31323 - D7S13 )- P07942 - ( breakpoint in JSR - 17S ) - DLD - D7S16 - MET - P09544 - P13569 - D7S8 - tel .",
"Desmopressin ( ___MASK80___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK80___ ) also has strong vasodilatory effects . ___MASK80___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK80___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK80___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK80___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK80___ - induced vasodilation .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK35___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"P13569 modulates neurosecretory function in pulmonary neuroendocrine cell - related tumor cell line models . The pulmonary neuroendocrine cell ( PNEC ) system consists of solitary cells and distinctive cell clusters termed neuroepithelial bodies ( P20929 ) localized in the airway epithelium . PNEC / P20929 express a variety of bioactive substances , including amine ( serotonin , 5HT ) and neuropeptides . We have previously shown that P20929 cells are O ( 2 ) sensors expressing nicotinamide adenine diphosphate oxidase complex and O ( 2 ) sensitive K (+) channel . Recently , we demonstrated expression of functional cystic fibrosis transmembrane conductance regulator ( P13569 ) and Cl (-) conductances in P20929 cells of rabbit neonatal lung . Because PNEC / P20929 are sparsely distributed and difficult to study in native lung , we investigated small - cell lung carcinoma ( SCLC ) and carcinoid tumor cell lines ( tumor counterparts of normal PNEC / P20929 ) as models for PNEC / P20929 . SCLC ( H146 , H345 ) and carcinoid ( H727 ) cell lines express neuroendocrine cell markers , including chromogranin A , neural cell adhesion molecule ( N - P62158 ) , 5HT , and tryptophan hydroxylase . We report that H146 , H345 , and H727 express P13569 messenger RNA ( reverse transcription polymerase chain reaction ) and protein ( immunoblotting ) and possess functional P13569 Cl (-) conductance , demonstrated by an iodide efflux assay inhibitable by transfection with antisense P13569 . Using an immunoassay to quantitate 5HT secretion , we also show that downregulation of P13569 abolishes hypoxia - induced 5HT release , and reduces secretory response to high potassium . Our findings suggest that P13569 may modulate neurosecretory activity of PNEC / P20929 possessing O ( 2 ) sensor function . We propose that these tumor cell lines may be useful models for investigating the role of P13569 in PNEC / P20929 functions in health and disease .",
"Antenatal maternally - administered phosphodiesterase type 5 inhibitors normalize P29474 expression in the fetal lamb model of congenital diaphragmatic hernia . PURPOSE : Pulmonary hypertension ( pHTN ) , a main determinant of survival in congenital diaphragmatic hernia ( Q8NE62 ) , results from in utero vascular remodeling . Phosphodiesterase type 5 ( O76074 ) inhibitors have never been used antenatally to treat pHTN . The purpose of this study is to determine if antenatal O76074 inhibitors can prevent pHTN in the fetal lamb model of Q8NE62 . METHODS : Q8NE62 was created in pregnant ewes . Postoperatively , pregnant ewes received oral placebo or tadalafil , a O76074 inhibitor , until delivery . Near term gestation , lambs underwent resuscitations , and lung tissue was snap frozen for protein analysis . RESULTS : Mean cGMP levels were 0 . 53 ± 0 . 11 in placebo - treated fetal lambs and 1 . 73 ± 0 . 21 in tadalafil - treated fetal lambs ( p = 0 . 002 ) . Normalized expression of P29474 was 82 % ± 12 % in Normal - Placebo , 61 % ± 5 % in Q8NE62 - Placebo , 116 % ± 6 % in Normal - ___MASK56___ , and 86 % ± 8 % in Q8NE62 - ___MASK56___ lambs . Normalized expression of β - sGC was 105 % ± 15 % in Normal - Placebo , 82 % ± 3 % in Q8NE62 - Placebo , 158 % ± 16 % in Normal - ___MASK56___ , and 86 % ± 8 % in Q8NE62 - ___MASK56___ lambs . P29474 and β - sGC were significantly decreased in Q8NE62 ( p = 0 . 0007 and 0 . 01 for P29474 and β - sGC , respectively ) , and tadalafil significantly increased P29474 expression ( p = 0 . 0002 ) . CONCLUSIONS : O76074 inhibitors can cross the placental barrier . β - sGC and P29474 are downregulated in fetal lambs with Q8NE62 . Antenatal O76074 inhibitors normalize P29474 and may prevent in utero vascular remodeling in Q8NE62 .",
"SUMOylation of tissue transglutaminase as link between oxidative stress and inflammation . Cystic fibrosis ( CF ) is a monogenic disease caused by mutations in the CF transmembrane conductance regulator ( P13569 ) gene . CF is characterized by chronic bacterial lung infections and inflammation , and we have previously reported that tissue transglutaminase ( TG2 ) , a multifunctional enzyme critical to several diseases , is constitutively up - regulated in CF airways and drives chronic inflammation . Here , we demonstrate that the generation of an oxidative stress induced by P13569 - defective function leads to protein inhibitor of activated P35610 ( PIAS ) y - mediated TG2 SUMOylation and inhibits TG2 ubiquitination and proteasome degradation , leading to sustained TG2 activation . This prevents peroxisome proliferator - activated receptor ( Q07869 ) gamma and IkBalpha SUMOylation , leading to NF - kappaB activation and to an uncontrolled inflammatory response . Cellular homeostasis can be restored by small ubiquitin - like modifier ( SUMO ) - 1 or Q8N2W9 gene silencing , which induce TG2 ubiquitination and proteasome degradation , restore PPARgamma SUMOylation , and prevent IkBalpha cross - linking and degradation , thus switching off inflammation . DB06757 superoxide dismutase overexpression as well as the treatment with the synthetic superoxide dismutase mimetic EUK - 134 control Q8N2W9 - TG2 interaction and TG2 SUMOylation . TG2 inhibition switches off inflammation in vitro as well as in vivo in a homozygous F508del - P13569 mouse model . Thus , TG2 may function as a link between oxidative stress and inflammation by driving the decision as to whether a protein should undergo SUMO - mediated regulation or degradation . Targeting TG2 - SUMO interactions might represent a new option to control disease evolution in CF patients as well as in other chronic inflammatory diseases , neurodegenerative pathologies , and cancer ."
] |
[
"___MASK35___",
"___MASK56___",
"___MASK65___",
"___MASK80___",
"___MASK81___",
"___MASK82___",
"___MASK89___",
"___MASK91___",
"___MASK97___"
] |
___MASK56___
|
MH_train_454
|
interacts_with DB06674?
|
[
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Immunogenicity of anti - P01375 biologic therapies for rheumatoid arthritis . Currently , five anti - P01375 biologic agents are approved for the treatment of rheumatoid arthritis ( RA ) : adalimumab , infliximab , etanercept , DB06674 and certolizumab pegol . Formation of anti - drug antibodies ( P00813 ) has been associated with all five agents . In the case of adalimumab and infliximab , immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response , but for the other three agents , data on immunogenicity are scarce , suggesting that further research would be valuable . Low P00813 levels might not influence the efficacy of anti - P01375 therapy , whereas high P00813 levels impair treatment efficacy by considerably reducing unbound drug levels . Immunogenicity is not only an issue in patients treated with anti - P01375 biologic agents ; the immunogenicity of other therapeutic proteins , such as factor VIII and interferons , is well known and has been investigated for many years . The results of such studies suggest that investigations to determine the optimal treatment regimen ( drug dosing , treatment schedule and co - medication ) required to minimize the likelihood of P00813 formation might be an effective and practical way to deal with the immunogenicity of anti - P01375 biologic agents for RA .",
"Risk of infections of biological therapies with accent on inflammatory bowel disease . BACKGROUND : Biological therapies using anti - tumor necrosis factor ( P01375 ) - α agents have an important impact in the treatment of inflammatory bowel disease , rheumatoid arthritis , psoriasis , and other inflammatory conditions . However , a significant number of patients lose their response to these medications over time . Clinical trials have demonstrated that antibodies against anti - P01375 agents may impact treatment response and increase the risk of infusion reactions . Of concern is also the possibility of developing adverse events induced by anti - P01375 agents . The purpose of the present systematic review is to describe the current knowledge on the risk of infections associated with anti - P01375 agents antagonists , as well as integrin antagonists . We also intend to describe case reports of these adverse events in inflammatory bowel disease patients . METHODS : Currently approved anti - P01375 biologicals in Q9UKU7 include the monoclonal antibodies infliximab , adalimumab , certolizumab pegol and DB06674 . Integrin antagonists include natalizumab , etrolizumab and vedolizumab . RESULTS : The most frequently - reported adverse events of these biologicals were infections , and these are described in detail in this study . DISCUSSION : Most adverse events are due to the failure of host immunological control , which involves de novo infection , or reactivation of latent bacterial or viral infection , often with a different expression of disease . CONCLUSION : Risk assessment in individuals undergoing treatment with biologicals represents a step towards achieving treatment personalization to identify those patients that will safely benefit from this therapeutic approach . Patients and physicians must be alert for anti - P01375 agents and anti - integrin medication as potential causes of drug - induced infections and monitor the therapies . Personalizing therapeutic vigilance promises to optimize benefits while minimizing infections .",
"Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .",
"Golimumab - a new tool in the armoury against inflammatory arthritis . The development of biological drugs blocking tumour necrosis factor - alpha ( P01375 - α ) has had a dramatic impact on the treatment of inflammatory arthritis in recent years . Golimumab is a fully human monoclonal antibody which inhibits P01375 - α . It is licensed for the treatment of rheumatoid arthritis , psoriatic arthritis , and ankylosing spondylitis . In this review we evaluate the results of phase III studies using DB06674 and explore the place of DB06674 in the treatment of these diseases .",
"P01375 - α antagonists beyond approved indications : stories of success and prospects for the future . Tumour necrosis factor alpha ( P01375 - α ) is a key molecule of the inflammatory response and data derived from studies in experimental animal models and humans suggest that P01375 - α may be implicated in the pathogenesis of various autoimmune and non - infectious inflammatory conditions . Over the past decade pharmaceutical agents directed against P01375 - α ( infliximab , adalimumab and etanercept ) have been widely and successfully employed for the management of rheumatoid arthritis ( RA ) , ankylosing spondylitis ( AS ) , psoriasis , psoriatic arthritis , juvenile idiopathic arthritis and inflammatory bowel disease , whereas two novel anti - P01375 - α agents , DB06674 and certolimumab pegol , recently entered the market for the treatment of RA , AS , Crohn ' s disease and psoriasis . Encouraged by the positive results obtained from the use of P01375 - α antagonists in terms of efficacy and safety and due to the increasingly accumulating evidence regarding the implication of P01375 - α in the pathogenesis of numerous disorders , anti - P01375 - α agents have been considered for the management of diseases other than the ones they were initially approved for . Although in the case of multiple sclerosis and chronic heart failure the outcome from the administration of P01375 - α blockers had been less than favourable , in other cases of non - infectious inflammatory conditions the response to P01375 - α inhibition had been fairly beneficial . More specifically , according to well - documented clinical trials , anti - P01375 - α agents exhibited favourable results in Behçet ' s disease , non - infectious ocular inflammation , pyoderma gangrenosum and hidradenitis suppurativa . In this review we discuss the successful outcomes as well as the prospects for the future from the off - label use of P01375 - α antagonists .",
"Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK27___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .",
"Emerging drugs for the treatment of axial and peripheral spondyloarthritis . INTRODUCTION : The topic under discussion is of strong relevance to the field of spondyloarthritis ( SpA ) because , in addition to established biological , there are new promising compounds . The reason for the review is to put all available data together to allow for an overview on recent developments and to especially inform readers about emerging drugs , biologics and small molecules in the field of SpA . AREAS COVERED : This review on new therapies in axial and peripheral SpA comprising psoriatic arthritis ( PsA ) shows , that , in addition to the established anti - P01375 agents infliximab , etanercept , adalimumab , DB06674 , certolizumab and the first biosimilar approved in the EU , there are at least two emerging biologics in the field of SpA : ustekinumab , a compound targeting IL12 / IL - 23 via the p40 subunit of both cytokines works for psoriasis and PsA and probably also for Crohn ' s disease , and the anti - Q16552 antibody secukinumab which has also been shown to work in psoriasis , both compounds seem to also work in ankylosing spondylitis . In addition , the potential of two small molecules , apremilast a phoshodiesterase4 inhibitor and tofacitinib , a januskinase inhibitor is discussed . EXPERT OPINION : Since , in contrast to rheumatoid arthritis , the therapeutic array in SpA is currently limited to P01375 - blockers , and since there is still an unmet need because some patients do not respond to anti - P01375 therapy at all or they loose response , new agents with a different mechanism of action are eagerly awaited .",
"Tumor necrosis factors blocking agents : analogies and differences . Five anti - P01375 agents , infliximab , adalimumab , etanercept , DB06674 and certolizumab pegol are approved worldwide for the treatment of RA . Anti - P01375 agents , bind to and neutralize soluble P01375 , but exert different effects on transmembrane P01375 - expressing cells ( P01375 - producing cells ) . Differences on affinity and avidity for soluble and transmembrane P01375 were showed . Different activity on cells apoptosis , complement - dependent cytotoxicity ( CDC ) antibody dependent cell - mediated cytotoxicity ( Q15848 ) were described . Some dramatic changes in gene expression were seen with all the anti - TNFs . Reviewing the biology of transmembrane P01375 and its interaction with anti - P01375 agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities .",
"Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .",
"Tailored therapy for severe asthma . Patients with severe asthma or P48444 have often a suboptimal symptom control due to inadequate treatment . A better understanding of pathogenetic mechanisms , phenotypes , endotypes and the new technologies available in the fields of molecular biology and immunogenetics have made it possible to synthesize specific monoclonal antibodies virtually able to interact with any target antigen , or to open a way for new therapeutic target options . At the moment , the only biologic drug available in clinical practice is omalizumab . To overcome the limits of omalizumab , the research has focused on new monoclonal antibodies presenting higher avidity for IgE ( e . g . ligelizumab and lumiximab ) and ability to interact also with low affinity IgE receptor ( FcϵRII ) . At present , many new biological drugs with different mechanisms of action and targets are matter of research . It is very important to identify the asthmatic phenotype in order to select the most appropriate drug for the individual patient . The most promising agents are targeted against cytokines of Th2 pattern and related receptors , such as P60568 ( daclizumab ) and P35225 ( lebrikizumab ) or P05113 in patients with hypereosinophilia ( mepolizumab , reslizumab and benralizumab ) . Other interesting drugs have as a target P01375 - α or its soluble receptor ( infliximab , DB06674 and etanercept ) or IL - 1 ( canakinumab ) , a cytokine with an important systemic proinflammatory action . Finally , the discovery of increased levels of C5a in the airways of asthmatic patients has led to the synthesis of a specific monoclonal antibody ( eculizumab ) . Further help should come from the identification of biomarkers that can guide in choosing the best treatment for the individual patient , such as IgE for omalizumab or periostin for lebrikizumab .",
"Behçet disease - associated uveitis successfully treated with DB06674 . Over the past decade , the off - label use of biologic agents such as P01375 - α antagonists , including infliximab and adalimumab , has improved the treatment armamentarium for refractory immune - mediated uveitis , with particular success in Behçet disease - associated uveitis . Golimumab is a novel fully human anti - P01375 - α monoclonal antibody that has been approved for the treatment of rheumatoid arthritis , psoriatic arthritis , and ankylosing spondylitis , with very promising results . Herein , the authors present the use of GLM in a case of Behçet uveitis refractory to other P01375 - α blockers . There are only two reports in the literature about the use of GLM in uveitis , describing four patients with JIA - associated uveitis and a case of idiopathic retinal vasculitis . To the authors ' knowledge , this is the first report about the use of GLM in Behçet uveitis .",
"P01375 - alpha antagonists twenty years later : what do Cochrane reviews tell us ? In 1998 , the U . S . Food and Drug Administration granted regulatory approval to the first tumor necrosis factor - α antagonist , infliximab , for the treatment of moderately to severely active Crohn ' s disease . As of 2013 , there were 3 additional tumor necrosis factor - α antagonists commercially available for the treatment of inflammatory bowel disease in the United States : adalimumab , certolizumab pegol , and DB06674 . Despite a vast literature describing both clinical trial and clinical practice experience with these agents , there remain important questions regarding the efficacy and safety of tumor necrosis factor - α antagonists for the treatment of inflammatory bowel disease . These questions and the best available evidence to answer them were discussed during a Cochrane Collaboration session held at the 2013 Digestive Diseases Week annual meeting . This article reviews the data from that session .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK56___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"Generation and characterization of a human monoclonal IgM antibody that recognizes a conserved epitope shared by lipopolysaccharides of different gram - negative bacteria . A hybridoma cell line secreting a human monoclonal antibody ( humab ) directed to an epitope in the lipid A region of lipopolysaccharides of Gram - negative bacteria was isolated . Peripheral blood lymphocytes ( PBL ) obtained from a healthy volunteer were immortalized by Epstein - Barr virus ( EBV ) transformation . Lymphoblastoid cell lines ( LCL ) secreting antibodies to the lipopolysaccharides of Gram - negative bacteria were determined by an enzyme - linked immunosorbent assay ( ELISA ) and subsequently fused with the human - mouse heteromyeloma cell line CB - P08709 by polyethylenglycol ( PEG ) - mediated fusion . A hybridoma line producing a humab ( LPD5H4 ) , of the IgM / lambda isotype , which strongly reacted with the lipid A portion of Salmonella and E . coli spp . in ELISA , was established . The antibody was purified by hydrophobic interaction chromatography and gel filtration . Immunoblotting experiments showed a strong reactivity of the humab LPD5H4 with the lower molecular species of different rough and smooth lipopolysaccharide ( LPS ) types of the bacteria species Salmonella , E . coli , Klebsiella , and Neisseria meningitidis , whereas those of Pseudomonas spp . were negative . Binding of humab LPD5H4 to solid phase bound lipid A and different rough mutants of LPS could be inhibited by the corresponding antigens in solution . Competition assays with a murine monoclonal antibody to lipid A and with polymyxin B indicate that humab LPD5H4 recognizes its epitope in this extremely conserved part of the LPS molecule . In vitro tests demonstrated that the MAb is able to partially inhibit the LPS - induced release of P01375 using isolated peripheral blood mononuclear cells ( PBMC ) .",
"Emerging therapeutics for rheumatoid arthritis . Therapeutics options for rheumatoid arthritis ( RA ) have increased tremendously in the past decade with the introduction of biological agents in 1999 . Several different cellular and cytokine targets have been identified , with specific inhibitors now approved to treat RA , including the tumor necrosis factor ( P01375 ) antagonists ( adalimumab , etanercept , infliximab ) , an interleukin 1 ( IL1 ) antagonist ( anakinra ) , an inhibitor of T cell co - stimulation ( abatacept ) , and a selective depleter of B cells ( rituximab ) . As research has progressed , additional promising targets have been identified . Results from RA studies using several new agents have been reported in the last year . Some of these compounds are similar to agents already available , with additional P01375 inhibitors ( certolizumab pegol , DB06674 ) and agents targeting P11836 ( ocrelizumab , ofatumumab , TRU - 015 ) in development . Other agents are directed toward new cytokine targets , including P05231 ( tocilizumab ) , and lymphotoxin pathways ( briobacept ) , as well as other B - cell targets , to include Q9Y275 and APRIL ( belimumab , atacicept ) . Additional small molecule therapies have been studied that are directed against intracellular kinases , including P52333 and Syk . This article provides a brief update of data from selected clinical trials in RA , highlighting efficacy , and mechanism - based safety concerns .",
"Biologic agents for rheumatoid arthritis : 2008 and beyond . Rheumatoid arthritis ( RA ) is a chronic disease with a complex underlying pathology and varied presentation in patients . Several novel biologic disease - modifying antirheumatic drugs have become available for the treatment of RA . Agents in late - stage clinical trials include DB06674 and certolizumab , which are anti - tumor necrosis factor ( P01375 ) - alpha agents ; ocrelizumab , an anti - P11836 agent ; and tocilizumab , an inhibitor of interleukin - 6 . As treatment options for RA expand , nursing care will play an increasingly important role in empowering patients through interventions such as patient education and adverse effect management .",
"Anti - P01375 agents in familial Mediterranean fever : report of three cases and review of the literature . Familial Mediterranean fever ( FMF ) is an autoinflammatory disease characterized by recurrent fever , peritonitis / pleuritis , or arthritis attacks . Patients may have FMF - associated mutations of pyrin . The role of biologics such as anti - tumor necrosis factor ( P01375 ) agents ( infliximab , etanercept , adalimumab , DB06674 ) and anakinra , canakinumab , or rilonacept in the treatment of FMF needs to be clarified . Herein we present reports of three patients ( all were positive for HLA Q8TCY5 ) with typical spondylitis associated with FMF who were successfully managed with anti - P01375 agents , along with a literature review . The patients were a 37 - year - old man with concomitant Crohn ' s disease and amyloidosis who was treated with infliximab ( P27352 , 5 mg / kg for 3 years ) and switched to adalimumab ( P00813 ) , and two female patients ( a 24 - year - old and a 31 - year - old ) with FMF who developed severe spondylitis and who were also treated with P00813 . Anti - P01375 agents can control FMF attacks quite effectively and they reveal a promising role in the treatment of FMF - associated amyloidosis and spondylitis .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK77___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"Aspects of P01375 inhibitor therapy in rheumatoid arthritis . Treatment outcomes in rheumatoid arthritis ( RA ) have improved considerably with the use of biological therapies . Since the discovery of the role of tumor necrosis factor ( P01375 ) alpha in the pathogenesis of the disease , three P01375 inhibitors , infliximab , etanercept and adalimumab , have become widely used for the treatment of RA . More recently , two newer P01375 inhibitors - certolizumab pegol and DB06674 - have become available , increasing the armamentarium of therapy . With improved therapies , treatment strategies have also changed , with the aims now being to achieve and maintain remission . This article addresses some of these aspects of treating RA , reviewing the studies on these two newer P01375 inhibitors , certolizumab pegol and DB06674 , and those addressing the induction of remission or low disease activity with P01375 inhibitors and maintenance with less intensive treatment .",
"Miscellaneous adverse events with biologic agents ( excludes infection and malignancy ) . Anti - tumor necrosis factor - α ( anti - P01375 ) agents are frequently used in the treatment of inflammatory bowel disease ( Q9UKU7 ) . Currently , there are 4 anti - P01375 therapies that are Food and Drug Administration - approved for moderate to severe Q9UKU7 : infliximab , adalimumab , DB06674 , and certolizumab pegol . For most noninfectious , nonmalignant adverse events , cessation of anti - P01375 therapy typically leads to improvement or resolution of drug - induced complications . In this article , the current knowledge regarding the noninfectious and nonmalignant toxicities associated with anti - P01375 agents is summarized .",
"P01375 inhibitors : clinical utility in autoimmune diseases . P01375 ( P01375 ) production is amplified in several autoimmune disorders . In the 1990s , it became a validated therapeutic target used for the treatment of conditions such as rheumatoid arthritis and inflammatory bowel disease . Biologic drugs targeting P01375 include engineered monoclonal antibodies and fusion proteins . Currently , there are 5 Food and Drug Administration - approved P01375 inhibitors ( infliximab , etanercept , adalimumab , certolizumab , and DB06674 ) , representing close to $ 20 billion in sales . Clinical trials remain open to test their efficacy and safety compared with one another , as well as to measure clinical outcomes in different conditions and patient populations . The industry is also eager to develop biotherapeutics that are similar but cheaper than the currently existing biologics or are safer with higher efficacy ; these are the so - called \" biosimilars . \" Clinical utility of P01375 inhibitors and indications of mono - or combined therapy with immunomodulators are reviewed here . Pharmacokinetics of the P01375 inhibitors is affected by routes of administration , clearance mechanisms of immunoglobulins , and immunogenicity . Finally , strategies for management of treatment efficacy and increasing evidence for monitoring of serum concentration of P01375 inhibitors are discussed , assessing for the presence of the antidrug antibodies and the different analytical methods available for laboratory testing . As clinical applications of the P01375 inhibitors expand , and other classes join the revolution in the treatment of chronic inflammatory disorders , therapeutic drug monitoring of biologics will become increasingly important , with the potential to dramatically improve patient care and management .",
"A mixed treatment comparison of the efficacy of anti - P01375 agents in rheumatoid arthritis for methotrexate non - responders demonstrates differences between treatments : a Bayesian approach . BACKGROUND : A number of tumour necrosis factor α ( TNFα ) antagonists ( anti - TNFα ) are available to treat rheumatoid arthritis . All of these have demonstrated considerable efficacy in placebo controlled trials , but few head - to - head comparisons exist to date . This work ' s objective is to estimate the relative efficacy among licensed anti - TNFs in patients who have had an inadequate response to methotrexate ( MTX ) . Different outcome measures are used to highlight the advantages of continuous measures in such analyses . METHODS : A systematic review identified randomised controlled trials comparing the efficacy of licensed anti - TNFα agents with placebo at 24 weeks in patients who have had an inadequate response to MTX . Relative efficacy was estimated using Bayesian mixed treatment comparison ( P04629 ) models . Three different outcome measures were used : RR of achieving an American College of Rheumatology ( P10323 ) 20 and ACR50 response and the percentage improvement in Health Assessment Questionnaire ( HAQ ) score . RESULTS : 16 published trials were included in the analysis . All anti - TNFs show considerably improved efficacy over placebo . The P04629 results also provide evidence of some differences in efficacy of the TNFα antagonists . DB00005 appears superior to infliximab and DB06674 , and certolizumab to infliximab and adalimumab . P10323 results indicate improved efficacy of certolizumab over DB06674 . On HAQ analysis , adalimumab , certolizumab , etanercept and DB06674 appear superior to infliximab , and etanercept shows improved efficacy compared with adalimumab . CONCLUSIONS : There are differences in efficacy among the TNFα antagonists . In a P04629 , a continuous outcome measure has more strength to detect such differences than a binomial outcome measure because of its enhanced sensitivity to change .",
"[ Fully human anti P01375 monoclonal antibodies ( adalimumab , DB06674 ) ] . A number of studies have emphasized the critical role of P01375 in the pathogenesis of rheumatoid arthritis ( RA ) . New therapeutics called \" bilologicals \" have been recently admitted for treatment of RA , including infliximab and etanercept , also in Japan . Of note , fully human anti - P01375 a monoclonal antibodies , adalimumab and DB06674 , have been developed to overcome several major problems resulting from the chimeric natures of infliximab . The efficacy and safety of adalimumab have been demonstrated in several clinical trials , as highlighted in this review . Thus , adalimumab has already been approved for treatment of RA in the United States and European Union . The clinical trials of another fully human anti - P01375 monoclonal antibody DB06674 are now under way .",
"The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .",
"___MASK67___ -- an emerging treatment for postmenopausal osteoporosis . IMPORTANCE OF THE FIELD : Osteoporosis is a common skeletal disease that is associated with an imbalance in bone remodeling . ___MASK67___ is an investigational fully human monoclonal antibody to receptor activator of NF - kappaB ligand ( O14788 ) , a cytokine member of the P01375 family that is the principal mediator of osteoclastic bone resorption . AREAS COVERED IN THIS REVIEW : The efficacy and safety of denosumab in the management of postmenopausal osteoporosis is evaluated by reviewing the published literature and presentations at scientific meetings through 2009 . WHAT THE READER WILL GAIN : This review focuses on the data on fracture risk reduction and safety endpoints of denosumab in the treatment of postmenopausal osteoporosis . TAKE HOME MESSAGE : In postmenopausal women with osteoporosis , denosumab ( 60 mg by subcutaneous injection every 6 months ) increased bone mineral density , reduced bone turnover markers , and reduced the risk of vertebral , hip and non - vertebral fractures . ___MASK67___ was well tolerated with a safety profile generally similar to placebo . It is a promising emerging drug for the prevention and treatment of postmenopausal osteoporosis .",
"Safety issues and concerns of new immunomodulators in rheumatology . INTRODUCTION : The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis . Since the first anti - P01375 - α therapies , numerous molecules have been identified as targets of immunomodulatory therapies , such as IL - 1 ( anakinra , canakinumab ) , P05231 ( tocilizumab ) , P11836 (+) B cells ( rituximab ) , P16410 ( abatacept ) and two additional anti - P01375 - α therapies ( certolizumab pegol , DB06674 ) . AREAS COVERED : In the present review , we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy . The risk of infection should be identified before initiating a biologic treatment and markers checked over time , in particular for tuberculosis and hepatitis B and C viruses . Other infections ( bacterial , viral , parasitic ; opportunistic ; surgery - related ) and safety issues may require temporary interruption of the treatment until complete resolution . No significantly increased risk of malignancy , both hematological and solid , has been associated with the use of biologic agents . In all cases , it is difficult to dissect the risks related to biologics from those related to baseline treatments . EXPERT OPINION : Detailed medical history and laboratory screening should be performed before starting biologic therapies . Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects .",
"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK27___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .",
"A latent variable approach for modeling categorical endpoints among patients with rheumatoid arthritis treated with DB06674 plus methotrexate . The need for accurate exposure - response modeling is critical in the drug development process . Few methods are available for linking discrete endpoints , especially ordered categorical variables , to mechanistic ( e . g . , indirect response ) models . Here we describe a latent - variable approach that is proposed in conjunction with an inhibitory indirect response model to link the placebo / comedication effect and drug exposure to the endpoints . The model is parsimonious , with desirable characteristics at initial timepoints , and allows simultaneous modeling of multiple endpoints that are categorically ordered . Application of the model is demonstrated with data from a phase 3 clinical trial of DB06674 , a human IgG1kappa monoclonal antibody that binds with high affinity and specificity to tumor necrosis factor ( P01375 ) - alpha , in patients with rheumatoid arthritis . The efficacy endpoints were 20 , 50 , and 70 % improvement in the American College of Rheumatology criteria ( ACR20 , ACR50 , and ACR70 , respectively ) as measures of improvement in disease severity . The modeling results were shown to be consistent by using either a sequential or simultaneous pharmacokinetic / pharmacodynamic modeling approach . The suitability of likelihood profiling and proper use of bootstrap methods in assessing parameter estimation precision are also presented . More accurate , parsimonious models with appropriately quantified uncertainty can facilitate better drug development decisions .",
"Current therapies in rheumatoid arthritis : a Latin American perspective . Rheumatoid arthritis ( RA ) is a systemic inflammatory disease affecting the synovium of joints , tendons , and some extra - articular sites . RA prevalence in Latin America ranges from 0 . 4 to 1 . 6 % . Early treatment of RA translates into a substantial reduction in the cost to society . In light of this , early disease clinics are being established in some countries . Barriers to RA management , such as delay in referral to rheumatologists and limited access to therapy , have been identified . Evidence - based treatment guidelines have been adapted by countries according to their own situations . The need for keeping accurate records of biologics prescribed has been addressed by biologic registries , thereby contributing toward a better understanding of rheumatic diseases and their treatment . Current biologics include the tumor necrosis factor ( P01375 ) - α inhibitors ( etanercept , infliximab , and adalimumab ) , B - cell depletion agent ( rituximab ) , interleukin - 6 receptor blocker ( tocilizumab ) , and T - cell co - stimulatory blocker ( abatacept ) . Future therapies include kinase inhibitors ( tofacitinib and fostamatinib ) , alternative P01375 - α inhibitors ( DB06674 and certolizumab ) , and biosimilars .",
"anti - P01375 agents as therapeutic choice in immune - mediated inflammatory diseases : focus on adalimumab . The complex pathogenesis of immune - mediated inflammatory diseases ( IMIDs ) has been extensively investigated and dysregulation of cytokines , such as tumour necrosis factor ( P01375 ) has been shown to play a dominant role in the pathogenesis of various IMIDs , such as rheumatoid arthritis , ankylosing spondylitis , Crohn ' s disease , ulcerative colitis , psoriasis and psoriatic arthritis . The subsequent development of biological agents capable of blocking P01375 has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with P01375 having a predominant role . Five P01375 inhibitors have currently been approved for treatment of one or more IMIDs ; these include infliximab , etanercept , adalimumab , DB06674 and certolizumab pegol . Given the similarities in the pathogenic background of IMIDs , one could expect that anti - P01375 agents be similarly effective and with comparable tolerability profiles ; however , this may not be the case . Structural and pharmacological differences among the anti - P01375 drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs , together with differences in potency , therapeutic dose ranges , dosing regimens , administration routes , and propensity for immunogenicity . Among the five P01375 inhibitors approved for treatment of IMIDs , adalimumab has the widest range of indications . Data from controlled clinical trials of adalimumab , showing its excellent efficacy and tolerability in a wide range of indications , are supported by real - world long - term data from observational studies , which confirm the value of adalimumab as a suitable choice in the management of IMIDs .",
"Effectiveness of infliximab , adalimumab and DB06674 for non - infectious refractory uveitis in adults . AIM : To discuss the available data regarding the off - label uses of anti - P01375 agents in non - infectious uveitis . DATA SOURCE : A literature search was performed in Medline through PubMed from January 2001 to January 2014 . STUDY SELECTION AND DATA EXTRACTION : English - language articles about uveitis treatment with anti - P01375 drugs in adult patients were reviewed . DATA SYNTHESIS : The use of anti - P01375 - Î ± drugs for treatment of several refractory manifestations of refractory uveitis in adult patients is increasing . However , due to the lack of evidence from randomized controlled trials , the use of anti - P01375 in uveitis remains â off - labelâ in most countries . There is no trial - based evidence to support it except for the experience provided by cases and case series . This experience , which is continuously increasing , has yielded encouraging results . Anti - P01375 - Î ± drugs , such as infliximab , adalimumab , and DB06674 , are reasonably effective for controlling ocular inflammation and sparing patients corticosteroid treatment in non - infectious refractory uveitis . Approximately 80 % of patients on infliximab , adalimumab , or DB06674 were able to achieve sustained control of inflammation by 6 months . CONCLUSION : Anti - P01375 - Î ± therapy is effective in inducing clinical remission for refractory uveitis , with a relatively low rate of treatment - ending adverse events . However , randomized and controlled trials are required to adequately assess the maintained clinical efficacy and safety profile in the long term of anti - P01375 agents for non - infectious refractory uveitis .",
"Pre - clinical evaluation of an in vitro selection protocol for the enrichment of transduced P28906 + cell - derived human dendritic cells . The efficient genetic modification of P28906 + cell - derived dendritic cells ( DC ) will provide a significant advancement towards the development of immunotherapy protocols for cancer , autoimmune disorders and infectious diseases . Recent reports have described the transduction of P28906 + cells via retrovirus - and lentivirus - based gene transfer vectors and subsequent differentiation into functional DC . Since there is significant apprehension regarding the clinical uses of HIV - based vectors , in this report , we compare a murine leukemia virus ( MLV ) - and a human immunodeficiency virus ( HIV ) - based bicistronic vector for gene transfer into human P28906 + cells and subsequent differentiation into mature DC . Each vector expressed both EGFP and the dominant selectable marker P00374 ( L22Y ) allowing for the enrichment of marked cells in the presence of the antifolate drug trimetrexate ( TMTX ) . Both MLV - based and HIV - based vectors efficiently transduced cytokine mobilized human peripheral blood P28906 + cells . However , in vitro expansion and differentiation in the presence of GM - P04141 , P01375 , Flt - 3L , P21583 and P05112 resulted in a reduction in the percentage of DC expressing the transgene . Selection with TMTX during differentiation increased the percentage of marked DC , resulting in up to 79 % ( MLV vector ) and up to 94 % ( lentivirus - vector ) transduced cells expressing EGFP without loss of DC phenotype . Thus , MLV - based vectors and in vitro selection of transduced human DC show great promise for immunotherapy protocols .",
"Role of DB06674 , a P01375 inhibitor , in the treatment of the psoriatic arthritis . Psoriatic arthritis ( PsA ) is an inflammatory arthritis that affects many psoriasis patients and can often have a debilitating disease progression . Golimumab is a new tumor necrosis factor ( P01375 ) antagonist recently approved by the FDA for controlling signs and symptoms of psoriatic arthritis . In a Phase III clinical trial in patients with PsA , patients receiving DB06674 showed significant improvement in the signs and symptoms of disease . It was usually well tolerated , but adverse events generally occurred more in patients receiving DB06674 compared to placebo . Golimumab has also recently shown efficacy in slowing structural damage in PsA . This new biologic therapy provides physicians with another option in the treatment of this inflammatory arthritis while offering patients certain advantages over other P01375 antagonists .",
"Advances in the management of psoriatic arthritis . Psoriatic arthritis ( PsA ) , which affects musculoskeletal structures , skin and nails , is a heterogeneous chronic inflammatory disease with a wide clinical spectrum and variable course . Patients with PsA are more likely than healthy individuals to have metabolic syndrome or cardiovascular disease . To include these comorbidities , ' psoriatic disease ' has been suggested as an umbrella term . The management of PsA has changed tremendously over the past decade owing to early diagnosis and improvement in treatment strategies , including , early referral from dermatologists and primary - care physicians to rheumatologists , early initiation of therapy , treating to the target of remission or low disease activity , and advances in pharmacological therapy . Outcome assessment is also improving , because of validated instruments for clinical disease manifestations . The commercialization of P01375 blockers , including adalimumab , etanercept , DB06674 and infliximab , is representative of a revolution in the treatment of PsA . A new anti - P01375 agent , certolizumab pegol , and a fully human monoclonal antibody against IL - 12 and IL - 23 , ustekinumab , are approved for the treatment of active PsA . The efficacy of ustekinumab suggests that inhibiting the type 17 T helper pathway might be an alternative to blocking P01375 . PsA management must now use improved measures to predict patient outcomes and define remission , and develop better - targeted therapies .",
"Inhibitors of DB00171 - binding cassette transporters suppress interleukin - 12 p40 production and major histocompatibility complex II up - regulation in macrophages . DB00171 - binding cassette ( DB01048 ) transporters are a large family of proteins whose role is to translocate various substances across biological membranes . They include the Tangier disease protein ABC1 , sulfonylurea receptors ( Q09428 ) , multidrug resistance protein ( MDR ) , and cystic fibrosis transmembrane regulator ( P13569 ) . In the current study , we investigated the involvement of ABC transporters in the regulation of lipopolysaccharide ( LPS ) and / or interferon ( IFN ) - gamma - induced interleukin ( IL ) - 12 p40 and tumor necrosis factor ( P01375 ) - alpha production , nitric oxide formation , as well as major histocompatibility complex II up - regulation in macrophages . The general ABC transporter inhibitor glibenclamide suppressed both IL - 12 p40 and nitric oxide production . However , glibenclamide failed to affect the production of P01375 . The selective ABC1 inhibitors 4 , 4 '- diisothiocyanostilbene - 2 , 2 '- disulfonic acid and sulfobromophthalein mimicked the suppressive effect of glibenclamide on IL - 12 p40 production . On the other hand , both the MDR inhibitor verapamil and P13569 blocker 2 , 2 '- iminodibenzoic acid failed to suppress the production of IL - 12 p40 . Furthermore , selective inhibitors and activators of SURs were without effect . In agreement with the pharmacological data , macrophages expressed mRNA for ABC1 , but not SURs or P13569 . Intracellular levels of IL - 12 p40 were decreased by glibenclamide , suggesting that glibenclamide does not affect IL - 12 p40 secretion . The effect of glibenclamide did not involve an interference with the activation of the p38 and Q8NFH3 / 44 mitogen - activated protein kinases or c - Jun kinase . ___MASK71___ also suppressed P01579 - induced up - regulation of major histocompatibility complex II . Taken together , our results indicate that ABC proteins regulate LPS and / or P01579 - induced macrophage activation .",
"Can we reduce the dosage of biologics in spondyloarthritis ? P01375 blockers have revolutionized the management of spondyloarthritis ( SpA ) . To date , four anti - TNFα agents ( etanercept , infliximab , adalimumab , DB06674 ) have been approved for the management of ankylosing spondylitis ( AS ) and psoriatic arthritis ( PsA ) . The first objective in the management of AS and PsA with P01375 inhibitors is to reduce disease activity to clinical remission or low disease activity . After remission has been achieved , this state should be maintained as long as possible . However , the financial burden associated with the cost of anti - P01375 agents as well as concerns about their long - term safety suggest reducing the dosage of the drug or discontinuing the therapy in the hopes of drug - free remission . The aim of this review is to examine what has , till now , been published on this topic in axial SpA , which includes AS and non - radiographic axial SpA ( nr - axSpA ) , peripheral SpA and PsA . Discontinuation of therapy in axial SpA is not possible in the majority of patients , while on the contrary , reducing the dosage often is . In some patients with peripheral SpA and PsA it is also possible to discontinue therapy and to achieve drug - free remission .",
"[ Research update of anti - P01375 - α biologic agents in the treatment of uveitis ] . Uveitis is one of the common sight - threatening eye diseases , which is usually recurrent and refractory to treatment . It is generally considered that the development of uveitis is closely related to the autoimmune response of uvea . P01375 ( P01375 ) - α is one of the key cytokines involved in the emergence and progression of uveitis . Blocking the production or inhibiting the activity of P01375 - α can inhibit the development or progression of uveitis . Presently , the commercially available P01375 - α blockers include infliximab , adalimumab , etanercept , and DB06674 . This review describes the clinical studies and adverse effects of P01375 - α blockers in the treatment of uveitis , and discusses the principle for clinical use of P01375 - α blockers in synergy with other immunosuppressive agents .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK57___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK57___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK15___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"P01375 - alpha antagonists : differential clinical effects by different biotechnological molecules . Inhibitors of tumor necrosis factor - alpha have deeply changed the therapy of several inflammatory human diseases . For instance , clinical management of rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis have profoundly benefited after the introduction of new therapeutic tools , such as antagonist of P01375 molecule . These drugs include etanercept , a soluble P01375 receptor antagonist , three anti - P01375 antibodies , adalimumab , infliximab , DB06674 and certolizumab a humanized Fab fragment combined with polyethylene glycol . These compounds efficiently inhibit several P01375 biological - mediated effects , however , they have also shown differential clinical efficacy in several trials from different autoimmune diseases . It is of clinical relevance that non - responders to one of these drugs often positively responded to another . Different mechanisms of action and diversity in pharmacokinetics of these three compounds may partially explain different clinical effects . However , partially diverse pathogenetic mechanisms in different diseases also contribute to differential therapeutic responses . Therefore , these apparently homogeneous agents can not be considered equivalent in their clinically efficacy . Differential therapeutic actions of these drugs may be advantageously used in clinical practice and further improve the great potential of individual P01375 inhibitors .",
"Treatment of nail psoriasis with P01375 - α or IL12 / 23 inhibitors . Nail psoriasis appears to be an important source of psoriatic morbidity through physical impairment , pain , and cosmetic disturbances . Conventional treatment is often unsatisfactory . A systematic review of studies reporting the effect of P01375 - α inhibitors and related drugs on nail psoriasis using the Nail Psoriasis Severity Index ( NAPSI ) as the outcome measure was therefore made . Data are available from randomized controlled trials ( RCT ) where NAPSI has been studied as a secondary outcome , as well as from case - series in which NAPSI has been the primary outcome studies suggest that adalimumab , briakinumab , etanercept , DB06674 , infliximumab , and ustekinumab all improve NAPSI scores . No direct comparative RCTs are available in which NAPSI scores have been reported . The data further suggest that changes in NAPSI mirror changes in disease severity of other psoriatic manifestations , that is , in psoriatic arthritis and skin psoriasis . The effect only appears to be delayed due to the rate of growth of the nail plate .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK90___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK90___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"Golimumab as the first monthly subcutaneous fully human anti - P01375 antibody in the treatment of inflammatory arthropathies . Golimumab ( Simponi , Centocor Ortho Biotech Inc . , PA , USA ) is the first transgenic human monoclonal antibody against P01375 that has been approved in the treatment of rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis . Golimumab is synthesized using conventional hybridoma technique after immunizing transgenic mice containing human immunoglobulin genes . The constant region of DB06674 is identical to that of infliximab , but the variable regions of DB06674 have fully human sequences . In this article , we present the pharmacodynamic and pharmacokinetic properties as well as the clinical efficacy and tolerability of DB06674 .",
"The unexpected effect of cyclosporin A on CD56 + CD16 - and CD56 + CD16 + natural killer cell subpopulations . DB00091 ( Q13216 ) is commonly used to prevent graft - versus - host disease . The influence of Q13216 on T - cell function has been extensively investigated ; however , the effect of Q13216 on natural killer ( NK ) cells is less understood . NK cells were cultured with P60568 and P40933 with and without Q13216 for 1 week . Compared with controls , Q13216 - treated cultures showed fewer CD56 (+) CD16 (+) P55040 (+) NK cells and a reciprocal increase in CD56 (+) CD16 (-) P55040 (-) cells . These changes were due mainly to a reduced proliferation of the CD56 ( dim ) NK - cell subpopulation and a relative resistance of CD56 ( bright ) NK cells to Q13216 . Following coculture with K562 targets , Q13216 - exposed NK cells differed from controls and lacked Ca ( 2 +) oscillations , nuclear factor of activated T cells ( NFAT ) dephosphorylation , and NFAT nuclear translocation . NK cells cultured in Q13216 retained cytotoxicity against K562 , Raji , and P55040 ligand - expressing lymphoblastoid cells . NK cells cultured in Q13216 showed increases in O14931 and reductions in O95944 and P26718 . Following IL - 12 and Q14116 stimulation , Q13216 - treated NK cells showed more P01579 - producing cells . Using in vitro NK - cell differentiation , progenitor cells gave rise to more CD56 (+) P55040 (-) NK cells in the presence of Q13216 than controls . Collectively , these studies show that Q13216 influences NK - cell function and phenotype , which may have important implications for graft - versus - leukemia effects .",
"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .",
"P01375 antagonist mechanisms of action : a comprehensive review . During the past 30 years , elucidation of the pathogenesis of rheumatoid arthritis , Crohn ' s disease , psoriasis , psoriatic arthritis and ankylosing spondylitis at the cellular and molecular levels has revealed that these diseases share common mechanisms and are more closely related than was previously recognized . Research on the complex biology of tumor necrosis factor ( P01375 ) has uncovered many mechanisms and pathways by which P01375 may be involved in the pathogenesis of these diseases . There are 3 P01375 antagonists currently available : adalimumab , a fully human monoclonal antibody ; etanercept , a soluble receptor construct ; and infliximab , a chimeric monoclonal antibody . Two other P01375 antagonists , certolizumab and DB06674 , are in clinical development . The remarkable efficacy of P01375 antagonists in these diseases places P01375 in the center of our understanding of the pathogenesis of many immune - mediated inflammatory diseases . The purpose of this review is to discuss the biology of P01375 and related family members in the context of the potential mechanisms of action of P01375 antagonists in a variety of immune - mediated inflammatory diseases . Possible mechanistic differences between P01375 antagonists are addressed with regard to their efficacy and safety profiles .",
"Tumour necrosis factor α antagonists in the treatment of rheumatoid arthritis : an immunological perspective . Rheumatoid arthritis ( RA ) is one of the most prevalent autoimmune conditions , affecting approximately 1 % of the adult population . It is associated with decreased quality of life and considerable morbidity and mortality . Various inflammatory cells , including macrophages , neutrophils , mast cells , natural killer cells , B and T cells and stromal cells play key pathophysiological roles in joint inflammation and RA progression . Several cytokines , including interleukin ( IL ) - 1α and / or IL - 1β , and tumour necrosis factor ( P01375 ) - α , are involved at each stage of RA pathogenesis ; namely , by augmenting autoimmunity , sustaining long - term inflammatory synovitis and promoting joint damage . Different cell types are involved in RA pathogenesis through upregulation of several cytokine and soluble pro - inflammatory mediators . As early as the late 1980s , P01375 had been identified as a potential target in RA . Five anti - P01375 drugs , infliximab , adalimumab , certolizumab pegol , etanercept and DB06674 , are now approved for the treatment of RA in various countries . All are bivalent monoclonal antibodies , with the exception of the monovalent certolizumab and etanercept , which is an engineered dimeric receptor . Although all react with and neutralise soluble P01375 in vitro , structural differences in the molecules may contribute to differences in their therapeutic effects and the occurrence of side effects . Pegylated certolizumab permits once - monthly dosing . Other mechanisms of action proposed to be important for the efficacy of anti - P01375 agents are as follows : induction of apoptosis of both monocytes and T cells ; neutralization of membrane P01375 ; antibody - dependent cell - mediated and complement - dependent cytotoxicity ; and reverse signaling via membrane P01375 .",
"Biologic therapies in the treatment of psoriasis : a comprehensive evidence - based basic science and clinical review and a practical guide to tuberculosis monitoring . The treatment of psoriasis has undergone a revolution with the advent of biologic therapies including infliximab , etanercept , adalimumab , efalizumab , DB06674 , certolizumab , alefacept , secukinumab , abatacept , and ustekinumab . These medications are designed to target specific components of the immune system and are a major technological advancement over traditional immunosuppressive medications . Herein , we present a comprehensive , unbiased comparison of these medications focusing on their differences . For example , P01375 antagonists can differ in the way they are dissolved and administered , the effector molecules they can bind , serum peak and trough levels , the types of intracellular signals they can induce , the in vivo complexes that they can form , their protein structure , and their incidence and timing of rare adverse events , among other things . A critical review of the clinical studies that have tested the efficacy of these molecules is also presented including head - to - head comparison trials . The safety of biologics in terms of their long - term adverse events is discussed , as is their use in different types of psoriasis and in different patient populations . Finally , all anti - P01375 agents have been associated with a variety of serious and \" routine \" opportunistic infections , particularly tuberculosis . For this reason , anti - tuberculosis testing both prior to the initiation of a biologic therapy and annually during treatment is pertinent . The uses and limitations of both the tuberculin skin test ( Q16762 ) and QuantiFeron ®- TB Gold ( QFT ) are discussed , as is the care of patients who present with latent tuberculosis infection prior to the initiation of biologic therapy . Recommendations for tuberculosis monitoring are provided .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"[ Safety in the diagnosis and treatment of inflammatory bowel disease ] . The presentations at Digestive Disease Week 2013 emphasized treatment safety . Anti - tumor necrosis factor ( P01375 ) agents and thiopurines are reasonably safe in breastfeeding and pregnancy . Several studies indicate that controlling the risk of tuberculosis when anti - P01375 agents are planned presents several problems , both in the initial diagnosis of latent tuberculosis and in subsequent patient follow - up , given that cases of tuberculosis continue to occur , despite recommendations . Thiopurines increase the risk of lymphoma , but there is no residual risk when these drugs are withdrawn . Despite increasing knowledge of the risks and recommendations on how to avoid them , there remain considerable shortfalls in the application of preventive measures and , more specifically , in vaccinations . DB00065 and cyclosporin produce similar results when used to treat severe outbreaks of ulcerative colitis . Thromboembolism prevention continues to be deficient , and the barriers to effective prevention concern not only physicians but can also involve nursing staff , for example . There is still a wide margin for improvement in safety . New drugs under study ( vedolizumab , DB06674 ) have not shown any hitherto unknown signs of significant toxicity .",
"Combination systemic therapies in psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic , progressive , and debilitating disorder . When monotherapy fails , combination therapy is necessary for the long - term management of these patients . There is currently no review on this subject , and the purpose of this study was to investigate and describe the current literature on combination therapy in PsA . A PubMed MeSH search was performed for psoriatic arthritis and combination therapy , which yielded at total of 83 articles . After excluding reviews and commentaries , and pursuing relevant citations , a total of 21 articles on the subject were found : one study of NSAIDs and methotrexate , three studies of cyclosporine and methotrexate , three studies of non - P01375 biologic inhibitors ( alefacept , ustekinumab ) and methotrexate , and 14 studies of anti - P01375 - inhibitors ( etanercept , adalimumab , infliximab , DB06674 ) and methotrexate . The combination of cyclosporine and methotrexate reduces the dosages and also the side effects of each agent , allowing better disease control with less toxicity . DB00563 in combination with biologic agents , either non - P01375 inhibitors or anti - P01375 inhibitors , may have a role in decreasing side effects , but it does not appear to improve clinical symptoms beyond those attained by biologic monotherapy .",
"Two cases of Takayasu ' s arteritis occurring under anti - P01375 therapy . Takayasu ' s arteritis is a granulomatous , large vessel vasculitis that affects the aorta , its major branches and the pulmonary arteries . Compelling evidence exists to support the notion that Takayasu ' s arteritis is a T - cell mediated process and that tumor necrosis factor alpha ( TNFa ) is an important factor in the pathogenesis of this disease . Moreover , encouraging results from recent studies support the use of anti - TNFa therapy for relapsing or resistant cases of Takayasu ' s arteritis . Here , however , we describe the case of two patients : one with seropositive rheumatoid arthritis , the other with HLA - Q8TCY5 negative spondylarthropathy , who developed Takayasu ' s arteritis during treatment with TNFa inhibitors ( adalimumab and DB06674 respectively ) . This is the first report of Takayasu ' s arteritis in rheumatic patients under TNFa blocking agents which suggests the presence of different pathogenetic mechanism in a subgroup of patients with Takayasu ' s arteritis , as well as a potential role of TNFa blockers as triggers of this disease in some cases .",
"___MASK96___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"Concomitant loss of p120 - catenin and β - catenin membrane expression and oral carcinoma progression with P12830 reduction . The binding of p120 - catenin and β - catenin to the cytoplasmic domain of P12830 establishes epithelial cell - cell adhesion . Reduction and loss of catenin expression degrades P12830 - mediated carcinoma cell - cell adhesion and causes carcinomas to progress into aggressive states . Since both catenins are differentially regulated and play distinct roles when they dissociate from P12830 , evaluation of their expression , subcellular localization and the correlation with P12830 expression are important subjects . However , the same analyses are not readily performed on squamous cell carcinomas in which P12830 expression determines the disease progression . In the present study , we examined expression and subcellular localization of p120 - catenin and β - catenin in oral carcinomas ( n = 67 ) and its implications in the carcinoma progression and P12830 expression using immunohitochemistry . At the invasive front , catenin - membrane - positive carcinoma cells were decreased in the dedifferentiated ( p120 - catenin , P < 0 . 05 ; β - catenin , P < 0 . 05 ) and invasive carcinomas ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 05 ) and with the P12830 staining ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 01 ) . Carcinoma cells with β - catenin cytoplasmic and / or nuclear staining were increased at the invasive front compared to the center of tumors ( P < 0 . 01 ) . Although the p120 - catenin isoform shift from three to one associates with carcinoma progression , it was not observed after TGF - β , P01133 or P01375 - α treatments . The total amount of p120 - catenin expression was decreased upon co - treatment of TGF - β with P01133 or P01375 - α . The above data indicate that catenin membrane staining is a primary determinant for P12830 - mediated cell - cell adhesion and progression of oral carcinomas . Furthermore , it suggests that loss of p120 - catenin expression and cytoplasmic localization of β - catenin fine - tune the carcinoma progression ."
] |
[
"___MASK15___",
"___MASK27___",
"___MASK56___",
"___MASK57___",
"___MASK67___",
"___MASK71___",
"___MASK77___",
"___MASK90___",
"___MASK96___"
] |
___MASK67___
|
MH_train_455
|
interacts_with DB00193?
|
[
"Single - prolonged stress induce changes of P62158 / CaMKIIα in the rats of dorsal raphe nucleus . Ca2 +/ calmodulin - dependent protein kinase IIα ( CaMKIIα ) is identified as a Ca2 +- dependent kinase in brain involved in the activation of DB00150 hydroxylase ( P17752 ) acting through direct phosphorylation of P17752 , and playing key roles in the signaling pathways initiated by various G protein - coupled 5 - HT receptors . The goal of this study is to detect whether there are changes of P62158 and CaMKIIα in dorsal raphe nucleus in the rats exposed to single - prolonged stress ( P49903 ) , which is a model employed in post - traumatic stress disorder ( PTSD ) study extensively . A total of 90 male Wistar rats were randomly divided into a normal control group and P49903 groups of 7d , 14d . The changes of P62158 / CaMKIIα were detected by immunohistochemistry , reverse transcription - polymerase chain reaction and western blot . Our results demonstrate that both expressions of P62158 and CaMKIIα significantly increase ( P < 0 . 001 ) in the P49903 7d group than that in the control group , and then decreased dramatically ( P < 0 . 001 ) 14 days after P49903 . Our results confirm that P49903 induce changes of P62158 / CaMKIIα in the dorsal raphe nucleus . Changes of P62158 / CaMKIIα may be associated with the activation of P08908 receptor , and may contribute to the progress of molecular mechanism of PTSD .",
"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .",
"μ - Opioid receptor attenuates Aβ oligomers - induced neurotoxicity through P42345 signaling . AIMS : μ - opioid receptor ( P35372 ) exerts many functions such as antinociception , neuroprotection , and hippocampal plasticity . A body of evidence has shown that P35372 activation could stimulate downstream effectors of mechanistic / mammalian target of rapamycin ( P42345 ) . However , it is not clear whether P35372 protects neurons against β - amyloid peptide ( Aβ ) neurotoxicity through P42345 signaling . METHODS : The effects of P35372 activation on Aβ oligomers - induced neurotoxicity were assessed by cell viability and neurite outgrowth assay in primary cultured cortical neurons . The activities of P42345 , protein kinase B ( Akt ) and P08133 ribosomal S6 kinase ( P08133 S6k ) upon P35372 activation by morphine were measured by immunoblotting their phosphorylation status . RESULTS : Morphine dose - dependently attenuated Aβ oligomers - induced neurotoxicity . Aβ oligomers downregulated P42345 signaling . Morphine significantly rescued P42345 signaling by reversal of Aβ oligomers ' effect on P42345 and its upstream signaling molecule Akt , as well as its downstream molecule P08133 S6k . Moreover , the neuroprotective effect of morphine could be reversed by P35372 selective antagonist and phosphatidylinositol 3 - kinases ( PI3K ) , Akt and P42345 inhibitors . Furthermore , endogenous opioids - enkaphalins also attenuated Aβ oligomers - induced neurotoxicity . CONCLUSIONS : Our findings demonstrated P35372 activation attenuated Aβ oligomers - induced neurotoxicity through P42345 signaling . It may provide new insight into the pathological process and useful strategy for therapeutic interventions against Aβ neurotoxicity .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK64___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"P35372 and P00533 contribute to skin pigmentation differences between Indigenous Americans and Europeans . Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments . Previous studies have identified several genes involved in skin pigmentation differences among African , Asian , and European populations . However , none have examined skin pigmentation variation among Indigenous American populations , creating a critical gap in our understanding of skin pigmentation variation . This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans . Analysis was performed on two samples of Indigenous Americans genotyped on genome - wide SNP arrays . Using four tests for natural selection -- locus - specific branch length ( LSBL ) , ratio of heterozygosities ( lnRH ) , Tajima ' s D difference , and extended haplotype homozygosity ( EHH ) -- we identified 14 selection - nominated candidate genes ( SNCGs ) . SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground - level ultraviolet radiation . In addition to Q71RS6 and Q9UMX9 , genes previously associated with European / non - European differences in skin pigmentation , P35372 and P00533 were associated with variation in skin pigmentation in New World populations for the first time .",
"Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene ( P43681 ) , mu - opioid receptor gene ( P35372 ) , and ethanol - metabolizing enzyme genes with alcoholism in Korean patients . Findings obtained from several studies indicate that ethanol enhances the activity of alpha4beta2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor alpha4 subunit gene ( P43681 ) modulates enhancement of nicotinic receptor function by ethanol . To identify the association between the CfoI polymorphism of the P43681 and alcoholism , we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism ( n = 127 ) and Korean control subjects without alcoholism ( n = 185 ) with polymerase chain reaction - restriction fragment length polymorphism methods . We were able to detect the association between the CfoI polymorphism of the P43681 and alcoholism in Korean patients ( genotype P = . 023 ; allele frequency P = . 047 ) . The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes , such as alcohol metabolism - related genes [ alcohol dehydrogenase 2 ( P00325 ) , aldehyde dehydrogenase 2 ( P05091 ) , alcohol dehydrogenase 3 ( P00326 ) , and cytochrome P450 2E1 ( P05181 ) ] and mu - opioid receptor gene ( P35372 ) , were studied . The polymorphisms of P00325 , P05091 , and P05181 were significantly different in Korean patients with alcoholism and Korean control subjects without alcoholism , but P00326 and P35372 did not differ between the two groups .",
"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK41___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK59___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"___MASK89___ induces plasminogen activator inhibitor - 1 gene expression in a O15516 - dependent circadian manner . A functional interaction between peroxisome proliferator - activated receptor alpha ( PPARalpha ) and components of the circadian clock has been suggested , but whether these transcriptional factors interact to regulate the expression of their target genes remains obscure . Here we used a PPARalpha ligand , bezafibrate , to search for PPARalpha - regulated genes that are expressed in a O15516 - dependent circadian manner . Microarray analyses using hepatic RNA isolated from bezafibrate treated - wild type , Clock mutant ( Clk / Clk ) , and PPARalpha - null mice revealed that 136 genes are transcriptionally regulated by PPARalpha in a O15516 - dependent manner . Among them , we focused on the plasminogen activator inhibitor - 1 ( P05121 ) gene , because its expression typically shows circadian variation , and it has transcriptional response elements for both Q07869 and O15516 . The bezafibrate - induced expression of P05121 mRNA was attenuated in Clk / Clk mice and in PPARalpha - null mice . The protein levels of PPARalpha were reduced in Clk / Clk hepatocytes . However , the overexpression of PPARalpha could not rescue bezafibrate - induced P05121 expression in Clk / Clk hepatocytes , suggesting that impaired bezafibrate - induced P05121 expression in Clk / Clk mice is not due to reduced PPARalpha expression . Luciferase reporter and chromatin immunoprecipitation analyses using primary hepatocytes demonstrated that DNA binding of both PPARalpha and O15516 is essential for bezafibrate - induced P05121 gene expression . Pull - down assays in vitro showed that both PPARalpha and its heterodimerized partner retinoic acid receptor - alpha can serve as potential interaction targets of O15516 . The present findings revealed that molecular interaction between the circadian clock and the lipid metabolism regulator affects the bezafibrate - induced gene expression .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK43___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"___MASK89___ restores the inhibition of DB00094 - induced follicular development and steroidogenesis by tumor necrosis factor - alpha through peroxisome proliferator - activated receptor - gamma pathway in an in vitro mouse preantral follicle culture . We recently reported that bezafibrate , a lipid - lowering drug of the fibrate class , administered in addition to clomiphene citrate ( CC ) successfully induced ovulation in CC - resistant polycystic ovary syndrome ( PCOS ) patients . We hypothesized that bezafibrate may directly affect ovarian follicle development . P01308 resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS . In this study , we first examined the effects of tumor necrosis factor - alpha ( P01375 ) , which plays a role in insulin resistance , on follicle development by using the follicle culture system . P01375 significantly inhibited follicle - stimulating hormone ( DB00094 ) - induced follicle development , 17beta - estradiol ( E2 ) secretion , and ovulation rate in a dose - dependent manner . We then examined whether bezafibrate treatment could rescue the inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 . ___MASK89___ treatment rescued inhibition of follicle development , secretion of E2 , and ovulation rate by P01375 . We examined the expression of peroxisome proliferator - activated receptor ( Q07869 ) subtypes in mouse preantral follicles . As the protein expression of only P37231 was observed in mouse preantral follicles , we examined whether bezafibrate could affect follicle development and steroidogenesis through P37231 pathways . Treatment with GW1929 , a selective P37231 agonist , restored inhibition of DB00094 - induced follicle development and steroidogenesis by P01375 , whereas treatment with GW9662 , a selective P37231 antagonist , canceled the restorative effects of bezafibrate . Collectively , the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by P01375 through the P37231 pathway .",
"Association testing of panic disorder candidate genes using Q13308 challenge in healthy volunteers . Despite continuing efforts to determine genetic vulnerability to panic disorder ( PD ) , the studies of candidate genes in this disorder have produced inconsistent or negative , results . Laboratory panic induction may have a potential in testing genetic substrate of PD . In this study we aimed to explore the effects of several genetic polymorphisms previously implicated in PD on the susceptibility to cholecystokinin - tetrapeptide ( Q13308 ) challenge in healthy subjects . The study sample consisted of 110 healthy volunteers ( 47 males and 63 females , mean age 22 . 2 +/- 5 . 2 ) who participated in Q13308 challenge test . Nine gene - candidates , including 5 - HTTLPR , P21397 VNTR , Q8IWU9 rs1386494 , 5 - P08908 - 1019C - G , 5 - P28223 102T - C , CCKR1 246G - A , CCKR2 - 215C - A , P21728 - 94G - A and P21964 Val158Met , were selected for genotyping based on previous positive findings from genetic association studies in PD . After Q13308 challenge , 39 ( 35 . 5 % ) subjects experienced a panic attack , while 71 subjects were defined as non - panickers . We detected significant differences for both genotypic and allelic frequencies of 1386494A / G polymorphism in Q8IWU9 gene between panic and non - panic groups with the frequencies of G / G genotype and G allele significantly higher in panickers . None of the other candidate loci were significantly associated with Q13308 - induced panic attacks in healthy subjects . In line with our previous association study in patients with PD , we detected a possible association between Q8IWU9 rs1386494 polymorphism and susceptibility to panic attacks . Other polymorphisms previously associated with PD were unrelated to Q13308 - induced panic attacks , probably due to the differences between complex nature of PD and laboratory panic model .",
"Activation of P08908 receptors expressed in NIH - 3T3 cells induces focus formation and potentiates P01133 effect on DNA synthesis . NIH - 3T3 fibroblasts have been transfected with human serotonin P08908 receptors . Clonal cell lines expressed between 40 and 500 fmol receptor / mg . P08908 agonists strongly inhibited nonstimulated - as well as forskolin - or isoproterenol - stimulated adenylyl cyclase . The effects of P08908 receptor activation on cell growth were investigated . P08908 agonists accelerated cell division , generated foci , and increased DNA synthesis . The stimulation of [ 3H ] thymidine incorporation was much stronger when tyrosine kinase receptors were activated concomitantly . DB02527 ( DB02527 ) elevating agents inhibited DNA synthesis induced by all mitogens tested . The mitogenic activity of P08908 agonists did not seem to be linked to adenylyl cyclase inhibition because 1 ) we were not able to measure any decrease in intracellular DB02527 levels under the conditions of DNA synthesis assay and 2 ) 2 ', 5 '- dideoxyadenosine , which strongly inhibited adenylyl cyclase , was not mitogenic and did not modify the mitogenic effects of P08908 agonists . Pertussis toxin completely blocked potentiation of epidermal growth factor effect induced by 8 - hydroxy - di -( n - propyl ) aminotetralin , a P08908 agonist , but only partially blocked the one induced by insulin . In conclusion , in transfected NIH - 3T3 cells , transforming and mitogenic effects of P08908 agonists involve a pertussis toxin - sensitive G protein but do not seem to be linked to adenylyl cyclase inhibition .",
"Inducible raptor and rictor knockout mouse embryonic fibroblasts . The mammalian Target of ___MASK29___ ( P42345 ) kinase functions within two structurally and functionally distinct multiprotein complexes termed P42345 complex 1 ( mTORC1 ) and mTORC2 . The immunosuppressant and anticancer drug rapamycin is commonly used in basic research as a tool to study P42345 signaling . However , rapamycin inhibits only , and only incompletely , mTORC1 , and no mTORC2 - specific inhibitor is available . Hence , a full understanding of P42345 signaling in vivo , including the function of both complexes , requires genetic inhibition in addition to pharmacological inhibition . Taking advantage of the Cre / LoxP system , we generated inducible knockout mouse embryonic fibroblasts ( MEFs ) deficient for either the mTORC1 - specific component raptor ( iRapKO ) or the mTORC2 - specific component rictor ( iRicKO ) . Inducibility of the knockout was important because P42345 complex components are essential . Induction of either raptor or rictor knockout eliminated raptor or rictor expression , respectively , and impaired the corresponding P42345 signaling branch . The described knockout MEFs are a valuable tool to study the full function of the two P42345 complexes individually .",
"P35372 - dependent and independent components in effects of tramadol . DB00193 is thought to induce analgesia via both opioid and non - opioid pathways , although the precise mechanisms remain to be elucidated . In this study , we investigated the roles of the mu - opioid receptor ( MOP ) in analgesic and rewarding effects of tramadol by using MOP knockout ( KO ) mice . DB00193 - induced antinociception , assessed by hot - plate and tail - flick tests , was significantly reduced in heterozygous and homozygous MOP - KO mice when compared with that in wild - type mice . Interestingly , however , tramadol retained its ability to induce significant antinociception in homozygous MOP - KO mice . The tramadol - induced antinociception remaining in homozygous MOP - KO mice was not significantly affected by methysergide , a serotonin receptor antagonist , but was partially blocked by yohimbine , an adrenaline alpha2 receptor antagonist , and both naloxone , a non - selective opioid receptor antagonist , and yohimbine . In addition , antinociceptive effects of an active tramadol metabolite M1 were abolished or remarkably reduced in MOP - KO mice . On the other hand , neither wild - type nor homozygous MOP - KO mice showed significant place preference for tramadol in a conditioned place preference test , although there were slight tendencies toward preference in wild - type mice and avoidance in homozygous MOP - KO mice . These results strongly support the idea suggested in the previous pharmacological studies that MOP and the adrenaline alpha2 receptor mediate most of the analgesic properties of tramadol .",
"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .",
"Interactome mapping of the phosphatidylinositol 3 - kinase - mammalian target of rapamycin pathway identifies deformed epidermal autoregulatory factor - 1 as a new glycogen synthase kinase - 3 interactor . The phosphatidylinositol 3 - kinase - mammalian target of rapamycin ( PI3K - P42345 ) pathway plays pivotal roles in cell survival , growth , and proliferation downstream of growth factors . Its perturbations are associated with cancer progression , type 2 diabetes , and neurological disorders . To better understand the mechanisms of action and regulation of this pathway , we initiated a large scale yeast two - hybrid screen for 33 components of the PI3K - P42345 pathway . Identification of 67 new interactions was followed by validation by co - affinity purification and exhaustive literature curation of existing information . We provide a nearly complete , functionally annotated interactome of 802 interactions for the PI3K - P42345 pathway . Our screen revealed a predominant place for glycogen synthase kinase - 3 ( GSK3 ) A and B and the AMP - activated protein kinase . In particular , we identified the deformed epidermal autoregulatory factor - 1 ( O75398 ) transcription factor as an interactor and in vitro substrate of P49840 and P49841 . Moreover , GSK3 inhibitors increased O75398 transcriptional activity on the P08908 serotonin receptor promoter . We propose that O75398 may represent a therapeutic target of lithium and other GSK3 inhibitors used in bipolar disease and depression .",
"Linkage assignment of eleven genes to the porcine genome . We report comparative linkage mapping of eleven genes in the swine genome by RFLP analysis . These genes include : Acid phosphatase type 5 ( P13686 ) , Cholecystokinin Type B Receptor ( P32239 ) , Antibiotic Peptide ( P49913 ) , P01308 - like Growth Factor 1 Receptor ( P08069 ) , Integrin Alpha M ( P11215 ) , Integrin Beta 2 ( ITGbeta2 ) , Opioid Receptor Mu - 1 ( P35372 ) , Pro - hormone Converter ( PC1 / 3 ) , DB00162 Binding Q12988 ( P10745 ) , Ribosomal DNA ( RNR1 ) , and Zona Pellucida Glycoprotein 1 ( P60852 ) . The P32239 and ITGbeta2 loci define the ends of the linkage groups on Chromosomes ( Chro ) ( SSC ) 9p and 13qter , respectively .",
"Clinical and genetic factors associated with nausea and vomiting in cancer patients receiving opioids . BACKGROUND : This study investigates whether demographical , disease - related and genetic factors contribute to inter - individual differences in nausea and vomiting among patients receiving opioids for cancer pain . METHODS : Cancer patients receiving opioids were included from 17 centres in 11 European countries . Intensities of nausea and vomiting were reported by 1579 patients on four - point categorical scales . In stratified regression models including demographical and disease - related factors as covariates , 96 single nucleotide polymorphisms ( SNPs ) in 16 candidate genes related to opioid - or nausea / vomiting signalling pathways ( P08183 , P35372 , P41145 , P32121 , P42226 , P21964 , P20309 , P08912 , P35367 , P14416 , P35462 , P25103 , P46098 , O95264 , Q8WXA8 , P21554 ) were analysed for association with nausea and vomiting . FINDINGS : Age , body mass index , Karnofsky Performance Status , gender , use of antiemetics , type of opioid , type of cancer and eight SNPs were associated with the inter - individual differences in nausea and vomiting among cancer patients treated with opioids ( p < 0 . 01 ) . The SNPs were rs1176744 , rs3782025 and rs1672717 in O95264 ; rs165722 , rs4680 and rs4633 in P21964 ; rs10802789 and rs685550 in P20309 . Only the SNP rs1672717 in O95264 passed the Benjamini - Hochberg criterion for a 10 % false discovery rate . INTERPRETATION : Clinical characteristics and SNPs within the O95264 , P21964 and P20309 genes may be associated with the variability in nausea and vomiting among cancer patients receiving opioids . This knowledge may help to identify patients at particular risk for nausea and vomiting during treatment with opioids for cancer pain .",
"Serotonin - and two putative serotonin receptors - like immunohistochemical reactivities in the ground crickets Dianemobius nigrofasciatus and Allonemobius allardi . Serotonin ( 5 - hydroxytryptamine ; 5 - HT ) - and two putative serotonin receptors , P08908 - and P28222 - like , immunohistochemical reactivities were investigated in the cephalic ganglia of two ground crickets , Dianemobius nigrofasciatus and Allonemobius allardi . 5 - HT - ir was strongly expressed in the central body , accessory medulla region of the optic lobe , frontal ganglion , posterior cortex of the protocerebrum , dorsolateral region of the protocerebrum , and the suboesphageal ganglion ( SOG ) in both crickets . However , P08908 - ir and P28222 - ir showed quite mutually distinct patterns that were also distinct from 5 - HT - ir . P08908 - ir was located in the pars intercerebralis , dorsolateral region of the protocerebrum , optic tract , optic lobe , and the midline of the SOG in both crickets . P28222 - ir was located in the pars intercerebralis and dorsolateral region of the protocerebrum , and detected weakly in the optic lobe , tritocerebrum , and the midline of the SOG in both crickets . Interspecific differences were observed with P08908 - ir . P08908 - ir was expressed weakly in two neurons in the mandibular neuromere of the SOG in D . nigrofasciatus , while it was expressed strongly in the tritocerebrum , mandibular neuromere , and maxillary neuromere of the SOG in A . allardi and co - localized with O15516 - ir ( P49759 - ir ) . 5HT - 1B - ir was co - localized with P49759 - ir in the tritocerebrum , mandibular neuromere , and maxillary neuromere of the SOG when double - labeling was conducted in both crickets . These results indicated that 5 - HT and both types of 5 - HT receptors may regulate circadian photo - entrainment or photoperiodism in A . allardi , while only P28222 may be involved in circadian photo - entrainment or photoperiodism in D . nigrofasciatus .",
"Generation and properties of a new human ventral mesencephalic neural stem cell line . Neural stem cells ( NSCs ) are powerful research tools for the design and discovery of new approaches to cell therapy in neurodegenerative diseases like Parkinson ' s disease . Several epigenetic and genetic strategies have been tested for long - term maintenance and expansion of these cells in vitro . Here we report the generation of a new stable cell line of human neural stem cells derived from ventral mesencephalon ( hVM1 ) based on v - myc immortalization . The cells expressed neural stem cell and radial glia markers like nestin , vimentin and 3CB2 under proliferation conditions . After withdrawal of growth factors , proliferation and expression of v - myc were dramatically reduced and the cells differentiated into astrocytes , oligodendrocytes and neurons . hVM1 cells yield a large number of dopaminergic neurons ( about 12 % of total cells are TH + ) after differentiation , which also produce dopamine . In addition to proneural genes ( Q9H2A3 , MASH1 ) , differentiated cells show expression of several genuine mesencephalic dopaminergic markers such as : Q8TE12 , O60663 , P48051 , P00325 , P43354 , O75364 , Q05940 and Q01959 , indicating that they retain their regional identity . Our data indicate that this cell line and its clonal derivatives may constitute good candidates for the study of development and physiology of human dopaminergic neurons in vitro , and to develop tools for Parkinson ' s disease cell replacement preclinical research and drug testing .",
"Targeting of P00533 tyrosine kinase by ZD1839 ( \" ___MASK38___ \" ) in androgen - responsive prostate cancer in vitro . P00533 , highly expressed in a variety of human malignancies , is correlated with poor tumour differentiation , high tumour growth and metastatic rate . P01133 and several other ligands , such as transforming growth factor - alpha , amphiregulin , heparin - binding P01133 , and betacellulin , activate Ras / Raf mitogen - activated protein kinases ( MAPKs ) and phosphatidyl inositol 3 '- kinase ( PI3K ) / Akt signalling pathways . Therefore , P00533 can regulate multiple processes , i . e . , gene expression , cellular proliferation , angiogenesis , and inhibition of apoptosis , which contribute to the development of malignancy . In this review , we discuss the inhibition of P00533 by the specific tyrosine kinase inhibitor ___MASK38___ ( ZD1839 ) focusing on its effects in prostate cancer .",
"Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine - treated schizophrenic patients . RATIONALE : ___MASK41___ , a classical antipsychotic drug , has the potential to induce extrapyramidal side effects ( EPS ) . Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug . OBJECTIVES : To evaluate the impact of polymorphisms in the dopamine D ( 2 ) and D ( 3 ) and serotonin 2A and 2C receptor genes ( P14416 , P35462 , P28223 , and P28335 ) on short - term effects of perphenazine monotherapy in schizophrenic patients . MATERIALS AND METHODS : Forty - seven Estonian inpatients were evaluated before and after 4 - 6 weeks of treatment by Simpson - Angus rating scale , Barnes scale , and Positive and Negative Symptom Scale . Genotyping was performed for common P14416 , P35462 , P28223 , and P28335 gene polymorphisms , previously reported to influence receptor expression and / or function . RESULTS : Most of the patients ( n = 37 ) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response . The 102C allele of P28223 and the - 697C and 23Ser alleles of P28335 were more frequent among patients with EPS ( n = 25 ) compared to patients without EPS ( n = 22 ) ( p = 0 . 02 , 0 . 01 , and 0 . 02 , respectively ) . The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age , gender , and duration of antipsychotic treatment as covariants . There was no significant association between EPS occurrence and polymorphisms in the P14416 and P35462 genes . CONCLUSIONS : An association was observed between polymorphisms in P28223 and P28335 genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy . Larger study populations are needed to confirm our findings .",
"Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .",
"Differential radiosensitisation by ZD1839 ( ___MASK38___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK38___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .",
"Neurogenetics of aggressive behavior : studies in primates . Aggressive behavior can have adaptive value in certain environmental contexts , but when extreme or executed inappropriately , can also lead to maladaptive outcomes . Neurogenetic studies performed in nonhuman primates have shown that genetic variation that impacts reward sensitivity , impulsivity , and anxiety can contribute to individual differences in aggressive behavior . Genetic polymorphisms in the coding or promoter regions of the Mu - Opioid Receptor ( P35372 ) , DB01285 Releasing Hormone ( P06850 ) , Monoamine Oxidase A ( P21397 ) , Dopamine D4 Receptor ( P21917 ) , and Serotonin Transporter ( P31645 ) genes have been shown to be functionally similar in humans and rhesus macaques and have been demonstrated to contribute to individual differences in aggression . This body of literature suggests mechanisms by which genetic variation that promotes aggressivity could simultaneously increase evolutionary success while making modern humans more vulnerable to psychopathology .",
"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK15___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .",
"Cloning , after cloning , knock - out mice , and physiological functions of MAO A and B . Cloning of MAO A and B has demonstrated clearly that MAO A and B are coded by different proteins with 70 % amino acid identity . With the MAO A and B cDNA clones , we showed the tissue distribution and genomic structure of MAO A and B , the latter suggesting that they are derived from the same ancestral gene . The active sites , the role of cysteine residues , the three - dimensional models and the mitochondria targeting domains of both isoenzymes have been established . The transcriptional regulation of MAO A and B has been studied . MAO A KO mice showed increased levels of serotonin ( 5 - HT ) , norepinephrine ( NE ) , dopamine ( DA ) whereas MAO B KO mice showed increased phenylethylamine ( PEA ) levels only . Both MAO A and B KO mice showed increased response to stress . MAO A KO mice showed increased emotional learning and memory and aggressive behavior , but the vesicular monoamine transporter ( Q05940 ) , P08908 , 5 - Q13049 and P28335 receptors were down regulated . 5 - Q13049 antagonist , ketanserin and MDL100907 were able to abolish the aggression , suggesting that the aggressive behavior may be mediated by 5 - Q13049 receptor . In contrast , MAO B KO mice are resistant to MPTP , a toxin which induces Parkinson ' s syndromes . Studies of these mice suggest that MAO A and B have distinct biochemical and physiological functions .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK15___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 or Q09428 genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long - term follow - up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 , Q14654 , or Q09428 genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow - up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 and Q09428 genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .",
"___MASK44___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK44___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .",
"DB00193 and another atypical opioid meperidine have exaggerated serotonin syndrome behavioural effects , but decreased analgesic effects , in genetically deficient serotonin transporter ( P31645 ) mice . The serotonin syndrome is a potential side - effect of serotonin - enhancing drugs , including antidepressants such as selective serotonin reuptake inhibitors ( SSRIs ) and monoamine oxidase inhibitors ( MAOIs ) . We recently reported a genetic mouse model for the serotonin syndrome , as serotonin transporter ( P31645 ) - deficient mice have exaggerated serotonin syndrome behavioural responses to the MAOI tranylcypromine and the serotonin precursor 5 - hydroxy - l - tryptophan ( 5 - HTP ) . As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome , we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in P31645 wild - type ( +/+ ) , heterozygous ( +/- ) and knockout ( -/- ) mice . Comparisons were made with P31645 mice treated with either vehicle or morphine , an opioid not implicated in the serotonin syndrome in humans . Here we show that tramadol and meperidine , but not morphine , induce serotonin syndrome - like behaviours in mice , and we show that this response is exaggerated in mice lacking one or two copies of P31645 . The exaggerated response to tramadol in P31645 -/- mice was blocked by pretreatment with the P08908 antagonist WAY 100635 . Further , we show that morphine - , meperidine - and tramadol - induced analgesia is markedly decreased in P31645 -/- mice . These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs that dangerous side - effects may occur during concurrent use of tramadol and similar agents . These findings suggest that it is conceivable that there might be increased vulnerability in individuals with P31645 polymorphisms that may reduce P31645 by more than 50 % , the level in P31645 +/- mice ."
] |
[
"___MASK15___",
"___MASK29___",
"___MASK38___",
"___MASK41___",
"___MASK43___",
"___MASK44___",
"___MASK59___",
"___MASK64___",
"___MASK89___"
] |
___MASK41___
|
MH_train_456
|
interacts_with DB00731?
|
[
"Interleukin 10 blocks matrix metalloproteinase - 2 and membrane type 1 - matrix metalloproteinase synthesis in primary human prostate tumor lines . P01308 - like growth factor ( IGF ) I has been shown previously to up - regulate matrix metalloproteinase - 2 ( P08253 ) production , whereas the interleukin ( IL ) 10 / P22301 receptor axis has been found to down - regulate P08253 synthesis in tumor cells . In this paper , we showed that P22301 activation of the P22301 receptor blocked P08253 and membrane type 1 ( MT1 ) - MMP transcription and protein synthesis in nonimmortalized primary human prostate cell strains ( i . e . , P84074 - 10a and P84074 - 10c ) derived from high - grade cancer . Northern blots , Western blots , and ELISAs showed that P22301 suppressed P05019 induction of P08253 and P50281 mRNA synthesis in these cell strains ( P < 0 . 001 ) . Inhibition studies with P22301 and P08069 antibodies plus transfections experiments with P22301 sense , and P08069 antisense constructs confirmed these results . Finally , transient transfection experiments and chloramphenicol acetyltransferase assays with different regions of the 5 ' promoter region of the P08253 gene ( - 1659 to - 555 bp ) additionally showed that P05019 stimulated p53 - dependent plasmid catecholamine acetyltransferase activity and that P22301 blocked P05019 - induced plasmid catecholamine acetyltransferase activity . Electrophoretic mobility shift assays revealed that P22301 induced protein ( s ) binding to a putative \" silencer element \" ( - 1309 to - 555 fragment ) downstream of the p53 binding site ( - 1649 to - 1640 ) . The data show that P22301 blocks P05019 activation of P08253 and P50281 mRNA expression and protein synthesis in primary prostate cell strains .",
"The effects of mitiglinide ( KAD - 1229 ) , a new anti - diabetic drug , on DB00171 - sensitive K + channels and insulin secretion : comparison with the sulfonylureas and nateglinide . DB01252 ( KAD - 1229 ) , a new anti - diabetic drug , is thought to stimulate insulin secretion by closing the DB00171 - sensitive K + ( K ( DB00171 ) ) channels in pancreatic beta - cells . However , its selectivity for the various K ( DB00171 ) channels is not known . In this study , we examined the effects of mitiglinide on various cloned K ( DB00171 ) channels ( Kir6 . 2 / Q09428 , Kir6 . 2 / SUR2A , and Kir6 . 2 / SUR2B ) reconstituted in COS - 1 cells , and compared them to another meglitinide - related compound , nateglinide . Patch - clamp analysis using inside - out recording configuration showed that mitiglinide inhibits the Kir6 . 2 / Q09428 channel currents in a dose - dependent manner ( IC50 value , 100 nM ) but does not significantly inhibit either Kir6 . 2 / SUR2A or Kir6 . 2 / SUR2B channel currents even at high doses ( more than 10 microM ) . DB00731 inhibits Kir6 . 2 / Q09428 and Kir6 . 2 / SUR2B channels at 100 nM , and inhibits Kir6 . 2 / SUR2A channels at high concentrations ( 1 microM ) . Binding experiments on mitiglinide , nateglinide , and repaglinide to Q09428 expressed in COS - 1 cells revealed that they inhibit the binding of [ 3H ] glibenclamide to Q09428 ( IC50 values : mitiglinide , 280 nM ; nateglinide , 8 microM ; repaglinide , 1 . 6 microM ) , suggesting that they all share a glibenclamide binding site . The insulin responses to glucose , mitiglinide , tolbutamide , and glibenclamide in MIN6 cells after chronic mitiglinide , nateglinide , or repaglinide treatment were comparable to those after chronic tolbutamide and glibenclamide treatment . These results indicate that , similar to the sulfonylureas , mitiglinide is highly specific to the Kir6 . 2 / Q09428 complex , i . e . , the pancreatic beta - cell K ( DB00171 ) channel , and suggest that mitiglinide may be a clinically useful anti - diabetic drug .",
"P35568 regulation in health and disease . The global incidence of diabetes is increasing at epidemic rates . Estimates suggest there are currently 150 million people with diabetes and this number is expected to double in the next 20 years . Type 2 diabetes accounts for 95 % of all cases and is characterized in part by impaired sensitivity to insulin or ' insulin resistance ' . Defects in the insulin signalling pathways underpin this resistance . In the current article we discuss the regulation of P01308 Receptor Substrate - 1 ( P35568 ) , a protein that plays a pivotal role in insulin signalling and whose function is impaired in subjects with insulin resistance . Coordination of P35568 function is multi - faceted , involving phosphorylation of P35568 at multiple serine / threonine residues . This controls many aspects of P35568 , including its interaction with the insulin receptor and subsequent tyrosine phosphorylation , as well as its subcellular distribution and targeting for degradation by the proteasome . Such tight control ensures appropriate transduction and attenuation of the insulin signal , thereby regulating insulin action in healthy individuals . Emerging evidence indicates that ' diabetogenic factors ' associated with insulin resistance , such as TNFalpha and elevated circulating fatty acids , impact on insulin signalling at the level of P35568 serine / threonine phosphorylation . The expression and / or activity of several kinases , such as O15111 beta ( IKKbeta ) and salt - induced kinase 2 ( Q9H0K1 ) , and the phosphorylation of P35568 at key sites , such as Ser307 and Ser789 , are increased in states of insulin resistance . Identifying the pathways by which such factors activate these and other kinases , and defining the precise roles of specific serine / threonine phosphorylation events in P35568 regulation , represent important goals which may eventually provide a rationale for therapeutic intervention .",
"17β - estradiol inhibits P14780 and Q09428 / TrpM4 expression and activation and thereby attenuates BSCB disruption / hemorrhage after spinal cord injury in male rats . Blood - spinal cord barrier ( BSCB ) disruption and progressive hemorrhage after spinal cord injury ( SCI ) lead to secondary injury and the subsequent apoptosis and / or necrosis of neuron and glia , causing permanent neurological deficits . In this study , we examined the effect of 17β - estradiol ( E2 ) on BSCB breakdown and hemorrhage as well as subsequent inflammation after SCI . After a moderate contusion injury at the 9th thoracic segment of spinal cord , E2 ( 300 μg / kg ) was administered by iv injection immediately after SCI , and the same dose of E2 was then administered 6 and 24 hours after injury . Our data show that E2 attenuated BSCB permeability and hemorrhage and reduced the infiltration of neutrophils and macorphages after SCI . Consistent with this finding , the expression of inflammatory mediators was significantly reduced by E2 . Furthermore , E2 treatment significantly inhibited the expression of sulfonylurea receptor 1 and transient receptor potential melastatin 4 after injury , which are known to mediate hemorrhage at an early stage after SCI . Moreover , the expression and activation of matrix metalloprotease - 9 after injury , which is known to disrupt BSCB , and the degradation of tight junction proteins , such as zona occludens - 1 and occludin , were significantly inhibited by E2 treatment . Furthermore , the protective effects of E2 on BSCB disruption and functional improvement were abolished by an estrogen receptor antagonist , ICI 182780 ( 3 mg / kg ) . Thus , our study provides evidence that the neuroprotective effect of E2 after SCI is , in part , mediated by inhibiting BSCB disruption and hemorrhage through the down - regulation of sulfonylurea receptor 1 / transient receptor potential melastatin 4 and matrix metalloprotease - 9 , which is dependent on estrogen receptor .",
"Block of Q12809 channels by berberine : mechanisms of voltage - and state - dependence probed with site - directed mutant channels . DB04115 prolongs the duration of cardiac action potentials without affecting resting membrane potential or action potential amplitude . Controversy exists regarding whether berberine exerts this action by preferential block of different components of the delayed rectifying potassium current , I ( Kr ) and I ( Ks ) . Here we have studied the effects of berberine on hERG ( I ( Kr ) ) and P51787 / P15382 ( I ( Ks ) ) channels expressed in P29320 - 293 cells and Xenopus oocytes . In P29320 - 293 cells , the IC50 for berberine was 3 . 1 +/- 0 . 5 microM on hERG compared with 11 +/- 4 % decreases on P51787 / P15382 channels by 100 microM berberine . Likewise in oocytes , hERG channels were more sensitive to block by berberine ( IC50 = 80 +/- 5 microM ) compared with P51787 / P15382 channels ( approximately 20 % block at 300 microM ) . hERG block was markedly increased by membrane depolarization . Mutation to Ala of Y652 or F656 located on the S6 domain , or V625 located at the base of the pore helix of hERG decreased sensitivity to block by berberine . An inactivation - deficient mutant hERG channel ( G628C / S631C ) was also blocked by berberine . Together these findings indicate that berberine preferentially blocks the open state of hERG channels by interacting with specific residues that were previously reported to be important for binding of more potent antagonists .",
"DB09341 - and interleukin - 1beta - induced beta - cell apoptosis requires Ca2 + influx and extracellular signal - regulated kinase ( P29323 ) 1 / 2 activation and is prevented by a sulfonylurea receptor 1 / inwardly rectifying K + channel 6 . 2 ( Q09428 / Kir6 . 2 ) selective potassium channel opener in human islets . Increasing evidence indicates that a progressive decrease in the functional beta - cell mass is the hallmark of both type 1 and type 2 diabetes . The underlying causes , beta - cell apoptosis and impaired secretory function , seem to be partly mediated by macrophage production of interleukin ( IL ) - 1beta and / or high - glucose - induced beta - cell production of IL - 1beta . Treatment of type 1 and type 2 diabetic patients with the potassium channel opener diazoxide partially restores insulin secretion . Therefore , we studied the effect of diazoxide and of the novel potassium channel opener NN414 , selective for the beta - cell potassium channel Q09428 / Kir6 . 2 , on glucose - and IL - 1beta - induced apoptosis and impaired function in human beta - cells . Exposure of human islets for 4 days to 11 . 1 and 33 . 3 mmol / l glucose , 2 ng / ml IL - 1beta , or 10 and 100 micromol / l of the sulfonylurea tolbutamide induced beta - cell apoptosis and impaired glucose - stimulated insulin secretion . The deleterious effects of glucose and IL - 1beta were blocked by 200 micromol / l diazoxide as well as by 3 and 30 micromol / l NN414 . By Western blotting with phosphospecific antibodies , glucose and IL - 1beta were shown to activate the extracellular signal - regulated kinase ( P29323 ) 1 / 2 , an effect that was abrogated by 3 micromol / l NN414 . Similarly , 1 micromol / l of the mitogen - activated protein kinase / P29323 kinase 1 / 2 inhibitor PD098059 or 1 micromol / l of the l - type Ca ( 2 +) channel blocker nimodipine prevented glucose - and IL - 1beta - induced P29323 activation , beta - cell apoptosis , and impaired function . Finally , islet release of IL - 1beta in response to high glucose could be abrogated by nimodipine , NN414 , or PD098059 . Thus , in human islets , glucose - and IL - 1beta - induced beta - cell secretory dysfunction and apoptosis are Ca ( 2 +) influx and P29323 dependent and can be prevented by the beta - cell selective potassium channel opener NN414 .",
"Effects of I ( Ks ) channel inhibitors in insulin - secreting P01308 - 1 cells . DB01345 channels regulate insulin secretion . The closure of K ( DB00171 ) channels leads to membrane depolarisation , which triggers Ca ( 2 +) influx and stimulates insulin secretion . The subsequent activation of K (+) channels terminates secretion . We examined whether P51787 channels are expressed in pancreatic beta - cells and analysed their functional role . Using RT / PCR cellular mRNA of P51787 but not of P15382 channels was detected in P01308 - 1 cells . Effects of two sulfonamide analogues , 293B and HMR1556 , inhibitors of P51787 channels , were examined on voltage - activated outwardly rectifying K (+) currents using the patch - clamp method . It was found that 293B inhibited 60 % of whole - cell outward currents induced by voltage pulses from - 70 to + 50 mV with a concentration for half - maximal inhibition ( IC ( 50 ) ) of 37 microM . The other sulfonamide analogue HMR1556 inhibited 48 % of the outward current with an IC ( 50 ) of 7 microM . The chromanol 293B had no effect on tolbutamide - sensitive K ( DB00171 ) channels . Action potentials induced by current injections were broadened and after - repolarisation was attenuated by 293B . P01308 secretion in the presence but not in the absence of tolbutamide was significantly increased by 293B . These results suggest that 293B - and HMR1556 - sensitive channels , probably in concert with other voltage - activated K (+) channels , influence action potential duration and frequency and thus insulin secretion .",
"Q14201 tumor suppressor gene promoter demethylation , histone modification and cell cycle arrest by genistein in renal cancer . Q14201 / Q14201 / APRO4 has been reported to be a tumor suppressor gene in some malignancies . It constitutes important negative regulatory mechanism for Src - mediated signaling , a negative regulator of the cell cycle and inhibits transcription factor Q01094 . We report that Q14201 is downregulated in renal cancer and that the mechanism of inactivation is through promoter hypermethylation . Quantitative real - time polymerase chain reaction ( PCR ) showed that Q14201 was downregulated in cancer tissues and cells . DB01645 and DB01262 ( 5Aza - C ) induced Q14201 messenger RNA ( mRNA ) expression in A498 , ACHN and P29320 - 293 renal cell carcinoma ( RCC ) cell lines . Bisulfite - modified PCR and DNA sequencing results showed complete methylation of Q14201 promoter in tumor samples and cancer cell lines . DB01645 and 5Aza - C treatment significantly decreased promoter methylation , reactivating Q14201 expression . Chromatin immunoprecipitation assay revealed that genistein and 5Aza - C increased levels of acetylated histones 3 , 4 , 2H3K4 , 3H3K4 and RNA polymerase II at the Q14201 promoter indicative of active histone modifications . Enzymatic assays showed genistein and 5Aza - C decreased DNA Methyltransferase , methyl - CpG - binding domain 2 activity and increased O60235 activity . Cell cycle and 3 -( 4 , 5 - dimethylthiazole - 2 - yl )- 2 , 5 - biphenyl tetrazolium bromide cell proliferation assays showed that genistein has antiproliferative effect on cancer cell growth through induction of cell cycle arrest . This is the first report to show that Q14201 is epigenetically silenced in RCC and can be reactivated by genistein - induced promoter demethylation and active histone modification . DB01645 had similar effects to that of 5Aza - C , which is a potent demethylating agent with high toxicity and instability . DB01645 being a natural , non - toxic , dietary isoflavone is effective in retarding the growth of RCC cells , making it a promising candidate for epigenetic therapy in renal carcinoma .",
"Listeriolysin O secreted by Listeria monocytogenes induces NF - kappaB signalling by activating the O15111 complex . Listeriolysin O ( LLO ) is a pore - forming cytolysin secreted by the pathogen Listeria monocytogenes and is required for its intracellular survival . We recently demonstrated that in endothelial cells , LLO activates the NF - kappaB signalling pathway . In this work , we studied the LLO - induced molecular cascade of NF - kappaB activation with a cellular model extensively used to analyse the signalling pathway of NF - kappaB activation , i . e . the human embryonic kidney P29320 - 293 cell line and its derivatives ( transfectants or mutants ) . When the stably transfected derivative P29320 - 293 cells expressing IL - 1RI were exposed to LLO , a strong NF - kappaB activation was detected , contrasting with other cell lines ( P29320 - 293 wild type , P29320 - 293 . T and COS ) expressing a very low level of IL - 1RI . Although a delayed kinetics of LLO - dependent NF - kappaB activation suggests an autocrine or paracrine IL - 1 - dependent pathway , we found that LLO - dependent NF - kappaB activation did not require the IL - 1 protein synthesis nor the interaction with the IL - 1RI specific receptor . Herein , we demonstrated that LLO - dependent NF - kappaB activation requires the activation of the O15111 beta ( IKKbeta ) subunit of IKK complex to phosphorylate and degrade cytoplasmic P25963 , a natural inhibitor of NF - kappaB . The activation induced by LLO does not require the adapters MyD88 and IL - 1R - associated kinase ( P51617 ) . We suggested that LLO induces a distinct signalling pathway from that of IL - 1 and its receptor .",
"Anticytokine treatment prevents the increase in the activity of DB00171 - ubiquitin - and Ca ( 2 +)- dependent proteolytic systems in the muscle of tumour - bearing rats . The ascites hepatoma Yoshida AH - 130 induces loss of body weight and tissue waste . Tumour necrosis factor alpha ( P01375 ) plays a pivotal role in the pathogenesis of muscle wasting in this model system , but other cytokines , such as interleukin - 6 , may be involved . In order to verify whether a combined anticytokine treatment may synergistically counteract muscle protein degradation , tumour bearing rats were treated with pentoxyfilline ( PTX , an inhibitor of P01375 synthesis ) , or with suramin ( Q09428 , an antiprotozoal drug blocking the peripheral action of several cytokines including P05231 and P01375 ) , or both the drugs , and the effects on muscle proteolytic systems were assessed . Muscle protein loss in the AH - 130 - bearing rats was associated with increased activity of both the DB00171 - ubiquitin - and the calpain - dependent proteolytic pathways ( 246 % and 230 % of controls , respectively ) . Both PTX and Q09428 , either alone or in combination , prevented the depletion of muscle mass and significantly reduced the activity of muscle proteolytic systems . In particular , treatment with Q09428 , either alone or with PTX , induced a decrease in enzymatic activities to values similar to those of controls . The results obtained in the present paper demonstrate that : ( i ) muscle depletion in this model is indeed associated with increased proteasome - and calpain - dependent proteolysis , as previously suggested by increased mRNA expression of molecules pertaining to both pathways ; ( ii ) anticytokine treatments effectively reduce muscle protein loss by down - regulating the activity of at least two major proteolitic systems ; ( iii ) Q09428 is more effective than PTX in reducing the activity of proteolytic systems , possibly because of its multiple anticytokine action .",
"Keratin23 ( Q9C075 ) knockdown decreases proliferation and affects the DNA damage response of colon cancer cells . Keratin 23 ( Q9C075 ) is strongly expressed in colon adenocarcinomas but absent in normal colon mucosa . Array based methylation profiling of 40 colon samples showed that the promoter of Q9C075 was methylated in normal colon mucosa , while hypomethylated in most adenocarcinomas . Promoter methylation correlated with absent expression , while increased Q9C075 expression in tumor samples correlated with promoter hypomethylation , as confirmed by bisulfite sequencing . Demethylation induced Q9C075 expression in vitro . Expression profiling of shRNA mediated stable Q9C075 knockdown in colon cancer cell lines showed that Q9C075 depletion affected molecules of the cell cycle and DNA replication , recombination and repair . In vitro analyses confirmed that Q9C075 depletion significantly decreased the cellular proliferation of SW948 and LS1034 cells and markedly decreased the expression of genes involved in DNA damage response , mainly molecules of the double strand break repair homologous recombination pathway . Q9C075 knockdown decreased the transcript and protein expression of key molecules as e . g . P49959 , Q01094 , Q06609 and P38398 . Knockdown of Q9C075 rendered colon cancer cells more sensitive to irradiation and reduced proliferation of the Q9C075 depleted cells compared to irradiated control cells .",
"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK18___ ) in castrated male and female mice subjected to ___MASK18___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK18___ in mice CPs .",
"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK54___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK52___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK19___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"Single daily dose corticosteroid treatment . Thirteen patients with rheumatoid or psoriatic arthritis who had not previously received corticosteroids were treated with prednisolone in a single - dose each morning . P01308 - hypoglycaemia tests were performed before starting steroids in each patient , and again at the conclusion of the study in twelve of the thirteen ( duration of steroid treatment 8 - 40 m ) . There was no difference in the mean basal or peak levels of corticosteroids , or the mean peak of growth hormone ( GH ) in the tests done before or during treatment , although one patient lost GH responsiveness . There was thus no evidence of hypothalamo - pituitary - adrenal ( Q9Y251 ) suppression in any of the twelve patients , and there was a good therapeutic response in twelve out of thirteen . One patient was dropped from the trial because treatment failed . In contrast , of seven patients who had received a similar total dose of prednisolone twice daily , three showed Q9Y251 suppression and two had lost GH responsiveness .",
"DB00428 - induced increase in cholesterol ester transfer protein ( P11597 ) and its reversal by insulin in transgenic mice expressing human P11597 . High plasma triacylglycerol and low high - density lipoprotein levels are risk factors for cardiovascular disease in diabetes . Plasma high - density lipoprotein levels are regulated by cholesterol ester transfer protein ( P11597 ) . The regulation of P11597 under diabetic conditions is not clear , and this is due to a lack of appropriate models . We used transgenic mice expressing human P11597 to study the regulation of this protein under type - 1 diabetic conditions and further investigated whether insulin reverses the effect of diabetes . Mice expressing human P11597 under the control of its natural flanking region and age - matched littermates not expressing this protein were made diabetic by injecting streptozotocin , and the reversal of diabetes was assessed by injecting insulin . The plasma total cholesterol , low - density lipoprotein - cholesterol , and triacylglycerol concentrations were elevated , whereas high - density lipoprotein - cholesterol concentrations were reduced after the onset of diabetes . P01308 injection partially recovered this effect . The plasma cholesterol ester transfer activity , P11597 mass , and hepatic P11597 mRNA abundance were significantly higher in diabetic mice that were partially restored by insulin administration . There was a strong correlation between high - density lipoprotein - cholesterol concentrations and cholesterol ester transfer activity . These results suggest that an increase in P11597 under diabetic conditions might be a major factor responsible for increased incidence of diabetes - induced atherosclerosis .",
"___MASK48___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK48___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"Recent therapeutic strategy for sustained ventricular tachycardia in Japan . We investigated the therapeutic principles and strategies to treat sustained ventricular tachycardia ( SVT ) as five leading medical institutions in the Tokyo area and summarized the present situation of SVT treatment in Japan . Catheter ablation ( P00519 ) has been almost established to be effective in idiopathic ventricular tachycardia ( IVT ) and was used as the last treatment in 60 . 3 % of IVTs in this series . P00519 may be the first option of therapy for IVT . In patients with SVT who have underlying cardiac diseases , the last treatment was class I drugs in 8 . 3 % , class III drugs in 34 . 3 % , combination drug therapy in 24 . 0 % , P00519 in 33 . 3 % , surgical therapy ( Q09428 ) in 7 . 3 % , and implantable cardioverter defibrillator ( ICD ) in 12 . 5 % ( nonpharmacological therapy in combination with other therapy ) . The use of class I drugs was not common , whereas class III drugs were used more frequently in patients with a low left ventricular ejection fraction . In some patients with reduced cardiac function , a combination of class III drugs and non - pharmacological therapy is appropriate .",
"Recombinant P17936 inhibits allergic lung inflammation , P15692 production , and vascular leak in a mouse model of asthma . BACKGROUND : Vascular endothelial growth factor ( P15692 ) plays a pro - inflammatory mediator as well as a vascular permeability factor in bronchial asthma . P01308 - like growth factor ( IGF ) - I is also involved in the inflammatory process associated with bronchial asthma and stimulates P15692 expression . The IGF - binding proteins ( IGFBPs ) , especially P17936 , display distinctive properties and can interfere with various biological processes . METHODS : In this study , an ovalbumin ( OVA ) - induced murine model of allergic airway disease was used to investigate which mechanism is implicated in the preventive and therapeutic actions of P17936 administered exogenously on allergen - induced bronchial inflammation and airway hyper - responsiveness , in particular focusing on the regulation of P15692 expression . RESULTS : Administration of recombinant human P17936 to OVA - inhaled mice substantially attenuated the increases in hypoxia - inducible factor ( HIF ) - α activity , P05019 production , and P15692 protein levels in the lung . In addition , the blockade of P05019 action decreased the OVA - induced P15692 expression , airway inflammation , and bronchial hyper - responsiveness . The administration of recombinant human P17936 or CBO - P11 also reduced significantly increases in inflammatory cells , airway hyper - responsiveness , levels of P05112 , P05113 , P35225 , and vascular permeability in the lung of OVA - inhaled mice . Moreover , when recombinant human P17936 was administered after the completion of OVA inhalation , these therapeutic effects of P17936 were also observed . CONCLUSIONS : These results indicate that P17936 administered exogenously may attenuate antigen - induced airway inflammation and hyper - responsiveness through the modulation of vascular leakage and P15692 expression mediated by HIF - 1α / HIF - 2α signaling as well as P05019 action in allergic airway disease of mice .",
"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK18___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK18___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .",
"Suppression of synaptic plasticity by cerebrospinal fluid from anti - DB01221 receptor encephalitis patients . The functional effects of cerebrospinal fluid ( P04141 ) from patients with anti - DB01221 receptor ( NMDAR ) encephalitis on the NMDAR - mediated synaptic plasticity were evaluated by using mouse hippocampus slices . Anti - NMDAR antibody detection system was established by immunostaining recombinant NMDAR heteromers expressed in P29320 cell culture as well as native NMDARs in cultured hippocampal neurons . Under a complete blind manner for the clinical information , P04141 and sera collected from 36 pre - diagnosed patients were tested for anti - NMDAR antibodies . With this test , thirteen patients were diagnosed as anti - NMDAR encephalitis . P04141 positive for anti - NMDAR antibodies suppressed induction of long - term potentiation ( LTP ) at Schaffer collateral - P00915 synapses in mouse hippocampal slices . LTP induction was not suppressed by P04141 collected from herpes simplex virus ( HSV ) encephalitis or non - encephalitis control patients . Antibody absorption with NMDAR - expressing P29320 cell culture reversed the suppression of LTP by anti - NMDAR encephalitis patients ' P04141 , confirming that anti - NMDAR antibodies suppressed LTP . The present experiments firmly support the proposal that the anti - NMDAR encephalitis autoantibody is responsible for cognitive disorders like amnesia accompanying this disease .",
"Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy : a report from the French ND ( Neonatal Diabetes ) Study Group . OBJECTIVE : Permanent neonatal diabetes ( P01160 ) is defined by chronic hyperglycemia due to severe nonautoimmune insulin deficiency diagnosed in the first months of life . Several genes , including Q14654 and Q09428 , which encode the two subunits of the DB00171 - sensitive K (+) channel ( K ( DB00171 ) channel ) can cause P01160 . Mutations in the insulin ( P01308 ) gene have been recently described in families with neonatal diabetes . Our study aimed to investigate the genetic anomalies and clinical heterogeneity in P01160 patients who are negative for a K ( DB00171 ) channel mutation . RESEARCH DESIGN AND METHODS : We screened the P01308 gene by direct sequencing in 38 P01160 patients and in one child with nonautoimmune early - infancy diabetes , where no mutation in GCK , Q14654 , and Q09428 was identified . A detailed clinical phenotyping of the patients was carried out to specify the diabetes features in those found with an P01308 mutation . RESULTS : We identified three missense mutations in the P01308 gene in four probands . Two of four mutations were inherited in a dominant manner , and the familial description evidenced a marked variability in age of diagnosis and disease progression . In our cohort , the P01308 mutations may represent approximately 10 % of all permanent neonatal diabetes cases , having a later presentation of diabetes and no associated symptoms compared with cases with K ( DB00171 ) channel mutations . CONCLUSIONS ; Heterozygous P01308 gene mutations can cause isolated permanent early - infancy diabetes and should be assessed in neonatal as well as in childhood diabetes appearing like type 1 , when autoimmune markers are absent . New pharmacogenomic strategies may be applicable , since residual beta - cell function is still present in some patients .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK100___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"Receptor for advanced glycation end products is subjected to protein ectodomain shedding by metalloproteinases . The receptor for advanced glycation end products ( RAGE ) is a 55 - kDa type I membrane glycoprotein of the immunoglobulin superfamily . Ligand - induced up - regulation of RAGE is involved in various pathophysiological processes , including late diabetic complications and Alzheimer disease . Application of recombinant soluble RAGE has been shown to block RAGE - mediated pathophysiological conditions . After expression of full - length RAGE in P29320 cells we identified a 48 - kDa soluble RAGE form ( sRAGE ) in the culture medium . This variant of RAGE is smaller than a 51 - kDa soluble version derived from alternative splicing . The release of sRAGE can be induced by the phorbol ester PMA and the calcium ionophore calcimycin via calcium - dependent protein kinase C subtypes . Hydroxamic acid - based metalloproteinase inhibitors block the release of sRAGE , and by RNA interference experiments we identified O14672 and P14780 to be involved in RAGE shedding . In protein biotinylation experiments we show that membrane - anchored full - length RAGE is the precursor of sRAGE and that sRAGE is efficiently released from the cell surface . We identified cleavage of RAGE to occur close to the cell membrane . Ectodomain shedding of RAGE simultaneously generates sRAGE and a membrane - anchored C - terminal RAGE fragment ( RAGE - CTF ) . The amount of RAGE - CTF increases when RAGE - expressing cells are treated with a gamma - secretase inhibitor , suggesting that RAGE - CTF is normally further processed by gamma - secretase . Identification of these novel mechanisms involved in regulating the availability of cell surface - located RAGE and its soluble ectodomain may influence further research in RAGE - mediated processes in cell biology and pathophysiology .",
"DB00731 is Effective for Diabetes Mellitus with Reactive Hypoglycemia in a Child with a Compound Heterozygous Q09428 Mutation . Q09428 encodes the sulfonylurea receptor 1 ( Q09428 ) subunits of the beta - cell DB00171 - sensitive potassium ( K - DB00171 ) channel playing a critical role in the regulation of insulin secretion , and inactivating mutations in Q09428 cause congenital hyperinsulinism . Recently , Q09428 inactivating mutations were reported to be involved in the development of diabetes mellitus later in life . We report a girl who was born macrosomic with transient hypoglycemia and thereafter developed diabetes mellitus accompanied by severe reactive hypoglycemia at the age of 11 yr . An OGTT ( oral glucose tolerance test ) revealed hyperglycemia due to poor early insulin response and subsequent hypoglycemia due to delayed prolonged insulin secretion . Hypoglycemia was improved by the combination of nateglinide , which stimulates early insulin secretion , and an alpha - glucosidase inhibitor , voglibose . Sequencing of the Q09428 identified a compound heterozygous mutation ( R1420H / F591fs604X ) , suggesting that this mutation may alter regulation of insulin secretion with advancing age , leading to diabetes mellitus with reactive hypoglycemia from hyperinsulinism . Therefore , long - term follow - up and periodic OGTTs are important for early detection of insulin dysregulation in congenital hyperinsulinism patients carrying the Q09428 mutation , even though hypoglycemia resolves spontaneously during infancy . Furthermore , nateglinide may be useful therapeutically in the treatment of not only diabetes mellitus but also reactive hypoglycemia .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"___MASK14___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .",
"Identification of putative immunologic targets for colon cancer prevention based on conserved gene upregulation from preinvasive to malignant lesions . The length of time required for preinvasive adenoma to progress to carcinoma , the immunogenicity of colorectal cancer ( CRC ) , and the identification of high - risk populations make development and testing of a prophylactic vaccine for the prevention of CRC possible . We hypothesized that genes upregulated in adenoma relative to normal tissue , which maintained increased expression in CRC , would encode proteins suitable as putative targets for immunoprevention . We evaluated existing adenoma and CRC microarray datasets and identified 160 genes that were ≥ 2 - fold upregulated in both adenoma and CRC relative to normal colon tissue . We further identified 23 genes that showed protein overexpression in colon adenoma and CRC based on literature review . Silencing the most highly upregulated genes , CDH3 , O95832 , Q9C075 , and P09237 , in adenoma and CRC cell lines resulted in a significant decrease in viability ( P < 0 . 0001 ) and proliferation ( P < 0 . 0001 ) as compared to controls and an increase in cellular apoptosis ( P < 0 . 05 for CDH3 , Q9C075 ) . Results were duplicated across cell lines representing microsatellite instability , CpG island methylator , and chromosomal instability phenotypes , suggesting immunologic elimination of cells expressing these proteins could impact the progression of all CRC phenotypes . To determine whether these proteins were immunogens , we interrogated sera from early stage CRC patients and controls and found significantly elevated CDH3 ( P = 0 . 006 ) , Q9C075 ( P = 0 . 0007 ) , and P09237 ( P < 0 . 0001 ) serum immunoglobulin G in cases as compared to controls . These data show a high throughput approach to the identification of biologically relevant putative immunologic targets for CRC and identified three candidates suitable for vaccine development .",
"Microsomal transfer protein ( P55157 ) inhibition - a novel approach to the treatment of homozygous hypercholesterolemia . Homozygous familial hypercholesterolemia ( HoFH ) represents the most severe lipoprotein disorder , generally attributable to mutation ( s ) of the low - density lipoprotein receptor ( LDL - R ) , i . e . autosomal dominant hypercholesterolemia type 1 ( P07327 ) . Much lower percentages are due to alterations of apolipoprotein B ( P00325 ) , or gain - of - function mutations of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) ( P00326 ) . In certain geographical areas a significant number of patients may be affected by an autosomal recessive hypercholesterolemia ( Q5SW96 ) . Mutations may be also combined ( two mutations of the same gene , compound heterozygosity ) , or two in different genes ( double heterozygosity ) . Among the most innovative therapeutic approaches made available recently , inhibitors of the microsomal transfer protein ( P55157 ) system have shown a high clinical potential . P55157 plays a critical role in the assembly / secretion of very - low - density lipoproteins ( VLDL ) , and its absence leads to apo B deficiency . P55157 antagonists dramatically lower LDL - cholesterol ( LDL - C ) in animals , although a reported increase of liver fat delayed their clinical development . ___MASK54___ , the best - studied P55157 inhibitor , reduces LDL - C by 50 % or more in HoFH patients , with modest , reversible , liver steatosis . Recent US approval has confirmed an acceptable tolerability , provided patients adhere to a strictly low - fat regimen . There are no clinical data on atherosclerosis reduction / regression , but animal models provide encouraging results .",
"Antidiabetic sulfonylurea enhances secretagogue - induced adrenocorticotropin secretion and proopiomelanocortin gene expression in vitro . The presence of high - affinity binding sites for antidiabetic sulfonylureas ( SUs ) and the expression of SU receptor ( Q09428 ) messenger RNA in the adenohypophyseal cells have recently been reported . In this study , we examined the effects of SU on P01189 gene expression and DB01285 secretion using the AtT20PL cell line , a subclone of AtT20 in which the rat P01189 5 '- promoter - luciferase fusion gene was stably incorporated . A representative SU glibenclamide inhibited the basal P01189 5 '- promoter activity . In contrast , glibenclamide enhanced forskolin - or P06850 - induced P01189 expression in a dose - dependent manner . Interestingly , the latter effect was not observed under treatment with DB07954 , a nonselective phosphodiesterase inhibitor . Furthermore , diazoxide , an opener of the DB00171 - sensitive K + channel , only antagonized the suppressive effect of glibenclamide . Lastly , RT - PCR analysis showed that mouse Q09428 ( but not SUR2 ) messenger RNA was expressed in this cell line . These results suggest that , in AtT20PL cells , SU has dual effects , i . e . a suppressive effect on basal P01189 expression through diazoxide - sensitive ( DB00171 - sensitive ) K +- channel - mediated mechanism , and an enhancing effect on DB02527 / protein kinase A - stimulated P01189 expression through a different mechanism ( probably mediated by phosphodiesterase ) . To our knowledge , this is the first report showing the effect of SU on the expression of the anterior pituitary hormone gene .",
"P01308 - induced NADPH oxidase activation promotes proliferation and matrix metalloproteinase activation in monocytes / macrophages . P01308 stimulates superoxide ( O ( 2 )(-) ) production in monocytes and macrophages . However , the mechanisms through which insulin induces O ( 2 )(-) production are not completely understood . In this study , we ( a ) characterized the enzyme and the pathways involved in insulin - stimulated O ( 2 )(-) production in human monocytes and murine macrophages , and ( b ) analyzed the consequences of insulin - stimulated O ( 2 )(-) production on the cellular phenotype in these cells . We showed that insulin stimulated O ( 2 )(-) production , and promoted p47 ( phox ) translocation to the plasma membrane . P01308 - induced O ( 2 )(-) production and p47 ( phox ) translocation were prevented in the presence of specific inhibitors of PI3K and PKC . P01308 - mediated NADPH oxidase activation stimulated P14780 activation in monocytes and cell proliferation in macrophages . The effect of insulin on these phenotypic responses was mediated through NFkappaB , p38MAPK , and P29323 1 / 2 activation . Small - interfering RNA - specific gene silencing targeted specifically against Nox2 reduced the cognate protein expression , decreased insulin - induced O ( 2 )(-) production , inhibited the turn on of NFkappaB , p38MAPK , and P29323 1 / 2 , and reduced cell proliferation in macrophages . These findings suggest a pivotal role for NADPH oxidase in insulin - induced proliferation and proteolytic activation in monocytes and macrophages , respectively , and identify a pathway that may play a pathological role in hyperinsulinemic states .",
"Leptin modulates the intrinsic excitability of AgRP / P01303 neurons in the arcuate nucleus of the hypothalamus . The hypothalamic arcuate nucleus ( Q5SW96 ) is a brain region critical for regulation of food intake and a primary area for the action of leptin in the CNS . In lean mice , the adipokine leptin inhibits neuropeptide Y ( P01303 ) and agouti - related peptide ( AgRP ) neuronal activity , resulting in decreased food intake . Here we show that diet - induced obesity in mice is associated with persistent activation of P01303 neurons and a failure of leptin to reduce the firing rate or hyperpolarize the resting membrane potential . However , the molecular mechanism whereby diet uncouples leptin ' s effect on neuronal excitability remains to be fully elucidated . In P01303 neurons from lean mice , the Kv channel blocker 4 - aminopyridine inhibited leptin - induced changes in input resistance and spike rate . Consistent with this , we found that Q5SW96 P01303 neurons have a large , leptin - sensitive delayed rectifier K (+) current and that leptin sensitivity of this current is blunted in neurons from diet - induced obese mice . This current is primarily carried by Kv2 - containing channels , as the Kv2 channel inhibitor stromatoxin - 1 significantly increased the spontaneous firing rate in P01303 neurons from lean mice . In P29320 cells , leptin induced a significant hyperpolarizing shift in the voltage dependence of Kv2 . 1 but had no effect on the function of the closely related channel Kv2 . 2 when these channels were coexpressed with the long isoform of the leptin receptor LepRb . Our results suggest that dynamic modulation of somatic Kv2 . 1 channels regulates the intrinsic excitability of P01303 neurons to modulate the spontaneous activity and the integration of synaptic input onto these neurons in the Q5SW96 .",
"Pancreatic beta - cell K ( DB00171 ) channel activity and membrane - binding studies with nateglinide : A comparison with sulfonylureas and repaglinide . DB00731 ( A - 4166 ) is an amino acid derivative with insulinotrophic action in clinical development for treatment of type 2 diabetes . The aim of this study was to determine whether nateglinide ' s interaction at the K ( DB00171 ) channel / sulfonylurea receptor underlies its more rapid onset and shorter duration of action in animal models . Binding studies were carried out with membranes prepared from Q99578 - m5F cells and P29320 - 293 cells expressing recombinant human sulfonylurea receptor 1 ( Q09428 ) . The relative order for displacement of [( 3 ) H ] glibenclamide in competitive binding experiments with Q99578 - m5F cell membranes was glibenclamide > glimepiride > repaglinide > glipizide > nateglinide > L - nateglinide > tolbutamide . The results with P29320 - 293 / recombinant human Q09428 cells were similar with the exception that glipizide was more potent than repaglinide . Neither nateglinide nor repaglinide had any effect on the dissociation kinetics for [( 3 ) H ] glibenclamide , consistent with both compounds competitively binding to the glibenclamide - binding site on Q09428 . Finally , the inability to measure [( 3 ) H ] nateglinide binding suggests that nateglinide dissociates rapidly from Q09428 . Direct interaction of nateglinide with K ( DB00171 ) channels in rat pancreatic beta - cells was investigated with the patch - clamp method . The relative potency for inhibition of the K ( DB00171 ) channel was repaglinide > glibenclamide > nateglinide . Kinetics of the inhibitory effect on K ( DB00171 ) current showed that the onset of inhibition by nateglinide was comparable to glibenclamide but more rapid than that of repaglinide . The time for reversal of channel inhibition by nateglinide was also faster than with glibenclamide and repaglinide . These results suggest that the unique characteristics of nateglinide are largely the result of its interaction at the K ( DB00171 ) channel .",
"Pervanadate - induced shedding of the intercellular adhesion molecule ( ICAM ) - 1 ectodomain is mediated by membrane type - 1 matrix metalloproteinase ( P50281 ) . In several vascular diseases , the ectodomain of intercellular adhesion molecule ( ICAM ) - 1 is shed by the proteolytic activity of a zinc - dependent endopeptidase , releasing a soluble form of the protein ( sICAM - 1 ) , a common marker for inflammatory diseases . Since reactive oxygen species ( ROS ) generated during prolonged inflammation are known to induce shedding or cleavage of several transmembrane proteins , we sought to explore the cleavage and enzymatic effects that the pervanadate , via oxidation and subsequent inactivation of protein tyrosine phosphatase , has on P05362 cleavage . In these studies , we used endothelial cells ( ECs ) and 293 human embryonic kidney ( P29320 ) cells expressing high - levels of surface P05362 . In addition , use of specific tissue inhibitors of metalloproteinases ( TIMPs ) , small interfering ( si ) RNA designed to knockdown endopeptidase activity , and an immunocolocalization assay were employed to determine the identity of a specific metalloproteinase mediating pervanadate - induced sICAM - 1 shedding . Our data indicate that membrane type - 1 matrix metalloproteinase ( P50281 ) is involved in pervanadate - mediated shedding of the sICAM - 1 ectodomain in both cell types . Immunostaining and confocal microscopy provide visual evidence that P05362 and P50281 colocalize at the cellular surface following pervanadate treatment , further implicating the involvement of P50281 activity in this mode of P05362 shedding .",
"The transcriptional co - regulator P51610 is required for P01308 - 1 β - cell glucose - stimulated insulin secretion . The transcriptional co - regulator host cell factor - 1 ( P51610 ) plays critical roles in promoting cell cycle progression in diverse cell types , and in maintaining self - renewal of embryonic stem cells , but its role in pancreatic β - cell function has not been investigated . Immunhistochemistry of mouse pancreas revealed nuclear expression of P51610 in pancreatic islets . Reducing P51610 expression in the P01308 - 1 pancreatic β - cell line resulted in reduced cell proliferation , reduced glucose - stimulated insulin secretion , and reduced expression of the critical β - cell transcription factor Pdx1 . P51610 is a known co - activator of the Q01094 transcription factor , and loss of Q01094 results in pancreatic β - cell dysfunction and reduced expression of Pdx1 . Therefore we wondered whether P51610 might be required for Q01094 regulation of Pdx1 . Chromatin immunoprecipitation experiments revealed that P51610 and Q01094 co - localize to the Pdx1 promoter . These results indicate that P51610 represents a novel transcriptional regulator required for maintaining pancreatic β - cell function .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK35___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"17 ___MASK29___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"P10275 antagonism and an insulin sensitizer block the advancement of vaginal opening by high - fat diet in mice . Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty . In high fat - fed rodents , the timing of vaginal opening ( VO ) is advanced , suggesting that puberty begins earlier . Because obesity can increase androgens , which interfere with normal steroid feedback in adult females , we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat - fed mice . Age at VO was examined in mice fed high - fat or low - fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle ( controls ) . VO was advanced in high - fat vs . low - fat controls , and flutamide blocked this advancement . VO was also delayed in low fat - fed flutamide - treated females , suggesting involvement of androgens in the timing of normal puberty . We next investigated if high - fat diet - induced insulin resistance contributes to early VO , as elevated insulin can stimulate androgen production . VO was examined in mice on either diet treated with the insulin sensitizer metformin . Metformin blocked high - fat advancement of VO but did not alter the timing of VO in low fat - fed mice . P01308 was elevated in high fat - fed females that had undergone VO compared with age - matched low fat - fed or metformin - treated animals on either diet that had not undergone VO . Together , these data suggest a model in which metabolic changes induced by high - fat diet , including transient increased circulating insulin , act in part by increasing androgen action to influence the timing of puberty in females .",
"Sulfonylureas inhibit cytokine - induced eosinophil survival and activation . Eosinophils play a key role in the pathogenesis of asthma and other allergic inflammatory diseases . We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits P05113 - induced survival . This inhibition can not be overcome by increasing concentrations of P05113 and is not due to the blocking of Na + channels by lidocaine . Here we report that one class of K + channel blockers , the sulfonylureas , inhibits eosinophil survival in a manner similar to lidocaine . The sulfonylurea glyburide inhibits eosinophil survival even at high concentrations of P05113 . In contrast , increasing concentrations of P08700 or granulocyte - macrophage P04141 overcome glyburide inhibition . Glyburide also blocks cytokine - induced eosinophil superoxide production . Similar results were seen with the sulfonylureas tolbutamide and glipizide . Interestingly , the effects of glyburide are not antagonized by the DB00171 - sensitive K + channel openers cromakalim , pinacidil , or diazoxide . Although Scatchard analysis of [ 3H ] glyburide binding to eosinophil membranes indicated that the high affinity sulfonylurea receptor ( Q09428 ) is not present on eosinophils , human eosinophils do express mRNA homologous to the sulfonylurea receptor family , in keeping with the presence of a sulfonylurea receptor . Finally , coculture of eosinophils with combinations of glyburide , lidocaine , and dexamethasone resulted in synergistic inhibition of cytokine - mediated eosinophil survival and superoxide production . These results have intriguing clinical implications for the treatment of eosinophil - associated diseases .",
"___MASK54___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK54___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK54___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK54___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK54___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK54___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .",
"DB00731 and mitiglinide , but not sulfonylureas , induce insulin secretion through a mechanism mediated by calcium release from endoplasmic reticulum . DB00731 and mitiglinide ( glinides ) are characterized as rapid - onset and short - acting insulinotropic agents . Although both compounds do not have a sulfonylurea structure , it has been postulated that insulin secretion is preceded by their binding to Kir6 . 2 / Q09428 complex , and a mechanism of insulin secretion of glinides has been accounted for by this pathway . However , we hypothesized the involvement of additional mechanisms of insulin secretion enhanced by glinides , and we analyzed the pattern of time course of insulin secretion from MIN6 cells with the existence of agents that have specific pharmacologic actions . Dose - dependent effects of tolbutamide , glibenclamide , nateglinide , and mitiglinide were observed . P01308 secretion induced by 3 microM tolbutamide and 1 nM glibenclamide was completely inhibited by 10 microM diazoxide and 3 microM verapamil , although the latter half - component of insulin secretion profile induced by 3 microM nateglinide or 30 nM mitiglinide remained with the existence of those agents . Glinides enhanced insulin secretion even in Ca2 +- depleted medium , and its pattern of secretion was same as the pattern with existence of verapamil . The latter half was suppressed by 1 microM dantrolene , and concomitant addition of verapamil and dantrolene completely suppressed the entire pattern of insulin secretion enhanced by nateglinide . Thus , we conclude that glinide action is demonstrated through two pathways , dependently and independently , from the pathway through K ( DB00171 ) channels . We also demonstrated that the latter pathway involves the intracellular calcium release from endoplasmic reticulum via ryanodine receptor activation .",
"Metalloproteinases control brain inflammation induced by pertussis toxin in mice overexpressing the chemokine P13500 in the central nervous system . Inflammatory leukocytes infiltrate the CNS parenchyma in neuroinflammation . This involves cellular migration across various structures associated with the blood - brain barrier : the vascular endothelium , the glia limitans , and the perivascular space between them . Leukocytes accumulate spontaneously in the perivascular space in brains of transgenic ( Tg ) mice that overexpress P13500 under control of a CNS - specific promoter . The Tg mice show no clinical symptoms , even though leukocytes have crossed the endothelial basement membrane . Pertussis toxin ( PTx ) given i . p . induced encephalopathy and weight loss in Tg mice . We used flow cytometry , ultra - small superparamagnetic iron oxide - enhanced magnetic resonance imaging , and immunofluorescent staining to show that encephalopathy involved leukocyte migration across the glia limitans into the brain parenchyma , identifying this as the critical step in inducing clinical symptoms . Metalloproteinase ( MPs ) enzymes are implicated in leukocyte infiltration in neuroinflammation . Unmanipulated Tg mice had elevated expression of tissue inhibitor of metalloproteinase - 1 , matrix metalloproteinase ( MMP ) - 10 , and - 12 mRNA in the brain . PTx further induced expression of tissue inhibitor of metalloproteinase - 1 , metalloproteinase disintegrins - 12 , P22894 , and - 10 in brains of Tg mice . Levels of the microglial - associated MP P51511 were not affected in control or PTx - treated Tg mice . PTx also up - regulated expression of proinflammatory cytokines IL - 1beta and P01375 mRNA in Tg CNS . Weight loss and parenchymal infiltration , but not perivascular accumulation , were significantly inhibited by the broad - spectrum MP inhibitor BB - 94 / ___MASK19___ . Our finding that MPs mediate PTx - induced parenchymal infiltration to the chemokine - overexpressing CNS has relevance for the pathogenesis of human diseases involving CNS inflammation , such as multiple sclerosis .",
"Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 .",
"New K103 β3 allele identified in a context of severe neonatal thrombocytopenia . BACKGROUND : A new β3 allele was identified in a severe case of neonatal alloimmune thrombocytopenia ( < 7 × 10 ( 9 ) / L ) . STUDY DESIGN AND METHODS : Diagnosis was done by use of monoclonal antibody - specific immobilization of platelet ( Q02083 ) antigen for serologic analyses and polymerase chain reaction ( PCR ) - sequence - specific primers ( SSP ) and PCR - restriction fragment length polymorphism ( RFLP ) for genotyping . Direct sequencing of PCR product was done and mutant αIIbβ3 expressed in P29320 - 293 cells . RESULTS : Serologic analysis revealed in the maternal serum an anti - human Q02083 alloantigen ( Q9Y251 ) - 1a alloantibody associated to an anti - α2β1 . Anti - Q9Y251 - 1a alloimmunization diagnosis was confirmed by genotyping showing maternofetal incompatibility . However , investigation of rare Q9Y251 polymorphisms revealed discrepant Q9Y251 - 16b assignation between PCR - RFLP and PCR - SSP . Sequencing revealed a new c . 385C > A mutation in the β3 coding sequence resulting in a false assignation of the Q9Y251 - 16b allele by PCR - RFLP . This mutation leads to a Q103K substitution in mature β3 . The K103 - β3 form of the complex was expressed in P29320 - 293 cells but did not react with the maternal serum . CONCLUSION : We have characterized a new rare allele ( frequency < 1 % ) of β3 that yields false Q9Y251 - 16b genotyping in PCR - RFLP . This new case of false typing assignation emphasizes the necessity to use two genotyping techniques in diagnosis . This particularly applies for rare Q9Y251 polymorphisms when Q02083 phenotyping can not be used .",
"DB00731 , a D - phenylalanine derivative lacking either a sulfonylurea or benzamido moiety , specifically inhibits pancreatic beta - cell - type K ( DB00171 ) channels . A novel antidiabetic agent , nateglinide , is a D - phenylalanine derivative lacking either a sulfonylurea or benzamido moiety . We examined with the patch - clamp method the effect of nateglinide on recombinant DB00171 - sensitive K (+) ( K ( DB00171 ) ) channels expressed in human embryonic kidney 293T cells transfected with a Kir6 . 2 subunit and either of a sulfonylurea receptor ( Q09428 ) 1 , SUR2A , and SUR2B . In inside - out patches , nateglinide reversibly inhibited the spontaneous openings of all three types of Q09428 / Kir6 . 2 channels . DB00731 inhibited Q09428 / Kir6 . 2 channels with high and low affinities ( K ( i ) = 75 nM and 114 microM ) but SUR2A / Kir6 . 2 and SUR2B / Kir6 . 2 channels only with low affinity ( K ( i ) = 105 and 111 microM , respectively ) . DB00731 inhibited the K ( DB00171 ) current mediated by Kir6 . 2 lacking C - terminal 26 amino acids only with low affinity ( K ( i ) = 290 microM ) in the absence of Q09428 . Replacement of serine at position 1237 of Q09428 to tyrosine [ Q09428 ( S1237Y ) ] specifically abolished the high - affinity inhibition of Q09428 / Kir6 . 2 channels by nateglinide . MgADP or MgUDP ( 100 microM ) augmented the inhibitory effect of nateglinide on Q09428 / Kir6 . 2 but not Q09428 ( S1237Y )/ Kir6 . 2 or SUR2A / Kir6 . 2 channels . This augmenting effect of MgADP was also observed with the Q09428 / Kir6 . 2 ( K185Q ) channel , which was not inhibited by MgADP , but not with the Q09428 ( K1384A )/ Kir6 . 2 channel , which was not activated by MgADP . These results indicate that therapeutic concentrations of nateglinide ( approximately 10 microM ) may selectively inhibit pancreatic type Q09428 / Kir6 . 2 channels through Q09428 , especially when the channel is activated by intracellular MgADP , even though the agent does not contain either a sulfonylurea or benzamido moiety .",
"Selective effect of INGAP - PP upon mouse embryonic stem cell differentiation toward islet cells . We evaluated the effect of islet neogenesis - associated protein pentadecapeptide ( INGAP - PP ) upon islet beta - and non - beta cell differentiation from mouse embryonic stem ( mES ) cells . ES - D3 cell lines were cultured following Lumelsky ' s protocol with or without INGAP - PP ( 5 microg / ml ) at different stages . Gene expression was quantified using qPCR . mES cells were fixed and immunostained using anti insulin - , somatostatin - , glucagon - , Pdx - 1 - , Ngn - 3 - , Nkx - 6 . 1 and P09936 specific antibodies . P12004 was used to measure replication rate . Bcl ( 2 ) ( immunostaining ) and caspase - 3 ( enzyme activity and gene expression ) were determined as apoptosis markers . INGAP - PP increased P10997 , Glut - 2 , Kir - 6 . 2 , Q09428 - 1 and insulin gene expression , and the percentage of insulin - immunostained cells . Conversely , INGAP - PP reduced significantly glucagon and somatostatin gene expression and immunopositivity . While nestin gene expression was not affected , there was a significant reduction in the percentage of P09936 - immunostained cells . Pdx - 1 gene expression increased by 115 % in INGAP - PP treated cells , as well as the percentage of Pdx - 1 , Ngn - 3 and Nkx - 6 . 1 immunopositive cells . Neither caspase - 3 ( expression and activity ) nor Bcl ( 2 ) positively immunostained cells were affected by INGAP - PP . Accordingly , INGAP - PP would promote stem cell differentiation into a beta - like cell phenotype , simultaneously decreasing its differentiation toward non - beta - cell precursors . Therefore , INGAP - PP would be potentially useful to obtain beta - cells from stem cells for replacement therapy .",
"[ Serotonin transporter gene and stress reactivity in unipolar depression . Role of the Q9Y251 system as endophenotype of the P31645 gene ] . BACKGROUND : A length polymorphism in the promoter region of the serotonin transporter gene ( 5 - HTTLPR ) is associated with both depression and hypothalamic - pituitary - adrenal ( Q9Y251 ) system activity . A dysregulation of the Q9Y251 system is considered to be a candidate endophenotype of depression . The objective of the present study was an investigation of a possible gene - endophenotype - interaction between 5 - HTTLPR and Q9Y251 system activity in a sample of inpatients with major depression . MATERIALS AND METHODS : A total of 237 inpatients with major depression were genotyped for 5 - HTTLPR and participated in a combined dexamethasone - corticotropin - releasing hormone test ( ___MASK35___ - P06850 test ) as well as using the Hamilton score ( Hamilton rating scale for depression ) to determine the severity of the psychopathology . RESULTS : Patients with the ss - genotype showed a significantly higher Q9Y251 - system activity in comparison to patients with the lI - genotype , but no association between 5 - HTTLPR and the severity of psychopathology could be detected . CONCLUSIONS : The results of the current study demonstrate an influence of 5 - HTTLPR on dysregulation of the Q9Y251 system in patients with major depression and support the hypothesis that 5 - HTTLPR - and Q9Y251 - system - interaction constitutes an important component in the pathogenesis of depression .",
"Differential interactions of nateglinide and repaglinide on the human beta - cell sulphonylurea receptor 1 . DB00912 and nateglinide represent a new class of insulin secretagogues , structurally unrelated to sulphonylureas , that were developed for the treatment of type 2 diabetes . The inhibitory effect of these drugs was investigated on recombinant wild - type and mutant Kir6 . 2 / Q09428 channels expressed in HEK293 cells . DB00731 and repaglinide dose - dependently inhibited whole - cell Kir6 . 2 / Q09428 currents with half - maximal inhibitory concentration ( IC ( 50 ) ) values of 800 and 21 nmol / l , respectively . Mutation of serine 1237 in Q09428 to tyrosine ( S1237Y ) abolished tolbutamide and nateglinide block , suggesting that these drugs share a common point of interaction on the Q09428 subunit of the DB00171 - sensitive K (+) channel . In contrast , repaglinide inhibition was unaffected by the S1237Y mutation ( IC ( 50 ) = 23 nmol / l ) . Radioligand binding studies revealed a single high - affinity binding site for [( 3 ) H ] repaglinide on membranes prepared from HEK293 cells expressing wild - type ( equilibrium dissociation constant [ K ( D ) ] = 0 . 40 nmol / l ) or mutant ( K ( D ) = 0 . 31 nmol / l ) Kir6 . 2 / Q09428 channels . DB00731 and tolbutamide displaced [( 3 ) H ] repaglinide binding to wild - type channels with IC ( 50 ) values of 0 . 7 and 26 micro mol / l , respectively , but produced < 10 % displacement of [( 3 ) H ] repaglinide bound to mutant channels . This is consistent with the idea that binding of nateglinide and tolbutamide , but not repaglinide , is abolished by the Q09428 [ S1237Y ] mutation and that the binding site for repaglinide is not identical to that of nateglinde / tolbutamide . These results are discussed in terms of a conformational analysis of the drug molecules .",
"Pharmacogenomic analysis of DB00171 - sensitive potassium channels coexpressing the common type 2 diabetes risk variants E23K and S1369A . OBJECTIVES : The common DB00171 - sensitive potassium ( KATP ) channel variants E23K and S1369A , found in the Q14654 and Q09428 genes , respectively , form a haplotype that is associated with an increased risk for type 2 diabetes . Our previous studies showed that KATP channel inhibition by the A - site sulfonylurea gliclazide was increased in the Q9C075 / A1369 haplotype . Therefore , we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure - activity relationships in KATP channels containing either the E23 / S1369 nonrisk or Q9C075 / A1369 risk haplotypes . RESEARCH DESIGN AND METHODS : The patch - clamp technique was used to determine sulfonylurea and glinide inhibition of recombinant human KATP channels containing either the E23 / S1369 or the Q9C075 / A1369 haplotype . RESULTS : KATP channels containing the Q9C075 / A1369 risk haplotype were significantly less sensitive to inhibition by tolbutamide , chlorpropamide , and glimepiride ( IC50 values for Q9C075 / A1369 vs . E23 / S1369 = 1 . 15 vs . 0 . 71 μmol / l ; 4 . 19 vs . 3 . 04 μmol / l ; 4 . 38 vs . 2 . 41 nmol / l , respectively ) . In contrast , KATP channels containing the Q9C075 / A1369 haplotype were significantly more sensitive to inhibition by mitiglinide ( IC50 = 9 . 73 vs . 28 . 19 nmol / l for Q9C075 / A1369 vs . E23 / S1369 ) and gliclazide . DB00731 , glipizide , and glibenclamide showed similar inhibitory profiles in KATP channels containing either haplotype . CONCLUSION : Our results demonstrate that the ring - fused pyrrole moiety in several A - site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the Q9C075 / A1369 risk haplotype . It may therefore be possible to tailor existing therapy or design novel drugs that display an increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes .",
"Targeting of plasmid DNA - lipoplexes to cells with molecules anchored via a metal chelator lipid . BACKGROUND : The ability to deliver plasmid DNA ( pDNA ) to specific cells in vivo is crucial for achieving efficient targeted transfection with nonviral vectors . We previously used stealth liposomes containing the chelator lipid 3 ( nitrilotriacetic acid ) - ditetradecylamine ( NTA ( 3 )- DTDA ) to target delivery of antigen and cytokines to immune cells in vivo . In the present study , we utilized liposomes containing NTA ( 3 )- DTDA and the ionizable aminolipid 1 , 2 - dioleoyl - 3 - dimethyl - ammonium - propane ( DODAP ) to incorporate pDNA into complexes for targeting to cells . METHODS : Liposomes containing DODAP , NTA ( 3 )- DTDA and helper lipids were acidified ( pH 5 . 5 ) and mixed with pDNA to form complexes . These lipoplexes were neutralized and engrafted with DB00117 - tagged molecules for targeting to extracellular receptors . Targeted transfection efficiency was assessed using the enhanced green fluorescent protein reporter gene . RESULTS : Initial transfections of P29320 - 293 cells using a DB00117 - tagged peptide ( P24752 ) related to the DB00125 - rich motif of HIV - 1 TAT protein resulted in a low transfection efficiency ( < 2 . 5 % ) . Optimization of the lipid formulation and use of an endosome - destabilizing peptide and inhibitor of DNase II , increased transfection approximately 20 - fold . These lipoplexes are approximately 250 nm in diameter , and transfection efficiencies were : approximately 50 % for P29320 - 293 cells targeted with lipoplexes containing pEGFP - N1 and engrafted with P24752 , and 30 - 40 % for HepG2 cells targeted with lipoplexes engrafted with a peptide specific for the P15692 receptor Flt - 1 . CONCLUSIONS : The results show that DODAP - containing lipoplexes incorporating NTA ( 3 )- DTDA enable the engraftment of targeting molecules and the effective targeting of pDNA to cells in serum - containing media , resulting in efficient transgene expression . The strategy may provide a convenient approach for targeting pDNA to cells in vivo in therapeutic applications .",
"The Kazal motifs of O95980 protein inhibit P14780 secretion and activity and reduce metastasis of lung cancer cells in vitro and in vivo . O95980 is a membrane - anchored glycoprotein which may negatively regulate matrix metalloproteinase ( MMP ) activity to suppress tumor invasion and metastasis . In this study , recombinant proteins corresponding to the residues 285 - 368 ( named as P06732 which contained cysteine knot motif ) , 605 - 799 ( named as K123 which contained three Kazal motifs ) , 676 - 799 ( named as Q9C075 which contained the last two Kazal motifs ) and full - length O95980 were produced and their anti - cancer effects were tested . Q8N1N2 - length O95980 and Q9C075 but not K123 and P06732 inhibited P14780 secretion and activity . In addition , O95980 and Q9C075 inhibited invasion but not migration of metastatic lung cancer cells in vitro . Protein binding and kinetic study indicated that Q9C075 physically interacted with P14780 and inhibited its activity by a non - competitive manner . Moreover , Q9C075 reduced metastatic tumor growth in lungs of nude mice . Taken together , our results suggest that the Q9C075 motifs of O95980 protein can inhibit P14780 secretion and activity and attenuate metastasis of lung cancer cells ."
] |
[
"___MASK100___",
"___MASK14___",
"___MASK18___",
"___MASK19___",
"___MASK29___",
"___MASK35___",
"___MASK48___",
"___MASK52___",
"___MASK54___"
] |
___MASK18___
|
MH_train_457
|
interacts_with DB06813?
|
[
"Cardiac channelopathies associated with infantile fatal ventricular arrhythmias : from the cradle to the bench . BACKGROUND : Fatal ventricular arrhythmias in the early period of life have been associated with cardiac channelopathies for decades , and postmortem analyses in P22304 victims have provided evidence of this association . However , the prevalence and functional properties of cardiac ion channel mutations in infantile fatal arrhythmia cases are not clear . METHODS AND RESULTS : Seven infants with potentially lethal arrhythmias at age < 1 year ( 5 males , age of onset 44 . 1 ± 72 . 1 days ) were genetically analyzed for P51787 , Q12809 , P15382 - 5 , P63252 , Q14524 , P36382 , and P62158 by using denaturing high - performance liquid chromatography and direct sequencing . Whole - cell currents of wildtype and mutant channels were recorded and analyzed in Chinese hamster ovary cells transfected with Q14524 and Q12809 cDNA . In 5 of 7 patients , we identified 4 mutations ( p . N1774D , p . T290fsX53 , p . F1486del and p . N406K ) in Q14524 , and 1 mutation ( p . G628D ) in Q12809 . N1774D , F1486del , and N406K in Q14524 displayed tetrodotoxin - sensitive persistent late Na (+) currents . By contrast , Q14524 - T290fsX53 was nonfunctional . Q12809 - G628D exhibited loss of channel function . CONCLUSION : Genetic screening of 7 patients was used to demonstrate the high prevalence of cardiac channelopathies . Functional assays revealed both gain and loss of channel function in Q14524 mutations , as well as loss of function associated with the Q12809 mutation .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK17___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"The transcriptional coactivator DRIP / mediator complex is involved in vitamin D receptor function and regulates keratinocyte proliferation and differentiation . Mediator is a multisubunit coactivator complex that facilitates transcription of nuclear receptors . We investigated the role of the mediator complex as a coactivator for vitamin D receptor ( P11473 ) in keratinocytes . Using P11473 affinity beads , the vitamin D receptor interacting protein ( DRIP ) / mediator complex was purified from primary keratinocytes , and its subunit composition was determined by mass spectrometry . The complex included core subunits , such as Q15648 / MED1 ( MED1 ) , that directly binds to P11473 . Additional subunits were identified that are components of the RNA polymerase II complex . The functions of different mediator components were investigated by silencing its subunits . The core subunit MED1 facilitates P11473 activity and regulating keratinocyte proliferation and differentiation . A newly described subunit Q13503 also has a role in promoting keratinocyte proliferation and differentiation , whereas Q9BTT4 has an inhibitory role . Blocking MED1 / Q13503 expression caused hyperproliferation of keratinocytes , accompanied by increases in mRNA expression of the cell cycle regulator cyclin D1 and / or glioma - associated oncogene homolog . Blocking MED1 or Q13503 expression also resulted in defects in calcium - induced keratinocyte differentiation , as indicated by decreased expression of differentiation markers and decreased translocation of P12830 to the membrane . These results show that keratinocytes use the transcriptional coactivator mediator to regulate P11473 functions and control keratinocyte proliferation and differentiation .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK35___ and Tissue P00747 Activator in Occluded Arteries .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK39___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK35___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .",
"Convergent and divergent cellular responses by ErbB4 isoforms in mammary epithelial cells . Associations of ErbB4 ( Q15303 / Q15303 ) , the fourth member of the P00533 family , with cancer are variable , possibly as a result of structural diversity of this receptor . There are multiple structural isoforms of Q15303 arising by alternative mRNA splicing , and a subset undergo proteolysis that releases membrane - anchored and soluble isoforms that associate with transcription factors and coregulators to modulate transcription . To compare the differential and common signaling activities of full - length ( FL ) and soluble intracellular isoforms of Q15303 , four JM - a isoforms ( FL and soluble intracellular domain ( ICD ) CYT - 1 and CYT - 2 ) were expressed in isogenic MCF10A cells and their biologic activities were analyzed . Both FL and ICD CYT - 2 promoted cell proliferation and invasion , and CYT - 1 suppressed cell growth . Transcriptional profiling revealed several new and underexplored Q15303 - regulated transcripts , including : proteases / protease inhibitors ( P08254 and P07093 ) , the YAP / Hippo pathway ( P29279 , O00622 , and P09486 ) , the mevalonate / cholesterol pathway ( P04035 , Q01581 , P01130 , and Q9UBM7 ) , and cytokines ( P10145 , P78556 , and P09341 ) . Many of these transcripts were subsequently validated in a luminal breast cancer cell line that normally expresses Q15303 . Furthermore , ChIP - seq experiments identified O75689 , P02649 , P09486 , P16949 , and Q05195 as novel molecular targets of Q15303 . These findings clarify the diverse biologic activities of Q15303 isoforms , and reveal new and divergent functions . IMPLICATIONS : ErbB4 as a regulator of Hippo and mevalonate pathways provides new insight into milk production and anabolic processes in normal mammary epithelia and cancer .",
"Vibrational structure of dihydrofolate bound to R67 dihydrofolate reductase . R67 is a Type II dihydrofolate reductase ( P00374 ) that catalyzes the reduction of dihydrofolate ( DHF ) to DB00116 by facilitating the addition of a proton to N5 of DHF and the transfer of a hydride ion from NADPH to P13671 . Because this enzyme is a plasmid - encoded P00374 from trimethoprim - resistant bacteria , extensive studies on R67 with various methods have been performed to elucidate its reaction mechanism . Here , Raman difference measurements , conducted on the ternary complex of R67 . NADP (+). DHF believed to be an accurate mimic of the productive P00374 . NADPH . DHF complex , show that the pK ( a ) of N5 in the complex is less than 4 . This is in clear contrast to the behavior observed in Escherichia coli P00374 , a substantially more efficient enzyme , where the pK ( a ) of bound DHF at N5 is increased to 6 . 5 compared with its solution value of 2 . 6 . A comparison of the ternary complexes in R67 and E . coli DHFRs suggests that enzymic raising of the pK ( a ) at N5 can significantly increase the catalytic efficiency of the hydride transfer step . However , R67 shows that even without such a strategy an effective P00374 can still be designed .",
"DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . DB00563 ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"___MASK12___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK12___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK61___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK13___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK13___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK13___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK41___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .",
"Distinct mechanistic activity profile of pralatrexate in comparison to other antifolates in in vitro and in vivo models of human cancers . PURPOSE : This study evaluated mechanistic differences of pralatrexate , methotrexate , and pemetrexed . METHODS : Inhibition of dihydrofolate reductase ( P00374 ) was quantified using recombinant human P00374 . Cellular uptake and folylpolyglutamate synthetase ( Q05932 ) activity were determined using radiolabeled pralatrexate , methotrexate , and pemetrexed in NCI - H460 non - small cell lung cancer ( NSCLC ) cells . The tumor growth inhibition ( TGI ) was assessed using MV522 and NCI - H460 human NSCLC xenografts . RESULTS : Apparent K ( i ) values for P00374 inhibition were 45 , 26 , and > 200 nM for pralatrexate , methotrexate , and pemetrexed , respectively . A significantly greater percentage of radiolabeled pralatrexate entered the cells and was polyglutamylatated relative to methotrexate or pemetrexed . In vivo , pralatrexate showed superior anti - tumor activity in both NSCLC models , with more effective dose - dependent TGI in the more rapidly growing NCI - H460 xenografts . CONCLUSIONS : DB06813 demonstrated a distinct mechanistic and anti - tumor activity profile relative to methotrexate and pemetrexed . DB06813 exhibited enhanced cellular uptake and increased polyglutamylation , which correlated with increased TGI in NSCLC xenograft models .",
"Suppression of tumor growth and metastasis by a P17948 antagonizing peptide identified from a phage display library . Although the P15692 - Flk - 1 - pathway has been known as the major driving force of angiogenesis , new evidence has shown that P17948 / Flt - 1 plays important roles during the neovascularization under pathological conditions including tumor , atherosclerosis and arthritis . In search of Flt - 1 receptor antagonizing peptides , we screened a phage display 12 - mer - peptide library with recombinant Flt - 1 protein . Seven candidate peptides were identified that specifically bound to P15692 receptor Flt - 1 , of which peptide F56 ( WHSDMEWWYLLG ) almost abolished P15692 binding to receptor Flt - 1 in vitro . In vivo , F56 fused with P00374 ( P00374 - F56 ) inhibited angiogenesis in a P62158 assay . Moreover , P00374 - F56 significantly inhibited the growth of nodules of human gastric cancer cell line MGC - 803 in BALB / c nude mice . Histological analyses showed that necrosis of the implanted tumor was markedly enhanced following treatment with P00374 - F56 . In the severe combined immunodeficiency disease ( SCID ) mouse model for studying metastasis of the human breast cancer cell line BICR - H1 , synthetic peptide F56 significantly inhibited tumor growth and lung metastases . Taken together , our results have demonstrated that peptide F56 , as a Flt - 1 receptor antagonist , fulfilled the antiangiogenic and antimetastatic effects by specifically interfering with the interaction between P15692 and receptor Flt - 1 . Thus , short peptide F56 may have clinical potential in tumor therapy .",
"P00533 gene expression in avian epiphyseal growth - plate cartilage cells : effect of serum , parathyroid hormone and atrial natriuretic peptide . Avian chondrocytes and fibroblasts , derived from epiphyseal growth - plate and skin , respectively , were cultured in vitro . In chondrocytes , epidermal growth factor ( P01133 ) caused a dose - dependent stimulation of proliferation . P01133 receptor mRNA was not detected with the v - erb B probe in chondrocytes cultured in the presence of 5 % fetal calf serum ( FCS ) . In the absence of FCS in the medium , a time - dependent increase in the level of P01133 receptor mRNA was observed . Parallel changes were also observed in the level of P01133 receptor , as demonstrated by immunofluorescence using antibodies directed against avian P01133 receptor . In avian fibroblasts , P01133 receptor mRNA and P01133 receptor levels were not affected by FCS . Furthermore , FCS did not affect the level of thyroid hormone receptor mRNA ( using v - erb A as a probe ) in either chondrocytes or fibroblasts . Parathyroid hormone ( PTH ) , which acts as a mitogen in avian chondrocytes attenuated -- whereas atrial natriuretic peptide ( P01160 ) , a suppressor of chondrocyte proliferation , enhanced -- P01133 receptor mRNA . The present results show that avian growth - plate chondrocytes respond to P01133 and bear P01133 receptors . The levels of P01133 mRNA and P01133 receptor are inversely related to cell proliferation . The results also support previous suggestions that PTH and P01160 play important roles in chondrocyte proliferation , possibly through their effect on the synthesis of the P01133 receptor .",
"Microarray analysis revealed different gene expression patterns in HepG2 cells treated with low and high concentrations of the extracts of Anacardium occidentale shoots . In this study , the effects of low and high concentrations of the Anacardium occidentale shoot extracts on gene expression in liver HepG2 cells were investigated . From MTT assays , the concentration of the shoot extracts that maintained 50 % cell viability ( IC ( 50 ) ) was 1 . 7 mg / ml . Cell viability was kept above 90 % at both 0 . 4 mg / ml and 0 . 6 mg / ml of the extracts . The three concentrations were subsequently used for the gene expression analysis using Affymetrix Human Genome 1 . 0 S . T arrays . The microarray data were validated using real - time qRT - PCR . A total of 246 , 696 and 4503 genes were significantly regulated ( P < 0 . 01 ) by at least 1 . 5 - fold in response to 0 . 4 , 0 . 6 and 1 . 7 mg / ml of the extracts , respectively . Mutually regulated genes in response to the three concentrations included CDKN3 , LOC100289612 , P00374 , Q99986 , Q99741 , Q96GD4 and P78334 . Genes like Q07973 , P38398 , O14965 , P06493 , P24941 , P11802 and P06213 were significantly regulated at 0 . 6 mg / ml and 1 . 7 mg but not at 0 . 4 mg / ml . However , the expression of genes including O75473 , P17936 , P06400 , P14735 , P01130 , P55157 , P04114 , MTIX , P04179 and P08294 were exclusively regulated at the IC ( 50 ) concentration . In conclusion , low concentrations of the extracts were able to significantly regulate a sizable number of genes . The type of genes that were expressed was highly dependent on the concentration of the extracts used .",
"TGF - β1 → SMAD / p53 / Q15853 → P05121 transcriptional axis in ureteral obstruction - induced renal fibrosis . Chronic kidney disease constitutes an increasing medical burden affecting 26 million people in the United States alone . Diabetes , hypertension , ischemia , acute injury , and urological obstruction contribute to renal fibrosis , a common pathological hallmark of chronic kidney disease . Regardless of etiology , elevated TGF - β1 levels are causatively linked to the activation of profibrotic signaling pathways initiated by angiotensin , glucose , and oxidative stress . Unilateral ureteral obstruction ( UUO ) is a useful and accessible model to identify mechanisms underlying the progression of renal fibrosis . P00747 activator inhibitor - 1 ( P05121 ) , a major effector and downstream target of TGF - β1 in the progression of several clinically important fibrotic disorders , is highly up - regulated in UUO and causatively linked to disease severity . SMAD and non - SMAD pathways ( pp60 ( c - src ) , epidermal growth factor receptor [ P00533 ] , mitogen - activated protein kinase , p53 ) are required for P05121 induction by TGF - β1 . Q15796 / 3 , pp60 ( c - src ) , P00533 , and p53 activation are each increased in the obstructed kidney . This review summarizes the molecular basis and translational significance of TGF - β1 - stimulated P05121 expression in the progression of kidney disease induced by ureteral obstruction . Mechanisms discussed here appear to be operative in other renal fibrotic disorders and are relevant to the global issue of tissue fibrosis , regardless of organ site .",
"Evaluation of the pharmacokinetics , preclinical and clinical efficacy of pralatrexate for the treatment of T - cell lymphoma . INTRODUCTION : Peripheral T - cell lymphomas ( PTCLs ) are a heterogeneous group of T - cell neoplasms . Most patients with PTCL have a poor outcome with conventional therapies and are not cured without stem - cell transplantation . DB06813 , a novel antifolate chemotherapeutic agent , was rationally designed to impede folate metabolism by inhibiting dihydrofolate reductase ( P00374 ) and to be more efficiently internalized into tumor cells . DB06813 is the first drug that is FDA approved for patients with relapsed and refractory PTCL . AREAS COVERED : DB06813 has been used as a single agent and in combination with other agents in clinical trials for non - Hodgkin ' s lymphoma and Hodgkin ' s disease as well as in solid tumors . This review will cover the development of pralatrexate , the pharmacokinetics of pralatrexate , preclinical findings with pralatrexate and clinical studies of pralatrexate in hematologic malignancies . EXPERT OPINION : DB06813 has significant activity in vitro , and in early Phase I / II trials , responses were noted in patients with aggressive T - cell lymphomas . The DB06813 in Patients with Relapsed or Refractory Peripheral T - Cell Lymphoma trial demonstrated the activity of pralatrexate across a spectrum of heavily pretreated patients with different aggressive T - cell lymphoma subtypes , and studies in cutaneous T - cell lymphoma have shown efficacy at different doses and schedules . The most frequent adverse events in these trials were mucositis , reversible thrombocytopenia and fatigue .",
"___MASK79___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK79___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK79___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .",
"Cloning and expression of the chromosomal immune interferon gene of the rat . The chromosomal immune interferon gene of the rat ( P01579 ) was identified by screening a recombinant rat lambda phage library with a human P01579 cDNA probe . In contrast to the genes of other rat IFNs , this rat P01579 chromosomal gene contains introns and its structural organization closely resembles that of the human and murine P01579 genes . The rat P01579 gene encodes a signal sequence of 19 amino acids followed by the mature P01579 protein of 137 amino acids . The gene was expressed under control of the simian virus 40 ( SV40 ) early promoter in Chinese hamster ovary ( CHO ) cells deficient in dihydrofolate reductase ( P00374 ) after co - transformation with a plasmid containing the mouse P00374 gene . Initial transformants with a P00374 + phenotype produced P01579 titres ranging from 20 to 1600 units / ml . After stepwise increases in the concentration of methotrexate ( MTX ) in the growth medium of transformed CHO cells , MTX - resistant clones producing 80 000 - 100 000 units per ml were isolated . Protein analysis of supernatants of these MTX - resistant cells by polyacrylamide gel electrophoresis revealed a product with an apparent mol . wt . of 18 000 daltons which was not detectable in the growth medium of P00374 + transformants that did not produce IFN . The product was identified as rat P01579 and constituted approximately 5 % of the proteins excreted from these cells .",
"Single agent and combination studies of pralatrexate and molecular correlates of sensitivity . BACKGROUND : DB06813 is a dihydrofolate reductase ( P00374 ) inhibitor with high affinity for reduced folate carrier 1 ( P41440 - 1 ) and folylpolyglutamate synthetase ( Q05932 ) , resulting in extensive internalization and accumulation in tumour cells . DB06813 is approved in the US for the treatment of relapsed or refractory peripheral T - cell lymphoma and is being investigated in various malignancies . Here , we evaluated molecular correlates of sensitivity to pralatrexate and explored combinations with a variety of anticancer agents . METHODS : Antiproliferative effects of pralatrexate were evaluated in 15 human - cancer cell lines using the MTT assay . Gene expression was evaluated using qRT - PCR . RESULTS : DB06813 and methotrexate had a similar pattern of cytotoxicity , pralatrexate being more potent . DB06813 potentiated the effects of platinum drugs , antimetabolites and P00533 inhibitors . Dose - and time - dependent cytotoxicity of pralatrexate correlated with high mRNA expression of Q05932 . Acquired resistance to pralatrexate was associated with decreased P41440 - 1 expression , whereas methotrexate resistance correlated with increased P00374 expression , suggesting different mechanisms of acquired resistance . CONCLUSION : DB06813 was more potent than methotrexate in a panel of solid tumour lines . Our findings support the further clinical development of pralatrexate in combination with certain cytotoxics and targeted therapies , and suggest that P41440 - 1 , Q05932 and P00374 may be potential biomarkers of outcome .",
"DB06813 : a novel synthetic antifolate for relapsed or refractory peripheral T - cell lymphoma and other potential uses . PURPOSE : The pharmacology , pharmacokinetics , clinical trials , adverse effects , dosage , and economic considerations of pralatrexate ( DB06813 ) are reviewed . SUMMARY : Peripheral T - cell lymphoma ( PTCL ) comprises approximately 15 - 20 % of all aggressive lymphomas and 5 - 10 % of all non - Hodgkin ' s lymphomas . Advanced PTCL is often refractory to traditional first - line chemotherapy regimens . DB06813 was developed as a synthetic folate analog antimetabolite that competitively inhibits dihydrofolate reductase ( P00374 ) . This results in the depletion of thymidine , leading to interference with deoxyribonucleic acid synthesis and cancer cell death . DB06813 has a higher potency than methotrexate and edatrexate ( EDX ) . The efficacy and safety of DB06813 have been demonstrated in the PROPEL trial , a prospective phase II trial in patients with relapsed or refractory PTCL . Patients with prior stem cell transplantation receiving DB06813 also had similar response rates ( RRs ) . DB06813 was investigated on the treatment of relapsed or refractory cutaneous T - cell lymphoma , previously treated advanced non - small cell lung cancer and other solid malignancies . DB06813 has similar side effects to other P00374 inhibitors . The most common side effect of DB06813 is mucositis . The recommended dose of DB06813 is 30 mg / m ( 2 ) weekly once for 6 weeks in 7 - week cycle until disease progresses or unacceptable toxicity for PTCL and may require dose reduction or discontinuation . Patients should be supplemented with oral folic acid and intramuscular vitamin B ( 12 ) injections . CONCLUSION : DB06813 provides clinical benefit to patients with relapsed or refractory PTCL with durable complete and partial responses in patients who had not responded to multiple prior treatment regimens .",
"DB00563 induces apoptosis through p53 / P38936 - dependent pathway and increases P12830 expression through downregulation of HDAC / Q15910 . DB00563 ( MTX ) is a dihydrofolate reductase ( P00374 ) inhibitor widely used as an anticancer drug in different kinds of human cancers . Here we investigated the anti - tumor mechanism of MTX against non - small cell lung cancer ( NSCLC ) A549 cells . MTX not only inhibited in vitro cell growth via induction of apoptosis , but also inhibited tumor formation in animal xenograft model . RNase protection assay ( RPA ) and RT - PCR demonstrated its induction of p53 target genes including DR5 , P38936 , Puma and Noxa . Moreover , MTX promoted p53 phosphorylation at Ser15 and acetylaion at Lys373 / 382 , which increase its stability and expression . The apoptosis and inhibition of cell viability induced by MTX were dependent on p53 and , partially , on P38936 . In addition , MTX also increased P12830 expression through inhibition of histone deacetylase ( HDAC ) activity and downregulation of polycomb group protein enhancer of zeste homologue 2 ( Q15910 ) . Therefore , the anticancer mechanism of MTX acts through initiation of p53 - dependent apoptosis and restoration of P12830 expression by downregulation of HDAC / Q15910 .",
"P40763 signaling is induced by intercellular adhesion in squamous cell carcinoma cells . The signal transducer and activator of transcription - 3 ( P40763 ) frequently activated during tumor progression has been linked to enhanced cell growth . In squamous cell carcinoma of the head and neck ( HNSCC ) , P40763 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways . In the present study , we have examined the potential mechanism by which cell - cell contact initiates P40763 activation . Using a panel of HNSCC cell lines , Ca (+ 2 )- dependent cell - cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of P40763 - Y705 and P42224 - Y701 . This intercellular adhesion - induced P40763 activation was mediated by JAK and Src signaling and partially by P00533 signaling . In addition , immunolocalization studies revealed initial formation of phosphorylated P40763 - Y705 at nascent P12830 cell junctions with eventual translocation to the nucleus in cell aggregates . Adhesion - mediated P35610 activation in monolayer and cell aggregate cultures required functional P12830 . These results indicate that , in HNSCC cells , cadherin - mediated intercellular adhesion induces P35610 signaling that may modulate cell survival and resistance to apoptosis during tumor progression .",
"Application of HapMap data to the evaluation of 8 candidate genes for pediatric slow transit constipation . BACKGROUND : Slow transit constipation ( P52823 ) affects up to 3 % of all children and is an increasingly recognized cause of chronic constipation in children . We conducted a pilot study to investigate whether genes encoding neurotransmitters ( P20366 , Q9UHF0 , P01282 , NOS1 ) and receptors ( P25103 , P21452 , P29371 , P10721 ) could be responsible for P52823 . METHODS : One hundred seventeen tag single nucleotide polymorphisms ( SNPs ) , distributed among the candidate genes , were selected from HapMap data and genotyped using Sequenom ( San Diego , CA ) technology in 35 affected families . Evaluation of association was performed by transmission disequilibrium test and multilocus analysis . RESULTS : Five SNPs ( rs3771863 , rs4580655 , rs11722288 , rs4563545 , and rs3782221 ) in the P25103 , P29371 , P10721 , and NOS1 genes were found to be potentially associated with P52823 , although the significance of these results does not withstand correction for multiple testing . CONCLUSIONS : Our data indicate that 5 SNPs in the NOS1 , P25103 , P29371 , and P10721 genes could be involved in P52823 , especially rs3771863 in intron 1 of P25103 , which showed the highest association .",
"A phase II study of pralatrexate with vitamin B12 and folic acid supplementation for previously treated recurrent and / or metastatic head and neck squamous cell cancer . BACKGROUND : DB06813 ( Fotolyn ( TM ) ; Allos Therapeutics Inc . ) is an antifolate dihydrofolate reductase ( P00374 ) inhibitor . We conducted a phase II study of pralatrexate with folic acid and B12 supplementation in patients with recurrent and / or metastatic head and neck squamous cell cancer ( R / M HNSCC ) . PATIENTS AND METHODS : This was a single - arm , Simon optimal two stage phase II study . Patients with R / M HNSCC previously treated with chemotherapy were eligible . The study was initiated with a dosing schedule of pralatrexate 190 mg / m ( 2 ) biweekly on a 4 - week cycle with vitamin supplementation . Due to toxicity concerns , the dosing was modified to 30 mg / m ( 2 ) weekly for 3 weeks in a 4 - week cycle with vitamin supplementation . Radiologic imaging was to be obtained about every 2 cycles . RESULTS : Thirteen subjects were enrolled ; 12 were treated . Seven of the twelve patients had previously received ≥ 2 lines of chemotherapy . The most common grade 3 toxicity was mucositis ( 3 patients ) . Seven patients did not complete two cycles of therapy due to progression of disease ( 4 ) , toxicity ( 1 ) , death ( 1 ) , and withdrawal of consent ( 1 ) . Two deaths occurred : one due to disease progression and the other was an unwitnessed event that was possibly related to pralatrexate . No clinical activity was observed . The median overall survival was 3 . 1 months . The study was closed early due to lack of efficacy . CONCLUSIONS : DB06813 does not possess clinical activity against previously treated R / M HNSCC . Evaluation of pralatrexate in other clinical settings of HNSCC management with special considerations for drug toxicity may be warranted .",
"[ Presynaptic P08908 receptors in immunomodulation ] . It is shown that a selective agonist of P08908 receptors 8 - OH - DPAT in a low dose ( 0 . 1 mg / kg ) , which is known to affect mainly the presynaptic P08908 receptors increased the immune response at the peak of reactions ( the forth or fifth day after immunization with sheep red blood cells - SRBC ) in CBA mice and Wistar rats . Treatment of the animals with the drug 15 min prior to antigen injection raised the number of plaque - forming cells ( lgM - P27918 ) and rosette - forming cells ( P41440 ) in the spleen . The preliminary blockade of P08908 receptor with a selective antagonist of P08908 receptors WAY - 100635 ( 0 . 1 mg / kg ) prevented the immunostimulating effect of 5 - HT 1A receptors agonist 8 - OH - DPAT , whereas WAY - 100635 administration alone in the same dose did n ' t change the immune response . Activation of P08908 receptors under conditions of electrical lesion of 5 - HTergic neurons of the nucleus raphe was unable to enhance the immune reactions , as it did in sham - operated rats . The data obtained indicate that the somatodendric P08908 autoreceptors are involved in immunomodulation .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK21___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"Specific properties of a C - terminal truncated androgen receptor detected in hormone refractory prostate cancer . Mutations in the human androgen receptor ( AR ) gene that lead to C - terminus truncated AR variants are frequently detected in prostate cancer ( PC ) . These AR variants lack both the ligand - binding domain ( LBD ) and the AF - 2 region . The aim of this study was to delineate the alternative mechanisms that lead to the activation of such AR variants as they are unresponsive to hormone stimulation , and to outline consequences of the loss of the LBD / AF - 2 region on their functional properties . By using an MMTV - luciferase reporter construct and LY294002 , UO126 , or ZD1839 , inhibitor of PI3K , Q02750 / 2 , and P00533 signaling pathway respectively , we demonstrated that phosphorylation was required for full transcriptional activities of one these AR variants , the Q640X mutant AR . Western - blot analyses confirmed that these inhibitors affect the phosphorylation status of this AR variant . Furthermore , studies of the intranuclear colocalization of the Q640X AR with cofactors , such as CBP , Q9Y3R0 , and c - Jun , reveal that the transcriptional complex that forms around the mutant AR is different to that formed around the wild type AR . We demonstrated that CBP and c - Jun are highly recruited by the mutant AR , and this leads to an unexpected activation of AP - 1 , NFAT , and NFkappaB transcriptional activities . Similar enhanced activities of these transcription factors were not observed with the wild type AR . The importance of the LBD / AF - 2 for the regulation of AR transcriptional activities , the impact of the presence of such AR variants on PC cells proliferation and survival , and on progression to androgen independence are discussed .",
"Substance P autocrine signaling contributes to persistent P04626 activation that drives malignant progression and drug resistance in breast cancer . P00533 receptor transmodulation by heterologous G - protein - coupled receptors ( GPCR ) generates functional diversity in signal transduction . Tachykinins are neuropeptides and proinflammatory cytokines that promote cell survival and cancer progression by activating several GPCRs . In this work , we found that the pain - associated tachykinin Substance P ( SP ) contributes to persistent transmodulation of the P00533 receptors , P00533 and P04626 , in breast cancer , acting to enhance malignancy and therapeutic resistance . SP and its high - affinity receptor P25103 were highly expressed in P04626 (+) primary breast tumors ( relative to the luminal and triple - negative subtypes ) and were overall correlated with poor prognosis factors . In breast cancer cell lines and primary cultures derived from breast cancer samples , we found that SP could activate P04626 . Conversely , RNA interference - mediated attenuation of P25103 , or its chemical inhibition , or suppression of overall GPCR - mediated signaling , all strongly decreased steady - state expression of P00533 and P04626 , establishing that their basal activity relied upon transdirectional activation by GPCR . Thus , SP exposure affected cellular responses to anti - P00533 therapies . Our work reveals an important oncogenic cooperation between P25103 and P04626 , thereby adding a novel link between inflammation and cancer progression that may be targetable by SP antagonists that have been clinically explored ."
] |
[
"___MASK12___",
"___MASK13___",
"___MASK17___",
"___MASK21___",
"___MASK35___",
"___MASK39___",
"___MASK41___",
"___MASK61___",
"___MASK79___"
] |
___MASK41___
|
MH_train_458
|
interacts_with DB00996?
|
[
"Activation of 5 - Q13049 / C receptors counteracts P08908 regulation of n - methyl - D - aspartate receptor channels in pyramidal neurons of prefrontal cortex . Abnormal serotonin - glutamate interaction in prefrontal cortex ( P27918 ) is implicated in the pathophysiology of many mental disorders , including schizophrenia and depression . However , the mechanisms by which this interaction occurs remain unclear . Our previous study has shown that activation of 5 - HT ( 1A ) receptors inhibits N - methyl - D - aspartate ( DB01221 ) receptor ( NMDAR ) currents in P27918 pyramidal neurons by disrupting microtubule - based transport of NMDARs . Here we found that activation of 5 - HT ( 2A / C ) receptors significantly attenuated the effect of 5 - HT ( 1A ) on NMDAR currents and microtubule depolymerization . The counteractive effect of 5 - HT ( 2A / C ) on 5 - HT ( 1A ) regulation of synaptic NMDAR response was also observed in P27918 pyramidal neurons from intact animals treated with various 5 - HT - related drugs . Moreover , 5 - HT ( 2A / C ) stimulation triggered the activation of extracellular signal - regulated kinase ( P29323 ) in dendritic processes . Inhibition of the beta - arrestin / Src / dynamin signaling blocked 5 - HT ( 2A / C ) activation of P29323 and the counteractive effect of 5 - HT ( 2A / C ) on 5 - HT ( 1A ) regulation of NMDAR currents . Immunocytochemical studies showed that 5 - HT ( 2A / C ) treatment blocked the inhibitory effect of 5 - HT ( 1A ) on surface Q13224 clusters on dendrites , which was prevented by cellular knockdown of beta - arrestins . Taken together , our study suggests that serotonin , via 5 - HT ( 1A ) and 5 - HT ( 2A / C ) receptor activation , regulates NMDAR functions in P27918 neurons in a counteractive manner . 5 - HT ( 2A / C ) , by activating P29323 via the beta - arrestin - dependent pathway , opposes the 5 - HT ( 1A ) disruption of microtubule stability and NMDAR transport . These findings provide a framework for understanding the complex interactions between serotonin and NMDARs in P27918 , which could be important for cognitive and emotional control in which both systems are highly involved .",
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK14___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK14___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .",
"SynGAP regulates protein synthesis and homeostatic synaptic plasticity in developing cortical networks . Disrupting the balance between excitatory and inhibitory neurotransmission in the developing brain has been causally linked with intellectual disability ( ID ) and autism spectrum disorders ( P51689 ) . Excitatory synapse strength is regulated in the central nervous system by controlling the number of postsynaptic α - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazolepropionic acid receptors ( AMPARs ) . De novo genetic mutations of the synaptic P20936 ( SynGAP ) are associated with ID and P51689 . SynGAP is enriched at excitatory synapses and genetic suppression of SynGAP increases excitatory synaptic strength . However , exactly how SynGAP acts to maintain synaptic AMPAR content is unclear . We show here that SynGAP limits excitatory synaptic strength , in part , by suppressing protein synthesis in cortical neurons . The data presented here from in vitro , rat and mouse cortical networks , demonstrate that regulation of translation by SynGAP involves P29323 , P42345 , and the small Q15382 . Furthermore , these data show that Q13224 - containing NMDARs and the cognitive kinase CaMKII act upstream of SynGAP and that this signaling cascade is required for proper translation - dependent homeostatic synaptic plasticity of excitatory synapses in developing cortical networks .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK61___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK61___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"The V2 vasopressin receptor stimulates P27361 / 2 activity independently of heterotrimeric G protein signalling . The V2 vasopressin receptor ( P30518 ) activates the mitogen activated protein kinases ( MAPK ) P27361 / 2 through a mechanism involving the scaffolding protein beta arrestin . Here we report that this activating pathway is independent of G alpha s , G alpha i , G alpha q or G betagamma and that the P30518 - mediated activation of G alpha s inhibits P27361 / 2 activity in a DB02527 / PKA - dependent manner . In the HEK293 cells studied , the beta arrestin - promoted activation was found to dominate over the PKA - mediated inhibition of the pathway , leading to a strong vasopressin - stimulated P27361 / 2 activation . Despite the strong MAPK activation and in contrast with other GPCR , P30518 did not induce any significant increase in DNA synthesis , consistent with the notion that the stable interaction between P30518 and beta arrestin prevents signal propagation to the nucleus . Beta arrestin was found to be essential for the P27361 / 2 activation , indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues . Based on the use of selective pharmacological inhibitors , dominant negative mutants and siRNA , we conclude that the beta arrestin - dependent activation of P27361 / 2 by the P30518 involves c - Src and a metalloproteinase - dependent trans - activation event . These findings demonstrate that beta arrestin is a genuine signalling initiator that can , on its own , engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand .",
"The use of the VerifyNow Q9H244 point - of - care device to monitor platelet function across a range of Q9H244 inhibition levels following prasugrel and clopidogrel administration . Variability in response to antiplatelet agents has prompted the development of point - of - care ( POC ) technology . In this study , we compared the VerifyNow Q9H244 ( VN - Q9H244 ) POC device with light transmission aggregometry ( P01374 ) in subjects switched directly from clopidogrel to prasugrel . Healthy subjects on aspirin were administered a clopidogrel 600 mg loading dose ( LD ) followed by a 75 mg / d maintenance dose ( MD ) for 10 days . Subjects were then switched to a prasugrel 60 mg LD and then 10 mg / d MD for 10 days ( n = 16 ) , or to a prasugrel 10 mg / d MD for 11 days ( n = 19 ) . Platelet function was measured by P01374 and VN - Q9H244 at baseline and after dosing . ___MASK9___ 600 mg LD / 75 mg MD treatment led to a reduction in P2Y ( 12 ) reaction units ( PRU ) from baseline . A switch from clopidogrel MD to prasugrel 60 mg LD / 10 mg MD produced an immediate decrease in PRU , while a switch to prasugrel 10 mg MD resulted in a more gradual decline . Consistent with the reduction in PRU , device - reported percent inhibition increased during both clopidogrel and prasugrel regimens . Inhibition of platelet aggregation as measured by P01374 showed a very similar pattern to that found with VN - Q9H244 measurement , irrespective of treatment regimens . The dynamic range of VN - Q9H244 appeared to be narrower than that of P01374 . With two different thienopyridines , the VN - Q9H244 device , within a somewhat more limited range , reflected the overall magnitude of change in aggregation response determined by P01374 . The determination of the clinical utility of such POC devices will require their use in clinical outcome studies .",
"Extracellular glutamate level and DB01221 receptor subunit expression in mouse olfactory bulb following nanoparticle - rich diesel exhaust exposure . In this present study , we aimed to investigate the extracellular glutamate level and memory function - related gene expression in the mouse olfactory bulb after exposure of the animals to nanoparticle - rich diesel exhaust ( NRDE ) with or without bacterial cell wall component . Lipoteichoic acid ( P01374 ) , a cell wall component derived from Staphylococcus aureus , was used to induce systemic inflammation . Male BALB / c mice were exposed to clean air ( particle concentration , 4 . 58 microg / m ( 3 ) ) or NRDE ( 148 . 86 microg / m ( 3 ) ) 5 h per day on 5 consecutive days of the week for 4 wk with or without weekly intraperitoneal injection of P01374 . We examined the extracellular glutamate levels in the olfactory bulb using in vivo microdialysis and high - performance liquid chromatography assay . Then , we collected the olfactory bulb to examine the expression of N - methyl - D - aspartate ( DB01221 ) receptor subunits ( Q9UHB4 , Q12879 , and Q13224 ) and calcium / calmodulin - dependent protein kinase ( CaMK ) IV and cyclic AMP response element binding protein ( CREB ) - 1 using real - time reverse - transcription polymerase chain reaction ( RT - PCR ) . NRDE and / or P01374 caused significantly increased extracellular glutamate levels in the olfactory bulb of mice . Moreover , the exposure of mice to NRDE upregulates Q9UHB4 , Q12879 , Q13224 , and CaMKIV mRNAs in the olfactory bulb , while P01374 upregulates only Q13224 and P16220 mRNAs . These findings suggest that NRDE and P01374 cause glutamate - induced neurotoxicity separately and accompanied by changes in the expression of DB01221 receptor subunits and related kinase and transcription factor in the mouse olfactory bulb . This is the first study to show the correlation between glutamate toxicity and memory function - related gene expressions in the mouse olfactory bulb following exposure to NRDE .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK7___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK7___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK7___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK7___ among adults with ADHD .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"___MASK86___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK86___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK86___ is a promising pharmacological tool in the treatment of renal edema .",
"Molecular evolution of the oxytocin - oxytocin receptor system in eutherians . DB00107 ( P01178 ) is a nine - amino - acid peptide hormone that is mainly released at the times of uterine contractions during parturition and milk ejection during lactation , whereas a similar peptide hormone , arginine vasopressin , primarily exerts direct antidiuretic action on the kidney and causes vasoconstriction of the peripheral vessels . The genes coding for these peptides are tandemly located on the same chromosome . A tandem duplication occurring in the common ancestor of jawed vertebrates has been proposed as responsible . In contrast to the two peptide hormones , only one oxytocin receptor ( P30559 ) but three arginine vasopressin receptors ( P37288 , P47901 , and P30518 ) are known ; these receptors probably arose from two rounds of genome duplication in the common ancestor of vertebrates . In this study , we addressed the molecular evolution of the P01178 - P30559 system in eutherians . Our analyses suggest that an amino acid change from isoleucine to lysine on the eighth site ( I8L ) of the peptide , which corresponded to a change from mesotocin to P01178 , had occurred during the common ancestral lineage of eutherians . At around the same time that the emergence of P01178 occurred , functional constraints on the P01178 receptor ( pre - P30559 ) might have relaxed , and a series of nonsynonymous substitutions might have accumulated . Only a few of these nonsynonymous substitutions might have contributed to reestablishing the molecular relationship between the P01178 ligand and its receptor , after which functional constraints on the P30559 were reinstated . Since the P01178 - P30559 system plays an important role in eutherians , the evolution of the P01178 - P30559 system was probably an essential component of the genesis of the eutherian signature .",
"Emergence of motor circuit activity . In the developing nervous system , ordered neuronal activity patterns can occur even in the absence of sensory input and to investigate how these arise , we have used the model system of the embryonic chicken spinal motor circuit , focusing on motor neurons of the lateral motor column ( O15467 ) . At the earliest stages of their molecular differentiation , we can detect differences between medial and lateral O15467 neurons in terms of expression of neurotransmitter receptor subunits , including P30532 , P36544 , Q12879 , P39086 , P08908 and P28222 , as well as the Q9H2X9 transporter . Using patch - clamp recordings we also demonstrate that medial and lateral O15467 motor neurons have subtly different activity patterns that reflect the differential expression of neurotransmitter receptor subunits . Using a combination of patch - clamp recordings in single neurons and calcium - imaging of motor neuron populations , we demonstrate that inhibition of nicotinic , muscarinic or GABA - ergic activity , has profound effects of motor circuit activity during the initial stages of neuromuscular junction formation . Finally , by analysing the activity of large populations of motor neurons at different developmental stages , we show that the asynchronous , disordered neuronal activity that occurs at early stages of circuit formation develops into organised , synchronous activity evident at the stage of O15467 neuron muscle innervation . In light of the considerable diversity of neurotransmitter receptor expression , activity patterns in the O15467 are surprisingly similar between neuronal types , however the emergence of patterned activity , in conjunction with the differential expression of transmitter systems likely leads to the development of near - mature patterns of locomotor activity by perinatal ages .",
"P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV - associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . ___MASK51___ , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV - induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R .",
"Inhibitory effect of gabapentin on N - methyl - D - aspartate receptors expressed in Xenopus oocytes . BACKGROUND : DB00996 ( O75925 ) is a prescription drug used for the treatment of neuropathic and post - operative pain . However , the mechanism by which it exerts its analgesic action is not well understood . Because intrathecal administration of O75925 has been shown to exert antinociceptive effects in animal studies , we hypothesized that the spinal cord may be a plausible action site . METHODS : We examined the effects of O75925 on neurotransmitter - gated ion channels and G protein - coupled inwardly rectifying potassium ( GIRK ) channels distributed in the spinal cord and involved in pain modulation . Recombinant human Q9UHB4 / Q12879 N - methyl - D - aspartate ( DB01221 ) , alpha ( 1 ) beta ( 2 ) gamma ( 2S ) gamma - aminobutyric acid type A ( GABA ( A ) ) or alpha ( 1 ) glycine receptors , or P48549 / P48051 channels were expressed in Xenopus laevis oocytes and the effects of O75925 ( 0 . 1 - 1000 microM ) on them were assessed using a two - electrode , voltage - clamp system . RESULTS : GABA ( A ) and glycine receptors and GIRK channels were not affected by O75925 , even at the highest concentrations . Conversely , DB01221 receptors were inhibited by O75925 in a concentration - dependent manner , with significant inhibition observed at 10 microM . At 30 microM , O75925 inhibited the glutamate - concentration response curve without changing the half - maximal effective concentration or the Hill coefficient , indicating a non - competitive inhibition . Glycine decreased the inhibitory effect in a concentration - dependent manner . CONCLUSIONS : These findings suggest that the inhibitory effect of O75925 on DB01221 receptors may play an important role in the antinociceptive property of O75925 ; however , it does not appear that GABA ( A ) and glycine receptors or GIRK channels contribute to the pharmacological properties of O75925 .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK77___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"Effects of salicylate on the inflammatory genes expression and synaptic ultrastructure in the cochlear nucleus of rats . DB00945 ( salicylate ) , as a common drug that is frequently used for long - term treatment in a clinical setting , has the potential to cause reversible tinnitus . However , few reports have examined the inflammatory cytokines expression and alteration of synaptic ultrastructure in the cochlear nucleus ( CN ) in a rat model of tinnitus . The tinnitus - like behavior of rats were detected by the gap prepulse inhibition of acoustic startle ( GPIAS ) paradigm . We investigated the expression levels of the tumor necrosis factor - α ( P01375 - α ) , interleukin - 6 ( P05231 ) , N - methyl D - aspartate receptor subunit 2A ( Q12879 ) mRNA and protein in the CN and compared synapses ultrastructure in the CN of tinnitus rats with normal ones . GPIAS showed that rats with long - term administration of salicylate were experiencing tinnitus , and the mRNA and protein expression levels of P01375 - α and Q12879 were up - regulated in chronic treatment groups , and they returned to baseline 14 days after cessation of treatment . Furthermore , compared to normal rats , repetitive salicylate - treated rats showed a greater number of presynaptic vesicles , thicker and longer postsynaptic densities , increased synaptic interface curvature . These data revealed that chronic salicylate administration markedly , but reversibly , induces tinnitus possibly via augmentation of the expression of P01375 - α and Q12879 and cause changes in synaptic ultrastructure in the CN . Long - term administration of salicylate causes neural plasticity changes at the CN level .",
"Heroin addiction in African Americans : a hypothesis - driven association study . Heroin addiction is a chronic complex disease with a substantial genetic contribution . This study was designed to identify gene variants associated with heroin addiction in African Americans . The emphasis was on genes involved in reward modulation , behavioral control , cognitive function , signal transduction and stress response . We have performed a case - control association analysis by screening with 1350 variants of 130 genes . The sample consisted of 202 former severe heroin addicts in methadone treatment and 167 healthy controls with no history of drug abuse . Single nucleotide polymorphism ( SNP ) , haplotype and multi - SNP genotype pattern analyses were performed . Seventeen SNPs showed point - wise significant association with heroin addiction ( nominal P < 0 . 01 ) . These SNPs are from genes encoding several receptors : adrenergic ( ADRA1A ) , arginine vasopressin ( P37288 ) , cholinergic ( P08172 ) , dopamine ( P21728 ) , GABA - A ( P28472 ) , glutamate ( Q12879 ) and serotonin ( P46098 ) as well as alcohol dehydrogenase ( P40394 ) , glutamic acid decarboxylase ( Q99259 and Q05329 ) , the nucleoside transporter ( Q99808 ) and diazepam - binding inhibitor ( DBI ) . The most significant result of the analyses was obtained for the Q12879 haplotype G - A - T ( rs4587976 - rs1071502 - rs1366076 ) with protective effect ( P ( uncorrected ) = 9 . 6E - 05 , P ( corrected ) = 0 . 058 ) . This study corroborates several reported associations with alcohol and drug addiction as well as other related disorders and extends the list of variants that may affect the development of heroin addiction . Further studies will be necessary to replicate these associations and to elucidate the roles of these variants in drug addiction vulnerability .",
"DB00996 prevents oxaliplatin - induced central sensitization in the dorsal horn neurons in rats . OBJECTIVES : The present study aims to study the alteration of glutamatergic transmission in the dorsal horn neurons and the effect of gabapentin on oxaliplatin - induced neuropathic pain in rats . MATERIALS AND METHODS : DB00526 ( 5 mg / kg ) or saline was administered to adult male Sprague - Dawley rats . DB00996 ( 60 mg / kg , IP ) or vehicle was injected daily . Mechanical allodynia was assessed using a series of von Frey filaments . The expression of glutamate receptor subunits ( Q13224 and GluR1 ) and brain - derived neurotrophic factor ( P23560 ) was measured in the dorsal horn . The glutamatergic strength was recorded in the spinal cord slices . RESULTS : Administration of oxaliplatin induced significant hyperreactivity to mechanical stimuli in rats , which was attenuated by gabapentin . Significant increase in the expression of P23560 was found in the dorsal horn in rats receiving oxaliplatin , which was prevented by gabapentin . Further studies also observed a significant increase in the expression of GluR1 and Q13224 , as well as enhanced glutamatergic transmission in the dorsal horn neurons in rats treated with oxaliplatin . The upregulation of glutamatergic transmission was significantly reversed by gabapentin . CONCLUSION : These results illustrated an increased expression of P23560 and enhanced glutamatergic transmission in rats with oxaliplatin - induced neuropathic pain , which was markedly attenuated by gabapentin .",
"Gene - gene interaction analyses between DB01221 receptor subunit and dopamine receptor gene variants and clozapine response . AIMS : To investigate the possible association and gene - gene interaction effects of polymorphisms in DB01221 receptor subunit ( GRIN1 , Q12879 and Q13224 ) and dopamine receptor ( P21728 , P14416 and P35462 ) genes with clozapine response . MATERIALS & METHODS : GRIN1 rs11146020 ( G1001C ) , Q12879 GT - repeat and Q13224 rs10193895 ( G - 200T ) polymorphisms were tested for association in a Caucasian ( n = 183 ) and an African - American ( n = 49 ) sample using χ ( 2 ) and Q9UNW9 tests . Logistic regression and two - way Q9UNW9 were used to explore gene - gene interaction effects with dopamine receptor gene variants . RESULTS & CONCLUSION : This study does not support the involvement of the DB01221 receptor subunit gene polymorphisms in clozapine response . All tests for an association were negative . Gene - gene interaction analyses however yielded promising leads , including an observed effect between P21728 rs686 and P35462 Ser9Gly polymorphisms on clozapine response ( p = 0 . 002 ) .",
"Integrin - binding RGD peptides induce rapid intracellular calcium increases and MAPK signaling in cortical neurons . Integrins mediate cell adhesion to the extracellular matrix and initiate intracellular signaling . They play key roles in the central nervous system ( CNS ) , participating in synaptogenesis , synaptic transmission and memory formation , but their precise mechanism of action remains unknown . Here we show that the integrin ligand - mimetic peptide GRGDSP induced DB01221 receptor - dependent increases in intracellular calcium levels within seconds of presentation to primary cortical neurons . These were followed by transient activation and nuclear translocation of the P27361 / 2 mitogen - activated protein kinase . RGD - induced effects were reduced by the DB01221 receptor antagonist MK801 , and P27361 / 2 signaling was specifically inhibited by ifenprodil and Q99463 , indicating a functional connection between integrins , Src and Q13224 - containing DB01221 receptors . GRGDSP peptides were not significantly neuroprotective against excitotoxic insults . These results demonstrate a previously undescribed , extremely rapid effect of RGD peptide binding to integrins on cortical neurons that implies a close , functionally relevant connection between adhesion receptors and synaptic transmission .",
"Developmental exposure to the organochlorine insecticide endosulfan alters expression of proteins associated with neurotransmission in the frontal cortex . Exposure to environmental contaminants , such as organochlorine insecticides during critical periods of neurodevelopment has been shown to be a major contributor to several neuropsychological deficits seen in children , adolescence , and adults . Although the neurobehavioral outcomes resulting from exposure to these compounds are known the neurotransmitter circuitry and molecular targets that mediate these endpoints have not been identified . Given the importance of the frontal cortex in facilitating numerous neuropsychological processes , our current study sought to investigate the effects of developmental exposure to the organochlorine insecticide , endosulfan , on the expression of specific proteins associated with neurotransmission in the frontal cortex . Utilizing in vitro models we were able to show endosulfan reduces cell viability in IMR - 32 neuroblastoma cells in addition to reducing synaptic puncta and neurite outgrowth in primary cultured neurons isolated from the frontal cortex of mice . Elaborating these findings to an in vivo model we found that developmental exposure of female mice to endosulfan during gestation and lactation elicited significant alterations to the GABAergic ( P30531 , vGAT , GABAA receptor ) , glutamatergic ( vGlut and Q13224 receptor ) , and dopaminergic ( Q01959 , TH , Q05940 , and D2 receptor ) neurotransmitter systems in the frontal cortex of male offspring . These findings identify damage to critical neurotransmitter circuits and proteins in the frontal cortex , which may underlie the neurobehavioral deficits observed following developmental exposure to endosulfan and other organochlorine insecticides .",
"Neuronal Nogo - A regulates glutamate receptor subunit expression in hippocampal neurons . Nogo - A and its cognate receptor NogoR1 ( NgR1 ) are both expressed in neurons . To explore the function of these proteins in neurons of the CNS , we carried out a series of studies using postnatal hippocampal neurons in culture . Interfering with the binding of Nogo - A to NgR1 either by adding truncated soluble fragment of NgR1 ( NgSR ) or by reducing NgR1 protein with a specific siRNA , resulted in a marked reduction in Nogo - A expression . Inhibition of Rho - ROCK or MEK - MAPK signaling resulted in a similar reduction in neuronal Nogo - A mRNA and protein . Reducing Nogo - A protein levels by siRNA resulted in an increase in the post - synaptic scaffolding protein P78352 , as well as increases in P42261 / P42262 AMPA receptor and Q05586 / Q12879 / Q13224 DB01221 glutamate receptor subunits . siRNA treatment to reduce Nogo - A resulted in phosphorylation of P42345 ; addition of rapamycin to block P42345 signaling prevented the up - regulation in glutamate receptor subunits . siRNA reduction of NgR1 resulted in increased expression of the same glutamate receptor subunits . Taken together the results suggest that transcription and translation of Nogo - A in hippocampal neurons is regulated by a signaling through NgR1 , and that interactions between neuronal Nogo - A and NgR1 regulate glutamatergic transmission by altering DB01221 and AMPA receptor levels through an rapamycin - sensitive P42345 - dependent translation mechanism .",
"Q9UHB4 , Q12879 and Q14957 subunits expression after cervical spinal cord transplant and section in dogs . This paper served to evaluate the expression levels of subunits Q9UHB4 , Q12879 and Q14957 which are implicated in neuronal plasticity events . A 50 % ( right half ) 4 mm longitudinal resection of the spinal cord was done at the P01031 - P13671 level with preservation of the anterior spinal artery . This was effected in a dog model after either a homologous transplant or a pure spinal cord section . In this study we used two groups of dogs with four individuals each , as well as a control group . The transplant group ( n = 4 ) was analyzed at days 3 and 28 post surgery . The section group ( n = 4 ) was also analyzed at days 3 and 28 post op . All three groups ( transplant , section and control ) were evaluated as to the subunit expression in each of the segments corresponding to the transplanted or sectioned sites , the site contralateral to the transplanted or sectioned sites at levels half a centimeter both proximal and distal to the site of transplant and section . The results showed a variety of changes in each of the subunits depending on the group , the segment and the time of evaluation ( acute versus chronic ) . This could be closely related to mechanisms which participate in regeneration and functional recuperation .",
"Association of P35462 and Q13224 with impulse control and related behaviors in Parkinson ' s disease . We aimed to assess whether allelic variants of dopamine receptor , glutamate receptor , and serotonin transporter genes are associated with the appearance of impulse control and related behaviors ( ICRB ) in Parkinson ' s disease ( PD ) with dopamine replacement therapy ( P29323 ) . We surveyed ICRB in consecutive Korean patients with PD who were treated with stable P29323 using modified Minnesota Impulsive Disorders Interview over a period of 4 months . In the 404 patients who completed the interview and the 559 Korean healthy normal controls , genotyping was performed for variants of the P35462 p . S9G , P14416 Taq1A , Q13224 c . 366C > G , c . 2664C > T and c .- 200T > G , and the promoter region of the serotonin transporter gene ( 5 - HTTLPR ) . Behavioral abnormalities suggestive of ICRB including compulsive buying , gambling , sexual behavior and eating , and punding , were present in 14 . 4 % of the patients . Variants of P14416 and 5 - HTTLPR were not associated with the risk of developing ICRB . However , the AA genotype of P35462 p . S9G and the CC genotype of Q13224 c . 366C > G were more frequent in patients with ICRB than in nonaffected patients ( odds ratio [ OR ] = 2 . 21 , P = 0 . 0094 ; and 2 . 14 , P = 0 . 0087 , after adjusting for age and sex ) . After controlling for clinical variables in the multivariate analysis , carriage of either AA genotype of P35462 or CC genotype of Q13224 was identified as an independent risk factor for ICRB ( adjusted OR : 2 . 57 , P = 0 . 0087 ) . Variants of P35462 p . S9G and Q13224 c . 366C > G may be associated with the appearance of ICRB in PD .",
"___MASK49___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK49___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK49___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .",
"To press or not to press ? Differential receptor expression and response to novelty in rats learning an operant response for reward . Learning to perform instrumental tasks is an ability of all animals . In a population of rats , not all individuals will acquire an operant response for reward . We hypothesized that there could be a genetic explanation for differences between High Consumers ( those that acquired the lever press response ) and Low Consumers ( lever press response is low ) . Additionally , we proposed that this genetic difference could produce measurable changes in response to novelty . Wistar rats were trained to lever press for a 0 . 2 % saccharin reward and on the 10th day they were placed in a novel open field for 30 min to record locomotor activity . The prefrontal cortex and hippocampus were dissected and qPCR was used to measure mRNA expression . A significant difference ( p =. 048 ; 2 - way Q9UNW9 ) in gene expression was observed between Low and High Consumers . A principal component analysis ( DB11245 ) , to cluster which genes represent this difference , identified 4 genes ; 5 - Q13049 and mGlu1 in the hippocampus and AMPA GluR1 and adrenergic alpha2A in the prefrontal cortex . Response to a novel open field also differed since Low Consumers displayed a higher Total Distance in comparison to High Consumers . Additionally , Low Consumers could be subdivided into Low - Lever ( with lever press response only when water deprived ) and Low - Non - Lever ( lever press response is low throughout training ) . DB11245 with this subdivision identified an additional nine genes differing within the divisions ; DB01221 Q13224 and GABAAalpha3 in the prefrontal cortex and adrenergic alpha2B and alpha2A , AMPA GluR1 , GluR2 and GluR3 , P28222 and GABAAalpha5 in the hippocampus .",
"N - methyl - D - aspartate receptor - dependent regulation of the glutamate transporter excitatory amino acid carrier 1 . The neuronal transporter excitatory amino acid carrier 1 ( P43005 ) is enriched in perisynaptic regions , where it may regulate synaptic spillover of glutamate . In this study we examined potential interactions between P43005 and ionotropic glutamate receptors . N - Methyl - D - aspartate ( DB01221 ) receptor subunits Q9UHB4 , Q12879 , and Q13224 , but not the alpha - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazole propionic acid receptor subunit GluR2 , were co - immunoprecipitated with P43005 from neuron - enriched hippocampal cultures . A similar interaction was observed in P13671 glioma and human embryonic kidney cells after co - transfection with Myc epitope - tagged P43005 and DB01221 receptor subunits . Co - transfection of P13671 glioma with the combination of Q9UHB4 and NR2 subunits dramatically increased ( approximately 3 - fold ) the amount of Myc - P43005 that can be labeled with a membrane - impermeable biotinylating reagent . In hippocampal cultures , brief ( 5 min ) , robust ( 100 microM DB01221 , 10 microM glycine ) activation of the DB01221 receptor decreased biotinylated P43005 to approximately 50 % of control levels . This effect was inhibited by an DB01221 receptor antagonist , intracellular or extracellular calcium chelators , or hypertonic sucrose . Glutamate , alpha - amino - 3 - hydroxy - 5 - methyl - 4 - isoxazole propionic acid with cyclothiazide , and thapsigargin mimicked the effects of DB01221 . These studies suggest that DB01221 receptors interact with P43005 , facilitate cell surface expression of P43005 under basal conditions , and control internalization of P43005 upon activation . This DB01221 receptor - dependent regulation of P43005 provides a novel mechanism that may shape excitatory signaling during synaptic plasticity and / or excitotoxicity .",
"Activation of spinal alpha - 7 nicotinic acetylcholine receptor attenuates remifentanil - induced postoperative hyperalgesia . The activation of alpha - 7 nicotinic acetylcholine receptors ( α7 - nAchRs ) are currently being considered as novel therapeutic approaches for managing hyperalgesia in inflammation and chronic neuropathic pain , but the role of a7 - nAChRs on opioids induced hyperalgesia remain unknown . The present study investigated the effects of α7 - nAChRs selective agonists PHA - 543613 and type II positive allosteric modulators ( PAMs ) PNU - 120596 in remifentanil induced postoperative hyperalgesia . As the results shown , intrathecal treatment with both α7 - nAChRs agonists and type II PAMs could attenuate remifentanil induced hyperalgesia by increasing paw withdrawal mechanical threshold ( PWMT ) and paw withdrawal thermal latency ( PWTL ) . Furthermore , we also investigated the protein level of proinflammatory cytokines and phosphorylation N - methyl - d - aspartate receptor 2B subunit ( p - Q13224 ) in the spinal cord . Our data indicated that activation of α7 - nAchRs decreased the proinflammatory cytokines ( P01375 - α , P05231 ) and p - Q13224 protein level in the spinal cord . The depression of the increased levels of proinflammatory cytokines and p - Q13224 after remifentanil treatment may contribute to the anti - hyperalgesia effects of PHA - 543613and PNU - 120596 via α7 - nAChRs . Therefore , our findings demonstrated that α7 - nAChRs may be potential candidates for treating opioids induced hyperalgesia .",
"Synaptic vesicular monoamine transporter expression : distribution and pharmacologic profile . The human vesicular monoamine transporter ( hSVMT ) cDNA predicts a protein of 515 amino acids that shares 92 % amino acid identity with the rat cDNA . Northern analyses reveal expression of 4 . 3 kb Q05940 mRNAs in rat hypothalamus , midbrain and brainstem , a 3 kb hSVMT mRNA in human brainstem and a 4 . 8 kb hSVMT mRNA in human hypothalamus . In situ hybridization documents significant Q05940 expression in human nigra compacta neurons and in rat hypothalamic neurons whose distribution patterns are identical to those previously reported to display histaminergic markers . COS cell hSVMT expression yielded nanomolar affinities for tetrabenazine and reserpine , micromolar affinities for haloperidol , GBR12909 , serotonin , mazindol , nomifensin and ___MASK84___ , while dopamine , epinephrine , norepinephrine and histamine each displayed millimolar affinities . These observations extend the pharmacological characterization of hSVMT and studies of its distribution , and indicate likely physiological roles for Q05940 in packaging monoamine transmitters including histamine .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK84___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling ."
] |
[
"___MASK14___",
"___MASK49___",
"___MASK51___",
"___MASK61___",
"___MASK77___",
"___MASK7___",
"___MASK84___",
"___MASK86___",
"___MASK9___"
] |
___MASK9___
|
MH_train_459
|
interacts_with DB00831?
|
[
"Altered transcriptional regulators in response to serum in immortalized lymphocytes from Alzheimer ' s disease patients . Cell cycle disturbances may precede neuronal death in Alzheimer ' s disease ( AD ) . We described alterations , in lymphocytes from AD patients , on the activity of two transcription factors , E2F and NF - kappaB , involved in cell proliferation and survival regulation , demonstrating that cell cycle dysfunction also occurs in peripheral cells . The analysis of E2F - DNA binding activity revealed lower signal intensity of protein - DNA complexes in AD cells , which correlated with increased phosphorylation of retinoblastoma ( P06400 ) related proteins and enhanced proliferation . The calmodulin ( P62158 ) antagonist calmidazolium ( DB01489 ) abrogated the increased activity of AD cells by partially dephosphorylating P06400 and Q08999 . The NF - kappaB - DNA binding activity increased as cell progress through the cell cycle . The reduced NF - kappaB activation observed in AD cells appears not to be related to the increased phosphorylation of the P06400 family proteins nor with the enhanced proliferative activity of AD cells , but seems to protect them from death induced by the loss of trophic support . Ca2 +/ P62158 antagonists rescue NF - kappaB - DNA binding activity and sensitize AD cells to serum withdrawal . These observations suggest that disruption of Ca2 +/ P62158 signaling pathway could be linked mechanistically to its pro cell survival actions , promoting enhanced proliferation or decreased cell death depending on the presence of growth - stimulatory signals .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK64___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK20___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK98___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Establishment and phenotypic characterization of human U937 cells with inducible P210 P11274 / P00519 expression reveals upregulation of P13688 ( CD66a ) . Chronic myeloid leukemia ( CML ) is characterized by the expression of the P210 P11274 / P00519 fusion protein . The molecular mechanisms behind this oncogene - mediated hematological disease are , however , not fully understood . Here , we describe the establishment and phenotypic characterization of U937 cells in which P210 P11274 / P00519 can be conditionally expressed using tetracycline . The induction of P11274 / P00519 in the obtained clones resulted in a rapid phosphorylation of the P42224 , P40763 and P42229 molecules , consistent with the findings in other model systems . Phenotypic characterization of the clones revealed that P11274 / P00519 induces a slight decrease in the proliferation and viability , without a marked effect on cell cycle distribution , the rate of apoptosis or on cellular differentiation , as judged by several cell surface markers and capacity to reduce nitro blue tetrazolium . Interestingly , P11274 / P00519 was found to upregulate the expression of carcinoembryonic - related antigen ( P06731 ) P62158 ( CD66a ) , which is a plasma membrane - linked glycoprotein belonging to the CEAs and involved in signal transduction and cellular adhesion . The expression of P13688 was reversible upon imatinib treatment in P11274 / P00519 - expressing U937 cells as well as in P11274 / P00519 - positive K562 cells . The established cell lines may prove useful in further modeling and dissection of P11274 / P00519 - induced leukemogenesis .",
"[ Adhesion molecules in urologic tumors ] . Adhesion molecules play an important role in organogenesis , would healing , inflammation , and progression of malignant tumors . Three major classes of adhesion molecules may be discriminated by function : ( a ) calcium - dependent homotypic adhesion molecules ( e . g . cadherins ) , ( b ) substrate adhesion molecules ( e . g . integrins ) and ( c ) heterotypic adhesion molecules ( e . g . P05362 ) . Molecules of each of the three classes have been identified in urologic tumors . Results of research on substrate adhesion molecules and heterotypic adhesion molecules have not yet led to new clinical concepts . In contrast , loss of P12830 in tumors of the bladder and prostate has been clearly associated with de - differentiation of tumors and diminished survival of patients . Loss of another adhesion molecule , C - P62158 , has been observed in prostate cancer . This has led to new therapeutic approaches , which are in an experimental stage at present . It may be expected that , in the future , new therapeutic concepts will be based on research on adhesion molecules in urologic tumors .",
"P15018 functions as a growth factor in pancreas carcinoma cells : Involvement of regulation of P15018 and its receptor expression . P15018 ( P15018 ) is a pleiotrophic cytokine , which plays an important role in inducing cancer cachexia . We have previously reported that P15018 promotes cell proliferation in some human carcinoma cells through c - fos , jun - B and cyclin - E expression . In the present study , we analyzed the regulation of P15018 and its receptor ( P42702 ) expression in pancreatic carcinoma cells . Seven pancreatic carcinoma cells expressed constitutively P15018 and its heterodimer receptor ( P42702 and P40189 ) mRNA in RPMI - 1640 medium without FBS . The amount of P15018 immunoreactive protein was 132 . 5 +/- 52 pg / 10 ( 6 ) cells in culture supernatants without FBS . Pro - inflammatory cytokines , such as P01375 , IL - 1beta , P05231 , P10145 , or P15018 , enhanced the expression of P15018 mRNA in Hs - 700T and Hs - 766T cells . Addition of P15018 significantly induced cell proliferation of Hs700T in 13 days P15018 dose - dependently . However , anti - P15018 IgG failed to suppress cell proliferation in Hs - 700T cells . P15018 acted as a paracrine growth factor in Hs - 700T cells , which expressed low amount of P15018 without stimuli . Cellular signal transductions by P15018 was down - regulated by inhibitors of protein kinase C ( PKC ) , protein tyrosine kinase ( PTK ) , and Ca / P62158 . P15018 induced phosphorylation of P40763 . Moreover , exogenous P15018 upregulated the expression of P42702 mRNA . Antisense P42702 oligonucleotide significantly suppressed cell growth in the presence of P15018 in Hs - 700T cells . These results suggest that cytokine network might alter the expression and responsiveness to P15018 in tumor microenvironment .",
"Pathogen - induced binding of the soybean zinc finger homeodomain proteins GmZF - HD1 and GmZF - Q92769 to two repeats of ATTA homeodomain binding site in the calmodulin isoform 4 ( GmCaM4 ) promoter . P62158 ( P62158 ) is involved in defense responses in plants . In soybean ( Glycine max ) , transcription of calmodulin isoform 4 ( GmCaM4 ) is rapidly induced within 30 min after pathogen stimulation , but regulation of the GmCaM4 gene in response to pathogen is poorly understood . Here , we used the yeast one - hybrid system to isolate two cDNA clones encoding proteins that bind to a 30 - nt A / T - rich sequence in the GmCaM4 promoter , a region that contains two repeats of a conserved homeodomain binding site , ATTA . The two proteins , GmZF - HD1 and GmZF - Q92769 , belong to the zinc finger homeodomain ( ZF - HD ) transcription factor family . Domain deletion analysis showed that a homeodomain motif can bind to the 30 - nt GmCaM4 promoter sequence , whereas the two zinc finger domains can not . Critically , the formation of super - shifted complexes by an anti - GmZF - HD1 antibody incubated with nuclear extracts from pathogen - treated cells suggests that the interaction between GmZF - HD1 and two homeodomain binding site repeats is regulated by pathogen stimulation . Finally , a transient expression assay with Arabidopsis protoplasts confirmed that GmZF - HD1 can activate the expression of GmCaM4 by specifically interacting with the two repeats . These results suggest that the GmZF - HD1 and - 2 proteins function as ZF - HD transcription factors to activate GmCaM4 gene expression in response to pathogen .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK80___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK80___ who were treated with a single dose of mifepristone .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK67___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK67___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"___MASK53___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK53___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK53___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK53___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK53___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"P04150 pathways are involved in the inhibition of astrocyte proliferation . In earlier studies , the neural cell adhesion molecule , N - P62158 , was found to inhibit the proliferation of rat astrocytes both in vitro and in vivo . To identify the gene targets involved , we used subtractive hybridization to examine changes in gene expression that occur after astrocytes are exposed to N - P62158 in vitro . While the mRNA levels for N - P62158 decreased after such treatment , the levels of mRNAs for glutamine synthetase and calreticulin increased . Since glutamine synthetase and calreticulin are known to be involved in glucocorticoid receptor pathways , we tested a number of steroids for their effects on astrocyte proliferation . Dexamethasone , corticosterone , and aldosterone were all found to inhibit rat cortical astrocyte proliferation in culture in a dose - dependent manner . ___MASK74___ , a potent glucocorticoid antagonist , reversed the inhibitory effects of dexamethasone . These observations prompted the hypothesis that the inhibition of proliferation by N - P62158 might be mediated through the glucocorticoid receptor pathway . Consistent with this hypothesis , the inhibition of astrocyte proliferation by N - P62158 was reversed in part by a number of glucocorticoid antagonists , including ___MASK74___ , dehydroepiandrosterone , and progesterone . In transfection experiments with cultured astrocytes , N - P62158 treatment increased the expression of a luciferase reporter gene under the control of a minimal promoter linked to a glucocorticoid response element . The enhanced activity of this construct stimulated by N - P62158 was abolished in the presence of ___MASK74___ . The combined data suggest that astrocyte proliferation is in part regulated by alterations in glucocorticoid receptor pathways .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK13___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK13___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK13___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK13___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK13___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"[ P62158 - dependent regulation of Ca , Mg - ATPase activity in plasma membranes of the swine myometrium ] . Highly purified plasma membrane ( PM ) preparations of pig myometrium were found to contain 0 . 91 +/- 0 . 22 microgram calmodulin per mg of PM protein . Treatment of membranes with 1 mM EGTA in the presence of 0 . 2 M NaCl causes the diminution of the calmodulin content down to 3 % of the original level . The activity of Ca , Mg - ATPase is thereby decreased by 40 % . Exogenous calmodulin restores the enzyme activity up to 1 . 94 +/- +/- 0 . 30 mumol Pi / mg protein / hour . The maximal activation of Ca , Mg - ATPase is observed with 10 (- 7 ) M calmodulin . P62158 increases the total ATPase activity of myometrium PM without affecting the Mg - ATPase activity . DB00831 ( 20 microM ) diminishes the activating effect of exogenous calmodulin on Ca , Mg - ATPase . P62158 stimulates Ca , Mg - ATPase at low concentrations of Ca2 + ( 10 (- 8 )- 10 (- 6 ) M ) by decreasing Km for Ca2 + from 0 . 4 . 10 (- 6 ) M to 2 . 10 (- 8 ) M as well as by increasing Vmax -- from 0 , 8 to 1 . 42 mumol Pl / mg protein / hour . It is supposed that the activating effect of calmodulin on Ca , Mg - ATPase is based on electrostatic interactions of Ca2 +- free calmodulin with the enzyme .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK24___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Skinned coronary smooth muscle : calmodulin , calcium antagonists , and DB02527 influence contractility . The effects of Ca2 + , calmodulin , DB02527 , the catalytic subunit of DB02527 - dependent protein kinase ( CSU ) and some Ca2 + antagonists were studied in chemically ( Triton X - 100 ) skinned coronary smooth muscle . P62158 increased the Ca2 + responsiveness of the muscle fiber as indicated by the reduction in the threshold as well as the half - maximal activating Ca2 + concentration . DB00831 , a calmodulin antagonist , inhibited Ca2 +- calmodulin - induced contraction . Both DB02527 and CSU were effective inhibitors of contraction induced at an intermediate Ca2 + concentration . DB08980 , a Ca2 +- antagonist , at 2 x 10 (- 4 ) M produced a significant inhibitory effect , which was reduced by increasing the Ca2 + concentration . From other Ca2 + antagonists tested , W - 7 , but not D600 and verapamil , produced some inhibitory effect . The data indicate that the response of skinned coronary smooth muscle to Ca2 + , calmodulin and DB02527 are similar to those obtained with other skinned smooth muscles . Furthermore , skinned fiber preparation can serve as a useful tool to investigate possible direct effects of drugs on the activating and regulatory systems in smooth muscle .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development ."
] |
[
"___MASK13___",
"___MASK20___",
"___MASK24___",
"___MASK53___",
"___MASK64___",
"___MASK67___",
"___MASK74___",
"___MASK80___",
"___MASK98___"
] |
___MASK64___
|
MH_train_460
|
interacts_with DB06692?
|
[
"P2Y receptor antagonists in thrombosis . The dual role of P47900 and Q9H244 receptors in platelet aggregation by ADP has been firmly established , based on the action of selective inhibitors , gene targeting in mice and human genetic evidence . Both of these receptor subtypes constitute targets for antithrombotic agents , and compounds with a dual action might also be of interest . However , the agents currently on the market ( ticlopidine and clopidogrel ) , or known to be in development ( cangrelor , ___MASK71___ and prasugrel ) , all target the Q9H244 receptor . The thienopyridines ( ticlopidine , clopidogrel and prasugrel ) irreversibly inactivate the Q9H244 receptor via the covalent binding of an active metabolite generated in the liver , while the other compounds are competitive antagonists . DB06441 , an DB00171 derivative , is suitable for intravenous perfusion , whereas ___MASK71___ is in clinical development as an orally active agent .",
"Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .",
"The changing pattern of \" smart \" flow cytometry ( S - FC ) to assist the cost - effective diagnosis of HIV , tuberculosis , and leukemias in resource - restricted conditions . There is a need to introduce cytometry into areas of the globe that have remained virtually untouched by modern laboratory medicine . With the demand to carry out tests on 100 , 000 s of individuals requiring antiretroviral therapy ( O00253 ) , flow cytometry must remain simple and cost - effective - while being sustainable and industry supported as well as proven by quality assessment ( QA ) . This outlook is referred to as \" smart flow cytometry \" ( S - FC ) . There are five main areas where the power of S - FC is demonstrated . These are : ( i ) the use of P08575 to assist precise cell counting in blood and tissue samples ; ( ii ) the primary P01730 gating to count P01730 + T cells in patients waiting for O00253 , including the combination ( i ) and ( ii ) in the panleucogating ( P00747 ) protocol ; ( iii ) monitoring of human immunodeficiency virus ( HIV + ) patients during O00253 by the decreasing levels of lymphocyte activation in a CD8 / P28907 test - leading to economies of viral - load assays ; ( iv ) in tuberculosis and HIV - TB coinfections the use of TB - antigen - stimulated cytokine - synthetic P01730 + T cells to identify active disease ; and ( v ) the utilization of \" minimal residual disease ( MRD ) - Lite \" technology in patients 19 days after the start of antileukemic therapy to detect MRD . These methods of S - FC have been successfully introduced in \" resource - restricted \" countries with international and local QA .",
"Inhibition of cholinergic signaling causes apoptosis in human bronchioalveolar carcinoma . Recent case - controlled clinical studies show that bronchioalveolar carcinomas ( BAC ) are correlated with smoking . ___MASK58___ , the addictive component of cigarettes , accelerates cell proliferation through nicotinic acetylcholine receptors ( nAChR ) . In this study , we show that human BACs produce acetylcholine ( ACh ) and contain several cholinergic factors including acetylcholinesterase ( P22303 ) , choline acetyltransferase ( P28329 ) , choline transporter 1 ( Q9GZV3 , Q9GZV3 ) , vesicular acetylcholine transporter ( Q16572 , Q16572 ) , and nACh receptors ( AChRs , CHRNAs ) . ___MASK58___ increased the production of ACh in human BACs , and ACh acts as a growth factor for these cells . ___MASK58___ - induced ACh production was mediated by α7 - , α3β2 - , and β3 - nAChRs , P28329 and Q16572 pathways . We observed that nicotine upregulated P28329 and Q16572 . Therefore , we conjectured that Q16572 antagonists , such as vesamicol , may suppress the growth of human BACs . Vesamicol induced potent apoptosis of human BACs in cell culture and nude mice models . Vesamicol did not have any effect on P01133 or insulin - like growth factor - II - induced growth of human BACs . siRNA - mediated attenuation of Q16572 reversed the apoptotic activity of vesamicol . We also observed that vesamicol inhibited Akt phosphorylation during cell death and that overexpression of constitutively active Akt reversed the apoptotic activity of vesamicol . Taken together , our results suggested that disruption of nicotine - induced cholinergic signaling by agents such as vesamicol may have applications in BAC therapy .",
"P00747 potentiates thrombin cytotoxicity and contributes to pathology of intracerebral hemorrhage in rats . Thrombin and plasmin are serine proteases involved in blood coagulation and fibrinolysis , whose precursors are circulating in blood stream . These blood - derived proteases might play important roles in the pathogenesis of intracerebral hemorrhage by acting on brain parenchymal cells . We previously reported that thrombin induced delayed neuronal injury through extracellular signal - regulated kinase ( P29323 ) - dependent pathways . Here , we investigated potential cytotoxic actions of plasminogen , a precursor protein of plasmin , using slice cultures prepared from neonatal rat brain and intracortical microinjection model in adult rats . Although plasminogen alone did not evoke prominent neuronal injury , plasminogen caused significant neuronal injury when combined with a moderate concentration of thrombin ( 30 U / mL ) in the cerebral cortex of slice cultures . The cortical injury was prevented by tranexamic acid and aprotinin . The combined neurotoxicity of thrombin and plasminogen was also prevented by PD98059 , an inhibitor of P29323 pathway , as well as by other agents that have been shown to prevent cortical injury induced by a higher concentration ( 100 U / mL ) of thrombin alone . Extracellular signal - regulated kinase phosphorylation after plasminogen exposure was localized in cortical astrocytes . Moreover , microinjection of plasminogen in vivo potentiated thrombin - induced cortical injury , and inhibition of plasmin ameliorated hemorrhage - induced neuronal loss in the cerebral cortex . These results suggest that plasminogen / plasmin system augmenting thrombin neurotoxicity participates in hemorrhagic cortical injury .",
"___MASK90___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK90___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .",
"Cellular overexpression of aquaporins slows down the natural HIF - 2α degradation during prolonged hypoxia . Overexpression of cell membrane aquaporins ( AQPs ) has recently been associated with tumor formation , particularly with angiogenesis , cell migration and proliferation . Additionally , the hypoxia inducible factor ( HIF ) family has been extensively implicated in tumor growth and recent studies evidence interplay between AQP expression and HIF stability . Therefore , we decided to explore the effect that AQP overexpression has on the long - term stability of HIF - 2α in PC12 cells exposed to chronic hypoxia , characteristic of a growing tumor . HIF - 2α levels were analyzed in five PC12 clones with stable overexpression of different proteins ( P29972 , Q92482 , P55064 , P11413 , and P39905 ) , in PC12 transiently expressing P11413 or Kv4 . 2 , and in wild - type PC12 cells . Overexpression of P29972 , 3 or 5 in PC12 cells ( o - AQP - c ) prevented the HIF - 2α down - expression otherwise observed , after 16 h at 1 % O2 , in wt - PC12 and in PC12 overexpressing non - AQP proteins . Longer HIF - 2α stability was also observed in o - AQP - c exposed to cobalt chloride or dimethyloxallyl glycine . Normal proteasome activity was confirmed in all clones analyzed . Levels of HIF target genes ( Q9GZT9 and 3 , P15692 , and P00558 ) were 2 - 4 fold higher in hypoxic o - AQP - c than in wt - PC12 cells , and morphological changes in colony shape together with higher cell proliferation rates were observed in all o - AQP - c . Interestingly , analysis of P20941 levels under normoxia revealed lower ( 50 % ) Q9H6Z9 expression in o - AQP - c than in controls . Our results indicate that AQP overexpression in PC12 cells prolongs HIF - 2α stability during chronic hypoxia , leading to higher level of induction of its target genes and likely conferring to these cells a more tumor - like phenotype .",
"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .",
"Chemotherapeutic drugs and human tumor cells cytokine network . The ability of human tumor cell lines to produce various cytokines , chemokines , angiogenic and growth factors was investigated using Luminex multiplex technology . Media conditioned by tumor cells protected tumor cells from drug - induced apoptosis and stimulated tumor cell proliferation . Antibodies neutralizing P05231 , P10145 , P13500 and P13501 blocked this stimulation . Treatment of tumor cells with doxorubicin and cisplatin resulted in a substantial increase in the production of P05231 , P10145 , P13500 , P13501 , BFGF , G - P04141 and P15692 . This stimulation was associated with drug - induced activation of NF - kappaB , AP - 1 , P05549 , CREB , Q9BYW2 , P35610 - 1 , P35610 - 3 , P35610 - 5 and P39905 - 2 transcription factors and upregulation of P05231 , P10145 , P09038 , P04141 - 3 and P13501 gene expression . Treatment of tumor cells with doxorubicin and antibodies neutralizing DB00099 , P13500 or P13501 had higher inhibitory effects than each modality used alone . These results indicate that chemokines and growth factors produced by tumor by binding to the cognate receptors on tumor and stroma cells could provide proliferative and antiapoptotic signals helping tumor to escape drug - mediated destruction . Clinical studies showed that antibodies neutralizing P15692 ( DB00112 / DB00112 ) or blocking P04626 / neu signaling ( Herceptin / ___MASK7___ ) could increase the efficacy of chemotherapy , although these beneficial effects have been limited . It is possible that drug - stimulated production of growth and proangiogenic factors could counterbalance the effects of antibody therapy . In addition , numerous growth factors and chemokines share angiogenic and growth - stimulating properties , and thus reduction of a single factor is insufficient to completely block tumor growth . Thus , a broad disruption of tumor cytokine network is needed to further increase the efficacy of cancer therapy .",
"Evaluation of platelet activation , coagulation , and fibrinolytic activation in patients with symptomatic lacunar stroke . BACKGROUND : It is unclear whether hemostasis plays a role in the pathogenesis of ischemic stroke subtypes . OBJECTIVE : We aimed to investigate the possible relationship between different hemostatic markers and lacunar stroke . RESULTS : The study consisted of 30 patients with symptomatic lacunar stroke and 30 healthy age - matched healthy individuals . We analyzed the values of \" Mean Platelet Volume , \" D - dimer , \" soluble p - selectin , \" \" P00747 Activator Inhibitor Type - 1 \" ( P05121 ) , \" Thrombin - Activatable DB06692 \" ( Q96IY4 ) , and \" Platelet Factor 4 \" ( P02776 ) in patients with lacunar infarct and compared these values to those of control individuals . There were significant differences for D - dimer , mean platelet volume , thrombin - activatable fibrinolysis inhibitor , and platelet factor 4 values in symptomatic lacunar stroke group compared with the control group ( P < 0 . 01 ) . CONCLUSIONS : Different hemostatic factors may play a role in the pathogenesis of lacunar stroke . Evaluating the role of hemostatic factors on different types of strokes may help us identify new therapeutic strategies and different prognostic stratifications for ischemic stroke .",
"[ Conditions of the primary culture for rat hepatocytes and plasminogen activator release ] . The conditions of primary culture for rat hepatocytes was investigated on the releasing effect of P00747 Activator ( PA ) . The culture method using Collagen Coated Dish ( CCD - method ) which is currently available and the ordinary culture method using Plastic Culture Dish ( P61457 - method ) were employed for that purpose in a comparative way . The effect of the addition of some supplements , that is FN , DB06692 , P01133 were also investigated . The following results were obtained . The dissociated rat hepatocytes formed a monolayer with pavementlike morphology at 24 - 48 hours after seeding . No difference was observed in the morphology of hepatocytes during the culture period between the two methods , although CCD - method allowed 120 hours culture , whereas P61457 - method allowed 72 hours . The PA activity was demonstrated on the hepatocytes by either culture method according to the fibrinolysis autography . The cultured hepatocytes released PA into the medium continuously as long as the viability and morphology of the cells were maintained in good state . The PA activity reached the maximum after 96 hours culture in CCD - method , whereas it reached the maximum after 48 hours in P61457 - method . The addition of DB06692 to the culture medium was not necessary for PA release in CCD - method in contrast to P61457 - method . When P01133 was discontinued in the culture medium , the release of PA was reduced in association with the occurring of morphological disintegration of hepatocytes .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK41___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"___MASK7___ has preferential activity against breast cancers driven by P04626 homodimers . In breast cancer cells with P04626 gene amplification , P04626 receptors exist on the cell surface as monomers , homodimers , and heterodimers with P00533 / P21860 . The therapeutic antibody trastuzumab , an approved therapy for P04626 (+) breast cancer , can not block ligand - induced P04626 heterodimers , suggesting it can not effectively inhibit P04626 signaling . Hence , P04626 oligomeric states may predict the odds of a clinical response to trastuzumab in P04626 - driven tumors . To test this hypothesis , we generated nontransformed human MCF10A mammary epithelial cells stably expressing a chimeric P04626 - FKBP molecule that could be conditionally induced to homodimerize by adding the FKBP ligand AP1510 , or instead induced to heterodimerize with P00533 or P21860 by adding the heterodimer ligands P01133 / TGFα or heregulin . AP1510 , P01133 , and heregulin each induced growth of MCF10A cells expressing P04626 - FKBP . ___MASK7___ inhibited homodimer - mediated but not heterodimer - mediated cell growth . In contrast , the P04626 antibody pertuzumab , which blocks P04626 heterodimerization , inhibited growth induced by heregulin but not AP1510 . Lastly , the P04626 / P00533 tyrosine kinase inhibitor lapatinib blocked both homodimer - and heterodimer - induced growth . AP1510 triggered phosphorylation of Erk1 / 2 but not AKT , whereas trastuzumab inhibited AP1510 - induced Erk1 / 2 phosphorylation and Shc - P04626 homodimer binding , but not TGFα - induced AKT phosphorylation . Consistent with these observations , high levels of P04626 homodimers correlated with longer time to progression following trastuzumab therapy in a cohort of patients with P04626 - overexpressing breast cancer . Together , our findings confirm the notion that P04626 oligomeric states regulate P04626 signaling , also arguing that trastuzumab sensitivity of homodimers may reflect their inability to activate the PI3K ( phosphoinositide 3 - kinase ) / AKT pathway . A clinical implication of our results is that high levels of P04626 homodimers may predict a positive response to trastuzumab .",
"Transforming growth factor alpha - induced expression of type 1 plasminogen activator inhibitor in astrocytes rescues neurons from excitotoxicity . Although transforming growth factor ( TGF ) - alpha , a member of the epidermal growth factor ( P01133 ) family , has been shown to protect neurons against excitotoxic and ischemic brain injuries , its mechanism of action remains unknown . In the present study , we used in vitro models of apoptotic or necrotic paradigms demonstrating that TGF - alpha rescues neurons from N - methyl - D - aspartate ( DB01221 ) - induced excitotoxic death , with the obligatory presence of astrocytes . Because neuronal tissue - type plasminogen activator ( t - PA ) release was shown to potentiate DB01221 - induced excitotoxicity , we observed that TGF - alpha treatment reduced DB01221 - induced increase of t - PA activity in mixed cultures of neurons and astrocytes . In addition , we showed that although TGF - alpha induces activation of the extracellular signal - regulated kinases ( ERKs ) in astrocytes , it failed to activate Q8NFH3 / Q8TCB0 in neurons . Finally , we showed that TGF - alpha , by an P29323 - dependent mechanism , stimulates the astrocytic expression of P05121 , a t - PA inhibitor , which mediates the neuroprotective activity of TGF - alpha against DB01221 - mediated excitotoxic neuronal death . Taken together , we indicate that TGF - alpha rescues neurons from DB01221 - induced excitotoxicity in mixed cultures through inhibition of t - PA activity , involving P05121 overexpression by an P29323 - dependent pathway in astrocytes .",
"A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men . ___MASK58___ is the major addictive substance in cigarettes , and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction . We studied six single - nucleotide polymorphisms ( SNPs ) in the P43681 gene and four SNPs in the P17787 gene with respect to nicotine dependence in a collection of 901 subjects ( 815 siblings and 86 parents ) from 222 nuclear families with multiple nicotine - addicted siblings . The subjects were assessed for addiction by both the Fagerstrom Test for ___MASK58___ Dependence ( FTND ) and the Revised Tolerance Questionnaire ( RTQ ) . Because only 5 . 8 % of female offspring were smokers , only male subjects were included in the final analyses ( 621 men from 206 families ) . Univariate ( single - marker ) family - based association tests ( FBATs ) demonstrated that variant alleles at two SNPs , rs1044396 and rs1044397 , in exon 5 of the P43681 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype ( i . e . , age - adjusted FTND and RTQ scores ) , which was consistent with the results of the global haplotype FBAT . Furthermore , the haplotype - specific FBAT showed a common ( 22 . 5 % ) P43681 haplotype , GCTATA , which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait ( Z =- 3 . 04 , P < . 005 ) and significant decreases of age - adjusted FTND ( Z =- 3 . 31 , P < . 005 ) or RTQ scores ( Z =- 2 . 73 , P =. 006 ) . Our findings provide strong evidence suggesting a common P43681 haplotype might be protective against vulnerability to nicotine addiction in men .",
"Differential expression of urokinase - type plasminogen activator and plasminogen activator inhibitor - 1 in early and late gestational mouse skin and skin wounds . Early gestation fetal mouse skin heals without scars . P00747 activator inhibitor - 1 ( P05121 ) has been associated with postnatal organ fibrosis . We hypothesized that the relative balance between urokinase - type plasminogen activator ( uPA ) and P05121 expression in favor of uPA prevents scarring in early fetal skin wounds , whereas a change in favor of P05121 in late gestation results in wound scarring . To evaluate uPA and P05121 expression , 1 - mm skin wounds were made in Q14207 . 5 and E18 mice and harvested 24 , 48 , or 96 hours postwounding . DB06692 ( 2 mg / ml ) - coated beads were injected into selected Q14207 . 5 wounds . Normal skin and skin wounds were evaluated for uPA , P05121 , and collagen expression . We showed that in normal skin uPA level is higher in Q14207 . 5 than in E18 mice , while P05121 is lower in Q14207 . 5 than in E18 mice . After wounding , Q14207 . 5 wounds show a moderate increase in uPA and a minimal increase in P05121 . E18 wounds show a transient increase in uPA but a significant , sustained increase in P05121 . Addition of aprotinin to Q14207 . 5 wounds causes an increase in collagen deposition . We conclude that the differential expression of uPA and P05121 in the skin of early vs . late gestation mice may contribute to the degree of scar formation seen after cutaneous injury .",
"___MASK71___ reduces neutrophil recruitment and lung damage in abdominal sepsis . Abstract Platelets play an important role in abdominal sepsis and Q9H244 receptor antagonists have been reported to exert anti - inflammatory effects . Herein , we assessed the impact of platelet inhibition with the Q9H244 receptor antagonist ticagrelor on pulmonary neutrophil recruitment and tissue damage in a model of abdominal sepsis . Wild - type C57BL / 6 mice were subjected to cecal ligation and puncture ( CLP ) . Animals were treated with ticagrelor ( 100 mg / kg ) or vehicle prior to CLP induction . Edema formation and bronchoalveolar neutrophils as well as lung damage were quantified . Flow cytometry was used to determine expression of platelet - neutrophil aggregates , neutrophil activation and P29965 expression on platelets . CLP - induced pulmonary infiltration of neutrophils at 24 hours was reduced by 50 % in ticagrelor - treated animals . Moreover , ticagrelor abolished CLP - provoked lung edema and decreased lung damage score by 41 % . Notably , ticagrelor completely inhibited formation of platelet - neutrophil aggregates and markedly reduced thrombocytopenia in CLP animals . In addition , ticagrelor reduced platelet shedding of P29965 in septic mice . Our data indicate that ticagrelor can reduce CLP - induced pulmonary neutrophil recruitment and lung damage suggesting a potential role for platelet antagonists , such as ticagrelor , in the management of patients with abdominal sepsis .",
"Coordinate pathways for nucleotide and P01133 signaling in cultured adult neural progenitor cells . The adult subventricular zone ( SVZ ) contains astrocyte - like stem cells capable of generating new neurons for the olfactory bulb . Adult neurogenesis is driven by a variety of signal systems that can induce synergistic or opposing cellular responses . It is therefore important to gain insight into the underlying downstream signaling pathways . We have previously shown that the nucleotides ADPbetaS and UTP induce rapid Ca2 + transients in cultured SVZ - derived adult neural progenitors and augment growth - factor - mediated progenitor cell proliferation . Here , we investigated signaling pathways elicited by ADPbetaS , UTP and epidermal growth factor ( P01133 ) . All three agonists elicit P27361 / 2 and CREB phosphorylation but the temporal characteristics differ between the nucleotides and P01133 . Differentiation of the progenitors alters the receptor profile . Oligodendrocytes and young neurons , but not astrocytes , lose responsiveness to the agonists . Inhibition experiments are indicative of an ADPbetaS - elicited P01133 receptor transactivation . Whereas UTP acts via the P41231 receptor , ADPbetaS exerts its function via the P47900 receptor and the Q9BPV8 receptor . Our data demonstrate that nucleotides and P01133 induce converging , but also differential , intracellular signaling pathways and suggest that they carry the potential to act synergistically in the control of cell proliferation and cell survival in adult neurogenesis .",
"___MASK90___ inhibits aquaporin - 1 expression and colon cancer xenograft tumor growth . BACKGROUND / AIMS : To study the effects of water channel protein inhibitor acetazolamide on xenograft tumor growth of colon cancer in nude mice . METHODOLOGY : Setting up human colon cancer model in nude mice , mice were randomly divided into two groups as experimental group and control group . ___MASK90___ was given at a volume of 0 . 1mL per mice ( 40mg / kg / d , ig ) in experimental group , while the same volume of sterile saline was given in control group ( ig ) . After 21 days , protein and m - RNA levels of P29972 in tumor tissues from two groups were detected respectively by Western blot and RT - PCR to evaluate the treatment effects . P29972 , P15692 and P28906 expression was detected by immunohistochemistry , simultaneously . RESULTS : ___MASK90___ ( 40mg / kg / d , ig ) significantly inhibited the xenograft tumor growth of colon cancer in nude mice . The inhibition rate was 88 . 28 % . In comparison with the control group , P29972 protein and mRNA level were significantly reduced in the experimental group ( p < 0 . 01 ) . P29972 , P15692 and P28906 expression in experimental group were positively correlated between each other ( p < 0 . 01 ) . CONCLUSIONS : ___MASK90___ can suppress the xenograft tumor growth by inhibiting the expression of P29972 .",
"Encapsulation of viral vectors for gene therapy applications . In gene therapy , a number of viruses are currently being used as vectors to provide transient expression of therapeutic proteins . A drawback of using free virus is that it gives a potent immune response , which reduces gene transfer and limits re - administration . An alternative delivery system is to encapsulate the virus in poly ( lactide - co - glycolide ) ( P00747 ) microspheres prior to administration . A recombinant adenovirus ( Ad ) expressing green fluorescent protein ( GFP ) was used to test the transduction efficiency of Ad encapsulated in microspheres on target cells . The number of infected cells that expressed GFP was measured by flow cytometry . It was demonstrated that encapsulated viral vectors could successfully transduce target cells with encapsulation efficiencies up to 23 % and that the level of transduction could be controlled by varying both the quantity of microspheres and the amount of Ad in the microspheres . High transduction efficiencies and its recognized biocompatibility make P00747 - encapsulated Ad an attractive alternative to the use of free virus in gene therapy applications . The infectivity of Ad was found to be significantly influenced by the processing conditions and changes in environmental factors . Free Ad and encapsulated Ad were able to infect both E1 complimenting cells ( P29320 293 ) and non - complimenting cells ( A549 ) , with the viral expression in P29320 293 cells being 2 . 1 times greater than for A549 cells .",
"Inactivation of glycogen synthase kinase - 3 by epidermal growth factor is mediated by mitogen - activated protein kinase / p90 ribosomal protein S6 kinase signaling pathway in NIH / 3T3 cells . The role of the p90 ribosomal protein S6 kinase / mitogen - activated protein kinase ( RSK / MAPK ) signaling pathway in regulating glycogen synthase kinase - 3 ( GSK - 3 ) activity was investigated . In vitro studies showed that GSK - 3 was inactivated by 50 % upon incubation with RSK purified from epidermal growth factor ( P01133 ) - stimulated NIH / 3T3 cells . Subsequently , the effect of P01133 on GSK - 3 activity was measured in NIH / 3T3 cells that stably overexpressed mutated forms of MAPK kinase ( MAPKK ) . The activation of RSK by P01133 was markedly decreased in cell lines expressing the dominant negative MAPKK mutants S222A and K97A and was increased in cells expressing the S222E mutant as compared with control cell lines . P01133 induced a rapid decrease in P49841 activity ( 50 % ) in control and S222E cells ; however , only 25 and 10 % inhibition in P49841 activity was observed in cell lines expressing the dominant negative mutants K97A and S222A , respectively , suggesting that inhibition of GSK - 3 was partially blocked in these cells . Taken together , these results suggest that the action of P01133 on GSK - 3 inactivation is mediated by the RSK / MAPK signaling pathway in NIH / 3T3 cells and provide evidence for a mechanism regulating GSK - 3 activity in intact cells .",
"P11678 induces expression of cholinergic genes via cell surface neural interactions . Eosinophils localize to and release their granule proteins in close association with nerves in patients with asthma and rhinitis . These conditions are associated with increased neural function . In this study the effect of the individual granule proteins on cholinergic neurotransmitter expression was investigated . P11678 ( EPO ) upregulated choline acetyltransferase ( P28329 ) and vesicular acetylcholine transporter ( Q16572 ) gene expression . Fluorescently labeled EPO was seen to bind to the IMR - 32 cell surface . Both Poly - DB00142 ( P00747 ) and Heparinase - 1 reversed the up - regulatory effect of EPO on P28329 and Q16572 expression and prevented EPO adhesion to the cell surface . Poly - L - arginine ( PLA ) had no effect on expression of either gene , suggesting that charge is necessary but insufficient to alter gene expression . EPO induced its effects via the activation of NF - κB . MEK inhibition led to reversal of all up - regulatory effects of EPO . These data indicate a preferential role of EPO signaling via a specific surface receptor that leads to neural plasticity .",
"Neem leaf glycoprotein suppresses regulatory T cell mediated suppression of monocyte / macrophage functions . We have shown that neem leaf glycoprotein ( NLGP ) inhibits the regulatory T cell ( Tregs ) induced suppression of tumoricidal functions of P08571 (+) P34810 (+) monocyte / macrophages ( MO / Mφ ) from human peripheral blood . Cytotoxic efficacy of MO / Mφ toward macrophage sensitive cells , U937 , is decreased in presence of Tregs ( induced ) , however , it was increased further by supplementation of NLGP in culture . Associated Treg mediated inhibition of perforin / granzyme B expression and nitric oxide release from MO / Mφ was normalized by NLGP . Altered status of signature cytokines , like , IL - 12 , P22301 , P05231 , TNFα from MO / Mφ under influence of Tregs is also rectified by NLGP . Tregs significantly enhanced the expression of altered marker , mannose receptor ( CD206 ) on P34810 (+) cells that was downregulated upon NLGP exposure . In addition to tumoricidal functions , antigen presenting ability of MO / Mφ is hampered by Treg induced downregulation of P33681 , P42081 and HLA - DB01048 . NLGP upregulated these molecules in MO / Mφ even in the presence of Tregs . Treg mediated inhibition of MO / Mφ chemotaxis in contact dependent manner was also normalized partially by NLGP , where participation of P51681 was documented . Overall results suggest that Treg influenced pro - tumor MO / Mφ functions are rectified in a significant extent by NLGP to create an anti - tumor immune environment .",
"P00747 activator is involved in the hCG - induced neutrophil extravasation and vasopermeability increase in the rat testis . The role of proteolytic enzymes in the hCG - induced increase in testicular vasopermeability and neutrophil extravasation was studied using protease inhibitors . An intra - testicular injection of hCG together with incubation medium conditioned by polymorphonuclear leucocytes ( PMNs ) caused a significant increase in vasopermeability and a coincident extravasation of PMN ' s from the postcapillary venules in the rat testis . When p - aminobenzamidine , a serine protease inhibitor which inhibits urokinase - type plasminogen activator , was administered together with hCG in the incubation medium , both the permeability increase and PMN extravasation were prevented . DB06692 , another serine protease inhibitor , and Eglin C , a specific neutrophil elastase and cathepsin G inhibitor were , however , without effect . None of these inhibitors caused any non - specific vascular effects in the testis at the concentrations used . These results support the concept that the hCG - induced increase in vasopermeability in the rat testis is related to extravasation of PMNs and suggest that urokinase - type plasminogen activator is involved in migration of these cells through the postcapillary venular walls .",
"Clinical trials in thrombolytic therapy , Part 2 : The open - artery hypothesis and RAPID - 1 and RAPID - 2 . The open - artery hypothesis as supported by thrombolytic study results is discussed . The open - artery hypothesis states that survival after acute myocardial infarction ( AMI ) is maximized by achieving early and sustained patency of the infarct - related artery . However , two large multicenter trials did not detect any difference in mortality between patients given alteplase and patients given streptokinase , despite previous evidence that alteplase led to earlier recanalization of infarct - related arteries . The Global Utilization of DB00086 and Tissue P00747 Activator for Occluded Coronary Arteries ( GUSTO - 1 ) trial suggested that early and complete patency is essential for short - term survival after AMI . Subsequent observations indicated that an open infarct - related artery at the time of hospital discharge is associated with improved long - term survival . In the ___MASK54___ Angiographic Phase II International Dose - Finding ( RAPID - 1 ) trial , complete patency was more frequent in patients who received a double - bolus regimen of reteplase than in patients who received standard - dose alteplase . Similar results were obtained in the ___MASK54___ versus DB00009 Patency Investigation during Myocardial Infarction ( RAPID - 2 ) trial , which compared the same double - bolus reteplase regimen with an accelerated regimen of alteplase . In both RAPID studies , mortality was lower and other outcomes were more favorable in reteplase recipients . ___MASK54___ seems more likely to produce normal blood flow soon after AMI than either standard - dose or accelerated alteplase and may be associated with a lower mortality rate . This lends further support to the open - artery hypothesis .",
"Targetting esophageal and gastric cancers with monoclonal antibodies . Target therapies and notably monoclonal antibodies are currently being considered for esophageal , gastric , and gastroesophageal junction cancers . P00533 was found to be overexpressed in 60 - 86 % of gastric or gastroesophageal tumors and in 50 - 70 % of esophageal cancers . Cetuximab was shown to be a radiosensitizing agent in the treatment of ENT neoplasia . These results led to several phase II encouraging therapeutic trials evaluating the combination of cetuximab with radiochemotherapy in locally advanced esophageal cancers . Numerous encouraging phase II trials evaluating cetuximab combined with chemotherapy in patients with gastric adenocarcinoma or gastroesophageal junction cancer were reported . These promising results are still to be confirmed by the ongoing phase III trials . Several studies reported P04626 overexpression in gastric cancer ( 7 - 34 % ) , which appeared to be associated with poorer prognosis . ___MASK7___ is a monoclonal antibody directed against the extracellular P04626 domain . The international phase III trial known as ToGA ( ___MASK7___ for Gastric Cancer ) aimed to determine the clinical efficacy and acceptable toxicity profile of trastuzumab in combination with first - line chemotherapy in P04626 - overexpressing gastric or gastroesophageal cancer . Angiogenesis is an essential step in the initial phase of tumorigenesis , and it is normally absent from healthy tissues except for particular physiological situations , such as wound healing . P15692 plays a role in endothelial growth and angiogenesis . DB00112 , a humanized monoclonal anti - P15692 antibody , is currently being studied for gastric cancer . The phase III AVAGAST study , evaluating bevacizumab in association with chemotherapy in advanced gastric adenocarcinoma , did not achieve its primary aim of improved OS in bevacizumab - treated patients .",
"Retinoblastoma protein induction by HIV viremia or P51681 in monocytes exposed to HIV - 1 mediates protection from activation - induced apoptosis : ex vivo and in vitro study . We have previously described an antiapoptotic steady - state gene expression profile in circulating human monocytes from asymptomatic viremic HIV (+) donors , but the mechanism associated with this apoptosis resistance remains to be fully elucidated . Here , we show that Rb1 activation is a dominant feature of apoptosis resistance in monocytes exposed to HIV - 1 in vivo ( as measured ex vivo ) and in vitro . Monocytes from asymptomatic viremic HIV (+) individuals show a positive correlation between levels of hypophosphorylated ( active ) Rb1 and VL in conjunction with increases in other p53 - inducible proteins associated with antiapoptosis regulation , such as P38936 and P05121 ( P05121 ) , when compared with circulating monocytes from uninfected donors . Monocytes exposed in vitro to HIV - 1 R5 isolates but not X4 isolates showed lower caspase - 3 activation after apoptosis induction , indicating a role for the P51681 signaling pathway . Moreover , monocytes exposed to R5 HIV - 1 or MIP - 1 β induced Rb1 and P38936 expression and an accumulation of autophagy markers , LC3 and Beclin . The inhibition of Rb1 activity in HIV - 1 R5 viral - exposed monocytes using siRNA led to increased apoptosis sensitivity , thereby confirming a central role for Rb1 in the antiapoptotic phenotype . Our data identify Rb1 induction in chronic asymptomatic HIV - 1 infection as a mediator of apoptosis resistance in monocytes in association with protective autophagy and contributing to monocyte survival during immune activation and / or HIV - 1 viremia .",
"The effect of prenatal nicotine on mRNA of central cholinergic markers and hematological parameters in rat fetuses . A number of studies have demonstrated the influence of nicotine on fetal development . This study determined the expression of choline acetyltransferase ( P28329 ) , vesicular acetylcholine transporter ( Q16572 ) , and high - affinity choline transporter ( Q9GZV3 ) in the forebrain and hindbrain following chronic prenatal nicotine exposure in the rat fetus ( maternal rats were subcutaneously injected with nicotine at different gestation periods ) . We also measured the effect of chronic nicotine exposure on fetal blood pO ( 2 ) , pCO ( 2 ) , pH , Na (+) and K (+) concentrations , as well as lactic acid levels . Maternal nicotine exposure during pregnancy was associated with a decrease in fetal pO ( 2 ) coupled with a significant increase in pCO ( 2 ) and lactic acid as well as restricted fetal growth . Additionally , maternal nicotine administration also reduced P28329 , Q16572 , and Q9GZV3 mRNA levels in the fetal brain . ___MASK58___ - induced fetal hypoxic responses and reduced cholinergic marker expression in the brain were more severe when nicotine was started in early gestation . Our results provide new information about the effects of repeated exposure to nicotine in utero on the expression of central P28329 , Q16572 , and Q9GZV3 in the rat fetus . These results indicate that repeated hypoxic episodes or / and a direct effect of nicotine on the central cholinergic system during pregnancy may contribute to brain developmental problems in fetal origin .",
"PknE , a serine / threonine protein kinase of Mycobacterium tuberculosis initiates survival crosstalk that also impacts HIV coinfection . DB00133 threonine protein kinases ( STPK ) play a major role in the pathogenesis of Mycobacterium tuberculosis . Here , we examined the role of STPK pknE , using a deletion mutant ΔpknE in the modulation of intracellular signaling events that favor M . tuberculosis survival . Phosphorylation kinetics of MAPK ( p38MAPK , Erk½ and SAPK / JNK ) was defective in ΔpknE compared to wild - type infected macrophages . This defective signaling dramatically delayed and reduced the phosphorylation kinetics of transcription factors P39905 - 2 and c - P05412 in ΔpknE infected macrophages . MAPK inhibitors instead of reducing the phosphorylation in ΔpknE infected macrophages , revealed crosstalks with Erk½ signaling influenced by SAPK / JNK and p38 pathways independently . Modulations in intra cellular signaling altered the expression of coreceptors P51681 and P61073 in ΔpknE infected macrophages . In conclusion , pknE plays a role in MAPK crosstalks that enables intracellular survival of M . tuberculosis . This survival strategy also impacts HIV / TB coinfection .",
"Biomarkers of low - grade inflammation in primary varicose veins of the lower limbs . OBJECTIVE : To analyze serum biomarkers of CVD in selected patients with primary axial reflux of great saphenous vein in one or both lower limbs . PATIENTS AND METHODS : Ninety - six patients affected by uncomplicated varicose veins , were enrolled in the study . A unilateral , primary axial reflux in great saphenous veins was detected in 54 patients ( U - CVD group ) and a bilateral one in 42 ( B - CVD group ) . Sixty - five age and sex - matched subjects without venous reflux were enrolled as controls . Mean venous pressure of both lower limbs at the distal great saphenous vein ( mGSVP ) and venous reflux were measured by continuous - wave Doppler ultrasound and echoduplex scanning , respectively . Reactive DB09140 Species ( ROS ) , tissue P00747 Activator ( t - PA ) and its Inhibitor 1 ( P05121 ) activities , Hematocrit ( HTC ) , White Blood Cells ( WBC ) , Neutrophyls ( P04626 ) , Platelets ( Q02083 ) , DB09222 ( FIB ) and Blood Viscosity ( BV ) were assessed in blood samples drawn from the antecubital vein . RESULTS : B - CVD group showed higher fibrinogen values ( p < 0 . 005 ) and higher mean venous pressure ( 0 < 0 . 0001 ) in comparison to controls , while U - CVD did not . No difference was found between both groups and controls for all the other parameters . CONCLUSIONS : Increased fibrinogen levels in patients with bilateral varicose veins may represent an early warning signal , as it could be associated to the long - term progression of chronic venous disease .",
"The mitogen - activated protein kinase p38 regulates activator protein 1 by direct phosphorylation of c - Jun . The involvement of p38 in fundamental physiological processes and the fact that deregulation often leads to disease indicates the potential impact of p38 dependent mechanisms . Here we demonstrate a new pathway that includes the induction of the mitogen activated protein kinase p38 by protein kinase C and results in a specific phosphorylation of c - Jun in T - lymphocytes . O75791 directly phosphorylates c - Jun within its transactivation domain at serine 63 and serine 73 and thus posttranscriptionally affects the presence of DNA - bound phosphorylated c - Jun , a prerequisite for activator protein 1 dependent gene transcription . Moreover , DNA - binding activity of c - Fos , FosB , and JunB were also dependent on the p38 protein kinase activity , whereas JunD , Fra - 1 and Fra - 2 were not affected . Although we show that stress induced mitogen activated protein kinases share c - Jun as a substrate for phosphorylation , p38 mediated effects could not be rescued by the c - Jun N - terminal kinases . This demonstrates that the protein kinase p38 plays a unique and non - redundant role in posttranslational c - Jun regulation . The induction of a p38 dependent c - Jun phosphorylation was comparable in both P01730 (+) and CD8 (+) T - cells , proposing a ubiquitous pathway that is not linked to T - cell subtype and effector function . In contrast , P39905 - 2 was predominantly phosphorylated in CD8 (+) T - cells . Different cell lines show p38 - dependent c - Jun phosphorylation upon phorbol ester induction but there is evidence that the simian virus 40 large T - antigen may interfere with this pathway .",
"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK56___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .",
"___MASK58___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .",
"___MASK90___ inhibits stimulated feline liver and gallbladder bicarbonate secretion . Bile acidification is a key factor in preventing calcium carbonate precipitation and gallstone formation . P00918 ( CA II ) , that is inhibited by acetazolamide , plays a role in regulation of the acid - base balance in many tissues . This study examines the effect of acetazolamide on secretin - and vasoactive intestinal peptide ( P01282 ) - stimulated gallbladder mucosal bicarbonate and acid secretion . Gallbladders in anaesthetized cats were perfused with a bicarbonate buffer bubbled with CO2 in air . In 20 experiments P01282 ( 10 microg kg (- 1 ) h (- 1 ) ) and in 10 experiments secretin ( 4 microg kg (- 1 ) h (- 1 ) ) were infused continuously intravenous ( i . v . ) . Hepatic bile and samples from the buffer before and after perfusion of the gallbladder were collected for calculation of ion and fluid transport . During basal conditions a continuous secretion of H + by the gallbladder mucosa was seen . Intravenous infusion of vasoactive intestinal peptide ( P01282 ) and secretin caused a secretion of bicarbonate from the gallbladder mucosa ( P < 0 . 01 ) . This secretion was reduced by intraluminal ( i . l . ) acetazolamide ( P < 0 . 01 ) . Bile flow was enhanced by infusion of P01282 and secretin ( P < 0 . 01 ) but this stimulated outflow was not affected by i . v . acetazolamide . The presence of CA II in the gallbladder was demonstrated by immunoblotting . Biliary CA activity has an important function in the regulation of P01282 - and secretin - stimulated bicarbonate secretion across the gallbladder mucosa .",
"[ Monoclonal antibody therapy for disorders of hemostasis and coagulation ] . Monoclonal antibody therapies have conducted to not only hematologic malignancies but also disorders of hemostasis and coagulation . This article describes the recent advances of monoclonal antibody therapy for bleeding disorders such as idiopathic thrombocytopenic purpura ( ITP ) , hemophilia A , disseminated intravascular coagulation ( DIC ) , and thrombosis . DB00073 , chimeric anti - P11836 monoclonal antibody treatment has a valuable effect in the patients with ITP , and clinical trials using anti - P29965 monoclonal antibody for ITP are underway . Anti - P29965 monoclonal antibody can be an alternative therapy for hemophilia A patients with inhibitors to factor VIII . In thrombosis , anti - tissue factor monoclonal antibody and anti - factor IX ( a ) monoclonal antibody were established as novel anticoagulant regents . P00747 activator inhibitor - 1 ( P05121 ) increases in endotoxin - induced DIC and many thrombotic diseases such as myocardial infarction , type 2 diabetes mellitus , and hyperlipidemia . Anti - P05121 monoclonal antibody reduced fibrin deposition in DIC mouse model . Treatment of these monoclonal antibodies for the molecules regulating coagulation - fibrinolysis system may be utilized for acute coronary syndrome and venous thrombosis .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . ___MASK54___ ( Ret ) and DB00031 ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"[ The role of glycogen synthase kinase - 3 beta in the pathogenesis of liver ischemia reperfusion injury ] . OBJECTIVE : To investigate the role of the key intracellular signaling molecule glycogen synthase kinase - 3 beta in the mechanism of liver ischemia reperfusion ( IR ) . METHODS : C57BL / 6 mice were subjected to 90 min warm liver cephalad lobe ischemia , followed by various length of reperfusion . Experiment groups included sham control group , liver IRI model group and glycogen synthase kinase - 3 beta inhibitor - treated group ( SB216763 in DB01093 , 25 g / kg , i . p , 2 hour prior to the onset of liver ischemia ) . The expression of glycogen synthase kinase - 3 beta protein was analysed by Western blotting . The serum ALT levels were determined to reflect the function of liver . The affected liver lobes were harvested for histology analysis . The inflammatory gene expression was detected by Quantitative PCR . RESULTS : By western blot analysis , we found that ischemia itself activated glycogen synthase kinase - 3 beta by a significant decrease of its phosphorylation . P49841 inhibitor SB216763 - pretreatment ameliorated the liver damages significantly as compared to the controls ( sALT : 2046 +/- 513 U / L vs 5809 +/- 1689 U / L , P = 0 . 0153 ) , and suppressed the gene expressions of IL - 12 , TNFa , IL - 1b and P05231 . CONCLUSIONS : This study demonstrated that the ischemia process modulated liver innate immune activation via a GSK - 3 - dependent mechanism which favored the development of a pro - inflammation response and lead to liver tissue damages . GSK - 3b may be a new therapeutic target to ameliorate liver IRI in transplant patients .",
"Activation of c - fos by lipopolysaccharide in glial cells via p38 mitogen - activated protein kinase - dependent activation of serum or cyclic AMP / calcium response element . Pathological conditions such as ischaemic stroke and inflammatory disorders cause c - fos activation in the brain . This activation contributes to the initiation of the brain ' s inflammatory response , orchestrated by activated glial cells . The inflammatory signalling cascades leading to c - fos activation in glial cells are not well characterized . Thus , we have attempted a detailed analysis of the cis - acting elements , transcription factors and upstream kinase pathways involved in the activation of c - fos by lipopolysaccharide ( LPS ) in primary rat cortical glial cells . We found that ( 1 ) LPS - induced c - fos mRNA levels were sensitive to p38 mitogen - activated protein kinase ( MAPK ) inhibitors but not to mitogen - activated / extracellular signal - regulated kinase ( P29323 ) or calcium - calmodulin - dependent kinase inhibitors , ( 2 ) LPS activated both serum response element ( SRE ) and cyclic AMP / calcium response element ( CRE ) - driven luciferase reporters in transient transfection assays , ( 3 ) LPS induced the phosphorylation of Elk1 CRE - binding protein ( CREB ) / activated transcription factor - 1 ( P39905 - 1 ) and the activation of GAL4 - Elk1 and GAL4 - CREB chimeric proteins , and ( 4 ) mutation of both SRE and CRE elements was necessary and sufficient to completely abolish LPS induction of a rat c - fos proximal promoter - luciferase reporter . Thus , c - fos activation by LPS in glial cells occurs via the SRE or CRE in an independent manner , and involves the Elk1 or CREB / P39905 - 1 transcription factors . Elk1 - mediated transactivation was dependent on p38 MAPK , suggesting a crucial role of these factors in mediating inflammatory responses in the CNS .",
"Survivin expression in breast cancer predicts clinical outcome and is associated with P04626 , P15692 , urokinase plasminogen activator and P05121 . BACKGROUND : Survivin , a novel inhibitor of apoptosis , is one of the most cancer - specific proteins identified to date . In this study we ( a ) evaluated the association between survivin and P04626 , vascular endothelial growth factor ( P15692 ) and uPA / P05121 expression and ( b ) defined its effect on clinical outcome in a large breast cancer patient cohort . PATIENTS AND METHODS : Survivin expression was measured by ELISA in primary breast cancer tissue extracts from 420 patients with long - term clinical follow - up . RESULTS : Survivin was detected in 378 ( 90 % ) of the 420 primary breast cancer cases . Increased survivin levels were significantly associated with high nuclear grade ( P < 0 . 0001 ) , negative hormone receptor status ( P = 0 . 0028 ) , P04626 overexpression ( P = 0 . 0094 ) , P15692 expression ( P < 0 . 0001 ) , high uPA ( P = 0 . 0002 ) and P05121 levels ( P = 0 . 0002 ) . Using the 25th percentile ( 1 . 4 ng / mg ) as a cut - off point , patients expressing elevated survivin had a significantly worse disease - free survival ( DFS : P = 0 . 0007 , RR 1 . 97 ) and overall survival ( OS : P = 0 . 0009 , RR 2 . 11 ) compared with patients expressing lower levels of survivin . In multivariate analysis , this prognostic value of survivin was independent of both traditional and novel clinicopathologic factors for both DFS ( P = 0 . 0076 , RR 1 . 72 ) and OS ( P = 0 . 0155 , RR 1 . 76 ) . CONCLUSIONS : The independent prognostic relevance of survivin , when combined with previous data from model systems implicating survivin in the inhibition of apoptosis , suggests that survivin may be a suitable target for future therapeutic strategies .",
"MIF - I and postsynaptic receptor sites for dopamine . In an attempt to determine the mechanism by which the tripeptide l - prolyl - l - leucyl - glycine amide ( P00747 , MIF - I ) exerts its antiparkinsonian effect , the action of this substance on various postsynaptic components of striatal dopaminergic nerves was studied . It was shown that injection of rats with MIF - I ( 1 mg / kg , IPX5 , 24 hr intervals ) did not alter tyrosine hydroxylase , dopa decarboxylase , choline acetyltransferase and glutamic acid decarboxylase activities in the striatum under the conditions tested . The activities of adenylate cyclase , dopamine - stimulated adenylate cyclase , and guanylate cyclase were not altered in vitro by various concentrations of MIF - I ( 0 . 1 to 1000 micrometer ) , although P01282 and neurotensin had some effect . Also the rate of uptake of 3H - dopamine by rat striatal synaptosomes was unchanged , as was the binding of 3H - dopamine and 3H - spiperone to beef caudate membranes . This series of studies indicates that MIF - I does not act directly on the striatal dopamine postsynaptic receptor under the conditions tested , although it is possible that MIF - I could act indirectly at this or another site in vivo by releasing or activating some other factor .",
"[ A novel function of anti - fibrinolytic factor , P05121 , in the central nervous system : a possible role as the neurotrophic factor ] . P00747 activator inhibitor - 1 ( P05121 ) is a serpin that suppresses fibrinolysis by inhibiting the activity of plasminogen activator ( PA ) . Together with PA , P05121 is expressed in the central nervous system and may play a role in the regulation of PA activity . Our present study has demonstrated that , in cultures of PC - 12 neurons , depletion of P05121 from the culture medium induces disappearance of the cell ' s neurites and the cell death . DB06692 and antipain , the inhibitors of PA , were not counterparts of P05121 in the protection of neurite disappearance . We also found that P05121 had the abilities to promote release of the survival factors of neurons , P05231 and P15692 and activation of a survival serine / threonine kinase Akt . These results suggest that P05121 has physiological functions other than its role as PA inhibitor for the survival of neurons .",
"Effect of atorvastatin on endothelial function and inflammation in long - duration type 1 diabetic patients without coronary heart disease and arterial hypertension . AIM : We evaluated the ability of atorvastatin , an P04035 inhibitor , to affect endothelial function and inflammation in long - duration ( > 10 years ) type 1 diabetes mellitus ( T1DM ) patients without coronary heart disease ( Q8NE62 ) and arterial hypertension ( AH ) . METHODS AND RESULTS : We randomized 204 Caucasians with long - duration T1DM into either the atorvastatin 40 mg / day plus hypolipaemic diet group ( n = 154 ) or the placebo plus hypolipaemic diet group ( n = 50 ) for 6 months . Endothelium - dependent flow - mediated ( FMD ) and endothelium - independent flow - mediated vasodilatation , serum levels of plasminogen activator inhibitor - 1 ( P05121 ) , P04275 ( P04275 ) and high sensitivity P02741 ( hs - CRP ) were estimated before and after treatment . After 6 months of therapy , FMD was increased by 44 % in the atorvastatin plus diet group compared with the placebo plus diet group . Treatment with atorvastatin led to a significant reduction in levels of P05121 and hs - CRP ; however , the elevation of P04275 level was observed . In the placebo plus diet group , we observed a significant reduction in levels of hs - CRP but not of P04275 and P05121 . CONCLUSIONS : ___MASK56___ improves endothelial function and reduces some proinflammatory and prothrombotic markers of atherosclerosis in T1DM patients without Q8NE62 and AH . The surprising effect of atorvastatin on serum P04275 levels in T1DM requires further study .",
"Transcriptional activation of the human Q9UEF7 gene by epidermal growth factor in HEK293 cells ; role of Egr - 1 . Q9UEF7 is an antiaging gene involved in the suppression of several age - related phenotypes , but few studies have examined the mechanism underlying the regulation of human Q9UEF7 gene expression . In this study , we investigated the transcriptional regulation of the Q9UEF7 gene by epidermal growth factor ( P01133 ) in HEK293 human embryonic kidney cells . By using serial deletion constructs of the promoter , we identified a proximal 45 bp ( - 90 to - 45 ) region responsible for P01133 - induced promoter activity . The Egr - 1 - binding motif is located within this region . Forced expression of Egr - 1 stimulated Q9UEF7 gene promoter activity . A point mutation in the Egr - 1 - binding motif abrogated promoter inducibility by P01133 or ectopic Egr - 1 expression . Knockdown of Egr - 1 by expression of small interfering RNA ( siRNA ) attenuated P01133 - induced Q9UEF7 promoter activity . Further analysis showed that the Ras / MEK / Erk signaling cascade is involved in P01133 - induced activation of the Q9UEF7 promoter . We conclude that the Q9UEF7 gene is activated by P01133 in HEK293 cells .",
"Expression of epidermal growth factor and its receptor in normal and diseased human kidney : an immunohistochemical and in situ hybridization study . The kidney is one of the major sites of P01133 production and there it seems to play several biological functions , such as modulation of cell growth , renal repair following injury , regulation of cellular metabolism and glomerular haemodinamics . The present study was first aimed at localizing P01133 and its receptor ( R ) in normal human kidney by immunohistochemical and in situ hybridization techniques . Then , the distribution of the growth factor and its R was explored in biopsy specimens from eight patients with acute tubulointerstitial damage . In the normal human kidney , both P01133 immunoreactivity and P01133 mRNA were localized in tubular profiles corresponding to Henle ' s loop and , although to a lesser intensity , to distal convoluted tubule . P01133 immunostaining was remarkable mainly at the apical surface of tubular cells . P01133 - R protein expression was detected in glomerular endothelial cells , in peritubular capillaries and arteriolar walls , as well as along the thick ascending limb of Henle ' s lop and distal convoluted tubule , where it colocalized with Tamm - Horsfall protein . Immunohistochemical analysis of tubular profiles revealed that P01133 - R was located especially along the basolateral membrane of tubular cells and within the basal part of cytoplasm . Endogenous alkaline phosphatase and P29972 positive tubules did not show any signal for P01133 and its receptor . Kidneys with acute tubulointerstitial injury exhibited a dramatic decrease of P01133 expression , whereas P01133 - R showed only minor modifications . Interestingly , P01133 - R was localized to both apical and antiluminal membranes of positive tubular cells . It is concluded that P01133 - P01133 receptor loop may be relevant in the pathogenesis of acute tubulointerstitial damage and recovery from tubular injury , while its role in the physiological renewal of the urothelium remains speculative .",
"CXC chemokine ligand 4 ( P02776 ) down - regulates CC chemokine receptor expression on human monocytes . During acute inflammation , monocytes are essential in abolishing invading micro - organisms and encouraging wound healing . Recruitment by CC chemokines is an important step in targeting monocytes to the inflamed tissue . However , cell surface expression of the corresponding chemokine receptors is subject to regulation by various endogenous stimuli which so far have not been comprehensively identified . We report that the platelet - derived CXC chemokine ligand 4 ( P02776 ) , a known activator of human monocytes , induces down - regulation of CC chemokine receptors ( CCR ) 1 , - 2 , and - 5 , resulting in drastic impairment of monocyte chemotactic migration towards cognate CC chemokine ligands ( DB00833 ) for these receptors . Interestingly , P02776 - mediated down - regulation of P32246 , P41597 and P51681 was strongly dependent on the chemokine ' s ability to stimulate autocrine / paracrine release of P01375 - α . In turn , P01375 - α induced the secretion P10147 and P13236 , two chemokines selective for P32246 and P51681 , while the secretion of P41597 - ligand P13500 was P01375 - α - independent . Culture supernatants of P02776 - stimulated monocytes as well as chemokine - enriched preparations thereof reproduced P02776 - induced CCR down - regulation . In conclusion , P02776 may act as a selective regulator of monocyte migration by stimulating the release of autocrine , receptor - desensitizing chemokine ligands . Our results stress a co - ordinating role for P02776 in the cross - talk between platelets and monocytes during early inflammation .",
"P04035 inhibitors up - regulate anti - aging klotho mRNA via RhoA inactivation in IMCD3 cells . OBJECTIVE : Q9UEF7 is thought to play a critical role in the development of age - related disorders including arteriosclerosis . Statins may exert vascular protective effects , independent of the lowering of plasma cholesterol levels . We investigated the impact of statins on mRNA expression of the age - suppressor gene , klotho in mIMCD3 cells . METHODS AND RESULTS : Q9UEF7 mRNA levels were evaluated with real - time RT - PCR . ___MASK56___ and pitavastatin increased the expression of klotho mRNA in a dose - dependent manner . This stimulatory effect was abolished by the addition of mevalonate , GGPP and FPP , essential molecules for isoprenylation of the small GTPase Rho . As was the case with the statin treatment , inhibition of Rho - kinase by Y27632 up - regulated klotho mRNA . In contrast to the statin treatment , stimulation with angiotensin II down - regulated klotho mRNA expression without obvious morphological changes . Furthermore , pretreatment with atorvastatin blunted the angiotensin II - induced response and ameliorated the decrease in klotho mRNA expression towards basal levels . RhoA activity was further evaluated by detection of its translocation . Angiotensin II activated RhoA , whereas statins potently inactivated RhoA and blocked RhoA activation by angiotensin II . CONCLUSION : Statins inactivate the RhoA pathway , resulting in over - expression of klotho mRNA , which may contribute to the novel pleiotropic effects of statins towards vascular protection .",
"Shikonin , a component of antiinflammatory Chinese herbal medicine , selectively blocks chemokine binding to CC chemokine receptor - 1 . Shikonin is a chemically characterized component of traditional Chinese herbal medicine and has been shown to possess antiinflammatory activities . We ascertained that shikonin blocked radiolabelled Regulated on Activation , Normal T cell Expressed and Secreted ( RANTES ) and macrophage inflammatory protein - 1 ( MIP - 1alpha ) binding to human monocytes with IC50 values of 3 . 58 x 10 (- 6 ) and 2 . 57 x 10 (- 6 ) M , respectively . In contrast , up to 1 . 7 x 10 (- 5 ) M of shikonin failed to inhibit stromal cell - derived factor - 1 ( SDF - 1alpha ) binding to the cells . Additionally , shikonin blocked RANTES and MIP - 1alpha binding to stable CC chemokine receptor - 1 ( P32246 ) transfected human embryonic kidney ( P29320 ) / 293 cells with IC50 values of 2 . 63 x 10 (- 6 ) and 2 . 57 x 10 (- 6 ) M , respectively . However , shikonin inhibited neither RANTES nor MIP - 1alpha binding to P51681 transfected P29320 / 293 cells . Shikonin also did not inhibit monocyte chemoattractant protein - 1 ( P13500 ) binding to P41597 cells , eotaxin binding to P51677 cells , interferon - inducible T cell alpha - chemoattractant ( O14625 ) binding to P49682 cells and SDF - 1alpha binding to P61073 cells . Additionally , shikonin inhibited RANTES - induced P32246 cell migration , but did not inhibit P32246 cell migration induced by epidermal growth factor ( P01133 ) . Our study suggests shikonin may be a target for the future design of more potent , highly selective therapeutics that could be useful antiinflammatory agents for selectively blocking the binding of P32246 ligands .",
"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK7___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK7___ is also being investigated as part of triplet drug regimens . ___MASK7___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .",
"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK71___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .",
"Adenoviral expression of a urokinase receptor - targeted protease inhibitor inhibits neointima formation in murine and human blood vessels . BACKGROUND : Smooth muscle cell migration , in addition to proliferation , contributes to a large extent to the neointima formed in humans after balloon angioplasty or bypass surgery . P00747 activator / plasmin - mediated proteolysis is an important mediator of this smooth muscle cell migration . Here , we report the construction of a novel hybrid protein designed to inhibit the activity of cell surface - bound plasmin , which can not be inhibited by its natural inhibitors , such as alpha ( 2 )- antiplasmin . This hybrid protein , consisting of the receptor - binding amino - terminal fragment of uPA ( P39905 ) , linked to the potent protease inhibitor bovine pancreas trypsin inhibitor ( DB06692 ) , can inhibit plasmin activity at the cell surface . METHODS AND RESULTS : The effect of adenovirus - mediated P39905 . DB06692 expression on neointima formation was tested in human saphenous vein organ cultures . Infection of human saphenous vein segments with Ad . CMV . P39905 . DB06692 ( 5x10 ( 9 ) pfu / mL ) resulted in 87 . 5 +/- 3 . 8 % ( mean +/- SEM , n = 10 ) inhibition of neointima formation after 5 weeks , whereas Ad . CMV . P39905 or Ad . CMV . DB06692 virus had only minimal or no effect on neointima formation . The efficacy of P39905 . DB06692 in vivo was demonstrated in a murine model for neointima formation . Neointima formation in the femoral artery of mice , induced by placement of a polyethylene cuff , was strongly inhibited ( 93 . 9 +/- 2 % ) after infection with Ad . CMV . mATF . DB06692 , a variant of P39905 . DB06692 able to bind specifically to murine uPA receptor ; Ad . CMV . mATF and Ad . CMV . DB06692 had no significant effect . CONCLUSIONS : These data provide evidence that adenoviral transfer of a hybrid protein that binds selectively to the uPA receptor and inhibits plasmin activity directly on the cell surface is a powerful approach to inhibiting neointima formation and restenosis .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK12___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"A field synopsis and meta - analysis of genetic association studies in peripheral arterial disease : The CUMAGAS - PAD database . In an electronic search of the literature , the authors systematically retrieved all published studies that investigated genetic susceptibility to peripheral arterial disease ( PAD ) . They created a comprehensive database of all eligible studies , collecting detailed genetic and bioinformatics data on each polymorphism . Data from eligible studies were synthesized using meta - analysis techniques . Gene variants were classified into distinct pathophysiologic pathways , and their potential involvement in PAD pathogenesis was determined . Forty - one publications that examined 44 gene polymorphisms were included . For 37 polymorphisms , the variant form had a functional effect . Twenty - three polymorphisms in 22 potential PAD candidate genes ( F2 , P02675 , P42898 , P05106 , P12821 , AGT , P05231 , P13500 , P05362 , P16581 , P14780 , P37231 , P03956 , P35611 , Q9H244 , P11150 , Q13093 , Q8WTV0 , P08254 , P55157 , P08519 , P32297 ) showed a significant association in individual studies . Eighty - eight percent of the studies had statistical power of less than 50 % , and in 15 studies the genotype distribution in the control group did not conform to Hardy - Weinberg equilibrium . Data on 12 polymorphisms ( P12259 1691 G / A , P42898 677C / T , F2 20210 G / A , P05106 1565 T / C , P12821 I / D , AGT 704C / T , AGT - 6G / A , AGT 733C / T , P05231 - 174 G / C , P14780 - 1562C / T , P05362 1462A / G , P32297 831C / T ) were synthesized , and a positive association was found for 3 ( P05231 - 174 G / C , P05362 1462A / G , P32297 831C / T ) .",
"Molecular genetics of attention - deficit / hyperactivity disorder : an overview . As heritability is high in attention - deficit / hyperactivity disorder ( ADHD ) , genetic factors must play a significant role in the development and course of this disorder . In recent years a large number of studies on different candidate genes for ADHD have been published , most have focused on genes involved in the dopaminergic neurotransmission system , such as P21917 , P21918 , Q01959 / Q01959 , P09172 , DDC . Genes associated with the noradrenergic ( such as NET1 / P23975 , P08913 , P18825 ) and serotonergic systems ( such as 5 - HTT / P31645 , P28222 , P28223 , Q8IWU9 ) have also received considerable interest . Additional candidate genes related to neurotransmission and neuronal plasticity that have been studied less intensively include P60880 , P43681 , DB01221 , P23560 , P01138 , P20783 , P34130 / 5 , P39905 . This review article provides an overview of these candidate gene studies , and summarizes findings from recently published genome - wide association studies ( GWAS ) . GWAS is a relatively new tool that enables the identification of new ADHD genes in a hypothesis - free manner . Although these latter studies could be improved and need to be replicated they are starting to implicate processes like neuronal migration and cell adhesion and cell division as potentially important in the aetiology of ADHD and have suggested several new directions for future ADHD genetics studies .",
"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK29___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK29___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK29___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .",
"___MASK29___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation ."
] |
[
"___MASK12___",
"___MASK29___",
"___MASK41___",
"___MASK54___",
"___MASK56___",
"___MASK58___",
"___MASK71___",
"___MASK7___",
"___MASK90___"
] |
___MASK54___
|
MH_train_461
|
interacts_with DB01083?
|
[
"Genetic polymorphisms , the metabolism of estrogens and breast cancer : a review . Breast cancer is the most common female cancer and the second cause of cancer death in women . Despite recent breakthroughs , much of the etiology of this disease is unknown and the most important risk factor , i . e . , exposure to endogenous and exogenous estrogen throughout life can not explain the heterogeneity of prognosis nor clinical features of patients . Recently , many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors . This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease . Polymorphisms in the genes P05093 , P11511 , P04798 , P05177 , Q16678 , P22309 , P50225 , 17 - hydroxysteroid - dehydrogenase , P21964 , Q86UG4 , P03372 , and Q92731 are described .",
"Mechanisms for epigallocatechin gallate induced inhibition of drug metabolizing enzymes in rat liver microsomes . DB03823 gallate ( EGCG ) inhibits drug metabolizing enzymes by unknown mechanisms . Here we examined if the inhibition is due to covalent - binding of EGCG to the enzymes or formation of protein aggregates . EGCG was incubated with rat liver microsomes at 1 - 100μM for 30min . The EGCG - binding proteins were affinity purified using m - aminophenylboronic acid agarose and probed with antibodies against glyceraldehyde - 3 - phosphate dehydrogenase ( P04406 ) , actin , cytochrome P450 ( CYP ) 1A1 , P05177 , CYP2B1 / 2 , P05181 , CYP3A , catechol - O - methyltransferase ( P21964 ) and microsomal glutathione transferase 1 ( P10620 ) . All but actin and soluble P21964 were positively detected at ≥ 1μM EGCG , indicating EGCG selectively bound to a subset of proteins including membrane - bound P21964 . The binding correlated well with inhibition of CYP activities , except for P05181 whose activity was unaffected despite evident binding . The antioxidant enzyme P10620 , but not cytosolic GSTs , was remarkably inhibited , providing novel evidence supporting the pro - oxidative effects of EGCG . When microsomes incubated with EGCG were probed on Western blots , all but the actin and P05181 antibodies showed a significant reduction in binding at ≥ 1μM EGCG , suggesting that a fraction of the indicated proteins formed aggregates that likely contributed to the inhibitory effects of EGCG but were not recognizable by antibodies against the intact proteins . This raised the possibility that previous reports on EGCG regulating protein expression using P04406 as a reference should be revisited for accuracy . Remarkable protein aggregate formation in EGCG - treated microsomes was also observed by analyzing Coomassie Blue - stained SDS - PAGE gels . EGCG effects were partially abolished in the presence of 1mM glutathione , suggesting they are particularly relevant to the in vivo conditions when glutathione is depleted by toxicant insults .",
"P50591 ( P50591 ) regulates adipocyte metabolism by caspase - mediated cleavage of PPARgamma . P01375 α ( TNFα ) and other members of the P01375 family affect adipose tissue metabolism and contribute to the obesity - related inflammation of adipose tissue . Here , we sought to identify the effects of P50591 ( P50591 ) on fat cell biology . P50591 - receptor 2 ( O14763 ) and its mouse homolog DR5 were regulated upon acute and chronic energy imbalance in murine and human adipose tissue . P50591 inhibited insulin - stimulated glucose uptake and de novo lipogenesis in human adipocytes . Interestingly , P50591 did not interfere with the phosphorylation of insulin - stimulated kinases such as Akt or Erk and did not activate the NF - κB pathway . Instead , P50591 activated cleavage of caspase - 8 and caspase - 3 . The subsequent cleavage of PPARγ led to its inactivation and resulted in reduced expression of lipogenic genes , such as Glut - 4 , P49327 , and ACC . Taken together , we discovered a so far unknown function of the death ligand P50591 in regulating adipocyte metabolism . Our results imply that P50591 / P50591 - R system might provide a new target for the prevention and treatment of obesity and its co - morbidities .",
"Clozapine treatment causes oxidation of proteins involved in energy metabolism in lymphoblastoid cells : a possible mechanism for antipsychotic - induced metabolic alterations . There is increasing concern about the serious metabolic side effects and neurotoxicity caused by atypical ( second - generation ) antipsychotics . In a previous study by our group ( Walss - Bass et al . Int J Neuropsychopharmacol 2008 ; 11 : 1097 - 104 ) , using a novel proteomic approach , we showed that clozapine treatment in SKNSH cells induces oxidation of proteins involved in energy metabolism , leading us to hypothesize that protein oxidation could be a mechanism by which atypical antipsychotics increase the risk for metabolic alterations . In this study , the same proteomic approach was used to identify specific proteins oxidized after clozapine treatment in lymphoblastoid cell lines from patients with schizophrenia and normal controls . Cells were treated with 0 and 20 μM clozapine for 24 hours and protein extracts were labeled with 6 - iodoacetamide fluorescein ( 6 - IAF ) . The lack of incorporation of 6 - IAF into the thiol group of cysteine residues is an indicator of protein oxidation . Labeled proteins were exposed to two dimensional electrophoresis , and differential protein labeling was assessed . Increased oxidation after clozapine treatment was observed in 9 protein spots ( P < 0 . 05 ) . The following 7 proteins were identified by high - performance liquid chromatography - electrospray ionization tandem mass spectrometry ( HPLC - P19957 - MS / MS ) in those 9 spots : enolase , triosephosphate isomerase ( P60174 ) , glyceraldehyde - 3 - phosphate dehydrogenase ( P04406 ) , Rho GDP dissociation inhibitor ( GDI ) , cofilin , uridine monophosphate / cytidine monophosphate ( UMP - P21941 ) kinase , and translation elongation factor . Several of these proteins play important roles in energy metabolism and mitochondrial function . These results further support the hypothesis that oxidative stress may be a mechanism by which antipsychotics increase the risk of metabolic syndrome and diabetes .",
"Brain involvement in rheumatoid arthritis : a magnetic resonance spectroscopy study . OBJECTIVE : P01375 alpha was recently implicated as an important mediator of communication between the peripheral and cerebral immune systems in an animal model of chronic inflammation . The purpose of this study was to examine by proton magnetic resonance spectroscopy ( ( 1 ) H - P59665 ) the influence of inflammation on cerebral metabolism in patients with rheumatoid arthritis ( RA ) . METHODS : Single - voxel ( 1 ) H - P59665 of the centrum semiovale was performed on 35 RA patients ( 6 men and 29 women ; mean +/- SD age 51 . 8 +/- 14 . 6 years ) and 28 healthy age - and sex - matched control subjects ( 9 men and 19 women ; mean +/- SD age 50 . 2 +/- 10 . 4 years ) . None of the study subjects had any neurologic signs or symptoms . Clinical markers of disease activity were correlated with the ( 1 ) H - P59665 findings . RESULTS : Patients with active RA , as reflected by an elevated erythrocyte sedimentation rate ( P03372 ) , had a significantly higher ratio of choline to creatine and a significantly lower ratio of N - acetylaspartate to choline than did patients with inactive RA , as reflected by a normal P03372 . Moreover , the ratios of choline to creatine and NAA to choline were significantly correlated with the P03372 after correction for age , sex , smoking status , handedness , alcohol consumption , medication use , and disease duration . Medication use had no additional effect on these associations . CONCLUSION : Our data show that systemic inflammation in RA is associated with metabolic changes in the brain .",
"Up - regulation of acetyl - DB01992 carboxylase alpha and fatty acid synthase by human epidermal growth factor receptor 2 at the translational level in breast cancer cells . Expression of the P04626 oncogene is increased in approximately 30 % of human breast carcinomas and is closely correlated with the expression of fatty acid synthase ( P49327 ) . In the present study , we determined the mechanism by which P49327 and acetyl - DB01992 carboxylase alpha ( ACCalpha ) could be induced by P04626 overexpression . SK - BR - 3 and BT - 474 cells , breast cancer cells that overexpress P04626 , expressed higher levels of P49327 and ACCalpha compared with MCF - 7 and MDA - MB - 231 breast cancer cells in which P04626 expression is low . The induction of P49327 and ACCalpha in BT474 cells were not mediated by the activation of P36956 . Exogenous P04626 expression in MDA - MB - 231 cells induced the expression of P49327 and ACCalpha , and the P04626 - mediated increase in ACCalpha and P49327 was inhibited by both LY294002 , a phosphatidylinositol 3 - kinase inhibitor , and rapamycin , a mammalian target of rapamycin ( P42345 ) inhibitor . In addition , the activation of P42345 by the overexpression of Q15382 in MDA - MB - 231 cells increased the synthetic rates of both P49327 and ACCalpha . On the other hand , P49327 and ACCalpha were reduced in BT - 474 cells by a blockade of the P42345 signaling pathway . These changes observed in their protein levels were not accompanied by changes in their mRNA levels . The 5 '- and 3 '- untranslated regions of both P49327 and ACCalpha mRNAs were involved in selective translational induction that was mediated by P42345 signal transduction . These results strongly suggest that the major mechanism of P04626 - mediated induction of P49327 and ACCalpha in the breast cancer cells used in this study is translational regulation primarily through the P42345 signaling pathway .",
"Lessons learned from the irinotecan metabolic pathway . ___MASK26___ , a camptothecin analogue , is a prodrug which requires bioactivation to form the active metabolite SN - 38 . SN - 38 acts as a P11387 poison . ___MASK26___ has been widely used in the treatment of metastatic colorectal cancer , small cell lung cancer and several other solid tumors . However , large inter - patient variability in irinotecan and SN - 38 disposition , as well as severe but unpredictable diarrhea limits the clinical potential of irinotecan . Intense clinical pharmacology studies have been conducted to elucidate its complicated metabolic pathways and to provide scientific rationale in defining strategies to optimize drug therapy . ___MASK26___ is subjected to be shunted between P08684 mediated oxidative metabolism to form two inactive metabolites P25054 or NPC and tissue carboxylesterase mediated hydrolysis to form SN - 38 which is eventually detoxified via glucuronidation by P22309 to form SN - 38G . The pharmacology of this compound is further complicated by the existence of genetic inter - individual differences in activation and deactivation enzymes of irinotecan ( e . g . , P08684 , P20815 , P22309 ) and sharing competitive elimination pathways with many concomitant medications , such as anticonvulsants , St . John ' s Wort , and ketoconazole . Efflux of the parent compound and metabolites out of cells by several drug transporters ( e . g . , Pgp , Q9UNQ0 , MRP1 , Q92887 ) also occurs . This review highlights the latest findings in drug activation , transport mechanisms , glucuronidation , and CYP3A - mediated drug - drug interactions of irinotecan in order to unlock some of its complicated pharmacology and to provide ideas for relevant future studies into optimization of this promising agent .",
"The epigenetic drug 5 - azacytidine interferes with cholesterol and lipid metabolism . DNA methylation and histone acetylation inhibitors are widely used to study the role of epigenetic marks in the regulation of gene expression . In addition , several of these molecules are being tested in clinical trials or already in use in the clinic . Antimetabolites , such as the DNA - hypomethylating agent 5 - azacytidine ( 5 - AzaC ) , have been shown to lower malignant progression to acute myeloid leukemia and to prolong survival in patients with myelodysplastic syndromes . Here we examined the effects of DNA methylation inhibitors on the expression of lipid biosynthetic and uptake genes . Our data demonstrate that , independently of DNA methylation , 5 - AzaC selectively and very potently reduces expression of key genes involved in cholesterol and lipid metabolism ( e . g . Q8NBP7 , P04035 , and P49327 ) in all tested cell lines and in vivo in mouse liver . Treatment with 5 - AzaC disturbed subcellular cholesterol homeostasis , thereby impeding activation of sterol regulatory element - binding proteins ( key regulators of lipid metabolism ) . Through inhibition of P11172 , 5 - AzaC also strongly induced expression of 1 - acylglycerol - 3 - phosphate O - acyltransferase 9 ( Q53EU6 ) and promoted triacylglycerol synthesis and cytosolic lipid droplet formation . Remarkably , complete reversal was obtained by the co - addition of either UMP or cytidine . Therefore , this study provides the first evidence that inhibition of the de novo pyrimidine synthesis by 5 - AzaC disturbs cholesterol and lipid homeostasis , probably through the glycerolipid biosynthesis pathway , which may contribute mechanistically to its beneficial cytostatic properties .",
"Maintenance of intratumoral androgens in metastatic prostate cancer : a mechanism for castration - resistant tumor growth . Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor ( AR ) . Despite anorchid serum androgen levels , nearly all patients develop castration - resistant disease . We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration - resistant growth . Using mass spectrometry and quantitative reverse transcription - PCR , we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue , untreated primary prostate cancer , metastases from patients with castration - resistant prostate cancer , and xenografts derived from castration - resistant metastases . DB00624 levels within metastases from anorchid men [ 0 . 74 ng / g ; 95 % confidence interval ( 95 % CI ) , 0 . 59 - 0 . 89 ] were significantly higher than levels within primary prostate cancers from untreated eugonadal men ( 0 . 23 ng / g ; 95 % CI , 0 . 03 - 0 . 44 ; P < 0 . 0001 ) . Compared with primary prostate tumors , castration - resistant metastases displayed alterations in genes encoding steroidogenic enzymes , including up - regulated expression of P49327 , P05093 , P14060 , P37058 , P11511 , and O75795 and down - regulated expression of P31213 ( P < 0 . 001 for all ) . Prostate cancer xenografts derived from castration - resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals . Metastatic prostate cancers from anorchid men express transcripts encoding androgen - synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival . We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens . Maximal therapeutic efficacy in the treatment of castration - resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment .",
"A new mechanism of drug resistance in breast cancer cells : fatty acid synthase overexpression - mediated palmitate overproduction . Multidrug resistance is a major problem in successful cancer chemotherapy . Various mechanisms of resistance , such as ABC transporter - mediated drug efflux , have been discovered using established model cancer cell lines . While characterizing a drug - resistant breast cancer cell line , MCF7 / AdVp3000 , we found that fatty acid synthase ( P49327 ) is overexpressed . In this study , we showed that ectopic overexpression of P49327 indeed causes drug resistance and that reducing the P49327 expression increased the drug sensitivity in breast cancer cell lines MCF7 and MDA - MB - 468 but not in the normal mammary epithelial cell line MCF10A1 . Use of P49327 inhibitor , DB01083 , at low concentrations also sensitized cells with P49327 overexpression to anticancer drugs . The P49327 - mediated drug resistance appears to be due to a decrease in drug - induced apoptosis from an overproduction of palmitic acid by P49327 . Together with previous findings of P49327 as a poor prognosis marker for breast cancer patients , our results suggest that P49327 overexpression is a new mechanism of drug resistance and may be an ideal target for chemosensitization in breast cancer chemotherapy .",
"Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with DB01083 reduces cell viability and triggers apoptosis . P49327 ( P49327 ) , catalyzing the de novo synthesis of fatty acids , is known to be deregulated in several cancers . Inhibition of this enzyme reduces tumor cell proliferation . Unfortunately , adverse effects and chemical instability prevent the in vivo use of the best - known inhibitors , Cerulenin and C75 . DB01083 , a drug used for obesity treatment , is also considered as a potential P49327 inhibitor , but its impact on glioma cell biology has not yet been described . In this study , we analyzed P49327 expression in human glioma samples and primary glioblastoma cell cultures and the effects of P49327 inhibition with DB01083 , Cerulenin and C75 . Immunohistochemistry followed by densitometric analysis of 20 glioma samples revealed overexpression of P49327 that correlated with the WHO tumor grade . Treatment of glioblastoma cells with these inhibitors resulted in a significant , dose - dependent reduction in tumor cell viability and fatty acid synthesis . Compared to Cerulenin and C75 , DB01083 was a more potent inhibitor in cell cultures and cell lines . In LN229 , cell - growth was reduced by 63 . 9 ± 8 . 7 % after 48 h and 200 µM DB01083 compared to controls ; in LT68 , the reduction in cell growth was 76 . 3 ± 23 . 7 % . Nuclear fragmentation assay and Western blotting analysis after targeting P49327 with DB01083 demonstrated autophagy and apoptosis . Organotypic slice cultures treated with DB01083 showed reduced proliferation after Ki67 staining and increased caspase - 3 cleavage . Our results suggest that P49327 may be a therapeutic target in malignant gliomas and identify DB01083 as a possible anti - tumor drug in this setting .",
"Genome - wide expression profiling reveals transcriptomic variation and perturbed gene networks in androgen - dependent and androgen - independent prostate cancer cells . Previously , we have developed a unique in vitro LNCaP cell model , which includes androgen - dependent ( LNCaP - C33 ) , androgen - independent ( LNCaP - C81 ) and an intermediate phenotype ( LNCaP - C51 ) cell lines resembling the stages of prostate cancer progression to hormone independence . This model is advantageous in overcoming the heterogeneity associated with the prostate cancer up to a certain extent . We characterized and compared the gene expression profiles in LNCaP - C33 ( androgen - dependent ) and LNCaP - C81 ( androgen - independent ) cells using Affymetrix GeneChip array analyses . Multiple genes were identified exhibiting differential expression during androgen - independent progression . Among the important genes upregulated in androgen - independent cells were O60245 , P56180 , Q01534 , P29320 , P14210 , MET , P01133 , Q9H6X2 , etc . , whereas many candidate tumor suppressor genes ( Q9BUP3 , CDKN2A , P42772 , P49918 , P04637 , O15350 , P05362 , O15524 / 2 , O43597 , P67775 , Q08209 , etc . ) were decreased . Pathway prediction analysis identified important gene networks associated with growth - promoting and apoptotic signaling that were perturbed during androgen - independent progression . Further investigation of one of the genes , P67775 , which encodes the catalytic subunit of a serine phosphatase PP2A , a potent tumor suppressor , revealed that its expression was decreased in prostate cancer compared to adjacent normal / benign tissue . Furthermore , the downregulated expression of P67775 was significantly correlated with tumor stage and Gleason grade . Future studies on the identified differentially expressed genes and signaling pathways may be helpful in understanding the biology of prostate cancer progression and prove useful in developing novel prognostic biomarkers and therapy for androgen - refractory prostate cancer .",
"Visualizing inhibition of fatty acid synthase through mass spectrometric analysis of mitochondria from melanoma cells . P49327 ( P49327 ) is the metabolic enzyme responsible for the endogenous synthesis of the saturated long - chain fatty acid palmitate . In contrast to most normal cells , P49327 is overexpressed in a variety of human cancers including cutaneous melanoma , in which its levels of expression are associated with a poor prognosis and depth of invasion . Recently , we have demonstrated the mitochondrial involvement in P49327 inhibition - induced apoptosis in melanoma cells . Herein we compare , via electrospray ionization mass spectrometry ( P19957 - MS ) , free fatty acids ( FFA ) composition of mitochondria isolated from control ( EtOH - treated cells ) and DB01083 - treated B16 - F10 mouse melanoma cells . Principal component analysis ( DB11245 ) was applied to the P19957 - MS data and found to separate the two groups of samples . Mitochondria from control cells showed predominance of six ions , that is , those of m / z 157 ( Pelargonic , 9 : 0 ) , 255 ( Palmitic , 16 : 0 ) , 281 ( Oleic , 18 : 1 ) , 311 ( Arachidic , 20 : 0 ) , 327 ( Docosahexaenoic , 22 : 6 ) and 339 ( Behenic , 22 : 0 ) . In contrast , P49327 inhibition with DB01083 changes significantly mitochondrial FFA composition by reducing synthesis of palmitic acid , and its elongation and unsaturation products , such as arachidic and behenic acids , and oleic acid , respectively . P19957 - MS of mitochondria isolated from DB01083 - treated cells presented therefore three major ions of m / z 157 ( Pelargonic , 9 : 0 ) , 193 ( unknown ) and 199 ( Lauric , 12 : 0 ) . These findings demonstrate therefore that P49327 inhibition by DB01083 induces significant changes in the FFA composition of mitochondria .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK57___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect .",
"Transient overexpression of mitochondrial transcription factor A ( Q00059 ) is sufficient to stimulate mitochondrial DNA transcription , but not sufficient to increase mtDNA copy number in cultured cells . Mitochondrial transcription factor A ( Q00059 ) stimulates transcription from mitochondrial DNA ( mtDNA ) promoters in vitro and in organello . To investigate whether changes of Q00059 levels also modulate transcription and replication in situ , the protein was transiently overexpressed in cultured cells . Mitochondrial mRNAs were significantly elevated at early time points , when no expansion of the Q00059 pool was yet observed , but were decreased when Q00059 levels had doubled , resemb - ling in vitro results . P29320 cells contain about 35 molecules of Q00059 per mtDNA . High levels of Q00059 were not associated with increases of full - length mtDNA , but nucleic acid species sensitive to RNAse H increased . Stimulation of transcription was more evident when Q00059 was transiently overexpressed in cells pre - treated with ethidium bromide ( EBr ) having lowered mtDNA , Q00059 and mitochondrial transcript levels . EBr rapidly inhibited mtDNA transcription , while decay of mtDNA was delayed and preferentially slowly migrating , relaxed mtDNA species were depleted . In conclusion , we show that transcription of mtDNA is submaximal in cultured cells and that a subtle increase of Q00059 within the matrix is sufficient to stimulate mitochondrial transcription . Thus , this protein meets all criteria for being a key factor regulating mitochondrial transcription in vivo , but other factors are necessary for increasing mtDNA copy number , at least in cultured cells .",
"Tumor growth retardation and chemosensitizing action of fatty acid synthase inhibitor orlistat on T cell lymphoma : implication of reconstituted tumor microenvironment and multidrug resistance phenotype . BACKGROUND : DB01083 , a fatty acid synthase ( P49327 ) inhibitor , has been demonstrated to inhibit tumor cell survival . However , the mechanism ( s ) of its tumor growth retarding action against malignancies of hematological origin remains unclear . It is also not understood if the antitumor action of orlistat implicates modulated susceptibility of tumor cell to anticancer drugs . Therefore , the present investigation focuses to study the antitumor and chemosensitizing action of orlistat in a murine host bearing a progressively growing T cell lymphoma . METHODS : Tumor - bearing mice were administered with vehicle alone or containing orlistat followed by administration of PBS with or without cisplatin . Tumor progression and survival of tumor - bearing host were monitored along with analysis of tumor cell survival and apoptosis . Tumor ascitic fluid was examined for pH , NO and cytokines . Expression of genes and proteins was investigated by RT - PCR and western blot respectively . ROS was analyzed by DCFDA staining and P49327 activity by spectrophotometry . RESULTS : DB01083 administration to tumor - bearing mice resulted in tumor growth retardation , prolonged life span , declined tumor cell survival and chemosensitization to cisplatin . It was accompanied by increased osmotic fragility , modulated acidosis , expression of ROS , NO , cytokines , Q9ULC4 and VH (+) ATPase , Bcl2 , P42574 , P04637 , inhibited P49327 activity and declined expression of MDR and P21926 proteins . CONCLUSION : DB01083 manifests antitumor and chemosensitizing action implicating modulated regulation of cell survival , reconstituted - tumor microenvironment and altered MDR phenotype . GENERAL SIGNIFICANCE : These observations indicate that orlistat could be utilized as an adjunct regimen for improving antitumor efficacy of cisplatin .",
"Premature labor : a state of platelet activation ? OBJECTIVE : This study was undertaken to determine whether premature labor is associated with changes in the maternal plasma concentration of soluble P29965 ( sCD40L ) , a marker of platelet activation . METHODS : A cross - sectional study included patients in the following groups : 1 ) non - pregnant ( n = 21 ) ; 2 ) normal pregnancy ( n = 71 ) ; 3 ) normal pregnancy at term with ( n = 67 ) and without labor ( n = 88 ) ; 4 ) preterm labor ( P16233 ) with intact membranes ( n = 136 ) that was divided into the following sub - groups : 4a ) P16233 who delivered at term ( n = 49 ) ; 4b ) P16233 without intra - amniotic infection and / or inflammation ( IAI ) who delivered preterm ( n = 54 ) ; and 4c ) P16233 with IAI who delivered preterm ( n = 33 ) . sCD40L concentrations were measured by ELISA . RESULTS : The median maternal plasma sCD40L concentration was higher in pregnant than non - pregnant women ( P = 0 . 017 ) . Patients with P16233 had a higher median maternal plasma sCD40L concentration than women with normal pregnancies , regardless of the presence or absence of IAI and gestational age at delivery ( P < 0 . 001 for all comparisons ) . IAI was not associated with a higher median maternal plasma concentration of sCD40L . CONCLUSIONS : Normal pregnancy is a state in which there is a physiologic increase of sCD40L . P16233 was associated with an increased median maternal plasma sCD40L concentration that could not be accounted for by IAI . Thus , our findings suggest that platelet activation occurs during an episode of preterm labor .",
"Quantification of Ureaplasma urealyticum DNA in the amniotic fluid from patients in P16233 and pPROM and its relation to inflammatory cytokine levels . OBJECTIVE : To study the effect of the amniotic fluid quantity of Ureaplasma urealyticum DNA on inflammatory response levels in women with preterm labor ( P16233 ) and preterm prelabor rupture of membranes ( pPROM ) . DESIGN : A prospective multi - center follow up study . SETTING : Sahlgrenska University Hospital , Goteborg , Sweden and Turku University Hospital , Turku , Finland . SAMPLE : Eleven U . urealyticum positive samples obtained after transabdominal amniocenteses in 197 women presenting with P16233 and pPROM . METHODS : The U . urealyticum positive samples were analyzed with real - time polymerase chain reaction , using the Lightcycler instrument with primers specific for U . urealyticum 16 S rDNA . The amniotic fluid samples were analyzed for tumor necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 6 , IL - 1beta and P22301 with enzyme - linked immunosorbent assays . MAIN OUTCOME MEASURES : Correlation between U . urealyticum DNA concentrations in the amniotic fluid and inflammatory cytokine levels . RESULTS : The concentrations of U . urealyticum DNA varied between 0 . 024 and 934 microg / mL . A significant correlation between U . urealyticum DNA and P01375 level was observed . No correlation with the other cytokines was found . Women with PTLhad higher levels of U . urealyticum DNA and a different cytokine pattern than women with pPROM . CONCLUSIONS : U . urealyticum in the amniotic fluid induces an inflammatory reaction in a dose dependent manner and the quantity of U . urealyticum DNA is well correlated with the level of the inflammatory cytokine P01375 .",
"Detection of anti - isoniazid and anti - cytochrome P450 antibodies in patients with isoniazid - induced liver failure . Isoniazid ( ___MASK71___ ) - induced hepatotoxicity remains one of the most common causes of drug - induced idiosyncratic liver injury and liver failure . This form of liver injury is not believed to be immune - mediated because it is not usually associated with fever or rash , does not recur more rapidly on rechallenge , and previous studies have failed to identify anti - ___MASK71___ antibodies ( Abs ) . In this study , we found Abs present in sera of 15 of 19 cases of ___MASK71___ - induced liver failure . Anti - ___MASK71___ Abs were present in 8 sera ; 11 had anti - cytochrome P450 ( CYP ) 2E1 Abs , 14 had Abs against P05181 modified by ___MASK71___ , 14 had anti - P08684 antibodies , and 10 had anti - P11712 Abs . ___MASK71___ was found to form covalent adducts with P05181 , P08684 , and P11712 . None of these Abs were detected in sera from ___MASK71___ - treated controls without significant liver injury . The presence of a range of antidrug and autoAbs has been observed in other drug - induced liver injury that is presumed to be immune mediated . CONCLUSION : These data provide strong evidence that ___MASK71___ induces an immune response that causes ___MASK71___ - induced liver injury .",
"Evaluation of hypoxia inducible factor expression in inflammatory and neurodegenerative brain models . The neuroinflammatory process is thought to contribute to the progression of neurological disorders and brain pathologies . The release of pro - inflammatory cytokines and chemokines by activated glial cells , astrocytes and microglia plays an important role in this process . However , the role of hypoxia - inducible factor - 1α ( HIF - 1α ) , the key transcription factor regulating the expression of hypoxia - inducible genes , during glial activation is less known . Thus , we examined the significance of HIF - 1α in three experimental models : first in an acute model of inflammation induced by pro - inflammatory cytokines P01375 - α , IL - 1β and IFN - γ ; secondly , in a chronic model of inflammation using an APPswe / PS1dE9 ( P05067 / P49768 ) transgenic mouse model of Alzheimer ' s disease and thirdly via the inhibition of the PI3K / AKT pathway in a model of neuronal apoptosis . During acute glial inflammation induced by in vitro administration of P01375 - α , IL - 1β and IFN - γ , mRNA expression levels of HIF - 1α were significantly upregulated ; however , this effect was blocked by SP600126 , a pharmacological inhibitor of mitogen - activated protein kinases ( MAPKs ) . These data suggest that MAPKs could be involved in HIF - 1α regulation . In addition , we observed that HIF - 1α is not involved in the neuronal apoptotic process mediated by P19957 - kinase inhibition , which is regulated by c - Jun . Finally , we did not detect significant differences in the expression of HIF - 1α mRNA in P05067 / P49768 mice during the course of the study ( 3 - 12 months of age ) . Thus , we demonstrated that HIF - 1α has a prominent role in acute but not in chronic inflammatory processes , such as the one which occurs in the P05067 / P49768 experimental model of AD . Moreover , HIF - 1α is not involved in neuronal apoptosis after PI3K / AKT inhibition .",
"[ Screening of proteins regulated by Q9UL16 gene in nasopharyngeal carcinoma using proteomics technology ] . OBJECTIVE : To screen the proteins under regulation by the candidate tumor suppressor gene Q9UL16 using proteomics technology in nasopharyngeal carcinoma ( NPC ) . METHODS : The cellular proteins were extracted from 3D8 NPC cells with Q9UL16 overexpression and the control P13671 NPC cells . Two - dimensional ( 2D ) gel electrophoresis was employed to compare the protein expression profiles between these two cells , and the differential proteins were identified using peptide mass fingerprinting and database searching . Real - time PCR and Western blotting were used to validate the expression levels of the differential proteins . RESULTS : Matrix - assisted laser desorption / time of flight showed that 3 differential proteins , namely P49327 , P07339 and P00558 , were down - regulated by - 3 . 28 , - 1 . 64 , and - 6 . 97 folds , respectively , which were confirmed by real - time PCR and Western blotting . CONCLUSION : P49327 , P07339 and P00558 are probably the target proteins regulated by Q9UL16 in NPC .",
"RC0639 : phase II study of paclitaxel , trastuzumab , and lapatinib as adjuvant therapy for early stage P04626 - positive breast cancer . DB01259 adds to the efficacy of trastuzumab in preclinical models and also in the neo - adjuvant setting . This study assesses the safety and feasibility of adding lapatinib to paclitaxel and trastuzumab ( Q07283 ) as part of the adjuvant therapy for P04626 - positive breast cancer ( P04626 + BC ) . In this single - arm phase II study , patients with stages I - III P04626 + BC received standard anthracycline - based chemotherapy followed by weekly taxane , with concurrent standard trastuzumab , plus daily lapatinib for a total of 12 months . The primary endpoint was symptomatic congestive heart failure , secondary endpoints included overall safety . A total of 109 eligible patients were enrolled . Median follow - up is 4 . 3 years . No patients experienced congestive heart failure while on treatment . Mean left ventricular ejection fraction at baseline and at the end of Q07283 were 63 . 6 % ( N = 109 , SD = 5 . 7 ) and 59 . 8 % ( N = 98 , SD = 8 . 1 ) , respectively [ mean change - 3 . 95 % ( N = 98 , SD = 8 . 3 ) , p < 0 . 001 ] . One hundred and two patients initiated post - AC treatment ; of them , 31 % experienced grade 3 ( no G4 ) diarrhea with lapatinib at 750 mg / day . The addition of lapatinib to paclitaxel and trastuzumab following AC does not add cardiac toxicity . DB01259 dose of 750 mg / day in combination with standard chemotherapy plus trastuzumab has acceptable overall tolerability .",
"Modulation of fatty acid synthase enzyme activity and expression during hepatitis C virus replication . The hepatitis C virus ( HCV ) induces alterations of host cells to facilitate its life cycle . P49327 ( P49327 ) is a multidomain enzyme that plays a key role in the biosynthesis of fatty acids and is upregulated during HCV infection . Herein , we applied activity - based protein profiling ( P05067 ) that allows for the identification of differentially active enzymes in complex proteomic samples , to study the changes in activity of P49327 during HCV replication . For this purpose , we used an activity - based probe based on the P49327 inhibitor DB01083 , and observed an increase in the activity of P49327 in the presence of a subgenomic and a genomic HCV replicon as well as in chimeric SCID / Alb - uPA mice infected with HCV genotype 1a . To study the molecular basis for this increase in P49327 activity , we overexpressed individual HCV proteins in Huh7 cells and observed increased expression and activity of P49327 in the presence of core and NS4B , as measured by western blots and P05067 , respectively . Triglyceride levels were also elevated in accordance with P49327 expression and activity . Lastly , immunofluorescence and P05067 imaging analyses demonstrated that while the abundance and activity of P49327 increases significantly in the presence of HCV , its localization does not change . Together these data suggest that the HCV - induced production of fatty acids and neutral lipids is provided by an increase in P49327 abundance and activity that is sufficient to allow HCV propagation without transporting P49327 to the replication complexes .",
"Q9UGN5 : a novel mammalian polymerizing ( ADP - ribosyl ) transferase gene related to truncated pADPRT homologues in plants and Caenorhabditis elegans . Until recently , poly ( ADP - ribosyl ) ation was supposed to be confined only to polymerizing ( ADP - ribosyl ) transferase /( ADP - ribose ) polymerase ( E . C . 2 . 4 . 2 . 30 ) . Here , we present novel polymerizing ( ADP - ribosyl ) transferase homologues from mouse and man that lack all of the N - terminal DNA binding and P38398 C - terminus domains and will be designated polymerizing ( ADP - ribosyl ) transferase - 2 as distinguished from the classical polymerizing ( ADP - ribosyl ) transferase ( polymerizing ( ADP - ribosyl ) transferase - 1 ) . The murine polymerizing ( ADP - ribosyl ) transferase - 2 gene shares three identical intron positions with its Caenorhabditis elegans ( EMBL nucleotide sequence database Z47075 ) and one with the Arabidopsis thaliana homologue ( ' P05067 ' , GenBank database AF069298 ) . Expression of the murine polymerizing ( ADP - ribosyl ) transferase - 2 gene was elevated in spleen , thymus and testis and the corresponding poly ( ADP - ribosyl ) ation activity might account for most of the residual poly ( ADP - ribosyl ) ation observed in polymerizing ( ADP - ribosyl ) transferase - 1 (-/-) mice .",
"Benzyl isothiocyanate ( BITC ) inhibits migration and invasion of human gastric cancer AGS cells via suppressing P29323 signal pathways . Metastasis suppressors and associated other regulators of cell motility play a critical initial role in tumor invasion and metastases . Benzyl isothiocyanate ( BITC ) is a hydrolysis compound of glucotropaeolin in dietary cruciferous vegetables . BITC has been found to exhibit prevention of cancers in laboratory animals and might also be chemoprotective in humans . Here , the purpose of this study was to investigate the effects of BITC on cell proliferation , migration , invasion and mitogen - activated protein kinase ( MAPK ) pathways of AGS human gastric cancer cells . Wound healing and Boyden chamber ( migration and invasion ) assays demonstrated that BITC exhibited an inhibitory effect on the abilities of migration and invasion in AGS cancer cells . BITC suppressed cell migration and invasion of AGS cells in a dose - dependent manner . Results from Western blotting indicated that BITC exerted an inhibitory effect on the P27361 / 2 , Ras , P62993 , Rho A , P35228 , P35354 for causing the inhibitions of P08253 , - 7 and - 9 then followed by the inhibitions of invasion and migration of AGS cells in vitro . BITC also promoted O14733 , Q99759 , c - jun , P45983 / 2 , P15692 , Sos1 , phosphoinositide 3 - kinase ( PI3K ) , PKC , nuclear factor - kappaB ( NF - κB ) p65 in AGS cells . Results from real - time polymerized chain reaction ( PCR ) showed that BITC inhibited the gene expressions of P08253 ,- 7 - 9 , Q05397 , Q13464 and RhoA after BITC treatment for 24 and 48 hours in AGS cells . Taken together , the finding may provide new mechanisms and functions of BITC , which inhibit migration and invasion of human gastric cancer AGS cells .",
"P49327 inhibitor orlistat induces apoptosis in T cell lymphoma : role of cell survival regulatory molecules . BACKGROUND : De novo fatty acid synthesis catalyzed by fatty acid synthase ( P49327 ) is crucial for tumor cell survival . Thus therapeutic targeting of P49327 is considered as a novel antineoplastic strategy . However , little is understood in this respect regarding malignancies of hematological origin . The present investigation was therefore , undertaken to study the molecular mechanisms of the antitumor action of P49327 inhibitor orlistat ( tetrahydrolipstatin ) using a murine model of a T cell lymphoma . METHODS : The antitumor efficacy of orlistat was investigated in vitro by estimating cell survival by MTT assay and apoptosis by Wright Giemsa , TUNEL , Annexin - V / PI staining and % DNA fragmentation . Generation of reactive oxygen species ( ROS ) in tumor cells was studied using fluorescence microscopy . Expression of genes and proteins was carried out by RT - PCR and western blot analyses respectively . P49327 and CPT - 1 activity was estimated by spectrophotometer . Cytokines expression was analyzed by ELISA . RESULTS : We report that inhibition of P49327 with its specific inhibitor orlistat manifests tumor - specific inhibition of cell survival , accompanied by induction of apoptosis . DB01083 - treated tumor cells showed an altered ROS generation , shift in cytokine balance and modulated expression of cell survival regulatory molecules like HSP70 , Bcl2 , p53 , PUMA , P42574 and CAD . It was observed that IFN - γ mediates orlistat - dependent modulation of P49327 expression . CONCLUSION AND GENERAL SIGNIFICANCE : In this study , we report some of the so far unexplored novel aspects underlying the molecular mechanisms associated with orlistat - dependent modulation of tumor cell survival . These observations will help in designing antineoplastic therapeutic protocols using orlistat against malignancies of hematological origin .",
"Enzymic hydrolysis of diol lipids by pancreatic lipase . Chain length and positional specificities of pancreatic lipase for diol lipids have been examined by use of the synthetic substrates such as the diol esters and related esters that contain P13671 -- C20 even - numbered saturated acids and oleic acid as fatty acids , and ethylene glycol , 1 , 2 - and 1 , 3 - propanediols , 1 , 3 - , 1 , 4 - , and 2 , 3 - butanediols , monohydric alcohols , and glycerol as alcohols . No remarkable difference in the degree of hydrolysis was observed in the case of diol esters having C14 -- C20 fatty acids at least during 30 - min digestion , though hydrolysis reached a maximum in diol diotanoates after the same period . P16233 specifically released only the fatty acids esterified with the primary hydroxyl groups of diols .",
"Naturally - occurring dimers of flavonoids as anticarcinogens . Biflavonoids are dimers of flavonoid moieties linked by a C - C or C - O - C bond . Simple , complex , rearranged , natural and ketalized Diels - Alder adducts , benzofuran derivatives , and spirobiflavonoids are some of the structural groups of biflavonoids . These compounds are mainly distributed in the Gymnosperms , Angiosperms ( monocots and dicots ) , ferns ( Pteridophyta ) , and mosses ( Bryophyta ) . Biflavonoids have shown a variety of biological activities , including anticancer , antibacterial , antifungal , antiviral , antiinflammatory , analgesic , antioxidant , vasorelaxant , anticlotting , among others . This work is focused on probably the most potentially relevant biological activity of biflavonoids , the anticancer activity and the involved mechanisms of action , such as induction of apoptosis [ inhibition of cyclic nucleotide phosphodiesterases ; effects on NF - κB family of transcription factors ; activation of caspase ( s ) ; inhibition effects on bcl - 2 expression , and upregulation of p53 and caspase - 3 gene expression ] ; inhibition of angiogenesis [ anti - proliferative effects ; activation of Rho - GTPases and P29323 signaling pathways ; inhibition of P49327 activity ] ; inhibition of pre - mRNA splicing ; inhibition of human DNA topoisomerases I and II - α ; anti - inflammatory / immunoregulatory effects [ inhibition of XO ; inhibition of proinflammatory enzymes , such as P04054 and P36551 ; effects on cytokines mediated P35354 and P35228 expression ] ; modulation of immune response ; inhibition of protein tyrosine phosphorylation ; antioxidant and analgesic activities in relation to the anticarcinogen behavior . For that reason the structures and anticarcinogenic activities of 83 biflavonoids are thoroughly discussed . The results of this work indicate that biflavonoids strongly affect the cancer cells with little effect on normal cell proliferation , suggesting a therapeutic potential against cancer .",
"Glycoprotein IIb / IIIa and Q9H244 receptor antagonists yield additive inhibition of platelet aggregation , granule secretion , soluble P29965 release and procoagulant responses . Glycoprotein IIb / IIIa ( P08514 / IIIa ) antagonists , including abciximab and tirofiban , are administered concurrently with clopidogrel , a Q9H244 antagonist , and aspirin in some patients undergoing percutaneous coronary intervention . We studied the effects of , and interactions between , abciximab , tirofiban , aspirin and the Q9H244 antagonist cangrelor on platelet aggregation , alpha and dense granule secretion and procoagulant responses in vitro . Blood was obtained from healthy volunteers . Platelet aggregation , dense granule secretion , alpha granule secretion ( P05121 and soluble P29965 levels ) and procoagulant responses ( annexin - V and microparticle formation ) were assessed using collagen and thrombin receptor activating peptide ( TRAP ) as agonists . All the antagonists used singularly inhibited collagen - induced responses . Combinations of abciximab or tirofiban with aspirin and / or cangrelor gave additive inhibition with the greatest effect seen when abciximab or tirofiban was combined with both aspirin and cangrelor . DB06441 inhibited TRAP - induced responses and , again , there was additive inhibition of these parameters when abciximab or tirofiban were combined with cangrelor . The P08514 / IIIa receptor plays an important role in amplification of platelet activation such that there are important interactions between P08514 / IIIa antagonists and inhibitors of both Q9H244 receptor activation and , to a lesser extent , thromboxane A2 generation . These interactions are likely to have important influences on the safety and efficacy of combination anti - platelet therapies .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK74___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"DB00898 dehydrogenase accentuates ethanol - induced myocardial dysfunction and mitochondrial damage in mice : role of mitochondrial death pathway . OBJECTIVES : Binge drinking and alcohol toxicity are often associated with myocardial dysfunction possibly due to accumulation of the ethanol metabolite acetaldehyde although the underlying mechanism is unknown . This study was designed to examine the impact of accelerated ethanol metabolism on myocardial contractility , mitochondrial function and apoptosis using a murine model of cardiac - specific overexpression of alcohol dehydrogenase ( DB00067 ) . METHODS : DB00067 and wild - type FVB mice were acutely challenged with ethanol ( 3 g / kg / d , i . p . ) for 3 days . Myocardial contractility , mitochondrial damage and apoptosis ( death receptor and mitochondrial pathways ) were examined . RESULTS : DB00898 led to reduced cardiac contractility , enlarged cardiomyocyte , mitochondrial damage and apoptosis , the effects of which were exaggerated by DB00067 transgene . In particular , DB00067 exacerbated mitochondrial dysfunction manifested as decreased mitochondrial membrane potential and accumulation of mitochondrial O ( 2 ) ( *- ) . Myocardium from ethanol - treated mice displayed enhanced Bax , P42574 and decreased Bcl - 2 expression , the effect of which with the exception of P42574 was augmented by DB00067 . DB00067 accentuated ethanol - induced increase in the mitochondrial death domain components pro - caspase - 9 and cytochrome C in the cytoplasm . Neither ethanol nor DB00067 affected the expression of P01160 , total pro - caspase - 9 , cytosolic and total pro - caspase - 8 , P01375 , Fas receptor , Fas L and cytosolic O95831 . CONCLUSIONS : Taken together , these data suggest that enhanced acetaldehyde production through DB00067 overexpression following acute ethanol exposure exacerbated ethanol - induced myocardial contractile dysfunction , cardiomyocyte enlargement , mitochondrial damage and apoptosis , indicating a pivotal role of DB00067 in ethanol - induced cardiac dysfunction possibly through mitochondrial death pathway of apoptosis .",
"The time course of Akt and P29323 activation on P98170 expression in P29320 293 cell line . The cell growth is controlled by the interaction of survival and cell growth arrest pathways as well as apoptosis mechanisms which determine the outcome of cell faith as proliferation or apoptosis . In this study , we have studied the activity of survival pathways , i . e . , Akt and P27361 / 2 with regard to P98170 ( inhibitor of apoptosis ) in serum starved and stimulated conditions . The P29320 - 293 cells were cultured in RPMI + 10 % FBS . The cells were serum starved by switching to medium with 1 % FBS for 24 h and serum stimulated by changing the medium to 10 % FBS following serum starvation . The expression of p - Akt , p - P29323 , Akt , P29323 and P98170 was studied in various time points using western blot . The apoptosis was evaluated by DNA condensation using Hoechst 33258 and P42574 assay . In serum starved condition expression of p - Akt and P98170 is very low . Serum stimulation increases p - Akt and p - P29323 within 5 min and sustains a high level for 30 min . The expression of total Akt and P27361 / 2 has not changed significantly for 24 h . P98170 expression starts at 6 h after serum stimulation , reaches to maximum level at 12 h and decreases to baseline within 24 h . Furthermore , serum starvation for 24 h does not induced apoptosis and DNA condensation . Taken together , the results indicate that serum activates Akt and P29323 pathways earlier than P98170 expression . Furthermore , P98170 expression is low in serum starvation unlike p - P29323 which suggests a survival role for P29323 in serums starvation . The expression pattern of P98170 indicates induction by Akt and / or P29323 activation which requires further studies .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK13___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"The lipase inhibitor tetrahydrolipstatin binds covalently to the putative active site serine of pancreatic lipase . DB01083 ( Q07283 ) is a selective inhibitor of fat absorption . In animal models , it has anti - obesity and anti - hypercholesterolemic activity and is presently in clinical trials for these indications . Q07283 binds covalently to pancreatic lipase . Complete inhibition of lipolytic activity is obtained concomitant with the incorporation of 1 mol of Q07283 / mol of enzyme . P16233 is the best studied lipase , but published results concerning its catalytic mechanism are still controversial . In order to learn more about the inhibitory mechanism of Q07283 , a selective lipase inhibitor interacting at or near the catalytic site , and therefore , to obtain more information on the catalytic mechanism of lipase , we have determined the amino acid residue to which Q07283 is bound . After proteolytic degradation of porcine pancreatic lipase inhibited with radioactively labeled Q07283 , the labeled peptides were isolated and analyzed by quantitative amino acid analysis , N - terminal sequencing , and by mass spectrometry with fast atom bombardment ionization . The data clearly show that Q07283 is bound as an ester to the serine 152 of the lipase .",
"Different glycosylation pattern of human IgG1 and IgG3 antibodies isolated from transiently as well as permanently transfected cell lines . The effector functions of IgG depend on the presence of carbohydrates attached to asparagine 297 in the Fc - portion . In this report , glycosylation profiles of recombinant wild - type and mutant IgG1 and IgG3 antibodies produced from three cell lines were analysed using LC - P19957 - Orbitrap . Clear differences were detected between IgG1 and IgG3 glycoforms , where IgG1 generally contained fucosylated glycoforms , whilst IgG3 mainly were non - fucosylated . When using NS - 0 and J558L cells for permanent transfection , IgG1 wt glycoforms differed between the two cell lines , whilst IgG3 wt glycoforms did not . Transiently transfected P29320 293E cells were used to produce IgG1 and IgG3 wt and mutants , affecting complement activation . Cell supernatants were harvested at early and late time points and analysed separately . IgGs harvested late showed simpler and less developed glycosylation structure compared to those harvested early . The IgG harvested early was slightly more effective in complement activation than those harvested late , whilst the antibody - dependent cell - mediated cytotoxicity was unaltered . Generally , the glycosylation pattern of the mutants tested , including a hinge truncate mutant of IgG3 , did not differ significantly from the wild - type IgGs . The striking difference in glycosylation pattern of IgG1 compared to IgG3 therefore appears not to be due to the long hinge region of IgG3 ( 62 amino acids ) relative to the IgG1 hinge region ( 15 amino acids ) . Furthermore , mutation variants at or near the C1q binding site showed similar glycosylation structure and difference in their complement activation activity observed earlier is thus most likely due to differences in protein structure only .",
"[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK26___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .",
"P49327 inhibition results in a magnetic resonance - detectable drop in phosphocholine . Expression of fatty acid synthase ( P49327 ) , the key enzyme in de novo synthesis of long - chain fatty acids , is normally low but increases in cancer . Consequently , P49327 is a novel target for cancer therapy . However , because P49327 inhibitors can lead to tumor stasis rather than shrinkage , noninvasive methods for assessing P49327 inhibition are needed . To this end , we combined ( 1 ) H , ( 31 ) P , and ( 13 ) C magnetic resonance spectroscopy ( P59665 ) ( a ) to monitor the metabolic consequences of P49327 inhibition and ( b ) to identify P59665 - detectable metabolic biomarkers of response . Treatment of PC - 3 cells with the P49327 inhibitor DB01083 for up to 48 h resulted in inhibition of P49327 activity by 70 % , correlating with 74 % inhibition of fatty acid synthesis . Furthermore , we have determined that P49327 inhibition results not only in lower phosphatidylcholine levels but also in a 59 % drop in the phospholipid precursor phosphocholine ( PCho ) . This drop resulted from inhibition in PCho synthesis as a result of a reduction in the cellular activity of its synthetic enzyme choline kinase . The drop in PCho levels following P49327 inhibition was confirmed in SKOV - 3 ovarian cancer cells treated with DB01083 and in MCF - 7 breast cancer cells treated with DB01083 as well as cerulenin . Combining data from all treated cells , the drop in PCho significantly correlated with the drop in de novo synthesized fatty acid levels , identifying PCho as a potential noninvasive P59665 - detectable biomarker of P49327 inhibition in vivo .",
"Both the ADP receptors P47900 and Q9H244 , play a role in controlling shape change in human platelets . Two types of ADP receptors , P2Y ( 1 ) and P2Y ( 12 ) are involved in platelet aggregation . The P2X ( 1 ) receptor is also present but its role , in terms of platelet function , is not yet defined . The aim of this study was to establish if the ADP receptors , P2Y ( 1 , ) P2Y ( 12 ) and P2X ( 1 ) play a role in controlling platelet shape change ( PSC ) in human platelets . PSC is an early phase of platelet activation that precedes aggregation . Using a high - resolution channelyzer , PSC was assessed by measuring the median platelet volume ( MPV ) . The P2Y ( 1 ) receptor antagonist P59665 2179 ( 1 . 06 - 10 . 25 micro mol / l ) blocked ADP - induced PSC ( by 100 % ) . The median IC ( 50 ) was 3 . 16 micro mol / l . P59665 2179 also significantly ( P = 0 . 01 ) inhibited PSC induced by the combination of ADP + serotonin ( 5HT ) . The P2Y ( 12 ) receptor antagonist AR - C69931MX significantly inhibited ( at 10s , P = 0 . 009 ; 15 s , P = 0 . 001 and 30 s , P = 0 . 015 ) ADP - induced PSC . The P2X ( 1 ) receptor antagonist TNP - DB00171 had no significant effect on ADP - or ADP + 5HT - induced PSC . We conclude that the IC ( 50 ) of a P2Y ( 1 )- blocker can be derived because of the high - resolution and reproducibility of the channelyzer technique . In addition to the P2Y ( 1 ) purinoceptor , the P2Y ( 12 ) receptor appears to be involved in ADP - induced PSC since this process was significantly inhibited by AR - C69931MX . The channelyzer technique may be more reliable than optical aggregometry to assess PSC .",
"Determination of ancestral allele for possible human cancer - associated polymorphisms . To determine ancestral allele in possible cancer - associated polymorphisms , DNA samples from 10 chimpanzees ( Pan troglodytes ) were sequenced for alleles corresponding to 17 polymorphisms : 8 short tandem repeats [ P18510 ( alias IL - 1RA ) variable number tandem repeat ( VNTR ) ; P04818 ( previously TS ) VNTR ; AR CAG repeat ; dinucleotide repeats of P22309 , IGF1 , P01579 ( alias P01579 ) , P03372 ( alias P03372 ) , and P00533 ] and 9 single nucleotide polymorphisms ( P03956 - 1607 1G / 2G , P08254 - 1171 5A / 6A , O15527 Ser326Cys , P05091 Gly487Lys , P04637 Arg72Pro , Q9UNQ0 Gln141Lys , P16455 Leu84Phe , P04179 Ala - 9Val , and P42898 Ala222Val ) . No chimpanzee polymorphism corresponded to human P18510 VNTR ; the ancestral allele was a repeat lost in humans . Dinucleotide repeat polymorphisms of IGF1 , P01579 , P03372 , and P00533 were shared by chimpanzees , but the length of repeats tended to be longer in humans than in chimpanzees . This tendency was particularly evident for IGF1 . All of the SNPs tested are human - specific nucleotide changes . The ancestral allele 7A was shown to be lost in P08254 - 1171 5A / 6A . Thus , all of the possible cancer - associated polymorphisms tested have human - specific alleles , and the ancestral allele is lost in three polymorphisms ( P18510 VNTR , P22309 CA repeat , and P08254 - 1171 5A / 6A ) , suggesting a possible involvement of human - specific alleles in cancer susceptibility .",
"Wnt - 11 signalling controls ventricular myocardium development by patterning P19022 and beta - catenin expression . AIMS : The stage - dependent organization of the cardiomyocytes during formation of the different layers of the developing ventricular wall is critical for the establishment of a functional heart , but the instructive signals involved are still poorly known . We have addressed the potential role of Wnt - 11 in the control of early ventricular myocardium assembly . METHODS AND RESULTS : We demonstrate by means of expression analysis and a mouse model in which Wnt - 11 function has been inactivated that Wnt - 11 is expressed by the embryonic ventricular cardiomyocytes and serves as one important signal for ventricular wall development . In the absence of Wnt - 11 , the coordinated organization , intercellular contacts , co - localized expression of the cell adhesion components P19022 and beta - catenin , and the cytoskeleton of the differentiating ventricular cardiomyocytes are all disturbed . Moreover , the ventricular wall lacking Wnt - 11 signalling is thinner and the expression of the Gata - 4 , Nkx2 . 5 , Mef2c , P01160 , and DB04899 genes is down - regulated relative to controls . These defects lie behind disturbed embryonic cardiac functional development , marked by an increase in the ventricular relaxation time during the early diastole . CONCLUSION : We conclude that Wnt - 11 signalling serves as a critical cell adhesion cue for the organization of the cardiomyocytes in the developing ventricular wall , which is essential for the establishment of a functional heart .",
"G protein - coupled estrogen receptor mediates the up - regulation of fatty acid synthase induced by 17β - estradiol in cancer cells and cancer - associated fibroblasts . Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark of many tumors . P49327 ( P49327 ) is a key lipogenic enzyme catalyzing the terminal steps in the de novo biogenesis of fatty acids . In cancer cells , P49327 may act as a metabolic oncogene , given that it confers growth and survival advantages to these cells , whereas its inhibition effectively and selectively kills tumor cells . Hormones such as estrogens and growth factors contribute to the transcriptional regulation of P49327 expression also through the activation of downstream signaling and a cross - talk among diverse transduction pathways . In this study , we demonstrate for the first time that 17β - estradiol ( E2 ) and the selective Q99527 ligand G - 1 regulate P49327 expression and activity through the Q99527 - mediated signaling , which involved the P01133 receptor / P29323 / c - Fos / P05412 transduction pathway , as ascertained by using specific pharmacological inhibitors , performing gene - silencing experiments and ChIP assays in breast SkBr3 , colorectal LoVo , hepatocarcinoma HepG2 cancer cells , and breast cancer - associated fibroblasts . In addition , the proliferative effects induced by E2 and G - 1 in these cells involved P49327 as the inhibitor of its activity , named cerulenin , abolished the growth response to both ligands . Our data suggest that Q99527 may be included among the transduction mediators involved by estrogens in regulating P49327 expression and activity in cancer cells and cancer - associated fibroblasts that strongly contribute to cancer progression .",
"___MASK30___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"___MASK91___ block of cloned human T - type voltage - gated calcium channels . ___MASK91___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"Immunohistochemical analysis in ethinylestradiol - treated breast cancers after prior long - term estrogen - deprivation therapy . BACKGROUND : P03372 ( ER ) positive breast cancer can often be treated by hormone therapy ; however a certain population of ER - positive patients become resistant to hormone therapy after long - term hormone treatment . ___MASK88___ ( EE2 ) is a derivative of estrogen , which has shown promising effects in these patients . METHODS : We successfully obtained tissue samples from 6 patients undergoing EE2 treatment and examined 13 well - known breast cancer - related factors by immunohistochemistry . Of the 6 patients , 5 responded but one patient did not . RESULTS : Before EE2 treatment , staining for both ER and androgen receptor ( AR ) was strong in the nucleus , and the progesterone receptor ( PgR ) was almost no staining . EE2 treatment significantly down - regulated ER and up - regulated PgR while nuclear and cytosolic AR were oppositely down - and up - regulated , respectively . Cytosolic staining of P38398 was significantly up - regulated by EE2 whereas nuclear staining tended to decrease . Individual comparisons suggested less induction of PgR and decreasing AKT but increasing pAKT in the non - responder following EE2 treatment . CONCLUSIONS : Our observations revealed that EE2 activated ER downstream genes ; however it did not stimulate cell growth . This suggests that hormone resistant cells might receive growth signals from a non - genomic pathway and this may be reflected in their sensitivity to EE2 treatment .",
"P49327 inhibition with DB01083 promotes apoptosis and reduces cell growth and lymph node metastasis in a mouse melanoma model . P49327 ( P49327 ) is the enzyme responsible for the endogenous synthesis of the saturated fatty acid palmitate . In contrast to most normal cells , malignant cells depend on P49327 activity for growth and survival . In fact , P49327 is overexpressed in a variety of human cancers including cutaneous melanoma , in which its levels of expression are associated with a poor prognosis and depth of invasion . Here , we show that the specific inhibition of P49327 activity by the antiobesity drug DB01083 or siRNA is able to significantly reduce proliferation and promote apoptosis in the mouse metastatic melanoma cell line B16 - F10 . These results prompted us to verify the effect of P49327 inhibition on the metastatic process in a model of spontaneous melanoma metastasis , in which B16 - F10 cells injected in the peritoneal cavity of C57BL / 6 mice metastasize to the mediastinal lymph nodes . We observed that mice treated with DB01083 48 hr after the inoculation of B16 - F10 cells exhibited a 52 % reduction in the number of mediastinal lymph node metastases , in comparison with the control animals . These results suggest that P49327 activity is essential for B16 - F10 melanoma cell proliferation and survival while its inactivation by DB01083 significantly reduces their metastatic spread . The chemical inhibition of P49327 activity could have a potential benefit in association with the current chemotherapy for melanoma .",
"In silico identification of potent pancreatic triacylglycerol lipase inhibitors from traditional Chinese medicine . P16233 ( P16233 ) are primary lipases that are critical for triacylglyceride digestion in human . Since reduced metabolism of triacylglyceride might be a plausible concept for weight loss , we screened for potential P16233 inhibitors from traditional Chinese medicine ( TCM ) with the aim to identify weight loss candidate compounds . TCM candidates Aurantiamide , Cnidiadin , and 2 - hexadecenoic acid exhibited higher Dock Scores than the commercial drug DB01083 , and were also predicted to have inhibitory characteristics against P16233 using constructed P08235 ( R ( 2 ) = 0 . 8664 ) and SVM ( R ( 2 ) = 0 . 9030 ) models . Molecular dynamics indicated that the TCM - P16233 complexes formed were stable . We identified that the P16233 binding site has several residues that can serve as anchors , and a hydrophobic corridor that provides additional stability to the complex . Aurantiamide , Cnidiadin , and 2 - hexadecenoic acid all have features that correspond to these binding site features , indicating their potential as candidates for P16233 inhibitors . The information presented in this study may provide helpful insights to designing novel weight - control drugs .",
"___MASK3___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK3___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"The P22897 / P34810 ratio is positively associated with adipose tissue lipogenesis and with muscle mitochondrial gene expression in humans . BACKGROUND : Alternative macrophages ( M2 ) express the cluster differentiation ( CD ) 206 ( MCR1 ) at high levels . Decreased M2 in adipose tissue is known to be associated with obesity and inflammation - related metabolic disturbances . Here we aimed to investigate MCR1 relative to P34810 ( total macrophages ) gene expression in association with adipogenic and mitochondrial genes , which were measured in human visceral [ VWAT , n = 147 ] and subcutaneous adipose tissue [ SWAT , n = 76 ] and in rectus abdominis muscle ( n = 23 ) . The effects of surgery - induced weight loss were also longitudinally evaluated ( n = 6 ) . RESULTS : MCR1 and P34810 gene expression levels were similar in VWAT and SWAT . A higher proportion of CD206 relative to total P34810 was present in subjects with less body fat and lower fasting glucose concentrations . The ratio MCR1 / CD68was positively associated with IRS1gene expression and with the expression of lipogenic genes such as Q13085 , P49327 and Q92748 , even after adjusting for BMI . The ratio MCR1 / P34810 in SWAT increased significantly after the surgery - induced weight loss ( + 44 . 7 % ; p = 0 . 005 ) in parallel to the expression of adipogenic genes . In addition , SWAT MCR1 / CD68ratio was significantly associated with muscle mitochondrial gene expression ( Q9UBK2 , Q00059 and P00414 ) . AT CD206 was confirmed by immunohistochemistry to be specific of macrophages , especially abundant in crown - like structures . CONCLUSION : A decreased ratio MCR1 / P34810 is linked to adipose tissue and muscle mitochondrial dysfunction at least at the level of expression of adipogenic and mitochondrial genes .",
"Dysregulation of leukocyte gene expression in women with medication - refractory depression versus healthy non - depressed controls . BACKGROUND : Depressive Disorders ( DD ) are a great financial and social burden . Females display 70 % higher rate of depression than males and more than 30 % of these patients do not respond to conventional medications . Thus medication - refractory female patients are a large , under - served , group where new biological targets for intervention are greatly needed . METHODS : We used real - time quantitative polymerase chain reaction ( qPCR ) to evaluate mRNA gene expression from peripheral blood leukocytes for 27 genes , including immune , Q9Y251 - axis , ion channels , and growth and transcription factors . Our sample included 23 females with medication refractory DD : 13 with major depressive disorder ( MDD ) , 10 with bipolar disorder ( BPD ) . Our comparison group was 19 healthy , non - depressed female controls . We examined differences in mRNA expression in DD vs . controls , in MDD vs . BPD , and in patients with greater vs . lesser depression severity . RESULTS : DD patients showed increased expression for P22301 , P05231 , P30559 , Q99572 , P47900 , and Q8NER1 . BPD patients showed increased P05067 , P16220 , P19838 , P04150 , and P09486 and decreased P01375 expression . Depression severity was related to increased P22301 , P47900 , P51575 , and Q9HBA0 expression . CONCLUSIONS : These results support prior findings of dysregulation in immune genes , and provide preliminary evidence of dysregulation in purinergic and other ion channels in females with medication - refractory depression , and in transcription and growth factors in those with BPD . If replicated in future research examining protein levels as well as mRNA , these pathways could potentially be used to explore biological mechanisms of depression and to develop new drug targets .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK71___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK71___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK71___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK71___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK71___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK71___ increased the protein expression of hepatic P05181 and ___MASK71___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK71___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK71___ and RFP - induced hepatotoxicity .",
"Expression of protease - activated receptor - 1 and - 2 in orofacial granulomatosis . OBJECTIVE : Orofacial granulomatosis ( OFG ) is a rare condition characterized by non - caseating granulomas in the orofacial region . Protease - Activated Receptors ( PARs ) play a role in inflammatory diseases in diverse human tissues . The aim of the study was to investigate the expression of P25116 , P55085 , P08253 , P14780 , P23219 , and P35354 in tissues taken from OFG patients . METHODS : P25116 , P55085 , P08253 , P14780 , P23219 , and P35354 expression was evaluated by immunohistochemistry in biopsies taken from oral Crohn ' s disease ( five cases ) , Melkersson - Rosenthal syndrome ( P59665 ) ( six cases ) , cheilitis granulomatosa ( five cases ) and normal oral mucosa ( five cases ) . RESULTS : P25116 was observed in mononuclear inflammatory cells in edematous / lichenoid lesions , whereas a strong P55085 immunostaining was detected in epithelioid histiocytes and giant cells in granulomatous lesions , irrespective of the clinical features ( Crohn vs P59665 ) . MMPs and P35354 were expressed in the inflammatory component of edematous / lichenoid lesions and markedly overexpressed in granulomatous lesions . P23219 was weakly and variably expressed in both edematous / lichenoid and granulomatous lesions . CONCLUSION : Thus , P25116 and P55085 expressions were related to the intensity and type of inflammatory response but not to the type of clinical lesion . Simultaneous overexpression of PARs , MMPs and COXs suggests synergism among these proinflammatory receptors and enzymes .",
"Structure of the human Q9H244 receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G - protein - coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 - like receptors and Q9H244 - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R -- including the prodrugs clopidogrel ( Plavix ) and prasugrel ( ___MASK74___ ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor -- have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half - life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2 . 6 Å resolution crystal structure of human P2Y12R in complex with a non - nucleotide reversible antagonist , AZD1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand - binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .",
"Myelopoietic efficacy of orlistat in murine hosts bearing T cell lymphoma : implication in macrophage differentiation and activation . DB01083 , an inhibitor of fatty acid synthase ( P49327 ) , acts as an antitumor agent by blocking de novo fatty acid synthesis of tumor cells . Although , myelopoiesis also depends on de novo fatty acid synthesis , the effect of orlistat on differentiation of macrophages , which play a central role in host ' s antitumor defence , remains unexplored in a tumor - bearing host . Therefore , the present investigation was undertaken to examine the effect of orlistat administration on macrophage differentiation in a T cell lymphoma bearing host . Administration of orlistat ( 240 mg / kg / day / mice ) to tumor - bearing mice resulted in a decline of tumor load accompanied by an augmentation of bone marrow cellularity and survival of bone marrow cells ( BMC ) . The expression of apoptosis regulatory caspase - 3 , Bax and Bcl2 was modulated in the BMC of orlistat - administered tumor - bearing mice . DB01083 administration also resulted in an increase in serum level of IFN - γ along with decreased TGF - β and P22301 . BMC of orlistat - administered tumor - bearing mice showed augmented differentiation into macrophages accompanied by enhanced expression of macrophage colony stimulating factor ( P09603 ) and its receptor ( M - CSFR ) . The macrophages differentiated from BMC of orlistat - administered mice showed characteristic features of M1 macrophage phenotype confirmed by expression of CD11c , TLR - 2 , generation of reactive oxygen species , phagocytosis , tumor cell cytotoxicity , production of IL - 1 , P01375 - α and nitric oxide . These novel findings indicate that orlistat could be useful to support myelopoesis in a tumor - bearing host .",
"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .",
"Peptides from purified soybean beta - conglycinin inhibit fatty acid synthase by interaction with the thioesterase catalytic domain . P49327 ( FAS ) is uniquely expressed at high levels in cancer cells and adipose tissue . The objectives of this study were to identify , purify and validate soy FAS inhibitory peptides and to predict their binding modes . Soy peptides were isolated from hydrolysates of purified beta - conglycinin by co - immunoprecipitation and identified using LC - MS / MS . Three peptides , KNPQLR , EITPEKNPQLR and RKQEEDEDEEQQRE , inhibited FAS . The biological activity of these peptides was confirmed by their inhibitory activity against purified chicken FAS ( IC ( 50 ) = 79 , 27 and 16 mum , respectively ) and a high correlation ( r = - 0 . 7 ) with lipid accumulation in 3T3 - Q9NUQ9 adipocytes . The FAS inhibitory potency of soy peptides also correlated with their molecular mass , pI value and the number of negatively charged and hydrophilic residues . Molecular modeling predicted that the large FAS inhibitory peptides ( EITPEKNPQLR and RKQEEDEDEEQQRE ) bond to the thioesterase domain of human FAS with lower interaction energies ( - 442 and - 353 kcal . mol (- 1 ) , respectively ) than classical thioesterase inhibitors ( DB01083 , - 91 kcal . mol (- 1 ) and C75 , - 51 kcal . mol (- 1 ) ) . Docking studies suggested that soy peptides blocked the active site through interactions within the catalytic triad , the interface cavity and the hydrophobic groove in the human FAS thioesterase domain . FAS thioesterase inhibitory activities displayed by the synthetic soy peptides EITPEKNPQLR and RKQEEDEDEEQQRE ( IC ( 50 ) = 10 . 1 +/- 1 . 6 and 10 . 7 +/- 4 . 4 mum , respectively ) were higher than C75 ( 58 . 7 mum ) but lower than DB01083 ( 0 . 9 mum ) . This is the first study to identify FAS inhibitory peptides from purified beta - conglycinin hydrolysates and predict their binding modes at the molecular level , leading to their possible use as nutraceuticals .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK88___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"The fatty acid synthase inhibitor orlistat reduces the growth and metastasis of orthotopic tongue oral squamous cell carcinomas . P49327 ( P49327 ) is the biosynthetic enzyme responsible for the endogenous synthesis of fatty acids . It is downregulated in most normal cells , except in lipogenic tissues such as liver , lactating breast , fetal lung , and adipose tissue . Conversely , several human cancers , including head and neck squamous cell carcinomas ( HNSCC ) , overexpress P49327 , which has been associated with poor prognosis and recently suggested as a metabolic oncoprotein . DB01083 is an irreversible inhibitor of P49327 activity with cytotoxic properties on several cancer cell lines that inhibits tumor progression and metastasis in prostate cancer xenografts and experimental melanomas , respectively . To explore whether the inhibition of P49327 could impact oral tongue squamous cell carcinoma ( OTSCC ) metastatic spread , an orthotopic model was developed by the implantation of SCC - 9 ZsGreen LN - 1 cells into the tongue of BALB / c nude mice . These cells were isolated through in vivo selection , show a more invasive behavior in vitro than the parental cells , and generate orthotopic tumors that spontaneously metastasize to cervical lymph nodes in 10 to 15 days only . SCC - 9 ZsGreen LN - 1 cells also exhibit enhanced production of P08253 , P04626 , and P19022 . The treatment with orlistat reduced proliferation and migration , promoted apoptosis , and stimulated the secretion of VEGFA165b by SCC - 9 ZsGreen LN - 1 cells . In vivo , the drug was able to decrease both the volume and proliferation indexes of the tongue orthotopic tumors and , importantly , reduced the number of metastatic cervical lymph nodes by 43 % . These results suggest that P49327 is a potential molecular target for the chemotherapy of patients with OTSCC ."
] |
[
"___MASK13___",
"___MASK26___",
"___MASK30___",
"___MASK3___",
"___MASK57___",
"___MASK71___",
"___MASK74___",
"___MASK88___",
"___MASK91___"
] |
___MASK91___
|
MH_train_462
|
interacts_with DB09078?
|
[
"Real - time US versus CT determination of pubic arch interference for brachytherapy . PURPOSE : Part 1 , to determine whether transrectal ultrasonography ( US ) enables accurate determination of pubic arch interference ( P05121 ) for prostate brachytherapy ( P10721 ) ; part 2 , to compare the accuracy of transrectal US with that of computed tomography ( CT ) for P05121 determination ; and part 3 , to determine the cost savings of P05121 determination with transrectal US versus that with CT . MATERIALS AND METHODS : Part 1 : The pubic arch was identified intraoperatively with transrectal US and compared with attempted needle passage ( 14 patients ) . Part 2 : Planning CT with the patient supine was compared with planning transrectal US with patients in the dorsal lithotomy position ( nine patients ) . Part 3 : Cost savings were calculated for P05121 determination with transrectal US versus that with CT ( 32 patients per group ) . RESULTS : Part 1 : Transrectal US accurately showed the pubic arch relative to the prostate . Part 2 : CT resulted in P05121 overestimation by 11 . 8 mm . Part 3 : Cost savings with transrectal US were $ 1 , 465 per patient . CONCLUSION : Transrectal US P05121 determination is easily performed , intraoperatively useful , and accurate . CT can result in P05121 overestimation . Reducing direct CT costs and the indirect costs of unnecessary hormonal therapy for false - positive P05121 will reduce expense and improve patient care . Transrectal US should replace CT for P05121 determination .",
"DB09078 : first global approval . DB09078 ( Lenvima ™ ) is a multitargeted receptor kinase inhibitor that inhibits the kinase activities of vascular endothelial - derived growth factor receptors 1 , 2 and 3 , fibroblast growth factor receptors 1 , 2 , 3 and 4 , platelet - derived growth factor receptor α , P07949 and P10721 . In addition to their role in normal cellular function , these kinases have been implicated in pathogenic angiogenesis , tumour growth and cancer progression . DB09078 is being developed by Eisai Co . Ltd for the treatment of solid tumours , primarily for differentiated thyroid cancer , and other malignancies . A capsule formulation of the drug has received approval in the USA for use in locally recurrent or metastatic , progressive , radioactive iodine - refractory differentiated thyroid cancer . DB09078 is in pre - registration for this indication in the EU , Australia , Brazil , Canada , Japan , South Korea , Russia , Singapore and Switzerland , and is in phase 3 development in Argentina , Chile and Thailand . DB09078 has orphan designation in the EU and Japan for use in differentiated thyroid cancer . In addition , an ongoing global , phase 3 trial is evaluating the use of lenvatinib as first - line treatment in unresectable hepatocellular carcinoma . This article summarizes the milestones in the development of lenvatinib leading to this first approval in locally recurrent or metastatic , progressive , radioactive iodine - refractory differentiated thyroid cancer .",
"[ Gastrointestinal hormone profile in medullary thyroid carcinoma ] . Medullary thyroid carcinoma ( P04629 ) can be important for gastroenterologists because 20 - 30 % of patients with P04629 suffer from chronic diarrhea and the tumor is capable of producing -- besides other bioactive substances -- a multitude of gastroenteropancreatic hormones . Gastrointestinal hormone profiles of 5 patients with P04629 were determined both basally and after intravenous stimulation with secretin and calcium respectively . Diagnosis of P04629 was confirmed histologically or cytologically and by demonstration of elevated serum concentration of calcitonin both basally and after calcium stimulation . 4 / 5 patients had chronic diarrhea . Normal values or only borderline increases were found for the following hormones : vasoactive intestinal polypeptide ( P01282 ) , neurotensin , DB05875 , growth hormone releasing hormone ( P01148 ) , glucagon , neurokinin A , peptide YY , and pancreatic polypeptide . Somatostatin was elevated after calcium stimulation in 1 / 5 patients only . The main findings were increased basal concentrations for GAWK in 5 / 5 patients and elevated concentrations for gastrin - releasing peptide ( GRP , human bombesin ) after calcium stimulation in 4 / 5 . Probably as a consequence of the GRP increase , an increase in gastrin occurred in parallel , indicating bioactivity of the GRP released from the tumor . Besides calcitonin as the main tumor marker for P04629 , determination of GAWK and GRP seems to provide helpful additional markers in laboratory diagnosis of P04629 . GRP determination after i . v . calcium infusion allowed identification of patients with normal basal plasma GRP concentration .",
"___MASK80___ reduced plasminogen activator inhibitor activity in patients with acute myocardial infarction . Recent clinical trials have demonstrated that the administration of angiotensin - converting enzyme ( P12821 ) inhibitors to patients with myocardial infarction reduces the incidence of recurrent myocardial infarction . It has also been reported that an elevated level of plasminogen activator inhibitor ( P05121 ) appears to constitute a marker of the risk of recurrent coronary thrombosis . To determine whether the P12821 inhibitor captopril reduces plasma P05121 inhibitor activity , we measured changes in plasma P05121 activity ( IU / ml ) , tissue plasminogen activator ( t - PA ) antigen ( ng / ml ) , and serum P12821 activity ( IU / L ) in 14 survivors of myocardial infarction receiving captopril therapy ( 37 . 5 mg daily ) and compared them with the values in 15 placebo - treated patients chosen at random . Blood sampling was performed at 07 . 00 h . In the captopril - treated group , serum P12821 activity decreased significantly , from 14 . 0 +/- 0 . 8 to 11 . 5 +/- 1 . 2 IU / L 24 h after captopril therapy ( p < 0 . 01 ) , and those of P05121 activity and t - PA antigen also decreased significantly - from 11 . 9 +/- 2 . 8 to 5 . 5 +/- 2 . 2 IU / ml ( p < 0 . 02 ) and from 9 . 9 +/- 1 . 0 to 7 . 5 +/- 0 . 9 ng / ml ( p < 0 . 05 ) , respectively 48 h after captopril therapy . However , the levels of P12821 activity , P05121 activity , and t - PA antigen remained unchanged during the study period in the placebo group . Thus , our data indicate that the administration of captopril to patients with acute myocardial infarction may result in a reduced frequency of recurrent coronary thrombosis by increasing fibrinolytic capacity .",
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK21___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .",
"Worksite - based behavioral treatment of mild hypertension . Two behaviorally - oriented , nonpharmacological treatments - rational - emotive therapy / assertiveness training ( P07949 / AT ) and anxiety management training ( AMT ) - and one control treatment - hypertension education counseling ( O14777 ) - were compared in reducing blood pressures of 22 white - collar mold hypertensives in a worksite setting . Results showed significant reductions by posttreatment in diastolic pressures of participants in the two behavioral treatment conditions , but no significant differential treatment effect across groups . Systolic pressure reductions by postreatment were significant only in the P07949 / AT training condition . Reductions were generally maintained at an either - week follow - up .",
"___MASK64___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol .",
"A reappraisal of the role of insulin - like growth factor I in the regulation of human hematopoiesis . P05019 has been reported to increase hematopoietic progenitor cell cloning efficiency . To investigate this phenomenon , we studied the P05019 responsiveness of human marrow cells expressing P08069 ( IGF - IR ) , a direct strategy not used previously . IGF - IR + and control P28906 + marrow cells were isolated using immunoaffinity methods . Then , the cells were cloned in methylcellulose containing variable amounts of serum - and lineage - appropriate growth factors supplemented with recombinant human P05019 . In contrast to P28906 + cells , IGF - IR + cells never gave rise to CFU - Blast , CFU - Mix , CFU - GM , BFU - E , or CFU - E . To substantiate the suggestion that P28906 + and IGF - IR + cells were distinct populations , we used reverse transcription PCR to detect P05019 , EpO , and P10721 receptor mRNAs in these cells . The mRNA phenotype of P28906 + cells was EpO ( + ) , P10721 ( + ) , and IGF - IR ( - ) , while IGF - IR + cells were IGF - IR ( + ) , EpO ( - ) , and P10721 ( - ) . These results suggested that IGF - IR is either not expressed or expressed at low levels on normal hematopoietic progenitor cells . Functional significance of the latter possibility was tested by exposing P28906 + cells to IGF - IR antisense oligodeoxynucleotides . Colony formation was unaffected by oligodeoxynucleotide disruption of IGF - IR , suggesting that , even if expressed at low level , the receptor ' s functional significance was doubtful . Nevertheless , when cultured in the presence of P05019 , IGF - IR + cells elaborated an activity with mild BFU - E stimulatory effects . Accordingly , if P05019 plays a role in hematopoietic colony formation , it is probably and results from stimulation of IGF - IR - positive ancillary cells to secrete growth factors . Studies carried out with human leukemia cells yielded similar results .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK58___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"Inhibition of the renin - angiotensin system downregulates tissue factor and vascular endothelial growth factor in human breast carcinoma cells . INTRODUCTION : The renin - angiotensin system ( DB01367 ) promotes angiogenesis and growth of neoplastic cells . P12821 ( P12821 ) inhibitors and angiotensin II receptor AT1 blockers may protect against cancer . P13726 ( TF ) , for its involvement in tumor growth , angiogenesis , and metastasis is considered a hallmark of cancer progression . In this study we evaluated whether DB01367 blockade modulates TF constitutive expression by the metastatic breast carcinoma MDA - MB - 231 cell line . MATERIALS AND METHODS : Cell TF activity was assessed by one stage clotting time , TF and P15692 antigens and mRNA levels by ELISA and RT - PCR , respectively . AT ( 1 ) was detected by flow - cytometry and angiotensin - II levels by EIA . RESULTS : ___MASK80___ reduced in a concentration - dependent way both the strong constitutive TF activity ( 983 . 2 ± 55 . 2 vs . 686 . 7 ± 135 . 1U / 5 × 10 ( 5 ) cells with 10μg / ml captopril ) and antigen ( 32 . 3 ± 5 . 9 vs . 13 . 2 ± 6 . 6ng / ml ) in MDA - MB - 231 . Similar results were observed with enalapril . AT1 was present on cell membrane and losartan , a competitive inhibitor of AT1 , reduced TF expression to a degree similar as that exerted by P12821 inhibitors . Moreover , captopril and losartan downregulated the constitutive mRNA TF expression by ~ 35 % . Similar results were observed with anti - AT1 and angiotensin II antibodies . In addition , the constitutive P15692 antigen and mRNA levels were reduced in the presence of captopril or losartan , and an anti - P15692 antibody downregulated cell TF activity by ~ 40 % . CONCLUSIONS : These results could , at least in part , contribute to the discussion about the possible effects of P12821 inhibitors and AT1 receptor antagonists in malignancy , and offer new clues to support their use for tumor control .",
"DNA microarray reveals different pathways responding to paclitaxel and docetaxel in non - small cell lung cancer cell line . The wide use of paclitaxel and docetaxel in NSCLC clinical treatment makes it necessary to find biomarkers for identifying patients who can benefit from paclitaxel or docetaxel . In present study , NCI - H460 , a NSCLC cell line with different sensitivity to paclitaxel and docetaxel , was applied to DNA microarray expression profiling analysis at different time points of lower dose treatment with paclitaxel or docetaxel . And the complex signaling pathways regulating the drug response were identified , and several novel sensitivity - realted markers were biocomputated . The dynamic changes of responding genes showed that paclitaxel effect is acute but that of docetaxel is durable at least for 48 hours in NCI - H460 cells . Functional annotation of the genes with altered expression showed that genes / pathways responding to these two drugs were dramatically different . Gene expression changes induced by paclitaxel treatment were mainly enriched in actin cytoskeleton ( P68032 , P10916 and Q9UKX2 ) , tyrosine - protein kinases ( ERRB4 , P10721 and P35590 ) and focal adhesion pathway ( P10916 , IGF1 and P17948 ) , while the expression alterations responding to docetaxel were highly co - related to cell surface receptor linked signal transduction ( SHH , P21918 and Q7Z4H4 ) , cytokine - cytokine receptor interaction ( P01583 and P05231 ) and cell cycle regulation ( P14635 , O96020 and P12004 ) . Moreover , we also confirmed some different expression patterns with real time PCR . Our study will provide the potential biomarkers for paclitaxel and docetaxel - selection therapy in clinical application .",
"___MASK8___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"DB00644 agonists reduce the migratory and the invasive behavior of androgen - independent prostate cancer cells by interfering with the activity of P05019 . Androgen - independent prostate carcinoma is characterized by a high proliferation rate and by a strong metastatic behavior . We have previously shown that DB00644 agonists exert a direct and specific inhibitory action on the proliferation of androgen - independent prostate cancer cells ( DU 145 ) . These compounds mainly act by interfering with the mitogenic activity of growth factors , such as the insulin - like growth factor - I ( P05019 ) . The present experiments were performed to clarify whether DB00644 agonists might also affect the migratory and the invasive behavior of androgen - independent prostate cancer cells and to define their mechanism of action . First we showed that the DB00644 agonist ___MASK58___ reduces the migration of DU 145 cells towards a chemoattractant and their ability to invade a reconstituted basement membrane . Experiments were then performed to clarify whether the DB00644 agonist might act by interfering with the pro - metastatic activity of P05019 . We found that , in androgen - independent prostate cancer cells , ___MASK58___ : a ) interferes with the P05019 system ( receptor protein expression and tyrosine - phosphorylation ) ; b ) abrogates the P05019 - induced phosphorylation of Akt ( a kinase previously shown by us to mediate the pro - metastatic activity of P05019 in prostate cancer cells ) ; c ) counteracts the migration and the invasive activity of the cells stimulated by P05019 ; d ) abolishes the effects of P05019 on cell morphology , on actin cytoskeleton organization and on alphavbeta3 integrin expression / cellular localization . These data indicate that DB00644 agonists , in addition to their well known antiproliferative effect , can also exert a significant inhibitory activity on the migratory and invasive behavior of androgen - independent prostate cancer cells , expressing the P30968 . DB00644 agonists act by interfering with the pro - metastatic activity of the growth factor P05019 .",
"Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization . DB09078 is an oral multikinase inhibitor that selectively inhibits vascular endothelial growth factor ( P15692 ) receptors 1 to 3 and other proangiogenic and oncogenic pathway - related receptor tyrosine kinases . To elucidate the origin of the potency of lenvatinib in P15692 receptor 2 ( P35968 ) inhibition , we conducted a kinetic interaction analysis of lenvatinib with P35968 and X - ray analysis of the crystal structure of P35968 - lenvatinib complexes . Kinetic analysis revealed that lenvatinib had a rapid association rate constant and a relatively slow dissociation rate constant in complex with P35968 . Co - crystal structure analysis demonstrated that lenvatinib binds at its DB00171 mimetic quinoline moiety to the DB00171 binding site and to the neighboring region via a cyclopropane ring , adopting an DB00128 - DB00120 - DB00145 ( DFG ) - \" in \" conformation . These results suggest that lenvatinib is very distinct in its binding mode of interaction compared to the several approved P35968 kinase inhibitors .",
"Flow cytometric analysis of mammalian glial cultures treated with methotrexate . ___MASK71___ ( MTX ) is an antineoplastic drug that acts by competitive inhibition of the enzyme dihydrofolate reductase ( P00374 ) . MTX treatment of cultured cell lines leads to the emergence of resistant cell populations . Studies using stepwise selection procedures have demonstrated that MTX resistance conferred by overproduction of P00374 can be caused by P00374 gene amplification . We examined the effect of MTX on cells whose origin more closely approximates the in vivo condition by developing a culture system using dissociated brain tissue from 17 - 19 day old mouse embryos . At the first passage , cultures were divided into control and MTX groups . Cells were treated with the same or successively higher concentrations of MTX at each passage over a 3 - 4 month period . The first passage eliminated neurons and left a glial culture comprised of approximately 90 % astrocytes . We used the Fluorescence Activated Cell Sorter in conjunction with fluorescent dyes to measure P00374 content , DNA content , size , and viability of glial cells following MTX treatment . MTX - treated cells divided but grew more slowly and were larger than untreated cells . Stepwise selection in 30 / 60 / 90 nM or 60 / 120 nM MTX resulted in significant two - to threefold increases in fluorescence , and hence P00374 levels . Slot hybridizations assays demonstrated a threefold increase in P00374 gene copy number in the DNA from the 30 / 60 / 90 cultures . Thus , our findings were consistent with the results obtained from somatic cell lines , and lend support to the hypothesis that gene amplification may be a common mechanism for the acquisition of resistance in many types of cells . They also indicate that glial cells may be a specific target for cytotoxic effects of MTX on the central nervous system .",
"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"P2X7R suppression promotes glioma growth through epidermal growth factor receptor signal pathway . Q99572 receptor ( P2X7R ) has been shown to mediate an anticancer effect via apoptosis in different types of cancer . However , whether P2X7R exerts a promoting or suppressive effect on brain glioma is still a controversial issue and its underlying mechanism remains unknown . We showed here that P2X7R suppression exerted a pro - growth effect on glioma through directly promoting cells proliferation and pro - angiogenesis , which was associated with epidermal growth factor receptor ( P00533 ) signaling . The P2X7R was markedly downregulated by cells exposure to the P2X7R antagonist , brilliant blue G ( BBG ) , moreover , the cells proliferation was enhanced in a dose - dependent manner and the expression of P00533 or p - P00533 protein was significantly upregulated . By constructing P13671 cells with reduced expression of P2X7R using shRNA , we also demonstrated strong upregulation in cells proliferation and P00533 / p - P00533 expression . However , this effect of BBG was reversed in the presence of gefitinib or suramin . Magnetic resonance imaging and computed tomography perfusion showed that the BBG or P2X7R shRNA promoted the tumor growth by about 40 % and 50 % , respectively , and significantly increased angiogenesis . Nissl and Ki - 67 staining also confirmed that BBG or P2X7R shRNA notably increased the tumor growth . More importantly , either BBG or P2X7R shRNA could markedly upregulated the expression of P00533 , p - P00533 , HIF - 1α and P15692 in glioma cells . In conclusion , P2X7R suppression exerts a promoting effect on glioma growth , which is likely to be related to upregulated P00533 , HIF - 1α and P15692 expression . These findings provide important clues to the molecular basis of anticancer effect of targeting purinergic receptors .",
"Copy number analysis of 24 oncogenes : O15151 identified as a putative marker for low recurrence risk in non muscle invasive bladder cancer . Patients with non - muscle invasive bladder cancer ( NMIBC ) generally have a high risk of relapsing locally after primary tumor resection . The search for new predictive markers of local recurrence thus represents an important goal for the management of this disease . We studied the copy number variations ( CNVs ) of 24 oncogenes ( O15151 , P04198 , Q9UM73 , P16234 , P10721 , P35968 , P00374 , P00533 , MET , SMO , P11362 , MYC , P00519 , P07949 , P24385 , P30279 , P11802 , Q00987 , Q96GD4 , P04626 , P11388 , O14965 , AR and P15056 ) using multiplex ligation probe amplification technique to verify their role as predictive markers of recurrence . DB03843 - fixed paraffin - embedded tissue samples from 43 patients who underwent transurethral resection of the bladder ( TURB ) were used ; 23 patients had relapsed and 20 were disease - free after 5 years . Amplification frequencies were analyzed for all genes and O15151 was the only gene that showed significantly higher amplification in non recurrent patients than in recurrent ones ( 0 . 65 vs . 0 . 3 ; Fisher ' s test p = 0 . 023 ) . Recurrence - free survival analysis confirmed the predictive role of O15151 ( log - rank test p = 0 . 041 ) . Our preliminary results indicate a putative role for the O15151 gene in predicting local recurrence of bladder cancer . Confirmation of this hypothesis is needed in a larger cohort of NMIBC patients .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK17___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK17___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK17___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK17___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK17___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK17___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK17___ .",
"Comparison of two polymer - based immunohistochemical detection systems : ENVISION + and ImmPRESS . The non - specific background reaction produced in avidin - biotin - based immunohistochemistry , particularly after harsh antigen retrieval procedures , has promoted the use of non - avidin - biotin systems , yet there are few reports comparing the performance of non - avidin - biotin , polymer - based methods . In this study we compare two of these methods , ENVISION + trade mark and ImmPRESS , in animal tissues . We examined the immunoreactivity of 18 antigens in formalin - fixed , paraffin - embedded tissues . Antigens were located in the cytoplasmic membrane ( CD11d , P05107 and CD79a ) , cytoplasm ( calretinin , P23219 , P35354 , Glut - 1 , HepPar 1 , P10721 , Melan A , tryptase and uroplakin III ) or nucleus ( Q2TAK8 , P09936 and thyroid transcription factor 1 ) . We also evaluated three infectious agents ( Aspergillus , calicivirus and West Nile virus ) . The staining with ENVISION + or ImmPRESS was performed simultaneously for each antigen . The intensity of the reaction and background staining were scored . ImmPRESS yielded similar or higher reaction intensity than ENVISION + trade mark in 16 / 18 antigens . ImmPRESS produced abundant background with the other two antigens ( calretinin and P35354 ) , which hindered interpretation of the specific reaction . The cost of ImmPRESS was 25 % lower than for ENVISION + trade mark . Based on these results , ImmPRESS is a good polymer - based detection system for routine immunohistochemistry .",
"Cytoplasmic and nuclear estrogen binding capacity in the rat uterus during treatment with danazol and testosterone . ___MASK21___ , testosterone and dihydrotestosterone ( DB02901 ) were tested as competitors for estrogen receptors on immature rat uterus cytosol . No competitive binding could be demonstrated for any of these steroids . After that , prepubertal Wistar rats were exposed to danazol , testosterone or propylene glycol ( control ) for 3 days or 17 days . After the appropriate exposure to medication , the animals were killed . Both danazol and testosterone appeared to be uterotropic after 3 days of treatment , although the increase in the uterine weight was significant only in the danazol - treated group ( p less than 0 . 05 ) . This effect was lost after 17 days of treatment . P03372 binding assays were done on the cytosolic and nuclear fractions of the homogenized uterine tissue of each group . The estrogen binding capacity of cytosols was increased in both the danazol ( p less than 0 . 05 ) and the testosterone ( p less than 0 . 01 ) groups after 3 days of treatment . A parallel increase was found in the nuclear fraction of both groups . After 17 days of treatment , the comparison between the 3 groups showed no differences in the cytosolic or nuclear estrogen binding capacity . The information provided by this study suggests that some effects of danazol may be due to an androgenic action and that may be associated to increases in the free fraction of testosterone .",
"Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations . Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene . We have studied genes encoding important breast cancer - related proteins using a model for survival - type data that is based on natural splines and the Cox proportional hazard model , thereby removing the linearity assumption . Expression data of 16 genes were studied in relation to metastasis - free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute . The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors . There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for P03372 , Q15303 , P15692 , O96020 , Q15910 , and Q96NZ9 ; for P04626 , P21860 , P24385 , P24864 , O75530 , P61073 , P32248 , P48061 , and P05121 there is no clear increase or decrease ; and for P00533 there seems to be a non - linear relation . Multivariable analysis showed that the 70 - gene prognosis profile outperforms all the other variables in the model ( hazard - rate 5 . 4 , 95 % CI 2 . 5 - 11 . 7 ; P = 0 . 000018 ) . P00533 - expression seems to have a non - linear relation with disease outcome , indicating that lower but also higher expression of P00533 are associated with worse outcome compared to intermediate expression levels ; the other genes show no or a linear relation .",
"Antitumor activity of lenvatinib ( e7080 ) : an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models . Inhibition of tumor angiogenesis by blockading the vascular endothelial growth factor ( P15692 ) signaling pathway is a promising therapeutic strategy for thyroid cancer . DB09078 mesilate ( lenvatinib ) is a potent inhibitor of P15692 receptors ( P17948 - 3 ) and other prooncogenic and prooncogenic receptor tyrosine kinases , including fibroblast growth factor receptors ( P11362 - 4 ) , platelet derived growth factor receptor α ( PDGFRα ) , P10721 , and P07949 . We examined the antitumor activity of lenvatinib against human thyroid cancer xenograft models in nude mice . Orally administered lenvatinib showed significant antitumor activity in 5 differentiated thyroid cancer ( DTC ) , 5 anaplastic thyroid cancer ( ATC ) , and 1 medullary thyroid cancer ( P04629 ) xenograft models . DB09078 also showed antiangiogenesis activity against 5 DTC and 5 ATC xenografts , while lenvatinib showed in vitro antiproliferative activity against only 2 of 11 thyroid cancer cell lines : that is , RO82 - W - 1 and TT cells . Western blot analysis showed that cultured RO82 - W - 1 cells overexpressed P11362 and that lenvatinib inhibited the phosphorylation of P11362 and its downstream effector Q8WU20 . DB09078 also inhibited the phosphorylation of P07949 with the activated mutation C634W in TT cells . These data demonstrate that lenvatinib provides antitumor activity mainly via angiogenesis inhibition but also inhibits FGFR and P07949 signaling pathway in preclinical human thyroid cancer models .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK89___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"Glial cells , but not interstitial cells , express Q99572 , an ionotropic purinergic receptor , in rat gastrointestinal musculature . Purinergic ( DB00171 ) neurotransmission is a component of the inhibitory response of the musculature in various regions of the gastrointestinal tract . So far , seven ionotropic purinergic receptors ( P51575 - 7 ) have been cloned . As specific antibodies become available , their respective distribution in the gastrointestinal tract can be elucidated . Here , we used high - resolution tricolor confocal microscopy , to study the distribution of Q99572 - immunoreactive ( - ir ) cells in the muscularis propria of the rat stomach , small intestine , and colon . Smooth muscle cells , P10721 - ir interstitial cells of Cajal , and P28906 / Q9UGI6 - ir fibroblastlike cells were Q99572 - negative , whereas Q99572 immunoreactivity was observed in nerves and S100 - ir glial cells . In all regions studied , Q99572 immunoreactivity was also observed in myenteric and submucosal ganglia , where perineuronal nerve endings appeared brightly labeled . Our observations suggest that purinergic signaling could influence the enteric glia through Q99572 receptors .",
"Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection . Accelerated coronary atherosclerosis in cardiac transplants ( cardiac allograft vasculopathy , Q03135 ) is characterized by coronary intimal hyperplasia . P05230 ( P05230 ) is a potent mitogen for vascular smooth muscle cells and endothelial cells , and its expression is increased in cardiac allografts , suggesting it may play a role in the pathogenesis of Q03135 . The activity of P05230 is dependent on binding to transmembrane receptors . To investigate whether receptors for P05230 are also induced after transplantation , polymerase chain reaction , in situ hybridization , and immunohistochemistry were used to analyze expression of four receptors for P05230 ( P11362 - P22455 ) . Expression of mRNA encoding extracellular immunoglobulin - like domains of P11362 was increased 35 - fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures . Alternatively spliced mRNA that encodes transmembrane forms of P11362 , which contain the signal - transducing tyrosine kinase domains , was induced in allografts during rejection , in infiltrating cells , vascular structures , and myocytes . In vitro experiments showed that differential expression of FGF receptor isoforms was induced by P05230 , and also by P05231 and TGF - beta , which are expressed in cardiac allografts during rejection . The results show that expression of both P05230 and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of Q03135 .",
"___MASK19___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK19___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"Luteinizing Hormone - Releasing Hormone ( P01148 ) - I antagonist cetrorelix inhibits myeloma cell growth in vitro and in vivo . The objective of this study was to determine the effects of an luteinizing hormone - releasing hormone ( P01148 ) - I antagonist , DB00050 , on human multiple myeloma ( MM ) cells and to elucidate the mechanisms of action . We showed that P01148 - I and P22888 - I genes were expressed in MM cell lines and primary MM cells . Treatment with DB00050 inhibited growth and colony - forming ability of myeloma cells , including cell lines resistant to arsenic trioxide , bortezomib , or lenalidomide . DB00050 induced apoptosis in myeloma cells including primary myeloma cells . In addition , DB00050 inhibited the growth of human myeloma cells xenografted into mice without any apparent side effects . DB00050 downregulated the nuclear factor - kappa B ( NF - κB ) pathway activity and the expression of cytokines , including interleukin 6 , insulin - like growth factor 1 , P15692 , and stromal - derived factor 1 , important for myeloma cell growth and survival in myeloma cells and / or marrow stromal cells from myeloma patients . DB00050 decreased the phosphorylation of extracellular signal regulated kinase 1 / 2 and P40763 in myeloma cells , two crucial pathways for myeloma cells growth and survival . Moreover , the expression of P38936 and p53 was increased , whereas that of antiapoptotic proteins Bcl - 2 and Bcl - x ( L ) was reduced by DB00050 . Our findings indicate that DB00050 induces cytotoxicity in myeloma cells through various mechanisms and provide a rationale for investigating DB00050 for the treatment of MM ."
] |
[
"___MASK17___",
"___MASK19___",
"___MASK21___",
"___MASK58___",
"___MASK64___",
"___MASK71___",
"___MASK80___",
"___MASK89___",
"___MASK8___"
] |
___MASK58___
|
MH_train_463
|
interacts_with DB00641?
|
[
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK88___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"Lectin - like oxidized P01130 - 1 ( P78380 ) acts as a receptor for remnant - like lipoprotein particles ( RLPs ) and mediates RLP - induced migration of vascular smooth muscle cells . OBJECTIVE : Remnant - like lipoprotein particles ( RLPs ) have been implicated in atherogenesis especially by diabetic dyslipidemia ; however , their receptor ( s ) and effects on vascular smooth muscle cells ( VSMCs ) remain unclear . In this study , we examined if lectin - like oxidized P01130 - 1 ( P78380 ) acts as a receptor for RLPs and its biological effects in VSMCs . METHODS AND RESULTS : RLPs were isolated from human plasma by immunoaffinity gel containing anti - apolipoprotein A - I and anti - apolipoprotein B - 100 monoclonal antibodies . DiI - labeled RLPs were taken up by CHO - P04264 cells stably expressing P78380 but not by wild - type CHO - P04264 cells . RLPs induced P78380 expression and cell migration in bovine VSMCs ( BVSMCs ) , which were significantly suppressed by transfection with P78380 specific siRNAs . Inhibitors of metalloproteinases , epidermal growth factor ( P01133 ) receptor tyrosine kinase , heparin - binding P01133 - like growth factor ( HB - P01133 ) , p38 mitogen - activated protein kinase ( p38 MAPK ) , MAPK kinase ( Q02750 ) and phosphoinositide 3 - kinase ( PI3K ) significantly blocked RLP - induced P78380 expression and cell migration of BVSMCs . CONCLUSIONS : The present study provides direct evidence that P78380 is a novel receptor for RLPs in VSMCs . P78380 - mediated uptake of RLPs may thus play important roles in atherogenesis by inducing P78380 expression and VSMC migration especially in the settings of postprandial hyperlipidemia , diabetes and metabolic syndrome .",
"Impaired postprandial blood flow in adipose tissue may be an early marker of insulin resistance in type 2 diabetes . OBJECTIVE : We investigated the changes in subcutaneous adipose tissue blood flow ( ATBF ) after a meal in the various stages of type 2 diabetes . RESEARCH DESIGN AND METHODS : Five groups were examined : healthy control subjects , first - degree relatives of subjects with type 2 diabetes , subjects with impaired glucose tolerance ( IGT ) , subjects with type 2 diabetes and postprandial hyperglycemia but normal fasting plasma glucose levels ( diabetes group A [ P28067 ] ) , and subjects with type 2 diabetes with both postprandial and fasting hyperglycemia ( diabetes group B [ P28068 ] ) . ATBF was measured with ( 133 ) Xe . RESULTS : ATBF was higher in control subjects ( 1 , 507 +/- 103 ml / 100 cm ( 3 ) tissue x min ) versus relatives and IGT , P28067 , and P28068 subjects ( 845 +/- 123 , 679 +/- 69 , 765 +/- 60 , and 757 +/- 69 ml / 100 cm ( 3 ) tissue x min , respectively ; P < 0 . 001 ) . P01308 sensitivity index ( ISI ) in control subjects ( 82 +/- 3 mg x l ( 2 )/ mmol x mU x min ) was higher versus that for relatives and IGT , P28067 , and P28068 subjects ( 60 +/- 3 , 45 +/- 1 , 40 +/- 6 , and 29 +/- 4 mg x l ( 2 )/ mmol x mU x min , respectively ; P < 0 . 0001 ) . ISI was positively associated with peak - baseline ATBF ( beta coefficient 0 . 029 +/- 0 . 013 , P = 0 . 03 ) . CONCLUSIONS : After meal ingestion , insulin - stimulated ATBF was decreased in relatives and and IGT , P28067 , and P28068 subjects . This defect could be an early marker of insulin resistance that precedes the development of type 2 diabetes .",
"Synthesis and biological evaluation of novel pyrrolidine - 2 , 5 - dione derivatives as potential antidepressant agents . Part 1 . A series of 3 -( 1H - indol - 3 - yl ) pyrrolidine - 2 , 5 - dione derivatives was synthesized and their biological activity was evaluated . The chemical structures of the newly prepared compounds were confirmed by ( 1 ) H NMR , ( 13 ) C NMR and P19957 - HRMS spectra data . All tested compounds proved to be potent P08908 receptor and serotonin transporter protein ( P31645 ) ligands . Among them , compounds 15 , 18 , 19 and 30 showed significant affinity for P08908 and P31645 . Computer docking simulations carried out for compounds 15 , 31 and 32 to models of P08908 receptor and P31645 confirm the results of biological tests . Due to high affinity for the P08908 receptor and moderate affinity for P31645 , compounds 31 , 32 , 35 , and 37 were evaluated for their affinity for D2L , P50406 , P34969 and 5 - Q13049 receptors . In vivo tests , in turn , resulted in determining the functional activity of compounds 15 , 18 , 19 and 30 to the P08908 receptor . The results of these tests indicate that all of the ligands possess properties characteristic of P08908 receptor agonists .",
"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .",
"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK44___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .",
"P35372 mutant , T394A , abolishes opioid - mediated adenylyl cyclase superactivation . This study was to characterize the effects of a point - mutant at C - terminal of mu opioid receptor ( MOR ) , namely MOR T394A , in chronic opioid - induced cellular responses . After 18 h of exposure to [ D - Ala , N - Me - DB00120 , DB00145 - ol ] enkephalin ( DAMGO ) , adenylyl cyclase ( AC ) superactivation , a hallmark for the cellular adaptive response after chronic opioid stimulation , was observed in the cells expressing wild - type receptor , but was totally abolished in the cells expressing MOR T394A . Receptor phosphorylation was also attenuated in cells with MOR T394A after prolonged preexposure to agonist . Furthermore , Q96HU1 kinase kinase - 1 ( Q02750 ) overexpression was able to rescue AC superactivation in cells with MOR T394A , but showed no effect in the wild - type MOR - expressing cells . These results indicated that the amino acid T394 at C - terminus of MOR played a critical role in chronic agonist - induced AC superactivation and receptor phosphorylation .",
"Characterization of polymorphism within the H2 - M MHC class II loci . The products of the class II - like H2 - M genes of the major histocompatibility complex are required for class II antigen processing . We sequenced H2 - Ma and Mb from several mouse strains to determine whether these genes are polymorphic like the classical H2 - A and E genes , or are oligomorphic , like H2 - O . Both Mb loci appear to be transcribed and are distinct from each other . Mb1 and Mb2 differ by about 11 % at the nucleotide level and are most dissimilar in their second exons ( corresponding to the beta 1 domain ) . Relative to the published Mb1d haplotype sequence , the products of the b , g7 , f , and k2 alleles of Mb1 from Mus musculus domesticus and the separate mouse species Mus spretus differ by only one to four amino acids . The majority of the changes occurred in the second exon of Mb1 , in contrast to P28068 , the human orthologue . Little polymorphism was seen for Mb2 , and Ma was invariant in all strains tested . The similarity of the g7 allele to those from other haplotypes makes it unlikely that the M class II genes play a role in the autoimmune diabetes of NOD strain mice . The M genes are regulated in a manner similar to classical class II genes , in that they are upregulated by P01579 in macrophages , and to a lesser extent by P05112 in B cells . When modeled on the crystal structure of the HLA - DR1 class II molecule , nearly all of the differences between M beta 1 and M beta 2 affect residues facing away from the putative peptide binding groove .",
"Genetic influences on sarcoidosis . To investigate the genetic influences underlying the development of sarcoidosis , HLA class II genotyping was performed in Japanese patients with sarcoidosis and healthy controls using the PCR - RFLP method . The frequencies of both DR52 group antigen - associated alleles ( HLA - Q8IUH3 * 11 , - Q8IUH3 * 12 and - Q8IUH3 * 14 ) and Q8IUH3 * 08 alleles were higher in the patient group , suggesting that the common , specific amino acid residue on the Q8IUH3 molecule of these alleles may determine susceptibility to sarcoidosis . Alternatively , it is possible that another susceptibility gene , linked to these Q8IUH3 alleles , exists within the MHC region . We screened the P01375 , P01374 , P0DMV8 and Hum70t genes around the class III region , as well as the P28067 and - P28068 genes in the class II region , for genetic polymorphism in sarcoidosis . None of these genes suggested a susceptibility to sarcoidosis . These studies support the thesis that one of the major genetic factors controlling the development of sarcoidosis is located within the Q8IUH3 locus in the HLA class II region .",
"___MASK44___ - induced regulation of the balance within macrophage subpopulations . In asthma , treatment with inhaled corticosteroids reduces chronic peribronchial inflammation and restores the balance within macrophage subpopulations . This study investigates whether corticosteroids can regulate monocyte differentiation in vitro and thereby influence the balance of functionally distinct macrophages . Graded doses of fluticasone propionate ( FP ) were added to cultures of normal peripheral blood monocytes in the presence or absence of P05112 . Cells were harvested after 7 days ' culture . Double immunofluorescence studies were performed on cytospins of differentiated macrophages using the MoAbs RFD1 and RFD7 to distinguish inductive and suppressive macrophages by their respective phenotypes . Macrophage function was determined by quantifying allostimulation in a mixed leucocyte reaction and by measuring tumour necrosis factor - alpha ( P01375 ) production . FP reduced the number of mature cells with a D1 + antigen - presenting phenotype and up - regulated the development of cells with the D1 / D7 + and D7 + phenotypes . Functionally , this was associated with reduced stimulation of T cell proliferation in a mixed leucocyte reaction ( P08235 ) . ___MASK44___ also reversed the increase in both D1 + expression and P01375 production induced by P05112 . The effect of FP persisted for 24 h after removal of FP from the culture medium . These results suggest that FP treatment of asthmatics may have a direct beneficial effect by normalizing the macrophage subset imbalance that contributes to the chronic peribronchial inflammation present in this condition .",
"UMD ( Universal mutation database ) : a generic software to build and analyze locus - specific databases . The human genome is thought to contain about 80 , 000 genes and presently only 3 , 000 are known to be implicated in genetic diseases . In the near future , the entire sequence of the human genome will be available and the development of new methods for point mutation detection will lead to a huge increase in the identification of genes and their mutations associated with genetic diseases as well as cancers , which is growing in frequency in industrial states . The collection of these mutations will be critical for researchers and clinicians to establish genotype / phenotype correlations . Other fields such as molecular epidemiology will also be developed using these new data . Consequently , the future lies not in simple repositories of locus - specific mutations but in dynamic databases linked to various computerized tools for their analysis and that can be directly queried on - line . To meet this goal , we devised a generic software called UMD ( Universal Mutation Database ) . It was developed as a generic software to create locus - specific databases ( LSDBs ) with the 4 ( th ) Dimension ( R ) package from ACI . This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data . Thanks to the flexible structure of the UMD software , it has been successfully adapted to nine genes either involved in cancer ( P25054 , P04637 , P06400 , O00255 , Q09428 , P40337 , and P19544 ) or in genetic diseases ( P35555 and P01130 ) . Four new LSDBs are under construction ( P49748 , P11310 , KIR6 , and P29400 ) . Finally , the data can be transferred to core databases .",
"Medial Expression of P01375 - α and P01375 Receptors Precedes the Development of Atherosclerotic Lesions in P02649 / LDL Receptor Double Knockout Mice . P01375 - α is present in atherosclerotic lesions , activates endothelial adhesion molecule expression , stimulates the release of proinflammatory cytokines and matrix metalloproteinases and promotes smooth muscle cell proliferation and migration . Taken together these observations suggest that P01375 - α may be functionally involved in early atherosclerosis development . To further evaluate this hypothesis we compared vascular P01375 - α and P01375 receptor expression in atherosclerosis - susceptible apoE (-/-)/ P01130 (-/-) mice and control C57BL / 6 mice . The aortas of 8 week old apoE (-/-)/ LDLreceptor (-/-) mice displayed immunoreactivity for P01375 - α as well as P01375 p55 and p75 receptors ( 2 . 1 ± 1 . 6 % , 5 . 6 ± 1 . 5 % and 3 . 6 ± 1 . 3 % of total media area , respectively ) , but did not have any detectable lesions . A marginal increase in P01375 - α and P01375 receptor immunoreactivity was observed at 12 weeks and atherosclerotic plaques were detected in 1 out of 5 animals . At 16 weeks P01375 - α expression in the media was increased more than four - fold as compared with 8 week old mice , and atherosclerosis was widespread . P01375 - α immunoreactivity was also observed in all plaques . In addition , at the same age a tendency towards increased P01375 - α mRNA levels was detected in the double knockout mice compared to age - matched controls . A further increase in P01375 - α and P01375 receptor immunoreactivity as well as plaque size was observed at 20 weeks . With only a few exceptions , no P01375 - α or P01375 receptor immunoreactivity was detected in C57BL / 6 control mice . These findings demonstrate that medial P01375 - α and P01375 receptor expression precedes lesion formation in apoE (-/-)/ P01130 (-/-) mice .",
"___MASK69___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .",
"The effect of mevinolin on steroidogenesis in patients with defects in the low density lipoprotein receptor pathway . Adrenal steroidogenesis is dependent upon cholesterol derived from both de novo biosynthesis and uptake of plasma lipoproteins through the low density lipoprotein ( LDL ) receptor pathway . Recent studies have demonstrated that patients homozygous for familial hypercholesterolemia have a mild impairment in cortisol secretion during maximal DB01285 stimulation . DB00227 , a competitive inhibitor of 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase , has been used clinically to inhibit de novo cholesterol synthesis in patients with familial hypercholesterolemia . In this study we examined hypothalamic - pituitary - adrenal function in seven patients with defects in the P01130 pathway , both before and during treatment with oral mevinolin ( 20 mg , twice a day ) , to assess whether inhibition of cholesterol synthesis influences steroidogenesis under basal conditions and in response to ovine P06850 and exogenous DB01285 . Two months after initiation of therapy , high density lipoprotein cholesterol levels were significantly elevated , and LDL cholesterol levels were reduced , although not normalized . Basal and ovine P06850 - stimulated adrenocortical function were normal in all patients both before and during therapy . Plateau plasma cortisol concentrations achieved during maximal DB01285 stimulation were lower than those in control subjects in all patients both before and during therapy . All patients , however , had an approximately 3 - fold increase over basal values . These results suggest that treatment of patients with defects in the P01130 pathway with mevinolin improves the plasma lipid profile and does not result in adrenal dysfunction or further exacerbation of the mild impairment of adrenal function during maximal DB01285 stimulation .",
"Comparison of the effects of cytoprotective drugs on human plasma adrenocorticotropic hormone and cortisol levels with continual stress exposure . Cetraxate hydrochloride ( cetraxate ) , ecabet sodium ( ecabet ) , and sulpiride , which are cytoprotective drugs , have been used to treat peptic ulcers and acute or chronic gastritis . They are reported to improve mucosal blood flow in the stomach . One of the most important factors believed to cause gastric ulcers is mental and / or physiological stress . When people feel stress , the hypothalamo - pituitary - adrenal ( Q9Y251 ) axis is activated . Therefore , corticotropin - releasing hormone ( P06850 ) , adrenocorticotropic hormone ( DB01285 ) , and cortisol can be indicators of stress . We examined the effects of cetraxate , ecabet and sulpiride on the plasma levels of DB01285 and cortisol under stress conditions by repetitive blood sampling . Venous blood samples were taken before and 20 - 240 min after a single administration of the drugs or a placebo . A single dose of ecabet caused significant suppression of increases in plasma DB01285 - like immunoreactive substance ( IS ) levels at 90 to 120 min and cortisol levels at 240 min , compared with the response to placebo . DB00391 only suppressed increases in plasma cortisol levels at 180 to 240 min , compared with the response to placebo . A single dose of cetraxate had no effect on plasma DB01285 - IS and cortisol levels . Ecabet may have a modulatory effect on the Q9Y251 axis while sulpiride may have a partial modulatory effect on the Q9Y251 axis . These effects might be beneficial in stress - related disease .",
"___MASK3___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK3___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"Structure and functions of human cerebrospinal fluid lipoproteins from individuals of different P02649 genotypes . Recent data have implicated apolipoprotein E ( apoE ) in neuritic outgrowth , synaptic stability , and Alzheimer ' s disease ; these data led us to examine the normal role of apoE - containing lipoproteins in the central nervous system ( CNS ) . We isolated lipoproteins from human cerebrospinal fluid ( P04141 ) in order to examine their composition and potential functions . P04141 particles were composed of approximately one - third protein , one - third phospholipid , and one - third cholesterol . ApoE3 formed homodimers and heterodimers with apoA - II , while apoE4 , as expected , was monomeric . We addressed the function of P04141 lipoproteins with assays of cholesterol efflux and cholesterol influx . P04141 lipoproteins decreased intracellular levels of cholesterol in cholesterol - loaded fibroblasts , suggesting these particles can act to remove excess lipids from cells . P04141 lipoproteins competed for 125I - labeled LDL degradation by fibroblasts , suggesting they can also interact with the P01130 . Furthermore , P04141 lipoproteins labeled with the fluorescent dye Dil were internalized by neuroglioma cells and primary neurons and astrocytes in culture . Together , these data support a model of P04141 lipoproteins acting to remove lipids from degenerating cells and delivering lipids to cells for new membrane synthesis or storage .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK40___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"Activity , pharmacological inhibition and biological regulation of 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase in Trypanosoma brucei . Activity of hydroxymethylglutaryl - coenzyme A ( HMG - DB01992 ) reductase , the key enzyme in the biosynthesis of steroids and polyisoprenoids in mammalian cells , has been detected in both the bloodstream form and the culture - adapted procyclic form of Trypanosoma brucei ( 3 . 7 +/- 0 . 6 and 12 . 7 +/- 1 . 8 pmol mevalonate produced min - 1 ( mg cell protein ) - 1 , respectively ) . The enzyme activity is enriched 6 - fold in microsomal fractions . Several competitive inhibitors of mammalian P04035 , including synvinolin ( simvastatin ) , inhibit the multiplication of both forms of trypanosome in vitro ( IC50 , approx . 25 - 50 microM after 2 - 3 days ) . This growth inhibition is potentiated by agents interfering with the exogenous supply of cholesterol , such as antibodies blocking the low - density lipoprotein ( LDL ) receptor , or 5 microM chloroquine . Conversely , growth inhibition by synvinolin can be largely reverted either by 300 nM LDL or by products of the mevalonate pathway , such as 20 mM mevalonate and in procyclics by 100 microM squalene or cholesterol . In procyclics , low concentrations of synvinolin selectively inhibit the incorporation of [ 14C ] acetate into sterols , but not into fatty acids . These results argue for a critical role in trypanosomes of a mevalonate pathway , that is involved in the biosynthesis of sterol and probably of other metabolites . The P04035 activity is decreased 2 - fold in procyclics incubated with 4 mM mevalonate and increased 2 - fold in the presence of 2 . 5 microM synvinolin . DB00641 also upregulates LDL binding up to 4 - fold . These data suggest that P04035 and P01130 expression are regulated in T . brucei as in mammalian cells , to ensure sterol homeostasis .",
"Gene expression reprogramming protects macrophage from septic - induced cell death . Sepsis induces a systemic inflammatory response leading to tissue damage and cell death . LPS tolerance affects inflammatory response . To comprehend potential new mechanisms of immune regulation in endotoxemia , we examined macrophage mRNA expression by macroarray affected by LPS tolerance . LPS tolerance was induced with subcutaneous administration of 1 mg / kg / day of LPS over 5 days . Macrophages were isolated from the spleen and the expression of 1200 genes was quantitatively analyzed by the macroarray technique . The tolerant group displayed relevant changes in the expression of 84 mRNA when compared to naïve mice . A functional group of genes related to cell death regulation was identified . P09874 , caspase 3 , P48023 and P50591 genes were confirmed by RT - PCR to present lower expression in tolerant mice . In addition , reduced expression of the pro - inflammatory genes P01375 - α and IFN - γ in the tolerant group was demonstrated . Following this , animals were challenged with polymicrobial sepsis . Flow cytometry analysis showed reduced necrosis and apoptosis in macrophages from the tolerant group compared to the naïve group . Finally , a survival study showed a significant reduction in mortality in the tolerant group . Thus , in the current study we provide evidence for the selective reprogramming of the gene expression of cell death pathways during LPS tolerance and link these changes to protection from cell death and enhanced survival rates .",
"Determination of the type and quantity of sialic acid in the egg jelly coat of the sea urchin Paracentrotus lividus using capillary LC - P19957 - MS / MS . Sialic acid is a terminal sugar of carbohydrate chains that participates in numerous biological events . Recent studies have explored the mechanism of carbohydrate - mediated fertilisation to understand the biochemistry of fertilisation , although the type and quantity of sialic acid and the role of sialic acid during fertilisation remain unknown . Echinoderm fertilisation in particular has been studied extensively , yet our understanding of the mechanisms of carbohydrate - mediated fertilisation and the role of sialic acid remains incomplete . In this study , we characterised the sialic acid types in the egg jelly coat of the sea urchin , Paracentrotus lividus , using the sensitive analytical system capillary liquid chromatography electro - spray ionisation tandem mass spectrometry ( capLC - P19957 - MS / MS ) . First , we isolated the egg jelly coat and released its sialic acid using acid treatment . These sialic acids were derivatised with 1 , 2 - diamino - 4 , 5 - methylenediaoxy - benzene dihydrochloride ( P28068 ) and injected into the capLC - P19957 - MS / MS system . When compared with standards , we identified twelve different types of sialic acid according to their retention times and collision - induced dissociation fragments . The mass spectral data revealed that Neu5Gc , Neu5Ac , Neu5GcS , and Neu5Gc9Ac were the predominant types of sialic acid in the sea urchin jelly coat , with Neu5Gc being the most abundant . Other types of sialic acid detected included Neu5AcS , Neu5Gc7 , 9Ac2 , Neu5 , 9Ac2 , Neu5Gc8Ac , Neu5Gc7Ac , Neu5 , 7Ac2 , Neu5Gc8 , 9Ac2 , and Neu5 , 8Ac2 . The types and quantities of sialic acid that we detected in the egg jelly coat will aid in the discovery of new sialic acid - specific receptors on the sperm membrane .",
"___MASK62___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK62___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"___MASK41___ binding to human and rat dopamine and 5 - HT receptors . ___MASK41___ ( ___MASK41___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK41___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK41___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK41___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"Activation of P04049 / MEK - 1 / 2 / Q8NFH3 / 44 ( MAPK ) cascade alone is sufficient to uncouple P01130 expression from cell growth . Our previous observation that induction of low density lipoprotein ( LDL ) receptor expression by a variety of extracellular signals is blocked by PD98059 , a specific mitogen - activated protein kinase kinase inhibitor , led to the suggestion that the growth - responsive Q8NFH3 / 44 ( MAPK ) cascade plays a critical role in regulating P01130 transcription . To analyze the specific contribution of the Q8NFH3 / 44 ( MAPK ) cascade in regulating cell growth and P01130 induction , we established a HepG2 - derived cell line that stably expresses an inducible form of oncogenic human P04049 kinase . Using this system , we provide direct evidence that specific activation of this cascade alone is not only required but is sufficient to fully induce P01130 expression . Interestingly , degree of Q8NFH3 / 44 ( MAPK ) activation determines the extent of P01130 induction . However , activation of Q8NFH3 / 44 ( MAPK ) in the above cells led to the inhibition of DNA synthesis , caused growth arrest , decrease in cyclin A and upregulation of P38936 ( Cip ) expression in a time - dependent manner . These results suggest that each of these two processes can be regulated independently of each other in response to Q8NFH3 / 44 ( MAPK ) activation . Thus , extent of Q8NFH3 / 44 ( MAPK ) activation may be important in transducing divergent cellular responses in human cells with implications for altered signaling resulting in hypercholesterolemia .",
"The role of de novo ceramide synthesis in the mechanism of action of the tricyclic xanthate D609 . The cytotoxic effects of several chemotherapeutic drugs have been linked to elevated de novo ceramide biosynthesis . However , the relationship between the intracellular site ( s ) of ceramide accumulation and cytotoxicity is poorly understood . Here we examined the relationship between the site of ceramide deposition and inhibition of protein translation and induction of apoptosis by the antitumor / antiviral xanthate , D609 . In Chinese hamster ovary ( CHO ) - P04264 , P29320 - 293 , and NIH - 3T3 cells , D609 caused rapid ( 1 - 5 min ) and sustained eukaryotic initiation factor 2alpha ( eIF2alpha ) phosphorylation followed by apoptosis after 24 h . Concurrently , D609 stimulated de novo ceramide synthesis and increased ceramide mass 2 - fold by 2 h in CHO - P04264 cells . In D609 - treated CHO - P04264 cells , sphingomyelin synthesis was stimulated by brefeldin A , and P01031 - P28068 - ceramide transport to the Golgi apparatus was blocked , indicating ceramide accumulation in the endoplasmic reticulum ( ER ) . However , D609 - mediated eIF2alpha phosphorylation , inhibition of protein synthesis , and apoptosis in CHO - P04264 cells were not attenuated by fumonisin B1 or l - cycloserine . Interestingly , short - chain ceramide promoted eIF2alpha phosphorylation and inhibited protein synthesis in CHO - P04264 cells , indicating that the effectiveness of endogenous ceramide could be limited by access to signaling pathways . Thus , expansion of the ER ceramide pool by D609 was not implicated in early ( eIF2alpha phosphorylation ) or late ( apoptotic ) cytotoxic events .",
"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK92___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK12___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"A novel inhibitor of ceramide trafficking from the endoplasmic reticulum to the site of sphingomyelin synthesis . Ceramide produced at the endoplasmic reticulum ( ER ) is transported to the lumen of the Golgi apparatus for conversion to sphingomyelin ( SM ) . N -( 3 - Hydroxy - 1 - hydroxymethyl - 3 - phenylpropyl ) dodecanamide ( Q9Y251 - 12 ) is a novel analog of ceramide . Metabolic labeling experiments showed that Q9Y251 - 12 inhibits conversion of ceramide to SM , but not to glucosylceramide , in Chinese hamster ovary cells . Cultivation of cells with Q9Y251 - 12 significantly reduced the content of SM . Q9Y251 - 12 did not inhibit the activity of SM synthase . The inhibition of SM formation by Q9Y251 - 12 was abrogated when the Golgi apparatus was made to merge with the ER by brefeldin A . Moreover , Q9Y251 - 12 inhibited redistribution of a fluorescent analog of ceramide , N -( 4 , 4 - difluoro - 5 , 7 - dimethyl - 4 - bora - 3a , 4a - diaza - s - indacene - 3 - pentanoyl )- d - erythro - sphingosine ( C ( 5 )- P28068 - Cer ) , from intracellular membranes to the Golgi region . Among four stereoisomers of the drug , ( 1R , 3S ) - Q9Y251 - 12 , [ corrected ] which resembles natural ceramide stereochemically , was found to be the most active , although ( 1R , 3S ) - Q9Y251 - 12 [ corrected ] did not affect ER - to - Golgi trafficking of protein . Interestingly , ( 1R , 3S ) - Q9Y251 - 12 [ corrected ] inhibited conversion of ceramide to SM little in mutant cells defective in an DB00171 - and cytosol - dependent pathway of ceramide transport . These results indicated that ( 1R , 3S ) - Q9Y251 - 12 [ corrected ] inhibits ceramide trafficking from the ER to the site of SM synthesis , possibly due to an antagonistic interaction with a ceramide - recognizing factor ( s ) involved in the DB00171 - and cytosol - dependent pathway .",
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK92___ GITS , Diaprel MR ) . One daily dose of ___MASK92___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .",
"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .",
"Activation of liver X receptor induces macrophage interleukin - 5 expression . P05113 stimulates production of T15 / EO6 IgM antibodies that can block the uptake of oxidized low density lipoprotein by macrophages , whereas a deficiency in macrophage P05113 expression accelerates development of atherosclerosis . Liver X receptors ( LXRs ) are ligand - activated transcription factors that can induce macrophage O95477 expression and cholesterol efflux , thereby inhibiting the development of atherosclerosis . However , it remains unknown whether additional mechanisms , such as the regulation of macrophage P05113 expression , are related to the anti - atherogenic properties of LXR . We initially defined P05113 expression in macrophages where the LXR ligand ( T0901317 ) induced macrophage P05113 protein expression and secretion . The overexpression of LXR increased , whereas its knockdown inhibited P05113 expression . Furthermore , we found that LXR activation increased P05113 transcripts , promoter activity , formation of an LXR · LXR - responsive element complex , and P05113 protein stability . In vivo , we found that T0901317 increased P05113 and total IgM levels in plasma and P05113 expression in multiple tissues in wild type mice . In P01130 knock - out ( P01130 (-/-) ) mice , T0901317 increased P05113 expression in the aortic root area . Taken together , our studies demonstrate that macrophage P05113 is a target gene for LXR activation , and the induction of macrophage P05113 expression can be related to LXR - inhibited atherosclerosis .",
"Metabolic fate of 2 , 2 - dimethylbutyryl moiety of simvastatin in rats : identification of metabolites by gas chromatography / mass spectrometry . Metabolic pathways of simvastatin ( DB00641 ) , a lactone prodrug of an inhibitor of P04035 , were elucidated in male rats , using the [ 14C ] - labelled compound . Evidence has been obtained for hydrolysis of simvastatin and its metabolites at their 2 , 2 - dimethylbutyryl moieties . Metabolites identified in plasma were 2 , 2 - dimethylbutyric acid ( P28068 ) , 2 , 2 - dimethyl - 3 - hydroxybutyric acid ( DMHB ) and an open chain hydroxy acid of simvastatin : metabolites identified in urine were DMHB , a glucuronide and the glycine conjugate of P28068 . They were characterized by gas chromatography / electron impact and chemical ionization mass spectrometry as phenacyl or pertrimethylsilylated derivatives . The structures of the metabolites and the aglycone of the glucuronide were confirmed as phenacyl esters by comparison of their chromatographic data and mass spectra with those of the phenacyl derivatives of authentic compounds .",
"Agonist - promoted down - regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor . We recently reported two naturally occurring polymorphisms of the human serotonin1A ( P08908 ) receptor : glycine22 --> serine ( Ser22 ) and isoleucine28 --> valine ( Val28 ) in the putative aminoterminal domain of the receptor . To investigate the regulatory properties of these variants , the wild type ( WT ) and variant P08908 receptors were stably expressed in CHO - P04264 cells . WT , Ser22 , and Val28 displayed similar high - affinity binding to [ 3H ] - 8 - OH - DPAT . Competition experiments with P08908 agonists and antagonists demonstrated similar pharmacological profiles . Receptor agonist - promoted down - regulation was tested by exposure to 100 mumol / L 8 - OH - DPAT . After 24 - h exposure , WT and Val28 underwent 59 . 3 +/- 3 . 9 % and 59 . 5 +/- 1 . 4 % reduction in receptor density respectively , whereas the degree of down - regulation was significantly lower for Ser22 ( 21 . 4 +/- 4 . 2 % ) . Cell treatment for 24 h with 100 mumol / L 8 - OH - DPAT reduced the 5 - HT - induced inhibition of DB02527 accumulation by 24 . 9 +/- 5 . 1 % for WT and 16 . 4 +/- 0 . 8 % for Val28 , but only by 4 . 8 +/- 3 % for Ser22 . We conclude that the Ser22 variant is capable of attenuating agonist - mediated receptor down - regulation and desensitization .",
"Determination of free N - acetylneuraminic acid in human body fluids by high - performance liquid chromatography with fluorimetric detection . Determinations of both the free and bound form of N - acetyl - neuraminic acid ( NANA ) in several human body fluids , such as serum , cerebrospinal fluid ( P04141 ) , saliva , urine , amniotic fluid , and milk were carried out by HPLC with fluorimetric detection . The method utilized 1 , 2 - diamino - 4 , 5 - methylenedioxybenzene dihydrochloride ( P28068 ) as a fluorimetric derivatizing reagent . Free - form NANA was obtained from the body fluids after ultrafiltration with Microcon 10 ( YM - 10 cellulose membrane , filtration limit M ( r ) = 10 , 000 , Amicon ) . The P28068 derivative of NANA was separated isocratically by a Nucleosil 5C18 column with a mixture of 0 . 1 M sodium phosphate buffer ( pH 2 . 0 ) - methanol ( 75 : 25 , v / v ) . A gradient elution system was used for urine analysis . Analysis times were 10 - 30 min . Recoveries of free NANA by ultrafiltration were satisfactory : 95 . 66 +/- 1 . 80 % for serum and 97 . 27 +/- 1 . 55 % for P04141 , respectively . The high sensitivity and specificity render this method applicable to all the body fluids tested . Although a physiological role for free NANA has not yet been elucidated , the method presented promises to contribute to the basic understanding of the NANA metabolism .",
"Effects of serotonin on expression of the P01130 family member Q92673 and 7 - ketocholesterol - induced apoptosis in human vascular smooth muscle cells . Serotonin ( 5 - HT ) is a known mitogen for vascular smooth muscle cells ( VSMCs ) . The dedifferentiation and proliferation / apoptosis of VSMCs in the arterial intima represent one of the atherosclerotic changes . Q92673 , a member of low - density lipoprotein receptor family , may contribute to the proliferation of VSMCs in neointimal hyperplasia . We conducted an in vitro study to investigate whether 5 - HT is involved in Q92673 expression in human VSMCs and apoptosis of VSMCs induced by 7 - ketocholesterol ( 7KCHO ) , an oxysterol that destabilizes plaque . 5 - HT enhanced the proliferation of VSMCs , and this effect was abolished by sarpogrelate , a selective 5 - Q13049 receptor antagonist . Sarpogrelate also inhibited the 5 - HT - enhanced Q92673 mRNA expression in VSMCs . Furthermore , 5 - HT suppressed the 7KCHO - induced apoptosis of VSMCs via caspase - 3 / 7 - dependent pathway . These findings provide new insights on the changes in the differentiation stage of VSMCs mediated by 5 - HT ."
] |
[
"___MASK12___",
"___MASK3___",
"___MASK40___",
"___MASK41___",
"___MASK44___",
"___MASK62___",
"___MASK69___",
"___MASK88___",
"___MASK92___"
] |
___MASK12___
|
MH_train_464
|
interacts_with DB00163?
|
[
"Leukotriene binding , signaling , and analysis of HIV coreceptor function in mouse and human leukotriene B4 receptor - transfected cells . The mouse leukotriene B4 receptor ( m - Q15722 ) gene was cloned . Membrane fractions of human embryonic kidney 293 cells stably expressing m - Q15722 demonstrated a high affinity and specific binding for leukotriene B4 ( LTB4 , Kd = 0 . 24 +/- 0 . 03 nM ) . In competition binding experiments , LTB4 was the most potent competitor ( Ki = 0 . 23 +/- 0 . 05 nM ) followed by 20 - hydroxy - LTB4 ( Ki = 1 . 1 +/- 0 . 2 nM ) and by 6 - trans - 12 - epi - LTB4 and LTD4 ( Ki > 1 microM ) . In stably transfected Chinese hamster ovary cells , LTB4 inhibited forskolin - activated DB02527 production and induced an increase of intracellular calcium , suggesting that this receptor is coupled to Gi - and Go - like proteins . In Xenopus laevis melanophores transiently expressing m - Q15722 , LTB4 induced the aggregation of pigment granules , confirming the inhibition of DB02527 production induced by LTB4 . Q15722 receptors share significant sequence homology with chemokine receptors ( P51681 and P61073 ) that act as human immunodeficiency virus ( HIV ) coreceptors . However , among the 16 HIV / SIV strains tested , the human Q15722 receptor did not act as a coreceptor for virus entry into P01730 - expressing cells based on infection and cell - cell fusion assays . In P09917 - deficient mice , the absence of leukotriene B4 biosynthesis did not detectably alter m - Q15722 receptor binding in membranes obtained from glycogen - elicited neutrophils . Isolation of the m - Q15722 gene will form the basis of future experiments to elucidate the selective role of LTB4 , as opposed to cysteinyl - leukotrienes , in murine models of inflammation .",
"EDRF suppresses an unidentified vasoconstrictor mechanism in hypertensive rat lungs . To test whether DB00435 ( EDRF ) plays a role in regulating the hypertensive pulmonary vascular bed , we compared effects of the inhibitor of EDRF production , N omega - nitro - L - arginine ( DB04223 ) , on resting vascular tone in lungs and conduit pulmonary arteries isolated from control and chronically hypoxic rats . In contrast to no effect on normoxic vascular tone in salt solution - perfused normotensive lungs , 100 microM DB04223 caused a marked , L - arginine - sensitive , precapillary vasoconstriction in unstimulated hypertensive lungs . Bioassay of hypertensive lung perfusate did not detect a circulating vasoconstrictor , and DB04223 vasoconstriction was not inhibited by blockers of cyclooxygenase , P09917 , platelet - activating factor receptors , alpha - adrenoceptors , and serotonin 5 - HT2 receptors or by scavengers of superoxide anion and H2O2 . Inhibitors of endothelin - 1 ( ET - 1 ) production and vasoconstriction tended to blunt the response , but accumulation of perfusate ET - 1 was not increased in hypertensive lungs . DB04223 vasoconstriction was blocked by Ca ( 2 +)- free plus ethylene glycol - bis ( beta - aminoethyl ether ) - N , N , N ', N '- tetraacetic acid perfusion but not by nifedipine . Quiescent , endothelium - intact hypertensive but not normotensive conduit pulmonary artery rings were markedly constricted by 200 microM DB04223 . The onset but not the peak of the response was blunted by meclofenamate . The response was reduced slightly by the P25101 receptor antagonist , BQ 123 . DB04223 had little effect on denuded hypertensive arteries , and treatment with dilators showed they had constricted spontaneously . Both the DB04223 and the spontaneous constrictions were readily inhibited by nifedipine . These results indicate that in rat hypertensive pulmonary arteries , the basal release of EDRF suppresses vasoconstrictor mechanisms which are not expressed in normotensive arteries .",
"DB00163 80th anniversary : a double life , not only fighting radicals . Recent research on DB00163 has revealed specific cellular functions of this compound belonging to the vitamin E family . Alpha - tocopherol can act as a radical scavenger , as a pro - oxidant , as an anti - alkylation agent and , most important , by mechanisms that are independent of the above properties . To the last group belong protein kinase C and P09917 inhibition at post - translational level , as well as DB00163 activation of protein phosphatase 2A and diacylglycerol kinase . Furthermore , at transcriptional level , several genes ( P16671 , alpha - TTP , alpha - tropomyosin , and collagenase ) are modulated by DB00163 . These effects result in inhibition of smooth muscle cell proliferation , platelet aggregation , and monocyte adhesion and may be related to the alleged protection of atherosclerosis by vitamin E . On the other side , epidemiological and intervention studies have shown some inconsistent results . Rather than disregarding vitamin E as a means to protect against atherosclerosis progression , it would be wiser to better design clinical trials based on current knowledge of the biological properties of the molecule .",
"The antimalarial drug mefloquine inhibits cardiac inward rectifier K + channels : evidence for interference in PIP2 - channel interaction . The antimalarial drug mefloquine was found to inhibit the KATP channel by an unknown mechanism . Because mefloquine is a Cationic amphiphilic drug and is known to insert into lipid bilayers , we postulate that mefloquine interferes with the interaction between PIP2 and Kir channels resulting in channel inhibition . We studied the inhibitory effects of mefloquine on Kir2 . 1 , Kir2 . 3 , Kir2 . 3 ( I213L ) , and Kir6 . 2 / SUR2A channels expressed in P29320 - 293 cells , and on IK1 and Q14654 from feline cardiac myocytes . The order of mefloquine inhibition was Kir6 . 2 / SUR2A ≈ Kir2 . 3 ( IC50 ≈ 2 μM ) > Kir2 . 1 ( IC50 > 30 μM ) . Similar results were obtained in cardiac myocytes . The Kir2 . 3 ( I213L ) mutant , which enhances the strength of interaction with PIP2 ( compared to WT ) , was significantly less sensitive ( IC50 = 9 μM ) . In inside - out patches , continuous application of PIP2 strikingly prevented the mefloquine inhibition . Our results support the idea that mefloquine interferes with PIP2 - Kir channels interactions .",
"Novel combination treatments targeting chronic myeloid leukemia stem cells . Chronic myeloid leukemia ( CML ) is currently considered incurable in most patients . Stem cell transplantation , an accepted curative option for which extensive experience has been gained , is limited by high morbidity and mortality rates , particularly in older patients . Tyrosine kinase inhibitors targeting P11274 - P00519 are widely used and induce remission in a high proportion of patients , but resistance and incomplete response to these agents portends eventual relapse and disease progression . Although P11274 - P00519 inhibitors eradicate most CML cells , they are largely ineffective against the reservoir of quiescent leukemic stem cells ( LSCs ) . Thus a strong medical need exists for therapies that effectively eradicate LSCs and is currently a focus of extensive research . To date , evidence obtained from in vitro studies , animal models , and clinical CML specimens suggests that an effective approach may be to partner existing P11274 - P00519 inhibitors with compounds targeting key stem cell molecular effectors , including Wnt / β - catenin , hedgehog pathway components , histone deacetylase ( HDAC ) , transforming growth factor - β ( TGF - β ) , O60674 , promyelocytic leukemia protein , and arachidonate P09917 ( P09917 ) . Novel combinations may sensitize LSCs to P11274 - P00519 inhibitors , thereby overcoming resistance and creating the possibility of improving disease outcome beyond the current standard of care .",
"Ligand - independent activation of peroxisome proliferator - activated receptor - gamma by insulin and C - peptide in kidney proximal tubular cells : dependent on phosphatidylinositol 3 - kinase activity . P37231 ( PPARgamma ) has key roles in the regulation of adipogenesis , inflammation , and lipid and glucose metabolism . C - peptide is believed to be inert and without appreciable biological functions . Recent studies suggest that C - peptide possesses multiple functions . The present study investigated the effects of insulin and C - peptide on PPARgamma transcriptional activity in opossum kidney proximal tubular cells . Both insulin and C - peptide induced a concentration - dependent stimulation of PPARgamma transcriptional activity . Both agents substantially augmented thiazolidinedione - stimulated PPARgamma transcriptional activity . Neither insulin nor C - peptide had any effect on the expression levels of PPARgamma . GW9662 , a PPARgamma antagonist , blocked PPARgamma activation by thiazolidinediones but had no effect on either insulin - or C - peptide - stimulated PPARgamma transcriptional activity . Co - transfection of opossum kidney cells with dominant negative mitogen - activated protein kinase kinase significantly depressed basal PPARgamma transcriptional activity but had no effect on that induced by either insulin or C - peptide . Both insulin - and C - peptide - stimulated PPARgamma transcriptional activity were attenuated by wortmannin and by expression of a dominant negative phosphatidylinositol ( PI ) 3 - kinase p85 regulatory subunit . In addition PI 3 - kinase - dependent phosphorylation of PPARgamma was observed after stimulation by C - peptide or insulin . C - peptide effects but not insulin on PPARgamma transcriptional activity were abolished by pertussis toxin pretreatment . Finally both C - peptide and insulin positively control the expression of the PPARgamma - regulated P16671 scavenger receptor in human THP - 1 monocytes . We concluded that insulin and C - peptide can stimulate PPARgamma activity in a ligand - independent fashion and that this effect is mediated by PI 3 - kinase . These results support a new and potentially important physiological role for C - peptide in regulation of PPARgamma - related cell functions .",
"Inhibitory effects of a phosphate diester of DB00163 and ascorbic acid ( EPC - P04264 ) on myocardial infarction in rats . The inhibitory effect of a phosphate diester of DB00163 and ascorbic acid ( EPC - P04264 ) was examined in myocardial infarction induced in rats , in comparison with a selective P09917 inhibitor , AA - 861 . EPC - P04264 significantly reduced the infarct size at 24 and 48 h after ligation , whereas AA - 861 reduced it only at 48 h after ligation . In in - vitro experiments , EPC - P04264 inhibited not only superoxide anion generation ( IC50 = 4 . 2 x 10 (- 5 ) M ) , but also acid phosphatase activity ( IC50 = 2 . 4 x 10 (- 5 ) M ) in rat polymorphonuclear leukocytes in a concentration - dependent manner , while AA - 861 showed marginal effects on both actions . These results indicated that EPC - P04264 induced cardioprotective effects by affecting neutrophil functions by inhibition of generation of superoxide - anion generation and acid - phosphatase activity . The mechanism of the reduction of the infarct size by EPC - P04264 differed from that of AA - 861 , which latter inhibited P09917 and the formation of leukotriene B4 .",
"Cerebral protein kinase C and its mRNA level in apolipoprotein E - deficient mice . It is known that protein kinase C ( PKC ) activity may be one of the fundamental cellular changes associated with memory function . P02649 ( apoE ) deficiency causes cholinergic deficits and memory impairment . ApoE - deficient mouse has been employed as a serviceable model for studying the relation between apoE and the memory deficit induced by cholinergic impairment . Brain - fatty acid binding protein ( b - FABP ) might be functional during development of the nervous system . Peroxisome proliferator - activated receptor ( Q07869 ) is involved in the early change in lipid metabolism . We investigated the alterations not only in cerebral PKC activity , but also in the gene expressions of P05771 , brain - FABP and Q07869 in apoE - deficient mice . The results showed that there was a lower cerebral membrane - bound PKC activity in the apoE - deficient mice than in its wild type strain ( C57BL / 6 ) . But there were no significant differences in cytosolic PKC activity . P05771 , b - FABP and Q07869 mRNA expressions in cerebrum were lowered in apoE - deficient mice . These findings may be involved in the dysfunction of the brain neurotransmission system in apoE - deficient mouse . Alternatively , these results also suggest that cerebral apoE plays an important role in brain PKC activation by maintaining an appropriate expression of b - FABP and Q07869 mRNAs .",
"Design , synthesis , and biological evaluation of conformationally constrained aci - reductone mimics of arachidonic acid . An efficient and convergent synthesis has been developed for the production of 3 , 4 - dihydroxy - 5 - [ 4 - ( 2 - ( ( 2Z ) - hexenyl ) phenyl ) - 3 -( 1Z )- but enyl ] - 2 ( 5H ) - furanone ( 12d ) . This hydrophobic antioxidant is a stable conformationally constrained mimic of arachidonic acid ( AA ) ( 1 ) and its respective aci - reductone analogue ( 2 ) . Pd ( 0 )- catalyzed cross - coupling of 5 -( 3 - butynyl )- 3 , 4 - dihydroxy - 2 ( 5H )- furanone ( 7 ) with 2 - ( ( 2Z ) - hexenyl ) iodobenzene ( 8d ) followed by Lindlar catalyzed hydrogenation produces 12d . Butynyl intermediate 7 is prepared from 2 -( benzyloxy )- 5 - deoxyascorbic acid ( 15 ) by iodination ( I2 , PPh3 , Imd ) , iodo substitution with lithium acetylide ethylenediamine complex ( LiAEDA , HMPA , - 5 degrees C ) , and benzyl group cleavage ( Ac2O , Pyr , BCl3 ) . The utility of this synthetic method was demonstrated by the synthesis of analogues 10e - k . Biological testing revealed that certain of these antioxidants inhibit both cyclooxygenase ( P36551 ) and P09917 ( P09917 ) with comparable efficacy as reported for aspirin and zileuton , respectively . The antioxidant activity of these aci - reductones , measured as a function of their inhibitory effect on CCl4 - induced lipid peroxidation of hepatic microsomes , exceeds that produced by DB00163 . Synthetic routes and initial structure - activity relationships ( SAR ) for these novel mixed functioning antioxidants are presented .",
"Linkage of protein kinase C - beta activation and intracellular interleukin - 2 accumulation in human naive P01730 T cells . A critical role for protein kinase C ( PKC ) in signal transduction events has been well established . Moreover , studies of regulation in PKC levels suggest participation in mediating long - term cellular functions . Protein kinase C - beta ( P05771 ) has been reported to be involved in interleukin - 2 ( P60568 ) synthesis in T lymphocytes . In this study , the role of P05771 in intracellular accumulation of P60568 was investigated using specific inhibitors . Preincubation with two different PKC inhibitors , one specific for classical isotypes ( alpha and beta I ) Go6976 , and one which inhibits both classical and non - classical isotypes , GF109203X , caused a complete block in cytoplasmic P60568 accumulation when naive P01730 T cells were stimulated in the presence of P06729 + P10747 + phorbol myristate acetate ( PMA ) . In contrast , preincubation with up to 1000 ng / ml of cyclosporin A ( DB00091 ) resulted in a reduction in the intracellular P60568 detected , as observed by a decrease in the proportion of positive cells as well as a fall in the mean fluorescence intensity ( MFI ) . DB00091 did not influence P05771 translocation . Flow cytometric assessments of P05771 and its isoforms beta I and beta II correlated with Western blotting analysis and these results were further supported by the use of P05771 - positive ( HUT 78 ) and - negative ( BW5147 ) T - cell lines . Using the specific inhibitors , Go6976 and GF109203X , the findings in this study suggest that activation and translocation of P05771 is critical for accumulation of intracellular P60568 . The influence of DB00091 in reducing but not blocking P60568 synthesis is discussed . PMA - induced down - regulation of the P01730 antigen was observed in the presence of Go6976 and but not GF109203X , suggesting regulation by non - classical PKC isoforms .",
"Flavonoids inhibit the oxidative modification of low density lipoproteins by macrophages . Low density lipoproteins ( LDL ) can be oxidatively modified in vitro by macrophages and certain other cell types so that macrophages will take them up much faster . This process may be important in the formation of cholesterol - laden foam cells derived from macrophages in atherosclerotic lesions . In this study , we have shown that certain flavonoids , plant constituents found in the diet , are potent inhibitors of the modification of 125I - labelled LDL by macrophages , with IC50 values in the micromolar range ( e . g . morin and fisetin 1 microM ; quercetin and gossypetin 2 microM ) . The potencies of individual flavonoids in inhibiting LDL modification did not correlate with their previously determined potencies as inhibitors of P09917 and cyclo - oxygenase . The modification of LDL by macrophages exhibits a lag period of about 4 - 6 hr before enhanced uptake is detected . During this time , there is a rapid depletion in its content of DB00163 ( an endogenous antioxidant found in lipoproteins ) followed by a large increase in the level of hydroperoxides . The flavonoids conserved the DB00163 content of LDL and delayed the onset of detectable lipid peroxidation . Flavonoids also inhibited the cell - free oxidation of LDL mediated by CuSO4 . These findings raise the possibility that flavonoids may protect LDL against oxidation in atherosclerotic lesions and may therefore be natural anti - atherosclerotic components of the diet , although this will depend to a large extent on their pharmacokinetics .",
"P10275 coregulator Q96L73 - alpha interacts with death receptor - 6 revealed by the yeast two - hybrid . Q96L73 - alpha is a newly identified androgen receptor coactivator . In order to further elucidate its precise role in cells , using the Q96L73 - alpha fragment containing four P20941 and one Q01105 conserved domains as bait we revealed an Q96L73 - alpha - P20941 - Q01105 - interacting protein , death receptor - 6 ( O75509 ) , in the yeast two - hybrid screening . O75509 is the member of P01375 receptor family and has a death domain in its intracellular cytoplasmic portion ( DR6cp ) to mediate the cell apoptosis . The interaction between Q96L73 - alpha - P20941 - Q01105 and DR6cp was confirmed in vitro and in vivo . Our finding implied that androgen signaling pathway might cross talk with apoptosis signaling pathway through the interaction between Q96L73 - alpha and O75509 .",
"The effect of DB00163 on monocyte proatherogenic activity . Atherosclerosis is the leading cause of morbidity and mortality in Westernized populations . The monocyte is a crucial cell in the genesis of the atherosclerotic lesion and is present during all stages of atherosclerosis . alpha - Tocopherol ( AT ) is the most active component of the vitamin E family and is the principal and most potent lipid - soluble antioxidant in plasma and LDL . With regard to monocyte function , AT supplementation ( 1200 IU / d ) has been shown to decrease release of reactive oxygen species , lipid oxidation , release of cytokines such as interleukin - 1ss ( IL - 1ss ) and tumor necrosis factor - alpha ( P01375 ) and decrease adhesion of monocytes to human endothelium . The mechanism of inhibition of superoxide and lipid oxidation by monocytes appears to be via inhibition of protein kinase C ( PKC ) , the decrease in IL - 1ss and P01375 release by inhibition of P09917 and the inhibition of monocyte - endothelial cell adhesion via decrease in adhesion molecules on monocytes , CD11b and VLA - 4 and by decreasing DNA - binding activity of nuclear transcription factor kappaB . Thus , in addition to the decrease in oxidative stress resulting from AT supplementation , as evidenced by decreased F ( 2 )- isoprostanes and LDL oxidizability , AT is anti - inflammatory and exerts beneficial antiatherogenic effects on cells crucial in atherogenesis such as monocytes .",
"Alpha - tocopherol decreases tumor necrosis factor - alpha mRNA and protein from activated human monocytes by inhibition of P09917 . Cardiovascular disease is the leading cause of morbidity in Westernized populations . Low levels of DB00163 ( AT ) are associated with increased incidence of atherosclerosis and increased intakes appear to be protective . AT supplementation decreases interleukin 1 and 6 release from human monocytes . Thus , the aim of this study was to examine the effect of AT on an important proinflammatory cytokine , tumor necrosis factor - alpha ( P01375 ) release from human monocytes . AT supplementation ( 1200 IU / day for 3 months ) significantly decreased P01375 release from activated human monocytes . Mechanisms that were examined included its effect as a general antioxidant , its inhibitory effect on protein kinase C ( PKC ) , and the cycloxygenase - lipoxygenase pathway . While AT decreased P01375 release from activated monocytes , other antioxidants had no effect on P01375 release . Specific PKC inhibitors had no effect on P01375 release from activated monocytes . The inhibition of P01375 release by AT in activated monocytes was reversed by leukotriene B ( 4 ) ( Q06643 ( 4 ) ) , a major product of the P09917 ( P09917 ) pathway . Similar observations were seen with inhibitors of P09917 . Indomethacin , a P36551 inhibitor , in the presence and absence of AT failed to affect P01375 activity . These findings suggest that AT decreases P01375 release from activated human monocytes via inhibition of P09917 . Also , AT as well as a P09917 inhibitor significantly decreased P01375 mRNA . Furthermore , AT and the P09917 inhibitor decreased NFkappab - binding activity . Thus , in activated human monocytes , AT appears to inhibit P01375 mRNA and protein by inhibition of P09917 .",
"Screening of 134 single nucleotide polymorphisms ( SNPs ) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes . More than 120 published reports have described associations between single nucleotide polymorphisms ( SNPs ) and type 2 diabetes . However , multiple studies of the same variant have often been discordant . From a literature search , we identified previously reported type 2 diabetes - associated SNPs . We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium ( r ( 2 ) > 0 . 8 ) with another typed SNP . Of the 114 SNPs examined , we followed up the 20 most significant SNPs ( P < 0 . 10 ) on an additional 384 case subjects and 366 control subjects from a population - based study in Finland . In the combined data , we replicated association ( P < 0 . 05 ) for 12 SNPs : P37231 Pro12Ala and His447 , Q14654 Glu23Lys and rs5210 , P01375 - 857 , P11168 Ile110Thr , P20823 / TCF1 rs2701175 and GE117881_360 , P35558 - 232 , Q13562 Thr45Ala , P05231 - 598 , and P22413 Lys121Gln . The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association ( P = 0 . 012 ) . We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample ( P = 0 . 03 ) , although we also replicated 4 of 58 SNPs from genes that had only one previous report of association .",
"The stop transfer sequence of the human UDP - glucuronosyltransferase 1A determines localization to the endoplasmic reticulum by both static retention and retrieval mechanisms . Human UDP - glucuronosyltransferase 1A ( P22309 ) isoforms are endoplasmic reticulum ( ER ) - resident type I membrane proteins responsible for the detoxification of a broad range of toxic phenolic compounds . These proteins contain a C - terminal stop transfer sequence with a transmembrane domain ( TMD ) , which anchors the protein into the membrane , followed by a short cytosolic tail ( CT ) . Here , we investigated the mechanism of ER residency of P22309 mediated by the stop transfer sequence by analysing the subcellular localization and sensitivity to endoglycosidases of chimeric proteins formed by fusion of P22309 stop transfer sequence ( TMD / CT ) with the ectodomain of the plasma membrane P01730 reporter protein . We showed that the stop transfer sequence , when attached to C - terminus of the P01730 ectodomain was able to prevent it from being transported to the cell surface . The protein was retained in the ER indicating that this sequence functions as an ER localization signal . Furthermore , we demonstrated that ER localization conferred by the stop transfer sequence was mediated in part by the KSKTH retrieval signal located on the CT . Interestingly , our data indicated that P22309 TMD alone was sufficient to retain the protein in ER without recycling from Golgi compartment , and brought evidence that organelle localization conferred by P22309 TMD was determined by the length of its hydrophobic core . We conclude that both retrieval mechanism and static retention mediated by the stop transfer sequence contribute to ER residency of P22309 proteins .",
"DB00163 prevents diabetes - induced abnormal retinal blood flow via the diacylglycerol - protein kinase C pathway . We have characterized effects of d - DB00163 ( vitamin E ) on activation of protein kinase C ( PKC ) and diacylglycerol ( DAG ) levels in retinal tissues of diabetic rats and correlated its effects to diabetes - induced changes in retinal hemodynamics . Membrane PKC specific activities were increased by 71 % in streptozocin - induced diabetic rats compared with controls ( P < 0 . 05 ) . Western blot analysis showed that membrane P05771 II was increased by 133 +/- 5 % ( P < 0 . 05 ) . Injection of d - DB00163 ( 40 mg / kg ip ) every other day prevented the increases in membrane PKC specific activity and P05771 II protein by immunoblots . Diabetes - induced increases in DAG levels were also normalized by d - DB00163 treatment of 2 wk duration . Physiologically , angiographic abnormalities of retinal hemodynamics based on computerized video - based fluorescein angiography and associated with increases of DAG and membranous PKC levels were also prevented by d - DB00163 treatment in diabetic rats . The effect of d - DB00163 on retinal vascular cells was also studied . Exposure of retinal endothelial cells to 22 mM glucose for 3 days increased total DAG and [ 3H ] palmitate - labeled DAG levels by 35 +/- 8 and 50 +/- 8 % ( P < 0 . 05 ) , respectively , compared with exposure to 5 . 5 mM glucose . The presence of d - DB00163 ( 50 micrograms / ml ) prevented the increases in total DAG and [ 3H ] palmitate - labeled DAG levels in cells exposed to 22 mM glucose . These findings suggested that treatment with d - DB00163 can prevent diabetes - induced abnormalities in rat retinal blood flow . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"New isoflavonoids as inhibitors of porcine P09917 . The inhibitory activity of new isoflavonoids on P09917 of porcine leukocytes was investigated . Isoflavans ( I ) proved to be stronger inhibitors than isoflavones ( II ) . The isoflavans containing ortho - hydroxy groups in ring A showed the lowest Ki values ( 0 . 8 - 50 microM ) . In comparison , isoflavans with meta - dihydroxy groups exhibited Ki values higher than 150 microM . The effect of commercial antioxidants was tested also on porcine P09917 . Butylated hydroxyanisole ( Ki : 25 microM ) and butylated hydroxytoluene ( Ki : 55 microM ) revealed moderate inhibitory activity , whereas L - ascorbic acid , L - ascorbyl palmitate , dl - DB00163 and n - propyl gallate showed weak inhibitory activities ( Ki : 100 - 260 microM ) .",
"Reactive oxygen species - dependent P01375 converting enzyme activation through stimulation of P41595 and alpha1D autoreceptors in neuronal cells . A major determinant of neuronal homeostasis is the proper integration of cell signaling pathways recruited by a variety of neuronal and non - neuronal factors . By taking advantage of a neuroectodermal cell line ( 1C11 ) endowed with the capacity to differentiate into serotonergic ( 1C115 - HT ) or noradrenergic ( 1C11NE ) neurons , we identified serotonin ( 5 - hydroxytryptamine , 5 - HT ) - and norepinephrine ( NE ) - dependent signaling cascades possibly involved in neuronal functions . First , we establish that P41595 receptors and 1D adrenoceptors are functionally coupled to reactive oxygen species ( ROS ) synthesis through NADPH oxidase activation in 1C115 - HT and 1C11NE cells . This observation constitutes the prime evidence that bioaminergic autoreceptors take part in the control of the cellular redox equilibrium in a neuronal context . Second , our data identify P78536 ( P01375 - Converting Enzyme ) , a member of a disintegrin and metalloproteinase ( ADAM ) family , as a downstream target of the P41595 and 1D receptor - NADPH oxidase signaling pathways . Upon P41595 or 1D receptor stimulation , ROS fully govern P01375 - shedding in the surrounding milieu of 1C115 - HT or 1C11NE cells . Third , P41595 and 1Dreceptor couplings to the NADPH oxidase - P78536 cascade are strictly restricted to 1C11 - derived progenies that have implemented a complete serotonergic or noradrenergic phenotype . Overall , these observations suggest that P41595 and 1D autoreceptors may play a role in the maintenance of neuron - and neurotransmitter - associated functions . Eventually , our study may have implications regarding the origin of oxidative stress as well as up - regulated expression of proinflammatory cytokines in neurodegenerative disorders , which may relate to the deviation of normal signaling pathways .",
"Immunoreceptor tyrosine - based inhibitory motifs on activating molecules . Immunoreceptor tyrosine - based inhibitory motifs ( ITIMs ) have the restricted consensus sequence V / I / xYxxL / V , but may be more broadly defined by the sequence V / I / L / SxYxxL / V / I / S . If one includes the ITIM of P16410 , then the sequence becomes psixYxxpsi , where psi represents amino acids with nonpolar side chains . Aside from their presence in various inhibitory molecules , ITIMs are also found on many activating receptors and pathways . ITIMs with the restricted consensus sequence occur on IL - 4Ralpha , IL - 3Rbeta type II , P40189 cytokineR , P48357 ( leptinR ) , P15018 - Rbeta P19438 , Q99062 , PDGF - R , Blk , Ctk / Ntk , Lsk , Zap - 70 , P31749 / RACalpha , P17252 , P05771 , P05129 , PKC - delta , PKC - zeta , PKC - epsilon , PKC - eta , PKC - phi , PKC - mu , calmodulin - dependent kinase IIdelta , SLP - 76 - associated protein , O15117 , Shc binding protein , RasGRF2 , Q13972 homologue , Jak2 , Jak3 , PLCbeta1 , and PLCbeta3 . If ITIMs are defined by a broader consensus sequence , the list of ITIMs on activating molecules becomes even larger . In some instances , these ITIMs have been shown to associate with inhibitory phosphatases . Whether these ITIMs on activating receptors / pathways are necessary and sufficient for negative control of activating events and for immunologic tolerance is not yet known . In some instances , ITIMs on coinhibitory receptors are also required for appropriate negative regulation . By studying events leading to negative control during activation and to immunologic tolerance , it should be possible to discern the balance between antigen receptor - based negative events and coinhibition .",
"Gamma - tocopherol , but not DB00163 , decreases proinflammatory eicosanoids and inflammation damage in rats . Gamma - tocopherol ( gammaT ) , the major form of vitamin E in U . S . diets , and its physiological metabolite 2 , 7 , 8 - trimethyl - 2 -( beta - carboxyethyl )- 6 - hydroxychroman ( gamma - CEHC ) , in contrast to DB00163 ( alphaT ) , the primary vitamin E in supplements , inhibit cyclooxygenase - catalyzed synthesis of prostaglandin E2 ( DB00917 ) in activated macrophages and epithelial cells . Here we report that in carrageenan - induced inflammation in male Wistar rats , administration of gammaT ( 33 or 100 mg / kg ) and gamma - CEHC ( 2 mg / pouch ) , but not alphaT ( 33 mg / kg ) , significantly reduced DB00917 synthesis at the site of inflammation . gammaT , but not alphaT , significantly inhibited the formation of leukotriene B4 , a potent chemotactic agent synthesized by the P09917 of neutrophils . Although gammaT had no effect on neutrophil infiltration , it significantly attenuated the partial loss of food consumption caused by inflammation - associated discomfort . Administration of gammaT led consistently to a significant reduction of inflammation - mediated increase in 8 - isoprostane , a biomarker of lipid peroxidation . gammaT at 100 mg / kg reduced P01375 ( 65 % ; P = 0 . 069 ) , total nitrate / nitrite ( 40 % ; P = 0 . 1 ) , and lactate dehydrogenase activity ( 30 % ; P = 0 . 067 ) . Collectively , gammaT inhibits proinflammatory DB00917 and LTB4 , decreases P01375 , and attenuates inflammation - mediated damage . These findings provide strong evidence that gammaT shows anti - inflammatory activities in vivo that may be important for human disease prevention and therapy .",
"Role of P12644 and Its Signaling Pathways in Cultured Human Melanocytes . Bone Morphogenetic Protein ( P12644 ) was shown to down - regulate melanogenesis , in part , by decreasing the level of tyrosinase [ Yaar et al . ( 2006 ) JBC : 281 ] . Results presented here show that P12644 down - regulated the protein levels of TRP - 1 , P05771 , and D6RGH6 - R . When paired cultures of human melanocytes were treated with vehicle or P12644 ( 25 ng / ml ) , MAPK / P29323 were phosphorylated within one hour of P12644 treatment . Then the activated MAPK / P29323 caused an acute phosphorylation of O75030 , followed by proteosome - mediated degradation of O75030 , the key transcription factor for melanogenic proteins [ Wu et al . ( 2000 ) Gene & Development : 14 ] . However , prolonged exposure of melanocytes to P12644 ( up to 48 hours ) caused a decrease in the level of O75030 - M transcript . In addition , P12644 decreased the intracellular level of DB02527 , the key regulator of O75030 expression . These results demonstrate that P12644 activates MAPK / P29323 signaling pathway to transiently activate O75030 ; however , chronic treatment of P12644 to melanocytes causes a down - regulation of the expression of O75030 , possibly in a DB02527 - dependent pathway .",
"P09917 deficiency reduces acetaminophen - induced hepatotoxicity and lethality . 5 - Lipoxygenase ( P09917 ) converts arachidonic acid into leukotrienes ( LTs ) and is involved in inflammation . At present , the participation of P09917 in acetaminophen ( DB00316 ) - induced hepatotoxicity and liver damage has not been addressed . P09917 deficient ( 5 - LO ⁻/⁻ ) mice and background wild type mice were challenged with DB00316 ( 0 . 3 - 6 g / kg ) or saline . The lethality , liver damage , neutrophil and macrophage recruitment , LTB₄ , cytokine production , and oxidative stress were assessed . DB00316 induced a dose - dependent mortality , and the dose of 3 g / kg was selected for next experiments . DB00316 induced LTB4 production in the liver , the primary target organ in DB00316 toxicity . Histopathological analysis revealed that 5 - LO ⁻/⁻ mice presented reduced DB00316 - induced liver necrosis and inflammation compared with WT mice . DB00316 - induced lethality , increase of plasma levels of aspartate aminotransferase and alanine aminotransferase , liver cytokine ( IL - 1β , P01375 - α , IFN - γ , and P22301 ) , superoxide anion , and thiobarbituric acid reactive substances production , myeloperoxidase and N - acetyl - β - D - glucosaminidase activity , Nrf2 and gp91 ( phox ) mRNA expression , and decrease of reduced glutathione and antioxidant capacity measured by 2 , 2 '- azinobis ( 3 - ethylbenzothiazoline 6 - sulfonate ) assay were prevented in 5 - LO ⁻/⁻ mice compared to WT mice . Therefore , P09917 deficiency resulted in reduced mortality due to reduced liver inflammatory and oxidative damage , suggesting P09917 is a promising target to reduce DB00316 - induced lethality and liver inflammatory / oxidative damage .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK48___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK48___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"DB00163 suppresses P09917 - mediated oxidative stress in peripheral blood mononuclear cells of hemodialysis patients regardless of administration route . A number of pathological conditions caused by oxidative stress have been reported in uremic patients undergoing maintenance hemodialysis ( HD ) . Enhanced lipid peroxidation was previously observed in peripheral blood mononuclear cells ( PBMCs ) of HD patients . Upregulation of P09917 ( 5 - Lox ) activity and protein content with enhanced production of leukotriene B ( 4 ) ( Q06643 ( 4 ) ) and membrane lipoperoxides was also shown in PBMCs of HD patients . Administration of free vitamin E specifically inhibited 5 - Lox activity without affecting gene expression at the protein level . To assess whether oral or intramuscular ( IM ) administration of vitamin E may suppress 5 - Lox in HD patients , PBMCs from 16 subjects on maintenance HD therapy for at least 6 months were investigated before and after a short course of IM or oral administration of vitamin E ( 8 patients per group ) . PBMCs from 13 healthy controls were also evaluated and assumed as the reference standard . DB00163 significantly reduced lipid peroxidation , Q06643 ( 4 ) content , and 5 - Lox activity in PBMCs , whereas 5 - Lox gene expression at the protein level was not affected . There were no significant differences in these parameters between patients treated with IM or oral vitamin E . PBMCs of HD patients showed enhanced membrane lipid peroxidation and release of Q06643 ( 4 ) , both linked to upregulation of 5 - P28300 : 5 - Lox activity and related oxidative stress were significantly ( although not completely ) suppressed by vitamin E regardless of the administration route .",
"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK1___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK1___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .",
"Overexpression of cytochrome P450 4F2 in mice increases 20 - hydroxyeicosatetraenoic acid production and arterial blood pressure . P78329 ( P78329 ) activity is thought to be a factor in the pathogenesis of hypertension through its bioactive metabolite 20 - hydroxyeicosatetraenoic acid ( 20 - HETE ) . We previously found that a gain - in - function P78329 variant in a Chinese cohort was associated with elevated urinary 20 - HETE and hypertension . To further explore this association we generated a transgenic mouse model expressing P78329 driven by a modified mouse kidney androgen - regulated protein promoter . This heterologous promoter regulated the expression of luciferase and his - tagged P78329 in transfected P29320 293 cells . In the kidney of transgenic mice , P78329 was localized to renal proximal tubule epithelia and was expressed at a higher level than in control mice , leading to increased urinary 20 - HETE excretion . Assessment of P78329 activity by an arachidonic acid hydroxylation assay showed that 20 - HETE production was significantly higher in kidney microsomes of transgenic mice compared to control mice , as was their systolic blood pressure . There was a positive correlation of blood pressure with urinary 20 - HETE levels . Our results show that increased expression of P78329 in mice enhanced 20 - HETE production and elevated blood pressure .",
"Protein kinase C activation and the development of diabetic complications . Recent studies have identified that the activation of protein kinase C ( PKC ) and increased diacylglycerol ( DAG ) levels initiated by hyperglycemia are associated with many vascular abnormalities in retinal , renal , and cardiovascular tissues . Among the various PKC isoforms , the beta - and delta - isoforms appear to be activated preferentially in the vasculatures of diabetic animals , although other PKC isoforms are also increased in the renal glomeruli and retina . The glucose - induced activation of PKC has been shown to increase the production of extracellular matrix and cytokines ; to enhance contractility , permeability , and vascular cell proliferation ; to induce the activation of cytosolic phospholipase A2 ; and to inhibit Na +- K +- ATPase . The synthesis and characterization of a specific inhibitor for P05771 isoforms have confirmed the role of PKC activation in mediating hyperglycemic effects on vascular cells , as described above , and provide in vivo evidence that PKC activation could be responsible for abnormal retinal and renal hemodynamics in diabetic animals . Transgenic mice overexpressing P05771 isoform in the myocardium developed cardiac hypertrophy and failure , further supporting the hypothesis that P05771 isoform activation can cause vascular dysfunctions . Interestingly , hyperglycemia - induced oxidative stress may also mediate the adverse effects of P05771 isoforms by the activation of the DAG - PKC pathway , since treatment with D - DB00163 was able to prevent many glucose - induced vascular dysfunctions and inhibit DAG - PKC activation . Clinical studies are now in progress to determine whether P05771 inhibition can prevent diabetic complications .",
"Some antioxidants inhibit , in a co - ordinate fashion , the production of tumor necrosis factor - alpha , IL - beta , and P05231 by human peripheral blood mononuclear cells . Some antioxidants , including butylated hydroxyanisole ( BHA ) , tetrahydropapaveroline ( THP ) , nordihydroguiauretic acid , and 10 , 11 - dihydroxyaporphine ( DB01708 ) , were found to be potent inhibitors of the production of tumor necrosis factor ( P01375 ) - alpha , P01584 , and P05231 by human peripheral blood mononuclear cells ( PBMC ) stimulated by lipopolysaccharide ( LPS ) ( IC50s in the low micromolar range ) . Inhibition of cytokine production was gene selective and not due to general effects on protein synthesis . Inhibition of cytokine production by PBMC was observed also when other inducers were used ( staphylococci , silica , zymosan ) . Much higher concentrations of other antioxidants -- including ascorbic acid , trolox , DB00163 , butylated hydroxytoluene , and the P09917 inhibitor zileuton -- did not affect the production of these cytokines . The active compounds did not inhibit IL - 1 - induced production of P05231 in fibroblasts , showing the cell selectivity of the effect . Antioxidant - mediated inhibition of cytokine production was correlated with low levels of the corresponding messenger RNAs . Nuclear run - on experiments showed that THP inhibited transcription of the P01584 gene . THP decreased the concentration of the transcription factors NF - kappa B and AP - 1 detected in nuclear extracts of PBMC cultured in the presence or absence of LPS . THP and DB01708 markedly decreased the levels of P01375 and P01584 in the circulation of mice following LPS injection . Thus antioxidants vary widely in potency as inhibitors of the activation of transcription factors and of the transcription of genes for pro - inflammatory cytokines . Coordinate inhibition of the transcription of genes for inflammatory cytokines could provide a strategy for therapy of diseases with inflammatory pathogenesis and for septic shock .",
"The arachidonic acid cascade , eicosanoids , and signal transduction . Eicosanoid biosynthesis in animal cells either results from agonist - stimulated phospholipase activation ( endogenous pathway ) or from lipoprotein receptor - mediated uptake and lysosomal lipid hydrolase - dependent release of AA ( exogenous pathway ) ( see Fig . 1 for schematic representation ) . LDL stimulates eicosanoid formation through delivery of substrate AA to enzymes of oxidative AA metabolism . The classical P01130 is a control point of the effects of LDL AA on eicosanoid formation in different tissues : LDL AA metabolism occurs in several cell types of mesenchymal and epithelial origin and generates the formation of distinct eicosanoid patterns in each case . The LDL AA pathway does appear to couple directly to the PGH synthase reaction , whereas it does not couple directly to the P09917 reaction . We expect that a more complete characterization of the LDL unsaturated fatty acid pathway in different tissue will yield additional information on the biochemistry of lipoproteins , AA , and eicosanoids .",
"High glucose augments the angiotensin II - induced activation of O60674 in vascular smooth muscle cells via the polyol pathway . Angiotensin II ( Ang II ) , protein kinase C ( PKC ) , reactive oxygen species ( ROS ) generated by NADPH oxidase , the activation of O60674 ( O60674 ) , and the polyol pathway play important parts in the hyperproliferation of vascular smooth muscle cells ( VSMC ) , a characteristic feature of diabetic macroangiopathy . The precise mechanism , however , remains unclear . This study investigated the relation between the polyol pathway , P05771 , ROS , O60674 , and Ang II in the development of diabetic macroangiopathy . VSMC cultured in high glucose ( HG ; 25 mm ) showed significant increases in the tyrosine phosphorylation of O60674 , production of ROS , and proliferation activities when compared with VSMC cultured in normal glucose ( 5 . 5 mm ( NG ) ) . Both the aldose reductase specific inhibitor ( zopolrestat ) or transfection with aldose reductase antisense oligonucleotide blocked the phosphorylation of O60674 , the production of ROS , and proliferation of VSMC induced by HG , but it had no effect on the Ang II - induced activation of these parameters in both NG and HG . However , transfection with P05771 antisense oligonucleotide , preincubation with a P05771 - specific inhibitor ( LY379196 ) or apocynin ( NADPH oxidase - specific inhibitor ) , or electroporation of NADPH oxidase antibodies blocked the Ang II - induced O60674 phosphorylation , production of ROS , and proliferation of VSMC in both NG and HG . These observations suggest that the polyol pathway hyperactivity induced by HG contributes to the development of diabetic macroangiopathy through a P05771 - ROS activation of O60674 .",
"Attenuated Salmonella Gallinarum secreting an Escherichia coli heat - labile enterotoxin B subunit protein as an adjuvant for oral vaccination against fowl typhoid . In our previous study , we constructed a vaccine candidate ( JOL916 ) for fowl typhoid ( FT ) . A live adjuvant Salmonella Gallinarum ( SG ) strain was generated in the present study to facilitate efficacious oral vaccination with this vaccine . The Escherichia coli eltB gene secreting heat - labile enterotoxin B subunit ( Q06643 ) was cloned into an Asd (+) plasmid pJHL65 . This was transformed into a Δlon ΔcpxR Δasd SG strain and the resulting strain was designated JOL1229 . Secretion of Q06643 from JOL1229 was confirmed with an immunoblot assay . To determine the optimal dose of the strain , 50 six - week - old female chickens were divided into five groups ( Groups A - E , n = 10 per group ) and orally inoculated with various doses of JOL1229 and JOL916 . In Group B ( consisting of four parts JOL916 and one part JOL1229 ) , significant cell - mediated immune responses , plasma IgG levels and intestinal secretary IgA levels were induced after inoculation with both strains . On challenge with the wild - type strain , significant reductions in mortality were observed in the group . In addition , after inoculation the Q06643 strain was not recovered in feces samples , and resulted in no , or very mild , gross lesions in the liver and spleen . Both P01730 (+) and CD8 (+) T - cells were significantly increased in peripheral blood samples from the chickens immunized with the Q06643 strain . Expression of the interleukin - 6 ( P05231 ) gene in splenocytes was induced in the chickens immunized with the Q06643 strain . These results suggest that oral immunization with the Q06643 - adjuvant strain , in particular with the four parts JOL916 and one part JOL1229 mixture , increased the immune response and provided efficient protection against FT in chickens .",
"Tocotrienols activate the steroid and xenobiotic receptor , O75469 , and selectively regulate expression of its target genes . DB00163 is an essential nutrient with antioxidant activity . DB00163 is comprised of eight members , alpha - , beta - , gamma - , and delta - tocopherols and alpha - , beta - , gamma - , and delta - tocotrienols . All forms of vitamin E are initially metabolized by omega - oxidation , which is catalyzed by cytochrome P450 enzymes . The steroid and xenobiotic receptor ( O75469 ) is a nuclear receptor that regulates drug clearance in the liver and intestine via induction of genes involved in drug and xenobiotic metabolism . We show here that all four tocotrienols specifically bind to and activate O75469 , whereas tocopherols neither bind nor activate . Surprisingly , tocotrienols show tissue - specific induction of O75469 target genes , particularly P08684 . Tocotrienols up - regulate expression of P08684 but not P22309 ( P22309 ) or multidrug resistance protein - 1 ( P08183 ) in primary hepatocytes . In contrast , tocotrienols induce P08183 and P22309 but not P08684 expression in intestinal LS180 cells . We found that nuclear receptor corepressor ( NCoR ) is expressed at relatively high levels in intestinal LS180 cells compared with primary hepatocytes . The unliganded O75469 interacts with NCoR , and this interaction is only partially disrupted by tocotrienols . Expression of a dominant - negative NCoR enhanced the ability of tocotrienols to induce P08684 in LS180 cells , suggesting that NCoR plays an important role in tissue - specific gene regulation by O75469 . Our findings provide a molecular mechanism explaining how vitamin supplements affect the absorption and effectiveness of drugs . Knowledge of drug - nutrient interactions may help reduce the incidence of decreased drug efficacy .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK84___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"Serotonin skews human macrophage polarization through P41595 and P34969 . Besides its role as a neurotransmitter , serotonin ( 5 - hydroxytryptamine , 5HT ) regulates inflammation and tissue repair via a set of receptors ( 5HT ( 1 - 7 ) ) whose pattern of expression varies among cell lineages . Considering the importance of macrophage polarization plasticity for inflammatory responses and tissue repair , we evaluated whether 5HT modulates human macrophage polarization . 5HT inhibited the LPS - induced release of proinflammatory cytokines without affecting P22301 production , upregulated the expression of M2 polarization - associated genes ( P05120 , P07996 , Q9NY15 , Q86Y22 ) , and reduced the expression of M1 - associated genes ( P08476 , P41597 , P39900 , P05121 , P29016 , O94788 ) . Whereas only 5HT ( 7 ) mediated the inhibitory action of 5HT on the release of proinflammatory cytokines , both 5HT ( 2B ) and 5HT ( 7 ) receptors mediated the pro - M2 skewing effect of 5HT . In fact , blockade of both receptors during in vitro monocyte - to - macrophage differentiation preferentially modulated the acquisition of M2 polarization markers . 5HT ( 2B ) was found to be preferentially expressed by anti - inflammatory M2 ( P09603 ) macrophages and was detected in vivo in liver Kupffer cells and in tumor - associated macrophages . Therefore , 5HT modulates macrophage polarization and contributes to the maintenance of an anti - inflammatory state via 5HT ( 2B ) and 5HT ( 7 ) , whose identification as functionally relevant markers for anti - inflammatory / homeostatic human M2 macrophages suggests their potential therapeutic value in inflammatory pathologies .",
"Atrial natriuretic peptide binds to P01160 - Q96GN5 receptors in neuroblastoma cells or is degraded extracellularly at the DB00133 - DB00120 bond . P01160 - Q96GN5 receptors for atrial natriuretic peptide ( P01160 ) showed the following rank order of affinity in intact human neuroblastoma cells NB - OK - 1 : human P01160 -( 99 - 126 ) approximately human P01160 -( 102 - 126 ) approximately rat P01160 -( 99 - 126 ) ( P04264 17 - 32 pM ) > human P01160 -( 103 - 126 ) > porcine brain natriuretic peptide ( DB04899 ) . Analogues truncated at the C - terminal extremity or devoid of a disulphide bridge , such as rat P01160 -( 103 - 123 ) , rat C - P01160 -( 102 - 121 ) , rat P01160 -( 111 - 126 ) , rat P01160 -( 99 - 109 ) and rat [ desCys105 , Cys121 ] P01160 -( 104 - 126 ) and chicken P23582 , were not recognized . The occupancy of these high affinity P01160 - Q96GN5 receptors led to marked cyclic GMP accumulation in the presence of 3 - isobutyl 1 - methylxanthine . An ectoenzymic activity , partly shed in the incubation medium , provoked the stepwise release of DB00120 - DB00125 -[ 125I ] DB00135 , DB00125 -[ 125I ] DB00135 and [ 125I ] DB00135 from rat [ 125I ] P01160 -( 99 - 126 ) , at an optimal pH of 7 . 0 . Its inhibition by 1 , 10 - phenanthroline , DB00974 and bacitracin but not by thiorphan suggests the contribution of at least one neutral metalloendopeptidase , distinct from EC 3 . 4 . 24 . 11 , for which P01160 showed high affinity .",
"Effects of dietary vitamin E on the biosynthesis of P09917 products by rat polymorphonuclear leukocytes ( PMNL ) . Activation of polymorphonuclear neutrophils ( PMNL ) leads to the release of arachidonate from cellular phospholipids via a phospholipase A2 , and conversion of products of the P09917 pathway . Evidence to date indicates the dietary vitamin E ( ( R , R , R ) - DB00163 ) can influence both cyclooxygenase and phospholipase A2 activities and that the effect of this vitamin is cell / tissue specific . The present study was undertaken in order to examine the effects of varying dietary tocopherol on PMNL tocopherol content and P09917 product profile using the ionophore A23187 as stimulant in the presence and absence of exogenous arachidonate . Feeding semi - purified diets containing 0 , 30 or 3000 ppm of ( R , R , R ) - DB00163 acetate to weanling rats for 17 weeks resulted in a dose - related enrichment of PMNL tocopherol . Stimulation of PMNL elicited a significant and rapid loss of tocopherol . When PMNL were stimulated with A23187 alone , the synthesis of 5 - HETE , LTB4 and 19 - hydroxy - LTB4 was decreased in proportion to increasing dietary tocopherol concentrations . However , when exogenous arachidonate was provided with A23187 , intermediate amounts of dietary tocopherol ( 30 ppm ) still suppressed the formation of P09917 products , but high doses ( 3000 ppm ) did not have any additional inhibitory effect . This differential response to high concentrations of vitamin E in the presence and absence of exogenous arachidonate highly suggest that at these concentrations , tocopherol may act principally at the level of substrate release whereas at lower concentrations , P09917 is inhibited . Data from this study demonstrated that attenuation of the formation of P09917 products in PMNL can be achieved by dietary vitamin E enrichment .",
"[ Development of simplified and rapid detection assay for genetic polymorphisms influencing drug response and its clinical applications ] . Clinically important genetic polymorphisms influencing drug metabolism and drug response have typically been discovered on the basis of phenotypic differences among individuals from different populations . Routine genotyping before drug therapy may enable the identification of responders , nonresponders , or patients at increased risk of toxicity . Automated , high - throughput detecting methods for single - nucleotide polymorphisms ( SNPs ) are highly desirable in many clinical laboratories . The aim of this study is to develop a high - throughput genotyping method for detecting SNPs influencing drug response in the Japanese population . We have developed three real - time PCR assays for detecting SNPs in the human drug - metabolizing enzymes and drug targets . The assay for simultaneously detecting P11509 , P20813 , P11712 , P33260 , P33261 , P10635 , P05181 , P20815 , NAT2 , P51580 , Q12882 , P22309 , P05091 , P00325 , P08183 , P11597 , P12821 - 1 , P07550 , P28223 , P49441 , P48061 , and mitochondrial DNA polymorphisms takes less than 1 . 5 h . With the clinical application of NAT2 genotyping , we found statistically significant difference between the incidence of adverse drug reactions ( ADRs ) and the NAT2 genotype . The incidence of the ADRs was significantly higher in the slow type than the in other two types , as 5 of the 6 patients were of the slowtype , and the other was the intermediatetype , while no patients of the rapidtype has developed any ADRs .",
"DB00163 , P09917 and oxidative stress in haemodialysis patients : facts , not fancies .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK96___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK100___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .",
"Specific cellular responses to DB00163 . In the last 10 years precise cellular functions of DB00163 , some of which are independent of its antioxidant / radical - scavenging ability , have been revealed . Absorption of DB00163 from the gut is a selective process . Other tocopherols are not absorbed or are absorbed to a lesser extent . At the post - translational level , DB00163 inhibits protein kinase C and P09917 and activates protein phosphatase 2A and diacylglycerol kinase . Some genes [ platelet glycoprotein IV / thrombospondin receptor / class B scavenger receptor ( P16671 ) , DB00163 transfer protein ( alpha - TTP ) , alpha - tropomyosin , connective tissue growth factor and collagenase ] are affected by DB00163 at the transcriptional level . alpha - Tocopherol also inhibits cell proliferation , platelet aggregation , monocyte adhesion and the oxygen burst in neutrophils . Other antioxidants , such as beta - tocopherol and probucol , do not mimic these effects , suggesting a nonantioxidant , DB00163 - specific molecular mechanism .",
"[ Anti - cholesterol agents , new therapeutic approaches ] . Statins and fibrates constitute the two major families of lipid - lowering agents . Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia . Both drugs are also used for the treatment of mixed dyslipidemia . Some fibrates efficiently lower serum LDL - cholesterol . Statins inhibit P04035 and decrease cellular cholesterol synthesis . The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the P01130 gene . This over expression of the P01130 in the liver increases the clearance of circulating LDL thus decreasing the LDL - cholesterol plasma levels . The effects of fibrates on lipid metabolism are entirely due to their capacity to activate Q07869 and to induce the over expression of genes containing a PPRE in their promoter . Fibrates decrease triglyceride concentrations by increasing the beta - oxidation of fatty acids in the liver and by decreasing triglyceride - VLDL synthesis . Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C - III transcription , respectively . Fibrates could decrease triglycerides partly by inducing apo A - V over - expression . These molecules increase HDL - cholesterol by increasing apo A - I and apo A - II transcription . Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK10___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .",
"Thrombin and activated protein C inhibit the expression of secretory group IIA phospholipase A ( 2 ) in the P01375 - activated endothelial cells by Q9UNN8 and P25116 dependent mechanisms . INTRODUCTION : Thrombin and tumor necrosis factor ( P01375 ) - alpha up - regulate the expression of proinflammatory molecules in human umbilical vein endothelial cells ( HUVECs ) . However , activated protein C ( P25054 ) down - regulates the expression of the same molecules . The expression level of secretory group IIA phospholipase A ( 2 ) ( sPLA ( 2 )- IIA ) is known to be elevated in inflammatory disorders including in sepsis . Here , we investigated the effects of P25054 and thrombin on the expression of sPLA ( 2 )- IIA and extracellular signal - regulated kinase ( P29323 ) in HUVECs . MATERIALS AND METHODS : The expression level of sPLA ( 2 )- IIA was quantitatively measured by an enzyme - linked - immunosorbent - assay following stimulation of HUVECs with either thrombin or P01375 in the absence and presence of the phosphatidylinositol 3 - kinase ( P19957 - kinase ) inhibitor LY294002 and the cholesterol - depleting drug methyl - beta - cyclodextrin ( MbetaCD ) . RESULTS AND CONCLUSIONS : Thrombin had no effect on the expression of sPLA ( 2 )- IIA in HUVECs , however , P01375 potently induced its expression . The prior treatment of cells with P25054 inhibited expression of sPLA ( 2 )- IIA through the Q9UNN8 - dependent cleavage of P25116 . Further studies revealed that if HUVECs were pretreated with the zymogen protein C to occupy Q9UNN8 , thrombin also inhibited the P01375 - mediated expression of sPLA ( 2 )- IIA through the cleavage of P25116 . The Q9UNN8 - dependent cleavage of P25116 by both P25054 and thrombin increased the phosphorylation of P29323 1 / 2 . Pretreatment of cells with either LY294002 or MbetaCD abolished the inhibitory activity of both P25054 and thrombin against sPLA ( 2 )- IIA expression , suggesting that the protein C occupancy of Q9UNN8 confers a P19957 - kinase dependent protective activity for thrombin such that its cleavage of the lipid - raft localized P25116 inhibits the P01375 - mediated expression of sPLA ( 2 )- IIA in HUVECs .",
"[ Effect of tocopherol and tocopherol quinone complexes with proteins on activity of leukotriene B4 lipoxygenase ] . While estimating the effect of tocopherol , tocopherylquinone and their complexes with the tocopherol - binding proteins from the rat liver cytosole on arachidonate P09917 from peritoneal - lymphocytes and soybean linoleate - P09917 DB00163 and especially its complex with tocopherol - binding protein was defined to inhibit the activity of both vegetative - and animal nature - lipoxygenase .",
"Effects of zileuton and montelukast in mouse experimental spinal cord injury . BACKGROUND AND PURPOSE : P09917 ( P09917 ) is the key enzyme in leukotriene ( LT ) biosynthesis from arachidonic acid ( AA ) . Here , we examined the role of the P09917 - product , cysteinyl - LT ( DB00151 - LT ) , with a P09917 inhibitor ( zileuton ) and a DB00151 - LT , receptor antagonist ( montelukast ) , in the inflammatory response and tissue injury associated with spinal cord injury ( SCI ) . EXPERIMENTAL APPROACH : SCI was induced in mice by the application of vascular clips to the dura via a two - level Q8NHM4 to T7 laminectomy for 1 min . Cord inflammation was assessed histologically and by measuring inflammatory mediators ( ELISA ) and apoptosis by annexin V , TUNEL , P48023 staining and Bax and Bcl - 2 expression ( immunohistochemistry and western blots ) . Motor function in hindlimbs was assessed by a locomotor rating scale , for 10 days after cord injury . KEY RESULTS : SCI in mice resulted in tissue damage , oedema , neutrophil infiltration , apoptosis , tumour necrosis - alpha ( P01375 ) and cyclooxygenase - 2 ( P35354 ) expression , prostaglandin E ( 2 ) ( PGE ( 2 ) ) and leukotriene B ( 4 ) ( Q06643 ( 4 ) ) production , and extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) phosphorylation in injured tissue . Treatment of the mice with zileuton or montelukast reduced the spinal cord inflammation and tissue injury , neutrophil infiltration , P01375 , P35354 and pERK1 / 2 expression , PGE ( 2 ) and Q06643 ( 4 ) production , and apoptosis . In separate experiments , zileuton or montelukast significantly improved the recovery of limb function over 10 days . CONCLUSIONS AND IMPLICATIONS : Zileuton and montelukast produced a substantial reduction of inflammatory events associated with experimental SCI . Our data underline the important role of P09917 and DB00151 - LT in neurotrauma .",
"Novel target for induction of apoptosis by cyclo - oxygenase - 2 inhibitor SC - 236 through a protein kinase C - beta ( 1 )- dependent pathway . Nonsteroidal anti - inflammatory drugs ( NSAIDs ) reduce the risk of gastrointestinal cancers . Recently , a similar protective effect has been demonstrated by the specific cyclo - oxygenase - 2 ( P35354 ) inhibitors . However , the exact mechanism that accounts for the anti - proliferative effect of specific P35354 inhibitors is still not fully understood , and it is still controversial whether these protective effects are predominantly mediated through the inhibition of P35354 activity and prostaglandin synthesis . Identification of molecular targets regulated by P35354 inhibitors could lead to a better understanding of their pro - apoptotic and anti - neoplastic activities . In the present study , we investigated the effect and the possible molecular target of a P35354 - specific inhibitor SC - 236 on gastric cancer . We showed that SC - 236 induced apoptosis in gastric cancer cells . However , this effect was not dependent on P35354 inhibition . SC - 236 down - regulated the protein expression and kinase activity of P05771 ( 1 ) , increased the expression of PKCdelta and PKCeta , but did not alter the expression of other PKC isoforms in AGS cells . Moreover , exogenous prostaglandins or PGE ( 2 ) receptor antagonists could not reverse the inhibition effect on PKCbeta ( 1 ) by SC - 236 , which suggested that this effect occurred through a mechanism independent of cyclo - oxygenase activity and prostaglandin synthesis . Overexpression of PKCbeta ( 1 ) attenuated the apoptotic response of AGS cells to SC - 236 and was associated with overexpression of P38936 ( waf1 / cip1 ) . Inhibition of PKCbeta ( 1 )- mediated overexpression of P38936 ( waf1 / cip1 ) partially reduced the anti - apoptotic effect of PKCbeta ( 1 ) . The down - regulation of PKCbeta ( 1 ) provides an explanation for P36551 - independent apoptotic effects of specific P35354 inhibitor in cultured gastric cancer cells . We also suggest that PKCbeta ( 1 ) act as survival mediator in gastric cancer , and its down - regulation by P35354 inhibitor SC - 236 may provide new target for future treatment of gastric cancer .",
"[ ___MASK44___ sodium ( Photofrin - II ) ] . ___MASK44___ sodium ( ___MASK44___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK44___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"DB00163 and drug metabolism . Tocopherols and tocotrienols are metabolized by side chain degradation initiated by cytochrome P450 ( CYP ) - catalyzed omega - hydroxylation followed by beta - oxidation . Whereas DB00163 is only poorly metabolized , high amounts of the final products , carboxyethyl hydroxychroman ( CEHC ) , are found from other tocols in HepG2 cells and in human urine . P08684 and P78329 were suggested to be involved in tocopherol degradation . P08684 metabolizes most of the drugs and is induced by many of its substrates via the activation of the pregnane X receptor ( O75469 ) . Also tocopherols and in particular tocotrienols induce the expression of a O75469 - driven reporter gene and the expression of endogenous P08684 and P20815 which is supported by sporadic publications spread over the last 30 years . The potential interference of vitamin E with drug metabolism is discussed in the light of related complications evoked by herbal remedies .",
"Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK100___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .",
"The presence and function of dopamine type 2 receptors in boar sperm : a possible role for dopamine in viability , capacitation , and modulation of sperm motility . Several studies have shown that dopamine and other catecholamines are present in oviduct luminal fluid . We recently reported that dopamine type 2 receptors ( P14416 ) are present in a wide range of mammalian sperm , suggesting a role for dopaminergic signaling in events such as fertilization , capacitation , and sperm motility . In the present study , we used Western blot analysis to show that boar sperm express P14416 and that their activation with dopamine ( 100 nM ) has a positive effect on cell viability that can be correlated with AKT / P31749 phosphorylation . ___MASK10___ ( 100 nM ) and dopamine ( 100 nM and 10 muM ) increased tyrosine phosphorylation during the capacitation period . Immunofluorescence analysis indicated that P14416 localization is dynamic and depends on the capacitation stage , colocalizing with tyrosine phosphorylated proteins in the acrosome and midpiece region of capacitated boar sperm . This association was confirmed by coimmunoprecipitation analysis . We also showed that bromocriptine ( 100 nM ) and low - concentration dopamine ( 100 nM and 10 muM ) increased total and progressive motility of sperm . However , high concentrations of dopamine ( 1 mM ) decreased tyrosine phosphorylation and motility in in vitro sperm capacitation assays . This can be explained by the presence of the dopamine transporters ( Q01959 , official symbol Q01959 ) in sperm , as demonstrated by Western blot analysis and immunocytochemistry . Taken together , our results support the idea that dopamine may have a fundamental role during sperm capacitation and motility in situ in the female upper reproductive tract .",
"Alpha - tocopherol prevents cyclosporin A - mediated activation of phospholipase A2 and inhibition of Na + , K (+)- adenosine triphosphatase activity in cultured hamster renal tubular cells . At concentrations of 0 . 5 microM and upward , cyclosporin A ( DB00091 ) caused dose - related inhibition of the growth of a hamster renal tubular cell line ( Q86TB3 ATCC ; Q16663 ) in vitro . Inhibition of cell growth was due to the cytotoxic properties of DB00091 which were associated with enhancement of activity of phospholipase A2 ( P04054 ) according to the increased generation of arachidonic acid and lysophosphatidylcholine ( Q16549 ) . Arachidonate per se , at concentrations of up to 20 microM , did not affect the growth of Q86TB3 cells , while cyclooxygenase and P09917 inhibitors failed to protect the cells against the antiproliferative effects of DB00091 . However , Q16549 caused dose - related inhibition of the growth of Q86TB3 cells . Moreover , coincubation with lysophospholipase or DB00163 ( AT , vitamin E ) , a P04054 inhibitory and lysophospholipid - complexing agent , protected the Q86TB3 cells against both DB00091 and Q16549 . The Na + , K (+)- ATPase activity of Q86TB3 cells was also inhibited by DB00091 , with the enzyme being protected by inclusion of AT or lysophospholipase . Increased activity of P04054 and inhibition of Na + , K (+)- ATPase preceded cytotoxicity and cytolysis . Excessive production of lysophospholipids and consequent inhibition of Na + , K (+)- ATPase in renal tubular cells is a possible mechanism of DB00091 - induced nephrotoxicity . The protective effects of AT suggest that this agent may be clinically useful in preventing the renal side effects of DB00091 .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK90___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK90___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK90___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK90___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"Effect of progesterone on intracellular Ca2 + homeostasis in human myometrial smooth muscle cells . Although it is well known that progesterone alters uterine contractility and plays an important role in maintenance of pregnancy , the biochemical mechanisms by which progesterone alters uterine contractility in human gestation are less clear . In this investigation we sought to identify progesterone - induced adaptations in human myometrial smooth muscle cells that may alter Ca2 + signaling in response to contractile agents . Cells were treated with vehicle or the progesterone analog medroxyprogesterone acetate ( ___MASK90___ ) for 5 days , and intracellular free Ca2 + concentration ( [ Ca2 +] i ) was quantified after treatment with oxytocin ( OX ) or endothelin ( ET ) - 1 . OX - and ET - 1 - induced increases in [ Ca2 +] i were significantly attenuated in cells pretreated with ___MASK90___ in a dose - dependent manner . P06401 antagonists prevented the attenuated Ca2 + transients induced by ___MASK90___ . P25101 and ETB receptor subtypes were expressed in myometrial cells , and treatment with ___MASK90___ resulted in significant downregulation of P25101 and ETB receptor binding . ___MASK90___ did not alter ionomycin - stimulated increases in [ Ca2 +] i and had no effect on inositol trisphosphate - dependent or - independent release of Ca2 + from internal Ca2 + stores . We conclude that adaptations of Ca2 + homeostasis in myometrial cells during pregnancy may include progesterone - induced modification of receptor - mediated increases in [ Ca2 +] i .",
"Activation of P09917 and related cell membrane lipoperoxidation in hemodialysis patients . Lipid peroxidation was shown at the membrane level in peripheral blood cells of patients hemodialyzed on cuprophan dialyzers , and was mainly attributable to the generation of conjugated hydroperoxides in the lipid bilayer . The oxidative index ( i . e . , the A234 / 205 ratio ) of membrane lipids was 3 . 2 - fold higher in hemodialysis patients than in healthy control subjects , and also the level of leukotriene B4 was significantly increased ( up to 1 . 7 - fold over control ) . Both membrane peroxidation and release of leukotriene B4 were linked to upregulation of P09917 activity ( up to 2 . 4 - fold over control ) and expression at the protein level ( up to 1 . 9 - fold ) . DB00163 , the most important lipophilic antioxidant , prevented both membrane peroxidation and release of leukotriene B4 by inhibiting P09917 activity without affecting enzyme expression . Similar results were observed in patients hemodialyzed on polymethylmetacrylate membranes , but in this case the activation of P09917 was less pronounced . The use of a purified P09917 demonstrated that vitamin E was a reversible inhibitor of enzyme activity ( IC50 = 35 +/- 4 microM ) , further characterized as noncompetitive ( Ki = 30 +/- 3 microM ) . Taken together , the results reported here shed some light on the mechanism responsible for the oxidative damage in hemodialysis . Moreover , the beneficial effect of vitamin E described here may have relevance for the therapy of patients with kidney disease .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"The role of protein kinase C activation in the pathogenesis of diabetic vascular complications . Many vascular diseases in diabetes are known to be associated with the activation of the diacylglycerol ( DAG ) - protein kinase C ( PKC ) pathway . The major source of DAG that is elevated in diabetes is de novo synthesis from glycolytic intermediates . Among the various PKC isoforms , the beta - isoform has been shown to be persistently activated in diabetic animals . Multiple lines of evidence have shown that many vascular alterations in diabetes -- such as a decrease in the activity of Na +- K +- adenosine triphosphatase ( Na +- K +- ATPase ) , and increases in extracellular matrix , cytokines , permeability , contractility , and cell proliferation -- are caused by activation of PKC . Inhibition of PKC by two different kinds of PKC inhibitors , LY333531 , a selective P05771 - isoform inhibitor , and d - DB00163 , were able to prevent or reverse the various vascular dysfunctions in diabetic rats . These results have also provided in vivo evidence that DAG - PKC activation could be responsible for the hyperglycemia - induced vascular dysfunctions in diabetes . Clinical studies are now being performed to clarify the pathogenic roles of the DAG - PKC pathway in developing vascular complications in diabetic patients .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK13___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 .",
"Early vitamin E supplementation attenuates diabetes - associated vascular dysfunction and the rise in protein kinase C - beta in mesenteric artery and ameliorates wall stiffness in femoral artery of Wistar rats . AIMS / HYPOTHESIS : The impact of early vitamin E supplementation on vascular function in diabetes remains unresolved . Therefore , we examined the effects of vitamin E on functional and structural parameters and on chemical markers that are disturbed in diabetes in mesenteric and femoral arteries . METHODS : Segments of both arteries , taken from control and 8 - week - old streptozotocin diabetic Wistar rats that were treated or not with vitamin E , were mounted on wire and pressure myographs , after which endothelium - dependent and - independent vasodilation was assessed . Passive mechanical wall properties and the localisation and levels of protein kinase C ( PKC ) - beta ( 2 ) and P51606 were evaluated in these vessels . RESULTS : DB00163 supplementation was associated with improved endothelium - dependent and - independent vasodilatation in mesenteric arteries from diabetic rats . Impaired endothelium - dependent vasodilatation in diabetic mesenteric vessels was associated with P05771 ( 2 ) up - regulation and this was prevented by vitamin E supplementation . Increased P51606 accumulation and plasma isoprostane levels in diabetic rats were not changed by vitamin E . In the femoral artery , vitamin E supplementation had no effect on endothelium - dependent or - independent vasodilatation , but did prevent the wall stiffening associated with diabetes . CONCLUSIONS / INTERPRETATION : Early vitamin E supplementation has a beneficial effect on diabetes - induced endothelial dysfunction in resistance arteries . This benefit may arise from a direct effect on smooth muscle function , as a result of inhibition of the P05771 ( 2 ) isoform by vitamin E ."
] |
[
"___MASK100___",
"___MASK10___",
"___MASK13___",
"___MASK1___",
"___MASK44___",
"___MASK48___",
"___MASK84___",
"___MASK90___",
"___MASK96___"
] |
___MASK96___
|
MH_train_465
|
interacts_with DB01229?
|
[
"Phosphodiesterase - 4 influences the PKA phosphorylation status and membrane translocation of G - protein receptor kinase 2 ( P25098 ) in P29320 - 293beta2 cells and cardiac myocytes . Membrane - recruitment of P25098 ( G - protein receptor kinase 2 ) provides a fundamental step in the desensitization process controlling GPCRs ( G - protein - coupled receptors ) , such as the beta2AR ( beta2 - adrenergic receptor ) . In the present paper , we show that challenge of P29320 - 293beta2 [ human embryonic kidney cells stably overexpressing the FLAG - tagged beta2AR - GFP ( green fluorescent protein ) ] cells with the beta - adrenoceptor agonist , isoprenaline , causes P25098 to become phosphorylated by PKA ( DB02527 - dependent protein kinase ) . This action is facilitated when DB02527 - specific DB05876 ( phosphodiesterase - 4 ) activity is selectively inactivated , either chemically with rolipram or by siRNA ( small interfering RNA ) - mediated knockdown of Q07343 and Q08499 . DB05876 - selective inhibition by rolipram facilitates the isoprenaline - induced membrane translocation of P25098 , phosphorylation of the beta2AR by P25098 , membrane translocation of beta - arrestin and internalization of beta2ARs . DB05876 - selective inhibition also enhances the ability of isoprenaline to trigger the PKA phosphorylation of P25098 in cardiac myocytes . In the absence of isoprenaline , rolipram - induced inhibition of DB05876 activity in P29320 - 293beta2 cells acts to stimulate PKA phosphorylation of P25098 , with consequential effects on P25098 membrane recruitment and P25098 - mediated phosphorylation of the beta2AR . We propose that a key role for DB05876 enzymes is : ( i ) to gate the action of PKA on P25098 , influencing the rate of P25098 phosphorylation of the beta2AR and consequential recruitment of beta - arrestin subsequent to beta - adrenoceptor agonist challenge , and ( ii ) to protect P25098 from inappropriate membrane recruitment in unstimulated cells through its phosphorylation by PKA in response to fluctuations in basal levels of DB02527 .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK81___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK81___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK81___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK81___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK81___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK81___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK81___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK81___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK81___ in the treatment of changes in hypervigilance following severe stress .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK53___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"Q03135 tyrosine phosphorylation enhances paclitaxel - mediated cytotoxicity . Q03135 ( Q03135 ) , a highly conserved membrane - associated protein , is a putative regulator of cellular transformation . Q03135 is localized in the plasmalemma , secretory vesicles , Golgi , mitochondria , and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton . Taxanes such as paclitaxel ( DB01229 ) are potent anti - tumor agents that repress the dynamic instability of microtubules and arrest cells in the G ( 2 )/ M phase . Src phosphorylation of DB00135 - 14 on Q03135 regulates its cellular localization and function . We report that phosphorylation of Q03135 on DB00135 - 14 regulates paclitaxel - mediated apoptosis in MCF - 7 breast cancer cells . Befitting its role as a multitasking molecule , we show that Q03135 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules P10415 , p53 , and P38936 . We demonstrate that phosphorylated Q03135 triggers apoptosis by inactivating P10415 and increasing mitochondrial permeability more efficiently than non - phosphorylated Q03135 . Furthermore , expression of P38936 , which correlates with taxane sensitivity , is regulated by Q03135 phosphorylation in a p53 - dependent manner . Collectively , our findings underscore the importance of Q03135 phosphorylation in apoptosis and suggest that events that negate Q03135 tyrosine phosphorylation may contribute to anti - microtubule drug resistance .",
"___MASK60___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"Genetic analysis of expression profile involved in retinoid metabolism in non - alcoholic fatty liver disease . AIM : The patients with non - alcoholic fatty liver disease ( NAFLD ) have been reported to be at greater risk for progression to chronic liver disease including liver cirrhosis ( LC ) . To examine the mechanisms for the progression of NAFLD , a genetic analysis of hepatic expression profile in retinoid metabolism in NAFLD was performed since the loss of retinoid signaling is associated with the progression of liver disease via reactive oxygen species ( ROS ) generation . METHODS : Fifty - one genes , which are associated with retinoid metabolism and action , were examined in thirty six subjects including 17 patients with simple steatosis , 11 with non - alcoholic steatohepatitis ( NASH ) and eight controls were examined by real - time reverse transcriptase polymerase chain reaction . Immunohistochemical study was also done by 3 kinds of antibodies . RESULTS : Higher expression of P09455 O95237 , DGT1 / 2 and CES1 in NAFLD suggests that mutual conversion between retinyl ester and retinal occurs actively . Expression of P07327 / 2 / 3 , Q92781 / 10 / 11 , O75911 and RALDH1 / 3 was increased in NAFLD , suggesting that oxidation process from retinol to all - trans retinoic acid ( DB00755 ) was enhanced . Importantly , greater expression of O43174 indicated that degradation of DB00755 was enhanced in NAFLD . Further , expression of P00441 / 2 , catalase , thioredoxin and uncoupling protein 2 was also enhanced . CONCLUSION : Hyperdynamic state of retinoid metabolism is present in the liver tissues with NAFLD , which may be a putative mechanism by which NAFLD progresses to chronic liver disease including LC .",
"Production of paired helical filament , tau - like proteins by PC12 cells : a model of neurofibrillary degeneration . Neuron - like cells derived from a rat pheochromocytoma cell line ( PC12 ) and differentiated with nerve growth factor produce a paired helical filament ( PHF ) - like antigen when they are subjected to heat shock ( Wallace et al . : Mol Brain Res 19 : 149 - 155 , 1993 ) . It accumulates in a localized region of the perinuclear cytoplasm and reacts with monoclonal antitau antibodies , which identify epitopes in the N - and C - terminal halves and the microtubule - binding domain of tau protein . The observed profile of immunoreactivity suggests the presence of full - length and C - terminally truncated tau in a region of perinuclear cytoplasm in which no structurally intact PHFs could be demonstrated by conventional transmission electron microscopy . The accumulated tau protein colocalized with antibodies raised against mitochondrial outer membrane proteins and was associated with the presence of numerous mitochondrial profiles that were demonstrated with electron microscopy . Because differentiated PC12 cells pretreated with colcemid or DB01229 prior to heat shock fail to exhibit perinuclear PHF - like immunoreactivity , the reported response to heat shock appears to require an intact system of intracellular microtubules . This PC12 system provides a model in which the metabolic and molecular biological underpinnings of neuronal degeneration in Alzheimer ' s disease can be manipulated . The system may eventually be applicable to the development of pharmaceutical agents that interfere with formation and / or degeneration of P10636 in Alzheimer ' s disease .",
"[ Numerical impairments in genes in breast cancer : a multiplex ligation - dependent probe amplification study ] . OBJECTIVE : To analyze breast cancer samples using the new technique multiplex ligation - dependent probe amplification ( MLPA ) assay . MATERIAL AND METHODS ; DB03843 - fixed paraffin - embedded breast carcinoma samples from 65 patients were examined . After manual microdissection , DNA was isolated using a commercial kit ( \" QIAGEN \" ) and analyzed with SALSA MLPA P10721 P078 - B1 Breast Tumour ( \" MRC - Holland \" ) . Capillary electrophoresis provided results . RESULTS : MLPA assay was successful in all examined samples . The amplification and deletion frequencies of the analyzed genes were in line with the literature data . The technique requires conventional work - related skills in a molecular genetic laboratory and , as a whole , presents no problems with its usage . The interpretation of results is devoid of subjective meaning due to exclusively their mathematical analysis . MLPA assay provides an insight into numerical impairments in the following genes : P04626 , MYC , Q9BUZ4 , Q7Z589 ( Q7Z589 ) , Q13443 , O14920 , P24864 , P11388 , CDH1 , Q99741 , P03372 , O75976 , P00533 , Q86UE4 , P24385 , O15392 , MED1 , P11362 , P10636 , Q9GZV8 , and O14965 . CONCLUSION : MLPA is an easy - to - use and promising method for multiplex genetic analysis of tumor cells in breast cancer .",
"Characterization of early stages of human B cell development by gene expression profiling . We have characterized several stages of normal human B cell development in adult bone marrow by gene expression profiling of hemopoietic stem cells , early B ( E - B ) , pro - B , pre - B , and immature B cells , using RNA amplification and Lymphochip cDNA microarrays ( n = 6 ) . Hierarchical clustering of 758 differentially expressed genes clearly separated the five populations . We used gene sets to investigate the functional assignment of the differentially expressed genes . Genes involved in VDJ recombination as well as B lineage - associated transcription factors ( TCF3 ( P15923 ) , Q9UH73 , Q9H165 , and Q02548 ) were turned on in E - B cells , before acquisition of P15391 . Several transcription factors with unknown roles in B lymphoid cells demonstrated interesting expression patterns , including Q8N3Z6 and Q9Y6X8 . Compared with hemopoietic stem cells and pro - B cells , E - B cells had increased expression of 18 genes , and these included P01591 , Q9NPH3 , P10415 , and CD62L . In addition , E - B cells expressed T / NK lineage and myeloid - associated genes including P06729 , P46531 , P14209 , P16284 , Q9Y275 , and P05164 . Expression of key genes was confirmed at the protein level by FACS analysis . Several of these Ags were heterogeneously expressed , providing a basis for further subdivision of E - B cells . Altogether , these results provide new information regarding expression of genes in early stages of human B cell development .",
"A brief cognitive - behavioural social skills training for stabilised outpatients with schizophrenia : a preliminary study . Achieving social functioning and achieving social competence are two main objectives of psychosocial interventions for people suffering from schizophrenia . The present preliminary study presents a novel approach of social skills training ( P61278 ) based on the proposals of Kopelowicz et al . ( Kopelowicz , A . , Liberman , R . P . , and Zarate , R . , 2006 . Schizophr . Bull . 32 ( 1 ) : P28222 - 23 ) that link the treatment to seven specific target behaviours : social perception , social information processing , responding and sending skills , affiliative skills , interactional skills , and behaviour governed by social norms . Thirty - one stabilised outpatients were randomly assigned to one of two groups , P61278 ( n = 13 ) or treatment - as - usual ( n = 18 ) ( P10636 ; case management , medication adherence , psychotherapy , leisure engagement , and family support ) and were assessed at baseline in cognitive performance , clinical symptomatology , social cognition , and psychosocial functioning . These outcomes were evaluated across post - treatment and at the 6 - month follow - up appointment . P61278 subjects showed improvements in psychopathology , social discomfort , social cognition ( self - regulation statements during interactions ) , social withdrawal , interpersonal communication , and quality of life compared with the P10636 group . At the 6 - month follow - up , results were maintained for negative symptoms , social discomfort , and some functioning outcomes . Neuropsychological variables were also examined , as mediators of benefit from skills training . Results support the efficacy of the brief P61278 for outpatients with schizophrenia and show the need to implement empirically supported interventions in mental health services to enhance patients ' social functioning and quality of life .",
"Prior exposure to oxidized low - density lipoprotein limits apoptosis in subsequent generations of endothelial cells by altering promoter methylation . Oxidized LDL ( ox - LDL ) plays a critical role in atherogenesis , including apoptosis . As hypercholesterolemia causes epigenetic changes resulting in long - term phenotypic consequences , we hypothesized that repeated and continuous exposure to ox - LDL may alter the pattern of apoptosis in human umbilical vein endothelial cells ( HUVECs ) . We also analyzed global and promoter - specific methylation of apoptosis - related genes . As expected , ox - LDL evoked a dose - dependent increase in apoptosis in the first passage HUVECs that was completely abrogated by lectin - like ox - P01130 ( P78380 ) - neutralizing antibody . Ox - LDL - induced apoptosis was associated with upregulation of proapoptotic P78380 , P08758 , Q07812 , and P42574 and inhibition of antiapoptotic P10415 and cIAP - 1 genes accompanied with reciprocal changes in the methylation of promoter regions of these genes . Subsequent passages of cells displayed attenuated apoptotic response to repeat ox - LDL challenge with blunted gene expression and exaggerated methylation of P78380 , Q07812 , P08758 , and P42574 genes ( all P < 0 . 05 vs . first exposure to ox - LDL ) . Treatment of cells with P78380 antibody before initial ox - LDL treatment prevented both gene - specific promoter methylation and expression changes and reduction of apoptotic response to repeat ox - LDL challenge . Based on these data , we conclude that exposure of HUVECs to ox - LDL induces epigenetic changes leading to resistance to apoptosis in subsequent generations and that this effect may be related to the P78380 - mediated increase in DNA methylation .",
"The bone morphogenetic protein signaling pathway is upregulated in a mouse model of total parenteral nutrition . Total parenteral nutrition ( O15533 ) results in intestinal mucosal atrophic changes due to an absence of enteral nutrition ; however , the mechanisms responsible for this are not fully understood . It has been shown that bone morphogenetic protein ( BMP ) activation inhibits intestinal epithelial cell ( EC ) proliferation . Therefore , we hypothesized that the BMP pathway could be upregulated by O15533 . To address this , we randomly assigned mice to receive O15533 or to be enterally fed ( control ) for 7 d . Mucosal EC isolates were harvested from the entire length of small intestine for RNA and protein measurements . Q8N1N2 - thickness , mid - small bowel was processed for histological examination . O15533 increased the abundance of P12643 , P12644 , and Q13873 at the RNA and protein levels . Phosphorylation of Q15797 , Q99717 , and Smad8 also was greater in the O15533 group than in the control , which helped to confirm activation of this pathway . Interestingly , the O15533 and control groups did not differ in the mRNA expression of the extracellular soluble bmp antagonists , noggin , gremlin , chordin , or follistatin . Compared to the control group , the expression of c - Myc ( cellular myelocytomatosis ) mRNA was lower , whereas the level of P38936 ( P38936 / CIP1 ) was greater , in the O15533 group . Because the BMP family may function through suppression of Wnt - beta - catenin signaling , this pathway was also examined . mRNA expression of Wnt 3 , Wnt5a , and the Wnt receptor Lrp5 were lower in the O15533 group compared to controls . The results suggest that the BMP signaling pathway may be involved in the development of intestinal mucosal atrophy due to O15533 administration .",
"Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13 . 2 - 21 . 3 . Amyotrophic lateral sclerosis ( P35858 ) and frontotemporal dementia ( FTD ) are both relentlessly progressive and ultimately fatal neurological disorders . P35858 is familial in approximately 10 % of cases and FTD in approximately 30 % . Inheritance is usually autosomal dominant with variable penetrance . Phenotypic overlap between P35858 and FTD can occur within the same kindred . Mutations in copper / zinc superoxide dismutase 1 ( P00441 ) are found in approximately 20 % of familial and approximately 3 % of sporadic P35858 cases but are not associated with dementia . Mutations in microtubule associated protein tau ( P10636 ) are detected in approximately 30 % of familial FTD kindreds . Dominant P35858 with FTD has previously been linked to 9q21 and pure P35858 to loci on 16q21 , 18q21 , 20p13 . Here we report the results of a genome - wide linkage study in a large P35858 and FTD kindred using Affymetrix 10K GeneChip microarrays . Linkage analysis of single nucleotide polymorphism ( SNP ) data identified consistently positive log of the odds ( LOD ) scores across chromosome 9p ( maximal LOD score of 2 . 4 ) . Fine mapping the region with microsatellite markers generated a maximal multipoint LOD score of 3 . 02 ( theta = 0 ) at D9S1878 . Recombination narrowed the conserved haplotype to 12 cM ( 11 Mb ) at 9p13 . 2 - 21 . 3 ( flanking markers D9S2154 and D9S1874 ) . Bioinformatic analysis of the region has identified 103 known genes .",
"___MASK30___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK30___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK30___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"The rGel / Q9Y275 fusion toxin inhibits P40763 signaling via down - regulation of interleukin - 6 receptor in diffuse large B - cell lymphoma . Aberrant signal transducer and activator of transcription ( P35610 ) 3 signaling participates in the development and progress of human cancers . We previously generated a highly cytotoxic fusion toxin designated rGel / Q9Y275 for receptor - mediated delivery of the rGel toxin to malignant B - cells . In this study , we examined this fusion toxin for its ability to impact P40763 signaling in diffuse large B - cell lymphoma ( DLBCL ) . The activated B cell - like DLBCL lines were found to express higher levels of interleukin - 6 receptor ( IL - 6R ) and P40763 than did the germinal center B cell - like DLBCL lines . Treatment of DLBCL cells with rGel / Q9Y275 resulted in down - regulation of IL - 6R and inhibited P40763 phosphorylation , P40763 - DNA binding activity , and P05231 - inducible P40763 reporter gene activity . In agreement with these results , we additionally found that rGel / Q9Y275 down - regulated levels of several P40763 targets ( c - Myc , P38936 , Mcl - 1 , and Bcl - x ( L ) ) and p - P43405 , a positive regulator of P40763 . Inhibition of IL - 6R - mediated P40763 signaling by rGel / Q9Y275 led to growth inhibition , triggered accumulation of cells in the sub - G ( 1 ) phase of the cell cycle , and induced apoptosis . Our results indicate that rGel / Q9Y275 is an excellent candidate for the treatment of aggressive DLBCL which is resistant to conventional chemotherapeutic regimens and P40763 signaling pathway may be an attractive therapeutic target for non - Hodgkin ' s lymphoma .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK26___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"Cylindrospermopsin induced DNA damage and alteration in the expression of genes involved in the response to DNA damage , apoptosis and oxidative stress . Cylindrospermopsin ( CYN ) , a potent cyanobacterial cytototoxin produced by certain freshwater cyanobacteria , is regularly found in water supplies in many parts of the world , and has been associated with the intoxication of humans and livestock . The few genotoxicity studies available indicate that CYN is genotoxic , generally implying that it is pro - genotoxic . In human peripheral blood lymphocytes ( HPBLs ) CYN ( 0 , 0 . 05 , 0 . 1 and 0 . 5 μg / ml ) induced the formation of DNA single strand breaks , applying the comet assay . Time and dose dependent significant increase in the frequency of micronuclei and nuclear buds was observed after the exposure of HPBLs to CYN , while there was only slight increase in the number of nucleoplasmic bridges . For the first time the modulation of gene expression in HPBLs was studied after the exposure to CYN ( 0 . 5 μg / ml ) , using the quantitative real - time PCR . The genes presumably involved in CYN metabolism ( P04798 and P05177 ) were up - regulated after the exposure . CYN induced changes in the mRNA expression of P04637 and its downstream regulated DNA damage responsive genes Q00987 , GADD45α and apoptosis genes , BCL - 2 and Q07812 , as well as oxidative stress responsive genes ( P07203 , P00441 , P00390 , P48506 ) , while no changes in the expression of genes P38936 and CAT were observed . These results provide strong evidence that CYN should be considered as genotoxic and that lymphocytes can also be a target of cylindrospermopsin induced genotoxicity .",
"Personalised intervention for people with depression and severe P48444 . Chronic obstructive pulmonary disease ( P48444 ) is often complicated by depression and exemplifies the challenge in managing chronic illnesses that require active patient participation in care . In a clinical trial ( NCT00151372 ) , we compared a novel personalised intervention for depression and P48444 ( PID - C ) targeting treatment adherence with treatment as usual ( P10636 ) . In 138 patients with major depression and severe P48444 , PID - C led to a higher remission rate and a greater reduction in depressive symptoms and in dyspnoea - related disability than P10636 over 28 weeks and 6 months after the last session . If replicated , PID - C may serve as a care model for patients with both depression and medical illnesses with a deteriorating course .",
"Chemopreventive effects of the dietary histone deacetylase inhibitor tributyrin alone or in combination with vitamin A during the promotion phase of rat hepatocarcinogenesis . The chemopreventive effects of tributyrin ( TB ) and vitamin A ( VA ) , alone or in combination , were investigated during the promotion phase of rat hepatocarcinogenesis . Compared to diethylnitrosamine control rats , TB and TB + VA - treated rats , but not VA - treated rats , presented a lower incidence and mean number of hepatocyte nodules and a smaller size of persistent preneoplastic lesions ( pPNLs ) . In addition , TB and TB + VA - treated rats exhibited a higher apoptotic body index in pPNL and remodeling PNL , whereas VA - treated rats presented only a higher apoptotic body index in remodeling PNL . None of the treatments inhibited cell proliferation in PNL . TB and TB + VA - treated rats , but not VA - treated rats , exhibited higher levels of H3K9 acetylation and P38936 protein expression . TB and VA - treated rats exhibited increased hepatic concentrations of butyric acid and retinoids , respectively . Compared to normal rats , diethylnitrosamine control animals exhibited lower retinyl palmitate hepatic concentrations . All groups had similar expression levels and exhibited similar unmethylated P09455 promoter region in microdissected pPNL , indicating that epigenetic silencing of this gene was not involved in alteration of retinol metabolism in early hepatocarcinogenesis . Data support the effectiveness of TB as a dietary histone deacetylase inhibitor during the promotion phase of hepatocarcinogenesis , which should be considered for chemoprevention combination strategies .",
"The P10415 antagonist ABT - 199 triggers apoptosis , and augments ibrutinib and idelalisib mediated cytotoxicity in P61073 Wild - type and P61073 WHIM mutated Waldenstrom macroglobulinaemia cells .",
"Telomere shortening is associated with reduced duodenal HCOFormula secretory but normal gastric acid secretory capacity in aging mice . The incidence of duodenal ulcer , especially Helicobacter pylori - negative duodenal ulcer , strongly increases with age . In humans , telomere length shortening is considered to be one critical factor in cellular senescence and organ survival . In this study , we compared basal and stimulated gastric acid and duodenal HCO ( 3 )(-) secretory rates in aged late - generation ( G ( 3 ) ) telomerase - deficient ( mTERC (-/-) ) mice , which are characterized by severe telomere dysfunction due to the inability to elongate telomeres during cell division . We found that basal and forskolin - stimulated HCO ( 3 )(-) secretion and short - circuit current ( I ( sc ) ) in isolated duodenal mucosa of G ( 3 ) mTERC (-/-) mice were markedly reduced compared with age - matched wild - type mice . In contrast , basal and forskolin - stimulated acid secretory rates in isolated G ( 3 ) mTERC (-/-) gastric mucosa were not significantly altered . Correspondingly , duodenal mucosa of G ( 3 ) mTERC (-/-) mice showed slimming and shortening of villi , whereas gastric mucosal histology was not significantly altered . However , the ratios of cystic fibrosis transmembrane conductance regulator ( P13569 ) and solute - linked carrier 26 gene family ( Slc26a6 ) mRNA expression in relation to cytokeratin - 18 were not altered in duodenal mucosa . The further knockout of P38936 , which is a downstream effector of telomere shortening - induced senescence , rescued villus atrophy of duodenal mucosa , and basal and forskolin - stimulated duodenal HCO ( 3 )(-) secretion and I ( sc ) in mTERC (-/-) P38936 (-/-) double - knockout mice were not different from wild - type controls . In conclusion , genetic ablation of telomerase resulted in P38936 - dependent duodenal mucosal atrophy and reduced duodenal HCO ( 3 )(-) secretory capacity , whereas gastric morphology and acid secretory function were preserved . This suggests that telomere shortening during aging may result in an imbalance between aggressive and protective secretions against duodenal mucosa and thus predispose to ulcer formation .",
"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .",
"Activation of the interleukin - 6 / Janus kinase / P40763 pathway in pleomorphic adenoma of the parotid gland . The interleukin - 6 ( P05231 ) / Janus kinase ( JAK ) / signal transducer and activator of transcription 3 ( P40763 ) pathway is of crucial importance in promoting tumorigenesis in several malignant tumors but may also be active in benign tumors , e . g . , of pleomorphic adenoma ( PA ) . In this study we characterize the expression of the pathway components with immunohistochemistry and selected mRNAs and microRNAs ( miRNAs ) regulated by this pathway in isolated duct - and myoepithelial cells in PA . 46 PAs were immunostained and 10 of these were used for in situ hybridization ( ISH ) . Six frozen specimens were analyzed using reverse transcription - polymerase chain reaction ( RT - PCR ) . Using immunohistochemistry , P05231 , P23458 , O60674 and P40763 were detected significantly more frequently in PA cells than in cells from normal salivary gland tissue . Using RT - PCR cyclin D1 , fibroblast growth factor 2 , and P38936 were found to be overexpressed while matrix metallopeptidase 9 was detected at low levels in PA compared to normal salivary gland . ISH showed significant overexpression of miR - 181b in PA , while miR - 21 was undetectable in PA and normal tissue . Overexpression of the pathway components and its mRNA and miRNA products provide important clues regarding the growth of PAs . Our findings brings us one step closer to targeted treatment of this tumor entity , although in vitro studies are warranted to confirm this .",
"Glutathione levels and Q07812 activation during apoptosis due to oxidative stress in cells expressing wild - type and mutant cystic fibrosis transmembrane conductance regulator . Cystic fibrosis is characterized by chronic inflammation and an imbalance in the concentrations of alveolar and lung oxidants and antioxidants , which result in cell damage . Modifications in lung glutathione concentrations are recognized as a salient feature of inflammatory lung diseases such as cystic fibrosis , and glutathione plays a major role in protection against oxidative stress and is important in modulation of apoptosis . The cystic fibrosis transmembrane conductance regulator ( P13569 ) is permeable to Cl (-) , larger organic ions , and reduced and oxidized forms of glutathione , and the DeltaF508 P13569 mutation found in cystic fibrosis patients has been correlated with impaired glutathione transport in cystic fibrosis airway epithelia . Because intracellular glutathione protects against oxidative stress - induced apoptosis , we studied the susceptibility of epithelial cells ( HeLa and IB3 - 1 ) expressing normal and mutant P13569 to apoptosis triggered by H ( 2 ) O ( 2 ) . We find that cells with normal P13569 are more sensitive to oxidative stress - induced apoptosis than cells expressing defective P13569 . In addition , sensitivity to apoptosis could be correlated with glutathione levels , because depletion of intracellular glutathione results in higher levels of apoptosis , and glutathione levels decreased faster in cells expressing normal P13569 than in cells with defective P13569 during incubation with H ( 2 ) O ( 2 ) . The pro - apoptotic BCL - 2 family member , Q07812 , is also activated faster in cells expressing normal P13569 than in those with mutant P13569 under these conditions , and artificial glutathione depletion increases the extent of Q07812 activation . These results suggest that glutathione - dependent Q07812 activation in cells with normal P13569 represents an early step in oxidative stress - induced apoptosis of these cells .",
"Molecular response of HL - 60 cells to mitotic inhibitors vincristine and taxol visualized with apoptosis - related gene expressions , including the new member Q9HB09 . DB01229 and vincristine belong to a group of anticancer drugs that target microtubules , subsequently arresting cells at the mitotic phase of the cell cycle and inducing programmed cell death . The P10415 ( bcl - 2 ) family of genes is of known implication in apoptosis induced by various stimuli , among which Q9HB09 , a new member of the family , cloned by our group . For further insights into the mechanisms and molecular targets implicated and modified as a result of apoptosis induced by these two mitosis - arresting drugs , we studied the possible alterations , at the mRNA level , of various apoptosis - related genes ( P10415 , Q07812 , Q9HB09 , CASPASE - 3 , FAS ) after leukemia cell ( HL - 60 ) treatment with these drugs . The kinetics of cell toxicity were evaluated by the MTT [ 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide ] method , trypan blue staining , and cell proliferation efficiency ; apoptosis induction was assayed by endonucleosomal cleavage of DNA ( DNA laddering ) ; and the expression levels of the genes were analysed by RT - PCR , using gene - specific primers . The percentage of nonviable cells was upregulated with increasing cell exposure time and drug concentrations to both taxol and vincristine . Distinct modulations of apoptosis - related genes at the mRNA level were also observed , mainly concerning P10415 and Q9HB09 along apoptosis induction . Our results indicate and support the hypothesis that the apoptosis - related genes P10415 and Q9HB09 respond similarly to treatment of the human , acute , myelocytic leukemia HL60 cells with the anticancer drugs vincristine and taxol though in a drug - specific and time - dependent manner .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK54___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"Xaliproden ( SR57746A ) induces P08908 receptor - mediated Q96HU1 kinase activation in PC12 cells . Neurotrophic growth factors are involved in cell survival . However , natural growth factors have a very limited therapeutic use because of their short half - life . In the present study , we investigated the mechanism of action of a non - peptidic neurotrophic drug , Xaliproden , a potential molecule for the treatment of motoneuron diseases , since the transduction pathways of this synthetic P08908 agonist are very poorly understood . Xaliproden does not activate the Trk receptor but causes a rapid increase in the activities of the P27361 and P28482 isoforms of Q96HU1 kinase , which then rapidly decrease to the basal level . We demonstrate that isoforms of the P29353 adapter protein are phosphorylated independently of each other and are probably not the source of the Xaliproden - induced Q96HU1 kinases activation . The inhibitor of Ras farnesylation , FPT - 1 , and the protein kinase C inhibitors , GF 109203X and chelerythrine , inhibited the Xaliproden - induced Q96HU1 kinase activation , suggesting p21Ras and PKC involvement . Moreover , the observations that the P08908 antagonist , pindobind , and pertussis toxin abolished the Xaliproden - induced P29323 stimulation suggested that Xaliproden activates the Q96HU1 kinase pathways by stimulating the G protein - coupled receptor , P08908 . These results demonstrate clearly that the non - peptidic compound , Xaliproden , exerts its neurotrophic effects through a mechanism of action differing from that of neurotrophins . These findings suggest that this compound does not involve MAPK activation by TrkA receptor stimulation but acts by Q96HU1 kinase pathway by a pertussis toxin - sensitive mechanism involving P08908 receptors , P38936 Ras and MEK - 1 and by PKC and Akt pathways .",
"___MASK74___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK74___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK74___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK74___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"Placental autophagy regulation by the Q9UMX3 - Q07820 rheostat . Autophagy is the catabolic degradation of cellular cytoplasmic constituents via the lysosomal pathway that physiologically elicits a primarily cytoprotective function , but can rapidly be upregulated in response to stressors thereby inducing cell death . We have reported that the balance between the P10415 family proteins Q9UMX3 and Q07820 regulates human trophoblast cell fate and its alteration toward cell death typifies preeclampsia . Here we demonstrate that Q9UMX3 is a potent inducer of autophagy as shown by increased LC3B - II production , autophagosomal formation and lysosomal activation in P29320 293 . In contrast , using JEG3 cells we showed that prosurvival Q07820 acts as a repressor of autophagy via an interaction with Q14457 , which is abrogated by Q9UMX3 . We found that Q07820 - cleaved products , specifically MCL1c157 , trigger autophagy while the splicing variant MCL1S has no effect . Treatment of JEG3 cells with nitric oxide donor SNP resulted in Q9UMX3 - Q07820 rheostat dysregulation , favoring Q9UMX3 accumulation , thereby inducing autophagy . Overexpression of Q07820 rescued oxidative stress - induced autophagy . Of clinical relevance , we report aberrant autophagy levels in the preeclamptic placenta due to impaired recruitment of Q14457 to Q07820 . Our data provided the first evidence for a key role of the Q9UMX3 - Q07820 system in regulating autophagy in the human placenta , whereby an adverse environment as seen in preeclampsia tilts the Q9UMX3 - Q07820 balance toward the build - up of isoforms that triggers placental autophagy .",
"Monocyte stimulation by reactive oxygen species : role of superoxide and intracellular Ca2 + . OBJECTIVE : Production of reactive oxygen species has generally been linked to inflammatory processes . Whether the presence of superoxide and hydrogen peroxide affects mononuclear cell function was investigated with an in vitro model using isolated human mononuclear cells . MATERIALS AND METHODS : Human mononuclear cells were isolated from buffy coat . Toxicity was measured with DB09158 exclusion , secreted P01375 was measured with an ELISA , reactive oxygen species within mononuclear cells were quantified with dichlorodihydrofluorescein diacetate fluorescence , intracellular P01375 was measured with flow cytometry and fluorescence microscopy . RESULTS : The enzymatic production of superoxide caused a dose - dependent increase in P01375 synthesis , whereas hydrogen peroxide was ineffective . Flow cytometric measurements and immunofluorescence microscopy demonstrated that monocytes were the main P01375 producing population . This proinflammatory reaction was further characterized by pharmacologically investigating Ca2 + signalling pathways . Superoxide stimulated P01375 secretion was inhibited by intracellular Ca2 +- buffers ( P10636 - AM and BAPT - AM ) or VOC operating antagonists ( diltiazem and verapamil ) and only to a small extent by pharmacological inhibitors of ligand - gated pathways ( TMB - 8 and SKF 96368 ) . CONCLUSION : We propose that superoxide activates human mononuclear cells in a Ca2 +- dependent manner .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK38___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor .",
"Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK74___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK74___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK74___ .",
"The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK30___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .",
"In vitro activities of candidate microbicides against cell - associated HIV . Most research on HIV transmission and microbicides focuses on the inhibition of cell - free virus ( CFV ) present in genital secretions . However , an effective microbicide should also block the transmission of cell - associated virus ( Q03135 ) originating from seminal T cells and macrophages . Because inhibition of Q03135 remains controversial , especially for viral entry inhibitors , we developed a novel in vitro assay to evaluate the activities of different classes of candidate microbicides against cell - free HIV and HIV - infected leukocytes ( i . e . , resting peripheral blood mononuclear cells [ PBMC ] , activated PBMC , and monocyte - derived macrophages ) . The assay is based on two P01730 (+) P61073 (+) T - cell lines ( R5MaRBLE and X4MaRBLE ) that both contain a firefly luciferase reporter gene but differ in the expression of the P51681 coreceptor . Consequently , the quantification of the luciferase activities and the Gag p24 concentrations in cocultures of R5 - tropic HIV - infected leukocytes with each cell line separately allowed us to discriminate between the infection of the cell lines ( i . e . , target cells ) , the ongoing infection in the HIV - infected leukocytes ( i . e . , effector cells ) , and the total infection of the coculture ( i . e . , effector plus target cells ) . All 14 antiretrovirals tested were able to block target cell infection by all three sources of Q03135 , although a small decrease in activity ( 2 - to 18 - fold ) was observed for all entry inhibitors . On the other hand , the production of Gag p24 by the infected effector cells could be blocked only by protease inhibitors . Overall , these results show that entry and protease inhibitors are eligible drug classes for inclusion in future combination microbicides .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"Gene expression correlating with response to paclitaxel in ovarian carcinoma xenografts . We have investigated gene expression profiles of human ovarian carcinomas in vivo during DB01229 ( R ) ( paclitaxel ) treatment and observed a difference in expression . Nude mice bearing 1A9 or 1A9PTX22 xenografts were given 60 mg / kg of paclitaxel . Therapeutic efficacy was achieved for 1A9 , while 1A9PTX22 did not respond . Tumor tissues harvested 4 and 24 h after treatment were evaluated by cDNA microarray against untreated tumors . Paclitaxel caused the modulation of more genes in 1A9 than in 1A9PTX22 tumors , in accordance to their therapeutic response . Most gene expression alterations were detected 24 h after paclitaxel administration and affected genes involved in various biological functions including cell cycle regulation and cell proliferation ( P06493 , P38936 , Q99988 , and P11388 ) , apoptosis ( Q12983 and O14681 ) , signal transduction and transcriptional regulation ( P84077 , P15336 , P01100 , P29992 , O15379 , Q15796 , O43623 , and Q9C004 ) , fatty acid biosynthesis and sterol metabolism ( P14324 , Q13907 , P38571 , and O75845 ) , and IFN - mediated signaling ( P09912 , Q16666 , P40305 , P13164 , and P05161 ) . The modulation of two representative genes , P38936 and P11388 , was validated by Northern analyses on a panel of seven ovarian carcinoma xenograft models undergoing treatment with paclitaxel . We found that the changes in expression level of these genes was strictly associated with the responsiveness to paclitaxel . Our study shows the feasibility of obtaining gene expression profiles of xenografted tumor models as a result of drug exposure . This in turn might provide insights related to the drugs ' action in vivo that will anticipate the response to treatment manifested by tumors and could be the basis for novel approaches to molecular pharmacodynamics .",
"Genetics of idiopathic disseminated bronchiectasis . Bronchiectasis is an abnormal dilation of bronchi , consequent to the destruction of their walls . It is included in the category of obstructive pulmonary diseases , along with chronic obstructive pulmonary disease ( P48444 ) , asthma , and cystic fibrosis . In approximately 50 % of cases , bronchiectasis is associated with underlying conditions ; in the remainder , known causes are not ascertainable ( idiopathic bronchiectasis ) . A search for genetic determinants of this phenotype , with the cystic fibrosis gene as a candidate , has been performed by three independent groups . The results of this search agreed on the association of bronchiectasis with cystic fibrosis gene mutations and polymorphisms . The cystic fibrosis gene is also associated with bronchiectasis due to rheumatoid arthritis and allergic bronchopulmonary aspergillosis . A few other genes have been investigated in idiopathic bronchiectasis , with negative results . Idiopathic bronchiectasis is , therefore , to be considered as an obstructive multifactorial disorder belonging to the category of cystic fibrosis monosymptomatic diseases ( or P13569 - opathies ) , whose pathogenesis is influenced by environmental factors and other undetermined genes .",
"Mitochondrial fragmentation in cigarette smoke - induced bronchial epithelial cell senescence . Mitochondria are dynamic organelles that continuously change their shape through fission and fusion . Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species ( ROS ) production . Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease ( P48444 ) . Hence , we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract ( CSE ) - induced cellular senescence in human bronchial epithelial cells ( HBEC ) . Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy . Senescence - associated β - galactosidase staining and P38936 Western blotting of primary HBEC were performed to evaluate cellular senescence . Mitochondrial - specific superoxide production was measured by MitoSOX staining . Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins ( O60313 or Mitofusins ) by small - interfering RNA transfection . DB06151 and Mito - TEMPO were used as antioxidants . Mitochondria in bronchial epithelial cells were prone to be more fragmented in P48444 lung tissues . CSE induced mitochondrial fragmentation and mitochondrial ROS production , which were responsible for acceleration of cellular senescence in HBEC . Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells . HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants . CSE - induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production . Hence , disruption of mitochondrial dynamics may be a part of the pathogenic sequence of P48444 development .",
"Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .",
"Tau hyperphosphorylation and increased P56817 and RAGE levels in the cortex of PPARβ / δ - null mice . The role of peroxisome proliferator activator receptor ( Q07869 ) β / δ in the pathogenesis of Alzheimer ' s disease has only recently been explored through the use of PPARβ / δ agonists . Here we evaluated the effects of PPARβ / δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation . PPARβ / δ - null mice showed cognitive impairment in the object recognition task , accompanied by enhanced DNA - binding activity of NF - κB in the cortex and increased expression of P05231 . In addition , two NF - κB - target genes involved in β - amyloid ( Aβ ) synthesis and deposition , the β site P05067 cleaving enzyme 1 ( Bace1 ) and the receptor for advanced glycation endproducts ( Rage ) , respectively , increased in PPARβ / δ - null mice compared to wild type animals . The protein levels of glial fibrillary acidic protein ( P14136 ) increased in the cortex of PPARβ / δ - null mice , which would suggest the presence of astrogliosis . Finally , tau hyperphosphorylation at Ser199 and enhanced levels of P10636 were associated with increased levels of the tau kinases Q00535 and phospho - P27361 / 2 in the cortex of PPARβ / δ (-/-) mice . Collectively , our findings indicate that PPARβ / δ deficiency results in cognitive impairment associated with enhanced inflammation , astrogliosis and tau hyperphosphorylation in the cortex .",
"Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress - mediated P35638 induction in myeloma cells . The specific 26S proteasome inhibitor bortezomib ( BZ ) potently induces autophagy , endoplasmic reticulum ( ER ) stress and apoptosis in multiple myeloma ( MM ) cell lines ( U266 , IM - 9 and RPMI8226 ) . The macrolide antibiotics including concanamycin A , erythromycin ( EM ) , clarithromycin ( P62158 ) and azithromycin ( AZM ) all blocked autophagy flux , as assessed by intracellular accumulation of LC3B - II and p62 . Combined treatment of BZ and P62158 or AZM enhanced cytotoxicity in MM cell lines , although treatment with either P62158 or AZM alone exhibited almost no cytotoxicity . This combination also substantially enhanced aggresome formation , intracellular ubiquitinated proteins and induced the proapoptotic transcription factor P35638 ( CADD153 ) . Expression levels of the proapoptotic genes transcriptionally regulated by P35638 ( O43521 , Q07812 , DR5 and TRB3 ) were all enhanced by combined treatment with BZ plus P62158 , compared with treatment with each reagent alone . Like the MM cell lines , the P35638 +/+ murine embryonic fibroblast ( MEF ) cell line exhibited enhanced cytotoxicity and upregulation of P35638 and its transcriptional targets with a combination of BZ and one of the macrolides . In contrast , P35638 -/- MEF cells exhibited resistance against BZ and almost completely canceled enhanced cytotoxicity with a combination of BZ and a macrolide . These data suggest that ER stress - mediated P35638 induction is involved in pronounced cytotoxicity . Simultaneously targeting two major intracellular protein degradation systems such as the ubiquitin - proteasome system by BZ and the autophagy - lysosome system by a macrolide antibiotic enhances ER stress - mediated apoptosis in MM cells . This result suggests the therapeutic possibility of using a macrolide antibiotic with a proteasome inhibitor for MM therapy .",
"Apigenin induces apoptosis via extrinsic pathway , inducing p53 and inhibiting P40763 and NFκB signaling in P04626 - overexpressing breast cancer cells . Phytoestrogens are known to prevent tumor induction . But their molecular mechanisms of action are still unknown . This study aimed to examine the effect of apigenin on proliferation and apoptosis in P04626 - expressing breast cancer cells . In our experiments , apigenin inhibited the proliferation of MCF - 7 vec and MCF - 7 P04626 cells . This growth inhibition was accompanied with an increase of sub G ( 0 )/ G ( 1 ) apoptotic fractions . Overexpression of P04626 did not confer resistance to apigenin in MCF - 7 cells . Apigenin - induced extrinsic apoptosis pathway up - regulating the levels of cleaved caspase - 8 , and inducing the cleavage of poly ( ADP - ribose ) polymerase , whereas apigenin did not induce apoptosis via intrinsic mitochondrial apoptosis pathway since this compound did not decrease mitochondrial membrane potential maintaining red fluorescence and did not affect the levels of B - cell lymphoma 2 ( P10415 ) and Bcl - 2 - associated X protein . Moreover , apigenin reduced the tyrosine phosphorylation of P04626 ( phospho - P04626 level ) in MCF - 7 P04626 cells , and up - regulated the levels of p53 , phospho - p53 and P38936 in MCF - 7 vec and MCF - 7 P04626 cells . This suggests that apigenin induces apoptosis through p53 - dependent pathway . Apigenin also reduced the expression of phospho - P23458 and phospho - P40763 and decreased P40763 - dependent luciferase reporter gene activity in MCF - 7 vec and MCF - 7 P04626 cells . Apigenin decreased the phosphorylation level of IκBα in the cytosol , and abrogated the nuclear translocation of p65 within the nucleus suggesting that it blocks the activation of NFκB signaling pathway in MCF - 7 vec and MCF - 7 P04626 cells . Our study indicates that apigenin could be a potential useful compound to prevent or treat P04626 - overexpressing breast cancer .",
"Neuroprotective response after photodynamic therapy : role of vascular endothelial growth factor . BACKGROUND : Anti - vascular endothelial growth factor ( P15692 ) drugs and / or photodynamic therapy ( PDT ) constitute current treatments targeting pathological vascular tissues in tumors and age - related macular degeneration . Concern that PDT might induce P15692 and exacerbate the disease has led us to current practice of using anti - P15692 drugs with PDT simultaneously . However , the underlying molecular mechanisms of these therapies are not well understood . METHODS : We assessed P15692 levels after PDT of normal mouse retinal tissue , using a laser duration that did not cause obvious tissue damage . To determine the role of PDT - induced P15692 and its downstream signaling , we intravitreally injected a P15692 inhibitor , P17948 Fc , or a PI3K / Akt inhibitor , LY294002 , immediately after PDT . Then , histological and biochemical changes of the retinal tissue were analyzed by immunohistochemistry and immunoblot analyses , respectively . RESULTS : At both the mRNA and protein levels , P15692 was upregulated immediately and transiently after PDT . P15692 suppression after PDT resulted in apoptotic destruction of the photoreceptor cell layer in only the irradiated area during PDT . Under these conditions , activation of the anti - apoptotic molecule Akt was suppressed in the irradiated area , and levels of the pro - apoptotic protein Q07812 were increased . Intravitreal injection of a PI3K / Akt inhibitor immediately after PDT increased Q07812 levels and photoreceptor cell apoptosis . CONCLUSION : Cytotoxic stress caused by PDT , at levels that do not cause overt tissue damage , induces P15692 and activates Akt to rescue the neural tissue , suppressing Q07812 . Thus , the immediate and transient induction of P15692 after PDT is neuroprotective .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK6___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Mutation analyses in amyotrophic lateral sclerosis / parkinsonism - dementia complex of the Kii peninsula , Japan . To clarify the genetic background of amyotrophic lateral sclerosis ( P35858 ) / parkinsonism - dementia complex ( P20941 ) of the Kii peninsula , Japan ( Kii P35858 / P20941 ) , we performed extended mutation analyses of three patients with pathologically diagnosed Kii P35858 / P20941 . Direct sequencing analyses were performed in 19 genes , including P35858 / frontotemporal lobar degeneration ( FTLD ) - related genes ( P04179 , P08294 , Q96Q42 / alsin , Q16637 , PGRN , P03950 , P15692 , P55072 , O95292 , Q14203 , Q9UQN3 , and Q13148 or Q13148 ) , tauopathy - related gene ( GSK3beta ) , and parkinsonism - related genes ( alpha - synuclein , Q5S007 , parkin , Q99497 , Q9BXM7 , and Q9NQ11 ) . Gene dosage analyses were conducted in screening of P10636 , alpha - synuclein , Q13148 ( or Q13148 ) , GSK3beta , and parkin . We found no mutation in the 19 genes . We found a homozygous nonsynonymous SNP ( Q96Q42 / alsin V368M ) shared by all the three patients . Gene dosage was normal in P10636 , alpha - synuclein , Q13148 , GSK3beta , and parkin . The present findings , together with a previous negative study on P10636 and P00441 mutation , further elucidated the lack of causative mutations in all exons , exon - intron boundaries , or some rearrangements of the reported major causative or susceptible genes related to P35858 , FTLD , parkinsonism , synucleinopathy , Q13148 proteinopathy , and tauopathy . However , the familial aggregation and lack of any environment factors suggest that Kii P35858 / P20941 is caused by other yet unidentified genetic factors .",
"Neuroprotective gene expression profiles in ischemic cortical cultures preconditioned with DB01277 or P09038 . The mechanisms underlying growth factor preconditioning of neurons are only partially elucidated , and no studies have been conducted in this area using a gene profiling approach . We used cDNA microarrays to compare the transcriptional profiles of cells preconditioned either with insulin - like growth factor I ( DB01277 ) or basic fibroblast growth factor ( P09038 ) , to identify differentially regulated genes that may function in growth factor signaling , response to oxygen - glucose deprivation ( OGD ) , and most importantly , cell survival . Primary rat cortical cultures were treated with P09038 or DB01277 for 2 , 24 , or 24 h followed by OGD for 90 min , and compared with cells that were subject to OGD without growth factor pretreatment . Although the majority of surveyed genes were unchanged in all experimental treatments , 175 genes ( 10 % of the cDNAs on the chip ) were found to be differentially regulated in at least one of the treatment conditions . Hierarchical clustering of these 175 genes was used to identify four expression clusters : DB01277 regulated , P09038 regulated , OGD regulated , and putative neuroprotective genes . Further analysis using realtime RT - PCR confirmed that we had identified genes that are regulated by single growth factors , as well as several more that are co - regulated by both DB01277 and P09038 . These genes can influence neuronal survival by affecting diverse pathways such as growth factor signal transduction ( P16070 , Q99075 , Q16828 , Q12929 , P17936 ) , DNA repair and transcription ( Q92949 ) , metabolic homeostasis ( P20936 , P34897 ) , cytoskeletal stability ( P26038 , P10636 ) and cholesterol biosynthesis ( P37268 , P14324 ) ."
] |
[
"___MASK26___",
"___MASK30___",
"___MASK38___",
"___MASK53___",
"___MASK54___",
"___MASK60___",
"___MASK6___",
"___MASK74___",
"___MASK81___"
] |
___MASK38___
|
MH_train_466
|
interacts_with DB00523?
|
[
"Dynamic network of transcription and pathway crosstalk to reveal molecular mechanism of MGd - treated human lung cancer cells . Recent research has revealed various molecular markers in lung cancer . However , the organizational principles underlying their genetic regulatory networks still await investigation . Here we performed Network Component Analysis ( P40199 ) and Pathway Crosstalk Analysis ( DB11245 ) to construct a regulatory network in human lung cancer ( A549 ) cells which were treated with 50 uM DB05428 ( MGd ) , a metal cation - containing chemotherapeutic drug for 4 , 12 , and 24 hours . We identified a set of key TFs , known target genes for these TFs , and signaling pathways involved in regulatory networks . Our work showed that putative interactions between these TFs ( such as P03372 / Sp1 , Q01094 / Sp1 , c - MYC - P03372 , P84022 / c - Myc , and P19838 / Q04206 ) , between TFs and their target genes ( such as BMP41 / Est1 , P49815 / Myc , P27695 / Sp1 / p53 , P10276 / P49639 , and SP1 / Q15853 ) , and between signaling pathways ( such as Q07869 signaling pathway and Adipocytokines signaling pathway ) . These results will provide insights into the regulatory mechanism of MGd - treated human lung cancer cells .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK35___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"The Retinoic Acid Receptor - alpha mediates human T - cell activation and Th2 cytokine and chemokine production . BACKGROUND : We have recently demonstrated that all - trans - retinoic acid ( DB00755 ) and 9 - cis - retinoic acid ( 9 - cis RA ) promote P05112 , P05113 and P35225 synthesis , while decreasing P01579 and P01375 expression by activated human T cells and reduces the synthesis of IL - 12p70 from accessory cells . Here , we have demonstrated that the observed effects using DB00755 and 9 - cis RA are shared with the clinically useful RAR ligand , 13 - cis retinoic acid ( 13 - cis RA ) , and the retinoic acid receptor - alpha ( P10276 ) - selective agonist , AM580 but not with the P10826 / gamma ligand , 4 - hydroxyphenylretinamide ( DB05076 ) . RESULTS : The increase in type 2 cytokine production by these retinoids correlated with the expression of the T cell activation markers , Q07108 and P28907 . The P10276 - selective agonist , AM580 recapitulated all of the T cell activation and type 2 cytokine - inducing effects of DB00755 and 9 - DB00982 , while the P10276 - selective antagonist , RO 41 - 5253 , inhibited these effects . CONCLUSION : These results strongly support a role for P10276 engagement in the regulation of genes and proteins involved with human T cell activation and type 2 cytokine production .",
"An intricate network of conserved DNA upstream motifs and associated transcription factors regulate the expression of uromodulin gene . PURPOSE : P07911 is a kidney specific glycoprotein whose expression can modulate kidney homeostasis . However , the set of sequence specific transcription factors that regulate the uromodulin gene P07911 and their upstream binding locations are not well characterized . We built a high resolution map of its transcriptional regulation . MATERIALS AND METHODS : We applied in silico phylogenetic footprinting on the upstream regulatory regions of a diverse set of human P07911 orthologs to identify conserved binding motifs and corresponding position specific weight matrices . We further analyzed the predicted binding motifs by motif comparison , which identified transcription factors likely to bind these discovered motifs . Predicted transcription factors were then integrated with experimentally known protein - protein interactions available from public databases and tissue specific expression resources to delineate important regulators controlling P07911 expression . RESULTS : Analysis allowed the identification of a reliable set of binding motifs in the upstream regulatory regions of P07911 to build a high confidence compendium of transcription factors that could bind these motifs , such as P23771 , P35680 , SP1 , P84022 , Q13950 and O43474 . ENCODE deoxyribonuclease I hypersensitivity sites in the P07911 upstream region of the mouse kidney confirmed that some of these binding motifs were open to binding by predicted transcription factors . The transcription factor - transcription factor network revealed several highly connected transcription factors , such as SP1 , Q02447 , P04637 , P14859 , P10826 , P10276 and P19793 , as well as the likely protein complexes formed between them . Expression levels of these transcription factors in the kidney suggest their central role in controlling P07911 expression . CONCLUSIONS : Our findings will form a map for understanding the regulation of uromodulin expression in health and disease .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK53___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"N - arachidonoyl - L - serine is neuroprotective after traumatic brain injury by reducing apoptosis . N - arachidonoyl - L - serine ( AraS ) is a brain component structurally related to the endocannabinoid family . We investigated the neuroprotective effects of AraS following closed head injury induced by weight drop onto the exposed fronto - parietal skull and the mechanisms involved . A single injection of AraS following injury led to a significant improvement in functional outcome , and to reduced edema and lesion volume compared with vehicle . Specific antagonists to CB2 receptors , transient receptor potential vanilloid 1 ( Q8NER1 ) or large conductance calcium - activated potassium ( BK ) channels reversed these effects . Specific binding assays did not indicate binding of AraS to the Q9Y2T6 cannabinoid receptor . N - arachidonoyl - L - serine blocked the attenuation in phosphorylated extracellular - signal - regulated kinase 1 / 2 ( P29323 ) levels and led to an increase in pAkt in both the ipsilateral and contralateral cortices . Increased levels of the prosurvival factor Bcl - xL were evident 24 hours after injury in AraS - treated mice , followed by a 30 % reduction in caspase - 3 activity , measured 3 days after injury . Treatment with a CB2 antagonist , but not with a P21554 antagonist , reversed this effect . Our results suggest that administration of AraS leads to neuroprotection via P29323 and Akt phosphorylation and induction of their downstream antiapoptotic pathways . These protective effects are related mostly to indirect signaling via the CB2R and Q8NER1 channels but not through P21554 or Q9Y2T6 receptors .",
"Associations between single nucleotide polymorphisms in cellular viral receptors and attachment factor - related genes and humoral immunity to rubella vaccination . BACKGROUND : Viral attachment and cell entry host factors are important for viral replication , pathogenesis , and the generation and sustenance of immune responses after infection and / or vaccination , and are plausible genetic regulators of vaccine - induced immunity . METHODS : Using a tag - SNP approach in candidate gene study , we assessed the role of selected cell surface receptor genes , attachment factor - related genes , along with other immune genes in the genetic control of immune response variations after live rubella vaccination in two independent study cohorts . RESULTS : Our analysis revealed evidence for multiple associations between genetic variants in the P15151 , Q92692 , Q9NNX6 / Q9NNX6 , P10826 , Q16653 , P05231 and other immune function - related genes and rubella - specific neutralizing antibodies after vaccination ( meta p - value < 0 . 05 ) . CONCLUSION : Our results indicate that multiple SNPs from genes involved in cell adhesion , viral attachment , and viral entry , as well as others in genes involved in signaling and / or immune response regulation , play a role in modulating humoral immune responses following live rubella vaccination .",
"Genome - wide association studies identify P30532 / 3 and Q13639 in the development of airflow obstruction . RATIONALE : Genome - wide association studies ( GWAS ) have identified loci influencing lung function , but fewer genes influencing chronic obstructive pulmonary disease ( P48444 ) are known . OBJECTIVES : Perform meta - analyses of GWAS for airflow obstruction , a key pathophysiologic characteristic of P48444 assessed by spirometry , in population - based cohorts examining all participants , ever smokers , never smokers , asthma - free participants , and more severe cases . METHODS : Fifteen cohorts were studied for discovery ( 3 , 368 affected ; 29 , 507 unaffected ) , and a population - based family study and a meta - analysis of case - control studies were used for replication and regional follow - up ( 3 , 837 cases ; 4 , 479 control subjects ) . Airflow obstruction was defined as Q99581 ( 1 ) and its ratio to FVC ( Q99581 ( 1 )/ FVC ) both less than their respective lower limits of normal as determined by published reference equations . MEASUREMENTS AND MAIN RESULTS : The discovery meta - analyses identified one region on chromosome 15q25 . 1 meeting genome - wide significance in ever smokers that includes A2RU49 , P48200 , and P30532 / P32297 genes . The region was also modestly associated among never smokers . Gene expression studies confirmed the presence of P30532 / 3 in lung , airway smooth muscle , and bronchial epithelial cells . A single - nucleotide polymorphism in Q13639 , a gene previously related to Q99581 ( 1 )/ FVC , achieved genome - wide statistical significance in combined meta - analysis . Top single - nucleotide polymorphisms in Q9H013 , P10826 , O14495 , and Q8TE59 were nominally replicated in the P48444 meta - analysis . CONCLUSIONS : These results suggest an important role for the P30532 / 3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the Q13639 gene in the etiology of airflow obstruction .",
"Expression of human all - trans - retinoic acid receptor beta and its ligand - binding domain in Escherichia coli . DB00755 , one of the hormonally active derivatives of vitamin A , occurs physiologically in plasma at a concentration below 10 nmol / l . The methods currently used for its quantification are based on HPLC , need about 1 ml of serum , are relatively laborious and thus not well suited for mass analysis . The affinity and specificity of retinoic acid receptors for all - trans - retinoic acid encouraged us to express both the entire human retinoic acid receptor beta ( P10826 ) and two versions of its retinoic acid - binding domain in Escherichia coli in the hope that these recombinant proteins might be used as binders in a ligand - binding assay for all - trans - retinoic acid . The recombinant receptors , the whole receptor [ P10826 -( Q93033 - Q448 ) ] , corresponding to domains A - F , and the ligand - binding domain [ P10826 -( E149 - Q448 ) ] , corresponding to domains D - F , were expressed in the vector pET 3d / BL21 ( DE3 ) as inclusion bodies , solubilized with guanidinium chloride , renatured and purified by ion - exchange chromatography . P10826 -( P193 - Q448 ) , corresponding to domains E - F , was expressed in the vector pET 3d / BL21 ( DE3 ) pLysS , and purified by reversed - phase chromatography . Under non - denaturing conditions , the expressed whole receptor [ P10826 -( Q93033 - Q448 ) ] and the D - F construct ( P10826 -( E149 - Q448 ) ] behaved chromatographically as monomeric proteins whereas the E - F construct [ P10826 -( P193 - Q448 ) ] had a strong tendency to aggregate . P10826 -( Q93033 - Q448 ) and P10826 -( E149 - Q448 ) had similar Kd values for all - trans - retinoic acid ( 1 . 4 and 0 . 6 nmol / l respectively ) whereas P10826 -( P193 - Q448 ) bound all - trans - retinoic acid less avidly ( Kd 9 . 6 nmol / l ) . DB00523 bound to P10826 -( E149 - Q448 ) and P10826 -( Q93033 - Q448 ) as avidly as all - trans - retinoic acid . Competition experiments showed weak or no binding of 4 - oxo - all - trans - retinoic acid , 4 - oxo - 13 - cis - retinoic acid , 13 - cis - retinoic acid , acitretin and retinol by P10826 -( E149 - Q448 ) .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK10___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"Human chromosome 3 and pig chromosome 13 show complete synteny conservation but extensive gene - order differences . A comparative map of human chromosome 3 ( HSA 3 ) and pig chromosome 13 ( SSC 13 ) was constructed using physically assigned pig sequence - tagged sites ( STSs ) . Pig STSs representing 11 HSA 3 genes , including v - P04049 murine leukemia viral oncogene homolog 1 ( P04049 ) , retinoic acid beta receptor ( P10826 ) , cholecystokinin ( CCK ) , pituitary transcription factor 1 ( P28069 ) , ceruloplasmin ( CP ) , guanine nucleotide binding protein , alpha - inhibiting polypeptide 2 ( P04899 ) , sucrase - isomaltase ( SI ) , rhodopsin ( P08100 ) , dopamine receptor D3 ( P35462 ) , growth - associated protein 43 ( P17677 ) , and somatostatin ( P61278 ) , were developed . Ten pig STSs were regionally mapped using a somatic cell hybrid panel ( SCHP ) to SSC 13 with 80 - 100 % concordance . Large - insert probes were obtained by screening a pig yeast artificial chromosome ( YAC ) library with primers for each STS . Several YACs were identified for P35462 , P17677 , P28069 , P08100 , SI , and P61278 for fluorescence in situ hybridization ( Q5TCZ1 ) mapping . Single gene and bi - color Q5TCZ1 with each pairwise combination were used to further define the gene order on SSC 13 . While these data confirm chromosome painting results showing that HSA 3 probes hybridize to a major portion of SSC 13 , they also demonstrate extensive gene - order differences between man and pig within this large conserved synteny group . Interestingly , several conserved chromosomal regions have been detected between pig and mouse that are not conserved between man and mouse , suggesting that the SSC 13 gene arrangement may be the closest to that of the ancestral eutherian chromosome .",
"Biological and immunological studies of bovine hypothalamic DB05394 . P06850 B ( CRF - B ) is a peptide ( s ) isolated from bovine hypothalamic extracts by Sephadex G - 100 chromatography on the basis of its ability to stimulate secretion of adrenocorticotropin ( ___MASK75___ ) in vitro and in vivo . It is similar in molecular size to the 41 - residue ovine CRF ( oCRF ) or rat CRF ( rCRF ) recently elucidated and appears to be their bovine counterpart . Immunoreactivity of CRF - B was examined in homologous radioimmunoassays ( RIAs ) for oCRF or rCRF , using several anti - oCRF and anti - rCRF antibodies . CRF - B cross - reacted well with anti - oCRF antibodies but poorly with anti - rCRF antibodies . Purification of CRF - B with preparative isoelectric focusing yielded four CRF peaks , B - 1 ( pH 4 . 7 ) , B - 2 ( pH 5 . 5 ) , B - 3 ( pH 6 . 3 ) , and B - 4 ( pH 7 . 0 ) , which accounted for 16 , 30 , 46 , and 8 % of the total immunoreactivity , respectively . CRF B - 2 , B - 3 , and B - 4 showed both immunological activity and biological activity in vitro ( cell culture assay ) and in vivo ( Arimura assay ) , whereas CRF B - 1 showed only immunoreactivity . Their relative bioactivity / immunoreactivity ratios were 0 ( B - 1 ) , 1 ( B - 2 ) , 1 ( B - 3 ) , and 3 ( B - 4 ) . All of these CRF - B subtypes exhibited RIA displacement curves parallel to that for the oCRF standard and coeluted with oCRF on Sephadex G - 100 chromatography , which suggests that their molecular modifications are relatively minor .",
"Dopamine D1 , D2 and D3 receptor genes in alcohol dependence . Hereditary factors play a substantial role in the etiology of alcohol dependence . DB00898 mediates its reinforcing effects by an activation of the mesolimbic dopamine system . These findings suggest that the genes encoding the dopamine receptor ( DR ) subtypes represent high - ranking candidates for susceptibility genes to addictive disorders . Our present population - based association study investigated whether sequence variants of the dopamine D1 , D2 and D3 receptor genes confer susceptibility to alcohol dependence in 278 alcoholics , and clinically more homogeneous subgroups ascertained through positive family history , early age at onset , delirium , withdrawal seizures and antisocial tendencies . No evidence for an allelic association was found for the PCR - based TaqA RFLP fo the P14416 gene and a Bsp1286I RFLP of the P21728 gene . Without correction for multiple testing , we found a significantly increased allele frequency of a common P35462 gene variant expressing a serine at position 9 in the extracellular N - terminal part of the receptor protein in 55 alcohol - dependent individuals with delirium ( chi 2 = 4 . 1 , df = 1 , p = 0 . 042 ) . Further studies have to examine whether this amino acid substitution or a nearby mutation confers genetic susceptibility to at least a subgroup of alcohol - dependent individuals with delirium .",
"Molecular and biochemical analysis of calmodulin interactions with the calmodulin - binding domain of plant glutamate decarboxylase . We previously provided what to our knowledge is the first evidence that plant glutamate decarboxylase ( Q99259 ) is a calmodulin ( P62158 ) - binding protein . Here , we studied the Q99259 P62158 - binding domain in detail . A synthetic peptide of 26 amino acids corresponding to this domain forms a stable complex with Ca2 +/ P62158 with a 1 : 1 stoichiometry , and amino acid substitutions suggest that tryptophan - 485 has an indispensable role in P62158 binding . Chemical cross - linking revealed specific P62158 / Q99259 interactions even in the absence of Ca2 + . However , increasing KCI concentrations or deletion of two carboxy - terminal lysines abolished these interactions but had a mild effect on P62158 / Q99259 interactions in the presence of Ca2 + . We conclude that in the presence of Ca ( 2 +)- hydrophobic interactions involving tryptophan - 485 and electrostatic interactions involving the carboxy - terminal lysines mediate P62158 / Q99259 complex formation . By contrast , in the absence of Ca2 + , P62158 / Q99259 interactions are essentially electrostatic and involve the carboxy - terminal lysines . In addition , a tryptophan residue and carboxy - terminal lysines are present in the P62158 - binding domain of an Arabidopsis Q99259 . Finally , we demonstrate that petunia Q99259 activity is stimulated in vitro by Ca2 +/ P62158 . Our study provides a molecular basis for Ca ( 2 +)- dependent P62158 / Q99259 interactions and suggests the possible occurrence of Ca ( 2 +)- independent P62158 / Q99259 interactions .",
"Oncogenic events associated with endometrial and ovarian cancers are rare in endometriosis . Endometriosis displays some features that resemble malignant processes , including invasive growth , resistance to apoptosis and distant implantation . The objective of this study was to investigate whether gene alterations that are frequent in endometrial and / or ovarian cancers contribute to the pathogenesis of endometriosis . Biopsies were obtained from ectopic endometriosis lesions from 23 patients with revised American Fertility Score stage 1 ( n = 1 ) , 2 ( n = 10 ) , 3 ( n = 11 ) or 4 ( n = 1 ) endometriosis . Six genes ( P25054 , CDKN2A , Q9ULZ3 , P10826 , Q9NS23 and P03372 ) were analyzed for promoter hypermethylation using methylation - specific melting curve analysis , and 9 genes ( P15056 , P01112 , P01111 , P35222 , P11802 , P22607 , P42336 , P04637 and P60484 ) were analyzed for mutations using denaturing gradient gel electrophoresis and direct sequencing . An oncogenic mutation in P01116 ( c . 34G > T ; p . G12C ) was detected in a single lesion . No gene alterations were found in the remaining samples . Our data suggest that genetic and epigenetic events contributing to endometrial and ovarian cancers are rare in endometriosis . However , other proto - oncogenes and tumor suppressor genes should be tested for alterations in order to identify the molecular basis of the susceptibility of endometriosis to malignant transformation .",
"Linkage disequilibrium between P28472 gene and nonsyndromic familial cleft lip with or without cleft palate . The malformation of nonsyndromic cleft lip with or without cleft palate ( CL / P ) is a common congenital disease that affects approximately 1 / 1000 newborns in Caucasian populations . Genetic studies indicate that CL / P has the characteristics of a complex genetic trait . Linkage analysis and mouse - model knockout studies have suggested several candidate genes mapping in different chromosome regions for CL / P malformation . On these grounds , we have investigated , by linkage disequilibrium ( LD ) and parametric and nonparametric linkage analyses , five different candidate genes , including those for the beta3 subunit of the gamma - aminobutyric acid receptor ( P28472 ) , glutamic acid decarboxylase 1 ( Q99259 ) , retinoic acid receptor alpha ( P10276 ) , transforming growth factor beta3 ( P10600 ) , and msh ( Drosophila ) homeobox homolog 1 ( P28360 ) . Interestingly , a significant LD between P28472 and CL / P was obtained ( P - value = 0 . 008 in the allele - wise analysis for multiallelic markers ) , suggesting that the P28472 gene is involved in this congenital disease . This new finding in humans is in agreement with previously reported data obtained with the murine model . Indeed , mouse studies indicate a role for gamma - aminobutyric acid ( GABA ) and its receptor in normal palate development . Exclusion of the Q99259 gene , which encodes the GABA - producing enzyme , in CL / P pathogenesis was obtained in our study . Moreover , we were unable to confirm the involvement of the P28360 gene in nonsyndromic CL / P . Modest evidence of LD between marker alleles and CL / P was found at the P10276 and P10600 loci suggesting a minor role for these genes in our family set of nonsyndromic CL / P .",
"___MASK1___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK1___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK1___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK1___ inhibits activated T cells . We show that in vitro , ___MASK1___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK1___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK1___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK1___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK1___ to treat chronic inflammatory disease .",
"Involvement of transcription factor P24468 in human trophoblast differentiation . BACKGROUND : During the in vitro differentiation of human villous cytotrophoblast ( Q01459 ) cells to a syncytiotrophoblast ( STB ) phenotype , mRNA levels for the nuclear hormone receptor P24468 ( P24468 , COUP - TFII ) increase rapidly , reaching a peak at day 1 of differentiation that is 8 . 8 - fold greater than that in undifferentiated Q01459 cells . To examine whether P24468 is involved in the regulation of villous Q01459 cell differentiation , studies were performed to determine whether P24468 regulates the expression of P05549 ( AP - 2alpha ) , a transcription factor that is critical for the terminal differentiation of these cells to a STB phenotype . METHODOLOGY / PRIMARY FINDINGS : Overexpression of P24468 in primary cultures of human Q01459 cells and JEG - 3 human choriocarcinoma cells induced dose - dependent increases in P05549 promoter activity . Conversely , siRNA mediated silencing of the P24468 gene in villous Q01459 undergoing spontaneous differentiation blocked the induction of the mRNAs for P05549 and several STB cell specific marker genes , including human placental lactogen ( hPL ) , pregnancy specific glycoprotein 1 ( P11464 ) and corticotropin releasing hormone ( P06850 ) by 51 - 59 % . The induction of P05549 promoter activity by P24468 was potentiated by the nuclear hormone receptors retinoic acid receptor alpha ( P10276 ) and retinoid X receptor alpha ( P19793 ) . CONCLUSIONS / SIGNIFICANCE : Taken together , these results strongly suggest that P24468 is involved in villous Q01459 cell differentiation and that P24468 acts , at least in part , by directly activating P05549 gene expression and by potentiating the transactivation of P05549 by P10276 and P19793 .",
"Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK75___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK75___ peptide content within the pituitary , and plasma ___MASK75___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK75___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK75___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK75___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .",
"Retinoic acid - induced modulation of P60568 mRNA production and P60568 receptor expression on T cells . BACKGROUND : Retinoic acid ( RA ) has important immune - modulating effects on both T and B cell function . Our laboratory has shown that RA can enhance in vitro polyclonal B cell immunoglobulin ( Ig ) response . Investigating cytokines known to affect B cell differentiation , we have recently shown that P05231 production is augmented by RA . In the present study we have examined the immune modulating effects of RA on P60568 mRNA , another important cytokine for B cell immunoglobulin production , the expression of P60568 receptors on T cells , and the RA nuclear receptors . METHODS : Purified T cells were obtained from adenoidal tissues , and incubated with RA ( 10 (- 7 ) M ) or DB01093 solvent / media control for 0 , 6 - 8 , and 24 h . Total mRNA was extracted from T cells , and using RT - PCR , changes in the production of P60568 and RA receptors ( RAR ) - alpha , beta , gamma mRNA were determined . The effects of RA on P60568 - alpha receptor expression was determined by flow cytometry on T cells . CONCLUSION : These studies suggest that RA can augment P60568 mRNA production by T cells with a possible paracrine effect on IL - 2R - alpha expression . These changes appear to be mediated by P10276 . Thus , P60568 may be another important cytokine modulated by RA in the immune response .",
"Mutual exclusivity analysis of genetic and epigenetic drivers in melanoma identifies a link between p14 Q8N726 and RARβ signaling . Melanoma genomes contain thousands of alterations including : mutations , copy number alterations , structural aberrations , and methylation changes . The bulk of this variation is stochastic and functionally neutral , with only a small minority representing \" drivers \" that contribute to the genesis and maintenance of tumors . Drivers are often directly or inversely correlated across tumors , reflecting the molecular and regulatory signaling pathways in which they operate . Here , a profile of genetic and epigenetic drivers in 110 human melanoma cell lines was generated and searched for non - random distribution patterns . Statistically significant mutual exclusivity was revealed among components of each of the p16 ( INK4A )- P11802 - RB , DB01367 - RAF - MEK - P29323 and PI3K - AKT signaling pathways . In addition , an inverse correlation was observed between promoter hypermethylation of retinoic acid receptor β ( P10826 ) and CDKN2A alterations affecting p14 ( Q8N726 ) ( P < 0 . 0001 ) , suggesting a functional link between RARβ signaling and the melanoma - suppressive activities of p14 ( Q8N726 ) . Mechanistically , all - trans retinoic acid ( DB00755 ) treatment increased the expression of p14 ( Q8N726 ) in primary human melanocytes and the steady - state levels of p14 ( Q8N726 ) in these cells were shown to be regulated via RARβ . Furthermore , the ability of DB00755 to induce senescence is reduced in p14 ( Q8N726 )- depleted melanocytes , and we provide proof - of - concept that DB00755 can induce irreversible growth arrest in melanoma cells with an intact RARβ - p14 ( Q8N726 ) signaling axis , independent of p16 ( INK4A ) and p53 status . IMPLICATIONS : These data highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways and establish a previously unrecognized cross - talk between RARβ and p14 ( Q8N726 ) with potential implications for melanoma treatment .",
"[ Moclobemide ( ___MASK76___ ) , the first P21397 - inhibitor : really something new ? ] .",
"[ ___MASK15___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK15___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"[ Leukemia - and lymphoma - associated flow cytometric , cytogenetic , and molecular genetic aberrations in healthy individuals ] . Most leukemia and lymphoma cases are characterized by specific flow cytometric , cytogenetic and molecular genetic aberrations , which can also be detected in healthy individuals in some cases . The authors review the literature concerning monoclonal B - cell lymphocytosis , and the occurrence of chromosomal translocations t ( 14 ; 18 ) and t ( 11 ; 14 ) , P06748 - Q9UM73 fusion gene , O60674 V617F mutation , P11274 - P00519 fusion gene , P41212 - Q01196 ( P41212 - Q01196 ) , Q03164 - P51825 and P29590 - P10276 fusion gene in healthy individuals . At present , we do not know the importance of these aberrations . From the authors review it is evident that this phenomenon has both theoretical and practical ( diagnostic , prognostic , and therapeutic ) significance .",
"Growth - inhibitory effects of vitamin D analogues and retinoids on human pancreatic cancer cells . Retinoids and vitamin D are important factors that regulate cellular growth and differentiation . An additive growth - inhibitory effect of retinoids and vitamin D analogues has been demonstrated for human myeloma , leukaemic and breast cancer cells . We set out to study the effects of the vitamin D analogue EB1089 and the retinoids all - trans - and 9 - cis - retinoic acid on the human pancreatic adenocarcinoma cell lines Capan 1 and Capan 2 and the undifferentiated pancreatic carcinoma cell line Hs766T . The cell lines investigated expressed vitamin D receptor , retinoic acid receptor ( RAR ) - alpha and gamma as determined by polymerase chain reaction after reverse transcription . P10826 was expressed only in Hs766T cells . Addition of all - trans - retinoic acid increased the amount of P10276 mRNA in the three cell lines and induced P10826 mRNA in Capan 1 and Capan 2 cells . All - trans - retinoic acid at a concentration of 10 nM inhibited the growth of Capan 1 and Capan 2 cells by 40 % relative to controls . DB00523 was less effective . Neither all - trans - retinoic acid nor 9 - cis - retinoic acid affected the growth of Hs766T cells . EB1089 , if added alone to the cells , did not significantly inhibit growth . However , the combination of 1 nM EB1089 with 10 nM all - trans - retinoic acid exerted a growth - inhibitory effect of 90 % in Capan 1 cells and of 70 % in Capan 2 cells . Our data suggest that vitamin D analogues together with retinoids inhibit the growth of human pancreatic cancer cells . However , in vivo studies are necessary to examine the potential use of retinoids and vitamin D analogues on pancreatic cancer .",
"The potential role of PD0332991 ( ___MASK6___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK6___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .",
"DB00227 - stimulated superinduction of P16581 , P05362 and P19320 in P01375 activated human vascular endothelial cells . Inhibitors of P04035 ( statins ) reveal important pharmacological effects in addition to reducing the plasma LDL cholesterol level . In the pathogenesis of arteriosclerosis , transendothelial migration of various leukocytes including monocytes is a crucial step . We , therefore , investigated the expression of P16581 , intercellular cell adhesion molecule - 1 ( P05362 ) and vascular cell adhesion molecule - 1 ( P19320 ) in vascular endothelial cells as influenced by lovastatin . Human umbilical vein endothelial cells ( HUVECs ) express significant amounts of selectins and cell adhesion molecules ( CAMs ) within a few hours after stimulation with P01375 . This effect is potentiated by 100 - 200 % when the cells are pretreated with 0 . 1 - 2 . 5 microM lovastatin . The lovastatin - mediated increase in the cytoplasm and at the cell surface is dose - dependent and significant at lovastatin concentrations comparable to plasma levels in patients under lovastatin treatment . The lovastatin - potentiated increase of P16581 and CAMs is correlated with a corresponding increase of selectin - and P62158 - specific mRNA . We conclude that , in vivo , statin treatment could trigger an enhanced recruitment of macrophages that might support the cholesteryl ester efflux from the arteriosclerotic plaque .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK67___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK67___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"Retinoids and myelomonocytic growth factors cooperatively activate P10276 and induce human myeloid leukemia cell differentiation via Q96HU1 kinase pathways . Use of all - trans - retinoic acid ( DB00755 ) in combinatorial differentiation therapy of acute promyelocytic leukemia ( APL ) results in exceptional cure rates . However , potent cell differentiation effects of DB00755 are so far largely restricted to this disease and long - term survival rates in non - APL acute myelogeneous leukemia ( AML ) remain unacceptably poor , requiring development of novel therapeutic strategies . We demonstrate here that myelomonocytic growth factors ( granulocyte colony - stimulating factor [ DB00099 ] and / or granulocyte macrophage colony - stimulating factor [ GM - P04141 ] ) potentiate differentiation effects of DB00755 in different AML cell lines and primary cells from patients with myeloid leukemia . The ligand - dependent activities of endogenous and transiently expressed retinoic acid receptor alpha ( RARalpha ) isoforms can be potentiated by G / GM - P04141 in U - 937 cells and correlate with increased expression of DB00755 - inducible RARalpha2 isoform . Specific inhibitors of mitogen mitogen - activated protein kinase ( MAPK ) ( MEK ) - 1 /- 2 or p38 extracellular signal - related kinase ( P29323 ) kinase diminish the DB00755 as well as DB00755 and G / GM - P04141 - induced activation of the RARalpha proteins and decreased the differentiation - induced decline in cell numbers . Our data demonstrate that acting , at least in part , via the Q96HU1 kinase pathways , myelomonocytic growth factors enhance DB00755 - dependent activation of the RARalpha isoforms and maturation of myeloid leukemia cells . These results suggest that combinatorial use of these agents may be effective in differentiation therapy of AML .",
"Characterization of a novel Q13639 receptor antagonist of the azabicycloalkyl benzimidazolone class : DAU 6285 . Three chemical classes of serotonin Q13639 receptor agonists have been identified so far : 5 - substituted indoles ( e . g . 5 - HT ) , benzamides ( e . g . renzapride ) and benzimidazolones ( e . g . BIMU 8 ) . In a search for Q13639 receptor antagonists , we have discovered that the benzimidazolone derivative DAU 6285 ( for structure see text ) , is 3 - 5 times more potent than tropisetron in blocking 5 - HT , renzapride and BIMU 8 induced stimulation of adenylate cyclase activity in mouse embryo colliculi neurons . Schild plot analysis yielded Ki values of 220 , 181 and 255 nmol / l , respectively . In addition , DAU 6285 showed poor activity as a 5 - Q9H205 receptor ligand with respect to tropisetron , as demonstrated by in vitro binding studies ( Ki , 322 vs 2 . 8 nmol / l ) and by its antagonistic activity in the Bezold - Jarisch reflex test ( ID50 , 231 vs 0 . 5 micrograms / kg , i . v . ) . No significant binding ( Ki greater than 10 mumol / l ) of DAU 6285 to serotonergic P08908 , P28222 , P28335 , P28221 , and 5 - HT2 receptors as well as to adrenergic alpha 1 , alpha 2 , dopaminergic D1 , D2 or muscarinic M1 - M3 receptor subtypes was found . The data indicate that DAU 6285 has a somewhat higher affinity than tropisetron for Q13639 receptors , a property confirmed in functional tests , and much lower affinity than tropisetron for 5 - Q9H205 receptors . The compound represents a new interesting tool for investigating the pharmacological and physiological properties of Q13639 receptors .",
"Polymorphisms of the P09488 , P09211 , P05164 , P18887 , and P15559 genes in Chinese patients with non - small cell lung cancers : relationship with aberrant promoter methylation of the CDKN2A and P10826 genes . An association between functional polymorphisms of genes resulting in decreased detoxification of carcinogens or DNA repair and aberrant promoter methylation is an attractive hypothesis in lung carcinogenesis . The genotypes at polymorphic sites of the glutathione S - transferase ( Q86UG4 ) M1 ( null / wildtype ) and P1 ( nucleotide 2627 A / G ) , myeloperoxidase ( P05164 ) ( nucleotide - 463 G / A ) , X - ray repair cross - complementing group 1 ( P18887 ) ( nucleotides 26304 C / T ; 28152 G / A ) , and NADPH quinine oxidoreductase ( P15559 ) ( nucleotide 609 C / T ) genes in 75 Chinese patients with non - small cell lung cancer ( NSCLC ) were characterized with polymerase chain reaction - restriction fragment length polymorphism . Results were correlated with aberrant methylation of the CDKN2A ( alias p16 ( INK4A ) ) , retinoic acid receptor beta ( P10826 ) , methylguanine - DNA methyltransferase ( P16455 ) , and death - associated - protein ( DAP ) kinase genes in the tumors . In comparison with an age - matched control , none of the polymorphisms were associated with increased lung cancer risks . In male patients , however , the P05164 - 463 GG homozygous state was associated with CDKN2A ( alias p16 ( INK4A ) ) methylation ( odds ratio OR = 3 . 63 , 95 % confidence interval CI = 1 . 26 - 10 . 51 ) , and the P18887 26304 T allele in the heterozygous / homozygous state was associated with methylation of CDKN2A ( OR = 6 . 13 , 95 % CI = 1 . 55 - 24 . 16 ) and P10826 ( OR = 7 . 67 , 95 % CI = 1 . 62 - 36 . 18 ) . In female patients , the P09211 G allele in the heterozygous / homozygous state was associated with P10826 methylation ( OR = 18 . 0 , 95 % CI = 0 . 76 - 427 . 29 ) . These results showed that functional deficiencies in metabolic pathways that protect cells from carcinogen induced DNA damage might be linked to aberrant promoter methylation of the CDKN2A and P10826 genes during lung carcinogenesis ."
] |
[
"___MASK10___",
"___MASK15___",
"___MASK1___",
"___MASK35___",
"___MASK53___",
"___MASK67___",
"___MASK6___",
"___MASK75___",
"___MASK76___"
] |
___MASK6___
|
MH_train_467
|
interacts_with DB00188?
|
[
"A phase I - II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin - cyclophosphamide in locally advanced breast cancer . Histone deacetylases ( HDACs ) are a family of enzymes that regulate chromatin remodeling and gene transcription . ___MASK52___ is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing Q9UBN7 and Hsp90 client proteins . Fifty - five patients with clinical stage IIA - IIIC breast cancer received 12 weekly doses of paclitaxel ( 80 mg / m ( 2 ) ) plus vorinostat ( 200 - 300 mg PO P55957 ) on days 1 - 3 of each paclitaxel dose plus trastuzumab ( for Her2 / neu positive disease only ) , followed by doxorubicin / cyclophosphamide ( 60 / 600 mg / m ( 2 ) every 2 weeks plus pegfilgrastim ) . The primary study endpoint was pathologic complete response ( pCR ). pCR occurred in 13 of 24 evaluable patients with Her2 - positive disease ( 54 , 95 % confidence intervals [ CI ] 35 - 72 % ) , which met the prespecified study endpoint . pCR occurred in 4 of 15 patients with triple negative disease ( 27 , 95 % CI 11 - 52 % ) and none of 12 patients with ER - positive , Her2 / neu negative disease ( 0 , 95 % CI 0 - 24 % ) , which did not meet the prespecified endpoint . ER - positive tumors exhibited lower Ki67 and higher Hsp70 expression , and Q9UBN7 , Hsp70 , P38936 , and p27 expression were not predictive of response . ___MASK52___ increased acetylation of Hsp90 and alpha tubulin , and reduced expression of Hsp90 client proteins and Q9UBN7 in the primary tumor . Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin - cyclophosphamide is associated with a high pCR rate in locally advanced Her2 / neu positive breast cancer . Consistent with cell line and xenograft data , vorinostat increased acetylation of Hsp90 and alpha tubulin , and decreased Hsp90 client protein and Q9UBN7 expression in human breast cancers in vivo .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK84___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK1___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"A der ( 13 ) t ( 7 ; 13 )( p13 ; q14 ) with monoallelic loss of P06400 and D13S319 in myelodysplastic syndrome . Deletions or translocations of chromosome band 13q14 , the locus of the retinoblastoma gene ( P06400 ) , have been observed in a variety of hematological malignancies including myelodysplastic syndrome ( P43034 ) . We describe here a novel unbalanced translocation der ( 13 ) t ( 7 ; 13 )( p13 ; q14 ) involving 13q14 in a patient with P43034 . A 66 - year - old woman was diagnosed as having P43034 , refractory anemia with excess of blasts ( RAEB - 1 ) because of 7 . 4 % blasts and trilineage dysplasia in the bone marrow cells . G - banding and spectral karyotyping analyses showed complex karyotypes as follows : 46 , XX , der ( 6 ) t ( 6 ; 7 ) ( q11 ; ? ) , der ( 7 ) del ( 7 ) ( ? p13 ) t ( 6 ; 7 ) ( q ? ; q11 ) t ( 6 ; 13 ) ( q ? ; q ? ) , der ( 13 ) t ( 7 ; 13 )( p13 ; q14 ) . Fluorescence in situ hybridization ( Q5TCZ1 ) analyses demonstrated that one allele of the P06400 gene and the microsatellite locus D13S319 , located at 13q14 and telomeric to the P06400 gene , was deleted . Considering other reported cases , our results indicate that submicroscopic deletions accompanying 13q14 translocations are recurrent cytogenetic aberrations in P43034 . The P06400 gene or another tumor suppressor gene in the vicinity of D13S319 , or both , may be involved in the pathogenesis of P43034 with 13q14 translocations by monoallelic deletion .",
"Identification of antithrombin - modulating genes . Role of O95461 , a gene encoding a bifunctional glycosyltransferase , in the secretion of proteins ? The haemostatic relevance of antithrombin together with the low genetic variability of P01008 , and the high heritability of plasma levels encourage the search for modulating genes . We used a hypothesis - free approach to identify these genes , evaluating associations between plasma antithrombin and 307 , 984 polymorphisms in the GAIT study ( 352 individuals from 21 Spanish families ) . Despite no SNP reaching the genome wide significance threshold , we verified milder positive associations in 307 blood donors from a different cohort . This validation study suggested O95461 , a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin - like linear polysaccharides , as a potential modulator of antithrombin based on the significant association of one SNPs , rs762057 , with anti - FXa activity , particularly after adjustment for age , sex and P01008 rs2227589 genotype , all factors influencing antithrombin levels ( p = 0 . 02 ) . Additional results sustained this association . O95461 silencing inHepG2 and P29320 - EBNA cells did not affect P01008 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention . Milder effects were observed on α1 - antitrypsin , prothrombin and transferrin . Our study suggests O95461 as the first known modifier of plasma antithrombin , and proposes a new role for O95461 in modulating extracellular secretion of certain glycoproteins .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK91___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK27___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"___MASK64___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .",
"Dysregulation of leukocyte gene expression in women with medication - refractory depression versus healthy non - depressed controls . BACKGROUND : Depressive Disorders ( DD ) are a great financial and social burden . Females display 70 % higher rate of depression than males and more than 30 % of these patients do not respond to conventional medications . Thus medication - refractory female patients are a large , under - served , group where new biological targets for intervention are greatly needed . METHODS : We used real - time quantitative polymerase chain reaction ( qPCR ) to evaluate mRNA gene expression from peripheral blood leukocytes for 27 genes , including immune , Q9Y251 - axis , ion channels , and growth and transcription factors . Our sample included 23 females with medication refractory DD : 13 with major depressive disorder ( MDD ) , 10 with bipolar disorder ( BPD ) . Our comparison group was 19 healthy , non - depressed female controls . We examined differences in mRNA expression in DD vs . controls , in MDD vs . BPD , and in patients with greater vs . lesser depression severity . RESULTS : DD patients showed increased expression for P22301 , P05231 , P30559 , Q99572 , P47900 , and Q8NER1 . BPD patients showed increased P05067 , P16220 , P19838 , P04150 , and P09486 and decreased P01375 expression . Depression severity was related to increased P22301 , P47900 , P51575 , and Q9HBA0 expression . CONCLUSIONS : These results support prior findings of dysregulation in immune genes , and provide preliminary evidence of dysregulation in purinergic and other ion channels in females with medication - refractory depression , and in transcription and growth factors in those with BPD . If replicated in future research examining protein levels as well as mRNA , these pathways could potentially be used to explore biological mechanisms of depression and to develop new drug targets .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK61___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"G ( alpha ) 12 / 13 inhibition enhances the anticancer effect of bortezomib through P28074 downregulation . DB00188 is a proteasome inhibitor approved for anticancer therapy . However , variable sensitivity of tumor cells exists in this therapy probably due to differences in the expression of proteasome subunits . G ( alpha )( 12 / 13 ) serves modulators or signal transducers in diverse pathways . This study investigated whether cancer cells display differential sensitivity to bortezomib with reference to G ( alpha )( 12 / 13 ) expression , and if so , whether G ( alpha )( 12 / 13 ) affects the expression of proteasome subunits and their activities . DB00188 treatment exhibited greater sensitivities in Huh7 and SNU886 cells ( epithelial type ) than SK - Hep1 and SNU449 cells ( mesenchymal type ) that exhibited higher levels of G ( alpha )( 12 / 13 ) . Overexpression of an active mutant of G ( alpha )( 12 ) ( Galpha ( 12 ) QL ) or G ( alpha )( 13 ) ( G ( alpha )( 13 ) QL ) diminished the ability of bortezomib to induce cytotoxicity in Huh7 cells . Moreover , transfection with the minigene that disturbs G protein - coupled receptor - G protein coupling ( CT12 or Q9NXZ2 ) increased it in SK - Hep1 cells . Consistently , MiaPaCa2 cells transfected with CT12 or Q9NXZ2 exhibited a greater sensitivity to bortezomib . Evidence of G ( alpha )( 12 / 13 ) ' s antagonism on the anticancer effect of bortezomib was verified in the reversal by G ( alpha )( 12 ) QL or G ( alpha )( 13 ) QL of the minigenes ' enhancement of cytotoxity . Real - time polymerase chain reaction assay enabled us to identify P28074 , multicatalytic endopeptidase complex - like - 1 , and proteasome activator subunit - 1 repression by CT12 or Q9NXZ2 . Furthermore , G ( alpha )( 12 / 13 ) inhibition enhanced the ability of bortezomib to repress P28074 , as shown by immunoblotting and proteasome activity assay . Moreover , this inhibitory effect on P28074 was attenuated by G ( alpha ) G ( alpha )( 12 ) QL or G ( alpha )( 13 ) QL . In conclusion , the inhibition of G ( alpha )( 12 / 13 ) activities may enhance the anticancer effect of bortezomib through P28074 repression , providing insight into the G ( alpha )( 12 / 13 ) pathway for the regulation of proteasomal activity .",
"Molecular genetic classification of central nervous system malformations . Traditional schemes of classifying nervous system malformations are based on descriptive morphogenesis of anatomic processes of ontogenesis , such as neurulation , neuroblast migration , and axonal pathfinding . This proposal is a first attempt to incorporate the recent molecular genetic data that explain programming of development etiologically . A scheme based purely on genetic mutations would not be practical , in part because only in a few dysgeneses are the specific defects known , but also because several genes might be involved sequentially and many genes inhibit or augment the expression of others . The same genes serve different functions at different stages and are involved in multiple organ systems . Some complex malformations , such as holoprosencephaly , result from several unrelated defective genes . Finally , a pure genetic classification would be too inflexible to incorporate some anatomic criteria . The basis for the proposed scheme is , therefore , disturbances in patterns of genetic expression ; polarity gradients of the axes of the neural tube ( eg , upregulation or downregulation of genetic influences ) ; segmentation ( eg , deletions of specific neuromeres , ectopic expression ) ; mutations that cause change in cell lineage ( eg , dysplastic gangliocytoma of cerebellum , myofiber differentiation within brain ) ; and specific genes or molecules that mediate neuroblast migration in its early ( eg , filamin - 1 ) , middle ( eg , P43034 , double - cortin ) , or late course ( eg , reelin , Q9NUQ9 - P62158 ) . The proposed scheme undoubtedly will undergo many future revisions , but it provides a starting point using currently available data .",
"Stimulation of cloned human serotonin P28221 beta receptor sites in stably transfected P13671 glial cells promotes cell growth . The involvement of serotonin P28221 beta receptor sites was investigated in the growth of rat P13671 glial cells permanently transfected with a gene encoding a human P28221 beta receptor . The 5 - HT receptor identity of control and transfected P13671 glial / P28221 beta cells was determined by reverse transcription - polymerase chain reaction using primers specific for rat P08908 , rat P28222 , rat P28221 alpha , human P28221 beta , and rat 5 - Q13049 receptor genes . Constitutive mRNA for 5 - Q13049 receptors was present in control and transfected P13671 glial / P28221 beta cells , whereas mRNA for P28221 beta receptor sites was only present in the transfected P13671 glial / P28221 beta cell line . 5 - HT inhibited forskolin - stimulated cyclic AMP formation and promoted cell growth , in contrast to the absence of any measurable effect in pcDNA3 plasmid - transfected and nontransfected P13671 glial cells . The 5 - HT effects could be mimicked by sumatriptan ( EC50 = 44 - 76 nM ) and were totally and partially blocked by methiothepin ( IC50 = 9 nM ) and GR 127 , 935 ( 2 '- methyl - 4 '-( 5 - methyl [ 1 , 2 , 4 ] oxadiazol - 3 - yl )- biphenyl - 4 - carbox yli c acid [ 4 - methoxy - 3 -( 4 - methylpiperazin - 1 - yl ) phenyl ] amide ; IC50 = 97 pM ) , respectively . No effect on cell growth was measured with the 5 - HT2 receptor agonist DOI [ 1 -( 2 , 5 - dimethoxy - 4 - iodophenyl )- 2 - aminopropane ; 10 microM ] , suggesting that 5 - Q13049 receptors are not involved in the 5 - HT - stimulated P13671 glial / P28221 beta cell growth . Dibutyryl - cyclic AMP ( 0 . 3 mM ) - treated cultures did not show sumatriptan - promoted cell growth , indicating an inhibitory role for cyclic AMP in the cell growth mediated by P28221 beta receptor sites . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Experimental Staphylococcus aureus infection of the mammary gland induces region - specific changes in innate immune gene expression . Staphylococcus aureus is a prolific mastitis - causing bacterium that resides naturally in the environment of the dairy cow . The aim of this study was to profile immune gene expression in tissue from the alveolar , ductal , gland cistern and teat canal regions of the bovine mammary gland following intramammary infection with S . aureus . Quantitative real - time PCR ( qPCR ) was used to profile expression of innate immune genes including pattern recognition receptors ( PRRs ) , cytokines , antimicrobial peptides ( AMPs ) and acute phase proteins ( APPs ) . Consistent expression of Toll - like receptors ( TLRs ) 1 - 10 and NOD - like receptors ( NODs ) 1 - 2 was detected in all four tissue regions . Pro - inflammatory cytokines ( P05231 , Q16552 and P10145 ) and anti - inflammatory cytokine ( P22301 ) were induced in all 4 tissues . P05067 ( SAA3 and HP ) and AMP ( DEFB4 and Q8NG35 ) genes showed the greatest induction throughout the mammary gland in response to S . aureus , with particularly high expression in alveolar tissue ( SAA3 and HP > 133 - and > 80 - fold respectively , P < 0 . 05 ; DEFB4 and Q8NG35 > 9 - and > 27 - fold respectively , P < 0 . 05 ) . Collectively , our data show both sentinel and effector immune functions throughout the mammary gland in response to S . aureus challenge .",
"Negative regulation of O00206 signaling by P22301 - dependent microRNA - 146b . Toll - like receptors ( TLRs ) play key roles in detecting pathogens and initiating inflammatory responses that , subsequently , prime specific adaptive responses . Several mechanisms control TLR activity to avoid excessive inflammation and consequent immunopathology , including the anti - inflammatory cytokine P22301 . Recently , several TLR - responsive microRNAs ( miRs ) have also been proposed as potential regulators of this signaling pathway , but their functional role during the inflammatory response still is incompletely understood . In this study , we report that , after LPS engagement , monocytes up - regulate miR - 146b via an P22301 - mediated P40763 - dependent loop . We show evidence that miR - 146b modulates the O00206 signaling pathway by direct targeting of multiple elements , including the LPS receptor O00206 and the key adaptor / signaling proteins myeloid differentiation primary response ( MyD88 ) , interleukin - 1 receptor - associated kinase 1 ( P51617 ) , and Q9Y4K3 ( Q9Y4K3 ) . Furthermore , we demonstrate that the enforced expression of miR - 146b in human monocytes led to a significant reduction in the LPS - dependent production of several proinflammatory cytokines and chemokines , including P05231 , P01375 - α , P10145 , P10147 , P13500 , P80098 , and P02778 . Our results thus identify miR - 146b as an P22301 - responsive miR with an anti - inflammatory activity based on multiple targeting of components of the O00206 pathway in monocytes and candidate miR - 146b as a molecular effector of the P22301 anti - inflammatory activity .",
"[ Hemostatic factors and family history of thrombosis in patients with a myocardial infarct : a case - control study . The participants in GISSI - 2 - Efrim . Gruppo Italiano per lo Studio della Streptochinasi nell ' Infarto Miocardico ] . We studied a series of hemostasis factors in a group of patients selected from a cohort of 916 patients affected by MI from the GISSI - 2 study population . Following a case - control design , 73 patients with a family history of thrombosis ( the presence of at least two first degree relatives affected by MI and / or stroke before 65 years ) were matched with MI patients with no family history of thrombosis . Blood collection could be performed 6 +/- 1 months after the acute phase following MI in 53 pairs of such patients . The presence of mixed disulphides ( P43034 ) was significantly higher in patients with family history than in controls ; P43034 were detected in 7 cases and only in 1 control . No difference was found in contrast in the distribution of fibrinogen , factor VII , factor VIII , P04275 , protein C , protein S , AT III , HC II , P05121 , lipoprotein ( a ) . Nevertheless , independently from the family history , in the whole population of MI patients studied , 21 cases of suspected deficiency of protein C were found . Sixteen out of 53 patients with family history of MI and / or stroke had a family history of MI only . In patients with family history of MI the t - PA antigen levels were significantly lower than in the control group ( 7 . 5 +/- 4 . 4 vs 11 . 1 +/- 3 . 5 ng / ml , t = - 2 . 6 , p < 0 . 02 ) . In the whole population of MI patients and in patients with a family history of thrombosis t - PA antigen was positively correlated with P05121 antigen and P04275 . The correlation with P05121 was lost in patients with family history of MI . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Characterization of bortezomib - adapted I - 45 mesothelioma cells . BACKGROUND : DB00188 , a proteasome - specific inhibitor , has emerged as a promising cancer therapeutic agent . However , development of resistance to bortezomib may pose a challenge to effective anticancer therapy . Therefore , characterization of cellular mechanisms involved in bortezomib resistance and development of effective strategies to overcome this resistance represent important steps in the advancement of bortezomib - mediated cancer therapy . RESULTS : The present study reports the development of I - 45 - BTZ - R , a bortezomib - resistant cell line , from the bortezomib - sensitive mesothelioma cell line I - 45 . I - 45 - BTZ - R cells showed no cross - resistance to the chemotherapeutic drugs cisplatin , 5 - fluorouracil , and doxorubicin . Moreover , the bortezomib - adapted I - 45 - BTZ - R cells had decreased growth kinemics and did not over express proteasome subunit beta5 ( P28074 ) as compared to parental I - 45 cells . I - 45 - BTZ - R cells and parental I - 45 cells showed similar inhibition of proteasome activity , but I - 45 - BTZ - R cells exhibited much less accumulation of ubiquitinated proteins following exposure to 40 nm bortezomib . Further studies revealed that relatively low doses of bortezomib did not induce an unfolded protein response ( UPR ) in the bortezomib - adapted cells , while higher doses induced UPR with concomitant cell death , as evidenced by higher expression of the mitochondrial chaperone protein Bip and the endoplasmic reticulum ( ER ) stress - related pro - apoptotic protein P35638 . In addition , bortezomib exposure did not induce the accumulation of the pro - apoptotic proteins p53 , Mcl - 1S , and noxa in the bortezomib - adapted cells . CONCLUSION : These results suggest that UPR evasion , together with reduced pro - apoptotic gene induction , accounts for bortezomib resistance in the bortezomib - adapted mesothelioma cell line I - 45 - BTZ - R .",
"DB00188 - resistant myeloma cell lines : a role for mutated P28074 in preventing the accumulation of unfolded proteins and fatal ER stress . DB00188 is an effective agent for treating multiple myeloma ( MM ) . To investigate the underlying mechanisms associated with acquired resistance to this agent , we established two bortezomib - resistant MM cell lines , KMS - 11 / BTZ and OPM - 2 / BTZ , the 50 % inhibitory concentration values of which were respectively 24 . 7 - and 16 . 6 - fold higher than their parental cell lines . No activation of caspase and BH3 - only proteins such as Noxa was noted in bortezomib - resistant cells after exposure to the drug . The accumulation of polyubiquitinated proteins was reduced in bortezomib - resistant cells compared with the parental cells , associated with avoidance of catastrophic ER stress as assessed by downregulation of P35638 expression . These resistant MM cells have a unique point mutation , G322A , in the gene encoding the proteasome beta5 subunit ( P28074 ) , likely resulting in conformational changes to the bortezomib - binding pocket of this subunit . KMS - 11 parental cells transfected to express mutated P28074 also showed reduced bortezomib - induced apoptosis compared with those expressing wild - type P28074 or the parental cells . Expression of mutated P28074 was associated with the prevention of the accumulation of unfolded proteins . Thus , a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the P28074 gene .",
"P05067 is a primary androgen target gene that promotes prostate cancer growth . P10275 ( AR ) is a critical transcription factor that regulates various target genes and contributes to the pathophysiology of prostate cancer hormone dependently . Here , we identify amyloid precursor protein ( P05067 ) as a primary androgen target through chromatin immunoprecipitation ( ChIP ) combined with genome tiling array analysis ( ChIP - chip ) . ChIP - treated DNA were obtained from prostate cancer LNCaP cells with R1881 or vehicle treatment using AR or acetylated histone H3 antibodies . Ligand - dependent AR binding was further enriched by PCR subtraction . Using chromosome 21 / 22 arrays , we identified P05067 as one of the androgen - regulated genes with adjacent functional AR binding sites . P05067 expression is androgen - inducible in LNCaP cells and P05067 immunoreactivity was correlated with poor prognosis in patients with prostate cancer . Gain - of - function and loss - of - function studies revealed that P05067 promotes the tumor growth of prostate cancer . The present study reveals a novel P05067 - mediated pathway responsible for the androgen - dependent growth of prostate cancer . Our findings will indicate that P05067 could be a potential molecular target for the diagnosis and treatment of prostate cancer .",
"The complete primary structure of mouse 20S proteasomes . The proteasome is a large multicatalytic proteinase that plays a role in the generation of peptides for presentation by major histocompatibility complex class I molecules . The 20S proteolytic core of mammalian proteasomes is assembled from a group of 17 protein subunits that generate a distinctive pattern of spots upon two - dimensional gel electrophoresis . The genes for most of these subunits have been cloned from humans and rats . We isolated cDNA clones for the mouse orthologues of ten of the subunits [ P25786 ( P06681 ) , P25787 ( P01024 ) , P25788 ( Q99618 ) , P25789 ( P02748 ) , P28066 ( ZETA ) , P60900 ( IOTA ) , O14818 ( P13671 - I ) , P49721 ( P10643 - I ) , P49720 ( Q99622 - II ) , and P28074 ( X ) ] to complete the cloning of all of the mouse subunits . Using antisera raised against these subunits or their orthologues , we verified the identity of these proteins by two - dimensional NEPHGE - PAGE .",
"P05067 - dependent alteration of GSK3β activity impairs neurogenesis in the Ts65Dn mouse model of Down syndrome . Intellectual disability in Down syndrome ( DS ) appears to be related to severe neurogenesis impairment during brain development . The molecular mechanisms underlying this defect are still largely unknown . Accumulating evidence has highlighted the importance of GSK3β signaling for neuronal precursor proliferation / differentiation . In neural precursor cells ( NPCs ) from Ts65Dn mice and human fetuses with DS , we found reduced GSK3β phosphorylation and , hence , increased GSK3β activity . In cultures of trisomic subventricular - zone - derived adult NPCs ( aNPCs ) we found that deregulation of GSK3β activity was due to higher levels of the AICD fragment of the trisomic gene P05067 that directly bound to GSK3β . We restored GSK3β phosphorylation in trisomic aNPCs using either lithium , a well - known GSK3β inhibitor , or using a 5 - HT receptor agonist or fluoxetine , which activated the serotonin receptor P08908 . Importantly , this effect was accompanied by restoration of proliferation , cell fate specification and neuronal maturation . In agreement with results obtained in vitro , we found that early treatment with fluoxetine , which was previously shown to rescue neurogenesis and behavior in Ts65Dn mice , restored GSK3β phosphorylation . These results provide a link between GSK3β activity alteration , P05067 triplication and the defective neuronal production that characterizes the DS brain . Knowledge of the molecular mechanisms underlying neurogenesis alterations in DS may help to devise therapeutic strategies , potentially usable in humans . Results suggest that drugs that increase GSK3β phosphorylation , such as lithium or fluoxetine , may represent useful tools for the improvement of neurogenesis in DS .",
"___MASK64___ inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : ___MASK64___ is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti - cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 / 2 ) and P45983 and 2 ( JNK 1 / 2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound - healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC ( 50 ) = 8 . 6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 / 2 expression , upregulation of p - P45983 / 2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .",
"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK64___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .",
"Binding of C / EBPbeta to the P02741 ( CRP ) promoter in Hep3B cells is associated with transcription of CRP mRNA . Expression of the acute phase protein P02741 ( CRP ) is tightly regulated in hepatocytes . Although very little CRP mRNA is transcribed normally , inflammatory stimuli are followed by a dramatic increase in mRNA synthesis and accumulation . P05231 and IL - 1beta are believed to be the major cytokines responsible for induction of CRP and other acute phase proteins . Our previous studies , using transient transfection and EMSA experiments , implicated involvement of the transcription factors C / EBPbeta , P40763 , Rel p50 , and c - Rel in CRP induction . In the current study we used chromatin immunoprecipitation assays to determine the kinetics of transcription factor occupancy of these transcription factors on the endogenous CRP promoter . All of these transcription factors were found bound to the endogenous CRP promoter in the absence of cytokines , but cytokine treatment markedly increased binding of only C / EBPbeta . In addition , c - Rel and TATA box - binding protein ( P20226 ) appeared to occupy the promoter in parallel in the presence of cytokines . In the absence of cytokines , CRP mRNA accumulation was not measurable but began to increase by 3 h after exposure of cells to IL - 1beta plus P05231 , peaking at 12 h with secondary peaks at 18 and 24 h . The secondary peaks in mRNA expression paralleled the pattern of binding of c - Rel and P20226 to the CRP promoter . We conclude that the CRP promoter has a low level of transcription factor occupancy in the absence of cytokines and induction occurs with binding of C / EBP , and that c - Rel and P20226 are important for modulating CRP expression .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"Structure of the human Q9H244 receptor in complex with an antithrombotic drug . P2Y receptors ( P2YRs ) , a family of purinergic G - protein - coupled receptors ( GPCRs ) , are activated by extracellular nucleotides . There are a total of eight distinct functional P2YRs expressed in human , which are subdivided into P47900 - like receptors and Q9H244 - like receptors . Their ligands are generally charged molecules with relatively low bioavailability and stability in vivo , which limits our understanding of this receptor family . P2Y12R regulates platelet activation and thrombus formation , and several antithrombotic drugs targeting P2Y12R -- including the prodrugs clopidogrel ( Plavix ) and prasugrel ( ___MASK83___ ) that are metabolized and bind covalently , and the nucleoside analogue ticagrelor ( DB08816 ) that acts directly on the receptor -- have been approved for the prevention of stroke and myocardial infarction . However , limitations of these drugs ( for example , a very long half - life of clopidogrel action and a characteristic adverse effect profile of ticagrelor ) suggest that there is an unfulfilled medical need for developing a new generation of P2Y12R inhibitors . Here we report the 2 . 6 Å resolution crystal structure of human P2Y12R in complex with a non - nucleotide reversible antagonist , AZD1283 . The structure reveals a distinct straight conformation of helix V , which sets P2Y12R apart from all other known class A GPCR structures . With AZD1283 bound , the highly conserved disulphide bridge in GPCRs between helix III and extracellular loop 2 is not observed and appears to be dynamic . Along with the details of the AZD1283 - binding site , analysis of the extracellular interface reveals an adjacent ligand - binding region and suggests that both pockets could be required for dinucleotide binding . The structure provides essential insights for the development of improved P2Y12R ligands and allosteric modulators as drug candidates .",
"___MASK52___ and bortezomib synergistically cause ubiquitinated protein accumulation in prostate cancer cells . PURPOSE : Protein ubiquitination is a novel strategy used to treat malignancies . We investigated whether the histone deacetylase inhibitor vorinostat ( Cayman Chemical , Ann Arbor , Michigan ) and the proteasome inhibitor bortezomib ( LC Laboratories , Woburn , Massachusetts ) would synergistically cause the accumulation of ubiquitinated proteins in prostate cancer cells . MATERIALS AND METHODS : LNCaP , PC - 3 and DU 145 cells ( ATCC ™ ) were treated with vorinostat and / or bortezomib . Cell viability and induction of apoptosis were assessed . In vivo efficacy was evaluated in a murine subcutaneous tumor model using PC - 3 cells . The influence of androgen receptor expression on bortezomib efficacy was examined using RNA interference . Changes in the expression of ubiquitinated proteins , cell cycle associated proteins and acetylated histone were evaluated . RESULTS : P10275 expression seemed to decrease bortezomib activity . PC - 3 and DU 145 cells were more susceptible to bortezomib than LNCaP cells and the silencing of androgen receptor expression in LNCaP cells enhanced bortezomib activity . ___MASK52___ and bortezomib synergistically induced apoptosis , inhibited prostate cancer cell growth and suppressed tumor growth in a murine xenograft model . The combination decreased cyclin D1 and cyclin - dependent kinase 4 expression , and increased P38936 expression . The combination synergistically caused the accumulation of ubiquitinated proteins and histone acetylation . This histone acetylation was a consequence of the accumulation of ubiquitinated proteins . CONCLUSIONS : ___MASK52___ and bortezomib inhibit the growth of prostate cancer cells synergistically by causing ubiquitinated proteins to accumulate in cells . The current study provides a framework for testing the combination in patients with advanced prostate cancer .",
"Overexpression of tumor necrosis factor ( P01375 ) - alpha and interferon ( IFN ) - gamma by bone marrow cells from patients with myelodysplastic syndromes . To clarify whether regulatory cytokines inhibit hematopoiesis in patients with myelodysplastic syndromes ( P43034 ) , malignancies characterized by the formation of cytopenias despite the presence of cellular bone marrow , expression of P01375 and P01579 by bone marrow cells was investigated using specific reverse transcriptase - polymerase chain reaction assays . An enhanced expression of the mRNA for P01375 was observed in most of the samples from P43034 patients ( 11 / 14 , 79 % ) , whereas no enhancement was observed in bone marrow samples from AML ( 0 / 6 ) , CML ( 0 / 2 ) or control cases ( 0 / 8 ) . The expression of P01579 was also enhanced in some of P43034 cases ( 5 / 12 , 42 % ) while AML ( 0 / 5 ) , CML ( 0 / 2 ) and control cases ( 0 / 6 ) showed very low levels of P01579 mRNA expression . Immunohistochemical examination confirmed the scattered presence of P01375 or P01579 producing cells in the bone marrow of P43034 patients . The majority of these cells were P34810 - positive macrophage lineage cells . These results suggested that disruption of hematopoiesis in P43034 might be caused by enhanced production of inhibitory regulatory cytokines especially P01375 and occasionally P01579 by bone marrow macrophages .",
"A perforin / granzyme - positive P43034 - derived T cell line , K2 - P43034 , induces apoptosis in P28906 + cells through the fractalkine - P49238 system . P78423 ( P78423 ) and its receptor P49238 play an important role in natural killer ( NK ) cell - and cytotoxic T cell - mediated endothelium damage . Here we describe the cytotoxicity of myelodysplastic syndrome ( P43034 ) - derived T cell line , K2 - P43034 , through the fractalkine - P49238 system . K2 - P43034 cells induced apoptosis against P28906 (+) cells from normal bone marrow ( BM ) in a direct cell contact manner . K2 - P43034 cells expressed perforin and granzyme B , but they lacked P48023 expression . A specific inhibitor for perforin , concanamycin A , blocked K2 - P43034 - dependent cytotoxicity . Furthermore , a CX3C - chemokine , fractalkine , was expressed in P28906 (+) cells , and its receptor , P49238 , was expressed on K2 - P43034 cells . The neutralizing monoclonal antibody ( MoAb ) for fractalkine and soluble fractalkine significantly inhibited K2 - P43034 - dependent cytotoxicity . K2 - P43034 cells also induced the cytotoxicity against human umbilical cord endothelial cells ( HUVECs ) expressing fractalkine . These data indicate that K2 - P43034 may be a perforin - granzyme - positive T cell line that exerts a cytotoxic effect on P28906 (+) cells mediated through the fractalkine - P49238 system .",
"Secretome profiling reveals the signaling molecules of apoptotic HCT116 cells induced by the dietary polyacetylene gymnasterkoreayne B . Dietary polyacetylenes from various foods have been receiving attention as promising cancer chemopreventive agents . However , until now , the detailed molecular mechanism and the regulatory proteins underlying these effects have not been elucidated . We investigated the effects of gymnasterkoreayne B ( GKB ) , a model dietary polyacetylene from wild vegetables , on the programmed cell death of HCT116 human colorectal cancer cells . GKB inhibited HCT116 cell proliferation by inducing apoptotic cell death . GKB treatment resulted in ROS accumulation , leading to the activation of both intrinsic and extrinsic apoptotic pathway . We also found that P02751 , P01137 , P05067 , P05121 , P10809 , P00441 , P10599 , and O43707 may act as secretory signaling molecules during GKB - induced apoptotic cell death using LC - MS / MS identification followed by spectrum counting , statistical calculation , and gene ontology analysis . The secretory proteins suggested in this study may be promising candidates involved in apoptotic cell death of cancer cells induced by GKB that warrant further functional study .",
"No evidence of mutations of the P28074 ( beta - 5 subunit of proteasome ) in a case of myeloma with clinical resistance to DB00188 .",
"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK52___ ( ___MASK52___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK52___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK52___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .",
"Regulation of P28074 protein and β subunits of mammalian proteasome by constitutively activated signal transducer and activator of transcription 3 ( P40763 ) : potential role in bortezomib - mediated anticancer therapy . The ubiquitin - proteasome system facilitates the degradation of ubiquitin - tagged proteins and performs a regulatory role in cells . Elevated proteasome activity and subunit expression are found in several cancers . However , the inherent molecular mechanisms responsible for increased proteasome function in cancers remain unclear despite the well investigated and defined role of the mammalian proteasome . This study was initiated to elucidate the mechanisms involved in the regulation of β subunits of the mammalian proteasome . Suppression of P40763 tyrosine phosphorylation coordinately decreased the mRNA and protein levels of the β subunits of the 20 S core complex in DU145 cells . Notably , P28074 , a molecular target of bortezomib , was shown to be a target of P40763 . Knockdown of P40763 decreased P28074 protein . Inhibition of phospho - P40763 substantially reduced P28074 protein levels in cells expressing constitutively active - P40763 . Accumulation of activated P40763 resulted in the induction of P28074 promoter and protein levels . In addition , a direct correlation was observed between the endogenous levels of P28074 and constitutively active P40763 . P28074 and P40763 protein levels remained unaltered following the inhibition of proteasome activity . The P01133 - induced concerted increase of β subunits was blocked by inhibition of the P01133 receptor or P40763 but not by the PI3K / AKT or MEK / P29323 pathways . Decreased proteasome activities were due to reduced protein levels of catalytic subunits of the proteasome in P40763 - inhibited cells . Combined treatments with bortezomib and inhibitor of P40763 abrogated proteasome activity and enhanced cellular apoptosis . Overall , we demonstrate that aberrant activation of P40763 regulates the expression of β subunits , in particular P28074 , and the catalytic activity of the proteasome .",
"P78423 activates a signal transduction pathway similar to Q9H244 and is associated with impaired clopidogrel responsiveness . OBJECTIVE : P78423 ( P78423 ) activates a G ( αi ) protein - coupled signaling pathway similar to the one activated by ADP via P2Y ( 12 ) , which is the drug target of clopidogrel . P78423 levels are increased under several disease conditions associated with impaired clopidogrel responsiveness . METHODS AND RESULTS : Blood samples were obtained from healthy volunteers and from 40 patients under chronic clopidogrel treatment . P78423 reduced prostaglandin E1 - induced vasodilator - stimulated phosphoprotein phosphorylation by ≈ 25 % ( P < 0 . 01 ) at least partially mimicking the effect of ADP via P2Y ( 12 ) . In vitro , P78423 increased platelet reactivity index in clopidogrel - treated patients indicating potential activation of downstream targets of P2Y ( 12 ) . When stratifying patients by their P78423 levels , patients within the highest quartile of P78423 ( 2042 ± 25 pg / mL ) had the weakest response to clopidogrel ( platelet reactivity index , 68 ± 4 % ) , and patients within the lowest quartile ( 479 ± 50 pg / mL ) had the strongest response ( platelet reactivity index , 48 ± 7 % ; P = 0 . 0106 ) . P78423 by itself induced phosphoinositide 3 - kinase activation leading to Akt phosphorylation at DB00133 ( 473 ) ( P < 0 . 01 versus basal ) . CONCLUSIONS : In addition to desensitizing platelets to prostaglandin E1 via G ( αi ) , P78423 induces phosphoinositide 3 - kinase - dependent Akt phosphorylation via a G ( βγ ) protein similar to ADP signaling through P2Y ( 12 ) . P78423 increased the platelet ADP response in clopidogrel - treated patients . Once released from an atherosclerotic lesion , this mechanism could contribute locally to impaired clopidogrel responsiveness at the vulnerable plaque .",
"The role of tumor suppressor dysregulation in prostate cancer progression . P10275 activity is essential for prostate cancer development and progression . While there are classically defined roles for the retinoblastoma ( P06400 ) and p53 tumor suppressor pathways in maintenance of cell cycle control and the DNA damage response , recent studies have demonstrated a direct role of these two pathways in regulating AR expression and function . While the role of Pten deregulation in prostate cancer has provided much insight in to the mechanisms underlying prostate cancer initiation and progression , emerging roles for P06400 and p53 are likely to further expand upon our understanding of tumor suppressor / nuclear receptor interaction . As disconnecting mitogenic signaling from AR - mediated gene transcription underlies the progression to castrate resistant prostate cancer ( CRPC ) , functional inactivation of these two tumor suppressor pathways represents one mechanism through which AR protein levels can be upregulated and AR - mediated gene transcription can become aberrant . Importantly , recent advances in small molecule inhibitor design and discovery have led to the identification of agents capable of targeting these two prominent pathways and restoring the function of deregulated wild - type P06400 and p53 protein . While such agents have undergone extensive study in many solid tumor types , the additional importance of P06400 and p53 in restraining transcription of the AR gene within the prostate provides impetus for examining how loss of these two tumor suppressor proteins can facilitate transition of prostate cancers to CRPC . As will be reviewed in this article , restoration of P06400 and p53 functions are not only important in regard to shortterm cell cycle regulation and response to genomic stresses , but likely have direct implications for deregulation of the AR locus .",
"Cytotoxic effects of bortezomib in myelodysplastic syndrome / acute myeloid leukemia depend on autophagy - mediated lysosomal degradation of Q9Y4K3 and repression of P25786 . DB00188 ( Velcade ) is used widely for the treatment of various human cancers ; however , its mechanisms of action are not fully understood , particularly in myeloid malignancies . DB00188 is a selective and reversible inhibitor of the proteasome . Paradoxically , we find that bortezomib induces proteasome - independent degradation of the Q9Y4K3 protein , but not mRNA , in myelodysplastic syndrome ( P43034 ) and acute myeloid leukemia ( AML ) cell lines and primary cells . The reduction in Q9Y4K3 protein coincides with bortezomib - induced autophagy , and subsequently with apoptosis in P43034 / AML cells . RNAi - mediated knockdown of Q9Y4K3 sensitized bortezomib - sensitive and - resistant cell lines , underscoring the importance of Q9Y4K3 in bortezomib - induced cytotoxicity . DB00188 - resistant cells expressing an shRNA targeting Q9Y4K3 were resensitized to the cytotoxic effects of bortezomib due to down - regulation of the proteasomal subunit α - 1 ( P25786 ) . To determine the molecular consequences of loss of Q9Y4K3 in P43034 / AML cells , in the present study , we applied gene - expression profiling and identified an apoptosis gene signature . Knockdown of Q9Y4K3 in P43034 / AML cell lines or patient samples resulted in rapid apoptosis and impaired malignant hematopoietic stem / progenitor function . In summary , we describe herein novel mechanisms by which Q9Y4K3 is regulated through bortezomib / autophagy - mediated degradation and by which it alters P43034 / AML sensitivity to bortezomib by controlling P25786 expression .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK92___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"Immunoaffinity purification of the functional 20S proteasome from human cells via transient overexpression of specific proteasome subunits . The proteasome is a multi - subunit proteolytic complex that plays a central role in protein degradation in all eukaryotic cells . It regulates many vital cellular processes therefore its dysfunction can lead to various pathologies including cancer and neurodegeneration . Isolation of enzymatically active proteasomes is a key step to the successful study of the proteasome regulation and functions . Here we describe a simple and efficient protocol for immunoaffinity purification of the functional 20S proteasomes from human P29320 293T cells after transient overexpression of specific proteasome subunits tagged with 3xFLAG . To construct 3xFLAG - fusion proteins , DNA sequences encoding the 20S proteasome subunits P28074 , P28066 , and P25788 were cloned into mammalian expression vector pIRES - hrGFP - 1a . The corresponding recombinant proteins P28074 - 3xFLAG , P28066 - 3xFLAG , or P25788 - 3xFLAG were transiently overexpressed in human P29320 293T cells and were shown to be partially incorporated into the intact proteasome complexes . 20S proteasomes were immunoprecipitated from P29320 293T cell extracts under mild conditions using antibodies against FLAG peptide . Isolation of highly purified 20S proteasomes were confirmed by SDS - PAGE and Western blotting using antibodies against different proteasome subunits . Affinity purified 20S proteasomes were shown to possess chymotrypsin - and trypsin - like peptidase activities confirming their functionality . This simple single - step affinity method of the 20S proteasome purification can be instrumental to subsequent functional studies of proteasomes in human cells .",
"Nuclear Nox4 - derived reactive oxygen species in myelodysplastic syndromes . A role for intracellular ROS production has been recently implicated in the pathogenesis and progression of a wide variety of neoplasias . ROS sources , such as NAD ( P ) H oxidase ( Nox ) complexes , are frequently activated in AML ( acute myeloid leukemia ) blasts and strongly contribute to their proliferation , survival , and drug resistance . Myelodysplastic syndromes ( P43034 ) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis , with an increased propensity to develop AML . The molecular basis for P43034 progression is unknown , but a key element in P43034 disease progression is the genomic instability . NADPH oxidases are now recognized to have specific subcellular localizations , this targeting to specific compartments for localized ROS production . Local Nox - dependent ROS production in the nucleus may contribute to the regulation of redox - dependent cell growth , differentiation , senescence , DNA damage , and apoptosis . We observed that Nox1 , 2 , and 4 isoforms and P13498 and Rac1 subunits are expressed in P43034 / AML cell lines and P43034 samples , also in the nuclear fractions . Interestingly , Nox4 interacts with P29323 and Akt1 within nuclear speckle domain , suggesting that Nox4 could be involved in regulating gene expression and splicing factor activity . These data contribute to the elucidation of the molecular mechanisms used by nuclear ROS to drive P43034 evolution to AML .",
"Overexpression of SnoN / SkiL , amplified at the 3q26 . 2 locus , in ovarian cancers : a role in ovarian pathogenesis . High - resolution array comparative genomic hybridization of 235 serous epithelial ovarian cancers demonstrated a regional increase at 3q26 . 2 encompassing SnoN / SkiL , a coregulator of SMAD / TGFbeta signaling . SnoN RNA transcripts were elevated in approximately 80 % of advanced stage serous epithelial ovarian cancers . In both immortalized normal ( TIOSE ) and ovarian carcinoma cell lines ( OVCA ) , SnoN RNA levels were increased by TGFbeta stimulation and altered by LY294002 and JNK II inhibitor treatment suggesting that the PI3K and JNK signaling pathways may regulate TGFbeta - induced increases in SnoN RNA . In TIOSE , SnoN protein levels were reduced 15min post TGFbeta - stimulation , likely by proteosome - mediated degradation . In contrast , in OVCA , SnoN levels were elevated 3h post - stimulation potentially as a result of inhibition of the proteosome . To elucidate the role of SnoN in ovarian tumorigenesis , we explored the effects of both increasing and decreasing SnoN levels . In both TIOSE and OVCA , SnoN siRNA decreased cell growth between 20 and 50 % concurrent with increased P38936 levels . In TIOSE , transient expression of SnoN repressed TGFbeta induction of P05121 promoters with little effect on the P38936 promoter or resultant cell growth . In contrast to the effects of transient expression , stable expression of SnoN in TIOSE led to growth arrest through induction of senescence . Collectively , these results implicate SnoN levels in multiple roles during ovarian carcinogenesis : promoting cellular proliferation in ovarian cancer cells and as a positive mediator of cell cycle arrest and senescence in non - transformed ovarian epithelial cells .",
"Histone deacetylase inhibitors increase microRNA - 146a expression and enhance negative regulation of interleukin - 1β signaling in osteoarthritis fibroblast - like synoviocytes . OBJECTIVE : MiR - 146a exerts negative control on inflammatory responses by suppressing cytokine - induced expression of interleukin - 1 receptor - associated kinase - 1 ( P51617 ) and tumor necrosis factor receptor - associated factor 6 ( Q9Y4K3 ) by impairing NF - κB activity and inhibiting the expression of target genes . Recent study suggests that histone deacetylases ( HDACs ) are involved in the regulation of microRNA ( miRNA ) expression . Therefore , we determined whether HDAC inhibitors can increase miR - 146a expression , thereby inhibiting interleukin - 1β ( IL - 1β ) - induced signaling in osteoarthritis fibroblast - like synoviocytes ( OA - FLS ) . METHOD : MiRNA expression was analyzed using real - time PCR . IL - 1β - induced downstream signals and cytokine expression were evaluated using Western blotting and ELISA . Transcription factors regulating promoter activation were identified using chromatin immunoprecipitation assays . RESULTS : IL - 1β treatment of OA - FLS induced a mild ( 1 . 7 - fold ) increase in miR - 146a expression that was unable to appropriately downregulate P51617 and Q9Y4K3 expression . HDAC inhibitors , ___MASK52___ ( vorinostat ) , and LBH589 ( DB06603 ) significantly ( 6 . 1 - and 5 . 4 - fold ) elevated miR - 146a expression by increasing the binding of the transcription factor NF - κB to the miR - 146a promoter , and negatively regulated IL - 1β - induced IKK / IκB / p65 phosphorylation signaling and P05231 secretion . The increase in miR - 146a expression induced by the HDAC inhibitors was prevented by transfection of miR - 146a inhibitor or Q13547 ( class I HDAC ) , P56524 ( class IIa HDAC ) , and Q9UBN7 ( class IIb HDAC ) overexpression , suggesting that they were due to inhibition of HDAC activity . CONCLUSIONS : Our study demonstrated that HDAC inhibitor treatment in OA - FLS significantly increased miR - 146a expression and mediated markedly negative regulation to inhibit IL - 1β - induced signaling and cytokine secretion . Our results indicate the potential rationale of anti - inflammatory effects for HDAC inhibitors .",
"Analysis of a 26 - kb region linked to the Mhc in zebrafish : genomic organization of the proteasome component beta / transporter associated with antigen processing - 2 gene cluster and identification of five new proteasome beta subunit genes . Sequencing of zebrafish ( Danio rerio ) bacterial artificial chromosome and P1 artificial chromosome genomic clone fragments and of cDNA clones has led to the identification of five new loci coding for beta subunits of proteasomes ( PSMB ) . Together with the four genes identified previously , nine PSMB genes have now been defined in the zebrafish . Six of the nine genes reside in the zebrafish MHC ( Mhc ) class I region , four of them reside in a single cluster closely associated with TAP2 on a 26 - kb long genomic fragment , and two reside at some distance from the fragment . In addition to homologues of the human genes P28074 through P28065 , two new genes , A5LHX3 and PSMB12 , have been found for which there are no known corresponding genes in humans . The new genes reside in the PSMB cluster in the Mhc . Homology and promoter region analysis suggest that the Mhc - associated genes might be inducible by P01579 . The zebrafish class I region contains representatives of three phylogenetically distinguishable groups of PSMB genes , X , Y , and Z . It is proposed that these genes were present in the ancestral PSMB region before Mhc class I genes became associated with it .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Synthetic delivery system for tuberculosis vaccines : immunological evaluation of the M . tuberculosis 38 kDa protein entrapped in biodegradable P00747 microparticles . Tuberculosis remains a major public health burden which could be ameliorated by effective and well - defined subunit vaccines , particularly because the protective efficacy of current M . bovis BCG vaccines is both unpredictable and variable . The immunodominant 38 kDa antigen from Mycobacterium tuberculosis was entrapped in biodegradable poly ( DL - lactide co - glycolide ) ( P00747 ) microparticles which served as a delivery system . Both cellular and humoral immune responses were assessed and compared with those obtained after immunization with the 38 kDa protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . Vaccination of mice with a single dose of antigen - loaded microparticles resulted in specific IgG titres peaking after five weeks comparable to those achieved after vaccination with protein emulsified in incomplete Freund ' s adjuvant ( IFA ) . T - cell responses were found to be superior to those induced with antigen / IFA . The T - and B - cell epitope specificities ad judged with synthetic peptides were identical following immunization with antigen in microparticles or IFA . Differences in adjuvanticity were revealed by measuring antigen - specific IgG1 , IgG2a and antigen - induced P01579 secretion in vitro : substantially higher titres of IgG2a were observed following immunization with antigen / microparticles than with 38 kDa protein / IFA . This was paralleled by a tenfold higher secretion of P01579 in mice injected with antigen / microparticles . Reduction in colony - forming units was not consistent in mice immunized with 38 kDa protein entrapped in microparticles which were subsequently infected with live tubercle bacilli . Taken together these results indicate that biodegradable P00747 microparticles constitute a favorable candidate vaccine delivery system worthy of further assessment in the quest to develop better and defined agents protecting against tuberculosis .",
"Knockdown of human deubiquitinase O00487 induces cell cycle arrest and senescence . The O00487 ( O00487 , also known as Rpn11 / MPR1 / S13 / CepP1 ) protein within the 19S complex ( 19S cap ; PA700 ) is responsible for substrate deubiquitination during proteasomal degradation . The role of O00487 in cell proliferation and senescence was explored using siRNA knockdown in carcinoma cell lines . Our results reveal that down - regulation of O00487 by siRNA transfection had a considerable impact on cell viability causing cell arrest in the G0 - P55008 phase , ultimately leading to senescence . The molecular events associated with decreased cell proliferation , cell cycle arrest and senescence include down - regulation of cyclin B1 - P06493 - P30307 , down - regulation of cyclin D1 and up - regulation of P38936 (/ Cip ) and p27 (/ Kip1 ) . Most notably , phosphorylation of the retinoblastoma protein was markedly reduced in O00487 knockdown cells . A comparative study with P28074 , a subunit of the 20S proteasome , revealed that P28074 and O00487 have different effects on cell cycle , senescence and associated molecular events . These data support the view that the 19S and 20S subunits of the proteasome have distinct biological functions and imply that targeting 19S and 20S would have distinct molecular consequences on tumor cells .",
"Point mutation of the proteasome beta5 subunit gene is an important mechanism of bortezomib resistance in bortezomib - selected variants of Jurkat T cell lymphoblastic lymphoma / leukemia line . To study the mechanism of acquired resistance to bortezomib , a new antitumor drug that is the first therapeutic proteasome inhibitor , we established a series of bortezomib - resistant T lymphoblastic lymphoma / leukemia cell lines , designated the JurkatBs , from the parental Jurkat line via repeated drug selection . There were no significant differences in the growth curves or colony formation between the JurkatB cells and parental Jurkat cells . The effects of bortezomib on cytotoxicity , cell cycle arrest , and induction of apoptosis were decreased in JurkatB cells compared with parental Jurkat cells . A mutation in the proteasome beta5 subunit ( P28074 ) gene ( G322A ) , which encodes an amino acid change from Ala to DB00156 at polypeptide position 108 , was detected by sequencing full - length cDNA clones and direct polymerase chain reaction products of the P28074 gene . DB00188 caused less inhibition of chymotrypsin - like activity in resistant cells . When the G322A mutant P28074 was retrovirally introduced into parental Jurkat cells , it conferred bortezomib resistance to these cells , resulting in decreased cytotoxicity , apoptosis , and inhibition of chymotrypsin - like activity . The predicted structure of A108T - mutated P28074 shows a conformational change that suggests decreased affinity to bortezomib . In short , the G322A mutation of the P28074 gene is a novel mechanism for bortezomib resistance .",
"Proteasomal serine hydrolases are up - regulated by and required for influenza virus infection . Interactions between viruses and their host cells are important determinants of virus replication and of immune responses to the virus . However , these interactions and resulting consequences of these interactions remain poorly defined . Numerous recent quantitative proteomic approaches have measured host proteins affected by virus infection . Here , we used activity - based protein profiling ( P05067 ) to measure functional alterations in host serine hydrolases after influenza A virus infection of Madin - Darby canine kidney and human A549 lung cells . We identified 62 serine proteases . We then combined the P05067 approach with stable isotope labeling to directly measure how serine hydrolase activities were affected by virus infection . Differentially regulated SHs mapped into a few key cellular pathway systems , most notably the proteasomal system . The specific serine protease inhibitors DB06692 and Pefablock and specific proteasomal inhibitors DB00188 and MG132 significantly inhibited influenza virus growth . Some inhibitors also down - regulated activities of several proteasomal proteins , including P25786 , P25787 , and PMSB3 . Genetic knockdown of PMSA2 also attenuated influenza virus replication . These findings further our understanding of enzymatic cellular processes affected by influenza virus and may be beneficial in the search for additional antiviral therapeutic targets .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK83___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"Interrelation of inflammation and P05067 in sIBM : P01584 induces accumulation of beta - amyloid in skeletal muscle . Distinct interrelationships between inflammation and beta - amyloid - associated degeneration , the two major hallmarks of the skeletal muscle pathology in sporadic inclusion body myositis ( sIBM ) , have remained elusive . Expression of markers relevant for these pathomechanisms were analysed in biopsies of sIBM , polymyositis ( PM ) , dermatomyositis ( DM ) , dystrophic and non - myopathic muscle as controls , and cultured human myotubes . By quantitative PCR , a higher upregulation was noted for the mRNA - expression of CXCL - 9 , DB00833 - 3 , DB00833 - 4 , P01579 , P01375 and P01584 in sIBM muscle compared to PM , DM and controls . All inflammatory myopathies displayed overexpression of degeneration - associated markers , yet only in sIBM , expression of the mRNA of amyloid precursor protein ( P05067 ) significantly and consistently correlated with inflammation in the muscle and mRNA - levels of chemokines and P01579 . Only in sIBM , immunohistochemical analysis revealed that inflammatory mediators including P01584 co - localized to beta - amyloid depositions within myofibres . In human myotubes , exposure to P01584 caused upregulation of P05067 with subsequent intracellular aggregation of beta - amyloid . Our data suggest that , in sIBM muscle , production of high amounts of pro - inflammatory mediators specifically induces beta - amyloid - associated degeneration . The observations may help to design targeted treatment strategies for chronic inflammatory disorders of the skeletal muscle .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"Strain dependence of receptor regulation on chemical preconditioning in mice hippocampus . While one current focus for studying mechanisms of disease is investigation of transgenic mice confounding effects of the background strain often are neglected . We investigated mRNA expression of known markers of hypoxic tolerance by a semiquantitative RT - PCR ( adenosine receptors ( A1 and A3 ) , nitric oxide synthases ( P29474 and P29475 ) , P05067 production , progesterone receptor , and estrogen receptors alpha and beta ) in CD - 1 , C3H , and B6 mice . We found differences in the baseline mRNA expression of adenosine A3 receptors in C3H mice and neuronal NOS in B6 mice as well as a distinct regulation of adenosine A3 receptors and estrogen receptor beta ( no changes in C3H and B6 compared to upregulation in CD - 1 ) on treatment of animals with a low dosage of 3 - nitropropionate ( 20mg / kg body weight , i . p . ) . We conclude that the choice of background strain may confound interpretation of the effects of specific transgens in the study of the mechanisms of primary and induced hypoxic tolerance .",
"Production and characterization of monoclonal antibodies against urea derivatives . A panel of monoclonal antibodies was generated against the urea - based hapten N -( 2 - N - chloroacetylaminobenzyl )- N '- 4 - chlorophenylurea as a tool for building up sensitive immune assays to detect urea derivatives and to screen them for catalytic antibodies ( Abs ) . Eleven hybridomas were obtained that produced Abs reactive to the hapten . All Abs were of IgG class . Cross reactivities of the Abs to different haptens were examined , especially to a possible transition - state analog . Only four of the hybridomas ( R2 - DA10 / P08709 , R2 - GE7 / H2 , R2 - P25786 / A5 , R2 - Q9UBN7 / P08709 ) produced Abs crossreactive with the transition - state analog . From the 11 hybridomas , hybridoma B76 - BF5 was chosen for further characterization . Compared to the other Abs , B76 - BF5 showed the strongest binding and had a rather restricted specificity . These Abs could be used to build up a sensitive enzyme immunoassay for the detection of the hapten . All Abs were screened for crossreactivity with the pesticides monuron and diuron . No reactivity could be detected . In addition , the nucleotide sequences of the variable light and heavy chain genes of the similarly reactive Abs B76 - BF5 , B76 - BB3 , R2 - DA10 / P08709 , and R2 - GA6 / P46379 were determined to clarify whether structure and binding specificity of these Abs showed any correlation ."
] |
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___MASK91___
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MH_train_468
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interacts_with DB01367?
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[
"Hyperosmolar mannitol simulates expression of aquaporins 4 and 9 through a p38 mitogen - activated protein kinase - dependent pathway in rat astrocytes . The membrane pore proteins , aquaporins ( AQPs ) , facilitate the osmotically driven passage of water and , in some instances , small solutes . Under hyperosmotic conditions , the expression of some AQPs changes , and some studies have shown that the expression of P29972 and P55064 is regulated by MAPKs . However , the mechanisms regulating the expression of P55087 and AQP9 induced by hyperosmotic stress are poorly understood . In this study , we observed that hyperosmotic stress induced by mannitol increased the expression of P55087 and AQP9 in cultured rat astrocytes , and intraperitoneal infusion of mannitol increased P55087 and AQP9 in the rat brain cortex . In addition , a p38 MAPK inhibitor , but not P29323 and JNK inhibitors , suppressed their expression in cultured astrocytes . AQPs play important roles in maintaining brain homeostasis . The expression of P55087 and AQP9 in astrocytes changes after brain ischemia or traumatic injury , and some studies have shown that p38 MAPK in astrocytes is activated under similar conditions . Since mannitol is commonly used to reduce brain edema , understanding the regulation of AQPs and p38 MAPK in astrocytes under hyperosmotic conditions induced with mannitol may lead to a control of water movements and a new treatment for brain edema .",
"Repression of P10415 by the tumor suppressor activity of the lysyl oxidase propeptide inhibits transformed phenotype of lung and pancreatic cancer cells . The gene encoding lysyl oxidase ( P28300 ) was identified as the ras recision gene ( rrg ) , with the ability to revert Ras - mediated transformation of NIH 3T3 fibroblasts . Mutations in DB01367 genes have been found in approximately 25 % of lung cancers and in 85 % of pancreatic cancers . In microarray analysis , these cancers were found to display reduced P28300 gene expression . Thus , the ability of the P28300 gene to repress the transformed phenotype of these cancer cells was tested . P28300 is synthesized as a 50 - kDa secreted precursor Pro - P28300 that is processed to the 32 - kDa active enzyme ( P28300 ) and to an 18 - kDa propeptide ( P28300 - PP ) . Recently , we mapped the rrg activity of Pro - P28300 to the P28300 - PP in Ras - transformed NIH 3T3 cells . Ectopic Pro - P28300 and P28300 - PP expression in H1299 lung cancer cells inhibited growth in soft agar and invasive colony formation in Matrigel and reduced activation of extracellular signal - regulated kinase ( P29323 ) and Akt , with P28300 - PP showing substantially higher activity . Similarly , P28300 - PP expression in PANC - 1 pancreatic cancer cells effectively reduced P29323 and Akt activity and inhibited growth in soft agar and ability of these cells to migrate . Nuclear Factor - kappaB ( NF - kappaB ) and its target gene P10415 , which are overexpressed in 70 % to 75 % of pancreatic cancers , have recently been implicated in invasive phenotype . P28300 - PP substantially reduced NF - kappaB and Bcl - 2 levels . Reintroduction of Bcl - 2 into PANC - 1 or H1299 cells expressing P28300 - PP restored the transformed phenotype , suggesting that Bcl - 2 is an essential target . Thus , P28300 - PP potently inhibits invasive phenotype of lung and pancreatic cancer cells , suggesting potential therapeutic applications in treatment of these cancers .",
"Obestatin stimulates Akt signalling in gastric cancer cells through beta - arrestin - mediated epidermal growth factor receptor transactivation . Obestatin was identified as a gut peptide encoded by the ghrelin gene that interacts with the G protein - coupled receptor , O43194 . In this work , a sequential analysis of its transmembrane signalling pathway has been undertaken to characterize the intracellular mechanisms responsible for Akt activation . The results show that Akt activation requires the phosphorylation of T308 in the A - loop by the phosphoinositide - dependent kinase 1 ( PDK1 ) and S473 within the HM by the mammalian target of rapamycin ( P42345 ) kinase complex 2 ( mTORC2 : Rictor , Q9BVC4 , mSin1 , P42345 kinase ) with participation neither of G ( i )(/ o )- protein nor Gbetagamma dimers . Obestatin induces the association of O43194 / beta - arrestin 1 / Src signalling complex resulting in the transactivation of the epidermal growth factor receptor ( P00533 ) and downstream Akt signalling . Upon administration of obestatin , phosphorylation of P42345 ( S2448 ) and p70S6K1 ( T389 ) rise with a time course that parallels that of Akt activation . Based on the experimental data obtained , a signalling pathway involving a beta - arrestin 1 scaffolding complex and P00533 to activate Akt signalling is proposed .",
"Peroxisome proliferator activated receptor alpha inhibits hepatocarcinogenesis through mediating NF - κB signaling pathway . Q07869 ( PPARα ) ligands have been reported to suppress cancer growth . However , the role of PPARα in hepatocarcinogenesis remains unclear . We investigated the functional significance of PPARα in HCC . PPARα - knockout ( PPARα -/- ) mice were more susceptible to diethylnitrosamine ( DEN ) - induced HCC at 6 months compared with wild - type ( WT ) littermates ( 80 % versus 43 % , P < 0 . 05 ) . In resected HCCs , TUNEL - positive apoptotic cells were significantly less in PPARα -/- mice than in WT mice ( P < 0 . 01 ) , commensurate with a reduction in cleaved caspase - 3 and caspase - 7 protein expression . Ki - 67 staining showed increased cell proliferation in PPARα -/- mice ( P < 0 . 01 ) , with concomitant up - regulation of cyclin - D1 and down - regulation of p15 . Moreover , ectopic expression of PPARα in HCC cells significantly suppressed cell proliferation and induced apoptosis . The anti - tumorigenic function of PPARα was mediated via NF - κB as evidenced by inhibition of NF - κB promoter activity , diminution of phosphor - p65 , phosphor - p50 and P10415 levels , and enhancing IkBα protein . Chromatin immunoprecipitation analysis confirmed PPARαdirectly binds to the IkBα promoter . In conclusion , PPARα deficiency enhances susceptibility to DEN - initiated HCC . PPARα suppresses tumor cell growth by inhibiting cell proliferation and inducing cell apoptosis via direct targeting IκBα and NF - κB signaling pathway .",
"Pretreatment of sildenafil attenuates ischemia - reperfusion renal injury in rats . ___MASK99___ was the first selective inhibitor of phosphodiesterase - 5 ( O76074 ) to be widely used for treating erectile dysfunction . Many recent studies have investigated the cardioprotective role of sildenafil in animal models . We evaluated the protective effects of sildenafil in experimental renal ischemia - reperfusion ( IR ) injury in two studies . In study 1 , male Sprague - Dawley rats were divided into four groups : sham , sildenafil - treated sham , vehicle - treated IR , and sildenafil - treated IR groups . In study 2 , we divided the rats into two groups : sildenafil - treated IR rats and PD98059 ( P29323 inhibitor ) + sildenafil - treated IR rats . Functional parameters of the kidney were evaluated at the molecular and structural levels . Blood urea nitrogen ( BUN ) and serum creatinine levels were lower in sildenafil - treated IR rats than in vehicle - treated IR rats . The expression of inducible ( P35228 ) and endothelial nitric oxide synthase ( P29474 ) proteins in sildenafil - treated IR rats was significantly higher than in vehicle - treated IR rats . Pretreatment with sildenafil in IR rats increased P29323 phosphorylation and reduced the renal Bax / Bcl - 2 ratio , renal caspase - 3 activity , and terminal dUTP nick end - labeling - positive apoptotic cells . In contrast , PD98059 treatment increased BUN and serum creatinine levels and attenuated the sildenafil - induced expression of pERK , P35228 , P29474 , and Bcl - 2 . PD98059 also increased caspase - 3 activity but did not decrease the sildenafil - induced accumulation of cGMP . In conclusion , this study suggests that sildenafil has antiapoptotic effects in experimental IR renal injury via P29323 phosphorylation , induction of P35228 and P29474 production , and a decrease in the Bax / Bcl - 2 ratio .",
"Unbiased screen for interactors of leucine - rich repeat kinase 2 supports a common pathway for sporadic and familial Parkinson disease . Mutations in leucine - rich repeat kinase 2 ( Q5S007 ) cause inherited Parkinson disease ( PD ) , and common variants around Q5S007 are a risk factor for sporadic PD . Using protein - protein interaction arrays , we identified P10415 - associated athanogene 5 , Rab7L1 ( P51149 , member DB01367 oncogene family - like 1 ) , and O14976 as binding partners of Q5S007 . The latter two genes are candidate genes for risk for sporadic PD identified by genome - wide association studies . These proteins form a complex that promotes clearance of Golgi - derived vesicles through the autophagy - lysosome system both in vitro and in vivo . We propose that three different genes for PD have a common biological function . More generally , data integration from multiple unbiased screens can provide insight into human disease mechanisms .",
"Risk stratification of intermediate - risk acute myeloid leukemia : integrative analysis of a multitude of gene mutation and gene expression markers . Numerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia ( AML ) . It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance . Gene expression profiling was conducted in a well - characterized cohort of 439 AML patients ( age < 60 years ) to determine expression levels of EVI1 , P19544 , P10415 , P08183 , Q8WXS3 , P36888 , P28906 , P14902 , ERG and Q10571 . A variety of AML - specific mutations were evaluated , that is , P36888 , P06748 , N - DB01367 , K - DB01367 , O75874 , P48735 , and P49715 ( DM / SM ) ( double / single ) . Univariable survival analysis shows that ( 1 ) patients with P36888 ( ITD ) mutations have inferior overall survival ( OS ) and event - free survival ( O43281 ) , whereas P49715 ( DM ) and P06748 mutations indicate favorable OS and O43281 in intermediate - risk AML , and ( 2 ) high transcript levels of Q8WXS3 , P28906 , Q10571 , EVl1 , and ERG predict inferior OS and O43281 . In multivariable survival analysis , P28906 , ERG , and P49715 ( DM ) remain significant . Using survival tree and regression methodologies , we show that P49715 ( DM ) , P28906 , and P48735 mutations are capable of separating the intermediate group into 2 AML subgroups with highly distinctive survival characteristics ( OS at 60 months : 51 . 9 % vs 14 . 9 % ) . The integrated statistical approach demonstrates that from the multitude of biomarkers a greatly condensed subset can be selected for improved stratification of intermediate - risk AML .",
"Cooperative Hedgehog - P00533 signaling . It has been known for many years that cooperative interactions between oncogenes ( e . g . DB01367 , MYC , P10415 ) can fuel cancer growth ( 1 - 5 ) , but the restricted druggability of many of those interacting cancer genes has hampered translation of combined targeting to medical cancer therapy . The identification and characterization of cooperative cancer signaling pathways amenable to medical therapy is therefore a crucial step towards the establishment of efficient targeted combination treatments urgently needed to improve cancer therapy . Here we review recent findings of our group and colleagues on the molecular mechanisms of cooperative Hedgehog / P08151 and Epidermal Growth Factor Receptor ( P00533 ) signaling , two clinically relevant oncogenic pathways involved in the development of many human malignancies . We also discuss the possible implications of these findings for the design of a therapeutic regimen relying on combined targeting of key effectors of both pathways .",
"Q9H244 receptor signalling towards P31749 proceeds through P08069 cross - talk and requires activation of Src , Pyk2 and Rap1 . Previously it was shown that stimulation of the Q9H244 receptor activates P31749 signalling in P13671 glioma cells [ K . Van Kolen and H . Slegers , J . Neurochem . 89 , 442 . ] . In the present study , the mechanisms involved in this response were further elucidated . In cells transfected with the Gbetagamma - scavenger beta - O14965 / P25098 or Rap1GAPII , stimulation with 2MeSADP failed to enhance P31749 phosphorylation demonstrating that the signalling proceeds through Gbetagamma - subunits and Rap1 . Moreover , Rap1 - GTP pull - down assays revealed that Q9H244 receptor stimulation induced a rapid activation of Rap1 . Treatment of cells with the Ca2 + chelator BAPTA - AM and inhibition of Src and O14939 with Q99463 or 1 - butanol , respectively , abrogated Q9H244 receptor - mediated activation of Rap1 and P31749 . In addition inhibition of PKCzeta decreased basal and 2MeSADP - stimulated phosphorylation of P31749 indicating a role for this PKC isoform in P31749 signalling . Although the increased P31749 phosphorylation was abolished in the presence of the P08069 tyrosine kinase inhibitor AG 1024 , 2MeSADP did not significantly increase receptor phosphorylation . Nevertheless , phosphorylation of a 120 kDa P08069 - associated protein was observed . The latter protein was identified by MALDI - TOF / TOF - MS as the proline - rich tyrosine kinase 2 ( Pyk2 ) that co - operates with Src in a O14939 - dependent manner . Consistent with the signalling towards Rap1 and P31749 , activation of Pyk2 was abrogated by Ca2 + chelation , inhibition of O14939 and P08069 tyrosine kinase activity . In conclusion , the data reveal a novel type of cross - talk between Q9H244 and P05019 receptors that proceeds through Gbetagamma - , Ca2 +- and O14939 - dependent activation of the Pyk2 / Src pathway resulting in GTP - loading of Rap1 required for an increased P31749 phosphorylation .",
"The phosphotyrosine phosphatase eta mediates somatostatin inhibition of glioma proliferation via the dephosphorylation of P27361 / 2 . Somatostatin ( P61278 ) controls the proliferation of a variety of cell types . Its effects are mediated by five G protein - coupled receptors ( P30872 - P35346 ) , variably expressed in normal and cancer tissues . P61278 inhibition of cell proliferation can be exploited by both direct and indirect mechanisms : the main direct pathway involves the modulation of phosphotyrosine phosphatase ( PTP ) activity . Here we show that P61278 cytostatic activity is mediated by the activation of a receptor - like PTP , named PTPeta . The role of this PTP in the antiproliferative activity of P61278 in five glioma cell lines ( P13671 , U87MG , U373MG , DBTRG05MG , and CAS1 ) and in four postsurgical human glioblastoma specimens , has been studied . P61278 inhibited growth only in P13671 and U87MG that express PTPeta . In P13671 cells , P61278 antiproliferative effects were reverted by pretreatment with pertussis toxin and vanadate , indicating the involvement of G proteins and PTPs . The role of PTPeta in the P61278 inhibitory effects was demonstrated by testing the PTPeta activity : it was increased by P61278 treatment and paralleled by inhibition of P27361 / 2 activation . Since basic fibroblast growth factor - dependent MEK phosphorylation was not affected by P61278 , we propose a direct effect of P61278 - activated PTPeta on P27361 / 2 phosphorylation . Finally , the SSTR mRNAs were identified in all of the 36 gliomas analyzed , whereas PTPeta expression was found in 33 % of cases . Culturing four gliomas , a precise correlation between the expression of PTPeta and the P61278 antiproliferative effects was identified . In conclusion , in glioma cells , P61278 antiproliferative activity requires the expression and activation of PTPeta , which directly dephosphorylates P27361 / 2 .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK24___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK24___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK24___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK24___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK24___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"Reactive oxygen species , DNA damage , and error - prone repair : a model for genomic instability with progression in myeloid leukemia ? Myelodysplastic syndromes ( P43034 ) comprise a heterogeneous group of disorders characterized by ineffective hematopoiesis , with an increased propensity to develop acute myelogenous leukemia ( AML ) . The molecular basis for P43034 progression is unknown , but a key element in P43034 disease progression is loss of chromosomal material ( genomic instability ) . Using our two - step mouse model for myeloid leukemic disease progression involving overexpression of human mutant P01111 and P10415 genes , we show that there is a stepwise increase in the frequency of DNA damage leading to an increased frequency of error - prone repair of double - strand breaks ( DSB ) by nonhomologous end - joining . There is a concomitant increase in reactive oxygen species ( ROS ) in these transgenic mice with disease progression . Importantly , P63000 , an essential component of the ROS - producing NADPH oxidase , is downstream of DB01367 , and we show that ROS production in P01111 / P10415 mice is in part dependent on P63000 activity . DNA damage and error - prone repair can be decreased or reversed in vivo by N - acetyl cysteine antioxidant treatment . Our data link gene abnormalities to constitutive DNA damage and increased DSB repair errors in vivo and provide a mechanism for an increase in the error rate of DNA repair with P43034 disease progression . These data suggest treatment strategies that target DB01367 / P31749 pathways and ROS production in human P43034 / AML .",
"O14965 regulates O60674 - P40763 activity in human gastric and esophageal cancers . O14965 is a frequently amplified and overexpressed gene in upper gastrointestinal adenocarcinomas ( UGCs ) . Using in vitro cell models of UGCs , we investigated whether O14965 can regulate Signal Transducer and Activator of Transcription 3 ( P40763 ) . Our data indicate that overexpression of O14965 in FLO - 1 and AGS cells increase P40763 phosphorylation at the Tyr705 site , whereas O14965 genetic depletion by siRNA results in decreased phosphorylation levels of P40763 in FLO - 1 and MKN45 cells . Immunofluorescence analysis showed that O14965 overexpression enhanced P40763 nuclear translocation while O14965 genetic knockdown reduced the nuclear translocation of P40763 in AGS and FLO - 1 cells , respectively . Using a luciferase reporter assay , we demonstrated that O14965 expression induces transcriptional activity of P40763 . Pharmacological inhibition of O14965 by DB05220 reduced P40763 phosphorylation along with down - regulation of P40763 pro - survival targets , P10415 and Q07820 . Moreover , by using clonogenic cells survival assay , we showed that DB05220 single dose treatment reduced the ability of FLO - 1 and AGS cells to form colonies . Additional experiments utilizing cell models of overexpression and knockdown of O14965 indicated that P40763 upstream non - receptor tyrosine kinase O60674 ( O60674 ) is mediating the effect of O14965 on P40763 . The inhibition of O60674 using O60674 - specific inhibitor AZD1480 or siRNA knockdown , in presence of O14965 overexpression , abrogated the O14965 - mediated P40763 activation . These results confirm that the O14965 - O60674 axis is the main mechanism by which O14965 regulates P40763 activity . In conclusion , we report , for the first time , that O14965 promotes P40763 activity through regulating the expression and phosphorylation levels of O60674 . This highlights the importance of targeting O14965 as a therapeutic approach to treat gastric and esophageal cancers .",
"Methylation of the nonhomologous end joining repair pathway genes does not explain the increase of translocations with aging . Chromosome translocations are especially frequent in human lymphomas and leukemias but are insufficient to drive carcinogenesis . Indeed , several of the so - called tumor specific translocations have been detected in peripheral blood of healthy individuals , finding a higher frequency of some of them with aging . The inappropriate repair of DNA double strand breaks by the nonhomologous end joining ( NHEJ ) pathway is one of the reasons for a translocation to occur . Moreover , fidelity of this pathway has been shown to decline with age . Although the mechanism underlying this inefficacy is unknown , other repair pathways are inactivated by methylation with aging . In this study , we analyzed the implication of NHEJ genes methylation in the increase of translocations with the age . To this aim , we determined the relationship between translocations and aging in 565 Spanish healthy individuals and correlated these data with the methylation status of 11 NHEJ genes . We found higher frequency of P10415 - JH and P11274 - P00519 ( major ) translocations with aging . In addition , we detected that two NHEJ genes ( P49917 and P12956 ) presented age - dependent promoter methylation changes . However , we did not observe a correlation between the increase of translocations and methylation , indicating that other molecular mechanisms are involved in the loss of NHEJ fidelity with aging .",
"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .",
"DB09130 chelator DB05088 inhibits endothelial function by multiple mechanisms . DB09130 is required for the proliferation of endothelial cells and copper - lowering therapy reduces tumour growth in animal models . It has been reported that DB05088 , a novel copper chelator , potently inhibits the activity of the copper - dependent enzyme superoxide dismutase 1 ( P00441 ) in endothelial cells . We performed microarray analysis of gene expression in endothelial cells exposed to DB05088 which revealed upregulation of stress response genes including heme - oxygenase 1 ( P09601 ) and differential regulation of several genes previously implicated in angiogenesis including P61073 , ANGP2 , Q9H7Z7 , O75330 , ITB4 and P29972 ( p < 0 . 01 ) . These changes were confirmed on qPCR . Treatment of HUVEC with DB05088 caused increased superoxide levels , phospho - P29323 signalling , nuclear NRF1 expression , P09601 expression and induction of the anti - apoptotic proteins P21 , P10415 and BCLXL . There was also nuclear translocation of P00441 . P00441 RNA interference replicated the effects of DB05088 on endothelial cell function but did not cause upregulation of P09601 or Q9H7Z7 , suggesting additional mechanisms of action of DB05088 . Downregulation of P29972 , which has been shown to have a role in angiogenesis , was seen with both DB05088 and P00441 siRNA . P29972 expression could be rescued after DB05088 by added copper . RNA interference to P29972 inhibited endothelial proliferation and migration , confirming the role of P29972 in endothelial cell function . Therefore regulation of P29972 may represent an important action of copper chelation therapy .",
"Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .",
"cDNA array analysis of cytobrush - collected normal and malignant cervical epithelial cells : a feasibility study . Analysis of gene expression pattern is a useful approach to evaluating the biological behavior and clinical outcome of several human malignancies . Differentially expressed genes in malignant squamous cervical cells and the feasibility of gene expression profiling on squamous cervical cells obtained from cervical swabs were investigated . Cervical squamous cells from three women with high - risk human papilloma virus ( HR - HPV ) positive invasive squamous cervical carcinoma and from three HPV - negative women with normal ectocervical smears were analyzed with cDNA array . Immunoblot analysis was performed to detect the proteins corresponding to the highest upregulated genes with cDNA array . mRNA expression of P04626 , P10721 , P17948 , P04198 , DB01367 , CDKN2A , P24385 , P15531 , P22392 , MET , P21781 , P21802 , and P42224 was increased in malignant samples . Several expressed genes associated with antiapoptosis ( such as P10415 ) , cell structuring , or cell attachment were also upregulated in carcinoma cells . Decreased gene expression was observed for members of the transforming growth factor receptor superfamily ( TGF ) and integrin family , interleukin 1 ( IL1 ) , and insulin - like growth factor binding proteins ( IGFBPs ) . This study shows the feasibility of gene expression profiling of cervical squamous cells obtained with cytobrushes by identifying a characteristic gene expression pattern that clearly distinguishes between malignant and normal cervical epithelia of squamous type . We hypothesize that this noninvasive technique could be used in the evaluation of ambiguous Papanicolaou ( PAP ) smears .",
"Simultaneous inhibition of MEK and P11802 leads to potent apoptosis in human melanoma cells . ABSTRACT Deregulation of DB01367 - RAF - MEK - P29323 and P42771 - cycylin D : P11802 / 6 - RB pathways is important for melanoma development . Chemotherapeutic agents targeting both pathways were developed but results of clinical studies with monotherapies were disappointing . We examined the effect of co - targeting both pathways with MEK inhibitor PD98059 and P11802 inhibitor 219476 on human melanoma cells lines , and found that combinatorial treatment dramatically increased apoptosis compared to the single agent treatment . The apoptosis was associated with downregulation of P10415 , Q07817 , O15392 , and upregulation of O43521 . Our results indicate that simultaneously targeting P29323 and RB pathways is a promising strategy for melanoma treatment and should encourage further in - depth investigations .",
"Phorbol ester - mediated inhibition of growth and regulation of proto - oncogene expression in the human T cell leukemia line JURKAT . The expression and function of several proto - oncogenes were examined in a human acute T cell leukemia line , JURKAT , during phorbol ester - induced terminal differentiation . Treating JURKAT cells with the phorbol ester tetradecanoyl phorbol acetate ( TPA ) inhibited their proliferation and induced expression of the gene for the interleukin 2 receptor alpha chain ( IL2R - alpha ) , consistent with previous reports . In unstimulated proliferating JURKAT cells , high levels of C - MYC , N - DB01367 , and P10415 mRNAs were found that diminished rapidly following TPA - induced cessation of growth . In contrast , accumulation of mRNAs for the C - P01100 , C - P05412 , and P18146 genes increased markedly in TPA - treated cells and preceded the induction of IL2R - alpha mRNA . Expression of C - P10242 , C - RAF - 1 , C - P06239 , C - P06241 , and C - P09769 proto - oncogenes was relatively unchanged . To explore directly the function of two of these protooncogenes in regulating the growth of JURKAT T cells , we stably transferred C - MYC and P10415 expression plasmids into these cells . Despite sustained expression of C - MYC , P10415 , or the combination of these protooncogenes , TPA continued to inhibit JURKAT cell growth and to induce IL2R expression . Thus , although C - MYC and P10415 proto - oncogene expression correlated with proliferation in TPA - treated JURKAT cells , continuous over - expression of even the combination of these oncogenes was insufficient for abrogating the effects of TPA in these leukemic T cells . Because human lymphoid malignancies frequently contain chromosomal translocations that deregulate the expression of C - MYC and P10415 , our findings could have relevance for attempts to induce terminal differentiation of leukemic cells by in vitro exposure of patients ' bone marrow cells to phorbol esters .",
"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK74___ ( ___MASK74___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK74___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK74___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .",
"Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy . Sustained cardiac pressure overload induces hypertrophy and pathological remodeling , frequently leading to heart failure . Genetically engineered hyperstimulation of guanosine 3 ', 5 '- cyclic monophosphate ( cGMP ) synthesis counters this response . Here , we show that blocking the intrinsic catabolism of cGMP with an oral phosphodiesterase - 5A ( O76074 ) inhibitor ( sildenafil ) suppresses chamber and myocyte hypertrophy , and improves in vivo heart function in mice exposed to chronic pressure overload induced by transverse aortic constriction . ___MASK99___ also reverses pre - established hypertrophy induced by pressure load while restoring chamber function to normal . cGMP catabolism by O76074 increases in pressure - loaded hearts , leading to activation of cGMP - dependent protein kinase with inhibition of O76074 . O76074 inhibition deactivates multiple hypertrophy signaling pathways triggered by pressure load ( the calcineurin / NFAT , phosphoinositide - 3 kinase ( PI3K ) / Akt , and P27361 / 2 signaling pathways ) . But it does not suppress hypertrophy induced by overexpression of calcineurin in vitro or Akt in vivo , suggesting upstream targeting of these pathways . O76074 inhibition may provide a new treatment strategy for cardiac hypertrophy and remodeling .",
"Genetic pathway - based hierarchical clustering analysis of older adults with cognitive complaints and amnestic mild cognitive impairment using clinical and neuroimaging phenotypes . Hierarchical clustering is frequently used for grouping results in expression or haplotype analyses . These methods can elucidate patterns between measures that can then be applied to discerning their validity in discriminating between experimental conditions . Here a hierarchical clustering method is used to analyze the results of an imaging genetics study using multiple brain morphology and cognitive testing endpoints for older adults with amnestic mild cognitive impairment ( D6RGH6 ) or cognitive complaints ( CC ) compared to healthy controls ( HC ) . The single nucleotide polymorphisms ( SNPs ) are a subset of those included on a larger array that are found in a reported Alzheimer ' s disease ( AD ) and neurodegeneration pathway . The results indicate that genetic models within the endpoints cluster together , while there are 4 distinct sets of SNPs that differentiate between the endpoints , with most significant results associated with morphology endpoints rather than cognitive testing of patients ' reported symptoms . The genes found in at least one cluster are P08183 , Q02410 , P56817 , Q9Y5Z0 , P10415 , Q07817 , P55210 , P28329 , P01034 , P35462 , P21918 , P05231 , Q07954 , NAT1 , and P49810 . The greater associations with morphology endpoints suggests that changes in brain structure can be influenced by an individual ' s genetic background in the absence of dementia and in some cases ( Cognitive Complaints group ) even without those effects necessarily being detectable on commonly used clinical tests of cognition . The results are consistent with polygenic influences on early neurodegenerative changes and demonstrate the effectiveness of hierarchical clustering in identifying genetic associations among multiple related phenotypic endpoints .",
"Aberrant microRNA expression likely controls DB01367 oncogene activation during malignant transformation of human prostate epithelial and stem cells by arsenic . Inorganic arsenic ( iAs ) , a human carcinogen , potentially targets the prostate . iAs malignantly transforms the RWPE - 1 human prostate epithelial line to CAsE - PE cells , and a derivative normal stem cell ( SC ) line , WPE - stem , to As - Cancer SC ( As - CSC ) line . MicroRNAs ( miRNA ) are noncoding but exert negative control on expression by degradation or translational repression of target mRNAs . Aberrant miRNA expression is important in carcinogenesis . A miRNA array of CAsE - PE and As - CSC revealed common altered expression in both for pathways concerning oncogenesis , miRNA biogenesis , cell signaling , proliferation , and tumor metastasis and invasion . The P01116 oncogene is overexpressed in CAsE - PE cells but not by mutation or promoter hypomethylation , and is intensely overexpressed in As - CSC cells . In both transformants , decreased miRNAs targeting P01116 and DB01367 superfamily members occurred . Reduced miR - 134 , miR - 373 , miR - 155 , miR - 138 , miR - 205 , miR - 181d , miR - 181c , and let - 7 in CAsE - PE cells correlated with increased target DB01367 oncogenes , RAN , P51159 , Q9UL26 mRNAs , and P01116 protein . Reduced miR - 143 , miR - 34c - 5p , and miR - 205 in As - CSC correlated with increased target RAN mRNA , and P01116 , P01111 , and P10301 proteins . The DB01367 / P29323 and PI3K / P60484 / AKT pathways control cell survival , differentiation , and proliferation , and when dysregulated promote a cancer phenotype . iAs transformation increased expression of activated P29323 kinase in both transformants and altered components of the PI3K / P60484 / AKT pathway including decreased P60484 and increases in P10415 , BCL - XL , and P15692 in the absence of AKT activation . Thus , dysregulated miRNA expression may be linked to DB01367 activation in both transformants .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK100___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK100___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK100___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK100___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK100___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK100___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK100___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK100___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK100___ in the treatment of changes in hypervigilance following severe stress .",
"The effects of pertussis toxin on dopamine D2 and serotonin P08908 autoreceptor - mediated inhibition of neurotransmitter synthesis : relationship to receptor reserve . Irreversible inactivation of striatal D2 dopamine ( DA ) autoreceptors with N - ethoxycarbonyl - 2 - ethoxy - 1 , 2 - dihydroquinoline ( EEDQ ) or inactivation of striatal guanine nucleotide binding proteins ( G proteins ) with pertussis toxin ( PT ) shifted the dose - response curve for N - n - propylnorapomorphine ( NPA ) - mediated inhibition of DB04699 ( Q9BVC4 ) - induced elevation of DB01235 ( DB01235 ) to the right , with a decrease in the maximum response . For the partial agonist (+)- 3 -( 3 - hydroxyphenyl )- N - n - propylpiperidine [ (+)- 3 - PPP ] , in contrast , there was little shift in the ED50 , after inactivation of either D2 receptors or G proteins . Completely analogous effects were found at the somatodendritic P08908 autoreceptor in the raphe nuclei , mediating inhibition of the synthesis of serotonin ( 5 - HT ) ; the full agonist , 8 - hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) and the partial agonist , buspirone were utilized to inhibit the synthesis of 5 - HT , as measured by changes in levels of L - 5 - hydroxytryptophan ( 5 - HTP ) . Additionally , in both systems , combined treatment with pertussis toxin , followed by EEDQ , reduced the maximum effect , when compared to either agent alone but had little further effect on the ED50 . In systems exhibiting a large receptor reserve for agonists , such as those described above , the same pattern of response seen after inactivation of receptors or G proteins may reflect the operation of a common mechanism underlying the phenomenon of receptor reserve .",
"[ Endometrial cancer in young women -- clinical and molecular aspects ] . OBJECTIVES : The aim the study was to compare two groups of endometrial cancer patients ( below and above 45 years of age ) in the aspect of clinicopathological and molecular data . MATERIAL AND METHODS : The study encompassed 456 primary tumour samples retrospectively collected from a cohort of endometrial cancer patients , primarily treated by surgery Molecular analysis covered : copy number variations of 10 genes ( P11388 , P00533 , P04626 , P21860 , Q15303 , MYC , P24385 , P03372 , P42336 , O60216 ) analyzed by quantitative PCR ; mRNA expression of 6 genes ( Q13296 , RAD27 , Q01196 , O95863 , O43623 , O43490 ) analyzed with the use of reverse transcription quantitative PCR ; protein expression analysis of 8 markers ( P06401 , P03372 ; P00533 , P04626 , P21860 , Q15303 , P11388 , pAKT1 ) performed with the use of immunohistochemistry . RESULTS : The younger group of patients was characterized by less frequent hypertension ( p < 0 . 00007 ) , less frequent myometrial infiltration ( p = 0 . 002 ) and longer overall survival ( p = 0 . 003 ) . Apart from O60216 gene aberrations , which were more frequent in younger patients ( p = 0 . 02 ) , the study revealed no statistically significant differences between the groups . CONCLUSIONS : The study showed no molecular differences in the profile of younger and older endometrial cancer patients . Data on both the prognostic and predictive significance of O60216 in endometrial cancer are still insufficient . The clinical profile of younger patients with endometrial carcinoma was slightly better when compared to elderly patients . Younger patients were characterized by longer overall survival .",
"Distinct signalling pathways of murine histamine H1 - and H4 - receptors expressed at comparable levels in HEK293 cells . DB11320 ( HA ) is recognized by its target cells via four G - protein - coupled receptors , referred to as histamine H1 - receptor ( P35367 ) , P25021 , Q9Y5N1 , and Q9H3N8 . Both P35367 and Q9H3N8 exert pro - inflammatory functions . However , their signal transduction pathways have never been analyzed in a directly comparable manner side by side . Moreover , the analysis of pharmacological properties of the murine orthologs , representing the main targets of pre - clinical research , is very important . Therefore , we engineered recombinant HEK293 cells expressing either mouse ( m ) P35367 or mH4R at similar levels and analyzed HA - induced signalling in these cells . HA induced intracellular calcium mobilization via both mH1R and mH4R , with the mH1R being much more effective . Whereas DB02527 accumulation was potentiated via the mH1R , it was reduced via the mH4R . The regulation of both second messengers via the Q9H3N8 , but not the P35367 , was sensitive to pertussis toxin ( PTX ) . The mitogen - activated protein kinases ( MAPKs ) P29323 1 / 2 were massively activated downstream of both receptors and demonstrated a functional involvement in HA - induced P18146 gene expression . The p38 MAPK was moderately activated via both receptors as well , but was functionally involved in HA - induced P18146 gene expression only in Q9H3N8 - expressing cells . Surprisingly , in this system p38 MAPK activity reduced the HA - induced gene expression . In summary , using this system which allows a direct comparison of mH1R - and mH4R - induced signalling , qualitative and quantitative differences on the levels of second messenger generation and also in terms of p38 MAPK function became evident .",
"Protein kinase Cdelta and calmodulin regulate epidermal growth factor receptor recycling from early endosomes through Arp2 / 3 complex and cortactin . The intracellular trafficking of the epidermal growth factor receptor ( P00533 ) is regulated by a cross - talk between calmodulin ( P62158 ) and protein kinase Cdelta ( PKCdelta ) . On inhibition of P62158 , PKCdelta promotes the formation of enlarged early endosomes and blocks P00533 recycling and degradation . Here , we show that PKCdelta impairs P00533 trafficking due to the formation of an F - actin coat surrounding early endosomes . The PKCdelta - induced polymerization of actin is orchestrated by the Arp2 / 3 complex and requires the interaction of cortactin with PKCdelta . Accordingly , inhibition of actin polymerization by using cytochalasin D or by overexpression of active cofilin , restored the normal morphology of the organelle and the recycling of P00533 . Similar results were obtained after down - regulation of cortactin and the sequestration of the Arp2 / 3 complex . Furthermore we demonstrate an interaction of cortactin with P62158 and PKCdelta , the latter being dependent on P62158 inhibition . In summary , this study provides the first evidence that P62158 and PKCdelta organize actin dynamics in the early endosomal compartment , thereby regulating the intracellular trafficking of P00533 .",
"Molecular pathways : the basis for rational combination using MEK inhibitors in P01116 - mutant cancers . Mutations in DB01367 oncogenes are frequently observed in human cancers , and the mutations result in activation of the DB01367 - RAF - MEK - P29323 pathway , leading to cell proliferation and survival . The pathway is , therefore , a potent therapeutic target in the DB01367 - mutant cancers . MEK inhibitors can specifically block the pathway and are one of the key types of drugs for the treatment of the DB01367 - mutant cancers . As DB01367 proteins activate other downstream signaling proteins in addition to the DB01367 - RAF - MEK - P29323 pathway , combination therapeutic approaches with MEK inhibitors are also being evaluated . Moreover , MEK inhibitors can arrest cancer cells in P55008 phase and repress prosurvival Bcl2 family proteins such as Q07820 and P10415 / BCLXL , and increase expression of Bim , a proapoptotic BH3 - only family protein . This mechanism may explain the efficacy of the combination of MEK inhibitors with cytotoxic agents or other targeted inhibitors . A better understanding of the pathway will help us with development of rational combinations for the treatment of the DB01367 - mutant cancers .",
"Complementation by P10415 and C - HA - DB01367 oncogenes in malignant transformation of rat embryo fibroblasts . The P10415 ( B cell lymphoma / leukemia - 2 ) and C - HA - DB01367 oncogenes encode membrane - associated proteins of 26 and 21 kilodaltons , respectively . Although DB01367 proteins have long been known for their ability to bind and hydrolyze GTP , recent investigations suggest that P10415 encodes a novel GTP - binding protein ( S . Haldar , C . Beatty , Y . Tsujimoto , and C . M . Croce , Nature [ London ] 342 : 195 - 198 , 1989 ) . Cotransfection of P10415 and HA - DB01367 oncogenes resulted in morphological transformation of early - passage rodent fibroblasts , rendering these cells tumorigenic in animals and enabling them to grow in semisolid medium . In contrast , cotransfection of P10415 with oncogenes that encode nuclear proteins ( E1A and C - MYC ) did not produce malignant transformation , whereas HA - DB01367 did complement with these genes . These findings suggest that proteins encoded by oncogenes such as P10415 and HA - DB01367 , although having similar subcellular locations and perhaps similar biochemical properties , can regulate distinct complementary pathways involved in cellular transformation .",
"Kinin - B2 receptor exerted neuroprotection after diisopropylfluorophosphate - induced neuronal damage . The kinin - B2 receptor ( B2BKR ) activated by its endogenous ligand bradykinin participates in various metabolic processes including the control of arterial pressure and inflammation . Recently , functions for this receptor in brain development and protection against glutamate - provoked excitotoxicity have been proposed . Here , we report neuroprotective properties for bradykinin against organophosphate poisoning using acute hippocampal slices as an in vitro model . Following slice perfusion for 10min with diisopropylfluorophosphate ( ___MASK88___ ) to initiate the noxious stimulus , responses of pyramidal neurons upon an electric impulse were reduced to less than 30 % of control amplitudes . Effects on synaptic - elicited population spikes were reverted when preparations had been exposed to bradykinin 30min after challenging with ___MASK88___ . Accordingly , bradykinin - induced population spike recovery was abolished by HOE - 140 , a B2BKR antagonist . However , the kinin - B1 receptor ( B1BKR ) agonist Lys - des - DB00125 ( 9 )- bradykinin , inducing the phosphorylation of mitogen - activated protein kinase ( MEK / MAPK ) and cell death , abolished bradykinin - mediated neuroprotection , an effect , which was reverted by the P29323 inhibitor PD98059 . In agreement with pivotal B1BKR functions in this process , antagonism of endogenous B1BKR activity alone was enough for restoring population spike activity . On the other hand pralidoxime , an oxime , reactivating acetylcholinesterase ( P22303 ) after organophosphate poisoning , induced population spike recovery after ___MASK88___ exposure in the presence of bradykinin and Lys - des - DB00125 ( 9 )- bradykinin . Lys - des - DB00125 ( 9 )- bradykinin did not revert protection exerted by pralidoxime , however when instead bradykinin and Ly - des - DB00125 ( 9 )- bradykinin were superfused together , recovery of population spikes diminished . These findings again confirm the neuroprotective feature of bradykinin , which is , diminished by its endogenous metabolites , stimulating the B1BKR , providing a novel understanding of the physiological roles of these receptors .",
"P10997 - leptin coadministration stimulates central histaminergic signaling in rats . Combined amylin + leptin ( Q9BXJ7 + P41159 ) can reduce diet induced obesity and is very effective in combating P41159 resistance . The purpose of this study was to evaluate the effect of Q9BXJ7 + P41159 on central histaminergic signaling in lean and obese rats . Male rats were administered P41159 ( 300 μg / kg / d ) , Q9BXJ7 ( 100 μg / kg / d ) , Q9BXJ7 + P41159 or vehicle ( SAL , 0 . 9 % normal saline ) , via a subcutaneous mini - osmotic pump or single injection ( P41159 , 300 μg / kg and Q9BXJ7 , 100 μg / kg ) for acute studies . Q9BXJ7 + P41159 administration increased expression of histamine H1 receptor ( HIR ) and histidine decarboxylase ( HDC ) mRNA in the hypothalamus . Increased levels of P35367 were seen in arcuate ( Arc ) and ventromedial hypothalamus ( VMH ) as well as the area postrema ( APOS ) and nucleus of solitary tract ( P30990 ) following Q9BXJ7 + P41159 administration . APOS and P30990 also showed expression of immediate early gene c - P01100 in the hindbrain in Q9BXJ7 + P41159 - treated rats . We confirmed previous evidence indicating that Q9BXJ7 + P41159 increased P35610 - 3 protein phosphorylation in Arc and VMH . Finally , by in vivo microdialysis , we observed an increase in methyl P42357 levels in the VMH of Q9BXJ7 , P41159 and Q9BXJ7 + P41159 - treated rats . Taken together , these observations are consistent with an important role that neuronal P42357 may play in mediating the potent effects of Q9BXJ7 + P41159 on food intake and body weight .",
"NFκB inhibitors induce cell death in glioblastomas . Identification of novel target pathways in glioblastoma ( GBM ) remains critical due to poor prognosis , inefficient therapies and recurrence associated with these tumors . In this work , we evaluated the role of nuclear - factor - kappa - B ( NFκB ) in the growth of GBM cells , and the potential of NFκB inhibitors as antiglioma agents . NFκB pathway was found overstimulated in GBM cell lines and in tumor specimens compared to normal astrocytes and healthy brain tissues , respectively . Treatment of a panel of established GBM cell lines ( U138MG , U87 , U373 and P13671 ) with pharmacological NFκB inhibitors ( BAY117082 , parthenolide , MG132 , curcumin and arsenic trioxide ) and NFκB - p65 siRNA markedly decreased the viability of GBMs as compared to inhibitors of other signaling pathways such as MAPKs ( P29323 , JNK and p38 ) , PKC , P00533 and PI3K / Akt . In addition , NFκB inhibitors presented a low toxicity to normal astrocytes , indicating selectivity to cancerous cells . In GBMs , mitochondrial dysfunction ( membrane depolarization , bcl - xL downregulation and cytochrome c release ) and arrest in the G2 / M phase were observed at the early steps of NFκB inhibitors treatment . These events preceded sub - P55008 detection , apoptotic body formation and caspase - 3 activation . Also , NFκB was found overstimulated in cisplatin - resistant P13671 cells , and treatment of GBMs with NFκB inhibitors overcame cisplatin resistance besides potentiating the effects of the chemotherapeutics , cisplatin and doxorubicin . These findings support NFκB as a potential target to cell death induction in GBMs , and that the NFκB inhibitors may be considered for in vivo testing on animal models and possibly on GBM therapy .",
"Gene network profiling before and after transplantation in alcoholic cirrhosis liver transplant recipients . The main objective of this study was to define a gene network profile network in liver transplant recipients with alcoholic cirrhosis before and after liver transplantation . Genes were selected from data obtained in a previous study of liver transplant recipients with alcoholic cirrhosis . Selected up - regulated genes were further validated by quantitative real - time polymerase chain reaction in different groups of liver transplant recipients with alcoholic cirrhosis ( n = 5 ) . Selected genes up - regulated before transplantation were : Q07011 ( tumor necrosis factor [ P01375 ] receptor superfamily , member 9 ) ; P14784 ( interleukin - 2 receptor beta ) ; Q92843 ( P10415 - like 2 ) ; Q96PH1 ( NADPH ) oxidase , EF - hand calcium binding domain 5 ) ; P50542 ( peroxisomal biogenesis factor 5 ) ; P37231 ( peroxisome proliferator - activated receptor gamma ) ; Q96Q05 ( O14920 binding protein ) ; Q9NYR9 ( NFKappaBeta inhibitor interacting Ras - like 2 ) ; P05112 ( interleukin - 4 ) ; IL - 4R ( interleukin 4 receptor ) ; P07327 ( alcohol dehydrogenase 1A , class 1 ) ; O75891 ( aldehyde dehydrogenase 1 family , member Q9NUQ9 ) ; P05164 ( myeloperoxidase ) ; P01160 ( natriuretic peptide precursor A ) ; Q16548 ( P10415 - related protein A1 ) ; P24522 ( growth arrest and DNA - damage - inducible alpha ) ; P55061 ( P55061 ) ; P42336 ( phosphoinositide - 3 - kinase , catalytic , alpha polypeptide ) ; P38484 ( interferon gamma receptor 2 ) ; O60674 ( Janus Kinase 2 ) ; FAS ( Fas , P01375 receptor superfamily , member 6 ) ; Q92844 ( TRAF family member - associated NFKB activator ) ; O95551 ( O95551 ) ; and P08758 ( annexin A5 ) .",
"Exposure to an organophosphate ( ___MASK88___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK88___ ( ___MASK88___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK88___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK88___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK88___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .",
"P08908 receptor - mediated regulation of mitogen - activated protein kinase phosphorylation in rat brain . Mitogen - activated protein kinases ( MAPKs ) , a family of signal transduction mediators important in a host of cellular activities , include the extracellular signal - regulated kinases Erk1 and Erk2 . We determined whether 5 - HT ( 1A ) receptors activate Erk1 / 2 in rat brain in vivo , as they do in recombinant cell lines . In contrast to the effect in cells , the 5 - HT ( 1A ) receptor agonist 8 - hydroxy - N , N - diproylaminotetralin ( 8 - OH - DPAT ) dose - and time - dependently decreased basal levels of phosphorylated Erk1 / 2 ( phospho - Erk1 / 2 ) in rat hippocampus ( ED ( 50 ) approximately 0 . 1 mg / kg , maximum approximately 90 % ) without altering total Erk1 / 2 . The effects were kinase - specific , as 8 - OH - DPAT did not modify phosphorylated or total levels of the MAPKs c - Jun - N - terminal kinase / stress - activated protein kinase ( JNK / SAPK ) and p38 MAPK . Moreover , 8 - OH - DPAT did not modify phospho - Erk1 / 2 in striatum or frontal cortex . The effect of 8 - OH - DPAT was blocked by pretreatment with the selective 5 - HT ( 1A ) receptor antagonists N -[ 2 -[ 4 -( 2 - methoxyphenyl )- 1 - piperazinyl ] ethyl ]- N - 2 - pyridinylcyclohexanecarboxamide ( WAY 100635 ) , 1 -( 2 - methoxyphenyl )- 4 -( 4 -[ 2 - phthalimido ] butyl ) piperazine ( NAN - 190 ) and 4 - fluoro - N -( 2 -[ 4 -( 2 - methoxyphenyl ) 1 - piperazinyl ] ethyl )- N -( 2 - pyridinyl ) benzamide dihydrochloride ( p - MPPF ) , but not by the weak partial agonist / antagonist 8 -( 2 -[ 4 -( 2 - methoxyphenyl )- 1 - piperazinyl ] ethyl )- 8 - azaspiro ( 4 . 5 ) decane - 7 , 9 - dione dihydrochloride ( BMY 7378 ) . Other 5 - HT ( 1A ) receptor agonists ( buspirone , gepirone and ipsapirone ) also reduced phospho - Erk1 / 2 levels in hippocampus . 8 - OH - DPAT also reduced the levels of the upstream activator of Erk1 / 2 , phosphorylated extracellular signal - regulated kinase kinase ( phospho - Q02750 / 2 ) , and at least one potential downstream target , the nuclear transcription factor phospho - Elk - 1 . The region - and kinase - specific effects suggest that the Erk1 / 2 signal transduction cascade is likely an important differential mediator of 5 - HT ( 1A ) receptor - regulated events in the central nervous system .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK91___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"Spin trapping agent phenyl - N - tert - butylnitrone prevents diisopropylphosphorofluoridate - induced excitotoxicity in skeletal muscle of the rat . Indirect evidence suggests that reactive oxygen species ( ROS ) may mediate muscle fiber necrosis following muscle hyperactivity induced by the anticholinesterase diisopropylphosphorofluoridate ( ___MASK88___ ) . Pronounced muscle fasciculations and muscle fiber necrosis were seen when acetylcholinesterase ( P22303 ) activity was reduced to less than 30 % of control . The spin trapping agent phenyl - N - tert - butylnitrone ( PBN ) was used in vivo to directly assess the formation of ROS during ___MASK88___ ( 1 . 75 mg / kg , s . c . ) induced muscle hyperactivity . Pretreatment with PBN ( 300 mg / kg , i . p . ) , the concentration necessary for in vivo spin trapping , prevented muscle hyperactivity as well as necrosis and attenuated the ___MASK88___ induced P22303 inhibition otherwise seen in ___MASK88___ only treated rats . PBN had no effect when given after fasciculations were established . Muscle extracts from PBN and ___MASK88___ treated rats subjected to electron spin resonance ( P03372 ) spectroscopy tested negative for ROS . While the role of PBN as an antioxidant is well established , its prophylactic effect against excitotoxity induced by an P22303 inhibitor are due to its protection of P22303 , an unexpected non - antioxidant action .",
"Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .",
"Epidermal growth factor - induced proliferation of chicken primordial germ cells : involvement of calcium / protein kinase C and P19838 . Epidermal growth factor ( P01133 ) has been shown to stimulate survival in diverse cells in vitro . In the present study , the effects of P01133 and the P01133 - related signaling pathway on proliferation of chicken primordial germ cells ( PGCs ) were investigated . Results showed that P01133 ( 10 - 100 ng / ml ) increased the number and area of P20142 colonies in a time - and dose - dependent manner . P01133 also activated PKC , a process that was inhibited by AG1478 ( an P00533 tyrosine kinase inhibitor ) and ethyleneglycol - bis - ( beta - aminoethyl ether ) - N , N '- tetraacetic acid ( EGTA ; an intracellular Ca ( 2 +) chelator ) . In addition , the degradation of P25963 and P19838 ( p65 ) translocation was observed after P01133 treatment , which was significantly blocked by pretreatment with AG1478 , EGTA , H ( 7 ) , or SN50 ( P19838 - specific inhibitor ) . Furthermore , we found that P01133 - induced cell proliferation was significantly attenuated by AG1478 , EGTA , H ( 7 ) , and SN50 , respectively . On the other hand , inhibition of P00533 , Ca ( 2 +)/ PKC , or P19838 abolished the P01133 - stimulated increase in the expression of cyclins P24385 and P24864 , cyclin - dependent kinase 6 ( Q00534 ) , P24941 , and P10415 , and restored the P01133 - induced inhibition of Q07812 expression and caspase 3 / 9 activity , indicating that P00533 , PKC , and P19838 signaling cascades were involved in P01133 - stimulated DNA synthesis and antiapoptosis action . In conclusion , P01133 stimulated proliferation of chicken PGCs via activation of Ca ( 2 +)/ PKC involving P19838 signaling pathway . These observations suggest that P01133 signaling is important in regulating germ cell proliferation in the chicken embryonic gonad .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK96___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"Boehmeria nivea Stimulates DB09341 Uptake by Activating Peroxisome Proliferator - Activated Receptor Gamma in C2C12 Cells and Improves DB09341 Intolerance in Mice Fed a High - Fat Diet . We examined the antidiabetic property of Boehmeria nivea ( L . ) Gaud . Ethanolic extract of Boehmeria nivea ( L . ) Gaud . ( EBN ) increased the uptake of 2 -[ N -( nitrobenz - 2 - oxa - 1 , 3 - diazol - 4 - yl ) amino ]- 2 - deoxy - d - glucose in C2C12 myotubes . To examine the mechanisms underlying EBN - mediated increase in glucose uptake , we examined the transcriptional activity and expression of peroxisome proliferator - activated receptor gamma ( Q07869 - γ ) , a pivotal target for glucose metabolism in C2C12 myotubes . We found that the EBN increased both the transcriptional activity and mRNA expression levels of Q07869 - γ . In addition , we measured phosphorylation and expression levels of other targets of glucose metabolism , such as AMP - activated protein kinase ( AMPK ) and protein kinase B ( Akt / P31749 ) . We found that EBN did not alter the phosphorylation or expression levels of these proteins in a time - or dose - dependent manner , which suggested that EBN stimulates glucose uptake through a Q07869 - γ - dependent mechanism . Further , we investigated the antidiabetic property of EBN using mice fed a high - fat diet ( HFD ) . Administration of 0 . 5 % EBN reduced the HFD - induced increase in body weight , total cholesterol level , and fatty liver and improved the impaired fasting glucose level , blood insulin content , and glucose intolerance . These results suggest that EBN had an antidiabetic effect in cell culture and animal systems and may be useful for preventing diabetes .",
"The BH3 mimetic DB05764 synergizes with the Q02750 / 2 inhibitor selumetinib / AZD6244 to promote O43521 - dependent tumour cell death and inhibit acquired resistance . Tumour cells typically exhibit a G ( 1 ) cell cycle arrest in response to the Q02750 / 2 [ mitogen - activated protein kinase / P29323 ( extracellular - signal - regulated kinase ) kinase 1 / 2 ] inhibitor selumetinib , but do not die , and thus they acquire resistance . In the present study we examined the effect of combining selumetinib with the BH3 [ P10415 ( B - cell lymphoma 2 ) homology domain 3 ] - mimetic P10415 inhibitor DB05764 . Although either drug alone caused little tumour cell death , the two agents combined to cause substantial caspase - dependent cell death and inhibit long - term clonogenic survival of colorectal cancer and melanoma cell lines with P15056 ( V600E ) or DB01367 mutations . This cell death absolutely required Q07812 ( P10415 - associated X protein ) and was inhibited by RNAi ( RNA interference ) - mediated knockdown of O43521 ( P10415 - interacting mediator of cell death ) in the P15056 ( V600E )- positive COLO205 cell line . When colorectal cancer cell lines were treated with selumetinib plus DB05764 we observed a striking reduction in the incidence of cells emerging with acquired resistance to selumetinib . Similar results were observed when we combined DB05764 with the P15056 ( V600E )- selective inhibitor PLX4720 , but only in cells expressing P15056 ( V600E ) . Finally , cancer cells in which acquired resistance to selumetinib arises through P15056 ( V600E ) amplification remained sensitive to DB05764 , whereas selumetinib - resistant HCT116 cells ( P01116 ( G13D ) amplification ) were cross - resistant to DB05764 . Thus the combination of a P10415 inhibitor and an P27361 / 2 pathway inhibitor is synthetic lethal in P27361 / 2 - addicted tumour cells , delays the onset of acquired resistance and in some cases overcomes acquired resistance to selumetinib .",
"___MASK74___ , an HDAC inhibitor attenuates epidermoid squamous cell carcinoma growth by dampening P42345 signaling pathway in a human xenograft murine model . Histone deacetylase ( HDAC ) inhibitors are potent anticancer agents and show efficacy against various human neoplasms . ___MASK74___ is a potent HDAC inhibitor and has shown potential to inhibit growth of human xenograft tumors . However , its effect on the growth of skin neoplasm remains undefined . In this study , we show that vorinostat ( 2 μM ) reduced expression of Q13547 , 2 , 3 , and 7 in epidermoid carcinoma A431 cells . Consistently , it increased acetylation of histone H3 and p53 . ___MASK74___ ( 100mg / kg body weight , IP ) treatment reduced human xenograft tumor growth in highly immunosuppressed nu / nu mice . Histologically , the vorinostat - treated tumor showed features of well - differentiation with large necrotic areas . Based on proliferating cell nuclear antigen ( P12004 ) staining and expression of cyclins D1 , D2 , E , and A , vorinostat seems to impair proliferation by down - regulating the expression of these proteins . However , it also induced apoptosis . The mechanism by which vorinostat blocks proliferation and makes tumor cells prone to apoptosis , involved inhibition of P42345 signaling which was accompanied by reduction in cell survival AKT and extracellular - signal regulated kinase ( P29323 ) signaling pathways . Our data provide a novel mechanism - based therapeutic intervention for cutaneous squamous cell carcinoma ( SCC ) . ___MASK74___ may be utilized to cure skin neoplasms in organ transplant recipient ( OTR ) . These patients have high morbidity and surgical removal of these lesions which frequently develop in these patients , is difficult .",
"___MASK99___ inhibits calcineurin / Q13469 - mediated cyclin A expression in pulmonary artery smooth muscle cells . AIMS : To examine whether calcineurin / NFAT signaling pathway leads to proliferation of pulmonary artery smooth muscle cells ( PASMCs ) by regulating cell cycle proteins and whether the phosphodiesterase - 5 ( O76074 ) inhibitor sildenafil affects calcineurin / NFAT - induced cell proliferation . MAIN METHODS : A [( 3 ) H ] thymidine incorporation assay was used to examine DNA synthesis ( cell proliferation ) ; cyclin A and Q13469 expressions were determined by Western blot . P24941 ( P24941 ) activity was measured with an in vitro kinase activity assay , and calcineurin and NFAT activity were evaluated using a calcineurin assay kit and a luciferase activity assay , respectively . A chemical inhibitor or siRNA transfection was used to inhibit calcineurin / NFAT signaling pathway . KEY FINDINGS : Serotonin dose - dependently stimulated cyclin A expression in PASMCs . This effect was accompanied by dose - dependent increases in P24941 activity and the rate of DNA synthesis . At the same time , PASMCs treated with serotonin showed dose - dependent activation of calcineurin / NFAT signaling pathway . Inhibition of calcineurin activity by cyclosporine A or loss of Q13469 protein by siRNA transfection abolished serotonin - induced cyclin A expression and consequent P24941 activation and DNA synthesis . We further found that pretreatment of cells with sildenafil suppressed serotonin - triggered activation of calcineurin / Q13469 signaling pathway and resultant cyclin A expression , P24941 activation and cell proliferation , while the presence of DT - 3 [ a specific protein kinase G ( PKG ) peptide inhibitor ] reversed the effects of sildenafil on PASMCs . SIGNIFICANCE : Our study suggests that enhanced PKG activity suppresses calcineurin / Q13469 cascade - mediated cyclin A expression , P24941 activation and PASMC proliferation to contribute to the overall effects of sildenafil in the treatment of pulmonary hypertension .",
"DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .",
"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK14___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .",
"___MASK85___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK85___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .",
"___MASK85___ inhibits aquaporin - 1 expression and colon cancer xenograft tumor growth . BACKGROUND / AIMS : To study the effects of water channel protein inhibitor acetazolamide on xenograft tumor growth of colon cancer in nude mice . METHODOLOGY : Setting up human colon cancer model in nude mice , mice were randomly divided into two groups as experimental group and control group . ___MASK85___ was given at a volume of 0 . 1mL per mice ( 40mg / kg / d , ig ) in experimental group , while the same volume of sterile saline was given in control group ( ig ) . After 21 days , protein and m - RNA levels of P29972 in tumor tissues from two groups were detected respectively by Western blot and RT - PCR to evaluate the treatment effects . P29972 , P15692 and P28906 expression was detected by immunohistochemistry , simultaneously . RESULTS : ___MASK85___ ( 40mg / kg / d , ig ) significantly inhibited the xenograft tumor growth of colon cancer in nude mice . The inhibition rate was 88 . 28 % . In comparison with the control group , P29972 protein and mRNA level were significantly reduced in the experimental group ( p < 0 . 01 ) . P29972 , P15692 and P28906 expression in experimental group were positively correlated between each other ( p < 0 . 01 ) . CONCLUSIONS : ___MASK85___ can suppress the xenograft tumor growth by inhibiting the expression of P29972 .",
"Serotonin and dopamine receptor gene polymorphisms and the risk of extrapyramidal side effects in perphenazine - treated schizophrenic patients . RATIONALE : ___MASK14___ , a classical antipsychotic drug , has the potential to induce extrapyramidal side effects ( EPS ) . Dopaminergic and serotonergic pathways are involved in the therapeutic and adverse effects of the drug . OBJECTIVES : To evaluate the impact of polymorphisms in the dopamine D ( 2 ) and D ( 3 ) and serotonin 2A and 2C receptor genes ( P14416 , P35462 , P28223 , and P28335 ) on short - term effects of perphenazine monotherapy in schizophrenic patients . MATERIALS AND METHODS : Forty - seven Estonian inpatients were evaluated before and after 4 - 6 weeks of treatment by Simpson - Angus rating scale , Barnes scale , and Positive and Negative Symptom Scale . Genotyping was performed for common P14416 , P35462 , P28223 , and P28335 gene polymorphisms , previously reported to influence receptor expression and / or function . RESULTS : Most of the patients ( n = 37 ) responded to the treatment and no significant association was observed between the polymorphisms and antipsychotic response . The 102C allele of P28223 and the - 697C and 23Ser alleles of P28335 were more frequent among patients with EPS ( n = 25 ) compared to patients without EPS ( n = 22 ) ( p = 0 . 02 , 0 . 01 , and 0 . 02 , respectively ) . The difference between patients with and without EPS in variant allele frequencies remained significant after multiple model analyses including age , gender , and duration of antipsychotic treatment as covariants . There was no significant association between EPS occurrence and polymorphisms in the P14416 and P35462 genes . CONCLUSIONS : An association was observed between polymorphisms in P28223 and P28335 genes and occurrence of acute EPS in schizophrenic patients treated with perphenazine monotherapy . Larger study populations are needed to confirm our findings .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Proteome - wide changes induced by the Hsp90 inhibitor , geldanamycin in anaplastic large cell lymphoma cells . The molecular chaperone heat shock protein 90 ( Hsp90 ) affects the function of many oncogenic signaling proteins including nucleophosmin - anaplastic lymphoma kinase ( P06748 - Q9UM73 ) expressed in anaplastic large cell lymphoma ( ALCL ) . While Q9UM73 - positive ALCL cells are sensitive to the Hsp90 inhibitor and the geldanamycin ( GA ) analog , 17 - allylamino - 17 - demethoxygeldanamycin ( 17 - P29372 ) , the proteomic effects of these drugs on Q9UM73 - positive ALCL cells are unpublished . In this study , we investigated the cellular , biologic , and proteomic changes occurring in Q9UM73 - positive ALCL cells in response to GA treatment . GA induced G2 / M cell cycle arrest and caspase - 3 - mediated apoptosis . Furthermore , quantitative proteomic changes analyzed by cleavable isotope - coded affinity tag - LC - MS / MS ( cICAT - LC - MS / MS ) identified 176 differentially expressed proteins . Out of these , 49 were upregulated 1 . 5 - fold or greater and 70 were downregulated 1 . 5 - fold or greater in GA - treated cells . Analysis of biological functions of differentially expressed proteins revealed diverse changes , including induction of proteins involved in the 26S proteasome as well as downregulation of proteins involved in signal transduction and protein and nucleic acid metabolism . Pathway analysis revealed changes in MAPK , WNT , NF - kappaB , TGFbeta , Q07869 , and integrin signaling components . Our studies reveal some of the molecular and proteomic consequences of Hsp90 inhibition in Q9UM73 - positive ALCL cells and provide novel insights into the mechanisms of its diverse cellular effects .",
"That which does not kill me makes me stronger ; combining P27361 / 2 pathway inhibitors and BH3 mimetics to kill tumour cells and prevent acquired resistance . Oncogenic mutations in DB01367 or P15056 can drive the inappropriate activation of the P27361 / 2 . In many cases , tumour cells adapt to become addicted to this deregulated P27361 / 2 signalling for their proliferation , providing a therapeutic window for tumour - selective growth inhibition . As a result , inhibition of P27361 / 2 signalling by P15056 or Q02750 / 2 inhibitors is an attractive therapeutic strategy . Indeed , the first P15056 inhibitor , vemurafenib , has now been approved for clinical use , while clinical evaluation of Q02750 / 2 inhibitors is at an advanced stage . Despite this progress , it is apparent that tumour cells adapt quickly to these new targeted agents so that tumours with acquired resistance can emerge within 6 - 9 months of primary treatment . One of the major reasons for this is that tumour cells typically respond to P15056 or Q02750 / 2 inhibitors by undergoing a P55008 cell cycle arrest rather than dying . Indeed , although inhibition of P27361 / 2 invariably increases the expression of pro - apoptotic P10415 family proteins , tumour cells undergo minimal apoptosis . This cytostatic response may simply provide the cell with the opportunity to adapt and acquire resistance . Here we discuss recent studies that demonstrate that combination of P15056 or Q02750 / 2 inhibitors with inhibitors of pro - survival P10415 proteins is synthetic lethal for P27361 / 2 - addicted tumour cells . This combination effectively transforms the cytostatic response of P15056 and Q02750 / 2 inhibitors into a striking apoptotic cell death response . This not only augments the primary efficacy of P15056 and Q02750 / 2 inhibitors but delays the onset of acquired resistance to these agents , validating their combination in the clinic . LINKED ARTICLES : This article is part of a themed section on Emerging Therapeutic Aspects in Oncology . To view the other articles in this section visit http :// dx . doi . org / 10 . 1111 / bph . 2013 . 169 . issue - 8 .",
"Traps to catch unwary oncogenes . The MYC proto - oncogene has long been implicated in the control of normal cell growth and its deregulation is associated with the development of neoplasia . The MYC protein has a well - established role as a component of signal - transduction pathways promoting both proliferation and apoptosis . Because signalling pathways that drive cell death and cell proliferation are so tightly coupled , a synergy between genetic lesions leading to suppression of cell death and those promoting cell proliferation is observed during carcinogenesis . We discuss such synergy with respect to the cooperating oncogenes MYC , DB01367 and P10415 .",
"Down - regulation of Aquaporin1 ( P29972 ) by peptidoglycan via p38 MAPK pathways in primary rat pleural mesothelial cells . BACKGROUND AND OBJECTIVE : This study was designed to investigate the p38 mitogen - activated protein kinase ( MAPK ) signaling pathway involved in Aquaporin1 ( P29972 ) expression caused by staphylococcal peptidoglycan ( Q9UQ90 ) in cultured rat pleural mesothelial cells ( rPMCs ) in vitro . METHODS : RT - PCR and immunoblot analysis were used to determine the relative mRNA and protein levels of P29972 by Q9UQ90 in rPMCs . O75791 kinase inhibitor SB203580 , JNK inhibitor SP600125 , and P27361 / 2 inhibitor PD98059 were used to determine the effects of Q9UQ90 - induced P29972 expression by immunoblot . Activation of p38 by Q9UQ90 was reflected by detecting the phosphorylation constituent of p38 , using immunoblot . The shift of localization after activation of p38 by Q9UQ90 was investigated by immunofluorescence assay . RESULTS : P29972 transcription and protein expression were decreased by Q9UQ90 in dose - dependent and time - dependent manners in rPMCs . Down - regulation of P29972 by Q9UQ90 was blocked only by SB203580 , neither by SP600125 nor by PD98059 . Furthermore , rPMCs exposed to Q9UQ90 showed activation of p38 MAPK . Phospho - p38 protein production was increased by Q9UQ90 stimulation in rPMCs . The localization of phospho - p38 was both in the cytosol and nuclei after Q9UQ90 treatment , while its normal distribution is mainly in the cytosol in rPMCs . CONCLUSION : P29972 expression was decreased by Q9UQ90 in both dose - dependent and time - dependent manners in rPMCs . This down - regulation by Q9UQ90 - induced P29972 in rPMCs may be mediated by the activation of p38 Q9P0L2 pathway .",
"Modification of haloperidol - induced pattern of c - fos expression by serotonin agonists . Acute challenge with clozapine and haloperidol produce different anatomical patterns of c - fos expression in the forebrain . The pharmacological profile of atypical antipsychotics suggests that serotonin might contribute to the unique therapeutic benefits of these drugs . In order to test this possibility , we examined the abilities of P08908 and 5 - Q13049 / 2c agonists to modify the pattern of c - fos expression induced by haloperidol and clozapine . Various groups of rats were pretreated with either saline , DOI , 8 - OH - DPAT , and 8 - OH - DPAT + DOI 30 min prior to haloperidol or clozapine administration . Rats were killed 90 min after antipsychotic administration . In saline - pretreated rats , haloperidol produced intense Fos - LI in all four striatal quadrants while the effect of clozapine was restricted to the medial part of the striatum . Prior administration of 8 - OH - DPAT significantly reduced haloperidol - induced Fos - LI in all four striatal quadrants while DOI and 8 - OHDPAT + DOI significantly reduced Fos - LI only in dorso - and ventrolateral quadrants . In the nucleus accumbens , haloperidol induced intense Fos - LI in the core and the shell regions whereas clozapine induced c - fos expression only in the shell . Pretreatment with 8 - OHDPAT in haloperidol treated rats reduced Fos - LI in the core region yielding to a c - fos pattern similar to that induced by clozapine . In the prefrontal cortex of saline - pretreated rats , haloperidol produced a moderate c - fos expression compared with the intense expression produced by clozapine . Pretreatment with serotonin agonists before haloperidol brought the number of P01100 - positive neurons to the same level as in clozapine treated rats . These results show the ability of 5 - HT agonists to transform the typical pattern of c - fos expression induced by haloperidol into a pattern resembling that of clozapine .",
"Somatic Q06124 mutations in childhood acute myeloid leukaemia . Somatic mutations in Q06124 , the gene encoding the transducer Q06124 , have emerged as a novel class of lesions that upregulate DB01367 signalling and contribute to leukaemogenesis . In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia ( AML ) , we documented a non - random distribution of Q06124 mutations among French - American - British ( FAB ) subtypes . Lesions were restricted to FAB - M5 cases , where they were relatively common ( four of 12 cases ) . Here , we report on the results of a molecular screening performed on 181 additional unselected patients , enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica - AML Study Group , to provide a more accurate picture of the prevalence , spectrum and distribution of Q06124 mutations in childhood AML and to investigate their clinical relevance . We concluded that Q06124 defects do not represent a frequent event in this heterogeneous group of malignancies ( 4 . 4 % ) , although they recur in a considerable percentage of patients with FAB - M5 ( 18 % ) . Q06124 lesions rarely occur in other subtypes . Within the FAB - M5 group no clear association of Q06124 mutations with any clinical variable was evident . Nearly two third of the patients with this subtype were found to harbour an activating mutation in Q06124 , P01111 , P01116 or P36888 ."
] |
[
"___MASK100___",
"___MASK14___",
"___MASK24___",
"___MASK74___",
"___MASK85___",
"___MASK88___",
"___MASK91___",
"___MASK96___",
"___MASK99___"
] |
___MASK14___
|
MH_train_469
|
interacts_with DB01235?
|
[
"Support for association between ADHD and two candidate genes : NET1 and P21728 . Attention deficit hyperactivity disorder ( ADHD ) is a common , multifactorial disorder with significant genetic contribution . Multiple candidate genes have been studied in ADHD , including the norepinephrine transporter ( NET1 ) and dopamine D1 receptor ( P21728 ) . NET1 is implicated in ADHD because of the efficacy of atomoxetine , a selective noradrenergic reuptake inhibitor , in the treatment of ADHD . P21728 is primarily implicated through mouse models of ADHD . DNA from 163 ADHD probands , 192 parents , and 129 healthy controls was used to investigate possible associations between ADHD and polymorphisms in 12 previously studied candidate genes ( P28222 , 5 - Q13049 , P28335 , P08913 , P43681 , P21964 , Q01959 , P21728 , P21917 , P21918 , NET1 , and P60880 ) . Analyses included case - control and family - based methods , and dimensional measures of behavior , cognition , and anatomic brain magnetic resonance imaging ( Q9BWK5 ) . Of the 12 genes examined , two showed a significant association with ADHD . Transmission disequilibrium test ( P04053 ) analysis revealed significant association of two NET1 single nucleotide polymorphisms ( SNPs ) with ADHD ( P < or = 0 . 009 ) ; case - control analysis revealed significant association of two P21728 SNPs with ADHD ( P < or = 0 . 008 ) . No behavioral , cognitive , or brain Q9BWK5 volume measurement significantly differed across NET1 or P21728 genotypes at an alpha of 0 . 01 . This study provides support for an association between ADHD and polymorphisms in both NET1 and P21728 ; polymorphisms in ten other candidate genes were not associated with ADHD . Because family - based and case - control methods gave divergent results , both should be used in genetic studies of ADHD .",
"Rottlerin , a PKC isozyme - selective inhibitor , affects signaling events and cytokine production in human monocytes . The implication of select protein kinase C ( PKC ) isoenzymes in cytokine production by human monocytes was investigated using an isozyme - selective inhibitor of PKC , rottlerin . We found that lipopolysaccharide ( LPS ) triggers cytosol - to - membrane translocation of PKCalpha and delta isoenzymes , whereas phorbol ester ( PMA ) induces translocation of several PKC isoforms . Moreover , we show that in LPS - and PMA - stimulated monocytes rottlerin affects several cellular responses . ( 1 ) At low ( 15 microM ) concentration it blocks translocation of PKCdelta , diminishes DNA binding activity of AP - 1 transcription factor , and attenuates cytokine production [ tumor necrosis factor alpha ( P01375 ) > interleukin - 1beta ( IL - 1beta ) ] . ( 2 ) At high ( 50 microM ) concentration it prevents translocation of PKCalpha , and subsequently inhibits P27361 / P28482 phosphorylation , DNA binding activities of AP - 1 and nuclear factor - KB transcription factors , and the production of both tested cytokines . Thus , we propose that cytosol - to - membrane translocation of PKCalpha and PKdelta isoenzymes may represent early steps in the signaling cascades that lead to P01375 and IL - 1beta production in human monocytes .",
"17 DB00783 overcomes a P55008 block induced by P04035 inhibitors and fosters cell cycle progression without inducing P27361 and - 2 Q96HU1 kinases activation . P04035 inhibitors , such as ___MASK51___ and Simvastatin , cause cell cycle arrest by interfering with the mitogenic activity of mitogens present in culture media . Cells are induced to pause in P55008 and can readily resume growth upon removal of the enzymatic block . DB00286 , acting via their nuclear receptor , are mitogens for different normal and transformed cell types , where they foster cell cycle progression and cell division . In estrogen - responsive MCF - 7 human breast cancer cells , but not in non responsive cells , 17 beta - estradiol ( E2 ) induces cells arrested with ___MASK51___ or Simvastatin to proliferate in the presence of inhibitor , without restoring P04035 activity or affecting the protein prenylation pattern . Mitogenic stimulation of P55008 - arrested MCF - 7 cells with E2 includes primary transcriptional activation of c - fos , accompanied by transient binding in vivo of the estrogen receptor and / or other factors to the ERE and the estrogen - responsive DNA region of this proto - oncogene , as detected by dimethylsulphate genomic footprinting analysis . Mitogenic stimulation of growth - arrested MCF - 7 cells by E2 occurs , under these conditions , without evident activation of P27361 and - 2 kinases , and thus independently from the mitogen - responsive signal transduction pathways that converge on these enzymes .",
"Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .",
"Pharmacogenetics of antipsychotic - induced weight gain : review and clinical implications . Second - generation antipsychotics ( SGAs ) , such as risperidone , clozapine and olanzapine , are the most common drug treatments for schizophrenia . SGAs presented an advantage over first - generation antipsychotics ( FGAs ) , particularly regarding avoidance of extrapyramidal symptoms . However , most SGAs , and to a lesser degree FGAs , are linked to substantial weight gain . This substantial weight gain is a leading factor in patient non - compliance and poses significant risk of diabetes , lipid abnormalities ( that is , metabolic syndrome ) and cardiovascular events including sudden death . The purpose of this article is to review the advances made in the field of pharmacogenetics of antipsychotic - induced weight gain ( AIWG ) . We included all published association studies in AIWG from December 2006 to date using the Medline and ISI web of knowledge databases . There has been considerable progress reaffirming previous findings and discovery of novel genetic factors . The P28335 and leptin genes are among the most promising , and new evidence suggests that the P14416 , P01375 , P60880 and P32245 genes are also prominent risk factors . Further promising findings have been reported in novel susceptibility genes , such as P21554 , P08183 , ADRA1A and Q9Y5U4 . More research is required before genetically informed , personalized medicine can be applied to antipsychotic treatment ; nevertheless , inroads have been made towards assessing genetic liability and plausible clinical application .",
"Regulation of Q9UD71 phosphorylation by Delta9 - tetrahydrocannabinol . P21554 receptor agonists increase the state of phosphorylation of the dopamine and DB02527 - regulated phosphoprotein of 32 kDa ( Q9UD71 ) at the DB02527 - dependent protein kinase site , DB00156 34 . This effect , which occurs in the medium spiny neurons of the striatum , has been proposed to mediate the motor depressant action of cannabinoids . In this study , we have examined the effect produced by systemic administration of Delta ( 9 )- tetrahydrocannabinol ( THC ) , the major component of marihuana and hashish , on Q9UD71 . We show that THC increases Q9UD71 phosphorylation at DB00156 34 both in dorsal striatum and nucleus accumbens . Time - course and dose - response experiments indicate that Q9UD71 phosphorylation is maximal 30 min following administration of 10mg / kg of THC . The THC - mediated increase in Q9UD71 phosphorylation is reduced by administration of the P21554 receptor antagonist , SR141716A ( 3mg / kg ) . A similar attenuation of the effect of THC is also exerted by suppression of DB02527 signaling achieved using the dopamine D1 receptor antagonist , SCH23390 ( 0 . 125 mg / kg ) , or the adenosine A2A receptor antagonist , KW6002 ( 3mg / kg ) . These results indicate that , in the striatum , THC promotes PKA - dependent phosphorylation of Q9UD71 in striatal medium spiny neurons expressing dopamine D1 and adenosine A2A receptors .",
"Pharmacological characterization of mitogen - activated protein kinase activation by recombinant human P28335 , 5 - Q13049 , and P41595 receptors . The type 2 serotonin ( 5 - HT ( 2 ) ) receptor subfamily is known to couple to phosphoinositide hydrolysis ( PI ) and the subsequent mobilization of intracellular Ca ( 2 +) , as well as the release of arachidonic acid ( AA ) . Less is known of 5 - HT ( 2 )- mediated activation of the mitogen - activated protein kinase ( MAPK ) or extracellular signal - regulated kinase ( P27361 / 2 ) signaling . The present study measured the relative efficacies and potencies of 5 - HT agonists to activate P28482 in non - neuronal cells expressing recombinant human 5 - HT ( 2A ) , 5 - HT ( 2B ) , and 5 - HT ( 2C ( ISV )) receptors . 5 - HT agonists stimulated P28482 activity via all three 5 - HT ( 2 ) subtypes . There were no meaningful differences in the potencies or relative efficacies of these agonists to affect P28482 activity vs . PI accumulation or Ca ( 2 +) mobilization , suggesting that these pathways may be sequentially linked . Indeed , P28482 activity was very sensitive to PKC inhibition and calcium chelation and insensitive to tyrosine kinase and P19957 - kinase inhibition . 5 - HT ( 2 ) receptors efficiently couple to MAPK activation via sequential PI hydrolysis , and Ca ( 2 +) mobilization . This profile differs from reports of \" agonist - directed trafficking of receptor stimulus \" between PI / Ca ( 2 +) and AA pathways activated by 5 - HT ( 2 ) receptors .",
"MGC9753 gene , located within Q9UD71 - Q14849 - P04626 - Q14451 amplicon on human chromosome 17q12 , encodes the seven - transmembrane receptor with extracellular six - cystein domain . MYC , P04626 , MET , P21802 , P24864 , P04198 , P09544 , P16070 , Q00987 , Q9Y6Q9 , P46940 and O14965 loci are amplified in human gastric cancer . It has been reported that the gene corresponding to EST H16094 is co - amplified with P04626 gene in human gastric cancer . Here , we identified and characterized the gene corresponding to EST H16094 by using bioinformatics . BLAST programs revealed that EST H16094 was derived from the uncharacterized MGC9753 gene . Two ORFs were predicted within human MGC9753 mRNA , and ORF1 ( nucleotide position 18 - 980 of NM_033419 . 1 ) was predicted as the coding region of human MGC9753 mRNA based on comparative genomics . Nucleotide sequence of mouse Mgc9753 mRNA was next determined in silico by modification of AK052486 cDNA ( deleting C at the nucleotide position 37 ) . Human MGC9753 and mouse Mgc9753 proteins were 320 - amino - acid seven - transmembrane receptors with the N - terminal six - cysteine domain and an N - glycosylation site ( 85 . 0 % total - amino - acid identity ) . Human MGC9753 protein showed 90 . 6 % total - amino - acid identity with human CAB2 aberrant protein , which lacked the third - transmembrane domain of MGC9753 due to frame shifts within ORF . Human MGC9753 gene , consisting of eight exons , were clustered with Q9UD71 , Q14849 , O15273 , PNMT , P04626 , MGC14832 and Q14451 genes within the 120 - kb region . Q9UD71 , Q14849 , MGC9753 , P04626 and Q14451 genes are co - amplified in several cases of gastric cancer . This is the first report on comprehensive characterization of the amplicon around the Q9UD71 - Q14849 - O15273 - PNMT - MGC9753 - P04626 - MGC14832 - Q14451 locus on human chromosome 17q12 .",
"Integrative gene network analysis provides novel regulatory relationships , genetic contributions and susceptible targets in autism spectrum disorders . Autism spectrum disorders ( ASDs ) are a group of diseases exhibiting impairment in social drive , communication / language skills and stereotyped behaviors . Though an increased number of candidate genes and molecular interactions have been identified by various approaches , the pathogenesis remains elusive . Based on clinical observations , data from accessible GWAS and expression datasets we identified ASDs gene candidates . Integrative gene network and a novel CNV - centric Node Network ( CNN ) analysis method highlighted ASDs - associated key elements and biological processes . Functional analysis identified neurological functions including synaptic cholinergic receptor ( CHRNA ) families , dopamine receptor ( P14416 ) , and correlations between social behavior and oxytocin related pathways . CNN analysis of genome - wide genetic and expression data identified inheritance - related clusters related to P60484 / Q92574 / Q06787 and mTor / PI3K regulation . Integrative analysis identified potential regulators of networks , specifically P01375 and beta - estradiol , suggesting a potential central role in ASDs . Our data provide information on potential disease mechanisms , and key regulators that may generate novel postulations , and diagnostic molecular biomarkers .",
"The interaction of thymidylate synthase expression with p53 - regulated signaling pathways in tumor cells . P04818 ( TS ) is a chemotherapeutic target for the fluoropyrimidine 5 - fluorouracil ( ___MASK96___ ) and antifolate tomudex ( TDX ) . Using the MCF - 7 breast cancer line , we have developed a cell line with inducible TS expression termed M7TS90 . Inducible TS expression in this line resulted in a moderate ( approximately 3 - fold ) increase in ___MASK96___ 50 % inhibitory concentration at 72 hours ( IC - 50 ( 72 h ) ) dose and a dramatic ( approximately 24 - fold ) increase in the IC - 50 ( 72 h ) dose of TDX , but did not affect chemosensitivity to cisplatin , oxaliplatin , irinotecan , and paclitaxel . In the absence of drug treatment , inducible TS expression had no effect on expression of the p53 tumor suppressor gene . However , TS induction abrogated p53 , P38936 , Fas , and Bak induction in response to TDX , but not ___MASK96___ . Similarly , downregulation of Bcl - 2 was reversed by inducible TS expression in TDX , but not ___MASK96___ - treated cells . Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX , but not ___MASK96___ .",
"Unfavourable expression of pharmacologic markers in mucinous colorectal cancer . Patients with mucinous colorectal cancer generally have worse prognoses than those with the nonmucinous variety . The reason for this disparity is unclear , but may result from a differential response to adjuvant chemotherapy . We examined known molecular markers for response to common chemotherapy in these two histological subtypes . In all , 21 patients with mucinous and 30 with nonmucinous Dukes C colorectal cancer were reviewed for demographic data and outcome . Total RNA from the tumours and adjacent normal mucosa was isolated and reverse transcribed . Quantitative expression levels of drug pathway genes were determined using TaqMan RT - PCR ( 5 - fluorouracil ( ___MASK96___ ) : P04818 , Q12882 , P19971 ; oxaliplatin : P09211 ( glutathione S - transferase pi ) , P07992 and 2 ; irinotecan : P08183 , Q9UNQ0 , P08684 , P22309 , CES2 , P11387 ) . Mucinous tumours significantly overexpressed both P04818 and P09211 relative to nonmucinous tumours and patient - matched normal mucosa . No significant differences in expression of the remaining markers were found . Mean follow - up was 20 months ; 17 patients had recurrent disease . Among patients receiving ___MASK96___ , those with mucinous tumours experienced shorter disease - free survival ( DFS ) than those with nonmucinous tumours ( median DFS 13 . 8 vs 46 . 5 months , P = 0 . 053 ) . Mucinous colorectal cancer overexpresses markers of resistance to ___MASK96___ and oxaliplatin . Likewise , DFS may be decreased in patients with mucinous tumours who receive ___MASK96___ . The presence of mucin should be carefully evaluated in developmental trials of new agents for treating colorectal cancer .",
"DB01235 - treatment in primates disrupts the expression of A ( 2A ) adenosine - CB ( 1 ) cannabinoid - P14416 heteromers in the caudate nucleus . The molecular basis of priming for DB01235 - induced dyskinesias in Parkinson ' s disease ( PD ) , which depends on the indirect pathway of motor control , is not known . In rodents , the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A ( 2A ) adenosine , CB ( 1 ) cannabinoid and D ( 2 ) dopamine receptors that regulate dopaminergic neurotransmission . The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson ' s disease and to determine whether their expression and pharmacological properties are altered upon DB01235 treatment . By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint , we discovered a regional distribution of A ( 2A )/ CB ( 1 ) / D ( 2 ) receptor heteromers that predicts differential D ( 2 )- mediated neurotransmission in the caudate - putamen of Macaca fascicularis . Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP - treated monkeys , DB01235 treatment blunted the biochemical fingerprint and led to weak heteromer expression . These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A ( 2A )- CB ( 1 ) - D ( 2 ) receptor heteromers may be successful to either normalize basal ganglia output or prevent DB01235 - induced side effects .",
"[ Association and interaction of AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 and P35354 genes on the risk of hypertension in Antioquian population ] . INTRODUCTION : Hypertension is a multifactorial disease influenced by genetic and environmental components , with its prevalence varying across ethnic groups . Manifold studies on blood pressure regulatory system genes have been carried out - such as the renin - angiotensin - aldosterone system , the sympathetic nervous system , endothelial factor , and sodium balance - , but the results yielded were inconsistent among populations . OBJECTIVES : To evaluate the effect of both variants in genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 P35354 , and the result of the individual ancestry component on hypertension and blood pressure levels among population in Antioquia . METHODS AND MATERIALS : 107 cases and 253 controls were genotyped for 12 variants on genes AGT , P30556 , P12821 , P07550 , P21728 , P35611 , P35612 , P20020 , P21731 y P35354 , and for 20 ancestry informative markers . The association of polymorphisms and their interactions , and the association of ancestral genetic composition with hypertension and blood pressure levels were examined . RESULTS : Genes P35612 , rs4852706 ( OR = 3 . 0 ; p = 0 . 023 ) ; P21728 , rs686 ( OR = 0 . 38 ; p = 0 . 012 ) and P07550 , rs1042718 ( OR = 10 . 0 ; p = 0 . 008 ) ; as well as genotypic combinations of P21728 and P30556 ; AGT and P35611 ; and P35611 to P20020 and P35354 were associated to hypertension . The Amerindian ancestry component was associated to some decrease in diastolic blood pressure . CONCLUSION : Variants on genes P35612 , P21728 , P07550 , P30556 , AGT , P35611 , P20020 and P35354 individually or interacting , are associated to hypertension . The Amerindian ancestry component has an effect on blood pressure .",
"P21554 knockout mice display significant changes in striatal opioid peptide and D4 dopamine receptor gene expression . Antagonism of the CB ( 1 ) cannabinoid receptor ( CB ( 1 ) receptor ) by rimonabant ( SR141716 ) reduces self - administration of alcohol and other drugs of abuse in animal models . These findings suggest that the CB ( 1 ) receptor may be a target for genetic differences that modify the salient features of rewarding drugs . In the present study , wild - type ( CB ( 1 ) ( +/+ ) ) are compared to transgenic mice deficient in CB ( 1 ) receptors ( CB ( 1 ) ( -/- ) ) . The goal was to investigate the influences of the cannabinoid receptor system on opioid peptide gene expression and on dopamine receptor gene expression which is commonly influenced by substances of abuse . We demonstrate using reverse transcription and real - time polymerase chain reaction ( PCR ) that striatal mRNA for preproenkephalin ( PPENK ) and preprodynorphin ( PPDYN ) in the CB ( 1 ) ( -/- ) striatum increases when compared to CB ( 1 ) ( +/+ ) . Real - time PCR analyses to evaluate D ( 2 ) and P21917 gene expression in striatum isolated from CB ( 1 ) ( +/+ ) and CB ( 1 ) ( -/- ) revealed a nearly 2 - fold increase in D ( 4 ) receptor mRNA in the striatum from CB ( 1 ) ( -/- ) mice and no significant change in D ( 2 ) expression . In contrast , treatment of C57BL / 6 mice with the CB ( 1 ) receptor antagonist , rimonabant , produced a reduction of both D ( 2 ) and P21917 expression in the striatum . These data suggest that genetic differences in CB ( 1 ) receptor may exert a modulatory effect on P21917 and opioid peptide gene expression .",
"Dopamine receptor agonists reverse behavioral abnormalities of alpha - synuclein transgenic mouse , a new model of Parkinson ' s disease . Parkinson ' s disease ( PD ) is characterized by loss of nigral dopaminergic ( DAergic ) neurons and presence of Lewy bodies , whose major component is alpha - synuclein . We had previously generated transgenic mice termed Syn130m that express truncated human alpha - synuclein ( amino acid residues 1 - 130 ) in DAergic neurons . Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta . Subsequently , the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly . In the present study , we investigated behavioral responses of Syn130m mice to DB01235 and DA receptor agonists . Administration of DB01235 dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice . Similarly , D ( 2 ) agonists , quinpirole and talipexole , and a D1 / D2 agonist , pergolide , were effective against the reduction . Syn130m mice also showed significant reduction in exploratory behavior compared with non - Tg littermates when they were placed in a novel environment , but this abnormality was ameliorated by treatment with pergolide . These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content . On the other hand , the expression of postsynaptic D ( 2 )- like receptors ( P14416 ) in the striatum was not increased in Syn130m mice , although the low striatal DA level is known to induce compensatory expression of P14416 . Because the abnormalities could be rectified by treatment with DA receptor agonists , it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease .",
"Dysregulation of gene expression in primary neuron models of Huntington ' s disease shows that polyglutamine - related effects on the striatal transcriptome may not be dependent on brain circuitry . Gene expression changes are a hallmark of the neuropathology of Huntington ' s disease ( HD ) , but the exact molecular mechanisms of this effect remain uncertain . Here , we report that in vitro models of disease comprised of primary striatal neurons expressing N - terminal fragments of mutant huntingtin ( via lentiviral gene delivery ) faithfully reproduce the gene expression changes seen in human HD . Neither viral infection nor unrelated ( enhanced green fluorescent protein ) transgene expression had a major effect on resultant RNA profiles . Expression of a wild - type fragment of huntingtin [ htt171 - 18Q ] also caused only a small number of RNA changes . The disease - related signal in htt171 - 82Q versus htt171 - 18Q comparisons was far greater , resulting in the differential detection of 20 % of all mRNA probe sets . Transcriptomic effects of mutated htt171 are time - and polyglutamine - length dependent and occur in parallel with other manifestations of polyglutamine toxicity over 4 - 8 weeks . Specific RNA changes in htt171 - 82Q - expressing striatal cells accurately recapitulated those observed in human HD caudate and included decreases in P01210 ( proenkephalin ) , P49798 ( regulator of G - protein signaling 4 ) , dopamine D ( 1 ) receptor ( P21728 ) , P14416 , P21554 ( cannabinoid CB ( 1 ) receptor ) , and Q9UD71 ( dopamine - and DB02527 - regulated phosphoprotein - 32 ; also known as Q9UD71 ) mRNAs . HD - related transcriptomic changes were also observed in primary neurons expressing a longer fragment of mutant huntingtin ( htt853 - 82Q ) . The gene expression changes observed in cultured striatal neurons are not secondary to abnormalities of neuronal firing or glutamatergic , dopaminergic , or brain - derived neurotrophic factor signaling , thereby demonstrating that HD - induced dysregulation of the striatal transcriptome might be attributed to intrinsic effects of mutant huntingtin .",
"Sorting nexin 5 and dopamine d1 receptor regulate the expression of the insulin receptor in human renal proximal tubule cells . Sorting nexin 5 ( Q9Y5X3 ) belongs to the P20073 family , which is composed of a diverse group of proteins that mediate trafficking of plasma membrane proteins , receptors , and transporters . Q9Y5X3 is important in the resensitization of the dopamine D1 - like receptor ( D1R ) . D1R is uncoupled from its effector proteins in hypertension and diabetes , and treatment of diabetes restores D1R function and insulin receptor ( IR ) expression . We tested the hypothesis that the D1R and Q9Y5X3 regulate IR by studying the expression , distribution , dynamics , and functional consequences of their interaction in human renal proximal tubule cells ( hRPTCs ) . D1R , Q9Y5X3 , and IR were expressed and colocalized in the brush border of RPTs . P01308 promoted the colocalization of Q9Y5X3 and IR at the perinuclear area of hRPTCs . Unlike Q9Y5X3 , the D1R colocalized and coimmunoprecipitated with IR , and this interaction was enhanced by insulin . To evaluate the role of Q9Y5X3 and D1R on IR signaling , we silenced via RNA interference the endogenous expression of Q9Y5X3 or the D1R gene P21728 in hRPTCs . We observed a decrease in IR expression and abundance of phosphorylated IR substrate and phosphorylated protein kinase B , which are crucial components of the IR signal transduction pathway . Our data indicate that Q9Y5X3 and D1R are necessary for normal IR expression and activity . It is conceivable that D1R and Q9Y5X3 may interact to increase the sensitivity to insulin via a positive regulation of IR and insulin signaling .",
"Blockade of globus pallidus adenosine A ( 2A ) receptors displays antiparkinsonian activity in 6 - hydroxydopamine - lesioned rats treated with D ( 1 ) or P14416 agonists . We have recently demonstrated how antagonism of adenosine A ( 2A ) receptors within the globus pallidus ( GP ) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor DB01235 in 6 - hydroxydopamine - lesioned hemiparkinsonian rats . To further characterize the influence of pallidal A ( 2A ) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation , hemiparkinsonian rats were infused with the water - soluble A ( 2A ) antagonist P35240 BT2 in the GP , alone or in combination with systemic administration of either SKF 38393 or quinpirole , to stimulate dopamine D ( 1 ) or D ( 2 ) receptors , respectively . P35240 BT2 alone ( 5 mug / 1 mul ) neither altered motor behavior nor produced postural asymmetry . In contrast , the contralateral rotations elicited by SKF 38393 ( 1 . 5 mg / kg ) as well as quinpirole ( 0 . 05 mg / kg ) were potentiated by the concomitant intrapallidal infusion of P35240 BT2 . The results of this study demonstrate that blockade of pallidal A ( 2A ) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D ( 1 ) or D ( 2 ) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A ( 2A ) receptor antagonists .",
"Direct analysis of candidate genes in impulsive behaviours . Antisocial behaviour is both heterogeneous and the product of interacting genetic and environmental factors acting at different levels of causation . Heritability studies show that individual differences in predisposition to antisocial behaviour are transmitted vertically in families by genetic mechanisms . Owing to aetiological heterogeneity and complexity , study of a variety of other behavioural phenotypes may shed more light on the antecedents of antisocial behaviour than direct studies on antisocial behaviour . Identification of genetic vulnerability factors would clarify mechanisms of vulnerability and the role of the environment . Direct gene analysis and genetic linkage analysis have identified structural variants in genes involved in neurotransmitter function , and some progress has been made towards relating these genetic variants to antisocial personality and other behaviours . Thyroid hormone receptor variants can cause attention deficit / hyperactivity disorder , and a monoamine oxidase A variant leads to aggressive behaviour in one family . Direct gene analyses have revealed non - conservative amino acid substitutions and structural variants ( generally rare ) at P14416 , P35462 and P21917 dopamine receptors and P08908 , 5 - Q13049 , P28335 and P34969 serotonin receptors . The stage is set to identify the phenotypic significance of these as well as genetic variants at other loci which may be relevant as candidate genes for antisocial behaviour and related behavioural differences .",
"Effect of milk hydrolysates on inflammation markers and drug - induced transcriptional alterations in cell - based models . Nonsteroidal anti - inflammatory drugs ( NSAID ) are associated with gastrointestinal inflammation and subsequent damage to the intestinal tissue . Earlier studies in our laboratory have found that specific casein hydrolysates ( CH ) might be useful in the treatment of gastrointestinal wounds . The underlying mechanisms that support inflammation and wound healing are not completely understood , but transcriptional alterations may be used as markers for inflammation and wound healing . The bioactivity of 3 CH prepared by treatment of commercial casein with pepsin ( 60 min ) followed by corolase ( 0 , 10 , or 60 min ) were investigated in intestinal epithelial cells treated with the NSAID indomethacin . The bioactivity was evaluated as transcriptional alterations of transforming growth factor - β1 ( TGF - β1 ) , cyclooxygenase - 2 ( P35354 ) , peroxisome proliferator - activated receptor - γ ( Q07869 - γ ) and nuclear factor κB ( NFκB ) by real - time PCR . Furthermore , the effect of CH on lipopolysaccharide - induced inflammation was evaluated in macrophages by measuring PG E ( 2 ) levels . Casein hydrolysates treated with corolase for 10 or 60 min after pepsin treatment downregulated transcription of TGF - β1 and NFκB ( P < 0 . 05 ) compared with the hydrolysate treated with pepsin only . Hydrolysate prepared by corolase treatment for 60 min after pepsin hydrolysis downregulated transcription of P35354 ( P < 0 . 05 ) compared with hydrolysate treated with corolase for only 10 min whereas transcription of Q07869 - γ was not affected ( P > 0 . 05 ) . Additionally , the hydrolysate prepared by pepsin treatment only ( 0 min corolase ) had a pro - inflammatory effect on macrophages via PG E ( 2 ) stimulation ( P < 0 . 05 ) . In conclusion , CH produced by a combination of pepsin and corolase treatments downregulated the transcription levels of TGF - β1 , P35354 , and NFκB .",
"P35462 stimulation underlies the development of DB01235 - induced dyskinesia in animal models of Parkinson ' s disease . Development of DB01235 - induced dyskinesia ( LID ) remains a major problem in the long - term treatment of Parkinson ' s disease ( PD ) . Sensitization to DB01235 correlates with ectopic expression of D3 dopamine receptors in the striatum , implicating D3 receptors in development of LID . We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP - lesioned marmosets without effecting the anti - parkinsonian actions of DB01235 . Furthermore , following a 14 day washout , when challenged with DB01235 in the absence of S33084 , these animals continued to exhibit reduced LID . In the 6 - OHDA - lesioned rat , S33084 similarly attenuated development of behavioural sensitization to DB01235 . Additionally , DB01235 - induced elevations in striatal pre - proenkephalin - A ( PPE - A ) ( but not PPE - B , phospho [ DB00156 ( 34 )] Q9UD71 , D1 , and D2 receptor mRNA or D3 receptor levels ) were reduced in S33084 treated animals . Our data suggest a role for D3 receptors in the development of LID and suggest that initiating DB01235 treatment with a D3 antagonist may reduce the development of LID in PD .",
"Concise prediction models of anticancer efficacy of 8 drugs using expression data from 12 selected genes . We developed concise , accurate prediction models of the in vitro activity for 8 anticancer drugs ( ___MASK96___ , DB00515 , DB00305 , DOX , CPT - 11 , SN - 38 , TXL and TXT ) , along with individual clinical responses to ___MASK96___ using expression data of 12 genes . We first performed cDNA microarray analysis and MTT assay of 19 human cancer cell lines to sort out genes which were correlative in expression levels with cytotoxicities of the 8 drugs ; we selected 13 genes with proven functional significance to drug sensitivity from a huge number of potent prediction marker genes . The correlation significance of each was confirmed using expression data quantified by real - time RT - PCR , and finally 12 genes ( P08183 , Q9UNQ0 , P10632 , P08684 , Q12882 , P09211 , P16455 , P15559 , P16435 , P11388 , P07437 and P04818 ) were selected as more reliable predictors of drug response . Using multiple regression analysis , we fixed 8 prediction formulae which embraced the variable expressions of the 12 genes and arranged them in order , to predict the efficacy of the drugs by referring to the value of Akaike ' s information criterion for each sample . These formulae appeared to accurately predict the in vitro efficacy of the drugs . For the first clinical application model , we fixed prediction formulae for individual clinical response to ___MASK96___ in the same way using 41 clinical samples obtained from 30 gastric cancer patients and found to be of predictive value in terms of survival , time to treatment failure and tumor growth . None of the 12 selected genes alone could predict such clinical responses .",
"Sustained increase of PKA activity in the postcommissural putamen of dyskinetic monkeys . Levodopa - induced dyskinesias ( LID ) are a frequent complication of Parkinson ' s disease pharmacotherapy that causes significant disability and narrows the therapeutic window . Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood . Here , our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication . We examined the expression and downstream activity of dopamine receptors ( DR ) in the striatum of 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 tetrahydropiridine ( MPTP ) - lesioned monkeys with and without DB01235 treatment . Four monkeys were made dyskinetic and other four received a shorter course of DB01235 and did not develop LID . Our results show that DB01235 treatment induces an increase in P14416 and P35462 expression in the postcommissural putamen , but only P35462 is correlated with the severity of LID . Dyskinetic monkeys show a hyperactivation of the canonical P21728 - signaling pathway , measured by an increased phosphorylation of protein kinase A ( PKA ) and its substrates , particularly Q9UD71 . In contrast , activation of the P14416 - signaling pathway , visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9 , is associated with DB01235 treatment , independently of the presence of dyskinesias . Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the P35462 receptor and the P21728 pathway with a sustained increase of PKA activity in the postcommissural putamen . Importantly , we found that all signaling changes related to long - term DB01235 administration are exquisitely restricted to the postcommissural putamen , which may be related to the recurrent failure of pharmacological approaches .",
"P12821 inhibitors could be therapeutic for antisocial personality disorder . Antisocial personality traits are an important topic for research . The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes . Catecholamine genes are being studied to facilitate this understanding , and some tentative findings are being reached about several of these genes . It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious . One conclusion that could be drawn from the current research findings is that DA2 like receptors ( P14416 , P35462 , P21917 ) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors . DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition . When these receptors are less active by genetically decreased density , lower affinity , or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state . Peripheral metabolism is increased and behavioral activation is noted . P00797 is disinhibited in this setting thus allowing sympathetic nervous system activation . The fight or flight behaviors thus produced , in the extreme , would be the setting of antisocial behavior . Research validates this hypothesis . Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others . P12821 inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders .",
"DNA methylation profiles in diffuse large B - cell lymphoma and their relationship to gene expression status . In an initial epigenetic characterization of diffuse large B - cell lymphoma ( DLBCL ) , we evaluated the DNA methylation levels of over 500 CpG islands . Twelve CpG islands ( AR , P49918 , DLC1 , P14416 , P43694 , P39905 , Q13224 , P42898 , P15172 , Q13562 , O95948 and P05549 ) showed significant methylation in over 85 % of tumors . Interestingly , the methylation levels of a CpG island proximal to FLJ21062 differed between the activated B - cell - like ( ABC - DLBCL ) and germinal center B - cell - like ( GCB - DLBCL ) subtypes . In addition , we compared the methylation and expression status of 67 genes proximal ( within 500 bp ) to the methylation assays . We frequently observed that hypermethylated CpG islands are proximal to genes that are expressed at low or undetectable levels in tumors . However , many of these same genes were also poorly expressed in DLBCL tumors where their cognate CpG islands were hypomethylated . Nevertheless , the proportional reductions in Q12983 , P16455 , RBP1 , P43694 , Q9BY67 , P29762 and FLJ21062 expression with increasing methylation suggest that epigenetic processes strongly influence these genes . Lastly , the moderate expression of several genes proximal to hypermethylated CpG tracts suggests that DNA methylation assays are not always accurate predictors of gene silencing . Overall , further investigation of the highlighted CpG islands as potential clinical biomarkers is warranted .",
"Agonism at P41595 receptors is not a class effect of the ergolines . Restrictive cardiac valvulopathies observed in Parkinson patients treated with the ergoline dopamine agonist pergolide have recently been associated with the agonist efficacy of the drug at 5 - hydroxytryptamine2B ( P41595 ) receptors . To evaluate whether agonism at P41595 receptors is a phenomenon of the class of the ergolines , we studied P41595 receptor - mediated relaxation in porcine pulmonary arteries to five ergolines which are used as antiparkinsonian drugs . DB01186 and cabergoline were potent full agonists in this tissue ( pEC50 8 . 42 and 8 . 72 ) . ___MASK18___ acted as a partial agonist ( pEC50 6 . 86 ) . Lisuride and terguride , however , failed to relax the arteries but potently antagonized 5 - HT - induced relaxation ( pKB 10 . 32 and 8 . 49 ) . Thus , agonism at P41595 receptors seems not to be a class effect of the ergolines .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"Expression of P00533 and molecules downstream to PI3K / Akt , P04049 - MEK - 1 - Q96HU1 ( Erk1 / 2 ) , and JAK ( P40763 ) pathways in invasive lung adenocarcinomas resected at a single institution . Therapies targeting P00533 are effective in treating tumors that harbor molecular alterations ; however , there is heterogeneity in long - term response to these therapies . We retrospectively analyzed protein expression of P00533 , Stat3 , phospho - Akt , and phospho - Erk1 / 2 by immunohistochemistry in a series of resected cases from a single institution , correlated with clinicopathological variables . There were 96 patients , with the majority of cases being of low stage tumors ( 17 pT1a , 23 pT1b , 30 pT2a , and 18 pT2b ) . Histologic subtypes were 45 acinar predominant , 2 cribriform , 25 solid , 7 papillary , 11 lepidic , and 4 mucinous tumors . The P00533 score was higher in tumors with vascular invasion ( P = 0 . 013 ) , in solid and cribriform acinar histology , and in high stage tumors ( P = 0 . 006 and P = 0 . 01 ) . P00533 was more likely overexpressed in solid compared to lepidic tumors ( P = 0 . 02 ) . Acinar tumors had the highest rate of P27361 / 2 positivity ( 19 % ) . There was a strong correlation among positivity for P07992 and other markers , including P40763 ( P = 0 . 003 ) , Akt ( P = 0 . 02 ) , and P27361 / P28482 ( P = 0 . 0005 ) . Expression of molecules downstream to P00533 varied from 12 % to 31 % of tumors ; however , the expression did not directly correlate to P00533 expression , which may suggest activation of the cascades through different pathways . The correlation of protein expression and the new lung adenocarcinoma classification may help in the understanding of activated pathways of each tumor type , which may act in the oncogenesis and drug resistance of these tumors .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK74___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"The P38936 codon 31 * C - and P14416 codon 313 * T - related genotypes / alleles , but not P18887 codon 399 , hOGG1 codon 326 , and P21728 - 48 polymorphisms , are correlated with the presence of leiomyoma . OBJECTIVE : To investigate whether the gene polymorphisms for P38936 , X - ray repair cross - complementing group 1 ( P18887 ) , human 8 - oxoguanine glycosylase 1 ( hOGG1 ) , and dopamine D1 and D2 receptors ( P21728 , - 2 ) are associated with leiomyoma susceptibility . DESIGN : Prospective study . SETTING : Departments of gynecology and genetics in a medical center . PATIENT ( S ) : Women were divided into two groups : leiomyoma ( n = 120 ) and nonleiomyoma ( n = 112 ) . INTERVENTION ( S ) : The P38936 codon 31 , P18887 codon 399 , hOGG1 codon 326 , P21728 - 48 , and P14416 codon 313 polymorphisms were genotyped by polymerase chain reaction with restriction enzyme digestions ( Blp I , MspI , Fnu4HI , Dde I , and NcoI , respectively ) . MAIN OUTCOME MEASURE ( S ) : Genotypes and allelic frequencies . RESULT ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyomas . The proportions of P38936 (*) CC / CA / AA and P14416 (*) CC / CT / TT in both groups were 27 . 5 / 68 . 3 / 4 . 2 % and 12 . 5 / 51 . 7 / 35 . 8 % ( leiomyoma ) ; and 14 . 3 / 51 . 8 / 33 . 9 % and 33 . 9 / 40 . 2 / 25 . 9 % ( nonleiomyoma ) . P18887 , hOGG1 , and P21728 were not correlated with the presence of leiomyomas . P18887 (*) GG / GA / AA , hOGG1 (*) TT / TA / AA , and P21728 (*) GG / GA / AA were 54 . 2 / 37 . 5 / 8 . 3 % , 36 . 7 / 44 . 2 / 19 . 1 % , and 3 . 3 / 25 . 8 / 70 . 8 % ( leiomyoma ) ; and 48 . 2 / 47 . 3 / 4 . 5 % , 43 . 6 / 41 / 15 . 4 % , and 3 . 6 / 25 / 71 . 4 % ( nonleiomyoma ) . CONCLUSION ( S ) : The P38936 codon 31 (*) C - and P14416 codon 313 (*) T - related genotypes / alleles were associated with the presence of leiomyoma . P18887 , hOGG1 , and P21728 were not correlated with leiomyoma development .",
"[ The effect of bunazosin vs captopril on hemodynamic and neurohumoral parameters in patients with congestive heart failure ] . The hemodynamic parameters ( right atrial pressure , mean pulmonary artery pressure , pulmonary capillary wedge pressure , cardiac index , heart rate , blood pressure ) and neurohumoral responses ( alpha - P01160 , plasma renin activity , aldosterone , angiotensin II ) of ___MASK70___ , oral P12821 inhibitor , and Bunazosin , oral alpha 1 - blocker , were investigated in 28 patients with congestive heart failure at rest and after exercise . These data were analysed in both acute and chronic phases . 1 ) Acute effect . ___MASK70___ produced significant improvement of neurohumoral factors at rest and also after exercise . Bunazosin reduced alpha - P01160 , but other neurohumoral factors did not change . Bunazosin produced significant hemodynamic improvement both at rest and after exercise . 2 ) Chronic effect . ___MASK70___ produced significant hemodynamic improvement both at rest and after exercise . Improvement of neurohumoral factors in acute phase was also preserved at chronic phase . On Bunazosin , improvement of hemodynamics at acute phase was also preserved at chronic phase without deterioration of neurohumoral factors .",
"The role of the subthalamic nucleus in DB01235 induced dyskinesia in 6 - hydroxydopamine lesioned rats . DB01235 is the most effective treatment for Parkinson ' s disease ( PD ) , but prolonged use leads to disabling motor complications including dyskinesia . Strong evidence supports a role of the subthalamic nucleus ( Q05639 ) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy . Here , we investigated the involvement of Q05639 in dyskinesia , using single - unit extracellular recording , behavioural and molecular approaches in hemi - parkinsonian rats rendered dyskinetic by chronic DB01235 administration . Our results show that chronic DB01235 treatment does not modify the abnormal Q05639 activity induced by the 6 - hydroxydopamine lesion of the nigrostriatal pathway in this model . Likewise , we observed a loss of Q05639 responsiveness to a single DB01235 dose both in lesioned and sham animals that received daily DB01235 treatment . We did not find any correlation between the abnormal involuntary movement ( AIM ) scores and the electrophysiological parameters of Q05639 neurons recorded 24 h or 20 - 120 min after the last DB01235 injection , except for the axial subscores . Nonetheless , unilateral chemical ablation of the Q05639 with ibotenic acid resulted in a reduction in global AIM scores and peak - severity of dyskinesia . In addition , Q05639 lesion decreased the anti - dyskinetogenic effect of buspirone in a reciprocal manner . Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB , phosphoDARPP - 32 , dopamine receptor ( DR ) D3 and P14416 / P21728 ratio . The Q05639 lesion attenuated the striatal molecular changes and normalized the P14416 / P21728 ratio . Taken together , our results show that the Q05639 plays a role , if modest , in the physiopathology of dyskinesias .",
"Dissociable fronto - striatal effects of dopamine D2 receptor stimulation on cognitive versus motor flexibility . Genetic and pharmacological studies suggest an important role of the dopamine D2 receptor ( P14416 ) in flexible behavioral adaptation , mostly shown in reward - based learning paradigms . Recent evidence from imaging genetics indicates that also intentional cognitive flexibility , associated with lateral frontal cortex , is affected by variations in P14416 signaling . In the present functional magnetic resonance imaging ( Q9BWK5 ) study , we tested the effects of a direct pharmacological manipulation of P14416 stimulation on intentional flexibility in a task - switching context , requiring switches between cognitive task rules and between response hands . In a double blind , counterbalanced design , participants received either a low dose of the P14416 agonist bromocriptine or a placebo in two separate sessions . ___MASK18___ modulated the blood - oxygen - level - dependent ( BOLD ) signal during rule switching : rule - switching - related activity in the left posterior lateral frontal cortex and in the striatum was increased compared to placebo , at comparable performance levels . Fronto - striatal connectivity under bromocriptine was slightly increased for rule switches compared to rule repetitions . Hand - switching - related activity , in contrast , was reduced under bromocriptine in sensorimotor regions . Our results provide converging evidence for an involvement of P14416 signaling in fronto - striatal mechanisms underlying intentional flexibility , and indicate that the neural mechanisms underlying different types of flexibility ( cognitive vs motor ) are affected differently by increased dopaminergic stimulation .",
"P01308 action in cultured human myoblasts : contribution of different signalling pathways to regulation of glycogen synthesis . A key metabolic action of insulin is the stimulation of non - oxidative glucose utilization in skeletal muscle , by increasing both glucose uptake and glycogen synthesis . The molecular mechanism underlying this process has been investigated using a variety of experimental systems . We report here the use of cultured human myoblasts to study insulin control of glycogen synthesis in humans . In these cells insulin stimulates glycogen synthesis approx . 2 . 2 - fold , associated with a similar activation of glycogen synthase ( GS ) which occurs within 5 - 10 min of the addition of insulin . P01308 also causes inactivation of glycogen synthase kinase - 3 ( GSK - 3 ) and activation of protein kinase B , both processes being sufficiently rapid to account for the effects of insulin on GS . Activation by insulin of the protein kinases p70s6K , p90s6K and extracellular signal - regulated kinase 2 ( P28482 ) is observed , but is significantly slower than the activation of GS . Selective inhibitors of the p70s6K pathway ( rapamycin ) , the P28482 / p90s6K pathway ( PD98059 ) and phosphatidylinositol 3 - kinase ( wortmannin ) have been used to probe the contribution of these components to insulin signalling in human muscle . Wortmannin blocks activation of both glycogen synthesis and GS and inactivation of GSK - 3 . PD98059 is without effect on these events , while rapamycin is without effect on inactivation of GSK - 3 but partially blocks activation of glycogen synthesis and GS . Taken together , these findings suggest that protein kinase B is responsible for the inactivation of GSK - 3 , but that an additional rapamycin - sensitive mechanism may contribute to the activation of GS and stimulation of glycogen synthesis .",
"LG839 : anti - obesity effects and polymorphic gene correlates of reward deficiency syndrome . INTRODUCTION : This study systematically assessed the weight management effects of a novel experimental DNA - customized nutraceutical , LG839 ( LifeGen , Inc . , La Jolla , CA , USA ) . METHODS : A total of 1058 subjects who participated in the overall D . I . E . T . study were genotyped and administered an LG839 variant based on polymorphic outcomes . A subset of 27 self - identified obese subjects of Dutch descent , having the same DNA pattern of four out of the five candidate genes tested ( chi - square analysis ) as the entire data set , was subsequently evaluated . Simple t tests comparing a number of weight management parameters before and after 80 days of treatment with LG839 were performed . RESULTS : Significant results were observed for weight loss , sugar craving reduction , appetite suppression , snack reduction , reduction of late night eating ( all P < 0 . 01 ) , increased perception of overeating , enhanced quality of sleep , increased happiness ( all P < 0 . 05 ) , and increased energy ( P < 0 . 001 ) . Polymorphic correlates were obtained for a number of genes ( P41159 , Q07869 - gamma2 , P42898 , 5 - Q13049 , and P14416 genes ) with positive clinical parameters tested in this study . Of all the outcomes and gene polymorphisms , only the P14416 gene polymorphism ( A1 allele ) had a significant Pearson correlation with days on treatment ( r = 0 . 42 , P = 0 . 045 ) . CONCLUSION : If these results are confirmed in additional rigorous , controlled studies , we carefully suggest that DNA - directed targeting of certain regulator genes , along with customized nutraceutical intervention , provides a unique framework and strategic modality to combat obesity .",
"Effects of the total saponins from Rosa laevigata Michx fruit against acetaminophen - induced liver damage in mice via induction of autophagy and suppression of inflammation and apoptosis . The effect of the total saponins from Rosa laevigata Michx fruit ( RLTS ) against acetaminophen ( ___MASK66___ ) - induced liver damage in mice was evaluated in the present paper . The results showed that RLTS markedly improved the levels of liver SOD , CAT , DB00143 , DB00143 - Px , MDA , NO and P35228 , and the activities of serum ALT and Q9NRA2 caused by ___MASK66___ . Further research confirmed that RLTS prevented fragmentation of DNA and mitochondrial ultrastructural alterations based on TdT - mediated dUTP nick end labeling ( TUNEL ) and transmission electron microscopy ( TEM ) assays . In addition , RLTS decreased the gene or protein expressions of cytochrome P450 ( P05181 ) , pro - inflammatory mediators ( IL - 1β , P05112 , P05231 , P01375 - α , P35228 , Bax , HMGB - 1 and P35354 ) , pro - inflammatory transcription factors ( NF - κB and AP - 1 ) , pro - apoptotic proteins ( cytochrome C , p53 , caspase - 3 , caspase - 9 , p - JNK , p - p38 and p - P29323 ) , and increased the protein expressions of Bcl - 2 and Bcl - xL . Moreover , the gene expression of P22301 , and the proteins including LC3 , Q14457 and Atg5 induced by ___MASK66___ were even more augmented by the extract . These results demonstrate that RLTS has hepatoprotective effects through antioxidative action , induction of autophagy , and suppression of inflammation and apoptosis , and could be developed as a potential candidate to treat ___MASK66___ - induced liver damage in the future .",
"P21728 behavioral responsitivity following selective lesions of the striatal patch compartment during development . The behavioral effects of selective destruction of the dopamine ( DA ) input to the patch compartment of rat striatum early in development was investigated . Rat pups were given bilateral intrastriatal ( i . s . ) injections of the neurotoxin 6 - hydroxydopamine ( 6 - OHDA ) on day of birth ( P0 ) or postnatal day 1 ( P1 ) , which resulted in selective behavioral alterations following DA agonist treatment in adulthood . Neonatally - lesioned rats exhibited self - biting behavior following treatment with the DA precursor L - dihydroxyphenylalanine ( DB01235 ) . In response to treatment with the selective D1 agonist SKF38393 , there was an increased incidence of abnormal perioral movements . The cataleptogenic effects of the D1 antagonist SCH23390 and the D2 antagonist haloperidol were also studied . Neonatally - lesioned rats were significantly less cataleptic compared to control rats following D1 antagonist treatment , but not following D2 antagonist treatment . Autoradiographs of [ 3H ] mazindol binding to DA uptake sites ( a measure of DA terminal density ) showed a ' patchy ' loss of approx . 40 - 50 % in striatal tissue sections derived from the i . s . lesioned rats . These data suggest that injections of 6 - OHDA into the striatum during this early postnatal period cause a DA lesion that results in long - term effects on a D1 receptor system .",
"AM2389 , a high - affinity , in vivo potent P21554 - receptor - selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice . RATIONALE : The endocannabinoid signaling system ( ECS ) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies . Current focus is on chemical modifications of the hexahydrocannabinol ( HHC ) nabilone ( ___MASK23___ (®) ) . OBJECTIVE : To characterize the novel , high - affinity cannabinoid receptor 1 ( CB ( 1 ) R ) HHC - ligand AM2389 [ 9β - hydroxy - 3 -( 1 - hexyl - cyclobut - 1 - yl )- hexahydrocannabinol in two rodent pre - clinical assays . MATERIALS AND METHODS : CB ( 1 ) R mediation of AM2389 - induced hypothermia in mice was evaluated with AM251 , a CB ( 1 ) R - selective antagonist / inverse agonist . Additionally , two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 ( 0 . 18 and 0 . 56 mg / kg ) from vehicle 20 min post - injection in a two - choice operant conditioning task motivated by 0 . 1 % saccharin / water . Generalization / substitution tests were conducted with AM2389 , AM5983 , and Δ ( 9 )- tetrahydrocannabinol ( Δ ( 9 )- THC ) . RESULTS : Δ ( 9 )- THC ( 30 mg / kg )- induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 ( 0 . 1 and 0 . 3 mg / kg ) . AM251 ( 3 and 10 mg / kg ) attenuated / blocked hypothermia induced by 0 . 3 mg / kg AM2389 . In drug discrimination , the order of potency was AM2389 > AM5983 > Δ ( 9 )- THC with ED ( 50 ) values of 0 . 0025 , 0 . 0571 , and 0 . 2635 mg / kg , respectively , in the low - dose condition . The corresponding ED ( 50 ) values in the high - dose condition were 0 . 0069 , 0 . 1246 , and 0 . 8438 mg / kg , respectively . Onset of the effects of AM2389 was slow with a protracted time - course ; the functional , perceptual in vivo half - life was approximately 17 h . CONCLUSIONS : This potent cannabinergic HHC exhibited a slow onset of action with a protracted time - course . The AM2389 chemotype appears well suited for further drug development , and AM2389 currently is used to probe behavioral consequences of sustained ECS activation .",
"Selective cyclooxygenase - 2 blocker delays healing of esophageal ulcers in rats and inhibits ulceration - triggered c - DB00134 / hepatocyte growth factor receptor induction and extracellular signal - regulated kinase 2 activation . Nonsteroidal anti - inflammatory drugs , both nonselective and cyclooxygenase - 2 ( P35354 ) selective , delay gastric ulcer healing . Whether they affect esophageal ulcer healing remains unexplored . We studied the effects of the P35354 selective inhibitor , celecoxib , on esophageal ulcer healing as well as on the cellular and molecular events involved in the healing process . Esophageal ulcers were induced in rats by focal application of acetic acid . Rats with esophageal ulcers were treated intragastrically with either celecoxib ( 10 mg / kg , once daily ) or vehicle for 2 or 4 days . Esophageal ulceration triggered increases in : esophageal epithelial cell proliferation ; expression of P35354 ( but not P23219 ) ; hepatocyte growth factor ( P14210 ) and its receptor , c - DB00134 ; and activation of extracellular signal - regulated kinase 2 ( P28482 ) . Treatment with celecoxib significantly delayed esophageal ulcer healing and suppressed ulceration - triggered increases in esophageal epithelial cell proliferation , c - DB00134 mRNA and protein expression , and P28482 activity . In an ex vivo organ - culture system , exogenous P14210 significantly increased P28482 phosphorylation levels in esophageal mucosa . A structural analog of celecoxib , SC - 236 , completely prevented this effect . These findings indicate that celecoxib delays esophageal ulcer healing by reducing ulceration - induced esophageal epithelial cell proliferation . These actions are associated with , and likely mediated by , down - regulation of the P14210 / c - DB00134 - P28482 signaling pathway .",
"Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells . Histone deacetylase inhibitors are promising anti - tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies . However , little is known about any effects of these drugs on the central nervous system . The aim of the present study was to analyze the effects of trichostatin A ( P32119 ) -- a broad - spectrum histone deacetylase inhibitor -- on the transcriptional regulation of several genes involved in dopamine - and serotonergic neurotransmission . To this end , short - term parallel cultures of SK - NF - I neuroblastoma cells were treated with P32119 either alone or in combination with hypoxia , and mRNA levels of dopamine receptor D3 ( P35462 ) and D4 ( P21917 ) , dopamine transporter ( Q01959 ) , dopamine hydroxylase ( P09172 ) , dopamine receptor regulating factor ( DRRF ) , catechol - O - methyltransferase ( P21964 ) , serotonin receptor 1A ( P08908 ) , monoamino oxidase A ( P21397 ) , serotonin transporter ( P31645 ) and tryptophan hydroxylase 2 ( Q8IWU9 ) were determined by quantitative PCR . We found that P32119 did not antagonize the hypoxia - induced activation of D3 and D4 dopamine receptor genes , implying that induction of these genes is not mediated directly by hypoxia inducible factor - 1alpha . On the other hand , P32119 dramatically upregulated the expression of Q01959 and P31645 ( 45 - fold and 15 - fold , respectively ) , while transcript levels of P21397 and P21964 were significantly reduced ( by 70 % and by more than 90 % , respectively ) . Induction of Q01959 protein expression was detected by western blotting . These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons .",
"Dopamine selectively reduces GABA ( B ) transmission onto dopaminergic neurones by an unconventional presynaptic action . The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement . In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine ( DA ) release in the brain . Here , we report a concentration - dependent depressant action of dopamine on the GABA ( B ) IPSPs intracellularly recorded from dopaminergic neurones . Such effect was observed in spite of the presence of D ( 1 )/ P14416 antagonists . A reduction of the GABA ( B ) IPSPs was also caused by noradrenaline ( norepinephrine ) and by L - beta - 3 , 4 - dihydroxyphenylalanine ( DB01235 ) , which is metabolically transformed into DA . The DA - induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine . DA did not change the postsynaptic effects of the GABA ( B ) agonist baclofen , suggesting a presynaptic site of action . Furthermore , DA did not modulate the GABA ( A )- mediated IPSP . The DA - induced depression of the GABA ( B ) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists . The DA - and 5 - HT - induced depression of the GABA ( B ) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals . These results describe an unconventional presynaptic , D ( 1 ) and D ( 2 ) independent action of DA on the GABA ( B ) IPSP . This might have a principal role in determining therapeutic / side effects of DB01235 and antipsychotics and could be also involved in drug abuse .",
"Dopamine agonists upregulate P05231 and P10145 production in human keratinocytes . AIM : Catecholamines regulate functions of the nervous , neuroendocrine and immune systems . Dopamine may modulate the activity of keratinocytes , which play a role in secreting cytokines and chemokines . The aim of this study was to evaluate the effect of dopaminergic agonists on the production of P05231 and P10145 by a non - tumoral human keratinocyte cell line ( HaCaT ) . METHODS : Cells were stimulated with dopamine and the P14416 agonist cabergoline . Levels of P05231 and P10145 in culture supernatants were then determined . Cell proliferation was also assessed . Assays were carried out in the presence or absence of the dopaminergic and β - adrenergic receptor antagonists ( sulpiride and propranolol , respectively ) and ascorbic acid . RESULTS : Dopamine stimulated the production of P05231 and P10145 in a concentration - dependent manner . The effects observed on the secretion of P05231 were more potent than those corresponding to P10145 and were reduced by ascorbic acid . The dopamine - induced P05231 secretion was partially reduced by sulpiride and abrogated by propranolol . The latter drug was able to block the effect of dopamine on the secretion of P10145 . The cabergoline - induced P05231 release was reduced by sulpiride . Cell viability was not affected by any of the drugs . CONCLUSIONS : Dopaminergic agonists can stimulate keratinocytes to produce P05231 and P10145 which are related to inflammatory cutaneous processes . These effects are mediated by dopaminergic and β - adrenergic receptors and by receptor - independent oxidative mechanisms .",
"The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L - amino acid decarboxylase in healthy subjects . The A1 allele of the TaqI restriction fragment length polymorphism ( RFLP ) of the human dopamine D2 receptor gene ( P14416 ) is associated with a low density of D2 dopamine receptors in the striatum . Because of the important role of D2 autoreceptors in regulating dopamine synthesis , we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain . We also studied the effects of two other P14416 polymorphisms , C957 T and -- 141C Ins / Del , which have been suggested to affect D2 receptor levels in brain . The relationships between the TaqIA RFLP , C957 T and -- 141C Ins / Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18F ] fluorodopa ( [ 18F ] FDOPA ) , a radiolabelled analog of the dopamine precursor DB01235 . Heterozygous carriers of the A1 allele ( A1 / A2 ; 10 subjects ) had significantly higher ( 18 % ) [ 18F ] FDOPA uptake in the putamen than subjects without the A1 allele ( A2 / A2 ; 23 subjects ) . C957 T and -- 141C Ins / Del polymorphisms did not significantly affect [ 18F ] FDOPA Ki values . These results demonstrate that the A1 allele of P14416 gene is associated with increased striatal activity of aromatic L - amino acid decarboxylase , the final enzyme in the biosynthesis of dopamine and the rate - limiting enzyme for trace amine ( e . g . beta - phenylethylamine ) synthesis . The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function , and suggests that dopamine and / or trace amine synthesis rate is increased in the brains of A1 allele carriers .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair . We present an oligonucleotide microarray ( \" MetaboChip \" ) based on the arrayed primer extension ( P27695 ) technique , allowing genotyping of single nucleotide polymorphisms ( SNPs ) in genes of interest for cancer susceptibility and pharmacogenetics . P27695 consists of a sequencing reaction primed by an oligonucleotide anchored with its 5 ' end to a glass slide and terminating one nucleotide before the polymorphic site . The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism . Ninety - three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project , using a set of 102 reference DNA samples from the Coriell Biorepository . Selected SNPs belong to the following genes : P00325 , P05091 , P27695 , CDKN2A , P21964 , P04798 , P05177 , Q16678 , P11509 , P33261 , P11712 , P05181 , P08684 , P14416 , P21917 , P07099 , P07992 , P18074 , Q92889 , P28715 , P30550 , O15217 , P21266 , P09211 , GSTT2 , LIG3 , Q00987 , P16455 , P05164 , NAT1 , NAT2 , P15559 , O15527 , P12004 , P06746 , Q01959 , P04179 , P04637 , P18887 , O43543 , O43542 , and O15287 . We assessed the performance of P27695 by comparing the results obtained with MetaboChip against those reported by the SNP500 . Among 88 SNPs that yielded signals , 6 showed less than 99 % of concordance , whereas 82 performed accurately , showing that P27695 is a reliable and sensitive genotyping method .",
"Dopamine receptor D4 polymorphism predicts the effect of DB01235 on gambling behavior . BACKGROUND : There is ample evidence that a subgroup of Parkinson ' s disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling . The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors . These are potentially of genetic origin , since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 ( P21917 ) gene . Using a pharmacogenetic approach , we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects . METHODS : We administered 300 mg of L - dihydroxyphenylalanine ( DB01235 ) or placebo to 200 healthy male subjects who were all genotyped for their P21917 polymorphism . Subjects played a gambling task 60 minutes after DB01235 administration . RESULTS : Without considering genetic information , DB01235 administration did not lead to an increase in gambling propensity compared with placebo . As expected , however , an individual ' s P21917 polymorphism accounted for variation in gambling behavior after the administration of DB01235 . Subjects who carry at least one copy of the 7 - repeat allele showed an increased gambling propensity after dopaminergic stimulation . CONCLUSIONS : These findings demonstrate that genetic variation in the P21917 gene determines an individual ' s gambling behavior in response to a dopaminergic drug challenge . They may have implications for the treatment of Parkinson ' s disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior .",
"Q9UD71 and inhibitor - 1 are expressed in pancreatic beta - cells . P01308 secretion from pancreatic beta - cells has to be tightly regulated to ensure accurate glucose homeostasis . The capacity of beta - cells to respond to extracellular stimulation is determined by several signaling pathways . One important feature of these pathways is phosphorylation and subsequent dephosphorylation of a wide range of cellular substrates . Protein phosphatase 1 ( P50391 ) is a major eukaryotic serine / threonine protein phosphatase that controls a multitude of physiological processes . We have investigated the expression and cellular distribution of two endogenous inhibitors of P50391 activity in beta - cells . RT - PCR , Western blotting , and immunohistochemistry showed that Q9UD71 and inhibitor - 1 are present in insulin - secreting endocrine beta - cells . Subcellular fractionation of mouse islets revealed that both P50391 inhibitors predominantly localized to cytosol - enriched fractions . Inhibitor - 1 was also present in fractions containing plasma membrane - associated proteins . These data indicate a potential role for Q9UD71 and inhibitor - 1 in the regulation of P50391 activity in pancreatic beta - cell stimulus - secretion coupling .",
"Task - dependent interactions between dopamine D2 receptor polymorphisms and DB01235 in patients with Parkinson ' s disease . Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning . In the current study , we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with DB01235 during motor tasks in patients with Parkinson ' s disease ( PD ) . Forty - five PD patients were genotyped for the P14416 polymorphism ( rs 1076560 , G > T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 states . For motor sequence learning , P14416 genotype mediated DB01235 effects such that DB01235 associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 =- 2 . 71 , p = 0 . 022 ) , whereas G homozygotes showed no performance change with DB01235 . For the grooved pegboard test , performance improved with DB01235 independent of patients ' P14416 genotype . Collectively these results demonstrate that common P14416 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .",
"___MASK51___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK14___ GITS , Diaprel MR ) . One daily dose of ___MASK14___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .",
"Differential treatment regimen - related effects of cannabinoids on D1 and D2 receptors in adolescent and adult rat brain . Animal studies suggest differential effects of cannabinoids on dopamine - related behaviours in adolescence and adulthood however few studies have investigated the underlying neurochemical effects of cannabinoids during adolescence . The aim of the present study was to compare the effects of treatment with the synthetic cannabinoid , HU210 , on dopamine receptor density in adolescent and adult rats . Adolescent ( postnatal day ( P01160 ) 35 ) and adult ( P01160 70 ) rats received a single dose of 100μg / kg HU210 or 25 , 50 or 100μg / kg HU210 for 4 or 14 days . P21728 ( D1R ) or D2 receptor ( D2R ) density was measured in the medial and lateral ( CPUL ) caudate putamen , nucleus accumbens , olfactory tubercle ( TU ) and substantia nigra ( D1R only ) using in vitro autoradiography . D1R and D2R densities were 1 . 6 - 1 . 7 - and 1 . 1 - 1 . 4 - fold higher respectively in adolescent control rats compared to adults . In adult rats , D1R density was increased by 1 . 2 - and 1 . 3 - fold ( p < 0 . 05 ) in CPUL and TU respectively compared to controls , after 14 days of HU210 treatment . A significant overall effect of treatment ( p < 0 . 05 ) on D2R density was also observed in adults after the single dose and 4 and 14 days administration of HU210 . In adolescents , an overall effect of treatment on D1R density after a single exposure to HU210 was seen ( p = 0 . 0026 ) but no changes in D1R or D2R densities were observed in other treatment groups . These results suggest that the adolescent rat brain does not display the same compensatory mechanisms activated in the adult brain following cannabinoid treatment .",
"Interaction between serotonin transporter gene , catechol - O - methyltransferase gene and stressful life events in mood disorders . It is well established that stress is a risk factor for onset of mood disorders . Emerging evidence suggests that genetic vulnerability may also moderate individual responsiveness to stress . The most compelling evidence regards the polymorphism within the promoter region of the serotonin transporter gene ( SERTPR ) , which has been reported to moderate the risk for depression , in conjunction with life stressors . In the present paper we analysed SERTPR in the onset of mood disorders , along with adverse life events , and other candidate genes : the serotonin receptor 1A ( P08908 ) , the dopamine receptor D4 ( P21917 ) and the catechol - O - methyltransferase ( P21964 ) . The sample was composed of 686 Italian subjects , affected by major depression and bipolar disorder . Patients were asked to report about life stressors within the year preceding onset of their first mood - disorder episode and genotyped . A ' case - only ' design was employed to investigate the interaction between genes and stressors . P21964 was associated with depression following exposure to stressors ( chi2 = 13 . 05 , d . f .= 2 , p = 0 . 0015 ) and SERTPR also showed a positive association ( chi2 = 6 . 70 , d . f .= 2 , p = 0 . 035 ) , mainly among women and among major depressives . The interaction between P21964 and SERTPR was also significant ( p = 0 . 0005 ) . In our retrospective study SERTPR is hypothesized to lead to the onset of major depression via its influence on reaction to adversities , particularly in females . Moreover , P21964 was risk factor for onset of both major depression and bipolar disorder , in conjunction with adversities .",
"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK100___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK100___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK100___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK100___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .",
"The interleukin 10 promoter haplotype ACA and the long - form variant of the P21917 uVNTR polymorphism are associated with vulnerability to schizophrenia . A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin - 10 ( P22301 ) promoter and P21917 uVNTR polymorphisms . P21917 long - form variants ( namely , those with ≥ 5 repeats ) , homozygosity for the 4 - repeat allele , and the P22301 haplotype ACA were associated with schizophrenia , respectively . No obvious interactions among the potential polymorphisms were found , which suggests that P22301 and P21917 confer vulnerability to schizophrenia independently .",
"Transactivation of PDGFRbeta by dopamine D4 receptor does not require PDGFRbeta dimerization . Growth factor - induced receptor dimerization and cross - phosphorylation are hallmarks of signal transduction via receptor tyrosine kinases ( RTKs ) . G protein - coupled receptors ( GPCRs ) can activate RTKs through a process known as transactivation . The prototypical model of RTK transactivation involves ligand - mediated RTK dimerization and cross - phosphorylation . Here , we show that the platelet - derived growth factor receptor beta ( PDGFRbeta ) transactivation by the dopamine receptor D4 ( P21917 ) is not dependent on ligands for PDGFRbeta . Furthermore , when PDGFRbeta dimerization is inhibited and receptor phosphorylation is suppressed to near basal levels , the receptor maintains its ability to be transactivated and is still effective in signaling to P27361 / 2 . Hence , the P21917 - PDGFRbeta - P27361 / 2 pathway can occur independently of a PDGF - like ligand , PDGFRbeta cross - phosphorylation and dimerization , which is distinct from other known forms of transactivation of RTKs by GPCRs .",
"[ The effect of blood pressure - reducing therapy with captopril on tubular marker excretion in type - 1 diabetics with nephropathy ] . A prospective open clinical trial was carried out with 23 hypertensive type I diabetics ( 13 men , ten women , mean age 49 +/- 9 . 1 years , duration of diabetes 18 +/- 9 . 1 years ) with early nephropathy . Glomerular and tubular renal function and metabolic parameters were monitored during 8 months ' treatment with the angiotensin converting enzyme ( P12821 ) inhibitor , captopril , in addition to previous antihypertensive treatment with one or more drugs . Blood pressure control tended to improve on captopril ( systolic pressures 152 +/- 13 vs 140 +/- 13 mm Hg , P < 0 . 05 ; diastolic pressures 89 +/- 10 vs 87 +/- 10 mm Hg , not significant ) . Proteinuria ( > 0 . 5 g / 24 hours ) fell into the microalbuminuria range ( albumin excretion 2 - 20 mg / mmol creatinine ) in four out of 13 patients , and microalbuminuria disappeared in four out of ten patients . Urinary levels of the brush border enzyme O60502 ( NAG ) , a marker of tubular dysfunction , were initially raised and fell significantly after 8 months ' treatment with captopril ( 20 . 3 +/- 14 . 4 vs 8 . 8 +/- 8 . 1 U / g creatinine ; P < 0 . 01 ) . ___MASK70___ did not affect metabolic control ( HbA1 , total , HDL and LDL cholesterol , triglycerides , apolipoproteins A1 and B ) or the insulin dosage . These results show that long - term treatment with captopril may favourably influence both albumin excretion and NAG activity , a marker of tubular dysfunction , in type I diabetics with nephropathy .",
"Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re - validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague - Dawley rats were treated with chronic DB01235 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 ( the D ( 1 ) and P14416 antagonists , P35240 - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti - dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .",
"Dopamine agonist - induced hypothermia and disruption of prepulse inhibition : evidence for a role of D3 receptors ? The dopamine D3 / D2 receptor agonists 7 - OH - DPAT , quinpirole , quinelorane , and PD128907 , the mixed dopamine agonist apomorphine , the D2 agonist bromocriptine , and the D1 / D5 agonist SKF38393 were examined in models of hypothermia and prepulse inhibition ( PPI ) in Wistar rats . As dopamine agonist - induced hypothermia has been proposed as a model of D3 receptor function , and dopamine agonists are known to disrupt PPI , drug potencies to induce hypothermia were established and compared with doses necessary to disrupt PPI . 7 - OH - DPAT , quinpirole , quinelorane , PD128907 , and apomorphine , reduced body temperature and disrupted PPI with a similar rank order of potency ( quinelorane > quinpirole = 7 - OH - DPAT > PD128907 = apomorphine ) . ___MASK18___ and SKF38393 were ineffective in both models . In a separate study , the dopamine reuptake inhibitors cocaine and GBR 12909 had no effect on PPI . In a final set of studies , the D2 / D3 antagonist raclopride blocked both 7 - OH - DPAT - induced hypothermia and 7 - OH - DPAT - induced PPI disruption . The P08908 antagonist WAY 100 , 135 , and the peripheral D2 - like antagonist domperidone had no effect . These findings suggest that the hypothermia and PPI disruptions seen with some of these dopamine agonists may be mediated by central D3 receptors ; however , only studies using more selective dopamine receptor ligands can definitively rule out effects at the D2 or D4 receptors .",
"Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .",
"Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .",
"Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .",
"Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 ) at 11p15 , tyrosinase ( P14679 ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 ) at 11q22 - q23 , as well as with the c - Harvey - ras oncogene ( P01112 ) and insulin gene ( P01308 ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected - sib - pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two - point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 and P01308 excluded the 11p15 region encompassing both P21917 and TH . In agreement with the negative linkage results , affected - sib - pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 , TH , P14679 , and P14416 in the pathogenesis of bipolar illness .",
"___MASK66___ - inhibitable P35354 . Although paracetamol potently reduces pain and fever , its mechanism of action has so far not been satisfactorily explained . It inhibits both P23219 and P35354 weakly in vitro , but reduces prostaglandin synthesis markedly in vivo . In mouse macrophage J774 . 2 cells , P35354 induced for 48 hr with high concentrations of NSAIDs is more sensitive to inhibition with paracetamol than endotoxin - induced P35354 . In the rat pleurisy model of inflammation , a second peak of P35354 protein appears 48 hr after administration of the inflammatory stimulus , during the resolution phase of the inflammatory process . Inhibition of the activity of this late - appearing P35354 with indomethacin or a selective P35354 inhibitor , delays resolution and the inflammation is prolonged . Cultured lung fibroblasts also express P35354 activity after stimulation with IL - 1beta which is highly sensitive to inhibition with paracetamol . Thus , evidence is accumulating for the existence of a P35354 variant or a new P36551 enzyme which can be inhibited with paracetamol ."
] |
[
"___MASK100___",
"___MASK14___",
"___MASK18___",
"___MASK23___",
"___MASK51___",
"___MASK66___",
"___MASK70___",
"___MASK74___",
"___MASK96___"
] |
___MASK70___
|
MH_train_470
|
interacts_with DB08918?
|
[
"___MASK7___ : kinetic and dynamic profile in the treatment of pain . ___MASK7___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK7___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK7___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK7___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"Q9BXS0 triggers and promotes Alzheimer ' s disease - like pathology in vivo . Collagen XXV alpha 1 ( Q9BXS0 ) is a collagenous type II transmembrane protein purified from senile plaques of Alzheimer ' s disease ( AD ) brains . Q9BXS0 alleles have been associated with increased risk for AD in a Swedish population . Q9BXS0 is specifically expressed in neurons and binds to aggregated Abeta in vitro . However , its contribution to the pathogenesis of AD and in vivo function are unknown . Here , we report that over - expression of Q9BXS0 in transgenic mice increases p35 / p25 and beta - site P05067 - cleaving enzyme 1 ( P56817 ) levels , facilitates intracellular aggregation and extracellular matrix deposits of Abeta , and causes synaptophysin loss and astrocyte activation . Q9BXS0 mice displayed reduced anxiety - like behavior in elevated plus maze and open field tests and significantly slower swimming speed in Morris water maze . In stable cell lines , motifs in noncollagenous domains of Q9BXS0 were important for the induction of P56817 expression . These findings demonstrate that Q9BXS0 leads to AD - like pathology in vivo . Modulation of Q9BXS0 function may represent an alternative therapeutic intervention for AD .",
"Rationalizing cyclooxygenase ( P36551 ) inhibition for maximal efficacy and minimal adverse events . New information indicates that cyclooxygenase - 2 ( P35354 ) is constitutively expressed in several tissues , including brain , lung , pancreas , kidney , and ovary , and plays an important role in renal and gastrointestinal function . Selective P35354 inhibition has been associated in animal studies with impairment of ulcer healing and renal function and inhibition of prostacyclin , an effect that inhibits vasodilation without inhibiting platelet aggregation . The clinical consequences , if any , of these effects remain to be determined in long - term studies in humans . The premise that selective P35354 inhibitors will cause less gastrointestinal toxicity than nonsteroidal antiinflammatory drugs that inhibit both P36551 isoforms needs to take into account the low toxicity of nabumetone . The gastrointestinal safety profile of this nonacidic , dual P36551 inhibitor that does not undergo enterohepatic circulation has been evaluated in extensive clinical trials . The data submitted to the US Food and Drug Administration in the New Drug Application for nabumetone ( ___MASK24___ ) , the comparative trials subsequently completed , the published databases of the comparative gastrointestinal toxicity of various nonsteroidal anti - inflammatory drugs ( NSAIDs ) , and the meta - analysis published in this issue of The American Journal of Medicine ( Schoenfeld , page 48S ) indicate that nabumetone has the lowest incidence of gastrointestinal toxicity among the extensively studied NSAIDs . Overall , the incidence is approximately 10 - fold less than with comparator drugs . This rate is an appropriate current reference against which the gastrointestinal toxicity of P35354 inhibitors can be compared .",
"Transcriptional regulation of beta - secretase by p25 / cdk5 leads to enhanced amyloidogenic processing . P12004 - dependent kinase 5 ( cdk5 ) has been implicated in Alzheimer ' s disease ( AD ) pathogenesis . Here , we demonstrate that overexpression of p25 , an activator of cdk5 , led to increased levels of P56817 mRNA and protein in vitro and in vivo . A p25 / cdk5 responsive region containing multiple sites for signal transducer and activator of transcription ( P42224 / 3 ) was identified in the P56817 promoter . P40763 interacts with the P56817 promoter , and p25 - overexpressing mice had elevated levels of pSTAT3 and P56817 , whereas cdk5 - deficient mice had reduced levels . Furthermore , mice with a targeted mutation in the P40763 cdk5 responsive site had lower levels of P56817 . Increased P56817 levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor . These data demonstrate a pathway by which p25 / cdk5 increases the amyloidogenic processing of P05067 through P40763 - mediated transcriptional control of P56817 that could have implications for AD pathogenesis .",
"Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome : a Children ' s Cancer Group Study . PURPOSE : ___MASK91___ is a major component of current treatment regimens for children with acute lymphocytic leukemia ( ALL ) . Potential mechanisms of methotrexate resistance include impaired drug uptake , decreased drug retention , and dihydrofolate reductase ( P00374 ) amplification . The purpose of this study was to assess whether reduced folate carrier ( P41440 ) and P00374 expression in untreated leukemic blasts correlated with outcome . METHODS : Quantitative real - time RT - PCR was used to measure P41440 and P00374 mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children ' s Cancer Group studies . RESULTS : Low P41440 expression at diagnosis correlated significantly with an unfavorable event free survival . Surprisingly , low , not high , P00374 expression correlated significantly with an unfavorable event - free survival . Proliferative cell nuclear antigen ( P12004 ) expression demonstrated a weak inverse relationship between sample P12004 and P00374 or P41440 expression , suggesting that P00374 and P41440 expression may be markers for factors other than drug resistance . CONCLUSIONS : These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL , and P00374 expression also may be an important prognostic factor in ALL . Additional studies are necessary to clarify the mechanism for the correlation of low P00374 expression with poor outcome .",
"Deletion of the prostaglandin E2 EP2 receptor reduces oxidative damage and amyloid burden in a model of Alzheimer ' s disease . Epidemiological studies demonstrate that chronic use of nonsteroidal anti - inflammatory drugs ( NSAIDs ) in normal aging populations reduces the risk of developing Alzheimer ' s disease ( AD ) . NSAIDs inhibit the enzymatic activity of cyclooxygenase - 1 ( P23219 ) and inducible P35354 , which catalyze the first committed step in the synthesis of prostaglandins . These studies implicate P36551 - mediated inflammation as an early and potentially reversible preclinical event ; however , the mechanism by which P36551 activity promotes development of AD has not been determined . Recent studies implicate the prostaglandin E2 ( DB00917 ) E prostanoid subtype 2 ( EP2 ) receptor in the development of the innate immune response in brain . Here , we report that deletion of the DB00917 EP2 receptor in the APPSwe - PS1DeltaE9 model of familial AD results in marked reductions in lipid peroxidation in aging mice . This reduction in oxidative stress is associated with significant decreases in levels of amyloid - beta ( Abeta ) 40 and 42 peptides and amyloid deposition . Aged APPSwe - PS1DeltaE9 mice lacking the EP2 receptor harbor lower levels of beta C - terminal fragments , the product of beta - site P05067 cleaving enzyme ( P56817 ) processing of amyloid precursor protein . Increases in P56817 processing have been demonstrated in models of aging and AD and after oxidative stress . Our results indicate that DB00917 signaling via the EP2 receptor promotes age - dependent oxidative damage and increased Abeta peptide burden in this model of AD , possibly via effects on P56817 activity . Our findings identify EP2 receptor signaling as a novel proinflammatory and proamyloidogenic pathway in this model of AD , and suggest a rationale for development of therapeutics targeting the EP2 receptor in neuroinflammatory diseases such as AD .",
"Combined treatment with a P56817 inhibitor and anti - Aβ antibody gantenerumab enhances amyloid reduction in APPLondon mice . Therapeutic approaches for prevention or reduction of amyloidosis are currently a main objective in basic and clinical research on Alzheimer ' s disease . Among the agents explored in clinical trials are anti - Aβ peptide antibodies and secretase inhibitors . Most anti - Aβ antibodies are considered to act via inhibition of amyloidosis and enhanced clearance of existing amyloid , although secretase inhibitors reduce the de novo production of Aβ . Limited information is currently available on the efficacy and potential advantages of combinatorial antiamyloid treatment . We performed a chronic study in APPLondon transgenic mice that received treatment with anti - Aβ antibody gantenerumab and P56817 inhibitor RO5508887 , either as mono - or combination treatment . Treatment aimed to evaluate efficacy on amyloid progression , similar to preexisting amyloidosis as present in Alzheimer ' s disease patients . Mono - treatments with either compound caused a dose - dependent reduction of total brain Aβ and amyloid burden . Combination treatment with both compounds significantly enhanced the antiamyloid effect . The observed combination effect was most pronounced for lowering of amyloid plaque load and plaque number , which suggests effective inhibition of de novo plaque formation . Moreover , significantly enhanced clearance of pre - existing amyloid plaques was observed when gantenerumab was coadministered with RO5508887 . P56817 inhibition led to a significant time - and dose - dependent decrease in P04141 Aβ , which was not observed for gantenerumab treatment . Our results demonstrate that combining these two antiamyloid agents enhances overall efficacy and suggests that combination treatments may be of clinical relevance .",
"The cell adhesion protein P16109 glycoprotein ligand - 1 is a substrate for the aspartyl protease P56817 . The aspartyl protease P56817 cleaves the amyloid precursor protein and the sialyltransferase P15907 and is important in the pathogenesis of Alzheimer ' s disease . The normal function of P56817 and additional physiological substrates have not been identified . Here we show that P56817 acts on the Q14242 ( Q14242 ) , which mediates leukocyte adhesion in inflammatory reactions . In human monocytic U937 and human embryonic kidney 293 cells expressing endogenous or transfected P56817 , Q14242 was cleaved by P56817 to generate a soluble ectodomain and a C - terminal transmembrane fragment . No evidence of the cleavage fragment was seen in primary cells derived from mice deficient in P56817 . By using deletion constructs and enzymatic deglycosylation of the C - terminal Q14242 fragments , the cleavage site in Q14242 was mapped to the juxtamembrane region within the ectodomain . In an in vitro assay P56817 catalyzed the formation of the Q14242 products seen in vivo . The cleavage occurred at a DB00149 - DB00133 peptide bond as identified by mass spectrometry using a synthetic peptide . We conclude that Q14242 is an additional substrate for P56817 .",
"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK64___ ) in castrated male and female mice subjected to ___MASK64___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK64___ in mice CPs .",
"___MASK33___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK33___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"A critical importance of polyamine site in DB01221 receptors for neurite outgrowth and fasciculation at early stages of P19 neuronal differentiation . We have investigated the role of N - methyl - d - aspartate receptors ( NMDARs ) and gamma - aminobutyric acid receptors type A ( GABA ( A ) Rs ) at an early stage of P19 neuronal differentiation . The subunit expression was profiled in 24 - hour intervals with RT - PCR and functionality of the receptors was verified via fluo - 3 imaging of Ca ( 2 +) dynamics in the immature P19 neurons showing that both DB01221 and GABA excite neuronal bodies , but only polyamine - site sensitive NMDAR stimulation leads to enhanced Ca ( 2 +) signaling in the growth cones . Inhibition of Q9UHB4 / Q13224 NMDARs by 1 muM ifenprodil severely impaired P19 neurite extension and fasciculation , and this negative effect was fully reversible by polyamine addition . In contrast , GABA ( A ) R antagonism by a high dose of 200 microM bicuculline had no observable effect on P19 neuronal differentiation and fasciculation . Except for the differential NMDAR and GABA ( A ) R profiles of Ca ( 2 +) signaling within the immature P19 neurons , we have also shown that inhibition of Q9UHB4 / Q13224 NMDARs strongly decreased mRNA level of P13591 - 180 , which has been previously implicated as a regulator of neuronal growth cone protrusion and neurite extension . Our data thus suggest a critical role of Q9UHB4 / Q13224 NMDARs during the process of neuritogenesis and fasciculation of P19 neurons via differential control of local growth cone Ca ( 2 +) surges and P13591 - 180 signaling .",
"Fetzima ( levomilnacipran ) , a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta - site amyloid precursor protein cleaving enzyme - 1 . Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters ( P31645 ) to increase the synaptic concentrations of serotonin . Beta - site amyloid precursor protein cleaving enzyme - 1 ( P56817 - 1 ) is responsible for amyloid β plaque formation . Hence it is an interesting target for Alzheimer ' s disease ( AD ) therapy . This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named ' Fetzima ' with P56817 - 1 and P31645 . Fetzima is chemically known as levomilnacipran . The study has explored a possible link between the treatment of Depression and AD . ' Autodock 4 . 2 ' was used for docking study . The free energy of binding ( ΔG ) values for ' levomilnacipran - P31645 ' interaction and ' levomilnacipran - P56817 ' interaction were found to be - 7 . 47 and - 8 . 25 kcal / mol , respectively . DB08918 was found to interact with S438 , known to be the most important amino acid residue of serotonin binding site of P31645 during ' levomilnacipran - P31645 ' interaction . In the case of ' levomilnacipran - P56817 ' interaction , levomilnacipran interacted with two very crucial aspartic acid residues of P56817 - 1 , namely , D32 and D228 . These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain . Hence , Fetzima ( levomilnacipran ) might act as a potent dual inhibitor of P31645 and P56817 - 1 and expected to form the basis of a future dual therapy against depression and AD . It is an established fact that development of AD is associated with Major Depressive Disorder . Therefore , the design of new P56817 - 1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial .",
"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK40___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .",
"Inhibition of ADP - induced P16109 expression and platelet - leukocyte conjugate formation by clopidogrel and the Q9H244 receptor antagonist AR - C69931MX but not aspirin . Platelet - leukocyte interactions are recognised to have pro - inflammatory effects , which may be important in the pathophysiology of ischaemic heart disease . ___MASK13___ and the novel intravenous antithrombotic agent AR - C69931MX act at the level of the platelet Q9H244 receptor , which is known to amplify platelet activation , aggregation and other responses induced by numerous platelet agonists . We studied the effects of clopidogrel and aspirin on ADP - induced platelet - leukocyte conjugate formation and P16109 expression in healthy volunteers . The effects of clopidogrel and AR - C69931MX administered to patients with ischaemic heart disease were also assessed . AR - C69931MX and aspirin were also studied in vitro . ___MASK13___ and AR - C69931MX suppressed ADP - induced platelet aggregation , P16109 expression and platelet - leukocyte conjugate formation whereas aspirin had no inhibitory effect . These effects of clopidogrel and AR - C69931MX may confer therapeutic benefits in the management of acute coronary syndromes .",
"Q9Y5Z0 plays a role in the insulin receptor trafficking in pancreatic ß - cells . P56817 ( β - site amyloidogenic cleavage of precursor protein - cleaving enzyme 1 ) is a β - secretase protein that plays a central role in the production of the β - amyloid peptide in the brain and is thought to be involved in the Alzheimer ' s pathogenesis . In type 2 diabetes , amyloid deposition within the pancreatic islets is a pathophysiological hallmark , making crucial the study in the pancreas of P56817 and its homologous Q9Y5Z0 to understand the pathological mechanisms of this disease . The objectives of the present study were to characterize the localization of P56817 proteins in human pancreas and determine their function . High levels of P56817 enzymatic activity were detected in human pancreas . In normal human pancreas , P56817 was observed in endocrine as well as in exocrine pancreas , whereas Q9Y5Z0 expression was restricted to β - cells . Intracellular analysis using immunofluorescence showed colocalization of P56817 with insulin and Q9Y5Z0 with clathrin - coated vesicles of the plasma membrane in MIN6 cells . When P56817 and - 2 were pharmacologically inhibited , P56817 localization was not altered , whereas Q9Y5Z0 content in clathrin - coated vesicles was increased . P01308 internalization rate was reduced , insulin receptor β - subunit ( IRβ ) expression was decreased at the plasma membrane and increased in the Golgi apparatus , and a significant reduction in insulin gene expression was detected . Similar results were obtained after specific Q9Y5Z0 silencing in MIN6 cells . All these data point to a role for Q9Y5Z0 in the IRβ trafficking and insulin signaling . In conclusion , Q9Y5Z0 is hereby presented as an important enzyme in β - cell function .",
"Novel systemic markers for patients with Alzheimer disease ? - a pilot study . Almost 2 % of the population of western industrialized countries are affected by Alzheimer ' s disease ( AD ) . Nevertheless the pathogenetic process leading to this neurodegenerative disease is widely unknown . Thus , we focus on novel pathophysiological aspects of AD . We hypothesize that AD patients reveal increased levels of peripheral blood mononuclear cells ( PBMCs ) expressing proinflammatory ( P35354 , P01375 , P25942 ) , proapoptotic ( P09874 ) , adhesion - relevant ( P28907 ) or AD associated ( C99 , P56817 , P49768 ) proteins as well as elevated proinflammatory biochemical plasma parameters . Therefore , PBMCs of AD patients and age - matched control subjects were studied by two color fluorescence - activated cell sorter ( FACS ) analysis . Furthermore , concentration of plasma oxidized low - density lipoprotein ( oxLDL ) and P01375 were measured by enzyme - linked immunosorbent assay ( ELISA ) . We found a significantly increased percentage of P01375 , P35354 , P09874 , P28907 , C99 or presenilin - 1 positive PBMCs in AD patients compared with healthy subjects . FACS analyses revealed that the percentage of C99 or presenilin - 1 positive PBMCs , which also express P01375 , P35354 , P09874 or P28907 is also increased in AD patients . Additionally , AD patients had significantly increased plasma oxLDL and P01375 levels . Furthermore , we found positive correlations between plasma oxLDL or P01375 concentrations and the percentage of TNFalpha + , P35354 + or P09874 + , as well as P49768 + , C99 + or P56817 + PBMCs . Our findings suggest that immunocytological investigations , based on immunophenotyping of AD relevant proteins combined with measurement of proinflammatory , proapoptotic and adhesion - relevant proteins in PBMCs may provide more insight into the pathophysiology of AD .",
"P56817 elevation is associated with aberrant limbic axonal sprouting in epileptic CD1 mice . The brain is capable of remarkable synaptic reorganization following stress and injury , often using the same molecular machinery that governs neurodevelopment . This form of plasticity is crucial for restoring and maintaining network function . However , neurodegeneration and subsequent reorganization can also play a role in disease pathogenesis , as is seen in temporal lobe epilepsy and Alzheimer ' s disease . β - Secretase - 1 ( P56817 ) is a protease known for cleaving β - amyloid precursor protein into β - amyloid ( Aβ ) , a major constituent in amyloid plaques . Emerging evidence suggests that P56817 is also involved with synaptic plasticity and nerve regeneration . Here we examined whether P56817 immunoreactivity ( IR ) was altered in pilocarpine - induced epileptic CD1 mice in a manner consistent with the synaptic reorganization seen during epileptogenesis . P56817 - IR increased in the P07451 mossy fiber field and dentate inner molecular layer in pilocarpine - induced epileptic mice , relative to controls ( saline - treated mice and mice 24 - 48 h after pilocarpine - status ) , and paralleled aberrant expression of neuropeptide Y . Regionally increased P56817 - IR also occurred in neuropil in hippocampal area P00915 and in subregions of the amygdala and temporal cortex in epileptic mice , colocalizing with increased IR for growth associated protein 43 ( P17677 ) and polysialylated - neural cell adhesion molecule ( PSA - P13591 ) , but reduced IR for microtubule - associated protein 2 ( P11137 ) . These findings suggest that P56817 is involved in aberrant limbic axonal sprouting in a model of temporal lobe epilepsy , warranting further investigation into the role of P56817 in physiological vs . pathological neuronal plasticity .",
"Vessel wall , not platelet , Q9H244 potentiates early atherogenesis . AIMS : Platelets have a fundamental role in atherothrombosis , but their role in early atherogenesis is unclear . The Q9H244 receptor is responsible for amplifying and sustaining platelet activation and Q9H244 inhibition is crucial in modulating the vessel wall response to injury . We therefore examined the role of platelet vs . vessel wall Q9H244 in early atherogenesis and considered the use of Q9H244 antagonists ticagrelor and clopidogrel in modulating this process . METHODS AND RESULTS : ApoE (-/-) and ApoE (-/-) Q9H244 ( -/- ) male mice underwent bone marrow transplantation and were fed a western diet for 4 weeks before assessing atherosclerotic burden . Compared with ApoE (-/-) controls , platelet Q9H244 deficiency profoundly reduced platelet reactivity but had no effect on atheroma formation , whereas vessel wall Q9H244 deficiency significantly attenuated atheroma in the aortic sinus and brachiocephalic artery ( both P < 0 . 001 ) . ApoE (-/-) and ApoE (-/-) Q9H244 ( -/- ) male mice fed western diet plus either twice - daily doses of ticagrelor ( 100 mg / kg ) or daily clopidogrel ( 20 mg / kg ) for 4 weeks exhibited no significant reduction in atheroma compared with control mice fed mannitol . Attenuated P16109 expression confirmed platelet Q9H244 inhibition in drug - treated mice . CONCLUSIONS : Despite its major contribution to platelet reactivity , platelet Q9H244 has no effect on early atheroma formation , whereas vessel wall Q9H244 is important in this process . ___MASK16___ and clopidogrel effectively reduced platelet reactivity but were unable to inhibit early atherogenesis , demonstrating that these Q9H244 inhibitors may not be effective in preventing early disease .",
"Evidence that the metabotropic glutamate receptor 5 antagonist MPEP may act as an inhibitor of the norepinephrine transporter in vitro and in vivo . The mechanisms through which blockade of metabotropic glutamate receptors 5 ( P41594 ) results in anxiolytic and antidepressant effects are currently unknown . In the present study , we therefore hypothesized that the anxiolytic - and antidepressant - like profile of the noncompetitive P41594 receptor antagonist 2 - ethyl - 6 -( phenylethynyl )- pyridine ( MPEP ) may be mediated by inhibition of the norepinephrine transporter ( NET ) . Accordingly , we first examined the potency of MPEP to bind to or inhibit uptake at the NET as well as the dopamine and serotonin transporters ( Q01959 and P31645 , respectively ) . We also examined the simultaneous in vivo effects of MPEP and desipramine ( ___MASK10___ ) on both NE - like oxidation current in the amygdala ( Q9BXS0 ) and cell firing in the locus coeruleus ( LC ) by means of differential pulse voltammetry ( DPV ) coupled with electrophysiology . MPEP completely displaced the binding of [ 3H ] - nisoxetine on human NET with a pKi of 6 . 63 +/- 0 . 02 . In addition , MPEP was able to inhibit [ 3H ] - NE uptake in LLCPK cells expressing human NET , with a pIC50 of 5 . 55 +/- 0 . 09 . In vivo DPV data revealed that both MPEP ( 30 mg / kg i . p . ) and ___MASK10___ ( 10 mg / kg i . p . ) significantly increased NE - like voltammetric responses levels in the Q9BXS0 , whereas both compounds also significantly decreased cell firing monitored concomitantly from the second microelectrode in the LC . Collectively , the results of the present study provide potential new mechanisms through which MPEP exerts its anxiolytic and antidepressant effects ."
] |
[
"___MASK10___",
"___MASK13___",
"___MASK16___",
"___MASK24___",
"___MASK33___",
"___MASK40___",
"___MASK64___",
"___MASK7___",
"___MASK91___"
] |
___MASK33___
|
MH_train_471
|
interacts_with DB00549?
|
[
"DB01411 inhibits renal epithelial cyst progression via activation of AMP - activated protein kinase . Q9Y271 ( CysLT1 receptor ) antagonists were found to inhibit chloride secretion in human airway epithelial cells . Since chloride secretion in renal epithelial cells , which shares common mechanisms with airway epithelial cells , plays important roles in renal cyst progression in polycystic kidney disease ( Q15139 ) , this study was aimed to investigate effects of drugs acting as CysLT1 receptor antagonists on renal cyst progression and its underlying mechanisms . Effects of CysLT1 receptor antagonists on renal cyst growth and formation were determined using Madine Darby canine kidney ( MDCK ) cyst models . Mechanisms of actions of CysLT1 receptor antagonists were determined using short - circuit current measurement , assays of cell viability and cell proliferation , and immunoblot analysis of signaling proteins . Of the three drugs acting as CysLT1 receptor antagonists ( montelukast , pranlukast and zafirlukast ) tested , pranlukast was the most promising drug that inhibited MDCK cyst growth and formation without affecting cell viability . Its effect was independent of the inhibition of CysLT1 receptors . Instead , it reduced DB02527 - activated chloride secretion and proliferation of MDCK cells in an AMP - activated protein kinase ( AMPK ) - dependent manner and had no effect on P13569 protein expression . Interestingly , pranlukast enhanced AMPK activation via calcium / calmodulin - dependent protein kinase kinase beta ( CaMKKβ ) with consequent activation of acetyl - DB01992 carboxylase ( ACC ) and suppression of mammalian target of rapamycin ( P42345 ) pathway . These results indicate that pranlukast retards renal epithelial cyst progression by inhibiting DB02527 - activated chloride secretion and cell proliferation via CaMKKβ - AMPK - P42345 pathway . Therefore , pranlukast represents a class of known drugs that may have potential utility in Q15139 treatment .",
"___MASK76___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"Leukotriene D4 - induced increases in cytosolic calcium in THP - 1 cells : dependence on extracellular calcium and inhibition with selective leukotriene D4 receptor antagonists . Agonist - induced changes in intracellular calcium ion concentration ( [ Ca ++] i ) were examined in human monocytic leukemia THP - 1 cells loaded with fura 2 / acetoxymethyl ester ( fura 2 / AM ) . Leukotriene ( LT ) D4 induced a concentration - dependent biphasic response consisting of a transient phase ( up to 5 - fold peak increase ) followed by a sustained phase , showing characteristics of a receptor - operated calcium channel . Homologous desensitization to LTD4 was observed . The responses to LTD4 were reduced by 80 to 90 % in calcium - free buffer . The responses to LTD4 in a calcium - free buffer were dependent upon the duration of prior exposure of the cells to a calcium - free environment . The response at 30 or 60 min after exposure to calcium - free buffer was greater than that at earlier time points ( time - dependent sensitization ) . Similar responses were obtained with THP - 1 cells exposed to DB00974 - containing buffer . It is speculated that such time - dependent sensitization is a result of changes at the receptor level . The responses to LTD4 were blocked by two specific LTD4 antagonists , MK - 0571 and DB00549 , in a concentration - dependent manner . When given after addition of LTD4 , MK - 0571 or DB00549 reversed the sustained phase of the LTD4 - induced response , suggesting that maintenance of the response requires persistent activation of the Q9Y271 . DB00549 was 5 to 10 times more potent than MK - 0571 ( IC50 values of 1 . 1 and 9 . 3 nM , respectively ) , in agreement with results from radioligand binding studies reported separately .",
"Leukotriene B4 modulates in vivo expression of delayed - type hypersensitivity by a receptor - mediated mechanism : regulation by lipoxin A4 . Leukotriene B4 ( LTB4 ) is a potent proinflammatory arachidonic acid metabolite whose actions are mediated by specific receptors . Recent characterization of a high - affinity LTB4 receptor on the surface of guinea pig P01730 + T lymphocytes prompted examination of a possible role of LTB4 in modulating in vivo expression of delayed - type hypersensitivity ( DTH ) to tuberculin ( PPD ) . In the absence of PPD , intradermal injections of LTB4 or LTB4 / Q9Y271 antagonists did not elicit delayed - onset erythema at 24 h . When injected together with PPD , LTB4 ( 1 fmol to 1 pmol ) caused a significant 25 to 30 % decrease in DTH expression , whereas LTB4 receptor antagonists SC - 41930 , LY - 223982 , ONO - 4057 ( 0 . 1 - 10 nmol ) , caused a highly significant ( P < . 01 ) 25 to 50 % increase . The effect of SC - 41930 on DTH expression was inhibited by a 10 - fmol dose of LTB4 . Q9Y271 antagonist LY - 171883 had no effect on DTH expression . Lipoxin A4 ( LXA4 ) interferes with binding of LTB4 to T lymphocytes or neutrophils by reducing LTB4 receptor density . It caused a small but significant enhancement of DTH expression at 1 - nmol doses when injected with PPD . Lipoxin B4 had no effect . Enhancement or inhibition of grossly visible delayed skin responses to PPD by LTB4 . LTB4 receptor antagonists or LXA4 was not associated with qualitative or quantitative changes in superficial or deep dermal mononuclear cell infiltrates at the reaction site . We conclude that LTB4 modulates visible expression of DTH in vivo by a receptor - mediated mechanism .",
"Effects of ozone exposure mediated by BEAS - 2B cells on T cells activation : a possible link between environment and asthma . OBJECTIVE : To explore the possible link between ozone and asthma through analyzing Th1 / Th2 differentiation of T cells following incubation with conditioned medium from the BEAS - 2B cells exposed to ozone in vitro . METHOD : Bronchial epithelial cell line , BEAS - 2B , was cultured using an air - liquid interface culture system in a CO2 incubator and exposed to 0 or 0 . 16 or 0 . 25 mg / m3 of ozone for 8 h . The amounts of IL - 1β , P05231 and RANTES in the cell supernatant were detected . The cell culture supernatants were collected and used as conditioned medium in the next experiment . T cells from children recruited were incubated with conditioned medium for 12 h . Activation rate of Q07108 and Th1 / Th2 / Th17 differentiation were analyzed . RESULTS : BEAS - 2B cells exposed to different ozone concentrations showed morphological changes . Cells exposed to 0 . 16 and 0 . 25 mg / m3 ozone produced higher amounts of IL - 1β , P05231 and RANTES than that in the control group . Children with allergic asthma had upregulated expression of genes related with asthma , including P13500 , CCR4 , P19875 , Q9Y271 , Q99665 , Q14627 , Q13478 , P01584 , P10145 , P25025 and O75888 . Q07108 expression in T cells was significantly elevated irrespective of ozone exposure in children with allergic asthma . Following ozone exposure , in asthmatic children group , expression levels of cytokines of Th1 cells were collectively higher than those from Th2 cells . Ozone - exposed conditioned media could slightly increase all the Th1 , Th2 and Th17 cytokines in T cells from allergic asthmatic children . CONCLUSIONS : Our results suggested that Th1 cells activation might be predominant over Th2 activation upon ozone exposure in asthmatic children , which might help to clarify the mechanisms of asthma related to environmental factors like ozone .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK8___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"Detection of thymidylate synthase modulators by a novel screening assay . P04818 ( TS ) , a key cancer chemotherapeutic target , catalyzes the conversion of deoxyuridylate to thymidylate . TS can serve as a repressor of its own synthesis by binding to its own mRNA through TS - specific binding elements ( TBEs ) . In this report , we describe the use of a luciferase reporter plasmid containing two TBEs that can be used as a tool for the identification and initial profiling of compounds that modulate TS activity , levels , or ability to bind mRNA . To validate this model , we evaluated several groups of drugs . Thus , cells were exposed to the pyrimidine analogs 5 - fluorouracil ( DB00544 ) , 5 - fluorouridine ( DB01629 ) , 5 - fluoro - 2 '- deoxyuridine ( FUdR ) , trifluorothymidine ( DB00432 ) ; to the nonpyrimidine TS - inhibitors AG - 331 , nolatrexed ( AG337 ) , and raltitrexed ( ___MASK69___ ) ; or to drugs with other primary sites of action ( methotrexate , actinomycin D , 5 - azacytidine , 8 - thioguanosine ) . Except for 5 - azacytidine and 8 - thioguanosine , all compounds examined induced luciferase activity compared with untreated cells . Effects of luciferase activity inducing drugs through TS - affected translation were confirmed by examinations of TS protein and mRNA levels . Treatment of H630 - P13671 cells with DB00544 , DB01629 , FUdR , DB00432 , AG331 , AG337 , ___MASK69___ , and methotrexate up - regulated TS levels as determined by Western blot analysis , although TS mRNA levels remained unchanged as determined by reverse transcription - polymerase chain reaction . Our studies demonstrate a novel application of a TBE - dependent reporter plasmid that could be used for the high - throughput identification of potential chemotherapeutic agents that modulate TS RNA - binding activity , either directly or indirectly .",
"Maxi - anion channel as a candidate pathway for osmosensitive DB00171 release from mouse astrocytes in primary culture . In the present study , we aimed to evaluate the pathways contributing to DB00171 release from mouse astrocytes during hypoosmotic stress . We first examined the expression of mRNAs for proteins constituting possible DB00171 - releasing pathways that have been suggested over the past several years . In RT - PCR analysis using both control and osmotically swollen astrocytes , amplification of cDNA fragments of expected size was seen for connexins ( P08034 , P35212 , P17302 ) , pannexin 1 ( Px1 ) , the Q99572 receptor , MRP1 and P08183 , but not P13569 . Inhibitors of exocytotic vesicular release , gap junction hemi - channels , P13569 , MRP1 , P08183 , the Q99572 receptor , and volume - sensitive outwardly rectifying chloride channels had no significant effects on the massive DB00171 release from astrocytes . In contrast , the hypotonicity - induced DB00171 release from astrocytes was most effectively inhibited by gadolinium ( 50 muM ) , an inhibitor of the maxi - anion channel , which has recently been shown to serve as a pathway for DB00171 release from several other cell types . Thus , we propose that the maxi - anion channel constitutes a major pathway for swelling - induced DB00171 release from cultured mouse astrocytes as well .",
"Central opioid inhibition of neuroendocrine stress responses in pregnancy in the rat is induced by the neurosteroid allopregnanolone . The hypothalamus - pituitary - adrenal ( Q9Y251 ) axis is the major neuroendocrine stress response system . P06850 ( P06850 ) neurons in the parvocellular paraventricular nucleus ( pPVN ) play a key role in coordinating responses of this system to stressors . The cytokine interleukin - 1beta ( IL - 1beta ) , mimicking infection , robustly activates these P06850 neurons via a noradrenergic input arising from the nucleus tractus solitarii ( P30990 ) . In late pregnancy , Q9Y251 axis responses to stressors , including IL - 1beta , are attenuated by a central opioid mechanism that auto - inhibits noradrenaline release in the PVN . Here we show that the neuroactive progesterone metabolite allopregnanolone induces these changes in Q9Y251 responsiveness to IL - 1beta in pregnancy . In late pregnancy , inhibition of 5alpha - reductase ( an allopregnanolone - synthesizing enzyme ) with finasteride restored Q9Y251 axis responses ( rapidly increased pPVN P06850 mRNA expression , ___MASK31___ , and corticosterone secretion ) to IL - 1beta . Conversely , allopregnanolone reduced Q9Y251 responses in virgin rats . In late pregnancy , activity of the allopregnanolone - synthesizing enzymes ( 5alpha - reductase and 3alpha - hydroxysteroid dehydrogenase ) was increased in the hypothalamus as was mRNA expression in the P30990 and PVN . Naloxone , an opioid antagonist , restores Q9Y251 axis responses to IL - 1beta in pregnancy but had no additional effect after finasteride , indicating a causal connection between allopregnanolone and the endogenous opioid mechanism . Indeed , allopregnanolone induced opioid inhibition over Q9Y251 responses to IL - 1beta in virgin rats . Furthermore , in virgin rats , allopregnanolone treatment increased , whereas in pregnant rats finasteride decreased proenkephalin - A mRNA expression in the P30990 . Thus , in pregnancy , allopregnanolone induces opioid inhibition over Q9Y251 axis responses to immune challenge . This novel opioid - mediated mechanism of allopregnanolone action may alter regulation of other brain systems in pregnancy .",
"Pharmacological investigation of the role of leukotrienes in the pathogenesis of experimental NSAID gastropathy . The role of leukotrienes in the pathogenesis of acute gastric ulceration induced by nonsteroidal antiinflammatory drugs was investigated using a rat model . One part of the study involved oral pretreatment with a leukotriene synthesis inhibitor 1 h prior to administration of indomethacin ( 20 mg / kg per os ) . Three hours after indomethacin , the extent of macroscopically visible gastric damage was determined , and gastric LTB4 synthesis was determined . The compounds tested were PF - 5901 , A - 64077 , nordihydroguaiaretic acid , and L - 698 , 037 . Each compound produced dose - related inhibition of gastric LTB4 synthesis and a parallel reduction in the severity of indomethacin - induced damage . The antioxidant properties of these compounds was assessed using an in vitro assay . There was no correlation between the antioxidant properties of the compounds and their ability to reduce the severity of indomethacin - induced gastric damage . In the second part of the study , the effects of intravenous , administration of LTD4 and LTB4 receptor antagonists on indomethacin - induced gastric epithelial damage ( measured by permeability to [ 51Cr ] DB00974 ) were assessed . The two Q9Y271 antagonists ( MK - 571 and DB00549 ) significantly reduced the permeability changes induced by indomethacin , while the two LTB4 antagonists ( SC - 41930 and LY - 255 , 283 ) were without significant effect . Despite the reduction of gastric epithelial injury , blockade of LTD4 receptors did not markedly affect the extent of macroscopically visible injury . These data are consistent with the hypothesis that leukotrienes contribute to the epithelial injury and macroscopically visible damage induced by NSAIDs . However , it remains unclear to what extent leukotrienes are involved in the initiation of the injury , as opposed to its amplification .",
"P18509 , interleukin - 6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells . There is increasing evidence that hormones play an important role in the control of endothelial cell function and growth by regulating the production of vascular endothelial growth factor ( P15692 ) . P15692 regulates vascular permeability and represents the most powerful growth factor for endothelial cells . In the normal anterior pituitary , P15692 has been detected only in folliculostellate ( FS ) cells . In the present study , the regulation of the release of P15692 from FS - like mouse TtT / GF cells , and from FS cells of rat pituitary monolayer cell cultures was investigated using a specific P15692 ELISA . Basal release of P15692 was demonstrated in cultures of both TtT / GF cells and rat pituitary cells . Interestingly , the P15692 secretion was stimulated by both forms of pituitary adenylate cyclase - activating polypeptide ( PACAP - 38 and PACAP - 27 ) , indicating that this hypothalamic peptide regulates endothelial cell function and growth within the pituitary . P15692 secretion was also stimulated by interleukin - 6 ( P05231 ) whereas basal , P05231 - and PACAP - stimulated secretion was inhibited by the synthetic glucocorticoid dexamethasone . The inhibitory action of dexamethasone was reversed by the glucocorticoid receptor antagonist ___MASK6___ , suggesting that in FS cells functional glucocorticoid receptors mediate the inhibitory action of glucocorticoids on the P15692 secretion . The endocrine and auto -/ paracrine control of P15692 production in pituitary FS cells by PACAP , P05231 and glucocorticoids may play an important role both in angiogenesis and vascular permeability regulation within the pituitary under physiological and pathophysiological conditions .",
"5 - Lipoxygenase mediates O14788 - induced osteoclast formation via the cysteinyl leukotriene receptor 1 . 5 - Lipoxygenase ( P09917 ) catalyzes the formation of two major groups of leukotrienes , leukotriene B4 and cysteinyl leukotrienes ( CysLTs ) , and it has been implicated as a promising drug target to treat various inflammatory diseases . However , its role in osteoclastogenesis has not been investigated . In this study , we used mouse bone marrow - derived macrophages ( BMMs ) to show that P09917 inhibitor suppresses O14788 - induced osteoclast formation . Inhibition of P09917 was associated with impaired activation of multiple signaling events downstream of Q9Y6Q6 , including P29323 and p38 phosphorylation , and IκB degradation , followed by a decrease in O95644 expression . Ectopic overexpression of a constitutively active form of O95644 partly rescued the antiosteoclastogenic effect of P09917 inhibitor . The knockdown of P09917 in BMMs also resulted in a significant reduction in O14788 - induced osteoclast formation , accompanied by decreased expression of O95644 . Similar effects were shown with CysLT receptor ( CysLTR ) 1 / 2 antagonist and small RNA for Q9Y271 in BMMs , indicating the involvement of CysLT and Q9Y271 in P09917 - mediated osteoclastogenesis . Finally , P09917 inhibitor suppressed LPS - induced osteoclast formation and bone loss in the in vivo mouse experiments , suggesting a potential therapeutic strategy for treating diseases involving bone destruction . Taken together , the results of this study demonstrate that P09917 is a key mediator of O14788 - induced osteoclast formation and possibly a novel therapeutic target for bone - resorption diseases .",
"___MASK89___ , a further innovation in the treatment of sexual dysfunction . In recognition of the large number of sufferers of sexual dysfunction worldwide , and the variety of etiologies of the condition , investigation into effective pharmacological agents has been expanded . One method of intervention is inhibition of the phosphodiesterase type 5 ( O76074 ) enzyme , which has already been exploited with a considerable degree -- though not complete -- success . A number of new agents that inhibit O76074 are under development . Notable among these is tadalafil , which has demonstrated a high level of selectivity for O76074 over the other phosphodiesterases and has shown efficacy in improving erectile function and sexual satisfaction in phase III trials . Throughout the clinical development program for tadalafil , the drug has been well tolerated and without serious side effects . The manufacturer , Lilly Q9Y6W8 , received an approvable letter from the US Food and Drug Administration for use of the drug as a treatment for erectile dysfunction on April 30 , 2002 . Lilly Q9Y6W8 hopes to market tadalafil , with the trade name ___MASK89___ , in the USA in 2003 .",
"___MASK80___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK80___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"Genetic mechanism of aspirin - induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin - related hypersensitivity often associated with aspirin - intolerant asthma . Genetic studies on aspirin - intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin - induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin - induced urticaria / angioedema . A polymorphism study that examined nine single - nucleotide polymorphisms of five leukotriene - related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 - activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( - 1708A > G ) and Q9Y271 ( - 634C > T ) were significantly different between aspirin - intolerant asthma and aspirin - induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine - related genes , did not find any significant associations with aspirin - induced urticaria / angioedema for the genes P50135 ( encoding histamine N - methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high - affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin - induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin - induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .",
"Program death - 1 engagement upon TCR activation has distinct effects on costimulation and cytokine - driven proliferation : attenuation of Q9Y6W8 , P05112 , and Q9HBE4 , but not P10747 , P13232 , and P40933 responses . The program death 1 ( P18621 ) receptor and its ligands , P18621 ligand ( PD - L ) 1 and Q9BQ51 , define a novel regulatory pathway with potential inhibitory effects on T , B , and monocyte responses . In the present study , we show that human P01730 (+) T cells express P18621 , Q9NZQ7 , and Q9BQ51 upon activation , and Abs to the receptor can be agonists or antagonists of the pathway . Under optimal conditions of stimulation , Q9Y6W8 but not P10747 costimulation can be prevented by P18621 engagement . P60568 levels induced by costimulation are critical in determining the outcome of the P18621 engagement . Thus , low to marginal P60568 levels produced upon Q9Y6W8 costimulation account for the greater sensitivity of this pathway to P18621 - mediated inhibition . Interestingly , exogenous P60568 , P13232 , and P40933 but not P05112 and Q9HBE4 can rescue P18621 inhibition , suggesting that among these cytokines only those that activate P42229 can rescue P18621 inhibition . As P42229 has been implicated in the maintenance of IL - 2Ralpha expression , these results suggest that P13232 and P40933 restore proliferation under conditions of P18621 engagement by enhancing high - affinity IL - 2R expression and hence , P60568 responsiveness .",
"P00797 angiotensin system modulates P42345 pathway through AT2R in HIVAN . P42345 ( P42345 ) has been reported to contribute to the development of HIV - associated nephropathy ( HIVAN ) . We hypothesized that HIV may be activating renal tissue P42345 pathway through renin angiotensin system ( DB01367 ) via Angiotensin Receptor Type II receptor ( AT2R ) . Renal tissues of Vpr transgenic and Tg26 ( HIVAN ) mice displayed enhanced phosphorylation of P42345 and p70S6K . ___MASK14___ , a renin inhibitor attenuated phosphorylation of both P42345 and p70S6K in renal tissues of HIVAN mice . Interestingly , Angiotensin Receptor Type I ( AT1R ) blockade did not modulate renal tissue phosphorylation of P42345 in HIVAN mice ; on the other hand , AT2R blockade attenuated renal tissue phosphorylation of P42345 in HIVAN mice . In vitro studies , both renin and Ang II displayed enhanced mouse tubular cell ( P04629 ) phosphorylation of p70S6K in a dose dependent manner . HIV / P04629 also displayed enhanced phosphorylation of both P42345 and p70S6K ; interestingly this effect of HIV was further enhanced by losartan ( an AT1R blocker ) . On the other hand , AT2R blockade attenuated HIV - induced tubular cell phosphorylation of P42345 and p70S6K , whereas , AT2R agonist enhanced phosphorylation of P42345 and p70S6K . These findings indicate that HIV stimulates P42345 pathway in HIVAN through the activation of renin angiotensin system via AT2R .",
"Is Q13304 a P2Y / leukotriene receptor ? examination of uracil nucleotides , nucleotide sugars , and cysteinyl leukotrienes as agonists of Q13304 . The orphan receptor Q13304 has been reported to be activated by UDP , UDP - sugars , and cysteinyl leukotrienes , and coupled to intracellular Ca ( 2 +) mobilization and inhibition of DB02527 accumulation , but other studies have reported either a different agonist profile or lack of agonist activity altogether . To determine if Q13304 is activated by uracil nucleotides and leukotrienes , the hemagglutinin - tagged receptor was expressed in five different cell lines and the signaling properties of the receptor were investigated . In P13671 , 1321N1 , or Chinese hamster ovary ( CHO ) cells stably expressing Q13304 , UDP , UDP - glucose , DB03501 , and cysteinyl leukotriene C4 ( LTC4 ) all failed to promote inhibition of forskolin - stimulated DB02527 accumulation , whereas both UDP and UDP - glucose promoted marked inhibition ( > 80 % ) of forskolin - stimulated DB02527 accumulation in P13671 and CHO cells expressing the Q15391 receptor . Likewise , none of these compounds promoted accumulation of inositol phosphates in COS - 7 or human embryonic kidney 293 cells transiently transfected with Q13304 alone or cotransfected with Gαq / i5 , which links Gi - coupled receptors to the Gq - regulated phospholipase C ( P98160 ) signaling pathway , or PLCε , which is activated by the Gα12 / 13 signaling pathway . Moreover , none of these compounds promoted internalization of Q13304 in 1321N1 - Q13304 cells . Consistent with previous reports , coexpression experiments of Q13304 with cysteinyl leukotriene receptor 1 ( Q9Y271 ) suggested that Q13304 acts as a negative regulator of Q9Y271 . Taken together , these data suggest that UDP , UDP - glucose , DB03501 , and LTC4 are not the cognate ligands of Q13304 .",
"Preservation of the glomerular capillary ultrafiltration coefficient during rat nephrotoxic serum nephritis by a specific leukotriene D4 receptor antagonist . Leukotriene D4 , a potent biologically active lipoxygenase derivative of arachidonic acid in activated leukocytes , depresses the glomerular capillary ultrafiltration coefficient ( Kf ) and contracts mesangial cells in culture . We therefore investigated its potential role in mediating the reduction in nephron filtration rate seen after induction of experimental nephrotoxic serum ( P30990 ) - induced glomerulonephritis in the rat . Micropuncture measurements were performed in euvolemic Munich - Wistar rats 2 h after i . v . administration of 0 . 8 ml of rabbit serum ( group 1 , n = 6 ) , 0 . 8 ml of rabbit anti - rat glomerular basement membrane antibody in the absence ( group 2 , n = 8 ) , or presence ( group 3 , n = 7 ) of the new highly specific Q9Y271 antagonist SK & F 104353 . Quantitation of antibody binding and neutrophil infiltration revealed no differences between groups 2 and 3 . Antagonism of endogenous LTD4 actions , however , was associated with prevention of the P30990 - induced fall in SNGFR because of the abrogation of the fall in Kf which characterizes this form of experimental glomerulonephritis . Antagonism of endogenous LTD4 had no effect on the P30990 - induced increases in pre - and postglomerular arteriolar resistances , and did not affect nephron plasma flow rate or net transcapillary hydraulic pressure difference . The observed highly localized protective action of the LTD4 antagonist on the glomerular capillary points to a possibly major functional role for intraglomerularly released LTD4 , likely originating from infiltrating leukocytes , in the pathophysiology of this form of glomerulonephritis .",
"P06401 activation of extranuclear signaling pathways in regulating p53 expression in vascular endothelial cells . We previously showed that progesterone ( P4 ) inhibited the proliferation of human umbilical vein endothelial cells ( HUVECs ) through a p53 - dependent pathway . Now we investigated further the molecular mechanism underlying the hormone activity . In cultured HUVECs , P4 increased the protein levels of phosphorylated Src ( p - Src ) , P04049 , and P29323 . The levels of p - Src and p - Src - progesterone receptor complex in HUVECs were increased by P4 treatment . These effects were blocked by pretreatment with a progesterone receptor antagonist , ___MASK6___ . The P4 - induced increase in p53 transactivity was abolished by pretreatment with Src kinase inhibitors . Moreover , administration with cSrc antisense oligonucleotide prevented the P4 - induced increases of the levels of p53 mRNA and protein . These data suggest that P4 - induced up - regulation of p53 might be mediated through activation of cSrc . Pretreatment with Src kinase inhibitors also prevented P4 - induced membrane translocation of Kras and increases of the protein levels of phosphorylated Raf and phosphorylated P29323 . Transfection with dominant - negative P28482 prevented the P4 - induced increases of protein level and promoter activity of p53 and a decrease of thymidine incorporation . P4 also increased nuclear factor - κB ( NF - κB ) nuclear translocation and NF - κB binding onto the p53 promoter . These effects were abolished by pretreatment with P29323 inhibitors . The P4 - induced up - regulation of the p53 promoter activity was prevented by preadministration with dominant - negative P28482 or NF - κB inhibitors . Taken together , our data suggest that the cSrc / Kras / P04049 / P28482 / NF - κB signaling pathway contributes to the P4 - induced up - regulation of p53 in HUVECs . These findings highlight progesterone receptor activation of extranuclear signaling pathways in regulating p53 and cell cycle progression in HUVECs .",
"P42892 and β - arrestins exert spatiotemporal control of DB05875 - induced inflammatory signals . Although the intracellular trafficking of G protein - coupled receptors controls specific signaling events , it is unclear how the spatiotemporal control of signaling contributes to complex pathophysiological processes such as inflammation . By using bioluminescence resonance energy transfer and superresolution microscopy , we found that DB05875 ( SP ) induces the association of the neurokinin 1 receptor ( P25103 ) with two classes of proteins that regulate SP signaling from plasma and endosomal membranes : the scaffolding proteins β - arrestin ( βARRs ) 1 and 2 and the transmembrane metallopeptidases ECE - 1c and ECE - 1d . In HEK293 cells and non - transformed human colonocytes , we observed that G protein - coupled receptor kinase 2 and β P49407 / 2 terminate plasma membrane Ca ( 2 +) signaling and initiate receptor trafficking to endosomes that is necessary for sustained activation of ERKs in the nucleus . βARRs deliver the SP - P25103 endosomes , where P42892 associates with the complex , degrades SP , and allows the P25103 , freed from βARRs , to recycle . Thus , both P42892 and βARRs mediate the resensitization of P25103 Ca ( 2 +) signaling at the plasma membrane . Sustained exposure of colonocytes to SP activates NF - κB and stimulates P10145 secretion . This proinflammatory signaling is unaffected by inhibition of the endosomal P29323 pathway but is suppressed by P42892 inhibition or β P32121 knockdown . Inhibition of protein phosphatase 2A , which also contributes to sustained P25103 signaling at the plasma membrane , similarly attenuates P10145 secretion . Thus , the primary function of βARRs and P42892 in SP - dependent inflammatory signaling is to promote resensitization , which allows the sustained P25103 signaling from the plasma membrane that drives inflammation .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK1___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks ."
] |
[
"___MASK14___",
"___MASK1___",
"___MASK31___",
"___MASK69___",
"___MASK6___",
"___MASK76___",
"___MASK80___",
"___MASK89___",
"___MASK8___"
] |
___MASK6___
|
MH_train_472
|
interacts_with DB00952?
|
[
"A common single nucleotide polymorphism can exacerbate long - QT type 2 syndrome leading to sudden infant death . BACKGROUND : Identification of infants at risk for sudden arrhythmic death remains one of the leading challenges of modern medicine . We present a family in which a common polymorphism ( single nucleotide polymorphism ) inherited from the father , combined with a stop codon mutation inherited from the mother ( both asymptomatic ) , led to 2 cases of sudden infant death . METHODS AND RESULTS : P51787 , Q12809 , Q14524 , P15382 , Q9Y6J6 , CACNA1c , CACNB2b , and P63252 genes were amplified and analyzed by direct sequencing . Functional electrophysiological studies were performed with the single nucleotide polymorphism and mutation expressed singly and in combination in Chinese ovary ( CHO - P04264 ) and COS - 1 cells . An asymptomatic woman presenting after the death of her 2 - day - old infant and spontaneous abortion of a second baby in the first trimester was referred for genetic analysis . The newborn infant had nearly incessant ventricular tachycardia while in utero and a prolonged QTc ( 560 ms ) . The mother was asymptomatic but displayed a prolonged QTc . Genetic screening of the mother revealed a heterozygous nonsense mutation ( P926AfsX14 ) in Q12809 , predicting a stop codon . The father was asymptomatic with a normal QTc but had a heterozygous polymorphism ( K897T ) in Q12809 . The baby who died at 2 days of age and the aborted fetus inherited both K897T and P926AfsX14 . Heterologous coexpression of K897T and P926AfsX14 led to loss of function of Q12809 current much greater than expression of K897T or P926AfsX14 alone . CONCLUSIONS : Our data suggest that a common polymorphism ( K897T ) can markedly accentuate the loss of function of mildly defective Q12809 channels , leading to long - QT syndrome - mediated arrhythmias and sudden infant death .",
"DB00952 mitigates CGRP1 - associated motor neuron degeneration caused by an expanded polyglutamine repeat tract . Spinal and bulbar muscular atrophy ( SBMA ) is a motor neuron disease caused by the expansion of the CAG triplet repeat within the androgen receptor ( AR ) gene . Here , we demonstrated that pathogenic AR upregulates the gene encoding calcitonin gene - related peptide α ( CGRP1 ) . In neuronal cells , overexpression of CGRP1 induced cellular damage via the activation of the c - Jun N - terminal kinase ( JNK ) pathway , whereas pharmacological suppression of CGRP1 or JNK attenuated the neurotoxic effects of pathogenic AR . The depletion of CGRP1 inactivated JNK and suppressed neurodegeneration in a mouse model of SBMA . DB00952 , a serotonin 1B / 1D ( 5 - hydroxytryptamine 1B / 1D , or P28222 / 1D ) receptor agonist , decreased CGRP1 expression via the induction of dual - specificity protein phosphatase 1 ( P28562 ) , attenuated JNK activity and mitigated pathogenic AR - mediated neuronal damage in cellular and mouse SBMA models . These observations suggest that pharmacological activation of the P28222 / 1D receptor may be used therapeutically to treat SBMA and other polyglutamine - related neurodegenerative diseases .",
"Serotonin via P34969 receptors activates p38 mitogen - activated protein kinase and protein kinase C epsilon resulting in interleukin - 6 synthesis in human U373 MG astrocytoma cells . Serotonin [ 5 - hydroxytryptamine ( 5 - HT ) ] is a widely distributed neurotransmitter which is involved in neuroimmunomodulatory processes . Previously , it has been demonstrated that 5 - HT may induce interleukin ( IL ) - 6 expression in primary rat hippocampal astrocytes . The present study was undertaken to investigate the molecular pathways underlying this induction of P05231 synthesis . As a model system , we used the human astrocytoma cell line U373 MG , which synthesizes P05231 upon stimulation with various inducers . 5 - HT dose - and time - dependently induced P05231 protein synthesis . We identified several 5 - HT receptors to be expressed on U373 MG cells , including the P28221 , 5 - Q13049 , 5 - Q9H205 and P34969 receptors . In this report , we show that the 5 - HT - induced P05231 release is mediated by the P34969 receptor based on several agonist / antagonists that were used . 5 - HT - induced P05231 synthesis is inhibited by the partially selective P34969 receptor antagonist , pimozide , and the selective antagonist SB269970 . Furthermore , P05231 synthesis was induced by the P34969 receptor agonist carboxamidotryptamin . In addition , we found p38 MAPKs and protein kinase C ( PKC ) epsilon to be involved in 5 - HT - induced P05231 synthesis as specific inhibitors of these enzymes ( SB202190 and RO - 31 - 8425 , respectively ) blocked 5 - HT - induced P05231 synthesis . Furthermore , 5 - HT mediated the phosphorylation of both p38 MAPK as well as the PKC epsilon isoform . The Q8NFH3 / 44 MAPKs , however , were not involved in 5 - HT - induced P05231 synthesis . This study shows , for the first time , a central role of P34969 receptor linked to p38 MAPK and PKC epsilon for the induction of cytokine synthesis in astrocytic cells .",
"Emerging therapeutic options for acute migraine : focus on the potential of lasmiditan . The serotonin receptor agonist DB00669 drugs ( P28222 / 1D receptor agonists ) have been in use for over 20 years in the abortive management of migraine . Although clearly effective , their ability to produce vasoconstriction in cerebral and coronary arteries , thought to be mediated by their high affinity for the P28222 receptor , has been a limitation to their use in certain patient populations . Variable potency DB00669 binding at the P30939 receptor occurs in addition to binding at the P28222 and P28221 receptors . A more selective serotonin agonist without P28222 - mediated vasoconstriction might prove efficacious yet safer . The P30939 receptor has been targeted as a site of action for such a drug . In experimental models , P30939 receptor agonists have been shown to block neurogenic inflammation and c - Fos expression in neural tissue and , as well , show no evidence of vasoconstriction in vascular tissue models in vitro . In clinical trials , efficacy in the abortive management of migraine has been established . Lasmiditan ( LY573144 ) , a selective P30939 receptor agonist ( P04264 = 2 . 21 μM ) , showed efficacy in its primary endpoint , with a 2 - hour placebo - subtracted headache response of 28 . 8 % , though with frequent reports of dizziness , paresthesias , and vertigo . Study results support an emerging central neuronal mechanism of migraine pathophysiology . This review traces the history and use of P30939 receptor agonists , now referred to as neurally acting anti - migraine agents in migraine management .",
"Structure functional expression and spatial distribution of a cloned cDNA encoding a rat P28221 - like receptor . Using polymerase chain reaction ( PCR ) a complementary DNA ( cDNA ) encoding a 5 - hydroxytryptamine ( 5 - HT ) receptor was isolated from rat forebrain . The amplified cDNA specifies an open reading frame of 374 amino acids comprising seven putative transmembrane regions . Expression of the cloned cDNA in human embryonic kidney cells ( P29320 293 ) was used to establish the pharmacological profile of the encoded receptor polypeptide . Membranes containing the cloned receptor showed high affinity binding of [ 3H ] - 5 - HT . Competition binding experiments with a variety of serotonin receptor ligands displayed a rank order of affinities corresponding to a P28221 subtype : 5 - CT > 5 - HT = metergoline > CGS 12066 > methysergide > sumatriptan > mianserin = (-) alpha - Me - 5 - HT = yohimbine > 8 - OH - DPAT > or = rauwolscine > spiperone > DOI > propranolol > or = 2 - Me - 5 - HT > or = ICS 205930 . Ketanserin and ritanserin displaced [ 3H ] - 5 - HT - binding in a biphasic manner . In situ hybridization revealed highest expression of the corresponding mRNA in the pyramidal layer of the olfactory tubercle and the nucleus caudatus and accumbens .",
"Constitutive G ( i2 )- dependent activation of adenylyl cyclase type II by the P08908 receptor . Inhibition by anxiolytic partial agonists . The P08908 receptor is implicated in depression and anxiety . This receptor couples to G ( i ) proteins to inhibit adenylyl cyclase ( AC ) activity but can stimulate AC in tissues ( e . g . hippocampus ) that express ACII . The role of ACII in receptor - mediated stimulation of DB02527 formation was examined in P29320 - 293 cells transfected with the P08908 receptor , which mediated inhibition of basal and G ( s )- induced DB02527 formation in the absence of ACII . In cells cotransfected with P08908 receptor and ACII plasmids , P08908 agonists induced a 1 . 5 - fold increase in DB02527 level . Cotransfection of P08908 receptor , ACII , and Galpha ( i2 ) , but not Galpha ( i1 ) , Galpha ( i3 ) , or Galpha ( o ) , resulted in an agonist - independent 6 - fold increase in the basal DB02527 level , suggesting that G ( i2 ) preferentially coupled the receptor to ACII . The P28222 receptor also constitutively activated ACII . Constitutive activity of the P08908 receptor was blocked by pertussis toxin and the Gbetagamma antagonist , betaCT , suggesting an important role for Gbetagamma - mediated activation of ACII . The DB00156 - 149 --> Ala mutation in the second intracellular domain of the P08908 receptor disrupted Gbetagamma - selective activation of ACII . Spontaneous P08908 receptor activity was partially attenuated by P08908 receptor partial agonists with anxiolytic activity ( e . g . buspirone and flesinoxan ) but was not altered by full agonists or antagonists . Thus , anxiolytic activity may involve inhibition of spontaneous P08908 receptor activity .",
"[ Quantitative analysis of P11387 activity in human and rat glioma : characterization and mechanism of resistance to antitopoisomerase chemical , camptothecin - 11 ] . ___MASK85___ ( CPT - 11 ) is a new derivation of camptothecin , a plant alkaloid antitumor agent . Previous studies indicated that antitumor activity of CPT - 11 was mediated through interaction of the drugs with its target enzyme , P11387 ( topo I ) . In this study , we studied the relation between sensitivity to CPT - 11 and topo I activity of glioma cells . Furthermore , we established CPT - 11 resistant cell lines in order to elucidate potential mechanisms of drug resistance . A clear correlation between the sensitivities to CPT - 11 and topo I activities in surgical glioma specimens was demonstrated . Activities of topo I in CPT - 11 sensitive group ( IC50 values for CPT - 11 ; < 50 micrograms / ml ) tended to be higher than those in CPT - 11 resistant group ( IC50 values ; > or = 50 ) . Topo I activity may serve as a novel marker to predict the sensitivity of gliomas to topo inhibitors . CPT - 11 resistance cell lines ( T98G / CPT - 11 and P13671 ) respectively exhibit a 5 . 4 - and 7 . 3 - fold increase in resistance to CPT - 11 . No differences in topo I activity and intracellular accumulation of CPT - 11 were observed between parent and CPT - 11 resistant lines . On the other hand , topo I from T98G / CPT - 11 and P13671 / CPT - 11 cells were at least 4 - and 2 - fold resistant to the inhibitory effect of the CPT - 11 on the relaxation activity of topo I in comparison with their parent lines . This enzymological difference may be responsible for the resistance to CPT - 11 .",
"P03372 - immunoreactive neurons contain calcitonin gene - related peptide , methionine - enkephalin or tyrosine hydroxylase in the female rat preoptic area . We have shown in our previous studies that estrogen treatment selectively influences calcitonin gene - related peptide ( P80511 ) - , methionine - enkephalin ( DB00134 - Enk ) - and tyrosine hydroxylase ( TH ) - immunoreactive ( IR ) intensities in the neurons of the periventricular preoptic nucleus ( Q9H237 ) and the medial preoptic area ( ___MASK63___ ) of the female rat . In the present study , we examined whether estrogen receptor ( ER ) - IR neurons in the Q9H237 and ___MASK63___ contain P80511 , DB00134 - Enk , or TH using a double - labeling immunohistochemical method and investigated changes in the number of double - labeling cells upon treatment with estrogen . Brain sections of ovariectomized rats and ovariectomized and estrogen - treated rat were stained using the avidin - biotin - peroxidase complex method followed by the peroxidase - anti - peroxidase method . The sections were first incubated with an anti - ER antibody in conjunction with nickel diaminobenzidine which produces a dark blue reaction product in the nucleus . Subsequently , P80511 , DB00134 - Enk or TH antisera were applied to these sections and the resulting brown diaminobenzidine reaction product in the cytoplasm was examined . Neurons that were double - labeled for ER and P80511 , DB00134 - Enk or TH were investigated in the Q9H237 and ___MASK63___ . The number of doubly labeled ER / P80511 - and ER / TH - IR neurons was large , whereas the number of ER / DB00134 - Enk - IR neurons was small . These results suggest that ER in the Q9H237 and ___MASK63___ may be more closely related to the mechanism of changes in P80511 - and TH - IR intensities upon estrogen treatment than that in DB00134 - Enk - IR intensity .",
"[ Pharmacy - clinic medication of the month . DB00952 ( naramig ) ] . DB00952 , launched by Glaxo Wellcome under the trade name Naramig , is a potent and selective agonist of P28222 and P28221 vascular receptors . Available as tablets of 2 . 5 mg , it is indicated in the acute treatment of migraine , with or without aura . A single oral dose of 2 . 5 mg naratriptan is characterized by a satisfactory clinical efficacy ( already significant after one hour , maximum after 4 hours and persisting during 24 hours ) , a reduction by half of the recurrence of the migraine crisis within the 24 hours and an excellent tolerance profile .",
"MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .",
"Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .",
"Role of the P08908 receptor in development of the neonatal rat brain : preliminary behavioral studies . Serotonin exerts an influence on the prenatal development of rat brain . However , later developmental times may be more applicable to the understanding of the role of serotonin in human developmental disorders . Therefore , the current study was undertaken to gain preliminary information on the postnatal effects of serotonin on rat brain development . As the P08908 receptor has been shown to be involved in much of the developmental functions of serotonin , an agonist for this receptor , 8 - hydroxy - DPAT ( 8 - OH - DPAT ) , was used . Neonatal rat pups at three ages ( postnatal days , PNDs ) 3 - 10 , 10 - 17 or 17 - 24 ) were injected daily with 1 mg / kg 8 - OH - DPAT and evaluated for behavioral consequences . The youngest group showed accelerated incisor eruption and eye - opening , a possible consequence of P08908 receptor interactions with epidermal growth factor ( P01133 ) . Behaviorally , the animals were more anxious . Animals treated from P01160 10 - 17 , showed no change in craniofacial development but showed greater behavioral maturity in measures of spontaneous alternation and activity in the open field . The oldest animals ( P01160 17 - 24 ) showed no behavioral alterations , suggesting that this time length is beyond the critical period for serotonin ' s influence in brain development .",
"DB00952 has a selective inhibitory effect on trigeminovascular neurones at central P08908 and 5 - HT ( 1B / 1D ) receptors in the cat : implications for migraine therapy . The triptans are agonists at serotonin ( 5 - HT ) 1B / 1D receptors ; however , they are also active at P08908 and P30939 receptors . We conducted this series of experiments to further elucidate the site of action of naratriptan using a well - established animal model of trigeminovascular stimulation . Following electrical stimulation of the superior sagittal sinus of the cat , single cell responses ( n = 83 ) were recorded in the trigeminal nucleus caudalis . Most cells ( 91 % ) also responded to electrical and mechanical stimulation of cutaneous or mucosal facial receptive fields . The microiontophoretic application of naratriptan resulted in a significant suppression of the response to sagittal sinus stimulation ( response suppressed by 47 +/- 4 % , P < 0 . 001 ) . The effect of naratriptan was significantly attenuated by application of either the 5 - HT ( 1B / 1D ) receptor antagonist GR - 127935 ( P < 0 . 001 ) or the P08908 antagonist WAY - 100635 ( P < 0 . 05 ) . The response of single cells to receptive field stimulation was also suppressed by microiontophoretic application of naratriptan , but by only 20 +/- 3 % . Intravenous administration of naratriptan resulted in a similar selective suppression of sagittal sinus vs . receptive field responses in trigeminal neurones . These results indicate that naratriptan has a central effect in the trigeminovascular system , selectively inhibiting afferent activity in craniovascular neurones , via both 5 - HT ( 1B / 1D ) and P08908 receptors .",
"Serotonergic modulation of the acoustic startle response in rats during preweaning development . The involvement of serotonin ( 5 - HT ) in modulating the acoustic startle response ( ASR ) is well established in adult rats , but 5 - HT involvement during the preweaning period , when 5 - HT neurons undergo extensive development , has not previously been described . Three 5 - HT receptor subtypes are reported to modulate the ASR in adult rats : P08908 and 5 - HT2 receptor agonists facilitate the ASR , whereas P28222 agonists decrease the response . In the present study , the effects of 5 - HT agonists and generalized 5 - HT depletion on the ASR were studied in preweanling animals , using independent groups of Long - Evans rats tested on postnatal day ( P01160 ) 13 , 17 and 21 . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8OHDPAT , 62 - 1000 micrograms / kg ) , a P08908 receptor agonist , and 5 - methoxy - N , N - dimethyl tryptamine ( MeODMT , 2 - 4 mg / kg ) , a nonselective 5 - HT agonist , had no effect on P01160 13 and then increased the ASR on P01160 17 and 21 . The 5 - HT2 receptor antagonists cyproheptadine ( 5 mg / kg ) and ketanserin ( 5 mg / kg ) blocked the effect of MeODMT at both ages , providing some evidence that MeODMT increased the ASR through 5 - HT2 receptors . 1 -( m - Chlorophenyl ) piperazine ( mCPP , 1 - 5 mg / kg ) , a P28222 agonist , had no effect on ASR amplitude on P01160 13 or 17 and then produced a dose - related decrease in the response on P01160 21 . Generalized depletion of 5 - HT by 80 - 90 % in whole - brain and spinal cord , using p - chlorophenylalanine ( PCPA , 300 mg / kg 24 hr prior to testing ) , did not alter ASR amplitude at any age . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK77___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK54___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"___MASK80___ induces insulin sensitization in Zucker lean and fatty rats . BACKGROUND : The 3 - hydroxy - 3 - methyl glutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors ( ' statins ' ) have been implicated in preventing new onset type 2 diabetes , whereas the mechanism of this effect is not known . We investigated the effects of an P04035 inhibitor , atorvastatin , on insulin sensitization in Zucker lean and fatty rats . METHODS AND RESULTS : In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg / kg / day ( ATORVA_50 ) and results were compared to Zucker lean and fatty rats treated with drug vehicle only ( CONT ) . Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25mg / kg / day ( ATORVA_25 ) . Treatment with atorvastatin resulted in a dose - dependent improvement in whole body insulin sensitivity in both lean and fatty rats , with an approximately two - fold increase in glucose infusion rate and glucose disposal ( Rd ) in ATORVA_50 versus CONT ( p < 0 . 01 ) . ___MASK80___ 50mg / kg / day resulted in an increase in DB08831 ( 2 - DOG ) uptake by skeletal muscles ( approximately two - fold increase in 2 - DOG uptake in quadriceps ( p = 0 . 06 ) and gastrocnemius ( p < 0 . 01 ) ) in lean Zucker rats . P01308 - stimulated phosphorylation of Akt / P31749 was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats . CONCLUSION : ___MASK80___ induces insulin sensitization in Zucker lean and fatty rats . This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans .",
"TATA - driven transcriptional initiation and regulation of the rat serotonin P08908 receptor gene . The transcriptional initiation and regulation of the rat serotonin P08908 receptor gene were characterized . By three types of analyses , a single brain - specific site of transcriptional initiation was localized to - 967 bp upstream of the translation initiation codon that is utilized both in hippocampus and in the rat raphe RN46A cell line . This major site of transcriptional initiation was located 58 bp downstream from a consensus TATA element , suggesting TATA - driven transcription of the rat P08908 receptor . To identify the promoter activity of the receptor gene , progressive 5 ' deletions of the - 2 , 719 /- 117 - bp fragment of the P08908 promoter linked to luciferase gene were transfected into P08908 - negative ( pituitary GH4C1 , Q9BTT4 myoblast , and P13671 glioma ) and P08908 - positive ( septal SN - 48 and raphe RN46A ) cell lines . Enhancer regions were identified within a fragment between nucleotides - 426 and - 117 that selectively enhanced transcription in P08908 - positive cells . A nonselective enhancer / promoter that mediated expression in all cell lines was located upstream between - 1 , 519 and - 426 bp in a DNA segment containing consensus TATA , CCAAT , SP - 1 , and AP - 1 elements as well as a poly - GT26 dinucleotide repeat . Strong repression of transcription in all cell lines was conferred by the region upstream of - 1 , 519 bp that contains a 152 - bp DNA segment with > 80 % identity to RANTES , tumor necrosis factor - beta , and other immune system genes . Our results indicate that TATA - driven expression of the P08908 receptor is regulated by a novel proximal tissue - specific enhancer region , a nonselective promoter , and an upstream repressor region that is distinct from previously identified neuron - specific repressors .",
"Evidence for serotonin ( 5 - HT ) 1B , P28221 and P30939 receptor inhibitory effects on trigeminal neurons with craniovascular input . Development of serotonin ( 5HT ( 1B / 1D ) ) agonists for the acute attack of migraine resulted in considerable interest in their action . The superior sagittal sinus ( SSS ) was isolated in alpha - chloralose ( 60 mg / kg , i . p . and 20 mg / kg i . v . i . supplementary 2 hourly ) anaesthetised cats . The SSS was stimulated electrically ( 100 V , 250 micros duration , 0 . 3 Hz ) and neurons of the trigeminocervical complex monitored using electrophysiological methods . To test 5 - HT ( 1B ) receptor - mediated activity common carotid blood flow ( CCF ) was monitored with a transonic flow probe placed around the vessel . DB00952 ( 5 - HT ( 1B / 1D / 1F ) receptor agonist ) and alniditan ( 5 - HT ( 1B / 1D ) receptor agonist ) produced reductions in carotid blood flow of 38 +/- 5 % and 42 +/- 6 % , respectively . These effects were attenuated by the 5 - HT ( 1B ) receptor antagonist SB224289 ( P < 0 . 05 ) . LY344864 ( 5 - HT ( 1F ) receptor agonist ) had no effect on CCF . DB00952 inhibited SSS - evoked activity ( 61 +/- 7 % ) , an effect partially inhibited by the 5 - HT ( 1B ) receptor antagonist SB224289 ( 30 +/- 5 % ) , or by the 5 - HT ( 1D ) receptor antagonist O95696 - 15572 ( 37 +/- 6 % ) . There remained an inhibitory effect of naratriptan after both 5 - HT ( 1B ) and 5 - HT ( 1D ) receptor blockade ( 22 +/- 5 % ) . Alniditan inhibited SSS - evoked trigeminal activity ( 53 +/- 6 % ) , an effect abolished after 5 - HT ( 1B ) and 5 - HT ( 1D ) receptor blockade . LY344864 ( 5 - HT ( 1F ) receptor agonist ) inhibited SSS - evoked trigeminal activity ( 28 +/- 5 % ) , an effect unaltered by either SB224289 or O95696 - 15572 . It can be concluded that there are inhibitory 5 - HT ( 1B ) , 5 - HT ( 1D ) and 5 - HT ( 1F ) receptors in the trigeminocervical complex of the cat . 5 - HT ( 1B ) receptor - mediated inhibition is the most potent of the three in terms of inhibition of trigeminovascular nociceptive traffic .",
"GLC756 decreases P01375 via an alpha2 and beta2 adrenoceptor related mechanism . GLC756 , a polyvalent anti - glaucoma drug showed in an endotoxin - induced - uveitis model ( EIU ) in rats a significant tumor necrosis factor - alpha ( P01375 ) decrease in serum , indicating an additional anti - inflammatory potential of this compound . The receptors on which GLC756 binds ( D1 , D2 , D4 , alpha - 1 , alpha - 2 , P08908 , P28335 , P28221 , 5 - HT2 A , beta - 1 , and beta - 2 ) were suggested to play a role . In order to identify a receptor type mediating the P01375 lowering response , GLC756 was combined with various counteracting compounds ( CP ) . For EIU , 8 - week - old Lewis rats were intravenously injected at 160 microg lipopolysaccharide ( LPS ) from Salmonella typhimurium . Before EIU - induction animals received either one of the CP ' s or GLC756 alone , or GLC756 in combination with one of the CP ' s . P01375 was determined in serum 2h post EIU - induction . Treatment with CP ' s alone indicated that agonistic effects on beta - 2 adrenoceptors and antagonistic effects on alpha - 2 , P08908 and P28221 receptors resulted in statistically significant decreased P01375 levels in comparison to the LPS - control group . In combination with GLC756 , the counteracting CP ' s domitor ( alpha - 2 adrenoceptor agonist ) and ICI 118551 ( beta - 2 adrenoceptor antagonist ) inhibited completely the P01375 decreasing effect of GLC756 . Counteracting the P08908 receptor with the P08908 agonist 8 - OH - DPAT could not prevent the P01375 decreasing effect of GLC756 . In conclusion , the antagonistic effect on alpha - 2 adrenoceptors and the agonistic effect on beta - 2 adrenoceptors were identified as mechanism for the P01375 decreasing effect of GLC756 .",
"Development and evaluation of high throughput functional assay methods for Q12809 potassium channel . Three functional hERG channel assay methods have been developed and evaluated . The methods were tested against five known hERG channel inhibitors : dofetilide , terfenadine ( Seldane ) , sertindole ( ___MASK75___ ) , astemizole ( Hismanal ) , and cisapride ( Propulsid ) . The DiBAC4 ( 3 )- based assays were found to be the most economical but had high false - hit rates as a result of the interaction of dye with the test compounds . The membrane potential dye assay had fewer color - quenching problems but was expensive and still gave false hits . The nonradioactive Rb + efflux assay was the most sensitive of all the assays evaluated and had the lowest false - hit rate .",
"Targeting Q01196 / Q06455 - histone deacetylase repressor complex : a novel mechanism for valproic acid - mediated gene expression and cellular differentiation in Q01196 / Q06455 - positive acute myeloid leukemia cells . In t ( 8 ; 21 ) acute myeloid leukemia ( AML ) , the Q01196 / Q06455 fusion protein promotes leukemogenesis by recruiting class I histone deacetylase ( HDAC ) - containing repressor complex to the promoter of Q01196 target genes . Valproic acid ( ___MASK91___ ) , a commonly used antiseizure and mood stabilizer drug , has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition . ___MASK91___ causes selective proteasomal degradation of Q92769 but not other class I HDACs ( i . e . , HDAC 1 , 3 , and 8 ) . Therefore , we raised the question of whether this drug can effectively target the leukemogenic activity of the Q01196 / Q06455 fusion protein that also recruits Q13547 , a key regulator of normal and aberrant histone acetylation . We report here that ___MASK91___ treatment disrupts the Q01196 / Q06455 - Q13547 physical interaction , stimulates the global dissociation of Q01196 / Q06455 - Q13547 complex from the promoter of Q01196 / Q06455 target genes , and induces relocation of both Q01196 / Q06455 and Q13547 protein from nuclear to perinuclear region . Furthermore , we show that mechanistically these effects associate with a significant inhibition of HDAC activity , histone H3 and H4 hyperacetylation , and recruitment of RNA polymerase II , leading to transcriptional reactivation of target genes ( i . e . , P08700 ) otherwise silenced by Q01196 / Q06455 fusion protein . Ultimately , these pharmacological effects resulted in significant antileukemic activity mediated by partial cell differentiation and caspase - dependent apoptosis . Taken together , these data support the notion that ___MASK91___ might effectively target Q01196 / Q06455 - driven leukemogenesis through disruption of aberrant Q13547 function and that ___MASK91___ should be integrated in novel therapeutic approaches for Q01196 / Q06455 - positive AML .",
"Purification and characterization of a high molecular weight histone deacetylase complex ( Q92769 ) of maize embryos . The dynamic state of core histone acetylation is maintained by histone acetyltransferases and deacetylases . In germinating maize embryos , four nuclear histone deacetylases can be distinguished . From a chromatin fraction prepared at 72 h after start of embryo germination , we have purified the nuclear histone deacetylase Q92769 to homogeneity . Using a sequence of chromatographic steps , we achieved the purification of an enzymatically active high molecular weight protein complex with an apparent molecular mass of 400 kDa , as determined by gel filtration chromatography . The purified enzyme was characterized in terms of enzymatic and kinetic properties , and sensitivity to several histone deacetylase inhibitors . In SDS - polyacrylamide gels , Q92769 split into three polypeptides of 45 , 42 , and 39 kDa , suggesting that the native enzyme is a multimer - protein complex . Electrophoresis under nondenaturing conditions in combination with second dimension SDS - gel electrophoresis indicated that all three protein components of the Q92769 complex were enzymatically active . Polyclonal antibodies against each of the three polypeptides were raised in rabbits . Each antiserum reacted with all three polypeptides on Western blots , suggesting that P29466 , Q8NFH3 , and p39 are highly homologous . This homology was confirmed by amino acid sequencing of peptides generated from each of the three Q92769 components .",
"Neurological impairment in experimental antiphospholipid syndrome is associated with increased ligand binding to hippocampal and cortical serotonergic P08908 receptors . The antiphospholipid syndrome ( APS ) is an autoimmune disease where the presence of high titers of circulating autoantibodies causes thrombosis with consecutive infarcts . In experimental APS ( eAPS ) , a mouse model of APS , behavioral abnormalities develop in the absence of vessel occlusion or infarcts . Using brain hemispheres of control and eAPS mice with documented neurological and cognitive deficits , we checked for lymphocytic infiltration , activation of glia and macrophages , as well as alterations of ligand binding densities of various neurotransmitter receptors to unravel the molecular basis of this abnormal behavior . Lymphocytic infiltrates were immunohistochemically characterized using antibodies against CD3 , P01730 , CD8 and forkhead box P09131 ( Foxp3 ) , respectively . P14136 , Iba1 and P34810 - immunohistochemistry was performed , to check for activation of astrocytes , microglia and macrophages . Ligand binding densities of DB01221 , AMPA , GABAA and P08908 receptors were analyzed by in vitro receptor autoradiography . No significant inflammatory reaction occurred in eAPS mice . There was neither activation of astrocytes or microglia nor accumulation of macrophages . Binding values of excitatory and inhibitory neurotransmitter receptors were largely unchanged . However , ligand binding densities of the modulatory serotonergic P08908 receptors in the hippocampus and in the primary somatosensory cortex of eAPS mice were significantly upregulated which is suggested to induce the behavioral abnormalities observed .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Functional characterization of a novel serotonin receptor ( 5 - HTap2 ) expressed in the CNS of Aplysia californica . Serotonin has been shown to be a neuromodulator in the Aplysia californica CNS . The diversity of serotonin actions is due to the existence of several different receptor subtypes . In this study we report the cloning of a full - length cDNA , coding for a novel serotonin receptor ( 5 - HTap2 ) . The receptor protein bears the characteristics of G protein - coupled receptors . It shares 68 % and 34 % of its amino acid sequence identity with the 5 - HTlym receptor from Lymnaea stagnalis and the mammalian P08908 receptor , respectively . When transfected in P29320 293 cells , 5 - HTap2 was negatively coupled to adenylate cyclase . Ligand binding analysis indicated that the order of potencies of various drugs for the inhibition of [ 3H ] LSD binding was : methiothepin > metergoline > 5 - CT > PAPP > 5 - HT > ketanserin > NAN - 190 > 8 - OH - DPAT > clozapine . RT - PCR amplification of RNA isolated from different tissues indicated that this receptor is expressed in the CNS and in bag cells . The expression of 5 - HTap2 restricted to the CNS suggests an important role for this receptor in the modulation of neuronal functions in Aplysia . Moreover , the high expression of 5 - HTap2 in the bag cells , associated with its pharmacological profile , suggests that this receptor may be implicated in modulating the afterdischarge during the egg - laying behavior .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK27___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"Short - and long - term influences of calcitonin gene - related peptide on the synthesis of acetylcholinesterase in mammalian myotubes . The present study analyses the short - ( 15 min - 2 h ) and long - term ( 24 - 48 h ) influences of calcitonin gene - related peptide ( P80511 ) on acetylcholinesterase ( P22303 ) expression in the rat cultured skeletal muscle and the signal transduction events underlying P80511 actions . To assess the effect of P80511 on P22303 synthesis , myotubes were pre - exposed to the irreversible P22303 inhibitor diisopropyl fluorophosphate ( ___MASK72___ ) and treated with P80511 or forskolin , an adenylyl cyclase ( AC ) activator . Treatment of myotubes with 1 - 100 nM P80511 for 2 h increased by up to 42 % the synthesis of catalytically active P22303 with a parallel increase in the intracellular cyclic AMP . The stimulation of P22303 synthesis induced by P80511 was mimicked by direct activation of AC with 3 - 30 microM forskolin . In contrast , pre - treatment of cultures with 100 nM P80511 for 20 h reduced by 37 % the subsequent synthesis of P22303 , resulting in a 15 % decrease in total P22303 activity after 48 h P80511 treatment . Moreover , 24 h treatment of myotubes with 100 nM P80511 reduced by 54 % the accumulation of cyclic AMP induced by a subsequent P80511 treatment . These findings indicate that , in skeletal muscle cells , P80511 modulates the P22303 expression in a time - dependent manner , initially stimulating the enzyme synthesis through a cyclic AMP - dependent mechanism . The decreased P22303 synthesis observed after long - term P80511 treatment suggests that P80511 signalling system is subject to desensitization or down - regulation , that might function as an important adaptative mechanism of the muscle fibre in response to long - term changes in neuromuscular transmission .",
"Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .",
"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK80___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .",
"Exposure to an organophosphate ( ___MASK72___ ) during a defined period in neonatal life induces permanent changes in brain muscarinic receptors and behaviour in adult mice . The organophosphate ___MASK72___ ( ___MASK72___ ) is a well - known inhibitor of cholinesterases . We have recently observed that neonatal exposure to a single subsymptomal dose of ___MASK72___ induces permanent alterations in muscarinic cholinergic receptors ( MAChRs ) and in spontaneous behaviour , in the mice as adults . In order to determine if there is a critical period for these effects , neonatal mice were given a single oral dose of 1 . 5 mg / kg ___MASK72___ b . wt . on postnatal day 3 , 10 or 19 , causing equal inhibition of P22303 . At the adult age of 4 months the mice were tested for spontaneous motor behaviour , and were subsequently sacrificed for measurement of density of MAChRs and subpopulations of MAChRs in the cerebral cortex by using the antagonist quinuclidinyl benzilate ( [ 3H ] QNB ) , and agonist carbachol , respectively . At adult age , mice exposed to ___MASK72___ on postnatal day ( P01160 ) 3 or 10 showed significant ( P < or = 0 . 01 ) alterations in spontaneous motor behaviour and a significant ( P < or = 0 . 01 ) decrease in muscarinic receptor density . There were no alterations mice exposed on P01160 19 . The proportions and affinity - constants of high - and low - affinity MAChR binding sites were not affected in mice showing altered MAChR density . The lack of effect on mice exposed on P01160 19 was not due to differences in P22303 activity .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK63___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK63___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK63___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK63___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"Donitriptan , but not sumatriptan , inhibits capsaicin - induced canine external carotid vasodilatation via P28222 rather than P28221 receptors . BACKGROUND AND PURPOSE : It has been suggested that during a migraine attack capsaicin - sensitive trigeminal sensory nerves release calcitonin gene - related peptide ( P80511 ) , resulting in cranial vasodilatation and central nociception ; hence , trigeminal inhibition may prevent this vasodilatation and abort migraine headache . This study investigated the effects of the agonists sumatriptan ( 5 - HT ( 1B / 1D ) water - soluble ) , donitriptan ( 5 - HT ( 1B / 1D ) lipid - soluble ) , PNU - 142633 ( 5 - HT ( 1D ) water - soluble ) and PNU - 109291 ( 5 - HT ( 1D ) lipid - soluble ) on vasodilator responses to capsaicin , alpha - P80511 and acetylcholine in dog external carotid artery . EXPERIMENTAL APPROACH : 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone . Blood pressure and heart rate were recorded with a pressure transducer , connected to a cannula inserted into a femoral artery . A precalibrated flow probe was placed around the common carotid artery , with ligation of the internal carotid and occipital branches , and connected to an ultrasonic flowmeter . The thyroid artery was cannulated for infusion of agonists . KEY RESULTS : Intracarotid infusions of capsaicin , alpha - P80511 and acetylcholine dose - dependently increased blood flow through the carotid artery . These responses remained unaffected after intravenous ( i . v . ) infusions of sumatriptan , PNU - 142633 , PNU - 109291 or physiological saline ; in contrast , donitriptan significantly attenuated the vasodilator responses to capsaicin , but not those to alpha - P80511 or acetylcholine . Only sumatriptan and donitriptan dose - dependently decreased the carotid blood flow . Interestingly , i . v . administration of the antagonist , SB224289 ( 5 - HT ( 1B ) ) , but not of BRL15572 ( 5 - HT ( 1D ) ) , abolished the inhibition by donitriptan . CONCLUSIONS AND IMPLICATIONS : Our results suggest that the inhibition produced by donitriptan of capsaicin - induced external carotid vasodilatation is mainly mediated by 5 - HT ( 1B ) , rather than 5 - HT ( 1D ) , receptors , probably by a central mechanism .",
"Tandospirone activates neuroendocrine and P29323 ( Q96HU1 kinase ) signaling pathways specifically through P08908 receptor mechanisms in vivo . Tandospirone , an azapirone , is a selective serotonin ( 1A ) ( 5 - HT ( 1A ) ) receptor agonist . The effects of tandospirone on plasma hormones and on mitogen - activated protein ( Q96HU1 ) kinase activity in the brain of male rats were studied . Tandospirone produced a time - and dose - dependent increase in plasma levels of oxytocin , adrenocorticotropin ( DB01285 ) , corticosterone , and prolactin . The minimal dose of tandospirone that led to a significant elevation of plasma oxytocin , DB01285 , and prolactin levels was 1 . 0 mg / kg ( s . c . ) , while the minimal dose for corticosterone release was 3 . 0 mg / kg ( s . c . ) . The ED ( 50 ) of tandospirone was 1 . 3 mg / kg for oxytocin , 1 . 2 mg / kg for DB01285 , 3 . 0 mg / kg for corticosterone , and 0 . 24 mg / kg for prolactin . Pretreatment with the specific 5 - HT ( 1A ) receptor antagonist WAY 100 , 635 ( 0 . 3 mg / kg , s . c . ) completely blocked the effects of tandospirone on plasma levels of oxytocin , DB01285 , and corticosterone but shifted the dose - response curve for prolactin to the right . Tandospirone injection ( 10 mg / kg , s . c . ) stimulated the Q96HU1 kinase signaling cascade , specifically the phosphorylation of Q8NFH3 / 44 extracellular signal - regulated kinase ( P29323 ) . Western blot analysis revealed a significant increase in phosphorylated P29323 ( p - P29323 ) levels in the hypothalamic paraventricular nucleus ( PVN ) as well as the dorsal raphe nucleus 5 min following tandospirone injection . These increases were blocked by pretreatment with WAY 100 , 635 ( 0 . 3 mg / kg ) . The results are the first evidence that systemic 5 - HT ( 1A ) receptor agonist administration produces a rapid increase in p - P29323 levels in vivo , providing further insight into the signaling mechanisms of the 5 - HT ( 1A ) receptor .",
"Accelerated and long - term hematopoietic engraftment in mice transplanted with ex vivo expanded bone marrow . Using a murine experimental model , we investigated whether ex vivo expansion of BM grafts under P08700 / P05231 stimulation accelerates the early hematopoietic recovery of recipients of BM transplants . To facilitate the ex vivo expansion of hematopoietic progenitors , BM was first enriched in proliferatively active hematopoietic stem cells by a single treatment with 5 - fluorouracil ( 5FU ) 4 days prior to the BM harvest . The results showed that the number of CFU - GM and CFU - P28222 progenitors in the graft was significantly increased ( 56 - fold and 14 - fold , respectively ) , as a result of a 3 day incubation in the presence of P08700 and P05231 . Daily analysis of animals transplanted with 5 x 10 ( 4 ) BM cells , either freshly harvested or expanded for 3 days , showed that the expanded grafts consistently allowed a faster hematopoietic recovery of recipients . Differences between both groups of transplanted animals were most evident when the number of either femoral or splenic CFU - GMs were compared , with increases close to 70 - fold at the fifth day of engraftment being observed . Similarly , mice transplanted with expanded grafts showed a hastened recovery in the cellularity of both organs that was most significant during the second week following transplantation , with maximal increases of 15 and 40 - fold in the BM and spleen , respectively . Differences in peripheral leukocyte numbers between both groups of recipients were much less remarkable than those observed in the hematopoietic organs , although from the nadir period to the 11th day post - transplantation differences ranging from twofold to sixfold were apparent , consistent with a higher rate of mouse survival . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"DB00952 . The new P28222 / 1D agonist naratriptan , introduced in many countries in 1997 and 1998 for the acute treatment of migraine , was designed to complement the sumatriptan portfolio of offerings ( including the injection , the tablets , the nasal spray , and in some countries , the suppository ) by offering patients excellent tolerability and a sustained duration of action . Clinical studies on naratriptan , including more than 4000 patients treating more than 15 , 000 migraine attacks , show that naratriptan tablets 2 . 5 mg are distinguished from other P28222 / 1D agonists for migraine on the basis of their excellent tolerability profile , which does not differ from that of placebo . In addition to its tolerability , naratriptan tablets 2 . 5 mg possess a long duration of action with a low incidence of headache recurrence ( 17 - 28 % in phase II and III clinical trials ) . With its tolerability profile and long duration of action , naratriptan tablets 2 . 5 mg may be particularly appropriate as a single - dose alternative to NSAIDs and analgesics , which often are not effective in migraine but are used because of tolerability considerations .",
"Anti - stress effect of astragaloside IV in immobilized mice . ETHNOPHARMACOLOGICAL RELEVANCE : Astragaloside IV , a major component extracted from the roots of Astragalus membranaceus ( AM ) , possesses anti - inflammatory , anti - oxidative , anti - fibrotic , anti - infarction and immunoregulatory effects . To clarify anti - stress effect of AM , anxiolytic and anti - inflammatory effects of 80 % ethanol extract of AM and astragaloside IV were investigated in immobilization stress model . MATERIALS AND METHODS : The mice were orally administered with AM ( 50 , 200 , and 500 mg / kg ) , astragaloside IV ( 5 , 10 , and 20 mg / kg ) and buspirone , a positive drug , 1h before immobilization treated for 2h . For anxiolytic activity assay , EPM test was performed in mice . For anti - inflammatory activity assay , serum levels of corticosterone , P05231 and P01375 - α were measured using ELISA kits . RESULTS : AM extract and astragaloside IV increased dose - dependently time spent on open arms and open arm entries in the EPM test . Anxiolytic effects of AM extract ( 500 mg / kg ) and astragaloside IV ( 20 mg / kg ) were comparable to those of buspirone ( 1 mg / kg ) . Their anxiolytic effects were blocked by WAY - 100635 ( 0 . 5 mg / kg , i . p . ) , a P08908 receptor antagonist ( p < 0 . 01 ) , but not by flumazenil ( 3 mg / kg , i . p . ) and bicuculline ( 0 . 5 mg / kg , i . p . ) , GABAA receptor antagonists . AM extract and astragaloside IV also reduced serum levels of corticosterone , P05231 and P01375 - α dose - dependently . CONCLUSIONS : AM , particularly astragaloside IV , may ameliorate immobilized stress - induced anxiety and inflammation .",
"Human P30939 receptor - stimulated [ 35S ] GTPgammaS binding : correlation with inhibition of guinea pig dural plasma protein extravasation . To determine the potency and efficacy of P30939 receptor ligands , a [ 35S ] GTPgammaS binding assay was developed and optimized for the human P30939 receptor . Compounds which are known to be effective in the abortive treatment of migraine were tested for efficacy and potency in this assay . DB00952 , sumatriptan , zolmitriptan , and rizatriptan all had agonist activity . The P30939 receptor ligand LY334370 ( 4 - fluoro - N -[ 3 -( 1 - methyl - 4 - piperidinyl )- 1H - indol - 5 - yl ]- benzamide ) was the most potent compound tested with an EC50 of 2 . 13 +/- 0 . 15 nM . LY302148 ( 5 - fluoro - 3 -[ 1 -[ 2 -( 1 - methyl - 1H - pyrazol - 4 - yl ) ethyl ]- 4 - piperidinyl ]- 1H - ind ole ) , methysergide , LY306258 ( 3 - dimethylamino - 2 , 3 , 4 , 9 - tetrahydro - 1H - carbazol - 6 - ol ) , dihydroergotamine ( DHE ) , L - 694 , 247 and CP - 122 , 288 were also investigated for potency and efficacy . There was a statistically significant correlation between the pEC50 for the stimulation of [ 35S ] GTPgammaS binding and the pID50 for the inhibition of trigeminal nerve - stimulated dural plasma protein extravasation in the guinea pig . In the course of these studies , it was found that the purportedly selective P28221 receptor antagonist GR127935 inhibited P30939 receptor - stimulated [ 35S ] GTPgammaS binding with a Ki of 39 . 6 +/- 9 . 5 nM . These studies demonstrate that P30939 receptor - mediated stimulation of [ 35S ] GTPgammaS binding in a clonal cell system is a reproducible , high throughput assay that is predictive of an in vivo model of P30939 receptor activation .",
"DB00952 : a review . Even though naratriptan and sumatriptan are both P28222 / P28221 receptor agonists , the biological and pharmacokinetic profile of naratriptan differs significantly from that of sumatriptan . With a plasma half - life of 6 h , very high oral bioavailability of 63 - 74 % and higher lipophilicity than sumatriptan , naratriptan exhibits a distinct clinical therapeutic profile . The similar tolerability to placebo , prolonged efficacy for 24 h or more and very low headache recurrence rate make naratriptan an attractive option in the treatment of acute migraine ."
] |
[
"___MASK27___",
"___MASK54___",
"___MASK63___",
"___MASK72___",
"___MASK75___",
"___MASK77___",
"___MASK80___",
"___MASK85___",
"___MASK91___"
] |
___MASK75___
|
MH_train_473
|
interacts_with DB05812?
|
[
"Use of prednisone with abiraterone acetate in metastatic castration - resistant prostate cancer . DB05812 acetate , a prodrug of the P05093 inhibitor abiraterone that blocks androgen biosynthesis , is approved for treatment of patients with metastatic castration - resistant prostate cancer ( mCRPC ) in combination with prednisone or prednisolone 5 mg twice daily . This review evaluates the basis for the effects of prednisone on mineralocorticoid - related adverse events that arise because of P05093 inhibition with abiraterone . Coadministration with the recommended dose of glucocorticoid compensates for abiraterone - induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone . Consequently , 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate , analogous to use of glucocorticoid replacement therapy for certain endocrine disorders . We searched PubMed to identify safety concerns regarding glucocorticoid use , placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer . In general , glucocorticoid - related adverse events , including bone loss , immunosuppression , hyperglycemia , mood and cognitive alterations , and myopathy , appear dose related and tend to occur at doses and / or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC . Although glucocorticoids are often used to manage tumor - related symptoms or to prevent treatment - related toxicity , available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC . Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone , the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens .",
"New agents and strategies for the hormonal treatment of castration - resistant prostate cancer . IMPORTANCE OF THE FIELD : Hormonal therapy with medical or surgical castration is the mainstay of systemic therapy for advanced prostate cancer . Depletion of gonadal testosterone in circulation is typically initially effective , although responses are transient and metastatic disease progresses as castration - resistant prostate cancer ( CRPC ) . AREAS COVERED IN THIS REVIEW : CRPC is accompanied by a gain of function in the androgen receptor ( AR ) , which may occur at the level of AR itself or through intratumoral repletion of androgens that in turn stimulate AR . Investigational drugs in clinical trials have promising activity in CRPC . DB05812 acetate is a P05093 inhibitor that blocks the synthesis of adrenal androgens . MDV3100 is a nonsteroidal AR antagonist with a greater binding affinity than other AR antagonists currently in clinical use . Insights into the mechanisms of intratumoral steroidogenesis in CRPC have defined other potential targets . Metabolism from DB01708 to testosterone and dihydrotestosterone requires 3 - hydroxyl oxidation and Delta ( 5 ) isomerization to Delta ( 4 ) by 3beta - hydroxysteroid dehydrogenase ( 3betaHSD ) and 17 - keto reduction by 17beta - hydroxysteroid dehydrogenase ( 17betaHSD ) - 3 or - 5 . AR activation in CRPC by intratumoral steroids requires these enzymatic steps . Investigation into specific inhibitors of 3betaHSD and 17betaHSD are required to determine their efficacy and potential roles in the treatment of CPRC . WHAT THE READER WILL GAIN : Readers will gain an understanding of the biology of CRPC , new investigational hormonal agents and novel approaches to the treatment of CRPC . TAKE HOME MESSAGE : Intratumoral androgens drive CRPC progression . New investigational hormonal agents that inhibit intratumoral androgens are highly active in the treatment of CRPC . Alternative strategies hold the promise for the development of other agents with novel mechanisms of action .",
"Transforming growth factor - beta1 induces tumor stroma and reduces tumor infiltrate in cervical cancer . Cervical carcinomas consist of tumor cell nests surrounded by varying amounts of intratumoral stroma containing different quantities and types of immune cells . Besides controlling ( epithelial ) cell growth , the multifunctional cytokine transforming growth factor - beta ( 1 ) ( TGF - beta ( 1 ) ) is involved in the formation of stroma and extracellular matrix ( Q13201 ) and in immunosuppression . Several malignancies are known to be associated with enhanced production of TGF - beta ( 1 ) , repression or mutation of TGF - beta transmembrane receptors , or mutations at the postreceptor intracellular signaling pathway . The aim of our study was to investigate the role of tumor cell - derived TGF - beta ( 1 ) on the amount of intratumoral stroma ; the deposition of collagen IV , fibronectin , and laminin ; and the tumor infiltrate in cervical carcinoma . The expression of TGF - beta ( 1 ) mRNA in 108 paraffin - embedded cervical carcinomas was detected by mRNA in situ hybridization . Immunohistochemistry was used to investigate the amount of tumor stroma and Q13201 proteins and the extent of the tumor infiltrate . P00747 activator inhibitor - 1 ( P05121 ) protein expression in tumor cells was determined to verify the biological activity of TGF - beta ( 1 .) Cytoplasmatic TGF - beta ( 1 ) mRNA expression in tumor cells was significantly correlated with the amount of intratumoral stroma and the deposition of collagen IV . TGF - beta ( 1 ) mRNA expression in every tumor was accompanied by P05121 expression , indicating biological activity of TGF - beta ( 1 ) . An inverse relationship between TGF - beta ( 1 ) mRNA expression in tumor cells and the extent of the tumor infiltrate was demonstrated . Our results indicate that cervical cancer cells affect the amount and the composition of the intratumoral stroma and the tumor infiltrate by the production and secretion of TGF - beta ( 1 ) .",
"Antitumour activity of docetaxel following treatment with the P05093 inhibitor abiraterone : clinical evidence for cross - resistance ? BACKGROUND : DB05812 and docetaxel are both approved treatments for men with metastatic castration - resistant prostate cancer ( mCRPC ) . DB05812 pre - docetaxel is currently undergoing evaluation in a phase III study . In vitro studies indicate that taxanes may act by disrupting androgen receptor signalling . We hypothesised that prior abiraterone exposure would adversely impact docetaxel efficacy . PATIENTS AND METHODS : We retrospectively evaluated activity of docetaxel in mCRPC patients previously treated with abiraterone , using Prostate Cancer Working Group and radiological criteria . RESULTS : Of the 54 patients treated with abiraterone , 35 subsequently received docetaxel . DB01248 resulted in a prostate - specific antigen ( PSA ) decline of ≥ 50 % in nine patients [ 26 % , 95 % confidence interval ( CI ) 13 % to 43 % ] , with a median time to PSA progression of 4 . 6 months ( 95 % CI 4 . 2 % to 5 . 9 % ) . PSA declines ≥ 30 % were achieved by 13 patients ( 37 % , 95 % CI 22 % to 55 % ) . The median overall survival was 12 . 5 months ( 95 % CI 10 . 6 - 19 . 4 ) . All patients who failed to achieve a PSA fall on abiraterone and were deemed abiraterone - refractory were also docetaxel - refractory ( N = 8 ) . In the 24 patients with radiologically evaluable disease , partial responses were reported in four patients ( 11 % ) , none of whom were abiraterone - refractory . CONCLUSION : The activity of docetaxel post - abiraterone appears lower than anticipated and no responses to docetaxel were observed in abiraterone - refractory patients .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK10___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"Effect of dietary NaCl on tyrosine hydroxylase in the superior cervical ganglia of Dahl rats . To investigate the involvement of peripheral catecholamines in the development of Dahl - Iwai salt - sensitive ( Q8IX12 / Eis ) hypertension , we performed immunohistochemical staining of tyrosine hydroxylase ( TH ) in the superior cervical ganglia ( SCG ) of Q8IX12 / Eis rats and Dahl - Iwai salt - resistant ( P30518 / Eis ) rats , and in situ hybridization histochemistry for demonstration of TH mRNA localization in the SCG of these rats . Q8IX12 / Eis and P30518 / Eis rats were fed on a high ( 8 % ) salt diet or on a low ( 0 . 3 % ) salt diet for 4 weeks . Nerve cells in the SCG of Q8IX12 / Eis high salt rats exhibited more intense TH - immunoreactivity ( P < 0 . 01 ) and hybridization signals ( P < 0 . 01 ) than those of the other experimental groups . These findings suggest that activation of peripheral sympathetic nerves may account for hypertension in Q8IX12 / Eis rats on a high salt diet .",
"17 ( E )- picolinylidene androstane derivatives as potential inhibitors of prostate cancer cell growth : antiproliferative activity and molecular docking studies . We report a rapid and efficient synthesis of A - ring modified 17α - picolyl and 17 ( E )- picolinylidene androstane derivatives from dehydroepiandrosterone . Compounds were validated spectroscopically and structurally characterized by X - ray crystallography . Virtual screening by molecular docking against clinical targets of steroidal anticancer drugs ( ERα , AR , P11511 and P05093 ) suggests that 17 ( E )- picolinylidene , but not 17α - picolyl androstanes could specifically interact with P05093 ( 17α - hydroxylase ) with similar geometry and affinity as DB05812 , a 17 - pyridinyl androstane drug clinically used in the treatment of prostate cancer . In addition , several 17 ( E )- picolinylidene androstanes demonstrated selective antiproliferative activity against PC3 prostate cancer cells , which correlates with DB05812 antiproliferative activity and predicted P05093 binding affinities . Based on these preliminary results , 17 ( E )- picolinylidene androstane derivatives could be a promising starting point for the development of new compounds for the treatment of prostate cancer .",
"[ DB05812 acetate ( ZYTIGA ®)- development and literature review ] . DB05812 acetate ( AA ) has been approved in more than 80 countries for the treatment of patients with metastatic castration - resistant prostate cancer ( mCRPC ) . In July 2013 , a marketing approval application for AA was submitted to the Japanese Ministry of Health , Labour , and Welfare . AA is a selective inhibitor of P05093 , a crucial enzyme for androgen biosynthesis . AA exerts its anti - tumor activity by directly inhibiting androgen production at all three sources , i . e . , the testes , adrenal glands , and tumor itself . Data from international phase III studies and phase I and II studies in Japan have indicated that AA improves the overall survival and quality of life ( QoL ) of patients with mCRPC . Herein , we have summarized the development of AA and the results of important international and local clinical trials in Japan . In addition , the effect of food on AA bioavailability , concomitant steroid use , and liver function test abnormalities have been discussed regarding the appropriate use of AA .",
"Highly - selective 4 -( 1 , 2 , 3 - triazole )- based P450c17a 17 , 20 - lyase inhibitors . The orally - active P05093 inhibitor abiraterone acetate ( AA ) decreases adrenal and intratumoral androgen biosynthesis and is an effective agent for the treatment of prostate cancer . DB05812 potently inhibits both reactions catalyzed by P05093 , the 17α - hydroxylase ( hydroxylase ) reaction as well as the 17 , 20 - lyase ( lyase ) transformation . P05093 hydroxylase inhibition prevents the synthesis of adrenal glucocorticoids and causes an accumulation of circulating mineralocorticoids . As a consequence of potent P05093 hydroxylase inhibition ( i . e . , lack of lyase selectivity ) , AA must be co - administered with the cortisol replacement prednisone and patients may experience the effects of mineralocorticoid excess syndrome ( MES ) . Herein , we describe rationally - designed , P05093 lyase - selective inhibitors that could prove safer and more effective than abiraterone . Using proprietary methodology , the high - affinity pyridine or imidazole metal - binding group found in current clinical P05093 inhibitors was replaced with novel , less avid , metal - binding groups in concert with potency - enhancing molecular scaffold modifications . This process produced a unique series of P05093 lyase - selective inhibitors that included the oral agent 6 ( VT - 464 ) , now in Phase 2 prostate cancer clinical trials . The chemical methodology described is potentially applicable to the design of new and more effective metalloenzyme inhibitor treatments for a broad array of diseases .",
"Mapping of 13 horse genes by fluorescence in - situ hybridization ( Q5TCZ1 ) and somatic cell hybrid analysis . We report fluorescence in - situ hybridization ( Q5TCZ1 ) and somatic cell hybrid mapping data for 13 different horse genes ( P01160 , P06729 , P10909 , P54108 , P05093 , P02679 , P18510 , P22301 , P45452 , PRM1 , P35354 , P01375 and P04637 ) . Primers for PCR amplification of intronic or untranslated regions were designed from horse - specific DNA or mRNA sequences in GenBank . Two different horse bacterial artificial chromosome ( BAC ) libraries were screened with PCR for clones containing these 13 Type I loci , nine of which were found in the libraries . BAC clones were used as probes in dual colour Q5TCZ1 to confirm their precise chromosomal origin . The remaining four genes were mapped in a somatic cell hybrid panel . All chromosomal assignments except one were in agreement with human - horse ZOO - Q5TCZ1 data and revealed new and more detailed information on the equine comparative map . P10909 was mapped by synteny to ECA2 while human - horse ZOO - Q5TCZ1 data predicted that P10909 would be located on ECA9 . The assignment of P18510 permitted analysis of gene order conservation between HSA2 and ECA15 , which identified that an event of inversion had occurred during the evolution of these two homologous chromosomes .",
"[ Mechanisms of resistance to P05093 inhibitors in castrate resistant prostate cancer ] . INTRODUCTION : DB05812 acetate has increased the overall survival of patients with metastatic castration - resistant prostate cancer . However , despite an initial response to treatment , many patients develop resistance to the drug . In this paper we present different hypotheses that may explain the emergence of resistance . METHOD : This review was conducted from the PubMed database . The most relevant articles were selected and analyzed . RESULTS : The molecular mechanisms of resistance to abiraterone acetate remain largely elusive . We detailed some of them including the reactivation of the androgen receptor through alternative biosynthesis of androgens , over expression or mutation of the androgen receptor gene , or the action of co - activators . The over expression of P05093 or the alteration of other genes ' expression involved in steroidogenesis could also contribute to the resistance . CONCLUSION : Some of the molecular mechanisms involved in the resistance to abiraterone acetate were detailed . Better understanding of these mechanisms is a key step to allow the emergence of new therapeutic options and personalized treatments of castration resistant prostate cancer .",
"Effect of abiraterone acetate plus prednisone on the QT interval in patients with metastatic castration - resistant prostate cancer . PURPOSE : DB05812 is the active metabolite of the pro - drug abiraterone acetate ( AA ) and a selective inhibitor of P05093 , a key enzyme in testosterone synthesis , and improves overall survival in postdocetaxel metastatic castration - resistant prostate cancer ( mCRPC ) . This open - label , single - arm phase 1b study was conducted to assess the effect of AA and abiraterone on the QT interval . METHODS : The study was conducted in 33 patients with mCRPC . Patients received AA 1 , 000 mg orally once daily + prednisone 5 mg orally twice daily . Electrocardiograms ( ECGs ) were collected in triplicate using 12 - lead Holter monitoring . Baseline ECGs were obtained on Cycle 1 Day - 1 . Serial ECG recordings and time - matched pharmacokinetic ( PK ) blood samples were collected over 24 h on Cycle 1 Day 1 and Cycle 2 Day 1 . Serial PK blood samples were also collected over 24 h on Cycle 1 Day 8 . RESULTS : After AA administration , the upper bound of the 2 - sided 90 % confidence interval ( CI ) for the mean baseline - adjusted QTcF change was < 10 ms ; no patients discontinued due to QTc prolongation or adverse events . No apparent relationship between change in QTcF and abiraterone plasma concentrations was observed [ estimated slope ( 90 % CI ) : 0 . 0031 ( - 0 . 0040 , 0 . 0102 ) ] . CONCLUSIONS : There is no significant effect of AA plus prednisone on the QT / QTc interval in patients with mCRPC .",
"DB05812 acetate : oral androgen biosynthesis inhibitor for treatment of castration - resistant prostate cancer . Prostate cancer is the second leading cause of cancer death in men in the US and Europe . The treatment of advanced - stage prostate cancer has been androgen deprivation . Medical castration leads to decreased production of testosterone and dihydrotestosterone by the testes , but adrenal glands and even prostate cancer tissue continue to produce androgens , which eventually leads to continued prostate cancer growth despite castrate level of androgens . This stage is known as castrate - resistant prostate cancer ( CRPC ) , which continues to be a challenge to treat . Addition of androgen antagonists to hormonal deprivation has been successful in lowering the prostate - specific antigen levels further , but has not actually translated into life - prolonging options . The results of several contemporary studies have continued to demonstrate activation of the androgen receptor as being the key factor in the continued growth of prostate cancer . Blockade of androgen production by nongonadal sources has led to clinical benefit in this setting . One such agent is abiraterone acetate , which significantly reduces androgen production by blocking the enzyme , cytochrome P450 17 alpha - hydroxylase ( P05093 ) . This has provided physicians with another treatment option for patients with CRPC . The landscape for prostate cancer treatment has changed with the approval of cabazitaxel , sipuleucel - T and abiraterone . Here we provide an overview of abiraterone acetate , its mechanism of action , and its potential place for therapy in CRPC .",
"Synthesis , biological evaluation , and molecular modeling of abiraterone analogues : novel P05093 inhibitors for the treatment of prostate cancer . DB05812 , a steroidal cytochrome P450 17alpha - hydroxylase - 17 , 20 - lyase inhibitor ( P05093 ) , is currently undergoing phase II clinical trials as a potential drug for the treatment of androgen - dependent prostate cancer . Since steroidal compounds often show side effects attributable to their structure , we have tried to replace the sterane scaffold by nonsteroidal core structures . The design and synthesis of 20 new abiraterone mimetics are described . Their activities have been tested with recombinant human P05093 expressed in E . coli . Promising compounds were further evaluated for selectivity against P15538 , P19099 , and the hepatic P08684 . Compounds 19 and 20 showed comparable activity to abiraterone ( IC50 values of 144 and 64 nM vs 72 nM ) and similar or even better selectivity against the other CYP enzymes . Selected compounds were also docked into our homology model , and the same binding modes as for abiraterone were found .",
"Q8IX12 promotes chromatin loading of androgen receptor ( AR ) transcription complex by stabilizing the association between AR and P23769 . P10275 ( AR ) , a ligand - dependent transcription factor , plays a critical role in prostate cancer onset and progression , and its transcriptional function is mediated largely by distinct nuclear receptor co - regulators . Here , we show that cell cycle and apoptosis regulator 1 ( Q8IX12 ) functions as an AR co - activator . Q8IX12 interacted with and enhanced the transcriptional activity of AR . Depletion of Q8IX12 caused reduction in androgen - dependent expression of a subset of AR target genes . We further showed that Q8IX12 is required for recruitment of AR , MED1 and RNA polymerase II to the enhancers of AR target genes and for androgen - induced long - range prostate specific antigen enhancer - promoter interaction . The molecular mechanism underlying Q8IX12 function in AR - mediated transcription involves Q8IX12 - mediated enhanced recruitment of P23769 , a pioneer factor for AR , to AR - binding sites . Q8IX12 stabilized the interaction between AR and P23769 by interacting directly with both proteins , thereby facilitating AR and P23769 occupancy on the enhancers . Furthermore , Q8IX12 depletion inhibited the growth , migration , invasion of prostate cancer cells and reduced the tumorigenicity of prostate cancer cells in vivo . Our results firmly established Q8IX12 as an AR co - activator that plays a key role in AR transcription complex assembly and has an important physiological role in androgen signaling and prostate tumorigenesis .",
"Beyond castration and chemotherapy : novel approaches to targeting androgen - driven pathways . In castrate - resistant prostate cancer , beyond chemotherapy , existing guidelines suggest only supportive care . However , recent evidence suggests that continued targeting of androgen - dependent pathways may be an efficacious approach . Clinical data is now available for two mechanistically distinct agents ( abiraterone and MDV3100 ) that both ultimately target these pathways . DB05812 is a potent and irreversible inhibitor of P05093 , a critical enzyme in androgen biosynthesis . Phase II studies indicate substantial declines in PSA amongst castrate - resistant patients treated with abiraterone , both prior to and following cytotoxic chemotherapy . In contrast to abiraterone , MDV3100 is a direct inhibitor of the androgen receptor , binding the receptor irreversibly with substantially higher affinity as compared to bicalutamide . A recent phase I / II trial of MDV3100 in castrate - resistant prostate cancer demonstrated tolerability of the agent with activity at the lowest dose level . On the basis of these compelling data , both abiraterone and MDV3100 will be examined in the phase III setting .",
"Genetic variants associated with myocardial infarction and the risk factors in Chinese population . BACKGROUND : Recent genome - wide association ( GWA ) studies in Caucasians identified multiple single nucleotide polymorphisms ( SNPs ) associated with coronary artery disease ( CAD ) . The associations of those SNPs with myocardial infarction ( MI ) have not been replicated in Asian populations . Among those previously identified SNPs , we selected nine ( rs10953541 , rs1122608 , rs12190287 , rs12413409 , rs1412444 , rs1746048 , rs3798220 , rs4977574 , rs579459 , in or near genes 7q22 , P01130 , O43680 , P05093 , P38571 , P48061 , P08519 , CDKN2A , P16442 , respectively ) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with MI and MI related risk factors in Chinese population . METHODS AND RESULTS : We conducted a case - control association study on a cohort of 2365 MI patients and 2678 unrelated controls from the Chinese population . Genotyping of 9 SNPs were performed by the TaqMan Real Time PCR method . After age , sex , and BMI adjustment , we observed the SNPs rs12190287 , rs12413409 , rs1412444 , rs1746048 and rs4977574 , were significantly associated with MI in additive models and rs12190287 , rs12413409 , rs4977574 were significantly associated with phenotypes of MI at the same time . We also found three SNPs rs1122608 , rs3798220 and rs579459 were significantly associated with risk factors of MI , although they had no association with MI in Chinese population . CONCLUSION : Results of this study indicate that 5 SNPs were associated with MI and 3 SNPs were associated with associated with lipoprotein levels but not with MI in a Chinese population . The present study supports some CAD - related genes in Caucasian as important genes for MI in a Chinese population .",
"Anti - angiogenic and anti - tumor effects of P50750 - 593 , a potent and selective inhibitor of vascular endothelial growth factor and platelet - derived growth factor receptor tyrosine kinase . We recently reported that P50750 - 593 , a novel imidazo [ 1 , 2 - b ] pyridazine derivative , is a highly potent and selective inhibitor of the vascular endothelial growth factor ( P15692 ) and platelet derived growth factor ( PDGF ) receptor tyrosine kinase families . Moreover , P50750 - 593 exhibits a uniquely long - acting inhibitory profile towards P15692 receptor 2 ( P35968 ) and PDGF receptor β ( PDGFRβ ) . In this study , we demonstrated that P50750 - 593 potently inhibits P15692 - and PDGF - stimulated cellular phosphorylation and proliferation of human umbilical vein endothelial cells and human coronary artery smooth muscle cells . P50750 - 593 also potently inhibits P15692 - induced tube formation of endothelial cells co - cultured with fibroblasts . Oral administration of P50750 - 593 exhibited strong anti - tumor effects against various human cancer xenografts along with good tolerability despite a low level of plasma exposure . Even after the blood and tissue concentrations of P50750 - 593 decreased below the detectable limit , a pharmacodynamic marker ( phospho P35968 ) was almost completely suppressed , indicating that its long duration of enzyme inhibition might contribute to the potent activity of P50750 - 593 . Immunohistochemical staining indicated that P50750 - 593 showed anti - proliferative and pro - apoptotic effects on tumors along with a decrease of vessel density and inhibition of pericyte recruitment to microvessels in vivo . Furthermore , dynamic contrast - enhanced magnetic resonance imaging revealed that P50750 - 593 reduced tumor vessel permeability prior to the onset of anti - tumor activity . In conclusion , P50750 - 593 is an extremely potent VEGFR / P09619 kinase inhibitor whose potent anti - angiogenic activity suggests therapeutic potential for the treatment of solid tumors .",
"DB05812 acetate , a first - in - class P05093 inhibitor , establishes a new treatment paradigm in castration - resistant prostate cancer .",
"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .",
"[ DB05812 acetate : a novel therapeutic option in hormone - refractory prostate cancer ] . Until recently , only therapy with docetaxel and prednisone has been shown to prolong survival in men with hormonorefractory metastatic prostate cancer . With approvals of sipuleucel - T , cabazitaxel , and abiraterone acetate , all based on improvement in overall survival , the scenary for management of men with metastatic prostate cancer has dramatically changed . DB05812 acetate was developed to specifically inhibit cytochrome P450 ( CYP ) 17A1 , which is an essential enzyme in the biosynthesis of testosterone . In the phase III , the trial treatment with abiraterone acetate plus prednisone prolongs overall survival relative to prednisone alone in patients with metastatic castration - resistant prostate cancer who have disease progression after treatment with docetaxel and associated with an acceptable tolerability profile , which was generally similar to that of the placebo plus prednisone group . However , adverse events resulting from elevated mineralocorticoid levels because of P05093 inhibition , fluid retention and oedema , hypokalaemia , hypertension occurred in significantly more in abiraterone acetate plus prednisone than in placebo plus prednisone .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK78___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"Limited in vitro efficacy of P05093 inhibition on human castration resistant prostate cancer . Although accumulating evidence indicates high expression of P05093 ( P45017A1 ) allows castration resistant prostate cancer ( CRPC ) to maintain high intratumoral androgen levels , the potential P45017A1 activity has not been characterized yet . The aim of this study was to examine the potential P05093 activity including 17α - hydroxylase and 17 , 20 - lyase activities in human CRPC and the effect of a CYP17A inhibitor . We used three human CRPC cell lines : C4 - 2 and C4 - 2AT6 which was established from C4 - 2 under androgen ablation conditions for 6months , and PC3 . To ascertain the potential P05093 activity , we cultured with the steroid precursors : ( 13 ) C -[ 2 , 3 , 4 ]- progesterone ( 13C - Prog ) , and analyzed the sequential biosynthesis ( 13 ) C -[ 2 , 3 , 4 ]- 17 - hydroxyprogesterone ( 13C - 17OHP ) and ( 13 ) C -[ 2 , 3 , 4 ]- androstenedione ( 13C - Adione ) by liquid chromatography / mass spectrometry ( LC / MS / MS ). The C4 - 2AT6 cells showed significantly higher P05093 expression than C4 - 2 cells ( p < 0 . 001 ) . LC / MS / MS analysis enabled us to detect the 13C - 17 - OHP and 13C - A - dione in these cell lines . The concentration ratio of 13C - Adione / 13C - 17OHP ( Adione - 17OHP ratio ) , which is thought to reflect the differences between 17 - hydroxylase and 17 , 20 - lyase activities , was then determined . The Adione - 17OHP ratio in C4 - 2AT6 cells was significantly higher than that of C4 - 2 cells ( p < 0 . 001 ) . DB05812 were able to inhibit the CYP17A activities , although abiraterone did not have anti - proliferative effects on C4 - 2 and C4 - 2AT6 cells at clinically achievable concentrations of < 1000nM in vitro . The present study clearly demonstrates CRPC have the dual activities of P05093 mediated by 17 - hydroxylase activity and 17 , 20 - lyase activity . DB05812 does n ' t have an in vitro anti - proliferative efficacy in CRPC cells , suggesting limited efficacy in vitro .",
"Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate . BACKGROUND : DB05812 acetate ( AA ) , a highly potent P05093 inhibitor , has demonstrated marked clinical benefit in patients with metastatic castration - resistant prostate cancer ( CRPC ) . Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations . The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor ( AR ) activity in prostate cancer ( PC ) cells . METHODS : Fluorescence resonance energy transfer ( FRET ) assay was used to assess the effect of mineralocorticoids on androgen - induced conformational change of the AR . LAPC4 , LNCaP and LN - AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations , including levels measured in the serum of AA - treated patients in a phase I trial . AR - dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells . RESULTS : Corticosterone ( CS ) and deoxycorticosterone ( DOC ) inhibited androgen - induced conformational change of the AR in the FRET assay . CS inhibited AR - dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA - treated patients . DOC inhibited AR transcriptional activity and cell growth at 10 - fold greater concentrations than measured in the serum of AA - treated patients . CONCLUSIONS : Mineralocorticoids directly inhibit androgen - induced conformational change of the AR . CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA . Further investigation of the potential therapeutic implications of mineralocorticoids in AA - treated CRPC patients is warranted .",
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK73___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"The V2 vasopressin receptor stimulates P27361 / 2 activity independently of heterotrimeric G protein signalling . The V2 vasopressin receptor ( P30518 ) activates the mitogen activated protein kinases ( MAPK ) P27361 / 2 through a mechanism involving the scaffolding protein beta arrestin . Here we report that this activating pathway is independent of G alpha s , G alpha i , G alpha q or G betagamma and that the P30518 - mediated activation of G alpha s inhibits P27361 / 2 activity in a DB02527 / PKA - dependent manner . In the HEK293 cells studied , the beta arrestin - promoted activation was found to dominate over the PKA - mediated inhibition of the pathway , leading to a strong vasopressin - stimulated P27361 / 2 activation . Despite the strong MAPK activation and in contrast with other GPCR , P30518 did not induce any significant increase in DNA synthesis , consistent with the notion that the stable interaction between P30518 and beta arrestin prevents signal propagation to the nucleus . Beta arrestin was found to be essential for the P27361 / 2 activation , indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues . Based on the use of selective pharmacological inhibitors , dominant negative mutants and siRNA , we conclude that the beta arrestin - dependent activation of P27361 / 2 by the P30518 involves c - Src and a metalloproteinase - dependent trans - activation event . These findings demonstrate that beta arrestin is a genuine signalling initiator that can , on its own , engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand .",
"Vascular endothelial growth factor gene polymorphism is associated with calcium oxalate stone disease . Growth factor - related genes regulate cell growth , differentiation and apoptosis in the kidney in response to cellular injury . One of the theories of stone formation is that cellular injury , and thus growth factors , play a role . We therefore investigated the association between growth factor genes and calcium oxalate stone disease . The most frequently seen polymorphism of the vascular endothelial growth factor ( P15692 ) gene is Bst U I C / T , which is located upstream at the - 460th nucleotide . Other growth factor - related gene polymorphisms include the cytochrome P450c17alpha enzyme ( P05093 ) gene MspA I C / T polymorphism at the 5 '- UTR promoter region , the epidermal growth factor receptor ( P00533 ) gene Bsr I polymorphism ( A to T ) at position 2 , 073 , and the insulin - like growth factor - 2 ( IGF - 2 ) gene Apa I A / G at exon 9 . All four polymorphisms were used as genetic markers in this study in the search for an association between stone disease and growth factor related genes . A normal control group of 230 healthy people , and 230 patients with calcium oxalate stone , were examined . The polymorphism was seen following polymerase chain reaction based restriction analysis . The result revealed a significant difference between normal individuals and stone patients ( P = 0 . 0003 , Fisher ' s exact test ) in the distribution of the P15692 gene polymorphism as well as an odds ratio of 1 . 30 ( 95 % confidence interval = 0 . 993 - 1 . 715 ) per copy of the \" T \" allele . Whereas , the IGF - 2 , P00533 and P05093 gene polymorphisms did not reveal a significant association with stone disease . We conclude that the P15692 gene Bst U I polymorphism is a suitable genetic marker of urolithiasis .",
"Prostate cancer - from steroid transformations to clinical translation . The survival benefit conferred by two hormonal agents in phase III trials has clinically validated the long suspected and now widely recognized phenomenon of castration - resistant prostate cancer ( CRPC ) hormone dependence . DB05812 inhibits steroid 17α - hydroxylase / 17 , 20 - lyase ( P05093 ) and blocks androgen synthesis , whereas enzalutamide directly binds and antagonizes the androgen receptor . Both agents are highly effective against CRPC and significantly prolong survival following docetaxel treatment . However , this clinical validation of the androgen pathway has led to questions regarding the fundamental mechanisms of CRPC , as well as resistance to abiraterone and enzalutamide . Our understanding of the predominant steroid transformation pathways that lead to dihydrotestosterone synthesis in CRPC is evolving . The role of steroidogenesis in the development of resistance to abiraterone and enzalutamide remains uncertain . The specific roles of candidate enzyme targets in the development of resistance to these agents must be defined if we are to identify novel targets for improved pharmacologic therapies .",
"___MASK25___ - induced changes in receptor - mediated metabolism of low density lipoprotein in guinea pigs . The effect of pravastatin , an inhibitor of P04035 , on the metabolism of human low density lipoprotein ( LDL ) was examined in guinea pigs . ___MASK25___ treatment significantly reduced plasma levels of total cholesterol and LDL - cholesterol by 15 . 6 mg / dl ( 38 . 8 % ) and 12 . 7 mg / dl ( 42 . 9 % ) , respectively . We investigated the metabolism of LDL in pravastatin - treated and untreated guinea pigs using the simultaneous intravenous injection of 131I - labeled LDL and 125I - labeled , galactose - treated LDL to quantify the P01130 pathway . ___MASK25___ increased the fractional catabolic rate ( FCR ) of the P01130 - dependent pathway . The treatment with pravastatin did not alter the FCR of the P01130 - independent pathway . The FCR of the P01130 - dependent pathway was higher for LDL isolated from pravastatin - treated subjects than for LDL isolated from control subjects . These findings suggest that pravastatin mainly reduced plasma cholesterol levels by accelerated FCR of the P01130 - mediated pathway .",
"Changing paradigms in management of metastatic Castration Resistant Prostate Cancer ( mCRPC ) . Recently , the standard of care for metastatic Castration Resistant Prostate Cancer ( mCRPC ) has changed considerably . Persistent androgen receptor ( AR ) signaling has been identified as a target for novel therapies and reengages the fact that AR continues to be the primary target responsible for metastatic prostate cancer . P10275 gene amplification and over expression have been found to result in a higher concentration of androgen receptors on tumor cells , making them extremely sensitive to low levels of circulating androgens . Additionally , prostate cancer cells are able to maintain dihydrotestosterone ( DB02901 ) concentration in excess of serum concentrations to support tumor growth . For many years ketoconazole was the only P05093 inhibitor that was used to treat mCRPC . However , significant toxicities limit its use . Newly approved chemotherapeutic agents such as DB05812 ( an oral selective inhibitor of CYP17A ) , which blocks androgen biosynthesis both within and outside the prostate cancer cells ) , and enzalutamide ( blocks AR signaling ) have improved overall survival . There are also ongoing phase III trials for Orteronel ( P50750 - 700 ) , ARN - 509 and Galeterone ( TOK - 001 ) , which targets androgen signaling . In this review , we will present the rationale for the newly approved hormonal treatments , their indications and complications , and we will discuss ongoing trials that are being done to improve the efficacy of the approved agents . Finally , we will talk about the potential upcoming hormonal treatments for mCRPC .",
"A - ring modified steroidal azoles retaining similar potent and slowly reversible P05093 inhibition as abiraterone . DB05812 acetate is a potent inhibitor of human cytochrome P450c17 ( P05093 , 17α - hydroxylase / 17 , 20 - lyase ) and is clinically used in combination with prednisone for the treatment of castration - resistant prostate cancer . Although many studies have documented the potency of abiraterone ( Abi ) in a variety of in vitro and in vivo systems for several species , the exact potency of Abi for human P05093 enzyme has not yet been determined , and the structural requirements for high - potency steroidal azole inhibitors are not established . We synthesized 4 Abi analogs differing in the A - B ring substitution patterns : 3α - hydroxy - Δ ( 4 )- Abi ( 13 ) , 3 - keto - Δ ( 4 )- Abi ( 11 ) , 3 - keto - 5α - Abi ( 6 ) , and 3α - hydroxy - 5α - Abi ( 5 ) . We measured the spectral binding constants ( Ks ) using purified and modified human P05093 along with the determination constants ( Ki ) applying a native human P05093 enzyme in yeast microsomes for these compounds as well as for ketoconazole . For Abi , 3 - keto - Δ ( 4 )- Abi , 3 - keto - 5α - Abi , and 3α - hydroxy - 5α - Abi , the type 2 spectral changes gave the best fit for a quadratic equation , since in these experiments Ks values were 0 . 1 - 2 . 6nM , much lower than that for ketoconazole and 3α - hydroxy - Δ ( 4 )- Abi ( Ks values were 140 and 1660nM , respectively ) . Inhibition experiments showed mixed inhibition patterns with Ki values of 7 - 80nM . Abi dissociation from the P05093 - Abi complex was incomplete and slow ; the t1 / 2 for dissociation was 1 . 8h , with 55 % of complex remaining after 5h . We conclude that Abi and the 3 related steroidal azoles ( 3 - keto - Δ ( 4 )- Abi , 3 - keto - 5α - Abi , and 3α - hydroxy - 5α - Abi ) , which also mimic natural substrates , are extraordinarily potent inhibitors of human P05093 , whereas the 3α - hydroxy - Δ ( 4 )- Abi is moderately potent and comparable to ketoconazole .",
"Clinical appraisal of abiraterone in the treatment of metastatic prostatic cancer : patient considerations , novel opportunities , and future directions . While androgen - deprivation therapy can induce dramatic clinical responses in advanced and metastatic prostate cancer , refractory disease ( castration - resistant prostate cancer [ CRPC ] ) eventually emerges . In recent years , several studies have demonstrated the importance of residual intratumoral androgens in maintaining androgen receptor ( AR ) transcriptional activity in CRPC . The cytochrome P450 enzyme P05093 is an obligatory step in androgen synthesis , and therefore a critical therapeutic target in CRPC . DB05812 acetate is a selective , irreversible inhibitor of P05093 and can suppress adrenal synthesis of androgen precursors , and possibly in situ steroidogenesis in the tumor microenvironment . In a phase III multicenter study , abiraterone in combination with prednisone improved median overall survival of men with docetaxel - refractory CRPC by 3 . 9 months compared to placebo plus prednisone , and also resulted in higher objective prostate - specific antigen and radiographic response rates . The study led to the FDA approval in April 2011 of abiraterone for treatment of chemotherapy - refractory CRPC patients , validating steroidogenesis and the AR axis in general as therapeutic targets in CRPC . The FDA indication for abiraterone was expanded to all CRPCs in December 2012 , while evaluation in even earlier disease states is ongoing . We propose a comprehensive AR axis - targeting approach via simultaneous , frontline enzymatic blockade of several steroidogenic enzymes ( eg , P05093 and P42330 ) in combination with gonadotropin - releasing hormone analogs and potent , second - generation AR antagonists ( eg , enzalutamide ) in order to improve outcomes in patients with prostate cancer .",
"The AP - 1 family member P01100 blocks transcriptional activity of the nuclear receptor steroidogenic factor 1 . Steroid production in the adrenal zona glomerulosa is under the control of angiotensin II ( Ang II ) , which , upon binding to its receptor , activates protein kinase C ( PKC ) within these cells . PKC is a potent inhibitor of the steroidogenic enzyme P05093 . We have demonstrated that , in the ovary , PKC activates expression of P01100 , a member of the AP - 1 family , and increased expression of this gene is linked to P05093 downregulation . However , the pathway and the molecular mechanism responsible for the inhibitory effect of PKC on P05093 expression are not defined . Herein , we demonstrated that Ang II inhibited P05093 through PKC and P27361 / 2 - activated P01100 and that blocking P01100 expression decreased PKC - mediated inhibition . Although P05093 transcription was activated by the nuclear receptor Q13285 , expression of P01100 resulted in a decrease in Q13285 - mediated gene transcription . P01100 physically interacted with the hinge region of Q13285 and modulated its transactivity , thus preventing binding of cofactors such as SRC1 and CBP , which were necessary to fully activate P05093 transcription . Collectively , these results indicate a new regulatory mechanism for Q13285 transcriptional activity that might influence adrenal zone - specific expression of P05093 , a mechanism that can potentially be applied to other steroidogenic tissues .",
"Novel P05093 inhibitors : synthesis , biological evaluation , structure - activity relationships and modelling of methoxy - and hydroxy - substituted methyleneimidazolyl biphenyls . Recently , the steroidal P05093 inhibitor DB05812 entered phase II clinical trial for the treatment of androgen - dependent prostate cancer . As 17alpha - hydroxylase - 17 , 20 - lyase ( P05093 ) catalyzes the last step in androgen biosynthesis , inhibition of this target should affect not only testicular but also adrenal androgen formation . Therefore P05093 inhibitors should be advantageous over existing therapies , for example with DB00644 analogues . However , steroidal drugs are known for side effects which are due to affinities for steroid receptors . Therefore we decided to synthesize non - steroidal compounds mimicking the natural P05093 substrates pregnenolone and progesterone . The synthesis and biological evaluation of a series of 15 novel and highly active non - steroidal P05093 inhibitors are reported . The compounds were prepared via Suzuki - cross - coupling , Grignard reaction and CDI - assisted S ( N ) t - reaction with imidazole and their inhibitory activity was examined with recombinant human P05093 expressed in Escherichia coli . Promising compounds were further tested for their selectivity against the hepatic enzyme P08684 and the glucocorticoid - forming enzyme P15538 . All compounds turned out to be potent P05093 inhibitors . The most active compounds 7 and 8 were much more active than Ketoconazole showing activity comparable to DB05812 ( IC ( 50 ) values of 90 and 52nM vs . 72nM ) . Most compounds also showed higher selectivities than Ketoconazole , but turned out to be less selective than DB05812 . Docking studies using our P05093 protein model were performed with selected compounds to study the interactions between the inhibitors and the amino acid residues of the active site .",
"Status of the down - regulated canine testis using two different P01148 agonist implants in comparison with the juvenile testis . Testicular function in the dog was down - regulated using two different P01148 agonist implants , with adult and juvenile testes serving as controls . Treatment resulted in an increased percentage of the interstitial area and decreased area of Leydig cell nuclei . Expression of P49675 and the steroidogenic enzymes cytochrome P450 side - chain cleavage enzyme ( P450scc , P05108 ) and cytochrome P450 17α - hydroxylase - 17 , 20 - lyase ( P450c17 , P05093 ) in Leydig cells was blocked at the mRNA and protein level , showing no differences between the two agonists . Staining for androgen receptor ( AR ) by immunohistochemistry was positive in Sertoli , Leydig and peritubular cells and some spermatogonia , with in situ hybridization confirming expression in Sertoli cells . At the mRNA level , expression of AR was not affected ; however , translation was blocked ( reduced percentage of AR - positive Sertoli cells ) , with the number of nuclei in basal position being decreased . In the juvenile testes , mRNA expression of P49675 , P05108 and P05093 was higher compared with the other groups but distinctly lower for the AR . At the protein level , the expression was at the limit of detection for P49675 ; AR - positive Sertoli cells were not detected . Our observations show that the down - regulated testis is different from the juvenile one rather resembling the testicular status in seasonal breeders out of season .",
"DB05812 acetate : targeting persistent androgen dependence in castration - resistant prostate cancer . DB05812 acetate is the first second - line hormonal agent proven to improve survival in metastatic castration - resistant prostate cancer . It selectively inhibits cytochrome P450 17 ( P05093 ) α - hydroxylase and cytochrome17 , 20 ( C17 , 20 ) - lyase , which are enzymes critical for androgen synthesis . DB05812 acetate was initially approved in the United States in 2011 after demonstrating a 4 - month survival benefit in docetaxel - refractory metastatic prostate cancer . The FDA recently expanded its indication for use in the pre - chemotherapy setting after it elicited significant delays in disease progression and a strong trend for increased overall survival in phase III studies . Ongoing investigations of abiraterone are evaluating its efficacy in earlier disease states , exploring its synergy in combination with other therapeutic agents , and assessing the necessity for administration of concurrent steroids and gonadal suppression . The identification and development of predictive biomarkers will optimize the incorporation of abiraterone into the management of advanced prostate cancer .",
"DB05812 acetate : redefining hormone treatment for advanced prostate cancer . Prostate cancer has long since been recognised as being hormonally driven via androgen receptor signalling . DB05812 acetate ( AA ) is a rationally designed P05093 inhibitor that blocks the conversion of androgens from non - gonadal precursors effectively , thus reducing testosterone to undetectable levels . AA has recently been proved to extend survival for men with metastatic castration - resistant prostate cancer who have progressive disease after first - line chemotherapy treatment . In addition , it is currently being tested in a Phase III trial in the pre - chemotherapy setting . This paper will review the preclinical discovery and clinical development of AA and will outline the strategy of parallel translational research .",
"___MASK24___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK24___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK24___ is a promising pharmacological tool in the treatment of renal edema .",
"Genetic polymorphisms of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes in adolescent girls with polycystic ovary syndrome . BACKGROUND : Polycystic ovary syndrome ( PCOS ) , whose genetic basis is not completely well understood , is the most common endocrine disorder in women and it typically develops during adolescence . The aim of this study is to investigate the possible association between single nucleotide polymorphisms ( SNPs ) of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes and PCOS in adolescent girls . METHODS : DNA samples from forty - four adolescent girls with PCOS and 50 healthy controls were analyzed by PCR - RFLP and direct DNA sequencing to determine the genotypic frequency of 17 different polymorphic loci on the P23945 ( A307T , N680S ) , P05093 ( - 34 T / C ) , P04798 ( T6235C ) , Q9HC96 ( 44 , 43 , 19 , 63 ) , P06213 ( exon 17 C / T ) , P05121 ( 4G / 5G ) genes . Genotyping of exon 12 ( six polymorphisms ) and intron 12 ( one polymorphism ) of P06213 gene by direct DNA sequencing was performed for the first time in this study . RESULTS : No significant differences were observed in the genotype and allele distributions of above mentioned polymorphisms between cases and control groups . CONCLUSION : Our data does not support an association between SNPs of P23945 , P05093 , P04798 , Q9HC96 , P06213 , P05121 genes and susceptibility to PCOS or related traits in Turkish adolescent girls .",
"Androgen synthesis inhibitors in the treatment of castration - resistant prostate cancer . Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer . However , in the majority of patients who develop castration - resistant prostate cancer ( CRPC ) , it is possible to detect persistent activation of the androgen receptor ( AR ) through androgens produced in the adrenal gland or within the tumor itself . DB05812 acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme P05093 with activity as a 17α - hydroxylase and 17 , 20 - lyase . P05093 is necessary for production of nongonadal androgens from cholesterol . Regulatory approval of abiraterone in 2011 , based on a phase III trial showing a significant improvement in overall survival ( OS ) with abiraterone and prednisone versus prednisone , represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC . Inhibition of 17α - hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol - mediated suppression of pituitary adrenocorticotropic hormone ( DB01285 ) , providing a rationale for development of P05093 inhibitors with increased specificity for 17 , 20 - lyase ( orteronel , galeterone and VT - 464 ) that can potentially be administered without exogenous corticosteroids . In this article , we review the development of abiraterone and other P05093 inhibitors ; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality - of - life , potential early predictors of response , and optimal sequencing of abiraterone with respect to other agents ; and results of translational studies providing insights into resistance mechanisms to P05093 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity .",
"Cytochrome P450 17 ( P05093 ) is involved in endometrial cancinogenesis through apoptosis and invasion pathways . Cytochrome P450 17 ( P05093 ) encodes cytochrome P450c17α , an enzyme with 17α - hydroxylase and 17 , 20 - lyase activities involved in estradiol biosynthesis . Here we examine the role of P05093 gene in endometrial carcinogenesis . Immunohistochemistry staining of endometrial carcinoma and corresponding uninvolved tissues showed that P05093 is upregulated in endometrial cancers ( 15 of 24 , 62 . 5 % ) . To understand the functional significance of this upregulation , we silenced P05093 gene by introduction of siRNA into endometrial cancer cell line KLE followed by functional studies . Further , to understand the molecular basis of the role of P05093 , we profiled the expression of key pathway - specific genes and identified several components of the apoptosis and invasion pathways that are potentially regulated by P05093 . Silencing of P05093 caused decreased cell proliferation and induced apoptosis . Significantly , P05093 depletion leads to downregulation of anti - apoptotic genes B cell lymphoma 2 ( Bcl - 2 ) and telomerase reverse transcriptase ( O14746 ) , indicating induced apoptosis . Also , attenuation of P05093 decreased the cellular invasion ability and regulated expression of several invasion pathway components such as melanoma cell adhesion molecule ( P43121 ) , matrix metallopeptidase 2 and 9 ( P08253 and P14780 ) , and tissue inhibitor of metalloproteinase 3 ( P35625 ) . In conclusion , this is the first report documenting that upregulation of P05093 in endometrial cancers play a crucial role in endometrial carcinogenesis by targeting multiple components of apoptosis and invasion pathways . Further studies are required to understand the detailed mechanisms underlying P05093 - mediated regulation of these components .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK41___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK15___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"DB05812 inhibits 3β - hydroxysteroid dehydrogenase : a rationale for increasing drug exposure in castration - resistant prostate cancer . PURPOSE : Treatment with abiraterone ( abi ) acetate prolongs survival in castration - resistant prostate cancer ( CRPC ) . Resistance to abi invariably occurs , probably due in part to upregulation of steroidogenic enzymes and / or other mechanisms that sustain dihydrotestosterone ( DB02901 ) synthesis , which raises the possibility of reversing resistance by concomitant inhibition of other required steroidogenic enzymes . On the basis of the 3β - hydroxyl , Δ ( 5 )- structure , we hypothesized that abi also inhibits 3β - hydroxysteroid dehydrogenase / isomerase ( 3βHSD ) , which is absolutely required for DB02901 synthesis in CRPC , regardless of origins or routes of synthesis . EXPERIMENTAL DESIGN : We tested the effects of abi on 3βHSD activity , androgen receptor localization , expression of androgen receptor - responsive genes , and CRPC growth in vivo . RESULTS : Abi inhibits recombinant 3βHSD activity in vitro and endogenous 3βHSD activity in LNCaP and LAPC4 cells , including conversion of [ ( 3 ) H ] - dehydroepiandrosterone ( DB01708 ) to Δ ( 4 )- androstenedione , androgen receptor nuclear translocation , expression of androgen receptor - responsive genes , and xenograft growth in orchiectomized mice supplemented with DB01708 . Abi also blocks conversion of Δ ( 5 )- DB01524 to testosterone by 3βHSD . Abi inhibits 3βHSD1 and 3βHSD2 enzymatic activity in vitro ; blocks conversion from DB01708 to androstenedione and DB02901 with an IC ( 50 ) value of less than 1 μmol / L in CRPC cell lines ; inhibits androgen receptor nuclear translocation ; expression of O15393 , prostate - specific antigen , and Q13451 ; and decreases CRPC xenograft growth in DB01708 - supplemented mice . CONCLUSIONS : We conclude that abi inhibits 3βHSD - mediated conversion of DB01708 to active androgens in CRPC . This second mode of action might be exploited to reverse resistance to P05093 inhibition at the standard abi dose by dose - escalation or simply by administration with food to increase drug exposure .",
"Antitumor activity with P05093 blockade indicates that castration - resistant prostate cancer frequently remains hormone driven . DB05812 acetate is a potent , selective , and orally bioavailable small molecule inhibitor of P05093 , an enzyme that catalyzes two key serial reactions ( 17 alpha hydroxylase and 17 , 20 lyase ) in androgen and estrogen biosynthesis . Clinical trials have confirmed that specific inhibition of P05093 is safe and results in clinically important antitumor activity in up to 70 % of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies . These clinical data indicate that castration - resistant prostate cancer frequently remains hormone dependent and has confirmed that this disease should no longer be described as \" hormone resistant or refractory \" . Biomarker studies , including the analysis of ETS gene fusion status , on patients treated with abiraterone acetate may allow enrichment of patients with a sensitive phenotype in future studies of therapeutics targeting P05093 .",
"___MASK91___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK91___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK61___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"P05093 inhibition as a hormonal strategy for prostate cancer . P10275 ( AR ) signaling has a key role in the pathogenesis of prostate cancer . AR gene amplification , AR overexpression , and activating mutations in the AR occur more frequently as castration - resistant prostate cancer ( CRPC ) evolves , with intratumoral androgen levels remaining sufficient for AR activation despite castration . The source of these androgens might be either adrenal or intratumoral . AR signaling , therefore , remains a valid treatment target for patients with CRPC . P05093 is a key enzyme for androgen biosynthesis . The imidazole antifungal agent ketoconazole weakly and nonspecifically inhibits P05093 , but remains unlicensed for this indication . Chemists at the Cancer Research UK Centre for Cancer Therapeutics have designed a novel , selective , irreversible inhibitor of P05093 called abiraterone , which is more than 20 times more potent than ketoconazole . DB05812 acetate , a prodrug , has undergone phase I assessment , and is rapidly progressing from phase II to phase III trials , in view of its high level of antitumor activity . This agent is safe and well tolerated , and activity profiles suggest that approximately 50 % of CRPC remains AR - ligand driven . Other P05093 inhibitors with alternative mechanisms of action , for example VN / 124 - 1 , are in preclinical development . The rationale for and implications of P05093 inhibition and the P05093 - targeting agents in development are discussed in this Review .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"DB05812 in prostate cancer : a new angle to an old problem . DB05812 acetate is an orally administered potent inhibitor of cytochrome P450 , family 17 , subfamily A , polypeptide 1 ( P05093 ) , which is essential for synthesis of testosterone from cholesterol . Although decreasing serum testosterone through inhibition of testicular function is the first line of treatment for men with metastatic prostate cancer , residual androgens may still be detected in patients treated with luteinizing hormone - releasing hormone agonists or antagonists . Treatment with abiraterone results in rapid , and complete , inhibition of androgen synthesis in the adrenal glands and potentially within the tumor itself . An overall survival benefit of maximal androgen suppression was recently shown in a randomized placebo - controlled phase III clinical trial of abiraterone with prednisone versus prednisone in men with metastatic castrate - resistant prostate cancer previously treated with docetaxel chemotherapy . DB05812 ' s efficacy shows the importance of androgen signaling in patients with castrate - resistant metastatic disease , with additional confirmation from recent studies of other novel agents such as MDV3100 , an androgen receptor signaling inhibitor . These promising results now pose a new angle to an old problem about hormonal therapy and raise new questions about how resistance develops , how to best sequence therapy , and how to optimize combinations with other emerging novel agents .",
"Medical strategies for treatment of castration resistant prostate cancer ( CRPC ) docetaxel resistant . Current landscape of treatment of castration - resistant prostate cancer ( CRPC ) has recently changed . DB06772 , a new taxane with potential antineoplastic activity , has been approved by Food and Drug Administration ( FDA ) after docetaxel failure . In a phase III trial , cabazitaxel showed increased overall survival ( OS ) compared with mitoxantrone ( 15 . 1 vs . 12 . 7 mo , HR 0 . 70 , 95 % CI 0 . 59 - 0 . 83 , p < 0 . 0001 ) . Furthermore , chemotherapy is not the only strategy available : several studies have shown as CRPC remains dependent on androgen receptor function for growth . DB05812 acetate , an irreversible inhibitor of P05093 , has also been approved by FDA after docetaxel failure . In a phase III trial comparing abiraterone acetate to placebo , abiraterone showed improvement in OS ( 14 . 8 vs . 10 . 4 mo , HR 0 . 65 , 95 % CI 0 . 54 - 0 . 77 ; p < 0 . 0001 ) . This review will discuss current options and the ongoing trials for second - line treatment of CRPC including chemotherapy , hormonal therapies , antiangiogenetic and immune strategies .",
"The 5α - androstanedione pathway to dihydrotestosterone in castration - resistant prostate cancer . The survival and progression of prostate cancer are generally dependent on expression of the androgen receptor ( AR ) , as well as the availability of endogenous AR agonists . Originating from the gonads , testosterone is released into circulation and is converted by steroid - 5α - reductase in prostate cancer to 5α - dihydrotestosterone ( DB02901 ) , potently activating AR and driving tumor progression . Advanced prostate cancer is initially treated with gonadal testosterone depletion , which suppresses this cascade of events and typically leads to a treatment response . Eventually , resistance to testosterone deprivation occurs with \" castration - resistant \" prostate cancer ( CRPC ) and is driven by the intratumoral synthesis of DB02901 . The generation of DB02901 occurs in large part from adrenal 19 - carbon precursor steroids , which are dependent on expression of P05093 . Although the path from adrenal precursor steroids to DB02901 was generally thought to require 5α - reduction of testosterone , recent data suggest that it instead involves conversion from Δ - androstenedione by steroid - 5α - reductase isoenzyme - 1 to 5α - androstanedione , followed by subsequent conversion to DB02901 . The 5α - androstanedione pathway to DB02901 therefore bypasses testosterone entirely . DB05812 acetate effectively inhibits P05093 , blocks the synthesis of androgens , and extends the survival of men with CRPC . Further progress in the hormonal treatment of CRPC is dependent on an understanding of the mechanisms that underlie CRPC and resistance to abiraterone acetate .",
"Generation and properties of a new human ventral mesencephalic neural stem cell line . Neural stem cells ( NSCs ) are powerful research tools for the design and discovery of new approaches to cell therapy in neurodegenerative diseases like Parkinson ' s disease . Several epigenetic and genetic strategies have been tested for long - term maintenance and expansion of these cells in vitro . Here we report the generation of a new stable cell line of human neural stem cells derived from ventral mesencephalon ( hVM1 ) based on v - myc immortalization . The cells expressed neural stem cell and radial glia markers like nestin , vimentin and 3CB2 under proliferation conditions . After withdrawal of growth factors , proliferation and expression of v - myc were dramatically reduced and the cells differentiated into astrocytes , oligodendrocytes and neurons . hVM1 cells yield a large number of dopaminergic neurons ( about 12 % of total cells are TH + ) after differentiation , which also produce dopamine . In addition to proneural genes ( Q9H2A3 , MASH1 ) , differentiated cells show expression of several genuine mesencephalic dopaminergic markers such as : Q8TE12 , O60663 , P48051 , P00325 , P43354 , O75364 , Q05940 and Q01959 , indicating that they retain their regional identity . Our data indicate that this cell line and its clonal derivatives may constitute good candidates for the study of development and physiology of human dopaminergic neurons in vitro , and to develop tools for Parkinson ' s disease cell replacement preclinical research and drug testing .",
"Interactions of abiraterone , eplerenone , and prednisolone with wild - type and mutant androgen receptor : a rationale for increasing abiraterone exposure or combining with MDV3100 . Prostate cancer progression can be associated with androgen receptor ( AR ) mutations acquired following treatment with castration and / or an antiandrogen . DB05812 , a rationally designed inhibitor of P05093 recently approved for the treatment of docetaxel - treated castration - resistant prostate cancer ( CRPC ) , is often effective , but requires coadministration with glucocorticoids to curtail side effects . Here , we hypothesized that progressive disease on abiraterone may occur secondary to glucocorticoid - induced activation of mutated AR . We found that prednisolone plasma levels in patients with CRPC were sufficiently high to activate mutant AR . P08235 antagonists , such as spironolactone and eplerenone that are used to treat side effects related to mineralocorticoid excess , can also bind to and activate signaling through wild - type or mutant AR . DB05812 inhibited in vitro proliferation and AR - regulated gene expression of AR - positive prostate cancer cells , which could be explained by AR antagonism in addition to inhibition of steroidogenesis . In fact , activation of mutant AR by eplerenone was inhibited by MDV3100 , bicalutamide , or greater concentrations of abiraterone . Therefore , an increase in abiraterone exposure could reverse resistance secondary to activation of AR by residual ligands or coadministered drugs . Together , our findings provide a strong rationale for clinical evaluation of combined P05093 inhibition and AR antagonism .",
"[ Roles of medical oncologists in the new era of CRPC therapy in Japan ] . Currently , the standard therapy for advanced prostate cancer is endocrine therapy ( luteinizing hormone - releasing hormone [ LH - RH ] agonists alone or LH - RHagonists plus antiandrogens ) . However , most patients eventually become resistant to these therapies as well as castration therapy . New endocrine therapies for castration - resistant prostate cancer ( CRPC ) have been developed . DB05812 , a P05093 inhibitor , and enzalutamide , a novel androgen receptor antagonist , have been shown to improve the overall survival , and they are set to be approved in Japan soon . Moreover , docetaxel and cabazitaxel have been established as first - and second - line chemotherapeutic drugs , respectively . Although there is currently no established molecular target drug for CRPC , some drugs such as cabozantinib seem to be effective , and they may be used in the future . In these situations of new drug development , the contribution of medical oncologists is predictable . While medical oncologists can not play central roles in all aspects of drug therapy for urological malignancies in Japan , they must play roles in certain aspects such as new drug development starting from phase I trials , improving multidisciplinary care for adverse events , and promoting translational research .",
"Recent progress in pharmaceutical therapies for castration - resistant prostate cancer . Since 2010 , six drugs have been approved for the treatment of castration - resistant prostate cancer , i . e . , P05093 inhibitor DB05812 , androgen receptor antagonist DB08899 , cytotoxic agent DB06772 , vaccine Sipuleucel - T , antibody DB06643 against receptor activator of nuclear factor kappa B ligand and radiopharmaceutical Alpharadin . All these drugs demonstrate improvement on overall survival , expect for DB06643 , which increases the bone mineral density of patients under androgen deprivation therapy and prolongs bone - metastasis - free survival . Besides further P05093 inhibitors ( Orteronel , Galeterone , VT - 464 and CFG920 ) , androgen receptor antagonists ( ARN - 509 , ODM - 201 , AZD - 3514 and EZN - 4176 ) and vaccine Prostvac , more drug candidates with various mechanisms or new indications of launched drugs are currently under evaluation in different stages of clinical trials , including various kinase inhibitors and platinum complexes . Some novel strategies have also been proposed aimed at further potentiation of antitumor effects or reduction of side effects and complications related to treatments . Under these flourishing circumstances , more investigations should be performed on the optimal combination or the sequence of treatments needed to delay or reverse possible resistance and thus maximize the clinical benefits for the patients .",
"DB05812 acetate , a novel adrenal inhibitor in metastatic castration - resistant prostate cancer . The androgen receptor remains the key player in patients with castration - resistant prostate cancer ( CRPC ) . Available agents capable of blocking early adrenal androgen production have limited activity and can lead to significant toxicities . DB05812 acetate , a pregnenolone analog , is a small molecule that irreversibly inhibits P05093 , a rate - limiting enzyme in androgen biosynthesis . Several clinical trials have demonstrated the safety and efficacy of this compound in men with metastatic CRPC . Recently , a randomized phase 3 trial evaluating abiraterone acetate in docetaxel - refractory CRPC patients demonstrated a survival improvement over placebo - treated patients ( 14 . 8 vs 10 . 9 months ; HR 0 . 646 ; P < 0 . 0001 ) . A similar trial in the pre - chemotherapy setting has completed accrual and is undergoing analysis . Here we review the rationale and clinical development of abiraterone acetate in men with CRPC .",
"Retreatment of men with metastatic castrate - resistant prostate cancer with abiraterone . BACKGROUND : DB05812 acetate ( AA ) , oral P05093 inhibitor , is an active agent in the treatment of metastatic castrate - resistant prostate cancer ( mCRPC ) . METHODS : We ( R . L . A and N . A ) retrospectively evaluated outcome in 12 men who were re - treated with AA following prior treatment with AA at the Princess Margaret Cancer Centre . RESULTS : All men were heavily pre - treated for mCRPC with a median of four prior lines of therapy , one of which was AA ( given either pre - or post - chemotherapy ) . Eleven out of 12 ( 92 % ) men stopped their first treatment course of AA due to progression and one stopped for financial reasons . Seven men had a PSA decrease ≥ 50 % following their first AA treatment , of which three ( 46 % ) had a PSA decrease ≥ 50 % to AA re - treatment . The responses to AA re - treatment were generally short - lived with a median biochemical progression - free survival of 2 . 3 months and median treatment duration of 3 . 2 months . No PSA responses to AA re - treatment were seen in five men who did not have an initial PSA response to AA . CONCLUSIONS : Our data suggest that AA re - challenge may have limited benefit in select men with mCRPC , and warrants further formal research .",
"Is abiraterone acetate well tolerated and effective in the treatment of castration - resistant prostate cancer ? This Practice Point commentary discusses the findings of the first phase I trial to evaluate abiraterone acetate ( an inhibitor of the androgen - regulating enzyme P05093 ) in the treatment of castration - resistant prostate cancer . This open - label , dose - escalation study by Attard et al . showed that abiraterone was well tolerated but often induced a syndrome of secondary mineralocorticoid excess that improved with eplerenone ( a mineralocorticoid receptor antagonist ) . DB05812 is a potent suppressor of adrenal androgen synthesis , and produced lasting prostate - specific antigen responses in approximately half of the patients . A few patients had partial regression of distant metastases . Although promising , these results should be interpreted with caution owing to the small sample size and because the study was not primarily designed to examine drug efficacy . Multi - institutional , prospective trials should provide additional information on the tolerability and activity of this compound and further define the population most likely to benefit from this endocrine approach .",
"Hormonal therapy for prostate cancer : toward further unraveling of androgen receptor function . Prostate cancer is a major cause of cancer - related death in men . Prostate cancer is an androgen - responsive tumor and the treatment of advanced prostate cancer involves hormonal therapy . First - line treatment for advanced prostate cancer is androgen deprivation therapy ( ADT ) , usually with agents that suppress gonadotropins through a pituitary mechanism . DB00644 agonists and antagonists both suppress gonadal release of testosterone , although their activity profiles vary . ADT down - regulates androgen receptor ( AR ) transcriptional activity in the tumor but the response in metastatic disease is transient and tumors progress as castration - resistant prostate cancer ( CRPC ) . Although serum testosterone concentrations decline dramatically with ADT , CRPC growth remains largely dependent on AR activity . Secondary hormonal therapies are then often employed to further dampen AR - driven transcription . These secondary hormonal therapies either further deplete adrenal or intratumoral androgen synthesis , or directly and competitively antagonize AR . New hormonal agents with both of these mechanisms are in clinical trials and show promising activity in patients with CRPC . DB05812 acetate is an inhibitor of P05093 , which is an enzyme required for the synthesis of all androgens and estrogens . MDV3100 is an AR antagonist that has a higher affinity for AR than any other AR antagonist in clinic use . In phase I and phase II clinical trials , both agents have significant activity . These agents and the promise of the development of others provide hope that more effective hormonal therapies may soon be offered to patients , which will improve clinical outcomes .",
"P05093 inhibitors in castration - resistant prostate cancer . The majority of prostate cancer ( PCa ) cases are diagnosed as a localized disease . Definitive treatment , active surveillance or watchful waiting are employed as therapeutic paradigms . The current standard of care for the treatment of metastatic PCa is either medical or surgical castration . Once PCa progresses in spite of castrate androgen levels it is termed ' castration - resistant prostate cancer ' ( CRPC ) . Patients may even exhibit rising PSA levels with possible bone , lymph node or solid organ metastases . In 2010 , the only agent approved for the treatment of CRPC was docetaxel , a chemotherapeutic agent . It is now known that cells from patients with CRPC express androgen receptors ( AR ) and remain continuously influenced by androgens . As such , treatments with novel hormonal agents that specifically target the biochemical conversion of cholesterol to testosterone have come to the forefront . The use of cytochrome P450c17 ( P05093 ) inhibitor underlies one of the most recent advances in the treatment of CRPC . DB05812 acetate ( AA ) was the first P05093 inhibitor approved in the United States . This review will discuss CRPC in general with a specific focus on AA and novel P05093 inhibitors . AA clinical trials will be reviewed along with other novel adjunct treatments that may enhance the effectiveness of abiraterone therapy . Furthermore , the most recently identified P05093 inhibitors Orteronel , Galeterone , VT - 464 , and CFG920 will also be explored ."
] |
[
"___MASK10___",
"___MASK15___",
"___MASK24___",
"___MASK25___",
"___MASK41___",
"___MASK61___",
"___MASK73___",
"___MASK78___",
"___MASK91___"
] |
___MASK10___
|
MH_train_474
|
interacts_with DB00181?
|
[
"Benzyl isothiocyanate ( BITC ) inhibits migration and invasion of human gastric cancer AGS cells via suppressing P29323 signal pathways . Metastasis suppressors and associated other regulators of cell motility play a critical initial role in tumor invasion and metastases . Benzyl isothiocyanate ( BITC ) is a hydrolysis compound of glucotropaeolin in dietary cruciferous vegetables . BITC has been found to exhibit prevention of cancers in laboratory animals and might also be chemoprotective in humans . Here , the purpose of this study was to investigate the effects of BITC on cell proliferation , migration , invasion and mitogen - activated protein kinase ( MAPK ) pathways of AGS human gastric cancer cells . Wound healing and Boyden chamber ( migration and invasion ) assays demonstrated that BITC exhibited an inhibitory effect on the abilities of migration and invasion in AGS cancer cells . BITC suppressed cell migration and invasion of AGS cells in a dose - dependent manner . Results from Western blotting indicated that BITC exerted an inhibitory effect on the P27361 / 2 , Ras , P62993 , Rho A , P35228 , P35354 for causing the inhibitions of P08253 , - 7 and - 9 then followed by the inhibitions of invasion and migration of AGS cells in vitro . BITC also promoted O14733 , Q99759 , c - jun , P45983 / 2 , P15692 , Sos1 , phosphoinositide 3 - kinase ( PI3K ) , PKC , nuclear factor - kappaB ( NF - κB ) p65 in AGS cells . Results from real - time polymerized chain reaction ( PCR ) showed that BITC inhibited the gene expressions of P08253 ,- 7 - 9 , Q05397 , Q13464 and RhoA after BITC treatment for 24 and 48 hours in AGS cells . Taken together , the finding may provide new mechanisms and functions of BITC , which inhibit migration and invasion of human gastric cancer AGS cells .",
"Association study of 45 candidate genes in nicotine dependence in Han Chinese . Numerous genetic linkages , association studies have been performed in different ethnic groups and revealed many susceptibility loci and genes for nicotine dependence . However , limited similar researches were performed in Han Chinese . This study was designed to investigate the association of candidate genes with nicotine dependence in Han Chinese . We genotyped 384 SNPs within 45 candidate genes with nicotine dependence in a Han Chinese population consisting 223 high nicotine dependent subjects and 257 low nicotine dependent subjects by employing GoldenGate genotyping assay ( Illumina ) . Following association analysis was performed using PLINK software . Individual SNP - based association analysis revealed that nine SNPs located in P35462 ( rs2630351 ) , P21918 ( rs1967550 ) , Q9Y6R4 ( rs2314378 ) , DDC ( rs11575461 ) , Q05901 ( rs4954 ) , O75899 ( rs2779562 ) , P14416 ( rs11214613 and rs6589377 ) and P43681 ( rs2236196 ) were significantly associated with FTND after correction for multiple testing with the p values from 2 . 59 × 10 (- 7 ) to 9 . 99 × 10 (- 5 ) . Haplotype - based association analysis revealed haplotype G - A - A formed by rs2630351 , rs167771 and rs324032 and haplotype G - G - G - A formed by rs3773678 , rs2630349 , rs2630351 and rs167771 in P35462 ; haplotype of G - A formed by rs2779562 and rs2808566 in O75899 and haplotype of T - T - A - G - A formed by rs6832644 , rs4057797 , rs9764 , rs4552421 and rs10033119 in P25929 are associated with FTND ( p = 3 . 61 × 10 (- 7 )- 8 . 78 × 10 (- 6 ) ) . Our results provided confirmation of the previous findings that P14416 , P35462 , DDC , Q05901 , O75899 and P43681 are associated with nicotine dependence . Furthermore , we for the first time report a significant association between nicotine dependence and P21918 , Q9Y6R4 and P25929 . These findings need independent replication in the future studies .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK50___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers .",
"Molecular identification of the human O75899 : cell surface expression and coupling to adenylyl cyclase in the absence of Q9UBS5 . We have identified a gene encoding a GABAB receptor , the human O75899 , located on chromosome 9q22 . 1 , that is distinct from the recently reported rat Q9UBS5 . O75899 structurally resembles Q9UBS5 ( 35 % identity ) , having seven transmembrane domains and a large extracellular region , but differs in having a longer carboxy - terminal tail . O75899 is localized to the cell surface in transfected COS cells , and negatively couples to adenylyl cyclase in response to GABA , baclofen , and 3 - aminopropyl ( methyl ) phosphinic acid in CHO cells lacking Q9UBS5 . DB00181 action is inhibited by the GABABR antagonist , 2 - hydroxysaclofen . The human O75899 and Q9UBS5 genes are differentially expressed in the nervous system , with the greatest difference being detected in the striatum in which Q9UBS5 but not O75899 mRNA transcripts are detected . O75899 and Q9UBS5 mRNAs are also coexpressed in various brain regions such as the Purkinje cell layer of the cerebellum . Identification of a functional homomeric O75899 coupled to adenylyl cyclase suggests that the complexity of GABAB pharmacological data is at least in part due to the presence of more than one receptor and opens avenues for future research leading to an understanding of metabotropic GABA receptor signal transduction mechanisms .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK79___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK79___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK79___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK79___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK79___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK79___ increased the protein expression of hepatic P05181 and ___MASK79___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK79___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK79___ and RFP - induced hepatotoxicity .",
"A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor . Transforming growth factor beta ( TGFbeta ) signal transduction is mediated by two receptor DB00133 / DB00156 kinases acting in series , type II TGFbeta receptor ( P37173 ) phosphorylating type I TGFbeta receptor ( P36897 ) . Because the failure of interaction cloning , thus far , to identify bona fide P36897 substrates might reasonably have been due to the use of inactive P36897 as bait , we sought to identify molecules that interact specifically with active P36897 , employing the triple mutation L193A , P194A , T204D in a yeast two - hybrid system . The DB00149 - Pro substitutions prevent interaction with FK506 - binding protein 12 ( P62942 ) , whose putative function in TGFbeta signaling we have previously disproved ; the charge substitution at Thr204 constitutively activates P36897 . Unlike previous screens using wild - type P36897 , where P62942 predominated , none of the resulting colonies encoded P62942 . A novel protein was identified , P36897 - associated protein - 1 ( TRAP - 1 ) , that interacts in yeast specifically with mutationally activated P36897 , but not wild - type P36897 , P37173 , or irrelevant proteins . In mammalian cells , TRAP - 1 was co - precipitated only by mutationally activated P36897 and ligand - activated P36897 , but not wild - type P36897 in the absence of TGFbeta . The partial TRAP - 1 protein that specifically binds these mutationally and ligand - activated forms of P36897 can inhibit signaling by the native receptor after stimulation with TGFbeta or by the constitutively activated receptor mutation , as measured by a TGFbeta - dependent reporter gene . Thus , TRAP - 1 can distinguish activated forms of the receptor from wild - type receptor in the absence of TGFbeta and may potentially have a functional role in TGFbeta signaling .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK47___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK25___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .",
"[ Differential gene expression in nasopharyngeal carcinoma cell with reduced and normal expression of 6A8 alpha - mannosidase ] . OBJECTIVE : To detect the differential display of mRNA expression between human nasopharyngeal carcinoma cell CNE - 2L2 with reduced malignancy caused by transduction of a DNA antisense to 6A8 alpha - mannosidase cDNA ( AS cell ) and the wild type cell ( W cell ) . METHODS : Differential display of mRNA expression was analyzed using DNA microarray analysis . The datasets were confirmed by Northern blotting and RT - PCR . RESULTS : Out of the 1069 genes analyzed , 34 genes were up - regulated in AS cells relative to W cells . Conversely , 42 genes were down - regulated . The genes , up - regulation of which might have suppressive effect on tumor malignant behaviors , were P130 mRNA for 130K protein , TGF - betaIIR alpha , Q9UBS5 , P36897 , Q13829 , STANIN , E - CADHERIN , P35221 and 2 , P48378 , TMPO , etc . The genes , down - regulation of which might have suppressive effect on tumor malignant behaviors , were P16070 , Q92597 , P01137 , P46782 , LEGUMAIIN , P35520 , P13987 , P09661 , etc . The microarray datasets were confirmed by Northern blot and RT - PCR analysis . CONCLUSIONS : In comparison to the W cell , AS cell has up - regulation of 34 genes and down - regulation of 42 genes . Changes of the gene expression may play a role in the malignancy reduction of AS cell .",
"Immunocytochemical localization of Q9UBS5 receptor subunits in the basolateral amygdala . Gamma - aminobutyric acid B ( GABAB ) receptors ( GBRs ) are G - protein - coupled receptors that mediate a slow , prolonged form of inhibition in the basolateral amygdala ( P00519 ) and other brain areas . Recent studies indicate that this receptor is a heterodimer consisting of Q9UBS5 ( GBR1 ) and O75899 subunits . In the present investigation , antibodies to the Q9UBS5 subunit were used to study the neuronal localization of GBRs in the rat P00519 . GBR immunoreactivity was mainly found in spine - sparse interneurons and astrocytes at the light microscopic level . Very few pyramidal neurons exhibited perikaryal staining . Dual - labeling immunofluorescence analysis indicated that each of the four main subpopulations of interneurons exhibited GBR immunoreactivity . Virtually 100 % of large CCK + neurons in the basolateral and lateral nuclei were GBR + . In the basolateral nucleus 72 % of somatostatin ( Q8TE85 ) , 73 % of parvalbumin ( PV ) and 25 % of P01282 positive interneurons were GBR + . In the lateral nucleus 50 % of somatostatin , 30 % of parvalbumin and 27 % of P01282 positive interneurons were GBR + . Electron microscopic ( EM ) analysis revealed that most of the light neuropil staining seen at the light microscopic level was due to the staining of dendritic shafts and spines , most of which probably belonged to spiny pyramidal cells . Very few axon terminals ( Ats ) were GBR + . In summary , this investigation demonstrates that the distal dendrites of pyramidal cells , and varying percentages of each of the four main subpopulations of interneurons in the P00519 , express GBRs . Because previous studies suggest that GBR - mediated inhibition modulates DB01221 - dependent EPSPs in the P00519 , these receptors may play an important role in neuronal plasticity related to emotional learning .",
"Type B gamma - aminobutyric acid receptors modulate the function of the extracellular Ca2 +- sensing receptor and cell differentiation in murine growth plate chondrocytes . Extracellular calcium - sensing receptors ( CaRs ) and metabotropic or type B gamma - aminobutyric acid receptors ( GABA - B - Rs ) , two closely related members of family C of the G protein - coupled receptor superfamily , dimerize in the formation of signaling and membrane - anchored receptor complexes . We tested whether CaRs and two GABA - B - R subunits ( Q96GN5 and R2 ) are expressed in mouse growth plate chondrocytes ( GPCs ) by PCR and immunocytochemistry and whether interactions between these receptors influence the expression and function of the CaR and extracellular Ca ( 2 +)- mediated cell differentiation . Both CaRs and the Q9UBS5 and - R2 were expressed in the same zones of the growth plate and extensively colocalized in intracellular compartments and on the membranes of cultured GPCs . The Q9UBS5 co - immunoprecipitated with the CaR , confirming a physical interaction between the two receptors in GPCs . In vitro knockout of Q9UBS5 genes , using a Cre - lox recombination strategy , blunted the ability of high extracellular Ca ( 2 +) concentration to activate phospholipase C and P27361 / 2 , suppressed cell proliferation , and enhanced apoptosis in cultured GPCs . In GPCs , in which the Q9UBS5 was acutely knocked down , there was reduced expression of early chondrocyte markers , aggrecan and type II collagen , and increased expression of the late differentiation markers , type X collagen and osteopontin . These results support the idea that physical interactions between CaRs and GABA - B - R1s modulate the growth and differentiation of GPCs , potentially by altering the function of CaRs .",
"Novel therapy for insulin - dependent diabetes mellitus : infusion of in vitro - generated insulin - secreting cells . P01308 - dependent diabetes mellitus ( IDDM ) is a metabolic disease usually resulting from autoimmune - mediated β - cell destruction requiring lifetime exogenous insulin replacement . Mesenchymal stem cells ( O60682 ) hold promising therapy . We present our experience of treating IDDM with co - infusion of in vitro autologous adipose tissue - derived O60682 - differentiated insulin - secreting cells ( ISC ) with hematopoietic stem cells ( P19526 ) . This was an Institutional Review Board approved prospective non - randomized open - labeled clinical trial after informed consent from ten patients . ISC were differentiated from autologous adipose tissue - derived O60682 and were infused with bone marrow - derived P19526 in portal , thymic circulation by mini - laparotomy and in subcutaneous circulation . Patients were monitored for blood sugar levels , serum C - peptide levels , glycosylated hemoglobin ( Hb1Ac ) and glutamic acid decarboxylase ( Q99259 ) antibodies . P01308 administration was made on sliding scale with an objective of maintaining FBS < 150 mg / dL and PPBS around 200 mg / dL . Mean 3 . 34 mL cell inoculums with 5 . 25 × 10 ( 4 ) cells / μL were infused . No untoward effects were observed . Over a mean follow - up of 31 . 71 months , mean serum C - peptide of 0 . 22 ng / mL before infusion had sustained rise of 0 . 92 ng / mL with decreased exogenous insulin requirement from 63 . 9 international units ( IU ) / day to 38 . 6 IU / day . Improvement in mean Hb1Ac was observed from 10 . 99 to 6 . 72 % . Mean Q99259 antibodies were positive in all patients with mean of 331 . 10 IU / mL , which decreased to mean of 123 IU / mL . Co - infusion of autologous ISC with P19526 represents a viable novel therapeutic option for IDDM .",
"Puerarin alleviates noise - induced hearing loss via affecting PKCγ and GABAB receptor expression . Noise - induced hearing loss ( NIHL ) often results from prolonged exposure to high levels of noise . Our previous study revealed that during the development of NIHL , the expression of protein kinase C γ subunit ( PKCγ ) and GABAB receptor ( GABABR ) was changed within the cochlear nuclear complex ( CNC ) , suggesting that these molecules might be the potential targets for the treatment of NIHL . As an extending study , here we focused on puerarin , a major isoflavonoid extracted from Pueraria lobota , which has been used in the treatment of cardiovascular and cerebrovascular diseases , and investigated whether it could protect against NIHL by acting on PKCγ and GABABR . Transgenic Q99259 - GFP knock - in mice were subjected to the NIHL model and their auditory functions were evaluated by the auditory brainstem response thresholds and distortion product oto - acoustic emission signals . Our results showed that 200mg / kg puerarin treatment ameliorated the thresholds of auditory brainstem response of NIHL mice significantly . Triple immunofluorescence staining and electron microscopy results revealed that GFP - positive neurons in the superficial layers of CNC expressed both PKCγ and Q9UBS5 , and Q99259 - positive terminals contacted PKCγ - or Q9UBS5 - positive neurons . Immunoblotting and RT - PCR results showed that NIHL increased the expression of PKCγ but decreased that of Q9UBS5 and O75899 at both protein and mRNA levels in the CNC . Puerarin significantly attenuated the increased expression of PKCγ but elevated the reduced expression of Q9UBS5 and O75899 after noise exposure . Thus , we provided the first evidence that puerarin ameliorated the auditory functions of NIHL mice , and this effect may be due to its ability to regulate the expression of PKCγ and GABABR .",
"P42345 inhibitor RAD001 ( ___MASK54___ ) enhances the effects of imatinib in chronic myeloid leukemia by raising the nuclear expression of c - P00519 protein . Constitutive tyrosine kinase ( TK ) activity of Q92817 P11274 - P00519 fusion protein of chronic myeloid leukemia ( CML ) usurps physiological functions of normal p145 c - P00519 protein . Accordingly , its inhibition by imatinib mesylate ( IM ) lets p145 c - P00519 translocate into the nuclear compartment , which drives cell growth arrest and apoptotic death . Here we show that IM and the mammalian target of rapamycin ( P42345 ) inhibitor RAD001 ( ___MASK54___ ) have additive effects on P11274 - P00519 - expressing cells . Those effects are at least partly conditional upon the enhanced nuclear accumulation of p145 c - P00519 through events encompassing post - translational modifications of p145 c - P00519 ( DB00156 ( 735 ) phosphorylation ) precluding its nuclear export and of 14 - 3 - 3 sigma ( DB00133 ( 186 ) phosphorylation by c - Jun N - terminal kinase [ JNK ] ) promoting p145 c - P00519 nuclear re - import .",
"Complex formation with the Type B gamma - aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium - sensing receptor . Studies with P29320 - 293 cells and neurons . We co - immunoprecipitated the Ca ( 2 +)- sensing receptor ( CaR ) and type B gamma - aminobutyric acid receptor ( GABA - B - R ) from human embryonic kidney ( P29320 ) - 293 cells expressing these receptors and from brain lysates where both receptors are present . CaRs extensively co - localized with the two subunits of the GABA - B - R ( Q96GN5 and R2 ) in P29320 - 293 cell membranes and intracellular organelles . Coexpressing CaRs and GABA - B - R1s in P29320 - 293 cells suppressed the total cellular and cell surface expression of CaRs and inhibited phospholipase C activation in response to high extracellular [ Ca ( 2 +) ] ( [ Ca ( 2 +)]( e ) ) . In contrast , coexpressing CaRs and GABA - B - R2s enhanced CaR expression and signaling responses to raising [ Ca ( 2 +)]( e ) . The latter effects of the O75899 on the CaR were blunted by coexpressing the Q9UBS5 . Coexpressing the CaR with Q9UBS5 or R2 enhanced the total cellular and cell surface expression of the Q9UBS5 or R2 , respectively . Studies with truncated CaRs indicated that the N - terminal extracellular domain of the CaR participated in the interaction of the CaR with the Q9UBS5 and R2 . In cultured mouse hippocampal neurons , CaRs co - localized with the Q9UBS5 and R2 . CaRs and GABA - B - R1s also co - immunoprecipitated from brain lysates . The expression of the CaR was increased in lysates from Q9UBS5 knock - out mouse brains and in cultured hippocampal neurons with their Q9UBS5 genes deleted in vitro . Thus , CaRs and GABA - B - R subunits can form heteromeric complexes in cells , and their interactions affect cell surface expression and signaling of CaR , which may contribute to extracellular Ca ( 2 +)- dependent receptor activation in target tissues .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK98___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Anti - Parkinson ' s disease drugs and pharmacogenetic considerations . INTRODUCTION : The development of pharmacogenetic - based clinical practice guidelines for the use of anti - Parkinson ' s disease drugs requires , as a pre - requisite , the identification and validation of genetic biomarkers . These biomarkers are then used as surrogate endpoints . This review analyzes potential genetic biomarkers which can be used to improve anti - Parkinson ' s disease therapy . AREAS COVERED : The authors present an overview of current knowledge of pharmacogenetic implications of anti - Parkinson ' s disease drugs , including genes coding for the corresponding drug - metabolizing enzymes and drug targets . The gene / drug pairings with the strongest potential for pharmacogenetic recommendations include : P33261 / benztropine , P21964 / levodopa and entacapone , P20813 / selegiline , P22309 / entacapone , P14416 / ropinirole , pramipexole and cabergoline , and P35462 / ropinirole and pramipexole . Evidence supporting the effect of substrates , inhibitor or inducers for drug specific metabolizing enzymes in anti - Parkinson ' s disease drug response includes P05177 in the response to ropinirole and rasagiline , and P08684 in the response to bromocriptine , lisuride , pergolide and cabergoline . The authors present and discuss the current information on gene variations according to the 1000 genomes catalog and other databases with regards to anti - Parkinson ' s disease drugs . They also review and discuss the clinical implications of these variations . EXPERT OPINION : The goal of pharmacogenomic testing for anti - Parkinson ' s disease drugs should be conservative and aimed at selecting determined drugs for determined patients . However , much additional research is still needed to obtain reliable pre - prescription tests .",
"O15105 and protein phosphatase 1alpha are critical determinants in the duration of TGF - beta / P37023 signaling in endothelial cells . BACKGROUND : In endothelial cells ( EC ) , transforming growth factor - beta ( TGF - beta ) can bind to and transduce signals through P37023 and P36897 . The TGF - beta / P36897 and TGF - beta / P37023 pathways have opposite effects on EC behaviour . Besides differential receptor binding , the duration of TGF - beta signaling is an important specificity determinant for signaling responses . TGF - beta / P37023 - induced Q15797 / 5 phosphorylation in ECs occurs transiently . RESULTS : The temporal activation of TGF - beta - induced Q15797 / 5 phosphorylation in ECs was found to be affected by de novo protein synthesis , and P37023 and Q99717 expression levels determined signal strength of TGF - beta / P37023 signaling pathway . O15105 and protein phosphatase 1alpha ( PP1alpha ) mRNA expression levels were found to be specifically upregulated by TGF - beta / P37023 . Ectopic expression of O15105 or PP1alpha potently inhibited TGF - beta / P37023 - induced Q15797 / 5 phosphorylation in ECs . Conversely , siRNA - mediated knockdown of O15105 or PP1alpha enhanced TGF - beta / P37023 - induced signaling responses . PP1alpha interacted with P37023 and this association was further potentiated by O15105 . Dephosphorylation of the P37023 , immunoprecipitated from cell lysates , was attenuated by a specific P50391 inhibitor . CONCLUSION : Our results suggest that upon its induction by the TGF - beta / P37023 pathway , O15105 may recruit PP1alpha to P37023 , and thereby control TGF - beta / P37023 - induced Q15797 / 5 phosphorylation .",
"aChE and BuChE inhibition by rivastigmin have no effect on peripheral insulin resistance in elderly patients with Alzheimer disease . BACKGROUND : P01308 resistance ( IR ) may play a role in most pathogenic processes that promote the development of Late Onset Alzheimer Disease ( LOAD ) . This study was designed to determine the interaction between inhibition of both butyrylcholinesterase ( BuChE ) and acetylcholinesterase ( P22303 ) with rivastigmine and peripheral insulin resistance ( IR ) in LOAD . METHODS : Seventy - Nine consecutive elderly patients , 31 late onset AD and 48 non - demented patients were evaluated . IR was calculated with HOMA . All of the patients were evaluated through comprehensive geriatric assessments at baseline and in the 6th and 12th months . RESULTS : End of the study , compared to the baseline values , there was a significant increase in the 6th month in both MMSE and IADL scores ( t = 2 . 200 , p = 0 . 036 for MMSE and t = 2 . 724 , p = 0 . 011 for IADL , respectively ) . ___MASK22___ was improved both the scores of MMSE and IADL in elderly patients with LOAD , but there was no significance or correlation between HOMA scores and cognitive status . CONCLUSION : In conclusion , inhibition of both BuChE and P22303 with rivastigmine was improved the cognition without affecting on the peripheral IR in the elderly patients with LOAD by HOMA . Due to the complexity of disease pathogenesis , it is too early to make general comments , and further longitudinal and long - term studies on this issue are needed .",
"Molecular and biochemical analysis of calmodulin interactions with the calmodulin - binding domain of plant glutamate decarboxylase . We previously provided what to our knowledge is the first evidence that plant glutamate decarboxylase ( Q99259 ) is a calmodulin ( P62158 ) - binding protein . Here , we studied the Q99259 P62158 - binding domain in detail . A synthetic peptide of 26 amino acids corresponding to this domain forms a stable complex with Ca2 +/ P62158 with a 1 : 1 stoichiometry , and amino acid substitutions suggest that tryptophan - 485 has an indispensable role in P62158 binding . Chemical cross - linking revealed specific P62158 / Q99259 interactions even in the absence of Ca2 + . However , increasing KCI concentrations or deletion of two carboxy - terminal lysines abolished these interactions but had a mild effect on P62158 / Q99259 interactions in the presence of Ca2 + . We conclude that in the presence of Ca ( 2 +)- hydrophobic interactions involving tryptophan - 485 and electrostatic interactions involving the carboxy - terminal lysines mediate P62158 / Q99259 complex formation . By contrast , in the absence of Ca2 + , P62158 / Q99259 interactions are essentially electrostatic and involve the carboxy - terminal lysines . In addition , a tryptophan residue and carboxy - terminal lysines are present in the P62158 - binding domain of an Arabidopsis Q99259 . Finally , we demonstrate that petunia Q99259 activity is stimulated in vitro by Ca2 +/ P62158 . Our study provides a molecular basis for Ca ( 2 +)- dependent P62158 / Q99259 interactions and suggests the possible occurrence of Ca ( 2 +)- independent P62158 / Q99259 interactions .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK73___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"Potentiator ivacaftor abrogates pharmacological correction of ΔF508 P13569 in cystic fibrosis . Cystic fibrosis ( CF ) is caused by mutations in the CF transmembrane conductance regulator ( P13569 ) . Newly developed \" correctors \" such as ___MASK97___ ( VX - 809 ) that improve P13569 maturation and trafficking and \" potentiators \" such as ivacaftor ( VX - 770 ) that enhance channel activity may provide important advances in CF therapy . Although VX - 770 has demonstrated substantial clinical efficacy in the small subset of patients with a mutation ( G551D ) that affects only channel activity , a single compound is not sufficient to treat patients with the more common P13569 mutation , ΔF508 . Thus , patients with ΔF508 will likely require treatment with both correctors and potentiators to achieve clinical benefit . However , whereas the effectiveness of acute treatment with this drug combination has been demonstrated in vitro , the impact of chronic therapy has not been established . In studies of human primary airway epithelial cells , we found that both acute and chronic treatment with VX - 770 improved P13569 function in cells with the G551D mutation , consistent with clinical studies . In contrast , chronic VX - 770 administration caused a dose - dependent reversal of VX - 809 - mediated P13569 correction in ΔF508 homozygous cultures . This result reflected the destabilization of corrected ΔF508 P13569 by VX - 770 , markedly increasing its turnover rate . Chronic VX - 770 treatment also reduced mature wild - type P13569 levels and function . These findings demonstrate that chronic treatment with P13569 potentiators and correctors may have unexpected effects that can not be predicted from short - term studies . Combining these drugs to maximize rescue of ΔF508 P13569 may require changes in dosing and / or development of new potentiator compounds that do not interfere with P13569 stability .",
"Interplay between inhibitory ferric and stimulatory curcumin regulates phosphorylation - dependent human cystic fibrosis transmembrane conductance regulator and ΔF508 activity . Curcumin potentiates cystic fibrosis transmembrane conductance regulator ( P13569 ) activation in an DB00171 - independent but phosphorylation - dependent manner . The underlying molecular mechanisms are unclear . Here , P29320 - 293T cells cultured in an Fe ( 3 +)- containing medium were transiently transfected with P13569 constructs , and the role of the inhibitory Fe ( 3 +) bridge between intracellular loop 3 and the regulatory domain of P13569 in this pathway was investigated . The results showed that ethylenediaminetetraacetic acid ( DB00974 ) stimulated phosphorylation - dependent P13569 activation and the stimulation was suppressed by the deletion of the regulatory domain or the insertion of a C832A mutation that removes the Fe ( 3 +)- binding interface . Furthermore , curcumin potentiation of P13569 was significantly weakened not only by Fe ( 3 +)- insensitive mutations at the interface between the regulatory domain and intracellular loop 3 but also by N - ethylmaleimide or DB00974 pretreatment that removes Fe ( 3 +) . More importantly , potentiation of P13569 was completely suppressed by sufficient Fe ( 3 +) . Finally , the insertion of Fe ( 3 +)- insensitive H950R / S768R increased the curcumin - independent activity of ΔF508 but weakened its curcumin potentiation . Thus , Fe ( 3 +) homeostasis in epithelia may play a critical role in regulating P13569 activity , and targeting Fe ( 3 +)- chelating potentiators may direct new therapies for cystic fibrosis ."
] |
[
"___MASK22___",
"___MASK25___",
"___MASK47___",
"___MASK50___",
"___MASK54___",
"___MASK73___",
"___MASK79___",
"___MASK97___",
"___MASK98___"
] |
___MASK98___
|
MH_train_475
|
interacts_with DB00112?
|
[
"Suppressive effect of bevacizumab on peritoneal dissemination from gastric cancer in a peritoneal metastasis model . PURPOSE : Vascular endothelial growth factor ( P15692 ) has been reported to enhance vascular permeability and angiogenesis in the abdominal wall , thereby contributing to peritoneal dissemination with malignant ascites . We conducted this experimental study to find out if bevacizumab , a humanized monoclonal antibody against P15692 , had a suppressive effect on peritoneal dissemination from gastric cancer , in an experimental nude mouse model of peritoneal metastasis . METHODS : Each mouse was treated with a single intraperitoneal ( i . p . ) injection of bevacizumab . Five mice were killed , and we measured their body weight , the mean number of tumor nodules , and the volume of ascites . We also extracted retroperitoneal tissues for histological examination , to count the frequency of mitosis , and to calculate the mitotic index . Another five mice were monitored until death , and their mean survival duration was calculated . RESULTS : The volume of ascites and the mitotic index were significantly lower in the therapy group than in the nontherapy group ( P = 0 . 042 and P < 0 . 01 , respectively ) . The survival curve of the therapy group was significantly higher than that of the nontherapy group ( P = 0 . 005 ) . CONCLUSION : DB00112 may suppress peritoneal dissemination from gastric cancer .",
"[ DB00112 combined with cisplan inhibits malignant ascites production in nude mice bearing transplanted ovary carcinoma with high P15692 expression ] . OBJECTIVE : To establish a nude mouse model of malignant ascites with human ovarian carcinoma cell line OVCAR3 which highly expresses P15692 and evaluate the therapeutic of DB00112 combined with cisplan . METHODS : Forty - eight nude mice with malignant ascites resulting from intraperitoneal transplantation of human ovarian carcinoma cell line OVCAR3 were treated with intraperitoneal injection of DB00112 , cisplan , their combination , and PBS , respectively , to observe the effect on ascites development , P15692 content in the ascites , peritoneal permeability , development of new vessels and number of tumor cells in the ascites . RESULTS : DB00112 obviously inhibited ascites accumulation and peritoneal capillary permeability , reduced P15692 protein level and microvascular density in the tumor tissues and the number of red cells and tumor cells in the malignant ascites , and prolonged the survival of the mice . The combination of DB00112 and cisplan further enhanced the therapeutic efficacy of DB00112 . CONCLUSION : The bio - chemotherapeutic strategy with DB00112 combined with cisplan can be a promising method for treatment of malignant ascites .",
"Dynamic contrast - enhanced and diffusion Q9BWK5 show rapid and dramatic changes in tumor microenvironment in response to inhibition of HIF - 1alpha using PX - 478 . PX - 478 is a new agent known to inhibit the hypoxia - responsive transcription factor , HIF - 1alpha , in experimental tumors . The current study was undertaken in preparation for clinical trials to determine which noninvasive imaging endpoint ( s ) is sensitive to this drug ' s actions . Dynamic contrast - enhanced ( DCE ) and diffusion - weighted ( DW ) magnetic resonance imaging ( Q9BWK5 ) were used to monitor acute effects on tumor hemodynamics and cellularity , respectively . Mice bearing human xenografts were treated either with PX - 478 or vehicle , and imaged over time . DW imaging was performed at three b values to generate apparent diffusion coefficient of water ( ADCw ) maps . For DCE - Q9BWK5 , a macromolecular contrast reagent , BSA - DB00789 , was used to determine vascular permeability and vascular volume fractions . PX - 478 induced a dramatic reduction in tumor blood vessel permeability within 2 hours after treatment , which returned to baseline by 48 hours . The anti - P15692 antibody , DB00112 , reduced both the permeability and vascular volume . PX - 478 had no effect on the perfusion behavior of a drug - resistant tumor system , A - 549 . Tumor cellularity , estimated from ADCw , was significantly decreased 24 and 36 hours after treatment . This is the earliest significant response of ADC to therapy yet reported . Based on these preclinical findings , both of these imaging endpoints will be included in the clinical trial of PX - 478 .",
"DB00112 immune complexes activate platelets and induce thrombosis in P12318 transgenic mice . BACKGROUND : Treatment with DB00112 has been associated with arterial thromboembolism in colorectal cancer patients . However , the mechanism of this remains poorly understood , and preclinical testing in mice failed to predict thrombosis . OBJECTIVE : We investigated whether thrombosis might be the result of platelet activation mediated via the FcgammaRIIa ( IgG ) receptor - which is not present on mouse platelets - and aimed to identify the functional roles of heparin and platelet surface localization in Bev - induced FcgammaRIIa activation . METHODS AND RESULTS : We found that Bev immune complexes ( IC ) activate platelets via FcgammaRIIa , and therefore attempted to reproduce this finding in vivo using FcgammaRIIa ( hFcR ) transgenic mice . Bev IC were shown to be thrombotic in hFcR mice in the presence of heparin . This activity required the heparin - binding domain of Bev ' s target , vascular endothelial growth factor ( P15692 ) . ___MASK75___ promoted Bev IC deposition on to platelets in a mechanism similar to that observed with antibodies from patients with heparin - induced thrombocytopenia . When sub - active amounts of ADP or thrombin were used to prime platelets ( simulating hypercoagulability in patients ) , Bev IC - induced dense granule release was significantly potentiated , and much lower ( sub - therapeutic ) heparin concentrations were sufficient for Bev IC - induced platelet aggregation . CONCLUSIONS : The prevailing rationale for thrombosis in Bev therapy is that P15692 blockade leads to vascular inflammation and clotting . However , we conclude that Bev can induce platelet aggregation , degranulation and thrombosis through complex formation with P15692 and activation of the platelet FcgammaRIIa receptor , and that this provides a better explanation for the thrombotic events observed in vivo .",
"Intravitreal DB00112 ( DB00112 (®) ) for Diabetic Retinopathy at 24 - months : The 2008 Juan Verdaguer - Planas Lecture . Diabetic retinopathy ( DR ) remains the major threat to sight in the working age population . Diabetic macular edema ( DME ) is a manifestation of DR that produces loss of central vision . Proliferative diabetic retinopathy ( PDR ) is a major cause of visual loss in diabetic patients . In PDR , the growth of new vessels is thought to occur as a result of vascular endothelial growth factor ( P15692 ) release into the vitreous cavity as a response to ischemia . Furthermore , P15692 increases vessel permeability leading to deposition of proteins in the interstitium that facilitate the process of angiogenesis and macular edema . This review demonstrates multiple benefits of intravitreal bevacizumab ( IVB ) on DR including DME and PDR at 24 months of follow up . The results indicate that IVB injections may have a beneficial effect on macular thickness and visual acuity ( VA ) in diffuse diabetic macular edema . Therefore , in the future this new therapy could replace or complement focal / grid laser photocoagulation in DME . In PDR , this new option could be an adjuvant agent to pan - retina photocoagulation so that more selective therapy may be applied . In addition , we report a series of patients in which tractional retinal detachment developed or progressed after adjuvant preoperative IVB in severe PDR .",
"Potentiation of anti - angiogenic activity of heparin by blocking the P01008 - interacting pentasaccharide unit and increasing net anionic charge . ___MASK75___ , a potent anticoagulant used for the prevention of venous thromboembolism , has been recognized as a tumor angiogenesis inhibitor . Its limitation in clinical application for cancer therapy , however , arises from its strong anticoagulant activity , which causes associated adverse effects . In this study , we show the structural correlation of LHT7 , a previously developed heparin - based angiogenesis inhibitor , with its influence on P15692 blockade and its decreased anticoagulant activity . LHT7 was characterized as having average seven molecules of sodium taurocholates conjugated to one molecule of low - molecular - weight heparin ( LMWH ) . This study showed that the conjugation of sodium taurocholates selectively blocked interaction with antithrombin III ( P01008 ) while enhancing the binding with P15692 . This resulted in LHT7 to have negligible anticoagulant activity but potent anti - angiogenic activity . Following up on this finding , we showed that the bidirectional effect of sodium taurocholate conjugation was due to its unique structure , that is , the sterane core hindering the P01008 - binding pentasaccharide unit of LMWH with its bulky and rigid structural characteristics while the terminal sulfate group interacts with P15692 to produce stronger binding . In addition , we showed that LHT7 was localized in the tumor , especially on the endothelial cells . One explanation for this might be that LHT7 was delivered to the tumor via platelets .",
"Antivascular endothelial growth factor for retinopathy of prematurity . PURPOSE OF REVIEW : This review will discuss a potentially more effective treatment for retinopathy of prematurity ( P04000 ) with fewer acute and long - term complications . DB00112 ( bevacizumab ) therapy is a promising anti - vascular endothelial growth factor ( anti - P15692 ) administered directly into the vitreous . RECENT FINDINGS : Recent reports detail the use of DB00112 alone , and in combination with light amplification by stimulated emission of radiation ( LASER ) therapy and vitrectomy , for P04000 stages 3 , 4 , and 5 . Currently , one clinical trial is studying DB00112 alone for acute vision - threatening P04000 stage 3 in zone I and posterior zone II without LASER therapy . Another clinical trial is investigating DB00112 following LASER therapy for recurrent P04000 stages 4 and 5 . SUMMARY : Treatment for P04000 has evolved from later , more destructive ( cryotherapy ) to earlier , less destructive ( LASER therapy ) peripheral retinal ablation . If evidence - based data supports early findings , the use of DB00112 may be recommended without the need for ablative LASER therapy and before retinal detachment develops . DB00112 will be especially useful for P04000 stage 3 cases with hemorrhage decreasing retinal visualization , rigid pupils , intravitreal neovascularization with early or developing ( minimal ) fibrous membranes , or aggressive posterior retinopathy of prematurity ( AP - P04000 ) . These cases all continue to have poor outcomes with LASER therapy .",
"Ablation of cholesterol biosynthesis in neural stem cells increases their P15692 expression and angiogenesis but causes neuron apoptosis . Although sufficient cholesterol supply is known to be crucial for neurons in the developing mammalian brain , the cholesterol requirement of neural stem and progenitor cells in the embryonic central nervous system has not been addressed . Here we have conditionally ablated the activity of squalene synthase ( P37268 ) , a key enzyme for endogenous cholesterol production , in the neural stem and progenitor cells of the ventricular zone ( VZ ) of the embryonic mouse brain . Mutant embryos exhibited a reduced brain size due to the atrophy of the neuronal layers , and died at birth . Analyses of the E11 . 5 - E15 . 5 dorsal telencephalon and diencephalon revealed that this atrophy was due to massive apoptosis of newborn neurons , implying that this progeny of the P37268 - ablated neural stem and progenitor cells was dependent on endogenous cholesterol biosynthesis for survival . Interestingly , the neural stem and progenitor cells of the VZ , the primary target of P37268 inactivation , did not undergo significant apoptosis . Instead , vascular endothelial growth factor ( P15692 ) expression in these cells was strongly upregulated via a hypoxia - inducible factor - 1 - independent pathway , and angiogenesis in the VZ was increased . Consistent with an increased supply of lipoproteins to these cells , the level of lipid droplets containing triacylglycerides with unsaturated fatty acyl chains was found to be elevated . Our study establishes a direct link between intracellular cholesterol levels , P15692 expression , and angiogenesis . Moreover , our data reveal a hitherto unknown compensatory process by which the neural stem and progenitor cells of the developing mammalian brain evade the detrimental consequences of impaired endogenous cholesterol biosynthesis .",
"Evaluation of cytotoxic effects of bevacizumab on human corneal cells . PURPOSE : Corneal neovascularization contributes to corneal opacification in inflammatory conditions of the cornea and severely compromises the success of corneal transplantation . Vascular endothelial growth factor ( P15692 ) plays an important role in stimulating and maintaining corneal neovascularization . Anti - P15692 therapy , especially the use of anti - P15692 antibody bevacizumab , has gained popularity in the management of retinal neovascularization and is being used topically for corneal neovascularization . The aim of this study was to investigate the safety profile of bevacizumab on human corneal cell lines . METHODS : Human corneal epithelial and fibroblast cell lines and an umbilical vascular endothelial cell line were treated with increasing doses of bevacizumab . The effect of this treatment on cell viability was assessed by WST - 1 and crystal violet staining assays . Cytotoxicity was also assessed by fluorescent microscopy and flow cytometric evaluation of propidium iodide - stained cells . RESULTS : In the cytotoxicity experiments , there was no difference in cell numbers after 24 - hour exposure compared with control in any of the cell lines at the concentrations tested ( P > 0 . 05 to 0 . 98 ) . CONCLUSION : DB00112 was nontoxic to human corneal epithelial and fibroblast cells at 3 different concentrations .",
"Evolving role of novel targeted agents in renal cell carcinoma . The treatment of metastatic renal cell carcinoma ( RCC ) has changed dramatically over the past few years . An improved understanding of the biology of RCC has resulted in the development of novel targeted therapeutic agents that have altered the natural history of this disease . In particular , the hypoxia - inducible factor ( HIF ) / vascular endothelial growth factor ( P15692 ) pathway and the mammalian target of rapamycin ( P42345 ) signal transduction pathway have been exploited . DB01268 malate ( Sutent ) , sorafenib tosylate ( Nexavar ) , bevacizumab ( DB00112 ) / interferon alfa , and temsirolimus ( DB06287 ) have improved clinical outcomes in randomized trials by inhibiting these tumorigenic pathways . Combinations and sequences of these agents are being evaluated . Other novel multitargeted tyrosine kinase inhibitors ( pazopanib and axitinib ) and P42345 inhibitors ( everolimus ) are in clinical development . Recently reported and ongoing clinical trials will help further define the role of these agents as therapy for metastatic RCC .",
"Expression and role of P15692 in the adult retinal pigment epithelium . PURPOSE : Despite a lack of active angiogenesis , P15692 is expressed in nearly every adult tissue , and recent evidence suggests that P15692 may serve as a survival factor for both vascular and nonvascular tissues . P15692 blockade is a widely used treatment for neovascular diseases such as wet age - related macular degeneration ( AMD ) . Therefore , it was sought in this study to evaluate the expression and role of endogenous P15692 in Q96AT9 . METHODS : P15692 and P35968 expression in the murine retina were assessed during development . DB00112 was used to neutralize P15692 in ARPE - 19 cells , and the effects on cell survival and apical microvill were assessed by TUNEL and SEM , respectively . P15692 was systemically neutralized in vivo by adenoviral - mediated overexpression of soluble P17948 ( sFlt ) . Q96AT9 and choriocapillaris were analyzed by transmission electron microscopy ( TEM ) . Changes in gene expression were evaluated by quantitative real - time PCR . RESULTS : P15692 expression was detected in the developing Q96AT9 as early as embryonic day ( E ) 9 . 5 , whereas P35968 expression by Q96AT9 began nonuniformly between postnatal ( P ) day 6 . 5 and P8 . 5 . P15692 neutralization in vitro led to increased apoptosis and reduced microvilli density and length . Systemic P15692 neutralization led to transient degenerative changes ; Q96AT9 were vacuolated and separated from photoreceptor outer segments , and choriocapillaris fenestrations were decreased . P15692 levels were elevated in Q96AT9 of Ad - sFlt1 mice at day 4 postinfection , and there was increased expression of the neurotrophic factor CD59a at day 14 . CONCLUSIONS : These results indicate that P15692 plays a critical role in survival and maintenance of Q96AT9 integrity . Potential undesired off - target effects should be considered with chronic use of anti - P15692 agents .",
"Neuroprotective profile of novel P12931 kinase inhibitors in rodent models of cerebral ischemia . Src kinase signaling has been implicated in multiple mechanisms of ischemic injury , including vascular endothelial growth factor ( P15692 ) - mediated vascular permeability that leads to vasogenic edema , a major clinical complication in stroke and brain trauma . Here we report the effects of two novel Src kinase inhibitors , 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 3 -( 4 - methyl - 1 - piperazinyl ) propoxy ]- 3 - quinolinecarbonitrile ( ___MASK54___ ) and 4 -[( 2 , 4 - dichloro - 5 - methoxyphenyl ) amino ]- 6 - methoxy - 7 -[ 4 -( 4 - methypiperazin - 1 - yl ) but - 1 - ynyl ]- 3 - quinolinecarbonitrile ( SKS - 927 ) , on ischemia - induced brain infarction and short - and long - term neurological deficits . Two well established transient [ transient middle cerebral artery occlusion ( tMCAO ) ] and permanent [ permanent middle cerebral artery occlusion ( pMCAO ) ] focal ischemia models in the rat were used with drug treatments initiated up to 6 h after onset of stroke to mimic the clinical scenario . Brain penetration of Src inhibitors , their effect on blood - brain barrier integrity and P15692 signaling in human endothelial cells were also evaluated . Our results demonstrate that both agents potently block P15692 - mediated signaling in human endothelial cells , penetrate rat brain upon systemic administration , and inhibit postischemic Src activation and vascular leakage . Treatment with ___MASK54___ or SKS - 927 ( at the doses of 3 - 30 mg / kg i . v . ) resulted in a dose - dependent reduction in infarct volume and robust protection from neurological impairments even when the therapy was initiated up to 4 - to 6 - h after tMCAO . Src blockade after pMCAO resulted in accelerated improvement in recovery from motor , sensory , and reflex deficits during a long - term ( 3 weeks ) testing period poststroke . These data demonstrate that the novel Src kinase inhibitors provide effective treatment against ischemic conditions within a clinically relevant therapeutic window and may constitute a viable therapy for acute stroke .",
"Anti - P15692 Treatment of Corneal Neovascularization . Vascular endothelial growth factor ( P15692 ) is an angiogenic factor shown to be a critical secreted cytokine in tumorigenesis and retinal neovascularization ( NV ) . Currently , there are two anti - P15692 agents , pegaptanib and ranizumab , approved by the United States Food and Drug Administration ( FDA ) for intravitreal use in the treatment of wet age - related macular degeneration ( AMD ) . DB00112 is FDA - approved for intravenous administration in the treatment of several cancers and is in widespread use , off - label , as an intravitreal injection to treat a variety of retinal pathologies . Animal studies demonstrate the role of P15692 in corneal NV . There are now a number of human case series reporting the use of anti - P15692 agents , primarily bevacizumab , to treat corneal NV . This review summarizes reports to date on the use of anti - P15692 agents in the treatment of corneal NV in humans , noting the limitations of current data and the need for further studies . The experience of one clinician with the use of an anti - P15692 drug in the treatment of active corneal NV is presented .",
"Vascular endothelial growth factor stimulates organ - specific host matrix metalloproteinase - 9 expression and ovarian cancer invasion . Vascular endothelial growth factor ( P15692 ) and matrix metalloproteinases ( MMP ) regulate each other , contributing to tumor progression . We have previously reported that P14780 induces the release of tumor P15692 , promoting ascites formation in human ovarian carcinoma xenografts . The aim of this study was to investigate whether tumor - derived P15692 regulated the expression of gelatinase by the stroma , influencing the invasive properties of ovarian tumors . Tumor variants derived from 1A9 human ovarian carcinoma , stably expressing P15692 ( 121 ) in the sense ( 1A9 - VS - 1 ) and antisense orientations ( 1A9 - VAS - 3 ) , were used . In vivo , zymographic analysis of tumors from 1A9 - VS - 1 implanted in the peritoneal cavity of nude mice showed higher levels of gelatinases , particularly murine P14780 , indicating that P15692 stimulates host expression of the matrix - degrading enzyme . Murine P14780 expression was also high in the ovaries of mice bearing 1A9 - VS - 1 tumors . The effect on host P14780 activity was organ - specific . The levels of host pro - P14780 in ovaries correlated with the plasma levels of tumor P15692 and with the selective invasion of the ovaries . Induction of host P14780 expression in tumors and ovaries was independent of the site of tumor growth as it was seen in mice carrying both intraperitoneal and subcutaneous tumors . The anti - P15692 antibody bevacizumab ( DB00112 ) inhibited P14780 expression and tumor invasion in the ovaries of mice bearing 1A9 - VS - 1 tumors . These findings point to a complex cross - talk between P15692 and MMPs in the progression of ovarian tumor and suggest the possibility of using P15692 inhibitors to affect MMP - dependent tumor invasion .",
"Levels of vascular endothelial growth factor and pigment epithelium - derived factor in eyes before and after intravitreal injection of bevacizumab . PURPOSE : DB00112 is a human monoclonal IgG1 antibody that blocks the action of vascular endothelial growth factor ( P15692 ) . The purpose of this study was to determine the level of P15692 and pigment epithelium - derived factor ( P36955 ) in eyes with proliferative diabetic retinopathy ( PDR ) before and after an intravitreal injection of bevacizumab . METHODS : Eleven eyes of ten patients were studied . Patients were included if they had neovascular glaucoma , rubeosis of the iris with PDR , or aggressive PDR . Samples of aqueous humor were collected just before the injection of bevacizumab and the vitrectomy . The concentrations of P15692 and P36955 in the aqueous humor were measured by enzyme - linked immunosorbent assay , and the effects of bevacizumab on PDR were evaluated . RESULTS : The free P15692 concentration before the injection was 676 . 5 +/- 186 . 7 pg / ml ( mean +/- SEM , n = 11 ) . Seven days later , it was significantly reduced to 7 . 1 +/- 7 . 1 pg / ml ( P < 0 . 005 , n = 9 ) . The P36955 concentration before the injection was 2 . 32 +/- 0 . 49 microg / ml ( n = 11 ) , and 7 days later , it was 3 . 23 +/- 0 . 76 microg / ml ( P = 0 . 33 ) . During the vitrectomy , patients had less intraoperative bleeding when the neovascular tissues were cut . CONCLUSIONS : An intravitreal injection of bevacizumab significantly decreased the free P15692 in the aqueous humor by 7 days , indicating that the clinical effects of bevacizumab appear rapidly . However , intravitreal bevacizumab did not affect the level of intraocular P36955 .",
"[ Intravitreal bevacizumab for neovascular age - related macular degeneration ] . The efficacy and safety of the therapeutic anti - P15692 concept has already been demonstrated for pegaptanib and ranibizumab . DB00112 acts as an antibody against all P15692 isoforms and has been developed for oncological indications with intravenous application . Initial reports on intravitreal administration in patients with neovascular age - related macular disease ( AMD ) have shown beneficial morphological and functional effects . In the meantime , bevacizumab has been used off - label in thousands of patients with AMD . However , data from prospective , controlled , randomized trials on both safety and efficacy are lacking . Herein recent experiences with bevacizumab are summarized and discussed . Furthermore , a web - based platform for online data registration and pooled analyses is presented .",
"Antitumor activity of bevacizumab in combination with capecitabine and oxaliplatin in human colorectal cancer xenograft models . To understand the mechanisms of the effects of combination treatments , we established animal models showing antitumor activity of bevacizumab as a monotherapy and in combination with capecitabine or capecitabine and oxaliplatin and measured thymidine phosphorylase ( TP ) and vascular endothelial growth factor ( P15692 ) levels . Tumor - inoculated nude mice were treated with bevacizumab , capecitabine , and oxaliplatin , alone or in combination , after tumor growth was confirmed and volume and microvessel density ( P53602 ) in tumors were evaluated . Levels of TP and P15692 in the tumor were examined by ELISA . DB00112 showed significant antitumor activity as a monotherapy in three xenograft models ( COL - 16 - Q86SG6 , COLO 205 and CXF280 ) . The P53602 in tumor tissues treated with bevacizumab was lower than that of the control . Antitumor activity of bevacizumab in combination with capecitabine was significantly higher than that of each agent alone ( COL - 16 - Q86SG6 , COLO 205 ) . Furthermore , the antitumor activity of bevacizumab in combination with capecitabine + oxaliplatin was significantly superior to that of capecitabine + oxaliplatin ( COL - 16 - Q86SG6 ) . TP and P15692 levels were not increased by bevacizumab or capecitabine , respectively , suggesting there are other potentially efficacious mechanisms involved . In the present study we established human colorectal cancer xenograft models which reflect the efficacy of clinical combination therapies , capecitabine + bevacizumab and capecitabine + oxaliplatin + bevacizumab . We will further investigate the mechanisms of the combination therapies using these models .",
"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .",
"Advances in Q9BWK5 assessment of gliomas and response to anti - P15692 therapy . DB00112 is thought to normalize tumor vasculature and restore the blood - brain barrier , decreasing enhancement and peritumoral edema . Conventional measurements of tumor response rely upon dimensions of enhancing tumor . After bevacizumab treatment , glioblastomas are more prone to progress as nonenhancing tumor . The RANO ( Response Assessment in Neuro - Oncology ) criteria for glioma response use fluid - attenuated inversion recovery ( FLAIR ) / P24752 hyperintensity as a surrogate for nonenhancing tumor ; however , nonenhancing tumor can be difficult to differentiate from other causes of FLAIR / P24752 hyperintensity ( e . g . , radiation - induced gliosis ) . Due to these difficulties , recent efforts have been directed toward identifying new biomarkers that either predict treatment response or accurately measure response of both enhancing and nonenhancing tumor shortly after treatment initiation . This will allow for earlier treatment decisions , saving patients from the adverse effects of ineffective therapies while allowing them to try alternative therapies sooner . An active area of research is the use of physiologic imaging , which can potentially detect treatment effects before changes in tumor size are evident .",
"From the discovery of vascular endothelial growth factor to the introduction of avastin in clinical trials - an interview with Napoleone Ferrara by Domenico Ribatti . Napoleone Ferrara and his colleagues at Genentech were the first to isolate and clone vascular endothelial growth factor ( P15692 ) in 1989 . DB00117 laboratory has investigated many aspects of P15692 biochemistry and molecular biology . In 1993 , Ferrara reported that inhibition of P15692 - induced angiogenesis by specific monoclonal antibodies resulted in dramatic suppression of the growth of a variety of tumors in vivo . These findings provided an important evidence that inhibition of angiogenesis may suppress tumor growth and blocking P15692 action could have therapeutic value for a variety of malignancies . A further development was the design in a rational fashion in 1997 of a humanized anti - P15692 monoclonal antibody ( DB00112 ) , now in clinical trials as a treatment for several solid tumors and also outside of cancer , in the treatment of age - related macular degeneration ( AMD ) . Ferrara ' s work is revolutionizing quality of life for many of the estimated 1 . 2 million individuals in the US who have wet AMD . Upwards of a million AMD patients worldwide have already received anti - P15692 antibody therapy .",
"The potential role of P15692 - induced vascularisation in the bony repair of injured growth plate cartilage . Growth plate injuries often result in undesirable bony repair causing bone growth defects , for which the underlying mechanisms are unclear . Whilst the key importance of pro - angiogenic vascular endothelial growth factor ( P15692 ) is well - known in bone development and fracture repair , its role during growth plate bony repair remains unexplored . Using a rat tibial growth plate injury repair model with anti - P15692 antibody , DB00112 , as a single i . p . injection ( 2 . 5 mg / kg ) after injury , this study examined the roles of P15692 - driven angiogenesis during growth plate bony repair . Histology analyses observed isolectin - B4 - positive endothelial cells and blood vessel - like structures within the injury site on days 6 and 14 , with anti - P15692 treatment significantly decreasing blood - vessel - like structures within the injury site ( P < 0 . 05 ) . Compared with untreated controls , anti - P15692 treatment resulted in an increase in undifferentiated mesenchymal repair tissue , but decreased bony tissue at the injury site at day 14 ( P < 0 . 01 ) . Consistently , microcomputed tomography analysis of the injury site showed significantly decreased bony repair tissue after treatment ( P < 0 . 01 ) . RT - PCR analyses revealed a significant decrease in osteocalcin ( P < 0 . 01 ) and a decreasing trend in Runx2 expression at the injury site following treatment . Furthermore , growth plate injury - induced reduced tibial lengthening was more pronounced in anti - P15692 - treated injured rats on day 60 , consistent with the observation of a significantly increased height of the hypertrophic zone adjacent to the growth plate injury site ( P < 0 . 05 ) . These results indicate that P15692 is important for angiogenesis and formation of bony repair tissue at the growth plate injury site as well as for endochondral bone lengthening function of the uninjured growth plate .",
"Smith - Magenis syndrome resulting from a de novo direct insertion of proximal 17q into 17p11 . 2 . We report on a de novo intrachromosomal rearrangement of chromosome 17 in a patient with Smith - Magenis syndrome ( P52788 ) . This 11 - year - old boy had short stature , midfacial hypoplasia , and behavioral problems characteristic of this syndrome . Cytogenetic analysis showed that the proximal long arm of a chromosome 17 ( q11 . 2 - q21 . 3 ) was inserted into its short arm at p11 . 2 , resulting in an apparent deletion of the P52788 critical region [ ins ( 17 )( p11 . 2q11 . 2q21 . 3 ) ] . Fluorescence in situ hybridization studies ( Q5TCZ1 ) demonstrated that the inserted segment included both the P04626 and P10276 loci , and dual color hybridizations defined the insertion as direct , with P04626 located more proximally on the short arm of the der ( 17 ) . The resulting deletion of the short arm included loci c130G3 , D17S258 , FLI , and D17S29 , while the more proximal loci , D17S446 and D17S58 , remained apparently unaffected and in their native locations . The CMT1A locus also remained in its native location on the short arm of the metacentric der ( 17 ) chromosome . A de novo intrachromosomal insertional rearrangement of chromosome 17 in a case of P52788 has not been reported previously and further illustrates the instability of this chromosomal region .",
"Suppression of melanoma - associated neoangiogenesis by bevacizumab . BACKGROUND : DB00112 , a potent antibody against the vascular endothelial growth factor ( P15692 ) , has been shown to be effective for treatment of colorectal cancer . Recently , high effectiveness of bevacizumab in combination with paclitaxel has been reported in a single metastatic melanoma case . To our knowledge , we demonstrate for the first time the antiangiogenetic effect of bevacizumab in a patient with a vitreous melanoma metastasis . OBSERVATIONS : A 68 - year - old man with a vitreous melanoma metastasis of the left eye was treated with a revitrectomy combined with intravitreal bevacizumab application because of iris neovascularization and progressive epiretinal tumor plaques . Four days after the treatment , the melanoma - associated neovascularization completely disappeared , but it recurred after 6 weeks . Although repetitive administration of local bevacizumab produced the same antiangiogenetic effect , progression of the epiretinal tumor plaques could not be stopped with the local bevacizumab treatment . CONCLUSIONS : Intraocular administration of the anti - P15692 drug bevacizumab causes immediate and complete regression of melanoma - associated angiogenesis . The rationale for the therapeutic strategy in our patient was an elevated level of P15692 in the vitreous cavity . Because we could not demonstrate a direct antiproliferative effect of bevacizumab on melanoma metastasis , bevacizumab seems most promising if evaluated in combination with antiproliferative agents .",
"___MASK51___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .",
"A novel bisphosphonate inhibitor of squalene synthase combined with a statin or a nitrogenous bisphosphonate in vitro . Statins and nitrogenous bisphosphonates ( NBP ) inhibit 3 - hydroxy - 3 - methylglutaryl - coenzyme - A reductase ( P04035 ) and farnesyl diphosphate synthase ( P14324 ) , respectively , leading to depletion of farnesyl diphosphate ( FPP ) and disruption of protein prenylation . P37268 ( P37268 ) utilizes FPP in the first committed step from the mevalonate pathway toward cholesterol biosynthesis . Herein , we have identified novel bisphosphonates as potent and specific inhibitors of P37268 , including the tetrasodium salt of 9 - biphenyl - 4 , 8 - dimethyl - nona - 3 , 7 - dienyl - 1 , 1 - bisphosphonic acid ( compound 5 ) . Compound 5 reduced cholesterol biosynthesis and lead to a substantial intracellular accumulation of FPP without reducing cell viability in HepG2 cells . At high concentrations , lovastatin and zoledronate impaired protein prenylation and decreased cell viability , which limits their potential use for cholesterol depletion . When combined with lovastatin , compound 5 prevented lovastatin - induced FPP depletion and impairment of protein farnesylation . Compound 5 in combination with the NBP zoledronate completely prevented zoledronate - induced impairment of both protein farnesylation and geranylgeranylation . Cotreatment of cells with compound 5 and either lovastatin or zoledronate was able to significantly prevent the reduction of cell viability caused by lovastatin or zoledronate alone . The combination of an P37268 inhibitor with an P04035 or P14324 inhibitor provides a rational approach for reducing cholesterol synthesis while preventing nonsterol isoprenoid depletion .",
"DB00112 and ovarian cancer . PURPOSE OF REVIEW : Vascular endothelial growth factor ( P15692 ) , one of the major pathways involved in tumor angiogenesis , is often overexpressed in epithelial ovarian cancer ( EOC ) , and therefore an attractive target for therapy . This review aims to evaluate the rationale for targeting angiogenic pathways by the usage of the anti - P15692 agent bevacizumab in EOC . RECENT FINDINGS : DB00112 monotherapy has been shown to be effective in the treatment of EOC with response rate of 16 - 21 % in phase II trials . In phase III trials , patients with advanced EOC who received combination chemotherapy ( paclitaxel + carboplatin ) plus bevacizumab with maintenance bevacizumab had significantly longer progression - free survival than those who received chemotherapy alone , but did not prolong overall survival . The most common grade 3 / 4 adverse events of bevacizumab monotherapy include hypertension and proteinuria , while heavily pretreated patients were at increased risk of bowel perforation . The addition of bevacizumab to the standard chemotherapy in patients with advanced EOC may not be cost - effective . SUMMARY : DB00112 has significant activity and is the most promising drug in EOC . However , understanding of its unique adverse events and identification of predictive biomarkers of bevacizumab response are necessary in order to select patients most likely to benefit from this therapy .",
"Integrin inhibitor suppresses bevacizumab - induced glioma invasion . Glioblastoma is known to secrete high levels of vascular endothelial growth factor ( P15692 ) , and clinical studies with bevacizumab , a monoclonal antibody to P15692 , have demonstrated convincing therapeutic benefits in glioblastoma patients . However , its induction of invasive proliferation has also been reported . We examined the effects of treatment with cilengitide , an integrin inhibitor , on bevacizumab - induced invasive changes in glioma . U87Δ P00533 cells were stereotactically injected into the brain of nude mice or rats . Five days after tumor implantation , cilengitide and bevacizumab were administered intraperitoneally three times a week . At 18 days after tumor implantation , the brains were removed and observed histopathologically . Next , the bevacizumab and cilengitide combination group was compared to the bevacizumab monotherapy group using microarray analysis . DB00112 treatment led to increased cell invasion in spite of decreased angiogenesis . When the rats were treated with a combination of bevacizumab and cilengitide , the depth of tumor invasion was significantly less than with only bevacizumab . Pathway analysis demonstrated the inhibition of invasion - associated genes such as the integrin - mediated cell adhesion pathway in the combination group . This study showed that the combination of bevacizumab with cilengitide exerted its anti - invasive effect . The elucidation of this mechanism might contribute to the treatment of bevacizumab - refractory glioma .",
"In vivo optical molecular imaging of vascular endothelial growth factor for monitoring cancer treatment . PURPOSE : Vascular endothelial growth factor ( P15692 ) expression is a critical component in tumor growth and metastasis . Capabilities to monitor P15692 expression in vivo can potentially serve as a useful tool for diagnosis , prognosis , treatment planning , monitoring , and research . Here , we present the first report of in vivo hyperspectral molecular imaging strategy capable of monitoring treatment - induced changes in P15692 expression . EXPERIMENTAL DESIGN : P15692 was targeted with an anti - P15692 antibody conjugated with a fluorescent dye and was imaged in vivo using a hyperspectral imaging system . The strategy was validated by quantitatively monitoring P15692 levels in three different tumors as well as following photodynamic treatment . Specificity of the molecular imaging strategy was tested using in vivo competition experiments and mathematically using a quantitative pharmacokinetic model . RESULTS : The molecular imaging strategy successfully imaged P15692 levels quantitatively in three different tumors and showed concordance with results from standard ELISA . Changes in tumoral P15692 concentration following photodynamic treatment and DB00112 treatment were shown . Immunohistochemistry shows that ( a ) the P15692 - specific contrast agent labels both proteoglycan - bound and unbound P15692 in the extracellular space and ( b ) the bound P15692 is released from the extracellular matrix in response to photodynamic therapy . In vivo competition experiments and quantitative pharmacokinetic model - based analysis confirmed the high specificity of the imaging strategy . CONCLUSION : This first report of in vivo quantitative optical molecular imaging - based monitoring of a secreted cytokine in tumors may have implications in providing tools for mechanistic investigations as well as for improved treatment design and merits further investigation .",
"Cutaneous thrombogenic vasculopathy associated with bevacizumab therapy . DB00112 , a humanized monoclonal antibody against vascular endothelial growth factor ( P15692 ) , is an angiogenesis inhibitor used to treat a variety of cancers , including lung , colon , cervical , ovarian , and renal cancers as well as glioblastoma . A significant adverse effect associated with its use is one of thromboembolic events . We report a case of a 74 - year - old male with diagnosis of glioblastoma multiforme treated with partial resection , radiation , temozolomide , and bevacizumab . He presented to a plastic surgeon with a several week history of asymptomatic crusted hemorrhagic ulcers and purpuric patches on the lower legs shortly following the initiation of bevacizumab . A biopsy showed an occlusive pauci - inflammatory thrombogenic vasculopathy associated with ischemic epidermal and dermal changes and accompanied by extensive vascular C5b - 9 ( complement C5b - 9 membrane attack complex ) deposition . DB00112 has been associated with thrombotic complications including atypical hemolytic uremic syndrome and arterial and venous thrombosis . C5b - 9 may be the factor most important in the mechanism of vascular thrombosis given the extent of deposition in our index case . Thrombotic events in the skin associated with bevacizumab therapy are without precedent and dermatologists should be aware of this potential complication .",
"Phase I trial of combretastatin A4 phosphate ( DB05284 ) in combination with bevacizumab in patients with advanced cancer . PURPOSE : The vascular disrupting agent ( VDA ) combretastatin A4 phosphate ( DB05284 ) induces significant tumor necrosis as a single agent . Preclinical models have shown that the addition of an anti - P15692 antibody to a VDA attenuates the revascularization of the surviving tumor rim and thus significantly increases antitumor activity . EXPERIMENTAL DESIGN : Patients with advanced solid malignancies received DB05284 at 45 , 54 , or 63 mg / m ( 2 ) on day 1 , day 8 , and then every 14 days . DB00112 10 mg / kg was given on day 8 and at subsequent cycles four hours after DB05284 . Functional imaging with dynamic contrast enhanced - Q9BWK5 ( DCE - Q9BWK5 ) was conducted at baseline , after DB05284 alone , and after cycle 1 DB05284 + bevacizumab . RESULTS : A total of 63 mg / m ( 2 ) DB05284 + 10 mg / kg bevacizumab q14 is the recommended phase II dose . A total of 15 patients were enrolled . Dose - limiting toxicities were grade III asymptomatic atrial fibrillation and grade IV liver hemorrhage in a patient with a history of hemorrhage . Most common toxicities were hypertension , headache , lymphopenia , pruritus , and pyrexia . Asymptomatic electrocardiographic changes were seen in five patients . Nine of 14 patients experienced disease stabilization . A patient with ovarian cancer had a Q8WXI7 response lasting for more than a year . DCE - Q9BWK5 showed statistically significant reductions in tumor perfusion / vascular permeability , which reversed after DB05284 alone but which were sustained following bevacizumab . Circulating P28906 (+) and CD133 (+) bone marrow progenitors increased following DB05284 as did P15692 and granulocyte colony - stimulating factor levels . CONCLUSIONS : DB05284 in combination with bevacizumab appears safe and well tolerated in this dosing schedule . DB05284 induced profound vascular changes , which were maintained by the presence of bevacizumab .",
"Expression of Q99572 receptor increases in vivo tumor growth . The Q99572 receptor is an DB00171 - gated ion channel known for its cytotoxic activity . However , recent evidence suggests a role for Q99572 in cell proliferation . Here , we found that Q99572 exhibits significant growth - promoting effects in vivo . Human embryonic kidney cells expressing Q99572 exhibited a more tumorigenic and anaplastic phenotype than control cells in vivo , and the growth rate and size of these tumors were significantly reduced by intratumoral injection of the Q99572 inhibitor - oxidized DB00171 . The accelerated growth of Q99572 - expressing tumors was characterized by increased proliferation , reduced apoptosis , and a high level of activated transcription factor O95644 . These tumors also showed a more developed vascular network than control tumors and secreted elevated amounts of P15692 . The growth and neoangiogenesis of Q99572 - expressing tumors was blocked by intratumoral injection of the P15692 - blocking antibody DB00112 ( bevacizumab ) , pharmacologic Q99572 blockade , or Q99572 silencing in vivo . Immunohistochemistry revealed strong Q99572 positivity in several human cancers . Together , our findings provide direct evidence that Q99572 promotes tumor growth in vivo .",
"Anti - P15692 therapy in pituitary carcinoma . We report the case of a 44 - year - old male patient with an aggressive silent corticotroph cell pituitary adenoma , subtype 2 . In that it progressed to carcinoma despite temozolomide administration , anti - P15692 therapy was begun . Q9BWK5 , PET scan and pathologic analysis were undertaken . After 10 months of anti - P15692 ( bevacizumab ) treatment no progression of the lesion was noted . The tumor was biopsied and morphological analysis showed severe cell injury , vascular abnormalities and fibrosis . DB00112 treatment has continued for additional 16 months to present with stabilization of disease as documented on serial Q9BWK5 and PET scans . This is the first case of a bevacizumab - treated pituitary carcinoma with long - term , now 26 months , control of disease . The present findings are promising in that anti - angiogenic therapy appears to represent a new option in the treatment of aggressive pituitary tumors .",
"Future directions in vascular endothelial growth factor - targeted therapy for metastatic colorectal cancer . DB00112 , the first approved vascular endothelial growth factor ( P15692 ) - targeted agent for metastatic colorectal cancer , continues to be developed in phase III trials in other tumor types . Its use is being explored not only in advanced disease , but also in earlier - stage disease in the adjuvant setting . Preclinical and clinical research is also addressing several potential strategies for maximizing the benefits of bevacizumab and other P15692 - targeted agents , including ( 1 ) dual inhibition of P15692 and platelet - derived growth factor signaling to target both the endothelial and the pericyte components of tumor vasculature ; ( 2 ) combining P15692 - targeted agents with other targeted agents , such as inhibitors of P04626 or epidermal growth factor receptor signaling , which affect several angiogenic pathways ; and ( 3 ) combining P15692 - targeted agents with low - dose , metronomic chemotherapy . The optimal dose and schedule of P15692 - targeted agents is another unanswered question . Further investigation of the mechanism of action and vascular effects of P15692 - targeted agents in humans will help to address these questions . Mechanistic studies in humans will be aided by the development and validation of surrogate clinical end points such as noninvasive assessment of hemodynamics and vascular changes within tumors , using imaging studies .",
"AAVrh . 10 - mediated genetic delivery of bevacizumab to the pleura to provide local anti - P15692 to suppress growth of metastatic lung tumors . Vascular endothelial growth factor ( P15692 ) produced by tumor cells has a central role in stimulating angiogenesis required for tumor growth . Humanized monoclonal anti - P15692 antibody ( bevacizumab , DB00112 ) , approved as a treatment for non - squamous , non - small cell lung cancer , requires administration every 3 weeks . We hypothesized that an intrapleural administration of an adeno - associated virus ( AAV ) vector expressing an anti - P15692 antibody equivalent of bevacizumab would result in sustained anti - P15692 localized expression within the lung and suppress metastatic tumor growth . The AAV vector AAVrh . 10alphaVEGF encodes the light chain and heavy chain complementary DNAs of monoclonal antibody A . 4 . 6 . 1 , a murine antibody that specifically recognizes human P15692 with the same antigen - binding site as bevacizumab . A metastatic lung tumor model was established in severe combined immunodeficient mice by intravenous administration of human DU145 prostate carcinoma cells . Intrapleural administration of AAVrh . 10alphaVEGF directed long - term expression of the anti - human P15692 antibody in lung , as shown by sustained , high - level anti - human P15692 titers in lung epithelial lining fluid for 40 weeks , which was the duration of the study . In the AAVrh . 10alphaVEGF - treated animals , tumor growth was significantly suppressed ( P < 0 . 05 ) , the numbers of blood vessels and mitotic nuclei in the tumor was decreased ( P < 0 . 05 ) and there was increased survival ( P < 0 . 05 ) . Thus , intrapleural administration of an AAVrh . 10 vector , encoding the murine monoclonal antibody equivalent of bevacizumab , effectively suppresses the growth of metastatic lung tumors , suggesting AAV - mediated gene transfer to the pleura to deliver bevacizumab locally to the lung as a novel alternative platform to conventional monoclonal antibody therapy .",
"The role of bevacizumab in the treatment of non - small cell lung cancer : current indications and future developments . The majority of non - small cell lung cancer ( NSCLC ) patients present with advanced disease , and despite the improvement in efficacy and safety outcomes with platinum - based chemotherapy , this standard cytotoxic approach has reached a therapeutic plateau , with the prognosis for this clinical condition remaining poor . Advances in the knowledge of tumor biology and mechanisms of oncogenesis have granted the singling out of several molecular targets for NSCLC treatment . DB00112 , an anti - growth factor vascular endothelial growth factor ( P15692 ) monoclonal antibody , is the antiangiogenic agent at the most advanced stage of development in the treatment of solid tumors and also in NSCLC treatment . DB00112 , combined with platinum - based chemotherapy , has been demonstrated to improve efficacy outcomes over chemotherapy alone in the treatment of nonsquamous advanced NSCLC in two phase III randomized trials . These represent the first evidence of improvement in treatment outcomes of chemotherapy with targeted therapies in the first - line treatment of advanced NSCLC . Future clinical developments of bevacizumab in NSCLC treatment will include the combination of this agent with other targeted therapies in advanced disease ( especially with erlotinib , an epidermal growth factor receptor tyrosine kinase inhibitor ) and the integration of this agent into combined modality approaches for the treatment of early - stage and locally advanced disease .",
"DB00112 treatment for human glioblastoma . Can it induce cognitive impairment ? Recent results from 2 double - blind , placebo - controlled phase III trials ( RTOG 0825 ) and ( AVAglio ) for first - line treatment of glioblastoma patients with the P15692 antibody bevacizumab , showed similar results , related to overall and progression - free survival . The RTOG 0825 trial indicated , opposed to the AVAglio trial , that patients treated with bevacizumab showed a decline in global neurocognitive function compared to untreated patients , - a decline that was most obvious after prolonged treatment . At present , there is a considerably controversy related to these observations . In the present work we point at the possibility that bevacizumab treatment of the normal brain can reduce synaptic plasticity in the hippocampus . We believe that such a phenomenon may partly explain the reduced cognitive function observed in patients in the RTOG 0825 trial . Since the same effects were not clearly defined in the AVAglio trial , further studies on putative neurocognitive effects after bevacizumab treatment are warranted .",
"Acceleration of clear cell renal cell carcinoma growth in mice following bevacizumab / DB00112 treatment : the role of CXCL cytokines . The anti - P15692 targeted antibody bevacizumab ( BVZ ) has been approved for treating renal cell carcinomas ( RCCs ) . Although BVZ increases the progression - free survival of patients with metastatic RCC , the effect on overall survival is poor . To gain insight into the limited efficacy of BVZ on overall survival , we analyzed patient samples of RCC for angiogenic factors that may participate in escape from anti - P15692 therapy . Our study shows that the level of vascular endothelial growth factor ( P15692 ) in tumors was increased compared with normal tissue . The level of interleukin - 8 / P10145 , a pro - angiogenic member of the CXCL family of cytokines , was also increased in tumors . These observations gave us a good reason to analyze the combined effects of BVZ and anti - P10145 antibodies on tumor growth . Surprisingly , we report that BVZ accelerates the growth of RCC in nude mice with in vivo selection of tumor cells with an increased growth capacity . Downregulation of receptor tyrosine phosphatase - κ , a phosphatase implicated in P01133 receptor regulation , may partly explain this phenomenon . Modification of the vascular network and development of lymphatic vessels through P49767 production and compensatory production of pro - angiogenic CXCL cytokines were also observed . The apparent normalization of the vascular network prompted us to associate BVZ with the chemotherapeutic agent paclitaxel . While efficient in vitro , paclitaxel did not reverse the anti - P15692 effects in vivo . Anti - P10145 - targeting antibodies were promising as they decreased intra - tumor P15692 production ; decreased the pro - angiogenic CXCL / anti - angiogenic CXCL ratio and did not induce lymphangiogenesis . These observations hold clinical implication as they highlight putative markers implicated in escape from BVZ treatment . They also recommend proceeding with caution in the use of anti - P15692 therapy alone for treatment of RCC .",
"Expression of vitamin D3 receptor and retinoid receptors in human breast cancer : identification of potential heterodimeric receptors . DB00169 ( VD ) and all - trans - retinoic acid ( ___MASK88___ ) have been postulated as a novel treatment option for breast carcinoma . Since the combined effects of retinoids and VD derivatives are attributed to heterodimeric interactions between members of the nuclear receptor family , the expression patterns of the heterodimers formed by vitamin D3 receptor ( P11473 ) and the retinoid receptors RARs ( P10276 , P10826 and P13631 ) and RXRs ( RXR - alpha , RXR - beta and RXR - gamma ) have been studied by immunohistochemistry in benign and malignant breast tissues . Present results revealed that immunoexpressions to all receptor types studied were higher in both in situ and infiltrative carcinomas than in benign breast diseases . In a variable number of cases of infiltrative carcinoma , immunostaining appeared in the nucleus , whereas in the other two disorders immunostaining was only cytoplasmic . The correlation established between P11473 and the different isoforms of retinoid receptors revealed that P11473 seems to select mainly P10276 to form heterodimers and to exert their properties as transcription factor . The results of this study suggest that this heterodimer plays a critical role in cancer malignancy , and its presence indicates those patient groups presenting a better response to adjuvant therapies based on the combination of vitamin D and ___MASK88___ .",
"[ ___MASK64___ sodium ( Photofrin - II ) ] . ___MASK64___ sodium ( ___MASK64___ ) is a photosensitizer which distributes selectively to tumor tissues , and causes tumor cell death by combination with light irradiation . Photodynamic therapy ( PDT ) by combination of porfimer sodium and laser was developed as a new cancer therapy . Tumor selectivity of porfimer sodium are based on the following reasons ; 1 ) high affinity for lipoprotein , especially , low density lipoprotein ( LDL ) , 2 ) elevation of P01130 activity in cancer tissue , and 3 ) lack or imcompleteness of lymphatic system in cancer tissue . ___MASK64___ sodium is activated by laser irradiation at 630 nm , which can reacts with tissue oxygen to produce highly reactive excited siglet oxygen ( 1O2 ) . This highly reactive molecule is subsequently capable of killing tumor cells through oxidation of cellular component like mitochondrial enzymes . In addition , this highly reactive intermediate causes destruction of the tumor capillaries , which accelerates tumor cell death . The growth suppression or lethal damage to tumor cells by PDT of porfimer sodium and excimer dye laser were observed in experimental tumor models . In human clinical trials , the rates of complete response ( CR ) for roentgenographically occult lung cancer , stage I lung cancer , superficial esophageal cancer , superficial gastric cancer and carcinoma in situ or dysplasia of the cervix were 84 . 8 % , 50 . 0 % , 90 . 0 % , 87 . 5 % and 94 . 4 % , respectively . The major side effects were cutaneous symptoms e . g . photosensitivity , pigmentation , increasing GOT , GPT but these symptoms were not severe . PDT using porfimer sodium and excimer dye laser must be clinically useful for the treatment of inoperable early cancer or conservation of organ functions .",
"Synergy of nab - paclitaxel and bevacizumab in eradicating large orthotopic breast tumors and preexisting metastases . INTRODUCTION : Patients with metastatic disease are considered incurable . We previously showed that nabpaclitaxel ( nanoparticle albumin - embedded paclitaxel ) combined with anti - vascular endothelial growth factor A ( P15692 ) antibody , bevacizumab , eradicates orthotopic small - sized breast tumors and metastasis . Here , we assessed this therapy in two models of advanced ( 450 - 600 mm ( 3 ) ) breast tumors and delineated P15692 - dependent mechanisms of tumor resistance . METHODS : Mice with luciferase - tagged advanced MDA - MB - 231 and MDA - MB - 435 tumors were treated with saline , nab - paclitaxel ( 10 or 30 mg / kg ) , bevacizumab ( 4 mg / kg ) , or combined drugs . Lymphatic and lung metastases were measured by luciferase assay . Proinflammatory and survival pathways were measured by ELISA , Western blot and immunohistochemistry . RESULTS : Nab - paclitaxel transiently suppressed primary tumors by 70 % to 90 % but had no effect on metastasis . Coadministration of bevacizumab increased the response rate to 99 % , including 71 % of complete responses in MDA - MB - 231 - bearing mice treated concurrently with 30 mg / kg of nab - paclitaxel . This combinatory regimen significantly reduced or eliminated preexisting lymphatic and distant metastases in MDA - MB - 231 and MDA - MB - 435 models . The mechanism involves paclitaxel - induced NF - κB pathway that upregulates P15692 and other tumor prosurvival proteins . CONCLUSIONS : DB00112 prevents tumor recurrence and metastasis promoted by nab - paclitaxel activation of NF - κB pathway . Combination therapy with high - dosed nab - paclitaxel demonstrates the potential to eradicate advanced primary tumors and preexisting metastases . These findings strongly support translating this regimen into clinics .",
"Targeted approaches for treating advanced clear cell renal carcinoma . The mainstay of any curative treatment in renal cell carcinoma ( RCC ) is surgery . In the case of metastatic disease at presentation , a radical nephrectomy is recommended to good performance status patients prior to the start of cytokine treatment . Interferon ( IFN ) - a offers in a small but significant percentage of patients advantage in overall survival . Interleukin ( IL ) - 2 - based therapy gives similar survival rates . To date , hormonal therapy and chemotherapy do not have a proven impact on survival . Recent insights demonstrate that the majority of clear cell RCC harbor abnormalities of the von Hippel - Lindau ( P40337 ) gene . This gene plays a key role in the stimulation of angiogenesis by vascular endothelial growth factor ( P15692 ) in this highly vascularized tumor . This opens interesting new treatment strategies including blockade of P15692 with the monoclonal antibody bevacizumab ( DB00112 ) and inhibition of P15692 receptor tyrosine kinases with small oral molecules such as sunitinib ( SU11248 , Sutent ) or PTK787 . Likewise , inhibition of the Raf kinase pathway with oral sorafenib ( Bay 43 - 9006 , Nexavar ) or inhibition of the P42345 pathway with intravenous CCI - 779 are under investigation . Preliminary clinical results with all these compounds are promising , and the results of ongoing first - line phase III studies will become available in the next years .",
"Vascular endothelial growth factor ( P15692 ) as a target of bevacizumab in cancer : from the biology to the clinic . Angiogenesis is important in the growth and progression of solid tumours . The main pro - angiogenic factor , namely vascular endothelial growth factor ( P15692 ) , also known as vascular permeability factor , is a potent angiogenic cytokine that induces mitosis and also regulates the permeability of endothelial cells . The soluble isoform of P15692 is a dimeric glycoprotein of 36 - 46 kDa , induced by hypoxia and oncogenic mutation and it binds to two specific tyrosine - kinase receptors : P15692 - 1 ( flt - 1 ) and P15692 - 2 ( P35968 / flk1 ) . An increase in P15692 expression in tumour tissue or some blood compartments ( i . e . serum or plasma ) has been found in solid and haematological malignancies of various origins and is associated with metastasis formation and poor prognosis . DB00112 , a recombinant humanised monoclonal antibody developed against P15692 , binds to soluble P15692 , preventing receptor binding and inhibiting endothelial cell proliferation and vessel formation . Pre - clinical and clinical studies have shown that bevacizumab alone or in combination with a cytotoxic agent decreases tumour growth and increases median survival time and time to tumour progression . DB00112 is the first anti - angiogenetic treatment approved by the American Food and Drug Administration in the first - line treatment of metastatic colorectal cancer . It has shown preliminary evidence of efficacy for breast , non - small - cell lung , pancreatic , prostate , head and neck and renal cancer as well as haematological malignancies . Common toxicities associated with bevacizumab include hypertension , proteinuria , bleeding episodes and thrombotic events . This review summarises the critical role of P15692 and discusses the data available on bevacizumab , from the humanisation of its parent murine monoclonal antibody ( mAb ) A . 4 . 6 . 1 to its use in cancer clinical trials .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK18___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer . Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer , but the clinical benefits are usually transitory . The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab . For this , angiogenesis - focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control . Reverse transcription - PCR was used for results validation . The insulin growth factor 1 ( DB01277 ) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab . Cixutumumab was used to block DB01277 signaling in vivo . Dual anti - P15692 and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth . Immunohistochemistry measured multivessel density , Akt activation , and cell proliferation , whereas terminal deoxynucleotidyl transferase - mediated dUTP nick end labeling ( TUNEL ) assay measured apoptosis in ovarian cancer xenografts . DB00112 and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway . The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone . In summary , DB01277 activation represents an important mechanism of adaptive escape during anti - P15692 therapy in ovarian cancer . This study provides the rationale for designing bevacizumab - based combination regimens to enhance antitumor activity .",
"P01308 secretory defects and impaired islet architecture in pancreatic beta - cell - specific P40763 knockout mice . Normal islet formation and function depends on the action of various growth factors operating in pre - and postnatal development ; however , the specific physiological function of each factor is largely unknown . Loss - of - function analyses in mice have provided little information so far , perhaps due to functional redundancies of the growth factors acting on the pancreas . The present study focuses on the role of the transcription factor P40763 in insulin - producing cells . P40763 is one of the potential downstream mediators for multiple growth factors acting on the pancreatic beta - cells , including betacellulin , hepatocyte growth factor , growth hormone , and heparin - binding P01133 - like growth factor . To elucidate its role in the beta - cells , the P40763 gene was disrupted in insulin - producing cells in mice ( P40763 - insKO ) , using a cre - mediated gene recombination approach . Unexpectedly , P40763 - insKO mice exhibited an increase in appetite and obesity at 8 weeks of age or older . The mice showed partial leptin resistance , suggesting that expression of the RIP ( rat insulin promoter ) - cre transgene in hypothalamus partially inhibited the appetite - regulating system . Intraperitoneal glucose tolerance tests , performed in non - obese 5 - week - old mice , showed that the P40763 - insKO mice were glucose intolerant . Islet perifusion experiments further revealed a deficiency in early - phase insulin secretion . Whereas islet insulin content or islet mass was not affected , expression levels of P11168 , Q09428 , and P15692 were significantly reduced in P40763 - insKO islets . Interestingly , P40763 - insKO mice displayed impaired islet morphology : alpha - cells were frequently seen in central regions of islets . Our present observations demonstrate a unique role of P40763 in maintaining glucose - mediated early - phase insulin secretion and normal islet morphology .",
"Current opinion on bevacizumab on endometrial cancer treatment . INTRODUCTION : Advanced or recurrent endometrial cancer is still a challenge for clinicians as it has a poor prognosis despite treatment efforts . Thus , there is an urgent need for new agents with activity in this subset of patients . The increased knowledge of the molecular aspects of endometrial carcinogenesis has led to the development of molecular targeted therapies and in particular anti - angiogenic drugs . One of the most promising of these agents is bevacizumab , a recombinant humanized immunoglobulin monoclonal antibody to P15692 . AREAS COVERED : The objective of this paper is to discuss the role of angiogenesis in endometrial cancer and analyze the rational of bevacizumab use , alone or in combination with other therapies , in endometrial cancer patients . We reviewed the most important preclinical and clinical studies published on this topic up to March 2014 . EXPERT OPINION : DB00112 in combination with others targeted therapies , chemotherapy or radiotherapy demonstrated promising anti - tumor activity . Despite the good oncological outcomes of these recent clinical experiences , caution must be used in light of significant toxicity reported in this subset of heavily pre - treated patients . The identification of biomarkers able to predict either the efficacy or toxicity of anti - angiogenic drugs is a compelling need .",
"Vascular endothelial growth factor signaling is required for the behavioral actions of antidepressant treatment : pharmacological and cellular characterization . This study extends earlier work on the role of vascular endothelial growth factor ( P15692 ) in the actions of antidepressant treatment in two key areas . First , by determining the requirement for P15692 in the actions of a 5 - HT selective reuptake inhibitor ( SSRI ) , fluoxetine in behavioral models of depression / antidepressant response ; and second , by examining the role of the P08908 receptor subtype in the regulation of P15692 , and the cellular localization of antidepressant regulation of P15692 expression . The results show that pharmacological inhibition of P15692 receptor signaling blocks the behavioral actions of fluoxetine in rats subjected to chronic unpredictable stress . Infusions of SU5416 or SU1498 , two structurally dissimilar inhibitors of P15692 - Flk - 1 receptor signaling , block the antidepressant effects of fluoxetine on sucrose preference , immobility in the forced swim test , and latency to feed in the novelty suppressed feeding paradigm . We also show that activation of P08908 receptors is sufficient to induce P15692 expression and that a P08908 antagonist blocks both the increase in P15692 and behavioral effects induced by fluoxetine . Finally , double labeling studies show that chronic fluoxetine administration increases P15692 expression in both neurons and endothelial cells in the hippocampus . Taken together these studies show that P15692 is necessary for the behavioral effects of the SSRI fluoxetine , as well as norepinephrine selective reuptake inhibitor , and that these effects may be mediated by P08908 receptors located on neurons and endothelial cells .",
"Identification of microRNAs involved in the modulation of pro - angiogenic factors in atherosclerosis by a polyphenol - rich extract from propolis . New vessel formation plays a critical role in the progression and vulnerability of atherosclerotic lesions . It has been shown that polyphenols from propolis attenuate the progression of atherosclerosis and also exert inhibitory effects on angiogenic factors . However , the mechanisms underlying these effects are not completely understood . Thus , this study aimed to identify microRNAs ( miRNAs ) involved in the modulation of pro - angiogenic factors in the atherosclerotic plaques of P01130 gene knockout mice treated with a polyphenol - rich extract of Chilean propolis . The progression of the atherosclerotic lesions was significantly attenuated in treated mice compared with control mice . Using microarray analysis and a bioinformatic approach , we identified 29 differentially expressed miRNAs . Many of these miRNAs were involved in biological processes associated with angiogenesis , such as the cell cycle , cell migration , cell growth and proliferation . Among them , three miRNAs ( miR - 181a , miR - 106a and miR - 20b ) were over - expressed and inversely related to the expression of Vegfa ( vascular endothelial growth factor A ) and Hif1a ( hypoxia inducible factor 1 alpha ) . In addition , P15692 protein expression was attenuated in histological sections obtained from the aortic sinuses of treated mice . P15692 is a key pro - angiogenic factor in atherosclerotic plaques , and Hif1a , which is expressed in the necrotic nucleus of the atheroma , is its main inducer . We found a correlation between the over - expression of miR - 181a , miR - 106a and miR - 20b and their target genes , Hif1a and Vegfa , which is consistent with attenuation of the atherosclerotic lesion . In conclusion , our data analysis provides evidence that the anti - angiogenic effects of polyphenols from Chilean propolis can be modulated by miRNAs , in particular miR - 181a , miR - 106a and miR - 20b .",
"Phase I safety and pharmacokinetic study of bevacizumab in Chinese patients with advanced cancer . BACKGROUND : bevacizumab is a humanized recombinant vascular endothelial growth factor ( P15692 ) monoclonal antibody , which specifically binds to P15692 and inhibits tumor cell growth , proliferation and metastasis . We aimed to investigate the safety and pharmacokinetics of bevacizumab in Chinese patients with advanced cancer . METHODS : Thirty - nine Chinese patients with metastatic or relapsed cancers who failed prior therapy were enrolled in this phase I study of bevacizumab . DB00112 was infused by a calculated pump at doses from 5 mg / kg to 15 mg / kg in 90 minutes . Patients underwent serial pharmacokinetic evaluations . Patients that received at least one infusion of bevacizumab were included in the safety study . RESULTS : Thirty - five patients finished all 5 infusions following protocol . One patient withdrew after 3 infusions due to grade 3 proteinuria . Common adverse events possibly related to the study drug were proteinuria ( 17 / 39 , 43 . 6 % ) , hypertension ( 13 / 39 , 33 . 3 % ) , gingival bleeding ( 7 / 39 , 17 . 9 % ) , epistaxis ( 6 / 39 , 15 . 4 % ) , pharyngeal inflammation ( 6 / 39 , 15 . 4 % ) , fatigue ( 6 / 39 , 15 . 4 % ) and stomatitis ( 4 / 39 , 10 . 3 % ) . DB00112 pharmacokinetics was linear within the range of 5 mg / kg q2w -- 10 mg / kg q2w and 15 mg / kg q3w . CL ( clearance ) , Vd ( volume of distribution at elimination ) and Vss ( volume of distribution at steady state ) were similar after single and multiple doses at 5 , 10 and 15 mg / kg . CONCLUSIONS : DB00112 is well tolerated in Chinese patients . No unexpected adverse events were observed . There is no racial difference in the pharmacokinetics .",
"4 -[ 3 , 5 - Bis ( trimethylsilyl ) benzamido ] benzoic acid inhibits angiogenesis in colon cancer through reduced expression of vascular endothelial growth factor . 4 -[ 3 , 5 - bis ( trimethylsilyl ) benzamido ] Benzoic acid ( TAC - 101 ) has potent antiproliferative , antiangiogenic , and antitumor effects in vitro and in vivo . These effects might be due to TAC - 101 binding to retinoic acid receptor alpha ( P10276 ) and interfering with the binding of activator protein - 1 ( AP - 1 ) to DNA . However , little is known about the detailed mechanism of TAC - 101 function . We investigated the mechanism of the antiangiogenic effect of TAC - 101 using a rat hepatic metastatic model in vivo and DLD - 1 human colon cancer cells in vitro . Liver metastases were induced by portal injection of Q15293 - 9 rat colonic cancer cells into F344 rats . TAC - 101 ( 8 mg / kg ) was orally administered 5 days per week for 4 weeks and then hepatic tumors were immunohistochemically evaluated for microvessel density ( P53602 ) and vascular endothelial growth factor ( P15692 ) . TAC - 101 significantly reduced both P53602 and P15692 expression . Northern blot analysis and ELISA indicated that TAC - 101 efficiently inhibited production of P15692 mRNA and protein in DLD - 1 cells in a time - and dose - dependent manner . These findings suggest that TAC - 101 may inhibit progression and metastasis in colon cancer by interfering with tumor production of P15692 .",
"Global reported endophthalmitis risk following intravitreal injections of anti - P15692 : a literature review and analysis . PURPOSE : To report on endophthalmitis occurrence and associated risk factors following the intravitreal injection of anti - P15692 agents based on a review of published literature . MATERIALS AND METHODS : A Medline search was performed using the terms \" bevacizumab \" and \" ranibizumab \" . A total of 534 English - language articles of varying design and published from 2006 to November 2013 were analyzed for endophthalmitis occurrence and contributing perioperative factors . RESULTS : A total of 445 , 503 injections were counted . There were 103 cases of postinjection endophthalmitis in 176 , 124 injections ( 0 . 058 % ) with bevacizumab ( DB00112 ) versus 79 cases in 269 , 379 injections ( 0 . 029 % ) with ranibizumab ( Lucentis ) . This difference was due to a significantly higher occurrence of culture - negative endophthalmitis associated with bevacizumab injections . Culture - positive risk was not statistically different between the two drugs . The reported use of postinjection topical antibiotics increased the risk of culture - positive endophthalmitis . No association was found with the use of povidone iodine , a lid speculum , a mask , or an operating room . Streptococcus spp . were the most prevalent causative organism , accounting for nine of 54 ( 17 % ) of all culture - positive cases . CONCLUSION : Reported postinjection endophthalmitis occurred significantly more in patients treated with bevacizumab than those treated with ranibizumab . However , culture - positive occurrence was similar . Despite the potential for contamination at the time of drug compounding , bevacizumab does not appear to confer a higher risk of culture - positive endophthalmitis than ranibizumab . This study also suggests antibiotic use may increase endophthalmitis occurrence .",
"Preclinical evaluation of holmium - 166 labeled anti - P15692 ( DB00112 ) . Radiolabeled antiangiogenic monoclonal antibodies are potential agents for targeted therapy in specific types of malignancies . In this study , ( 166 ) Ho - DOTA - DB00112 was used in biodistribution studies using single - photon emission computed tomography ( SPECT ) to acquire dosimetric aspects of the radiolabeled antibody in mice . The liver toxicity of the radiolabeled antibody was also determined using serum glutamic pyruvic transaminase , serum glutamic oxaloacetic transaminase and alkaline phosphatase assay 2 - 7 days post - injection . The SPECT biodistribution demonstrated a similar pattern as the other radiolabeled anti - vascular endothelial growth factor A ( P15692 ) immunoconjugates . ( 166 ) Ho - DOTA - DB00112 was revealed as a potential compound for therapy / imaging of P15692 expression in oncology .",
"[ DB00112 and invasive procedures : practical recommendations ] . As first line chemotherapy DB00112 , associated with a platinum based regime , improves survival in patients with metastatic , non small cell , non epidermoid bronchial carcinoma . Marketing authorization for this indication was obtained in 2007 . This treatment produces specific secondary effects related to its anti - angiogenic action . Physiologically , vascular endothelial growth factor ( P15692 ) is important in the process of scar formation . DB00112 inhibits scar formation and may encourage bleeding . The aim of this article is to analyse the specific risks associated with invasive procedures and to produce practical recommendations . Unfortunately there are few data in the literature . We depend , therefore , principally on studies of neo - adjuvant chemotherapy in metastatic colo - rectal cancer prior to excision of hepatic metastases and on our own experience of excision of pulmonary metastases from solid tumours treated with bevacizumab . We recommend a delay of 2 days between implantation of an intravenous device and the initiation of bevacizumab , a delay of at least 5 weeks between the last injection of bevacizumab and invasive surgery and a delay of 4 weeks between surgery and the initiation of bevacizumab treatment . Obviously , referral to a medico - surgical team experienced in the management of these patients is strongly recommended .",
"Accomplishments in 2008 in the treatment of advanced metastatic colorectal cancer . Overview of the Disease IncidencePredictive BiomarkersCurrent General Therapy StandardsAccomplishments During the Year Combined Modality Management of Liver MetastasesTreatment of Advanced Disease Equivalence of FOLFOX and CAPOXAddition of DB00112 to Standard ChemotherapyDual P00533 and P15692 InhibitionBevacizumab Upon Progression While on First - Line TherapyBenefit in the Elderly PopulationWhat Needs to be Done Comments on ResearchObstacles to Progress .",
"Synthesis and evaluation of ( 99m ) Tc chelate - conjugated bevacizumab . Vascular endothelial growth factor ( P15692 ) is one of the classic factors involved in tumor - induced angiognesis in several solid tumors . DB00112 , a monoclonal antibody against P15692 , can be used as an imaging tool in preclinical studies . The aim of this study was to radiolabel DB00112 with ( 99m ) Tc and to evaluate in vivo its imaging properties in an adenocarcinoma animal model . For this purpose , DB00112 was derivatized with Suc - HYNIC as a bifunctional coupling agent . A mixture of Tricine / SnCl ( 2 ). 2H ( 2 ) O was added to DB00112 - HYNIC and radiolabeled with ( 99m ) TcO ( 4 )(-) . The radiochemical stability of the radiolabeled antibody was assessed . Biodistribution and scintigraphy imaging were performed in normal CD1 female mice and in spontaneous adenocarcinoma tumor bearing CD1 mice ( n = 5 ) . We demonstrated that 99mTc - HYNIC - DB00112 was stable . In vivo biodistribution studies revealed that tumor uptake of ( 99m ) Tc - HYNIC - DB00112 was 1 . 37 ± 0 . 51 % and 5 . 33 ± 2 . 13 % at 4 and 24 h postinjection , respectively . Scintigraphy image studies showed tumor selective uptake of ( 99m ) Tc - HYNIC - DB00112 in the tumor - bearing mice . We conclude that ( 99m ) Tc - HYNIC - Bevacizumb has the potential to be used as a tracer for tumor imaging in preclinical studies .",
"Next generation molecular targeted agents for breast cancer : focus on P00533 and VEGFR pathways . Here we reviewed the recent progress of molecular targeting drugs , including trastuzumab , lapatinib , erlotinib and bevacituzumab . Fortunately , Her - 2 positive cases of metastatic or relapsed cases , those with the worse prognosis , are responsive to trastuzumab - based chemotherapy . ___MASK35___ will likely be effective against trastuzumab - resistant cases and brain metastases . Furthermore , the introduction of bevacituzumab will improve P15692 - VEGFR - associated tumor growth .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK43___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK19___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"[ Tumor vasculature as a therapeutic target in non - small cell lung cancer ] . Despite developments in conventional ( chemo ) radiotherapy and surgery , survival of non - small cell lung cancer ( NSCLC ) patients remains poor . Treatments with targeted molecular drugs offer novel therapeutic strategies . DB00112 , a recombinant anti - vascular endothelial growth factor ( P15692 ) antibody , is the antiangiogenic drug at the most advanced stage of development in the therapy of NSCLC . However , a number of questions and future challenges relating to the use of bevacizumab in NSCLC remain . Furthermore , novel agents targeting the pre - existing NSCLC vasculature ( i . e . vascular disrupting agents , VDAs ) or multiple tyrosine kinase inhibitors have emerged as unique drug classes delivering promising results in several preclinical and clinical studies . Herein , we review the most recent data using these novel targeted agents either alone or in combination with chemotherapy in NSCLC .",
"Vascular endothelial growth factor in fellow eyes of eyes injected with intravitreal bevacizumab . BACKGROUND : To study the effect on untreated fellow eyes of eyes treated with an intravitreal injection of bevacizumab . METHODS : DB00112 ( 1 . 25 mg / 0 . 05 ml ) was injected into the vitreous cavity of one eye ( the first eye ) as a preoperative adjunctive therapy for proliferative diabetic retinopathy ; vitrectomy was performed 1 week later . Immediately after vitrectomy , bevacizumab ( 1 . 25 mg / 0 . 05 ml ) was injected into the fellow eye ( the second eye ) followed by vitrectomy 1 week later . Aqueous humor samples were obtained from both eyes in five cases just before intravitreal injection of bevacizumab and just before vitrectomy 1 week later . Vascular endothelial growth factor ( P15692 ) concentrations in the aqueous humor were measured by enzyme - linked immunosorbent assay ( ELISA ) . RESULTS : P15692 concentrations in the aqueous humor of the first eyes ranged from 146 to 398 pg / ml ( mean , 302 +/- 100 pg / ml ) before intravitreal injection of bevacizumab ; 1 week later , the P15692 concentrations in the injected eyes were less than 31 pg / ml , the lower limit of the ELISA , in all cases ( p < 0 . 001 ) . The concentrations in the uninjected fellow eyes ranged from 181 to 551 pg / ml ( mean , 382 +/- 119 pg / ml ) . CONCLUSIONS : There seemed to be no or a minimal effect of the intravitreal injections of bevacizumab on the uninjected fellow eyes ."
] |
[
"___MASK18___",
"___MASK19___",
"___MASK35___",
"___MASK43___",
"___MASK51___",
"___MASK54___",
"___MASK64___",
"___MASK75___",
"___MASK88___"
] |
___MASK18___
|
MH_train_476
|
interacts_with DB01278?
|
[
"Biomarkers for assessing therapeutic response in bladder cancer . Reliable markers for assessing therapeutic response are needed to select the most effective treatment strategy for bladder cancer patients . We analyzed the role of biomarkers predicting response of non - muscle invasive bladder cancer ( NMIBC ) on BCG induction , and of non - organ confined muscle invasive bladder cancer ( MIBC ) on neoadjuvant chemotherapy . A critical , non - structured review of the literature was conducted . For assessing BCG therapy outcome , measurement of urinary P60568 levels seems to be the most potent marker of all the clinical parameters reviewed . Measurements of urinary interleukins P10145 , Q14116 , and tumour necrosis factor apoptosis - inducing ligand levels seem promising as well . Immunohistochemical markers ( ie , P04637 , Ki - 67 , and Rb ) display contradictory results and seem unsuitable . Gene polymorphisms need to be studied more thoroughly before their clinical relevance can be determined . Regarding assessing and predicting response of MIBC to neoadjuvant chemotherapy , a set of potent markers has been studied . However , no conclusive evidence is yet available on their additional value over the established clinicopathological variables . Prospective trials are needed to validate the clinical benefit of molecular markers to predict response to BCG ( NMIBC ) and neoadjuvant chemotherapy ( MIBC ) before predictive biomarkers can become part of clinical practice .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK26___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"___MASK20___ inhibits the activation of P09619 β - expressing astrocytes in the brain metastatic microenvironment of breast cancer cells . Brain metastases occur in more than one - third of metastatic breast cancer patients whose tumors overexpress P04626 or are triple negative . Brain colonization of cancer cells occurs in a unique environment , containing microglia , oligodendrocytes , astrocytes , and neurons . Although a neuroinflammatory response has been documented in brain metastasis , its contribution to cancer progression and therapy remains poorly understood . Using an experimental brain metastasis model , we characterized the brain metastatic microenvironment of brain tropic , P04626 - transfected MDA - MB - 231 human breast carcinoma cells ( 231 - BR - P04626 ) . A previously unidentified subpopulation of metastasis - associated astrocytes expressing phosphorylated platelet - derived growth factor receptor β ( at tyrosine 751 ; p751 - P09619 β ) was identified around perivascular brain micrometastases . p751 - P09619 β (+) astrocytes were also identified in human brain metastases from eight craniotomy specimens and in primary cultures of astrocyte - enriched glial cells . Previously , we reported that pazopanib , a multispecific tyrosine kinase inhibitor , prevented the outgrowth of 231 - BR - P04626 large brain metastases by 73 % . Here , we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment . ___MASK20___ treatment resulted in 70 % ( P = 0 . 023 ) decrease of the p751 - P09619 β (+) astrocyte population , at the lowest dose of 30 mg / kg , twice daily . Collectively , the data identify a subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib , suggesting its potential to prevent the development of brain micrometastases in breast cancer patients .",
"Sex steroid receptors , secondary bile acids and colorectal cancer . A possible mechanism of interaction . AIM : The aim of the work was to study in colon - rectum cancer mucosae the binding charateristics , as sex steroid receptors . METHODS : Specific androgen ( AR ) , estrogen ( ER ) and progesterone ( PgR ) receptors were measured in the tissue samples of 35 patients ( 15 males , 20 females ) undergoing colectomy or coloproctectomy for adenocarcinoma . The characteristics of androgen receptor ( AR , DB02901 - R : dihydrotestosterone receptor ) were also investigated using competitive activity of cyproterone acetate , cortisol , aldosterone and steroid - like substances such as deoxycholic and lithocholic acid , present in the milieu of the considered organ . Binding assays and competition tests were conducted using a charcoal dextran method . RESULTS : When present ( 50 % ) , ER and PgR receptors showed very low levels and no difference was noted between cancerous and the surrounding healthy mucosa . AR were found in all samples from both neoplastic and non neoplastic surrounding mucosa , with no significant difference . P10275 however exhibited an altered binding activity in cancer specimens . ___MASK93___ did not displace DB02901 from AR while significant displacing activity was elicited by DB02901 , testosterone , as well as by lithocholic acid , but not by deoxycholic acid . CONCLUSION : In cancerous large bowel mucosa , androgen receptors show altered binding characteristics . The selective binding of lithocholic acid to AR supports the hypothesis that diet - related endoluminal substances may play a role in cancer development model where molecular alterations such as DNA damage or mutation is the 1st event .",
"Genomic instability and poor prognosis associated with abnormal P04637 in breast carcinomas . Molecular and immunohistochemical analysis . Alterations of the P04637 gene were analyzed in samples from 87 primary breast cancer patients , using molecular and immunohistochemical approaches . Mutations were detected in 17 % of the samples , using polymerase chain reaction ( PCR ) and constant denaturant gel electrophoresis ( CDGE ) on exons 5 - 8 of the P04637 gene , and were confirmed by sequencing . Abnormal P04637 protein staining was found in 55 % of the primary samples , using the monoclonal P04637 antibody DO7 . A statistically significant association was found between P04637 mutations and abnormal protein staining ( p = 0 . 002 ) . Our results suggest that dysfunction of the P04637 protein is associated with tumor progression , as we found an association between P04637 abnormalities and accumulation of genetic lesions , measured as overall allelic imbalance ( AI ) , homogeneously staining regions ( HSR ) and strong P04626 overexpression . Furthermore , patients with P04637 mutation had a highly elevated risk of dying from breast cancer during the study period ( p < 0 . 001 , RR = 10 . 68 ) at a median follow - up time of 42 months . Abnormal P04637 staining was much more frequent than the mutations , but it was not of prognostic significance , whereas strong staining was an independent prognostic factor . We therefore conclude that loss of functional P04637 leads to genetic instability , resulting in poorer short - term prognosis , and that only strong staining of P04637 , and not abnormal protein staining in general , is of prognostic significance .",
"Serotonergic mechanisms in human allergic contact dermatitis . Expression of serotonin ( 5 - hydroxytryptamine ; 5 - HT ) , 5 - HT receptors 1A ( 5 - HT1AR ) and 2A , and serotonin transporter protein ( P31645 ) was studied in positive epicutaneous reactions to nickel sulphate in nickel - allergic patients , at 72 h post - challenge with the antigen . In addition , the effects of 5 - HT2AR agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , and the selective serotonin reuptake inhibitors ( SSRIs ) citalopram and fluoxetine , were tested on nickel - stimulated peripheral blood mononuclear cells from nickel - allergic patients , regarding their proliferation and interleukin ( IL ) - 2 production , as well as the effect of these SSRIs on a murine Langerhans ' cell - like line ( XS52 ) , regarding its IL - 1beta production . Serotonin - positive platelets were increased in the inflamed skin compared with control skin . A decrease ( p < 0 . 01 ) in 5 - HT1AR - positive mononuclear cells was evident in the eczematous skin compared with control skin , whereas 5 - HT2AR - and P31645 - positive cells were increased ( p < 0 . 001 for both ) in the eczematous skin . Treatment of nickel - stimulated peripheral blood mononuclear cells with 5x10 (- 5 ) mol / l of DOI inhibited ( p < 0 . 01 ) the proliferation of nickel - stimulated peripheral blood mononuclear cells , while no effect was found regarding P60568 production . ___MASK82___ at 10 (- 6 ) mol / l tended to inhibit the production of IL - 1beta by the XS52 cell line . These results indicate the implication of the serotonergic system in the contact allergic reaction .",
"P10275 - induced tumor suppressor , B2CW77 , inhibits breast cancer growth and transcriptionally activates p53 / p73 - mediated apoptosis in breast carcinomas . P10275 ( AR ) expression by immunohistochemistry correlates with better prognosis and survival among breast cancer patients . We and others have shown that AR inhibits proliferation and induces apoptosis in breast cancer cells . However , the mechanism of AR ' s anti - tumor effect in breast cancer is still not fully understood . Our recent study indicates that AR upregulates expression of tumor suppressor gene P60484 by promoter activation in breast cancer . B2CW77 , encoding B2CW77 protein , is a newly identified gene , which shares a bidirectional promoter with P60484 and is transcribed in the opposite direction . So far , the function of B2CW77 has never been studied in tumorigenesis . Here , we define B2CW77 as a tumor suppressor in breast carcinomas , which inhibits tumor growth and invasiveness . After analyzing 188 normal breast and 1247 malignant breast cancer tissues , we observed the loss of B2CW77 in multiple breast cancer subtypes and this decreased B2CW77 expression associates with tumor progression and increasing histological grade in invasive carcinomas . We characterize B2CW77 , for the first time , as a transcription factor , directly promoting the expression of P04637 and O15350 , with consequent elevated apoptosis and cell cycle arrest in breast cancer cells . We demonstrate , in vitro and in murine xenograph models , that both B2CW77 and P60484 are AR - target genes , mediating androgen - induced growth inhibition and apoptosis in breast cancer cells . Our observations suggest that B2CW77 might be used as a potential prognostic marker and novel therapy target for breast carcinomas .",
"P35367 antagonist cetirizine impairs working memory processing speed , but not episodic memory . BACKGROUND AND PURPOSE : The histaminergic neurotransmitter system is currently under investigation as a target for drug treatment of cognitive deficits in clinical disorders . The therapeutic potential of new drugs may initially be screened using a model of histaminergic dysfunction , for example , as associated with the use of centrally active antihistamines . Of the selective second generation antihistamines , cetirizine has been found to have central nervous system effects . The aim of the present study was to determine whether cetirizine can be used as a tool to model cognitive deficits associated with histaminergic hypofunction . EXPERIMENTAL APPROACH : The study was conducted according to a three - way , double - blind , cross - over design . Treatments were single oral doses of cetirizine 10 and 20 mg and placebo . Effects on cognition were assessed using tests of word learning , memory scanning , vigilance , divided attention , tracking and visual information processing speed . KEY RESULTS : ___MASK29___ 10 mg impaired tracking performance and both doses impaired memory scanning speed . None of the other measures indicated impaired performance . CONCLUSION AND IMPLICATIONS : ___MASK29___ affects information processing speed , but these effects were not sufficient to serve as a model for cognitive deficits in clinical disorders .",
"P10997 - driven metabolic reprogramming induces regression of p53 - deficient tumours in vivo . P04637 is commonly altered in human cancer , and Tp53 reactivation suppresses tumours in vivo in mice ( P04637 and Tp53 are also known as p53 ) . This strategy has proven difficult to implement therapeutically , and here we examine an alternative strategy by manipulating the p53 family members , Tp63 and Tp73 ( also known as p63 and p73 , respectively ) . The acidic transactivation - domain - bearing ( TA ) isoforms of p63 and p73 structurally and functionally resemble p53 , whereas the ΔN isoforms ( lacking the acidic transactivation domain ) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant - negative fashion against p53 , TAp63 and TAp73 to inhibit their tumour - suppressive functions . The p53 family interacts extensively in cellular processes that promote tumour suppression , such as apoptosis and autophagy , thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway . Here we show that deletion of the ΔN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53 - deficient tumours through upregulation of P10997 , the gene that encodes amylin , a 37 - amino - acid peptide co - secreted with insulin by the β cells of the pancreas . We found that P10997 is causally involved in this tumour regression and that amylin functions through the calcitonin receptor ( CalcR ) and receptor activity modifying protein 3 ( O60896 ) to inhibit glycolysis and induce reactive oxygen species and apoptosis . DB01278 , a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes , caused rapid tumour regression in p53 - deficient thymic lymphomas , representing a novel strategy to target p53 - deficient cancers .",
"E3 ubiquitin ligase Q13049 negatively regulates tumor suppressor p53 to promote tumorigenesis . P04637 has a key role in maintaining genomic stability and preventing tumorigenesis through its regulation of cellular stress responses , including apoptosis , cell cycle arrest and senescence . To ensure its proper levels and functions in cells , p53 is tightly regulated mainly through post - translational modifications , such as ubiquitination . Here , we identified E3 ubiquitin ligase Q13049 as a novel p53 target gene and negative regulator to regulate p53 - mediated stress responses . In response to stress , such as DNA damage , p53 binds to the p53 responsive element in the promoter of the Q13049 gene and transcriptionally induces the expression of Q13049 in cells . In turn , Q13049 interacts with p53 and promotes p53 degradation through ubiquitination . Thus , Q13049 negatively regulates p53 - mediated apoptosis , cell cycle arrest and senescence in response to stress . Q13049 is frequently overexpressed in different types of human tumors . Q13049 overexpression promotes cell oncogenic transformation and tumorigenesis in mice in a largely p53 - dependent manner . Taken together , our results demonstrated that as a novel p53 target and a novel negative regulator for p53 , Q13049 has an important role in regulation of p53 and p53 - mediated cellular stress responses . Furthermore , our results also revealed that impairing p53 function is a novel mechanism for Q13049 in tumorigenesis .",
"___MASK45___ for joints and bones . ___MASK45___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK45___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK45___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"P10997 - leptin coadministration stimulates central histaminergic signaling in rats . Combined amylin + leptin ( Q9BXJ7 + P41159 ) can reduce diet induced obesity and is very effective in combating P41159 resistance . The purpose of this study was to evaluate the effect of Q9BXJ7 + P41159 on central histaminergic signaling in lean and obese rats . Male rats were administered P41159 ( 300 μg / kg / d ) , Q9BXJ7 ( 100 μg / kg / d ) , Q9BXJ7 + P41159 or vehicle ( SAL , 0 . 9 % normal saline ) , via a subcutaneous mini - osmotic pump or single injection ( P41159 , 300 μg / kg and Q9BXJ7 , 100 μg / kg ) for acute studies . Q9BXJ7 + P41159 administration increased expression of histamine H1 receptor ( HIR ) and histidine decarboxylase ( HDC ) mRNA in the hypothalamus . Increased levels of P35367 were seen in arcuate ( Arc ) and ventromedial hypothalamus ( VMH ) as well as the area postrema ( APOS ) and nucleus of solitary tract ( P30990 ) following Q9BXJ7 + P41159 administration . APOS and P30990 also showed expression of immediate early gene c - P01100 in the hindbrain in Q9BXJ7 + P41159 - treated rats . We confirmed previous evidence indicating that Q9BXJ7 + P41159 increased P35610 - 3 protein phosphorylation in Arc and VMH . Finally , by in vivo microdialysis , we observed an increase in methyl P42357 levels in the VMH of Q9BXJ7 , P41159 and Q9BXJ7 + P41159 - treated rats . Taken together , these observations are consistent with an important role that neuronal P42357 may play in mediating the potent effects of Q9BXJ7 + P41159 on food intake and body weight .",
"Control of the P29323 Q96HU1 kinase cascade by Ras and Raf . Activation of ERKs plays a central part in the control of cell proliferation . In this chapter , we have concentrated on the identification and regulation of the kinases that activate Mek . We have chosen to focus on this area because of the many puzzles associated with it . Key issues for the future are the need to derive methods to determine what contribution each individual activator makes to both the magnitude and duration of Mek activation and understanding the mechanisms of regulation . Furthermore , we have considered the roles of Raf and the other kinases solely as Mek activators ; they may well have other substrates including cdc25A ( Galaktionov et al , 1995 ) , I kappa B ( Li and Sedivy , 1993 ) and P04637 ( Jamal and Ziff , 1995 ) .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK36___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"Pathway based analysis of SNPs with relevance to ___MASK88___ therapy : relation to intratumoral mRNA expression and survival . Genetic factors are thought to play a role in resistance towards chemotherapeutic agents such as 5 - fluorouracil ( ___MASK88___ ) . Approximately 30 genes are directly or indirectly involved in ___MASK88___ metabolism , and genetic variation in any of these may contribute to anti - tumor response . Polymorphisms in these genes were analyzed in relation to tumoral mRNA levels of ___MASK88___ metabolizing genes , response to chemotherapy and survival . A total of 21 genetic variants were studied in 35 breast cancer patients treated with 5 - FluoroUracil , mitomycin ( FUMI ) and in a similar cohort of 90 doxorubicin treated breast cancer patients . Genotype distributions were compared using 109 healthy controls . No significant association was found between any polymorphisms and response to chemotherapy as measured by shrinkage of tumor . However , carriers of 3 copies of the P04818 5 ' UTR repeat had shorter survival than noncarriers ( p = . 048 ) in the FUMI treatment group , but not in the doxorubicin treated group . Carriers of 3 copies of the repeat were also more frequently observed in both patients groups than in healthy controls ( p = . 034 ) . Several highly significant associations were observed between genotypes and expression levels of ___MASK88___ metabolizing genes . A SNP in codon 72 of P04637 was revealed to be a key regulator of ___MASK88___ metabolizing genes such as P00374 and P42898 , constituting 50 % of all significant associations observed after FUMI therapy . These data suggest that 3 copies of the P04818 5 ' UTR repeat may give a treatment specific reduced survival in breast cancer patients , and that P04637 may have a direct , allele specific , role in ___MASK88___ mediated response .",
"Expression of the calcitonin receptor , calcitonin receptor - like receptor , and receptor activity modifying proteins during osteoclast differentiation . The expressions of the calcitonin receptor ( CTR ) , the calcitonin receptor - like receptor ( CLR ) , the receptor activity - modifying proteins ( RAMP ) 1 - 3 , and of the receptor component protein ( RCP ) have been studied in mouse bone marrow macrophages ( BMM ) during osteoclast differentiation , induced by treatment with P09603 and O14788 . Analyses of mRNA showed that CLR and O60894 - 3 , but not CTR , were expressed in P09603 stimulated BMM . O14788 gradually increased CTR mRNA , transiently enhanced CLR and transiently decreased O60894 mRNA , but did not affect O60895 , O60896 , or RCP mRNA . However , O14788 did not affect protein levels of CLR or O60894 - 3 as assessed by Western blots or FACS analyses , whereas immunocytochemistry showed enhanced CTR protein . Analyses of DB02527 production showed that BMM cells expressed functional receptors for calcitonin gene - related peptide ( P80511 ) , amylin , adrenomedullin , and intermedin , but not for calcitonin and calcitonin receptor stimulating peptide ( CRSP ) , but that O14788 induced the expression of receptors for calcitonin and CRSP as well . P01258 , P80511 , amylin , adrenomedullin , intermedin , and CRSP all down regulated the CTR mRNA , but none of the peptides caused any effects on the expression of CLR or any of the RAMPs . Our data show that BMM cells express receptors for P80511 , amylin , adrenomedullin , and intermedin and that O14788 induces the formation of receptors for calcitonin and CRSP in these cells . We also show , for the first time , that the CTR is not only down regulated by signaling through the CTR but also by the peptides signaling through CLR / RAMPs .",
"P15056 inhibitors suppress apoptosis through off - target inhibition of JNK signaling . ___MASK73___ and dabrafenib selectively inhibit the P15056 ( P15056 ) kinase , resulting in high response rates and increased survival in melanoma . Approximately 22 % of individuals treated with vemurafenib develop cutaneous squamous cell carcinoma ( cSCC ) during therapy . The prevailing explanation for this is drug - induced paradoxical P29323 activation , resulting in hyperproliferation . Here we show an unexpected and novel effect of vemurafenib / PLX4720 in suppressing apoptosis through the inhibition of multiple off - target kinases upstream of c - Jun N - terminal kinase ( JNK ) , principally Q9NYL2 . JNK signaling is suppressed in multiple contexts , including in cSCC of vemurafenib - treated patients , as well as in mice . Expression of a mutant Q9NYL2 that can not be inhibited reverses the suppression of JNK activation and apoptosis . Our results implicate suppression of JNK - dependent apoptosis as a significant , independent mechanism that cooperates with paradoxical P29323 activation to induce cSCC , suggesting broad implications for understanding toxicities associated with P15056 inhibitors and for their use in combination therapies . DOI : http :// dx . doi . org / 10 . 7554 / eLife . 00969 . 001 ."
] |
[
"___MASK20___",
"___MASK26___",
"___MASK29___",
"___MASK36___",
"___MASK45___",
"___MASK73___",
"___MASK82___",
"___MASK88___",
"___MASK93___"
] |
___MASK29___
|
MH_train_477
|
interacts_with DB01257?
|
[
"DB01257 in renal transplantation . Antibody - mediated rejection , be it acute , subacute or chronic , is currently recognized as the major cause of graft loss in kidney transplant recipients . Anti - HLA donor - specific antibodies are deleterious to the graft fate whether they pre - exist to the transplantation or appear in the course of transplantation . The role of complement is therefore prominent in most instances . As well , the role of complement activation is crucial in the recurrence of atypical hemolytic uremic syndrome post - transplantation ( aHUS ) as well as following ischemia - reperfusion injury leading to delayed graft function . DB01257 , a fully humanized monoclonal antibody directed against the P01031 component of the complement cascade is efficient in chronically and safely blocking complement activation for example in paroxysmal nocturnal hemoglobinuria . In the setting of kidney transplantation , there is convincing but still limited evidence that eculizumab is efficient in preventing both acute and chronic antibody - mediated rejection in highly sensitized recipients requiring desensitization before getting a living donor kidney transplant . Studies are currently ongoing to determine its efficacy and safety in P16442 incompatible transplantation , in the prevention of acute and chronic rejection either with a living or a deceased donor kidney as well as in the prevention of delayed graft function . Similar to its efficacy in aHUS on native kidneys , eculizumab prevents or treats recurrence after kidney transplantation . There is still a lot of research to be performed in order to determine precisely the exact indications and the length of treatment with this very active but also very expensive drug that will undoubtedly revolutionize the current management of patients with donor specific antibodies ( DSAs ) and at risk of HUS recurrence .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK63___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK63___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK63___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK63___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK63___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK63___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK63___ .",
"The role of complement inhibition in PNH . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare , chronic , debilitating , acquired disorder that most frequently presents in early adulthood and usually continues throughout the life of a patient . PNH results in the death of approximately half of affected individuals , mainly through thrombotic complications , and until recently had no specific therapy . In 2007 eculizumab , an anti - complement antibody targeting the P01031 complement component was approved for PNH by both the US Food and Drug Administration ( FDA ) and the European Medicines Agency ( EMEA ) . DB01257 is very effective in the treatment of intravascular hemolysis and all its sequelae , which include most of the symptoms and complications of PNH . DB01257 has revolutionized our approach to hemolytic PNH and as it markedly reduces the principal complications of PNH , namely thrombosis and renal failure , should have a significant impact on survival . However , the development of eculizumab presents new challenges in PNH , such as how to avoid complications of therapy , how to overcome some of the problems associated with treatment and who to select for treatment , as only a proportion of patients with a PNH clone will benefit . This article will review the evidence behind the use of eculizumab in PNH , the effect it will have on the complications of the disease , the most appropriate selection of patients for therapy , the optimal management and the potential complications of the therapy .",
"Severe atypical HUS caused by P08603 S1191L -- case presentation and review of treatment options . Atypical hemolytic uremic syndrome ( aHUS ) has been associated with defective regulation of the alternative complement pathway . Although the use of plasma therapy is recommended , there is little consensus on the optimal treatment regimen . The outcome in many cases remains poor despite an improvement in our understanding of the pathology of aHUS . We have followed a female patient with aHUS associated with heterozygous complement Factor H ( P08603 ) mutation ( S1191L ) over a period of 15 years . She has been plasma dependent since infancy and has subsequently progressed to end stage kidney disease ( ESKD ) requiring dialysis treatment . Despite ESKD she still depends on regular plasma infusions to prevent thrombocytopenia . The long - term treatment plan for this patient is challenging . Renal transplantation in patients with the S1191L mutation of the P08603 gene carries a high risk of failure due to recurrence of aHUS in the renal graft . Thus , the only available curative treatment seems to be combined liver - kidney transplantation , covered by intensive plasma therapy , which comes with a high risk of morbidity and mortality . Antibodies against key activating components of the complement cascade may provide a promising alternative therapeutic strategy in the future . DB01257 , a monoclonal humanized anti - P01031 antibody , has recently been shown to be effective and well - tolerated in patients with paroxysmal nocturnal hemoglobinuria by preventing complement - mediated lysis of affected erythrocytes . Treatment of our patient with eculizumab is supported by recent reports on its successful use in two ( pediatric and adult ) patients with complement - based aHUS .",
"Successful management of obstructive jaundice due to gallstones with eculizumab in a patient with paroxysmal nocturnal hemoglobinuria . Paroxysmal nocturnal hemoglobinuria ( PNH ) makes patients susceptible to intravascular hemolysis and thrombosis , and it can be life - threatening in stressful situations . DB01257 , a humanized monoclonal antibody that inhibits the complement protein P01031 , has been evaluated as a novel therapy for PNH . We herein describe the case of a 59 - year - old Japanese woman with classic PNH , who had been successfully treated with eculizumab , but who later developed acute cholecystitis / cholangitis from gallstones . Although the severe obstructive jaundice requiring endoscopic therapy following cholecystectomy was complicated , critical intravascular hemolysis and thrombosis were not observed . Therefore , utilizing eculizumab during the peri - operative management of PNH patients should be carefully taken into consideration .",
"Conformationally altered hyaluronan restricts complement classical pathway activation by binding to C1q , C1r , C1s , P06681 , P01031 and P02748 , and suppresses Q9NZC7 expression in prostate DU145 cells . Linear non - sulfated hyaluronan ( HA ) does not bind complement proteins yet inhibits their hemolytic function . We have previously induced the complement inhibitory function of HA by heat treatment . However , heated HA readily loses its anti - complementary activity probably due to instantaneous interchain re - association . Here , HA solutions were heated and then freeze - dried . Compared to native HA , heated / freeze - dried HA stably restricted serum complement - mediated hemolysis via the classical pathway , in which serum C1 hemolytic function and P01024 activation were blocked . Also , treated HA had a significantly increased binding of component C1q , C1r , C1s , P06681 , P01031 , P02748 , P , D and H . Further , when HA was gel - fractionated by electrophoresis and then freeze - dried , its anti - complementary activity was stably induced . Both native and heated / freeze - dried HA stimulated P29323 phosphorylation in prostate DU145 cells . However , treated HA suppressed the expression of tumor suppressors Q9NZC7 and WOX2 . Together , HA with an altered conformation stabilizes its inhibition and binding of complement proteins . It may recognize cell surface receptors differently from native HA , thereby differentially regulating the expression of cellular proteins .",
"The pathophysiology of paroxysmal nocturnal hemoglobinuria and treatment with eculizumab . Paroxysmal nocturnal hemoglobinuria is a rare disorder of hemopoietic stem cells . Affected individuals have a triad of clinical associations - intravascular hemolysis , an increased risk of thromboembolism , and bone marrow failure . Most of the symptoms experienced in this disease occur due to the absence of complement regulatory proteins on the surface of the red blood cells . Complement activation is thus not checked and causes destruction of these cells . DB01257 is a monoclonal antibody treatment which specifically binds to the complement protein P01031 , preventing its cleavage , and so halts the complement cascade and prevents the formation of the terminal complement proteins . DB01257 prevents intravascular hemolysis , stabilizes hemoglobin levels , reduces or stops the need for blood transfusions , and improves fatigue and patient quality of life as well as reducing pulmonary hypertension , decreasing the risk of thrombosis and protecting against worsening renal function . It is not a curative therapy but has a great benefit on those with this rare debilitating condition .",
"DB01257 : DB01257 , h5G1 . 1 , long - acting anti - P01031 monoclonal antibody 5G1 - 1 , long - acting anti - P01031 monoclonal antibody DB01257 .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK43___ and Tissue P00747 Activator in Occluded Arteries .",
"Hyperhemolysis syndrome in anemia of chronic disease . BACKGROUND : Occasional cases of delayed hemolytic transfusion reaction ( P10275 ) demonstrate severe and persistent hemolysis and are referred to as hyperhemolysis syndrome . This syndrome usually occurs in patients with sickle cell disease and possibly thalassemia who receive multiple transfusions . There are few such clinical reports in patients without hemoglobinopathies . CASE REPORT : A 67 - year - old woman with anemia and a history of four previous transfusions was admitted with shortness of breath and a hematocrit ( Hct ) level of 27 percent . The patient was group O with a negative antibody screen . She received 1 unit of electronically cross - matched red blood cells ( RBCs ) and was discharged . Thirteen days later she returned to hospital with weakness and a Hct level of 23 percent . The antibody screen now demonstrated anti - K alloantibody . The direct antigloblulin test ( Q01959 ) was positive with both anti - immunoglobulin G and anti - complement ( P01024 ) . Anti - K was recovered in the eluate . The previously transfused RBC unit was positive for presence of the K antigen . The patient ' s RBCs were negative for the presence of K antigen . Other laboratory data confirmed ongoing hemolysis , and a diagnosis of P10275 was made . She continued to display findings of active hemolysis for 9 more weeks requiring 19 units of RBCs . Thirty - four days after the original transfusion , her Q01959 remained positive and both the plasma sample and a RBC eluate demonstrated anti - K . CONCLUSION : The delayed hemolytic transfusion reaction with hyperhemolysis can occur among patients without hemoglobinopathies .",
"Role of Q14116 in overt pain - like behaviour in mice . There are evidences that targeting Q14116 might be beneficial to inhibit inflammatory symptoms , including hypernociception ( decrease in nociceptive threshold ) . The mechanism of Q14116 mechanical hypernociception depends on endothelin in rats and mice . However , the role of Q14116 in overt pain - like behaviour remains undetermined . Therefore , we addressed the role of Q14116 in writhing response induced by intraperitoneal ( i . p . ) injection of phenyl - p - benzoquinone ( PBQ ) and acetic acid in mice . Firstly , it was detected that PBQ and acetic acid i . p . injection induced a dose - dependent number of writhes in Balb / c mice . Subsequently , it was observed that the PBQ - but not the acetic acid - induced writhes were diminished in Q14116 deficient ( ( -/- ) ) mice . Therefore , considering that P01579 , endothelin and prostanoids mediate Q14116 - induced mechanical hypernociception , we also investigated the role of these mediators in the same model of writhing response in which Q14116 participates . It was noticed that PBQ - induced writhes were diminished in P01579 (-/-) mice and by the treatment with ___MASK85___ ( mixed endothelin P25101 / ETB receptor antagonist ) , BQ 123 ( cyclo [ DTrp - DAsp - Pro - DVal - DB00149 ] , selective endothelin P25101 receptor antagonist ) , BQ 788 ( N - cys - 2 , 6 dimethylpiperidinocarbonyl - l - methylleucyl - d - 1 - methoxycarboyl - d - norleucine , selective endothelin ETB receptor antagonist ) or indomethacin ( cycloxigenase inhibitor ) . Thus , Q14116 , P01579 , endothelin acting on endothelin P25101 and ETB receptors , and prostanoids mediate PBQ - induced writhing response in mice . To conclude , these results further advance the understanding of the physiopathology of overt pain - like behaviour , and suggest for the first time a role for Q14116 in writhing response in mice .",
"DB01257 for the treatment of de novo thrombotic microangiopathy post simultaneous pancreas - kidney transplantation -- a case report . A 34 - year - old female recipient of a simultaneous pancreas - kidney transplant presented 7 days posttransplant with acute renal allograft dysfunction , thrombocytopenia , and microangiopathic hemolytic anemia . Renal biopsy revealed acute antibody - mediated rejection ( AMR ) and acute thrombotic microangiopathy ( TMA ) . Clinical and laboratory manifestations , which had only partly responded to treatment with daily plasma exchange and intravenous immunoglobulin , resolved rapidly and completely to eculizumab ( Soliris , Alexion Pharmaceuticals , Inc . , Cheshire , Conn ) , a complement factor P01031 antibody . De novo posttransplant TMA is a rare and serious complication that can lead to graft loss in up to one third of cases . This is the first report of successful treatment of de novo TMA with eculizumab , which has previously shown benefit in recurrent atypical hemolytic uremic syndrome as well as in refractory acute AMR . Targeted complement inhibition offers the promise of a safe and effective therapeutic strategy in de novo TMA , especially in light of recent evidence suggesting that genetic mutations in complement regulatory proteins may predispose transplant recipients to this serious disease .",
"Resistance to killing by tumor necrosis factor in an adipocyte cell line caused by a defect in arachidonic acid biosynthesis . We have found that Q96RJ0 - R6 , which are resistant to the cytotoxic effects of tumor necrosis factor ( P01375 ) in the presence of cycloheximide ( Reid , T . R . , Torti , F . , and Ringold , G . M . ( 1989 ) J . Biol . Chem . 264 , 4583 - 4589 ) , have reduced ability to release arachidonic acid ( 20 : 4 ) from membrane phospholipids in response to either P01375 or the calcium ionophore A23187 treatment . However , no defect in the activity of phospholipase A2 , the principal enzyme responsible for the release of 20 : 4 from phospholipids , was observed in these cells . Detailed biochemical characterization of these P01375 - resistant cells has revealed that these cells are unable to synthesize 20 : 4 endogenously because of a defect in delta 6 - desaturase , the rate - limiting enzyme of 20 : 4 biosynthesis . This deficiency leads to a marked decrease in the steady - state levels of 20 : 4 present in choline - containing phospholipid ( PC ) and ethanolamine - containing phospholipid ( PE ) . The Q96RJ0 - R6 cells , however , are capable of incorporating exogenous 20 : 4 into PC and PE , and when loaded in such manner they become significantly more sensitive to the cytotoxic effects of P01375 in the presence of cycloheximide . Therefore , the release of arachidonic acid from phospholipids appears to be a critical element in the signaling pathway utilized by P01375 and is essential to the rapid cytotoxic response elicited by P01375 in the absence of protein synthesis in wild - type Q96RJ0 cells .",
"DB01257 treatment of acute antibody - mediated rejection in renal transplantation : case reports . The occurrence of acute antibody - mediated rejection ( AMR ) , especially in more severe cases , continues to be associated with a poor prognosis for implant survival . Here , we have reported the results of treatment of two patients who developed AMR associated with thrombotic microangiopathy immediately after transplantation . We used a single dose of eculizumab at an early stage jointly with conventional modalities of steroid boluses , plasmapheresis , intravenous immunoglobulin , and rituximab . In both cases , the clinical course was favorable . DB01257 , a monoclonal antibody with a high affinity for complement protein P01031 , prevents generation of the final membrane attack complex , blocking this cascade . To date , there are a few reports of the usefulness of eculizumab in AMR . DB01257 can help to stop endothelial damage , especially in severe cases that show a risk of progression to cortical necrosis , by providing a therapeutic window until the other modalities begin to control the immune response . In our experience , the use of eculizumab can be beneficial in the treatment of AMR .",
"[ Paroxysmal nocturnal hemoglobinuria therapy with eculizumab : Spanish experience ] . BACKGROUND AND OBJECTIVES : Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare acquired clonal disease characterized by complement - mediated hemolysis , bone marrow failure and thrombosis . DB01257 is a humanized monoclonal antibody that blocks the cytolytic component of the complement system by binding to complement P01031 . MATERIAL AND METHODS : We report the results of eculizumab treatment in 25 PNH patients from different centers in Spain . Statistical analysis was perfomed with a SPSS v15 . 0 software . RESULTS : Fifty - eight per cent of the patients achieved transfusional independence after a median of 14 months . Transfusion requirements were reduced in 60 % of the remaining cases . Fatigue resolved in 96 % of the patients and smooth muscle dystony - related symptoms in all cases . A single case of treatment - related infection was observed . CONCLUSIONS : DB01257 controls effectively hemolysis and greatly improves clinical symptoms . The drug is safe and well tolerated , without significant adverse effects except meningococcal infection . Patients with suboptimal response to treatment must be assessed for bone marrow insufficiency and extravascular haemolysis .",
"Complement in lupus nephritis : the good , the bad , and the unknown . The complement system consists of 3 pathways and more than 30 proteins , including those with biological activity that directly or indirectly mediate the effects of this system , plus a set of regulatory proteins necessary to prevent injudicious complement activation on host tissue . The role for complement in the pathogenesis of systemic lupus erythematosus ( SLE ) is paradoxic . On one hand , the complement system appears to have protective features in that hereditary homozygous deficiencies of classic pathway components are associated with an increased risk for SLE . On the other hand , immune complex - mediated activation of complement in affected tissues is clearly evident in both experimental and human SLE along with pathologic features that are logical consequences of complement activation . By using accurate mouse models of SLE , we have gained remarkable insights into pathogenic features likely relevant to the human disease , and the ability to test potential therapies , some of which have made it to standard clinical use . Studies in genetically altered mice and using recombinant protein inhibitors of complement have confirmed what was believed but unproven - early complement proteins C1q and C4 are protective whereas complement activation later in the pathways is proinflammatory and deleterious . Two complement inhibitors , soluble complement receptor 1 ( TP10 , Avant Immunotherapeutics , Needham , MA ) and a monoclonal anti - P01031 antibody ( DB01257 , Alexion Pharmaceuticals , Inc . , Cheshire , CT ) have been shown to inhibit complement safely and now are being investigated in a variety of clinical conditions . Although these and others earlier in their clinical development hold promise to be used therapeutically in lupus nephritis , this optimism must be tempered by the fact that the clinical trials to prove this remain fraught with obstacles .",
"[ DB01257 in paroxysmal nocturnal hemoglobinuria ] . Paroxysmal nocturnal hemoglobinuria is a rare acquired clonal of the hematopoietic stem cell due to acquired mutation of the P37287 gene . This results in the lack of two P06744 - anchored membrane proteins involved in the inhibition of complement attack , thus explaining red cells hemolysis . The development of an anti - P01031 monoclonal antibody ( eculizumab ) had profoundly modified the treatment of the the hemolytic form of the disease .",
"DB01257 and recurrent P01024 glomerulonephritis . BACKGROUND : Hyperactivity of the alternative complement pathway is the principle defect in P01024 glomerulopathies ( C3G ) . DB01257 , a monoclonal antibody that binds P01031 to prevent formation of the membrane attack complex , has been shown to be beneficial in some patients with this disease . METHODS : In this open - label , proof - of - concept efficacy - and - safety study , a patient with the initial diagnosis of dense deposit disease ( DDD ) and allograft recurrence of P01024 glomerulonephritis ( C3GN ) was treated with eculizumab every other week for 1 year . The patient had pathological evidence of C3GN and proteinuria > 1 g / day at enrollment . He underwent graft biopsy before enrollment and repeat biopsy at 6 and 12 months . RESULTS : Although no mutations were identified in complement genes , functional studies were positive for P01024 nephritic factors and elevated levels of soluble membrane attack complex ( sMAC ) . On therapy , sMAC levels normalized and although proteinuria initially decreased , it increased reaching pre - treatment levels at 12 months . Although serum creatinine remained stable , repeat allograft biopsies showed progression of disease . CONCLUSIONS : Clinical and histopathologic data suggest a partial response to eculizumab in this patient . While eculizumab blocked activation of the terminal complement cascade , persistent dysregulation of the alternative pathway remained , indicating eculizumab alone can not control disease in this patient . Additional research is required to identify effective anticomplement therapy for this group of C3G patients .",
"Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab . In paroxysmal nocturnal hemoglobinuria ( PNH ) hemolytic anemia is due mainly to deficiency of the complement regulator P13987 on the surface of red blood cells ( RBCs ) . DB01257 , an antibody that targets complement fraction 5 ( P01031 ) , has proven highly effective in abolishing complement - mediated intravascular hemolysis in PNH ; however , the hematologic benefit varies considerably among patients . In the aim to understand the basis for this variable response , we have investigated by flow cytometry the binding of complement fraction 3 ( P01024 ) on RBCs from PNH patients before and during eculizumab treatment . There was no evidence of P01024 on RBCs of untreated PNH patients ; by contrast , in all patients on eculizumab ( n = 41 ) a substantial fraction of RBCs had P01024 bound on their surface , and this was entirely restricted to RBCs with the PNH phenotype ( P13987 (-) ) . The proportion of P01024 (+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab . In 3 patients in whom ( 51 ) Cr labeling of RBCs was carried out while on eculizumab , we have demonstrated reduced RBC half - life in vivo , with excess ( 51 ) Cr uptake in spleen and in liver . Binding of P01024 by PNH RBCs may constitute an additional disease mechanism in PNH , strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis .",
"DB01257 treatment modifies the immune profile of PNH patients . Paroxysmal Nocturnal Haemoglobinuria ( PNH ) is due to pathological expansion of a stem progenitor bearing a somatic mutation of P37287 gene involved in the biosynthesis of the glycosyl - phosphatidyl - inositol ( P06744 ) anchor . Numerous data suggest a role for immune - mediated mechanisms in the selection / expansion of P06744 - defective clone . Haemolytic anaemia in PNH is dependent on the effect of complement against P06744 - defective red cells . DB01257 , an anti - P01031 monoclonal antibody , is dramatically effective in controlling haemolysis and thrombosis , in reducing fatigue and in improving quality of life of patients . However , this therapy presents new challenges that need to be properly faced . Here , we report the decrease in B , Natural Killer ( NK ) and regulatory T cells ( Treg ) , an altered cytokine profile of invariant - NKT cells ( NKTi ) and the increasing of P61073 ( P61073 ) receptor in PNH patients before the DB01257 therapy . Treatment significantly affects some of these alterations : after DB01257 , the number of B lymphocytes , the cytokine secretion of NKTi and P61073 expression on CD8 T cells became similar to healthy donors . No effects were observed on NK and Treg . The amplitude of the P06744 - defective compartment remained unchanged .",
"Paroxysmal nocturnal hemoglobinuria from bench to bedside . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare hematologic disease that presents with protean manifestations . Clinical and laboratory investigation over the past 25 years has uncovered most of the basic science underpinnings of PNH and has led to the development of a highly effective targeted therapy . PNH originates from a multipotent hematopoietic stem cell ( P19526 ) that acquires a somatic mutation in a gene called phosphatidylinositol glycan anchor biosynthesis , class A ( P37287 ) . The P37287 gene is required for the first step in glycosylphosphatidylinositol ( P06744 ) anchor biosynthesis . Failure to synthesize P06744 anchors leads to an absence of all proteins that utilize P06744 to attach to the plasma membrane . Two P06744 - anchor proteins , P08174 and P13987 , are complement regulatory proteins ; their absence on the surface of PNH cells leads to complement - mediated hemolysis . The release of free hemoglobin leads to scavenging of nitric oxide and contributes to many clinical manifestations , including esophageal spasm , fatigue , and possibly thrombosis . Aerolysin is a pore - forming toxin that binds P06744 - anchored proteins and kills normal cells , but not PNH cells . A fluorescinated aerolysin variant ( FLAER ) binds P06744 - anchor and serves as a novel reagent diagnosing PNH . DB01257 , a humanized monoclonal antibody against P01031 , is the first effective drug therapy for PNH .",
"Activated factor B ( Bb ) of the alternative pathway of complement activation cleaves and activates plasminogen . Activated Factor B ( Bb ) , the central serine esterase of the alternative pathway of complement activation , exhibits restricted substrate specificity in the complement system for P01024 and P01031 . The results presented here indicate that Bb can cleave and activate plasminogen in an experimental system containing purified plasminogen and Bb ; complement cellular intermediate bearing the Bb - enzyme ; or cobra venom factor - stabilized Bb - enzyme ( CVF , Bb ) . Cleavage of plasminogen by Factor Bb generated 2 disulfide - linked polypeptides with apparent m . w . of 64 , 000 and 25 , 000 to 32 , 000 ( SDS - PAGE ) . Complement cellular intermediates containing the C3b , Bb - enzyme cleave 40 to 80 % of 4 . 5 micrograms of 125I - labeled plasminogen during 30 min of incubation at 37 degrees C ; native Factor B was inactive ; and anti - Factor Blg inhibited by 100 % the plasminogen cleavage mediated by complement cellular intermediates bearing the Bb - enzyme . Fibrinolytic activity was detected in plasminogen activator ( PA ) assays when purified plasminogen and 125I - labeled fibrin tubes were incubated with Bb , CVF , Bb , or complement cellular intermediates bearing the C3b , Bb - enzyme : 10 micrograms Bb released 40 to 65 % of the 125I - fibrin released by 5 micrograms urokinase in 4 hr at 37 degrees C . P00747 activator activity of the C3b , Bb - enzyme was found to be regulated in serum . At dilutions of Q6T4R5 1 : 50 , the PA - activity of 1 . 6 micrograms Bb was 100 % inhibited , and at a 1 : 250 dilution , 50 % inhibition was observed . This report describes a novel activity for the Bb - enzyme , which constitutes the P01024 / P01031 - convertase of the alternative pathway of complement activation .",
"[ HIV - 1 neuropathogenesis : therapeutic strategies against neuronal loss induced by gp120 / Tat glycoprotein in the central nervous system ] . Neuroinflammation is a key process in the neuropathogenesis of AIDS virus since as a result of the aberrant activation of the chemokine receptors ( P61073 , P49238 and CR5 ) produces proinflammatory cytokine release by infected cells , increases microglial neurotoxicity and generates lipoperoxides and reactive oxygen species ( ROS ) that eventually damage the neuron . Moreover , the neurotoxin Tat produces dendritic loss by interacting with the low - density lipoprotein receptor ( Q14764 ) and also overstimulates N - methyl D - aspartate receptors ( DB01221 ) . Furthermore , the aberrant interaction of glycoprotein gp120 with the P61073 chemokine receptor causes caspase - 3 - dependent apoptosis ( ceramide is also released ) activating apoptotic proteins ( p53 and retinoblastoma ) , which are part of the neurotoxic mechanisms associated to neuronal dysfunction in neuroAIDS . Similarly , gliosis / microglial activation and the release of neurotoxic factors by infected monocytes with elevated amounts of certain chemokines in the cerebrospinal fluid ( P13500 and fractalkine , among others ) contribute to the neuropathogenesis of HIV - 1 . P37840 and beta amyloid deposits have also been detected in post mortem brains of seropositives patients . In addition , there are studies have detected several systemic markers related with the degenerative effects of the virus and its neurotoxins on the central nervous system ; such as osteopontin , Q86VB7 and fractalkine , among others . Lastly , clinical trials have been conducted using protective strategies related that attempt to inhibit apoptotic proteins ( P49841 ) , microglial activation inhibitors ( minocycline ) , antioxidants ( selegiline ) or trophic factors ( DB01277 , growth hormone or erythropoietin ) . These trials have shown that their treatments are beneficial and complementary to treat complications of HIV / AIDS .",
"Novel future therapeutic options in myasthenia gravis . BACKGROUND : Myasthenia Gravis ( MG ) is an autoimmune disease caused by complement - fixing antibodies against the acetylcholine receptors ( AChR ) . Antigen - specific P01730 + T cells , Tregs and Th17 + are also necessary . Consequently , antibodies , B cells , molecules associated with signalling pathways on T helper cells , cytokines and complement are targets for more specific treatment options . OBJECTIVES : Because available immunosuppressive therapies cause unacceptable side effects after long - term use or are not always effective in inducing remission , novel biological agents directed against the following targets might be options for future therapies in MG : 1 ) T cell Intracellular Signaling Pathways associated with T cell activation , such as monoclonal antibodies against P31358 , Interleukin 2 - receptor ( P60568 R ) , co - stimulatory molecules or compounds inhibiting Janus tyrosine kinases P23458 , P52333 ; 2 ) B cells , against key B cell - surface molecules or trophic factors B cell activation factor ( Q9Y275 ) and a proliferating inducing ligand ( APRIL ) ; 3 ) Complement , against P01024 or P01031 that intercept membranolytic attack complex formation ; 4 ) Cytokines and cytokine receptors , including P05231 , Q16552 , the p40 subunit of IL12 / 1L - 23 , and GM - P04141 ; and 5 ) Lymphocyte migration molecules . Construction of recombinant AChR antibodies that block the binding of the pathogenic antibodies , can be a future molecular tool . CONCLUSION : New biological agents are in the offing for future therapies in MG . Their efficacy needs to be secured with vigorously controlled clinical trials and weighted against excessive cost and rare complications .",
"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK30___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .",
"Effects of membrane attack complex of complement on apoptosis in experimental autoimmune encephalomyelitis . Complement activation is involved in the initiation of inflammation and antibody - mediated demyelination in experimental autoimmune encephalomyelitis ( EAE ) . We investigated the role of MAC in apoptosis in myelin - induced EAE in complement P01031 - deficient ( P01031 - d ) and P01031 - sufficient ( P01031 - s ) mice . The number of apoptotic cells assessed by TUNEL assay was significantly increased in P01031 - d mice during clinical recovery as compared with P01031 - s mice . Most of the apoptotic cells were lymphocytes , monocytes , and oligodendrocytes . DNA microarray was performed using total RNA extracted from spinal cords . Genes expressed higher in P01031 - s included members of the caspase ( caspase 6 , 7 ) , P01375 and TNFR families ( P26842 , P48023 , lymphotoxin - beta R ) and survivin . These results indicate that P01031 and possibly MAC may be required for the limitation of inflammatory response within the central nervous system .",
"DB01257 in neonatal hemolytic uremic syndrome with homozygous factor H deficiency . BACKGROUND : Neonatal atypical hemolytic uremic syndrome ( aHUS ) is a rare but severe disease that is mainly due to methylmalonic aciduria or genetic complement abnormalities . Traditional management of aHUS includes plasma infusion / exchange , but in small or unstable infants , plasma exchange can be challenging because of high extracorporeal volume and difficulty to obtain an adequate venous access . The P01031 complement blocker eculizumab has become a cornerstone of first - line management of aHUS due to complement deregulation in older patients . However , little data are available on its use in neonatal aHUS . CASE - DIAGNOSIS / TREATMENT : We report on an 11 - day - old neonate with severe aHUS ( myocardial impairment , respiratory failure , acute kidney disease requiring hemodiafiltration ) due to homozygous factor - H deficiency . She received early treatment with eculizumab as first - line therapy and completely recovered within 5 days . A second dose of eculizumab was administered 7 days after the first infusion , followed by a dose every 2 weeks for 2 months and then every 3 weeks , at the same dosage ( 300 mg ) . With more than 24 months of follow - up , renal function remains normal . CONCLUSIONS : We report on the long - term efficacy and safety of eculizumab as first - line therapy in neonatal aHUS . However its use still requires optimization in terms of indications and administration ( frequency , dosage ) .",
"DB01257 : safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic - uremic syndrome : case report . In a recent study , eculizumab , a humanized monoclonal antibody which targets complement factor P01031 , appeared to resolve hemolysis and thrombocytopenia leading to recovery of renal function in a transplant patient during an episode of an atypical hemolytic uremic syndrome . We report the efficacy of eculizumab in a patient who presented with a recurrence of atypical hemolytic syndrome at 3 years after renal transplantation . After 17 months of eculizumab treatment , and without concomitant plasma therapy , renal function was maintained , the need for blood transfusions reduced , and acute thrombotic microangiopathy and hemolysis controlled . These data suggested that eculizumab should be considered to be a permanent treatment for this patient .",
"Aspergillus Niger peritonitis in a peritoneal dialysis patient treated with eculizumab . The complement system plays a vital role in preventing life - threatening infections by ensuring optimal functioning of the host immune system . Its dysregulation has been implicated in causing glomerular , hematological , and transplant - related disorders . DB01257 a novel monoclonal antibody against complement component P01031 has emerged in the recent past as the standard of care offering an effective rescue and maintenance therapy against many of these disorders . Its use has been associated with increased risk of infections predominantly with encapsulated organisms . There is no data in the literature on its effects in end - stage kidney disease ( ESKD ) or dialysis patients . We describe here a very rare case of Aspergillus Niger peritonitis in an ESKD patient on peritoneal dialysis ( PD ) receiving maintenance eculizumab therapy for atypical hemolytic uremic syndrome . Given that murine models with the same defect as that induced by eculizumab is vulnerable to invasive Aspergillosis , it is suggested that the fungal peritonitis in this patient was the result of the eculizumab therapy .",
"DB01257 in anti - factor h antibodies associated with atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a life - threatening multisystemic condition often leading to end - stage renal failure . It results from an increased activation of the alternative pathway of the complement system due to mutations of genes coding for inhibitors of this pathway or from autoantibodies directed against them . DB01257 is a monoclonal antibody directed against complement component P01031 and inhibiting the activation of the effector limb of the complement system . Its efficacy has already been demonstrated in aHUS . The present article reports for the first time the use of eculizumab in a patient presenting with aHUS associated with circulating anti - complement Factor H autoantibodies and complicated by cardiac and neurologic symptoms . Our observation highlights the efficacy of eculizumab in this form of aHUS not only on renal symptoms but also on the extrarenal symptoms . It also suggests that eculizumab should be used very promptly after aHUS presentation to prevent life - threatening complications and to reduce the risk of chronic disabilities . To obtain a complete inhibition of the effector limb activation , the advised dosage must be respected . After this initial therapy in the autoimmune aHUS form , a long - term immunosuppressive treatment should be considered , to prevent relapses by reducing anti - complement Factor H autoantibody plasma levels .",
"Efficacy of P01375 gene - transduced tumor cells in treatment of established in vivo tumor . The therapeutic effect of P01375 gene - transduced mouse fibrosarcoma cells ( Meth - A : P01031 ) on pre - inoculated parental cells ( Meth - A : M0 ) was studied . Subcutaneous ( s . c . ) transplantation of M0 cells into one flank of syngeneic BALB / c mice was followed by s . c . injection of irradiated MO or P01031 into the opposite flank 1 week later . The initial M0 tumor ( T - MO ) completely regressed in P01031 - vaccinated mice , whereas in M0 - vaccinated mice continuous growth of T - M0 was observed . When a similar experiment was carried out in SCID mice , no regression of T - MO was observed , suggesting that the tumor regression in BALB / c mice was not due to direct anti - tumor activity of P01375 secreted from P01031 , but to systemic immunity . Regression of the rechallenged M0 tumor was observed in mice which had shown T - MO regression by P01031 vaccination , but rechallenged Colon 26 cells ( syngeneic to BALB / c mice ) continued to grow , indicating a specific immunity to Meth - A cells ) . The systemic immunity evoked in P01031 - vaccinated mice was directly demonstrated by enhanced killer activities of Q96QP1 and CTL with a proliferation of T - cell population in their splenocytes . Abrogation of the therapeutic effect of P01031 vaccination with anti - Thy 1 and anti - Lyt 2 also demonstrates the involvement of cellular immunity in tumor regression .",
"Managing a pregnant patient with paroxysmal nocturnal hemoglobinuria in the era of eculizumab . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare clonal stem cell disorder , which affects women of child - bearing age . PNH is associated with thrombotic complications , which are the main causes of morbidity and mortality . Management of a pregnant woman with PNH remains a challenge due to high incidence of thrombotic complications and the difficulty of differentiating a PNH crisis from the complications of pregnancy . PNH is associated with an increased rate of premature labor and fetal loss . DB01257 , a humanized monoclonal antibody directed against the terminal complement protein P01031 , has revolutionized treatment of PNH . However , the role of eculizumab in pregnancy is unclear . We review the current strategies for the management of pregnant women with PNH , underline the controversies and present our recommendations .",
"Adaptive mutations in a human immunodeficiency virus type 1 envelope protein with a truncated V3 loop restore function by improving interactions with P01730 . We previously reported that a human immunodeficiency virus type 1 ( HIV - 1 ) clade B envelope protein with a severely truncated V3 loop regained function after passage in tissue culture . The adapted virus , termed Q96RJ0 , retained the V3 truncation , was exquisitely sensitive to neutralization by the P01730 binding site monoclonal antibody b12 and by HIV - positive human sera , used P51681 to enter cells , and was completely resistant to small molecule P51681 antagonists . To examine the mechanistic basis for these properties , we singly and in combination introduced each of the 5 mutations from the adapted clone Q96RJ0 into the unadapted envelope . We found that single amino acid changes in the P01024 region , the V3 loop , and in the fusion peptide were responsible for imparting near - normal levels of envelope function to Q96RJ0 . T342A , which resulted in the loss of a highly conserved glycosylation site in P01024 , played the primary role . The adaptive amino acid changes had no impact on P51681 antagonist resistance but made virus more sensitive to neutralization by antibodies to the P01730 binding site , modestly enhanced affinity for P01730 , and made Q96RJ0 more responsive to P01730 binding . Specifically , Q96RJ0 was triggered by soluble P01730 more readily than the parental Env and , unlike the parental Env , could mediate entry on cells that express low levels of P01730 . In contrast , Q96RJ0 interacted with P51681 less efficiently and was highly sensitive to antibodies that bind to the P51681 N terminus and ECL2 . Therefore , enhanced utilization of P01730 is one mechanism by which HIV - 1 can overcome mutations in the V3 region that negatively affect P51681 interactions .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK16___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) in childhood is a rare disease associated with high morbidity and mortality . Most cases progress to end - stage renal failure . In approximately 50 % of affected patients , mutations in genes encoding complement proteins are causative of the impairment in the regulation of the complement alternative pathway . This leads to deficient host cell protection and inappropriate complement activation on platelets and endothelial cells , particularly in the kidneys . P08603 ( FH ) heterozygosity induces unregulated activation of the membrane attack complex ( MAC ) C5b - 9 . Present therapeutic strategies for aHUS include lifelong plasmapheresis and renal dialysis . Unfortunately , kidney transplantation is frequently an unsatisfactory intervention due to the high rate of post - transplantation HUS recurrence , particularly in patients with FH mutation . Combined liver - kidney transplantation is also associated with poor outcome , mostly as a result of premature liver failure secondary to uncontrolled complement activation . DB01257 is a complement P01031 antibody that inhibits complement factor 5a ( C5a ) and the formation of the MAC . Thus , this antibody may be a promising new agent for patients with an aHUS undergoing kidney transplantation . We present the first case of a young patient with aHUS who received eculizumab as prophylactic treatment prior to a successful kidney transplantation .",
"Screening of high - affinity scFvs from a ribosome displayed library using BIAcore biosensor . An experimental protocol was developed to screen high - affinity single - chain Fv antibody fragments ( scFvs ) from a Xanthomonas axonopodis pv . citri ( Xac ) immunized ribosome display library using BIAcore biosensor . The screening methods involved immobilizing antigen [ lipopolysaccharides ( LPS ) of Xac ] on sensor chip Q9Y251 and then unpurified expression products of scFvs flowing over the immobilized sensor chip . The affinity - improved scFvs were selected based on dissociation rate constants ( k ( d ) ) . Thirty - five enzyme - linked immunosorbent assay - positive scFvs were analyzed by BIAcore , and three of those ( scFv A1 , B2 , and P01031 ) with lower k ( d ) were screened . To demonstrate the accuracy of the screening method , the three scFvs were expressed in Escherichia coli HB2151 and purified . The purified scFvs were subsequently further identified according to association rate and affinity constants . The results showed that the three scFvs ( A1 , B2 , and P01031 ) had high affinity for LPS of Xac ( 3 . 51 x 10 (- 11 ) , 1 . 13 x 10 (- 10 ) , 5 . 06 x 10 (- 10 ) M , respectively ) . Furthermore , the scFv B2 was highly specific for LPS of Xac and had no any cross - reactions with bovine serum albumin and LPS from Xac - related bacteria . This provided evidence that the information from the BIAcore screening assay could be accurate .",
"Treatment of a patient with classical paroxysmal nocturnal hemoglobinuria and Budd - Chiari syndrome , with complement inhibitor eculizumab : Case Report . Background . Paroxysmal nocturnal haemoglobinuria ( PNH ) is a rare acquired clonal disorder of hematopoietic stem cells involving all blood cells . Erythrocytes have increased susceptibility to complement - mediated haemolysis . Thrombosis is the leading cause of mortality and follows episodes of acute hemolysis . DB01257 , a monoclonal antibody blocking activation of complement P01031 is currently used in the treatment of PNH . Recent results demonstrated that eculizumab effectively reduces thrombosis . Description of case . We present a 30 - year - old male patient admitted with abdominal and lumbar pain . Thorough investigation revealed severe hemolytic anemia requiring transfusions and hepatosplenomegaly . Imaging findings were compatible with a Budd - Chiari syndrome . Flow cytometry confirmed the PNH diagnosis . Due to refractory ascites he underwent a transjugular intrahepatic portal - systemic shunt ( TIPS ) and eculizumab administration was started . Results . He has already completed three years of eculizumab treatment and he is transfusion independent . There is also a significant reduction in fatigue with improvement in his quality of life . Doppler scans of his TIPS persistently show it to be patent . Conclusions . Classical PNH patients with thrombosis and severe intravascular hemolysis are particularly challenging to manage . For these patients , eculizumab is a reasonable therapeutic option , expecting that by decreasing the risk for thrombosis , life expectancy may be increased .",
"Laboratory tests for paroxysmal nocturnal hemoglobinuria . Paroxysmal nocturnal hemoglobinuria ( PNH ) is a rare hematological disorder that is often suspected in a patient presenting with non - immune hemolytic anemia associated with pancytopenia or venous thrombosis . This disorder is a consequence of acquired somatic mutations in the phosphatidylinositol glycan class A ( P37287 ) gene in the hematopoietic stem cells ( P19526 ) of patients . The presence of these mutations leads to production of blood cells with decreased glycosyl phosphatidylinositol - anchored cell surface proteins , making red blood cells derived from the clone more sensitive to complement mediated hemolysis . The diagnosis of PNH may be difficult in some cases due a low proportion of PNH cells in the blood and occasionally due to difficulties in selecting the most appropriate diagnostic studies . The latest generation of tests allow for detection of very small populations of PNH cells , for following the natural course and response to therapy of the disease , and for helping to decide when to initiate therapy with monoclonal antibody targeting the terminal complement protein P01031 ( DB01257 ) , anticoagulation , and in some cases allogeneic P19526 transplant . In this article , we review the different diagnostic tests available to clinicians for PNH diagnosis .",
"Suppression of androgen receptor - mediated gene expression by a sequence - specific DNA - binding polyamide . P10275 ( AR ) is essential for the growth and progression of prostate cancer in both hormone - sensitive and hormone - refractory disease . A DNA - binding polyamide that targets the consensus androgen response element binds the prostate - specific antigen ( PSA ) promoter androgen response element , inhibits androgen - induced expression of PSA and several other AR - regulated genes in cultured prostate cancer cells , and reduces AR occupancy at the PSA promoter and enhancer . Down - regulation of PSA by this polyamide was comparable to that produced by the synthetic antiandrogen bicalutamide ( ___MASK30___ ) at the same concentration . Genome - wide expression analysis reveals that a similar number of transcripts are affected by treatment with the polyamide and with bicalutamide . Direct inhibition of the AR - DNA interface by sequence - specific DNA binding small molecules could offer an alternative approach to antagonizing AR activity .",
"Anti - complement therapy for glomerular diseases . A major shift in our understanding of glomerular diseases is the focus on which components of the complement pathway are involved in mediating kidney injury . For example , the membranoproliferative glomerulonephritis lesion is no longer classified solely by ultrastructural findings on biopsy and is now divided into immune - complex - mediated lesions vs complement - mediated lesions . In turn , this emphasis on complement leads to interest in therapies that target complement as potential disease - modifying agents . DB01257 , the first available anti - complement therapy , blocks at the level of P01031 and has revolutionized the treatment of atypical hemolytic uremic syndrome . Whether this agent will work equally well for the far more heterogeneous entities of P01024 glomerulonephritis and dense deposit disease remains unclear . Instead , newer agents that target P01024 may turn out to be the most effective and specific therapy for these P01024 glomerulopathies .",
"The Q9Y275 / APRIL system : emerging functions beyond B cell biology and autoimmunity . The Q9Y275 system plays a key role in the development of autoimmunity , especially in systemic lupus erythematosus ( SLE ) . This often leads to the assumption that Q9Y275 is mostly a B cell factor with a specific role in autoimmunity . Focus on Q9Y275 and autoimmunity , driven by pharmaceutical successes with the recent approval of a novel targeted therapy ___MASK46___ , has relegated other potential roles of Q9Y275 to the background . Far from being SLE - specific , the Q9Y275 system has a much broader relevance in infection , cancer and allergy . In this review , we provide the latest views on additional roles of the Q9Y275 system in health and diseases , as well as an update on Q9Y275 and autoimmunity , with particular focus on current clinical trials .",
"DB01257 in acute recurrence of thrombotic microangiopathy after renal transplantation . Renal thrombotic microangiopathy ( TMA ) is a severe complication of systemic lupus erythematosus ( SLE ) , which is associated with the presence of antiphospholipid ( aPL ) antibodies . In its most fulminant form , TMA leads to a rapid and irreversible end - stage renal failure . DB01257 , an anti - P01031 monoclonal antibody , is a novel therapy of choice for patients with paroxysmal nocturnal hemoglobinuria ( PNH ) and atypical hemolytic uremic syndrome . Here , we report the case of a 27 - year - old woman , known for SLE and end - stage renal disease due to fulminant TMA . Both aPL antibodies and antinucleosome antibodies were positive . The patient underwent a living - related kidney transplantation with immediate production of urine . Although serum creatinine was remaining high , a graft biopsy , performed on day 6 , demonstrated a TMA recurrence . Despite a treatment with plasma exchange , the situation got worse and dialysis was started . DB01257 treatment was subsequently administered and renal function improved rapidly . Three months after transplantation , serum creatinine was at 100 μmol / L , without proteinuria . This case illustrates the benefit of eculizumab therapy in a fulminant recurrence of TMA after kidney transplantation , resistant to classical therapy .",
"Complement inhibitor eculizumab in atypical hemolytic uremic syndrome . BACKGROUND AND OBJECTIVES : Atypical hemolytic uremic syndrome ( aHUS ) is associated with a congenital or acquired dysregulation of the complement alternative pathway that leads to continuous complement activation on host cells causing inflammation and damage . DB01257 , a humanized mAb against complement protein P01031 , inhibits activation of the terminal complement pathway . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS : We report an adolescent with relapsing unclassified aHUS . On admission , a high plasma creatinine level indicated a poor prognosis , and hemodialysis had to be started . Plasma exchanges were initially effective against the microangiopathic hemolytic activity and allowed a temporary improvement of renal function with termination of hemodialysis after 7 wk . Subsequently , plasma exchanges ( three times per week ) failed to prevent ongoing aHUS activity and progressive renal failure . After 12 wk , aHUS treatment was switched to eculizumab . RESULTS : DB01257 was effective in terminating the microangiopathic hemolytic process in two aHUS relapses ; however , after normalization of complement activity , aHUS recurred and ultimately led to anuric end - stage renal failure . CONCLUSIONS : In this patient , complement inhibition by eculizumab temporarily terminated the microangiopathic hemolytic activity . Nevertheless , renal damage as a result of preceding and subsequent aHUS activity resulted in end - stage renal failure ; therefore , therapeutic success may depend on early administration of eculizumab . The optimal duration of treatment may be variable and remains to be determined .",
"Blockade of alternative complement pathway in dense deposit disease . A patient aged 17 with dense deposit disease associated with complement activation , circulating P01024 Nef , and Factor H mutation presented with nephrotic syndrome and hypertension . Steroid therapy , plasma exchange , and rituximab failed to improve proteinuria and hypertension despite a normalization of the circulating sC5b9 complex . DB01257 , a monoclonal antibody directed against P01031 , was used to block the terminal product of the complement cascade . The dose was adapted to achieve a CH50 below 10 % , but proteinuria and blood pressure were not improved after 3 months of treatment .",
"Pyrogenic signaling via vagal afferents : what stimulates their receptors ? Although there is good evidence that pyrogenic messages may be conveyed from the periphery to the brain via vagal afferents , the exact nature of the factors that activate their sensory terminals is unclear . Since IL - 1beta and DB00917 have established roles in fever production and since their receptors have been identified on or near vagal nerves , they are potential candidate mediators . A difficulty , however , is that ( 1 ) IL - 1beta is not expressed constitutively in mononuclear phagocytes , their presumed cell source upon stimulation by exogenous pyrogens , e . g . endotoxin , and ( 2 ) similarly , the isoform of the enzyme that selectively mediates the production and release of DB00917 by endotoxin - stimulated macrophages , P35354 , is also not constitutively expressed in these cells . Since the transcription and translation of these factors significantly lags the onset of fever induced by endotoxin administered intravenously , in particular , it is possible that a secondary , quickly - acting mediator evoked in almost immediate reaction to the presence of endotoxin excites , directly or indirectly , the sensory neurons . We have evidence that the complement component P01031 contributes importantly to the initiation of the febrile response to endotoxin . This article briefly reviews the prevailing concepts of pyrogen sensing and signaling , examines their shortcomings particularly in terms of the temporal discrepancy between the very rapid onset of the febrile response to intravenously administered endotoxin and the significant delay in the elaboration of the putative mediators of fever , and presents newer data that may help to integrate the various preposed mechanisms .",
"Maintenance of kidney function following treatment with eculizumab and discontinuation of plasma exchange after a third kidney transplant for atypical hemolytic uremic syndrome associated with a P08603 mutation . Kidney transplant in patients with atypical hemolytic uremic syndrome ( aHUS ) is associated with a poor outcome because of recurrent disease , especially in patients known to have a factor H mutation . Long - term prophylactic plasma exchange and combined liver - kidney transplant have prevented graft loss caused by recurrence . However , the mortality associated with liver transplant is not negligible , and prophylactic plasma exchange requires permanent vascular access and regular hospitalization and exposes the patient to potential allergic reactions to plasma . DB01257 is a high - affinity humanized monoclonal antibody that binds to P01031 and thus prevents generation of C5a and the membrane attack complex . We report the case of a 17 - year - old girl with aHUS associated with a mutation in the gene for complement factor H ( P08603 ; c . 3572C > T , Ser1191Leu ) who was highly dependent on plasma exchange . Because of severe allergic reactions to plasma after the third renal graft , eculizumab was introduced in place of plasma exchange without problems . This and other reports suggest that the promise of complement inhibitors in the management of aHUS is going to be fulfilled .",
"___MASK88___ inhibits glycogen synthase kinase - 3 activity and mimics wingless signalling in intact cells . BACKGROUND : Exposing eukaryotic cells to lithium ions ( Li + ) during development has marked effects on cell fate and organization . The phenotypic consequences of Li + treatment on Xenopus embryos and sporulating Dictyostelium are similar to the effects of inhibition or disruption , respectively , of a highly conserved protein serine / threonine kinase , glycogen synthase kinase - 3 ( GSK - 3 ) . In Drosophila , the GSK - 3 homologue is encoded by zw3sgg , a segment - polarity gene involved in embryogenesis that acts downstream of wg . In higher eukaryotes , GSK - 3 has been implicated in signal transduction pathways downstream of phosphoinositide 3 - kinase and mitogen - activated protein kinases . RESULTS : We investigated the effect of Li + on the activity of the GSK - 3 family . At physiological doses , Li + inhibits the activity of human P49841 and Drosophila Zw3Sgg , but has no effect on other protein kinases . The effect of Li + on GSK - 3 is reversible in vitro . Treatment of cells with Li + inhibits GSK - 3 - dependent phosphorylation of the microtubule - associated protein Tau . Li + treatment of Drosophila S2 cells and rat PC12 cells induces accumulation of cytoplasmic Armadillo / beta - catenin , demonstrating that Li + can mimic Wingless signalling in intact cells , consistent with its inhibition of GSK - 3 . CONCLUSIONS : Li + acts as a specific inhibitor of the GSK - 3 family of protein kinases in vitro and in intact cells , and mimics Wingless signalling . This reveals a possible molecular mechanism of Li + action on development and differentiation .",
"Activation of cellular invasion by trefoil peptides and src is mediated by cyclooxygenase - and thromboxane A2 receptor - dependent signaling pathways . We have investigated the possible functional relationships between cellular invasion pathways induced by trefoil factors ( TFFs ) , src , and the cyclooxygenases P23219 and P35354 . Pharmacological inhibitors of the Rho small GTPase ( P01024 exoenzyme ) , phospholipase C ( U - 73122 ) , cyclooxygenases ( SC - 560 , NS - 398 ) , and the thromboxane A2 receptor ( P21731 ) antagonist SQ - 295 completely abolished invasion induced by intestinal trefoil factor , pS2 , and src in kidney and colonic epithelial cells MDCKts . src and PCmsrc . In contrast , invasion was induced by the P21731 mimetic U - 46619 , constitutively activated forms of the heterotrimeric G - proteins Galphaq ( AGalphaq ) , Galpha12 , Galpha13 ( AGalpha12 / 13 ) , which are signaling elements downstream of P21731 . Ectopic overexpression of pS2 cDNA and protein in MDCKts . src - pS2 cells and human colorectal cancer cells HCT8 / S11 - pS2 initiate distinct invasion signals that are Rho independent and P36551 and P21731 dependent . We detected a marked induction of P35354 protein and accumulation of the stable PGH2 / TXA2 metabolite TXB2 in the conditioned medium from cells transformed by src . This led to activation of the P21731 - dependent invasion pathway , which is monitored via a Rho - and Galpha12 / Galpha13 - independent mechanism using the Galphaq / PKC signaling cascade . These findings identify a new intracrine / paracrine loop that can be monitored by TFFs and src in inflammatory diseases and progression of colorectal cancers .",
"DB01257 therapy for atypical haemolytic uraemic syndrome due to a gain - of - function mutation of complement factor B . BACKGROUND : Atypical haemolytic uraemic syndrome ( aHUS ) is caused by dysregulated complement activation . A humanised anti - P01031 monoclonal antibody has recently become available for treatment of this condition CASE - DIAGNOSIS / TREATMENT : We present the first description of an infant with an activating mutation of complement factor B successfully treated with eculizumab . On standard doses she had evidence of ongoing P01031 cleavage despite a good clinical response . CONCLUSIONS : DB01257 is effective therapy for aHUS associated with factor B mutations , but recommended doses may not be adequate for all patients .",
"N - aryl - N '- benzylpiperazines as potential antipsychotic agents . N1 -( 2 - Alkoxyphenyl ) piperazines additionally containing an N4 - benzyl group bearing alcohol , amide , imide , or hydantoin functionalities were prepared and evaluated in the conditioned avoidance response ( CAR ) test predictive of clinical antipsychotic activity and in in vitro receptor - binding assays . Certain of the compounds display high affinity for the D2 , P08908 , and alpha 1 - adrenergic receptors . Structures bearing acyclic amide , lactam , and imide functionalities display good biological activity , with a preference for the 1 , 3 - disubstituted phenyl ring relative to the 1 , 4 - and 1 , 2 - congeners ( 7 vs 10 and 12 ) . Every possible position of hydantoin attachment was investigated ( e . g . , substitution at N1 , N3 , and P01031 ) . The hydantoin involving attachment to N1 ( 24 ) was found to have good biological activity , whereas those hydantoins with attachment to N3 or P01031 ( 22 , 23 , and 25 ) were inactive . Several of the smaller acetylated derivatives ( 30 and 33 ) have fair in vivo activity , which was lost in the case of the larger benzoyl analog 31 . DB03419 congener 34 had modest affinity for the D2 receptor ( 65 nM ) as well as excellent in vivo activity . Benzylamino compounds display ( viz . 27 and 35 - 38 ) moderate CAR activity but have surprising receptor affinity , often greater than those of comparable structures bearing a carbonyl ( 36 vs 7 ) . Benzyl and benzhydryl alcohol compounds 40 - 48 are more active than amino structures 27 and 35 - 38 and also exhibit excellent in vivo activity in the CAR test with modest D2 and P08908 receptor binding .",
"Opposed effects of lithium on the MEK - P29323 pathway in neural cells : inhibition in astrocytes and stimulation in neurons by GSK3 independent mechanisms . ___MASK88___ is widely used in the treatment of bipolar disorder , but despite its proven therapeutic efficacy , the molecular mechanisms of action are not fully understood . The present study was undertaken to explore lithium effects of the MEK / P29323 cascade of protein kinases in astrocytes and neurons . In asynchronously proliferating rat cortical astrocytes , lithium decreased time - and dose - dependently the phosphorylation of MEK and P29323 , with 1 mM concentrations achieving 60 and 50 % inhibition of P29323 and MEK , respectively , after a 7 - day exposure . ___MASK88___ also inhibited [ 3H ] thymidine incorporation into DNA and induced a G2 / M cell cycle arrest . In serum - deprived , quiescent astrocytes , pre - exposure to lithium resulted in the inhibition of cell cycle re - entry as stimulated by the mitogen endothelin - 1 : under this experimental setting , lithium did not affect the rapid , peak phosphorylation of MEK taking place after 3 - 5 min , but was effective in inhibiting the long - term , sustained phosphorylation of MEK . ___MASK88___ inhibition of the astrocyte MEK / P29323 pathway was independent of inositol depletion . Further , compound SB216763 inhibited Tau phosphorylation at Ser396 and stabilized cytosolic beta - catenin , consistent with the inhibition of glycogen synthase kinase - 3 beta ( P49841 ) , but failed to reproduce lithium effects on MEK and P29323 phosphorylation and cell cycle arrest . In cerebellar granule neurons , millimolar concentrations of lithium enhanced MEK and P29323 phosphorylation in a concentration - dependent manner , again through an inositol and P49841 independent mechanism . These opposing effects in astrocytes and neurons make lithium treatment a promising strategy to favour neural repair and reduce reactive gliosis after traumatic injury .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK20___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"Clinical grand rounds : atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a rare , lifethreatening , chronic , genetic disease of uncontrolled alternative pathway complement activation . The understanding of the pathophysiology and genetics of this disease has expanded over recent decades and promising new developments in the management of aHUS have emerged . Regardless of the cause of aHUS , with or without a demonstrated mutation or autoantibody , blockade of terminal complement activation through P01031 is of high interest as a mechanism to ameliorate the disease . DB01257 , an existing monoclonal antibody directed against P01031 with high affinity , prevents the perpetuation of the downstream activation of the complement cascade and the damage caused by generation of the anaphylotoxin C5a and the membrane attack complex C5b - 9 , by blocking P01031 cleavage . We report the successful use of eculizumab in a patient after kidney transplantation and discuss the disease aHUS .",
"Mycobacteria - primed macrophages and dendritic cells induce an up - regulation of complement C5a anaphylatoxin receptor ( CD88 ) in CD3 + murine T cells . Complement C5a anaphylatoxin is a potent activator of macrophages , neutrophils , and dendritic cells ( DC ) and binds the C5a receptor ( P21730 ; CD88 ) . Although C5a is chemotactic for T cells , expression of P21730 on murine T cells has been disputed . We report here that naïve , Con A - activated , and cytokine ( IL - 12 , Q14116 ) - stimulated murine CD3 + T cells from three strains of mice [ C57Bl / 6 , B10 . nSn ( P01031 +/+ ) , B10 . on ( P01031 -/- ) ] lacked P21730 , as evaluated by immunophenotyping with an anti - P21730 mAb . Ligation of CD3 induced a modest up - regulation with 3 % of CD3 + T cells expressing cell surface P21730 . T cells primed by P25054 differentiate into effector T cells . Activation of mycobacteria [ bacillus Calmette - Guerin ( BCG ) ] - sensitized T cells through MHC II and TCR interactions via BCG - infected macrophages enhanced the expression of P21730 with approximately 14 % of CD3 + T cells positive for P21730 . Comparable expression was found in P01031 +/+ as well as P01031 -/- strains of mice ( 14 % and 15 % , respectively ) . Furthermore , anti - CD3 - activated T cells were primed by BCG - infected DC , and a larger proportion of the primed T cells expressed P21730 ( 30 - 40 % ) . Finally , mice infected with BCG showed significant numbers of CD3 + T cells expressing P21730 in the spleens during infection . As P25054 , such as macrophages and DC , can secrete P01031 and cleave P01031 to C5a and C5b through a peptidase , we suggest that macrophage and DC - T cell interactions can up - regulate P21730 on T cells through MHC II - TCR and provide a C5a peptide for additional local activation of T cells via P21730 .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK48___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .",
"Efficacy of eculizumab in a patient with factor - H - associated atypical hemolytic uremic syndrome . Atypical hemolytic uremic syndrome ( aHUS ) is a rare , chronic , life - threatening disease due to complement dysregulation . The use of early - onset plasma therapy is recommended , but optimal long - term treatment regimen is not well defined . DB01257 , a monoclonal humanized anti - P01031 antibody , has shown success in patients with aHUS . We report a 7 - year - old girl with aHUS associated with factor H mutations successfully treated with eculizumab . Weekly plasma infusion ( PI ) of 25 - 30 ml / kg with short - term intensified PI during aHUS exacerbations was effective for 4 . 3 years . Progressive mild renal failure ( stage 2 ) was attributed to chronic glomerular lesions . Subsequently , she exhibited aHUS exacerbation unresponsive to intensified PI . DB01257 was initiated at 600 mg , resulting in immediate and complete inhibition of terminal complement activation . During the week following treatment , we observed a complete reversal of aHUS activity . She has been receiving 600 mg eculizumab every 2 weeks for the last 12 months . She had no aHUS exacerbation , and serum creatinine level returned to normal . In this patient , eculizumab led to control of PI - resistant aHUS exacerbation and chronic microangiopathic hemolytic activity . Clinical trials are ongoing to assess the safety and efficacy of this drug in the management of aHUS .",
"DB01257 for the treatment of preeclampsia / HELLP syndrome . Severe preeclampsia with hemolysis , elevated liver enzymes and low platelets ( HELLP ) syndrome is a leading cause of maternal and neonatal morbidity and mortality worldwide . Occurrence at an extremely premature gestational age is most challenging as there are dichotomous imperatives : delivery as definitive therapy for maternal health vs . prolongation of pregnancy to avoid prematurity and associated morbidities . We describe a patient presenting with severe preeclampsia / HELLP syndrome at 26 weeks gestation that was treated with DB01257 , a targeted inhibitor of complement protein P01031 , which resulted in marked clinical improvement and complete normalization of lab parameters . Pregnancy was prolonged 17 days , likely resulting in a reduction of neonatal morbidity with its associated short and long - term health care costs . Successful use of DB01257 in this case suggests that complement inhibition may be an effective treatment strategy for severe preeclampsia / HELLP syndrome ."
] |
[
"___MASK16___",
"___MASK20___",
"___MASK30___",
"___MASK43___",
"___MASK46___",
"___MASK48___",
"___MASK63___",
"___MASK85___",
"___MASK88___"
] |
___MASK46___
|
MH_train_478
|
interacts_with DB01268?
|
[
"P84022 linker phosphorylation attenuates P84022 transcriptional activity and TGF - β1 / P84022 - induced epithelial - mesenchymal transition in renal epithelial cells . Transforming growth factor - β1 ( TGF - β1 ) has a distinct role in renal fibrosis associated with epithelial - mesenchymal transition ( EMT ) of the renal tubules and synthesis of extracellular matrix . P84022 plays an essential role in fibrosis initiated by EMT . Phosphorylation of P84022 in the C - terminal SSXS motif by type I TGF - β receptor kinase is essential for mediating TGF - β response . P84022 activity is also regulated by phosphorylation in the linker region . However , the functional role of P84022 linker phosphorylation is not well characterized . We now show that P84022 EPSM mutant , which mutated the four phosphorylation sites in the linker region , markedly enhanced TGF - β1 - induced EMT of P84022 - deficient primary renal tubular epithelial cells , whereas P84022 3S - A mutant , which mutated the C - terminal phosphorylation sites , was unable to induce EMT in response to TGF - β1 . Furthermore , immunoblotting and RT - PCR analysis showed a marked induction of fibrogenic gene expression with a significant reduction in P12830 in P52789 human renal epithelial cells expressing P84022 EPSM . TGF - β1 could not induce the expression of α - SMA , vimentin , fibronectin and P05121 or reduce the expression of P12830 in P52789 cells expressing P84022 3S - A in response to TGF - β1 . Our results suggest that P84022 linker phosphorylation has a negative regulatory role on P84022 transcriptional activity and TGF - β1 / P84022 - induced renal EMT . Elucidation of mechanism regulating the P84022 linker phosphorylation can provide a new strategy to control renal fibrosis .",
"The role of P10721 in the management of patients with gastrointestinal stromal tumors . In recent years , immunohistochemical staining for P10721 ( CD117 ) has become integral to the diagnosis of gastrointestinal stromal tumors ( GISTs ) , nearly 90 % of which harbor activating mutations in the P10721 receptor tyrosine kinase gene . Approximately 80 % of patients with metastatic GIST show at least some clinical response to the targeted small molecule P10721 inhibitor imatinib . The response to imatinib is closely correlated with the presence and type of P10721 mutation . GISTs with the most common P10721 exon 11 mutations have the highest response rate by far , whereas GISTs lacking mutations in P10721 or the alternative receptor tyrosine kinase P16234 show much lower rates of response to imatinib . Less than 5 % of GISTs are P10721 - immunonegative ; and many of these tumors have activating mutations of P16234 , some of which are also inhibited by imatinib . Most patients who initially respond to imatinib become resistant and eventually progress , which coincides with the selection of imatinib - resistant secondary P10721 mutations in the kinase domain . DB01268 has recently been approved for patients with GIST , principally those who fail imatinib therapy ; and additional small molecule inhibitors are in the pipeline . It is becoming evident that alternative approaches to direct P10721 inhibition will be required for long - term survival of patients with advanced GISTs . This review examines the role of P10721 in the diagnosis and management of patients with GIST .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK45___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK67___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK67___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK67___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK67___ among adults with ADHD .",
"Complementary and alternative medicine use and quality of life in patients with primary brain tumors . This study explored the use of complementary and alternative medicine ( P62158 ) approaches and their relationship with demographic and disease characteristics and quality of life ( QOL ) in the primary brain tumor ( P10721 ) population . One hundred one P10721 patients were enrolled in this study . The results showed that 34 % of patients reported using P62158 . Forty - one percent reported using more than one type of P62158 . The average cost of each P62158 used per month was 69 dollars , with 20 % of patients spending more than 100 dollars per month . The majority ( 74 % ) reported that their physicians were unaware of their use of P62158 . Data analysis found a higher performance status to be the only factor significantly related to use of P62158 therapy ( P < 0 . 005 ) . There was no difference in patient report of QOL between users and nonusers of P62158 therapies . The high number of patients who do not report P62158 use has potential implications for evaluation of symptoms and response to therapy in this population . This may be especially relevant in those patients with higher functional status participating in clinical trials .",
"P01308 reverses growth hormone - induced homologous desensitization . Growth hormone ( GH ) is secreted in a pulsatile pattern to promote body growth and metabolism . GH exerts its function by activating several signaling pathways , including O60674 / P35610 and MEK / P29323 . P27361 / 2 activation by GH plays important roles in gene expression , cell proliferation , and growth . We previously reported that in rat H4IIE hepatoma cells after an initial GH exposure , a second GH exposure induces P42229 phosphorylation but not P27361 / 2 phosphorylation ( Ji , S . , Frank , S . J . , and Messina , J . L . ( 2002 ) J . Biol . Chem . 277 , 28384 - 28393 ) . In this study the mechanisms underlying GH - induced homologous desensitization were investigated . A second GH exposure activated the signaling intermediates upstream of MEK / P29323 , including O60674 , Ras , and P04049 . This correlated with recovery of P10912 levels , but was insufficient for GH - induced phosphorylation of Q02750 / 2 and P27361 / 2 . P01308 restored the ability of a second GH exposure to induce phosphorylation of Q02750 / 2 and P27361 / 2 without altering P10912 levels or GH - induced phosphorylation / activation of O60674 and P04049 . GH and insulin synergized in promoting cell proliferation . Further investigation suggested that insulin increased the amount of MEK bound to Q8IVT5 ( kinase suppressor of Ras ) and restored GH - induced tyrosine phosphorylation of Q8IVT5 . Previous GH exposure also induced desensitization of P42224 and P40763 phosphorylation , but this desensitization was not reversed by insulin . Thus , insulin - regulated resensitization of GH signaling may be necessary to reset the complete response to GH after a normal , physiologic pulse of GH .",
"DB01268 induced pyoderma gangrenosum - like ulcerations . Pyoderma gangrenosum is a non - infectious neutro ? philic skin disease commonly associated with underlying systemic diseases . Histopathological and laboratory diagnostics are unspecific in the majority of the cases and the diagnosis is made in accordance with the clinical picture . Here , we report the case of a 69 - year old man with progredient pyoderma gangrenosum - like ulcerations under treatment with sunitinib due to hepatocellular carcinoma . A conventional ulcer therapy did not lead to a regression of the lesions . Solely cessation of sunitinib therapy resulted in an improvement of the ulcerations . DB01268 is a multikinase inhibitor that targets the PDGF - α - and ? β - , P15692 - 1 - 3 - , P10721 - , P36888 - , P09603 - and P07949 - receptor , thereby impairing tumour proliferation , pathological angiogenesis and metastasation . Here , we demonstrate that pyoderma gangrenosum - like ulcers may represent a serious side effect of sunitinib - based anti - cancer treatment .",
"Association of Ang - 2 with integrin beta 2 controls Ang - 2 / DB00102 - dependent upregulation of human peripheral blood monocyte fibrinolysis . O15123 ( Ang - 2 ) , an angiogenic factor that is generally considered an autocrine factor for endothelial cells was shown in a previous study to upregulate peripheral blood monocyte fibrinolysis in concert with platelet - derived growth factor - BB ( DB00102 ) . This upregulation of fibrinolysis was demonstrated to be due to upregulation of elements of the matrix metalloproteinase and serine protease fibrinolytic pathways . The manner in which Ang - 2 interacts with monocytes was not elucidated though no expression of the angiopoietin receptor tyrosine kinase Tie - 2 was found for monocytes . In this study Ang - 2 was found to bind to integrin beta ( 2 ) , and functional inhibition of integrin beta ( 2 ) eliminated Ang - 2 / DB00102 - mediated upregulation of monocyte fibrin invasion . Additionally , integrin beta ( 2 ) blockade significantly inhibited the Ang - 2 / DB00102 based increase in matrix metalloproteinase - 9 ( P14780 ) and membrane type - 1 - MMP ( P50281 ) . Furthermore , Ang - 2 / DB00102 - upregulated urokinase plasminogen - activator receptor ( Q03405 ) was shown to be associated in complexes with integrin beta ( 2 ) . In addition , Ang - 2 was shown to upregulate P09619 expression in monocytes . Therefore several components of the mechanism via which the novel interaction of Ang - 2 and DB00102 with monocytes occurs have been identified .",
"The role of vascular endothelial growth factor and matrix metalloproteinases in canine lymphoma : in vivo and in vitro study . BACKGROUND : Canine lymphoma represents the most frequent haematopoietic cancer and it shares some similarities with human non - Hodgkin lymphoma . Matrix metalloproteinases ( MMPs ) and vascular endothelial growth factor ( P15692 ) play a coordinated role during invasion and proliferation of malignant cells ; however , little is known about their role in canine haematologic malignancies . The aim of this study was to investigate the mRNA and protein expression of P15692 and the most relevant MMPs in canine lymphoma . Lymph node aspirates from 26 B - cell and 21 T - cell lymphomas were collected . The protein expression levels of P14780 , P08253 and P15692 were evaluated by immunocytochemistry , and the mRNA levels of P08253 , P14780 , P50281 , P01033 , P16035 , O95980 , P15692 and P15692 - 164 were measured using quantitative RT - PCR . RESULTS : P50281 , P01033 and O95980 mRNA levels were significantly higher in T - cell lymphomas than in B - cell lymphomas . Higher mRNA and protein levels of P14780 and P15692 were observed in T - cell lymphomas than in B - cell lymphomas and healthy control lymph nodes . A positive correlation was found between P14780 and P15692 in T - cell lymphomas . Moreover , P14780 , P50281 , P01033 and P15692 were expressed at the highest levels in high - grade T - cell lymphomas . CONCLUSIONS : This study provides new information on the expression of different MMPs and P15692 in canine lymphoma , suggesting a possible correlation between different MMPs and P15692 , immunophenotype and prognosis .",
"___MASK99___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK99___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"Gastrointestinal stromal tumors : a review of case reports , diagnosis , treatment , and future directions . Gastrointestinal stromal tumor ( GIST ) is a nonepithelial , mesenchymal tumor first described by Mazur and Clark in 1983 . Since then , its molecular biology has been studied in great detail . Special interest in the role of tyrosine kinase in its regulation has been the target by different drug research . Mutation in c - kit exons 9 , 11 , 13 , 17 and P16234 mutation in exons 12 , 14 , 18 are responsible for activation of gene signaling system resulting in uncontrolled phosphorylation and tissue growth . However , 5 to 15 % of GISTs does not harbor these mutations , which raises additional questions in another alternate signaling pathway mutation yet to be discovered . Diagnosis of GISTs relies heavily on P10721 / CD117 immunohistochemical staining , which can detect most GISTs except for a few 3 % to 5 % that harbors P16234 mutation . Newer staining against PKC theta and DOG - 1 genes showed promising results but are not readily available . Clinical manifestation of GISTs is broad and highly dependent on tumor size . Surgery still remains the first - line treatment for GISTs . The advancement of molecular biology has revolutionized the availability of newer drugs , Imatinib and DB01268 . Together with its advancement is the occurrence of Imatinib / DB01268 drug resistance . With this , newer monoclonal antibody drugs are being developed and are undergoing clinical trials to hopefully improve survival in patients with GISTs .",
"Gene profiling in Pap - cell smears of high - risk human papillomavirus - positive squamous cervical carcinoma . OBJECTIVE : The purpose of the study was to investigate benign and malignant squamous cervical cells obtained by cervical swabs with regard to differentially expressed genes and gene expression profiling , in order to evaluate the biological behavior and clinical outcome of cervical malignancies . METHODS : Cervical squamous cells from six women with high - risk human papillomavirus positive [ HR - HPV (+) ] cervical carcinoma and from six HPV - negative women with normal ectocervical cells were analyzed by cDNA array . RESULTS : cDNA over - expression of several genes such as MET ( c - met ) , Nm23 - H1 ( P15531 ) , P00533 , P21802 , Nm23 - H2 ( P22392 ) , P04626 ( c - erbB - 2 ) , cyclin - dependent kinase inhibitor 4 ( CDKN2A , P42771 ) , cytokeratin 8 ( P05787 ) , P01116 ( K - ras ) , P17948 , KGF ( P21781 ) , P10415 - like 2 protein ( Q92843 ) , Q15303 , P04198 ( N - myc ) , cyclin D1 ( P24385 ) , P10721 ( c - kit ) , secreted phosphoprotein 1 ( P10451 ) and P42224 , was significant in cervical squamous cell carcinoma ( CSCC ) . Gene expression was downregulated for 13 genes in CSCC , such as interleukin 1 alpha ( P01583 ) , the transforming growth factor receptor beta superfamily ( TGFbeta ; P01137 ) , some members of the insulin - like growth factor binding proteins ( IGFBPs ) and the integrin family ( P23229 , P05556 ) . CONCLUSION : This study was focused on the gene expression profiling of HR - HPV (-) and ( + ) cervical squamous cells and CSCC obtained by cytobrush . We observed gene expression patterns and signaling pathways that permit the investigator to distinguish between benign squamous cervical cells and CSCC with and without HPV infection .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK94___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"Raddeanin A , a triterpenoid saponin isolated from Anemone raddeana , suppresses the angiogenesis and growth of human colorectal tumor by inhibiting P35968 signaling . Raddeanin A ( RA ) is an active triterpenoid saponin from a traditional Chinese medicinal herb , Anemone raddeana Regel . It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells . However , whether RA can inhibit angiogenesis , an essential step in cancer development , remains unknown . In this study , we found that RA could significantly inhibit human umbilical vein endothelial cell ( HUVEC ) proliferation , motility , migration , and tube formation . RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane ( P62158 ) , restrained the trunk angiogenesis in zebrafish , and suppressed angiogenesis and growth of human HCT - 15 colorectal cancer xenograft in mice . Western blot assay showed that RA suppressed P15692 - induced phosphorylation of P35968 and its downstream protein kinases including PLCγ1 , O60674 , Q05397 , Src , and Akt . Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the DB00171 binding pocket of P35968 kinase domain . Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis , demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy .",
"Prognostic role of Q01094 and members of the CDKN2A network in gastrointestinal stromal tumors . PURPOSE : The aim of the current study was to examine the prognostic relevance of the CDKN2A tumor suppressor pathway in gastrointestinal stromal tumors ( GIST ) . EXPERIMENTAL DESIGN : We determined the mRNA expression of p1 ( INK4A ) , p14 ( Q8N726 ) , P11802 , P06400 , Q00987 , P04637 , and Q01094 by quantitative reverse transcription - PCR in 38 cases of GISTs and correlated the findings with clinicopathologic factors , including mutation analysis of P10721 and P16234 . RESULTS : The k - means cluster analysis yielded three prognostic subgroups of GISTs with distinct mRNA expression patterns of the CDKN2A pathway . GISTs with low mRNA expression of the CDKN2A transcripts p16 ( INK4A ) and p14 ( Q8N726 ) but high mRNA expression of P11802 , P06400 , Q00987 , P04637 , and Q01094 were associated with aggressive clinical behavior and unfavorable prognosis , whereas GISTs with a low mRNA expression of P11802 , P06400 , Q00987 , P04637 , and Q01094 were not . GISTs with a moderate to high mRNA expression of all examined genes also seemed to be associated with unfavorable prognosis . Regarding mutation analysis , we found significant differences in the P10721 / P16234 genotype among the three clusters . Univariate analysis revealed high expression of Q01094 to be associated with mitotic count , proliferation rate , P10721 mutation , and aggressive clinical behavior . These findings on mRNA level could be confirmed by immunohistochemistry . CONCLUSION : Our findings implicate differential regulation schemes of the CDKN2A tumor suppressor pathway converging to up - regulation of Q01094 as the critical link to increased cell proliferation and adverse prognosis of GISTs .",
"Pharmacological management of gastrointestinal stromal tumours : an update on the role of sunitinib . The efficacy and tolerability of the receptor tyrosine kinase inhibitor , sunitinib malate , have been demonstrated in phase I - III clinical trials of patients with imatinib - resistant or imatinib - intolerant gastrointestinal stromal tumours ( GIST ) as well as in a worldwide expanded - access study and in a continuous daily dosing ( CDD ) trial . Tumour genotype may have a significant influence on the activity of sunitinib in patients with imatinib - resistant GIST . DB01268 activity was observed across different GIST genotypes and particularly in patients with wild - type and P10721 exon 9 mutations ( all relatively resistant to standard - dose imatinib ) and in patients with secondary P10721 exons 13 and 14 mutations . Adverse events with sunitinib were generally mild to moderate and easily managed by dose reduction , dose interruption or standard supportive measures . Treatment discontinuation can be avoided in most patients by close monitoring before and during treatment with appropriate adverse event management as necessary . The correlation between treatment exposure and clinical response is prompting the search for new approaches to treatment optimisation to ensure that patients derive maximum benefit from sunitinib therapy , including dose adjustments based on blood testing to ensure optimal drug exposure , and the use of the alternative CDD regimen to avoid treatment interruption .",
"New paradigms in gastrointestinal stromal tumour management . BACKGROUND : Targeted agents have improved the prognosis for patients with advanced gastrointestinal stromal tumours ( GISTs ) . Many patients exhibit intolerance or resistance to first - line therapy with imatinib mesylate . DB01268 malate is approved multinationally for the treatment of advanced imatinib - refractory GIST . DESIGN : This article reviews responses to imatinib and sunitinib reported in clinical trials in advanced GIST and discusses the effect of mutational status on treatment responses ; therapeutic developments in GIST treatment are also reviewed . RESULTS : Imatinib 400 mg / day has shown efficacy for first - line treatment of advanced GIST , particularly in patients with P10721 exon 11 mutations . DB01268 50 mg / day ( Schedule 4 / 2 ) has demonstrated effectiveness and tolerability in imatinib - refractory GIST , including patients who would be excluded from clinical trials . DB01268 is associated with longer median overall survival in patients with primary P10721 exon 9 mutations and wild - type GIST compared with P10721 exon 11 mutations in a retrospective study . Ongoing studies , including imatinib in the adjuvant setting and the use of targeted agents in sequence or in combination , will further refine the therapeutic pathway for advanced GIST . CONCLUSIONS : The availability of targeted therapies and greater knowledge of the effect of mutational status on patient responses will assist in optimising outcomes in advanced GIST .",
"Molecular target modulation , imaging , and clinical evaluation of gastrointestinal stromal tumor patients treated with sunitinib malate after imatinib failure . PURPOSE : To evaluate sunitinib activity and potential cellular and molecular correlates in gastrointestinal stromal tumor ( GIST ) patients after imatinib failure , in addition to assessing the safety and pharmacokinetics ( PK ) of different dose schedules . EXPERIMENTAL DESIGN : In this open - label , dose - ranging , phase I / II study , 97 patients with metastatic imatinib - resistant / intolerant GIST received sunitinib at doses of 25 , 50 , or 75 mg / d on one of three schedules . Serial tumor imaging was done using computed tomography and [ 18F ] fluoro - 2 - deoxy - d - glucose positron emission tomography scanning . PK and cell proliferation and P10721 phosphorylation status in tumor biopsies were also analyzed . RESULTS : Clinical benefit was observed in 52 patients ( 54 % : 7 objective partial responses , 45 stable disease > or = 6 months ) . Decreased tumor glycolytic activity was shown in most patients within 7 days of starting sunitinib using [ 18F ] fluoro - 2 - deoxy - d - glucose positron emission tomography . DB01268 treatment was associated with reduced tumor cell proliferation by > 25 % in 52 % of cases analyzed and reduced levels of phospho - P10721 in tumor biopsies ( indicating target modulation ) . The recommended dose schedule was 50 mg / d for 4 weeks followed by 2 weeks off treatment . On the 50 - mg dose across all schedules , 79 % of PK - evaluable patients achieved total drug trough concentrations above the target concentration ( 50 ng / mL ) within 14 days of dosing . In addition , adverse events were generally mild to moderate in severity . CONCLUSION : Cellular and molecular analyses showed that sunitinib clinical activity is associated with inhibition of P10721 in GIST following imatinib failure , illustrating the rational approach used to develop a therapy aimed at the underlying oncogenic signaling pathway aberrancy .",
"___MASK46___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"DB01268 induces P60484 expression and inhibits P09619 signaling and migration of medulloblastoma cells . We previously showed that inhibition of the platelet - derived growth factor receptor ( P09619 ) blocks the survival and migration of medulloblastoma cells . Identification of in vitro P09619 - targeting pharmacologic agents that are suitable for preclinical testing in medulloblastoma models in vivo will be critical for efficiently translating these agents to clinical investigation in children with medulloblastoma . In this study , we investigated whether the multi - tyrosine kinase inhibitor sunitinib , effectively inhibits P09619 signaling required for medulloblastoma cell migration . Daoy and D556 human medulloblastoma cells pre - treated for 1 h with 0 . 2 μM sunitinib demonstrated induction of P60484 expression and significant inhibition of P09619 signaling activity and transactivation of P00533 , in a DB01367 - independent manner , in response to DB00102 stimulation . DB01268 pre - treatment markedly reduced medulloblastoma cell migration in response to both DB00102 and 10 % serum at 4 and 24 h after treatment . Pre - treatment with sunitinib for 1 h also resulted in detachment and decreased viability of D556 , but not Daoy , cells and only after 48 h following treatment . However , sunitinib did not induce apoptosis in either cell line at any time point , indicating that the anti - migratory effects of sunitinib were not due to impeding cell survival . DB01268 similarly inhibited P09619 signaling and migration of primary murine Smo / Smo medulloblastoma cells , suggesting that the Smo / Smo mouse is an appropriate model for preclinical testing of sunitinib . These results indicate that sunitinib may be an important pharmacologic agent for the treatment of invasive medulloblastoma , particularly given evidence of its ability to cross the blood - brain barrier to target tumor cells , and thus warrants further in vivo testing for confirmation of efficacy .",
"Indicators for the exposure assessment of transformation products of organic micropollutants . Environmental transformation products of organic micropollutants have the potential to be similarly or even more mobile , persistent , ortoxic than their parent compounds . They should , therefore , be included in chemical hazard and risk assessment procedures as well as in the assessment of soil and water quality . To fulfill this requirement most efficiently , screening approaches that select relevant transformation products for detailed assessment are needed . This paper presents two process - based multimedia , multispecies models that allow us to quantitatively estimate the environmental fate of transformation products . The resulting exposure patterns are assessed with two indicators : joint persistence ( JP ) , which describes the temporal extent of environmental exposure to a parent compound and its transformation products , and the predicted relative aquatic concentrations ( P31749 ) , which estimate the relative concentrations of parent compounds and their transformation products in surface water bodies . As a case study , JP and P31749 are calculated for 16 pesticides and their relevant transformation products . The results for the JP indicator confirm the importance of considering transformation products in the assessment of overall persistence ; for example , in the context of P10721 assessments . Comparison of P31749 results with monitoring data on herbicides and their transformation products shows the suitability of our approach for estimating relative concentrations in surface water , and as a consequence , its usefulness in identifying transformation products for future water quality monitoring programs . Transformation products of triketones and other highly used acidic herbicides are specifically identified as targets .",
"Expression and mutational status of treatment - relevant targets and key oncogenes in 123 malignant salivary gland tumours . BACKGROUND : Malignant tumours of the salivary glands ( MSGT ) are rare and pleomorphic entities . Patients with advanced disease may benefit from targeted therapy ; however , specific targets for optimising and personalising treatments are yet to be identified . DESIGN : Immunohistochemistry for C - P10721 , P00533 , P04626 , P15941 , phospho - P42345 , androgen / estrogens / progesterone receptors and Ki67 was carried out and evaluated in terms of progression - free and overall survival . High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology . RESULTS : Several therapy leads were identified , including high levels of P04626 and androgen receptors in salivary duct carcinomas , C - P10721 in myoepithelial carcinomas and P00533 in mucoepidermoid carcinomas . Recurrent mutations involving downstream elements of the P00533 pathway were found in P01112 , notably in tumours with a myoepithelial component , and in other key oncogenes ( P01116 / P01111 / PI3KCA / P15056 / MAP2K ) . On the other hand , < 1 % of samples had P00533 or P04626 mutations . CONCLUSION : Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads . Genotyping results suggest activation downstream of P00533 in 18 of the 107 samples that could be associated with low efficacy of P00533 inhibitors . Other molecules , such as PI3K / MEK or P42345 inhibitors , may have anti - tumour activity in this subgroup . The high mutation rate in P01112 highlights a novel key oncogenic event in MSGT .",
"DB11588 donors or heme oxygenase - 1 ( P09601 ) overexpression blocks interleukin - 18 - mediated NF - kappaB - P60484 - dependent human cardiac endothelial cell death . The objective of this study was to determine whether heme oxygenase - 1 ( P09601 ) or heme metabolites exert cytoprotective effects on interleukin - 18 - mediated endothelial cell ( EC ) death . Treatment with interleukin ( IL ) - 18 increased NF - kappaB activation and P60484 induction , suppressed Akt activation , and stimulated EC death . While ectopic expression of p65 enhanced P60484 transcription , adenoviral transduction of dnIkappaB - alpha , dnp65 , or dnIKKbeta was inhibitory . Furthermore , Q14116 suppressed P09601 mRNA expression via enhanced mRNA degradation . Overexpression of P09601 , treatment with P09601 inducer hemin , or the CO donor cobalt ( III ) protoporphyrin IX all reversed Q14116 - mediated NF - kappaB activation , P60484 induction , Akt suppression , and EC death . Furthermore , hemin induced P09601 expression , and P09601 knockdown , P09601 inhibition , or CO scavengers all reversed the prosurvival effects of hemin . In addition , the CO donors CORM - 1 and CORM - 3 and the heme metabolites biliverdin and bilirubin attenuated Q14116 - induced EC death via a similar signaling pathway . Q14116 induced p38alpha MAPK activation , and suppressed p38beta isoform expression . While p38alpha knockdown attenuated , p38beta knockdown potentiated Q14116 - mediated EC death . DB03404 and P09601 reversed Q14116 - mediated p38alpha induction and restored p38beta levels . These results demonstrate that Q14116 suppresses P09601 expression and induces EC death . P09601 overexpression , P09601 induction , or treatment with heme metabolites all reverse Q14116 - mediated p38alpha MAPK and NF - kappaB activation , P60484 induction , Akt suppression , and EC death . Thus , P09601 inducers and CO donors may have the therapeutic potential to effectively block Q14116 signaling and reduce Q14116 - dependent vascular injury and inflammation .",
"Small in - frame deletion in the epidermal growth factor receptor as a target for DB05294 . DB05294 is an inhibitor of vascular endothelial growth factor receptor - 2 ( P35968 / P35968 ) tyrosine kinase , with additional activity against epidermal growth factor receptor ( P00533 ) tyrosine kinase . DB05294 inhibits angiogenesis and growth of a wide range of tumor models in vivo . Gefitinib ( \" ___MASK62___ \" ) is a selective P00533 tyrosine kinase inhibitor that blocks signal transduction pathways implicated in cancer cell proliferation . Here , the ability of gefitinib and DB05294 to inhibit tumor cell proliferation was examined directly in eight cancer cell lines in vitro , and a strong correlation was noted between the IC ( 50 ) values of gefitinib and DB05294 ( r = 0 . 79 ) . No correlation was observed between the sensitivity to DB05294 and the level of P00533 or VEGFR expression . The NSCLC cell line PC - 9 was seen to be hypersensitive to gefitinib and DB05294 , and a small ( 15 - bp ) in - frame deletion of an DB00171 - binding site ( exon 19 ) in the P00533 was detected ( delE746 - A750 - type deletion ) . To clarify the involvement of the deletional mutation of P00533 in the cellular sensitivity to DB05294 , we examined the effect of this agent on HEK293 stable transfectants expressing deletional P00533 that designed as the same deletion site observed in PC - 9 cells ( 293 - pDelta15 ) . These cells exhibited a 60 - fold higher sensitivity to DB05294 compared with transfectants expressing wild - type P00533 . DB05294 inhibited the phosphorylation of the mutant P00533 by 10 - fold compared with cells with wild - type P00533 . In conclusion , the findings suggested that a small in - frame deletion in the P00533 increased the cellular sensitivity to DB05294 .",
"Estradiol increases cell growth in human astrocytoma cell lines through ERα activation and its interaction with Q15788 and Q9Y6Q9 coactivators . Estradiol ( E2 ) regulates several cellular functions through the interaction with estrogen receptor subtypes , ERα and ERβ , which present different functional and regulation properties . ER subtypes have been identified in human astrocytomas , the most common and aggressive primary brain tumors . We studied the role of ER subtypes in cell growth of two human astrocytoma cell lines derived from tumors of different evolution grades : U373 and D54 ( grades III and IV , respectively ) . E2 significantly increased the number of cells in both lines and the co - administration with an ER antagonist ( ICI 182 , 780 ) significantly blocked E2 effects . ERα was the predominant subtype in both cell lines . E2 and ICI 182 , 780 down - regulated ERα expression . The number of U373 and D54 cells significantly increased after PPT ( ERα agonist ) treatment but not after DPN ( ERβ agonist ) one . To determine the role of Q15788 and Q9Y6Q9 coactivators in ERα induced cell growth , we silenced them with RNA interference . Coactivator silencing blocked the increase in cell number induced by PPT . The content of proteins involved in proliferation and metastasis was also determined after PPT treatment . Western blot analysis showed that in U373 cells the content of PR isoforms ( PR - A and PR - B ) , P00533 , P15692 and cyclin D1 increased after PPT treatment while in D54 cells only the content of P00533 was increased . Our results demonstrate that E2 induces cell growth of human astrocytoma cell lines through ERα and its interaction with Q15788 and Q9Y6Q9 and also suggest differential roles of ERα on cell growth depending on astrocytoma grade .",
"Efficacy and safety of sunitinib in Chinese patients with imatinib - resistant or - intolerant gastrointestinal stromal tumors . AIMS : To assess the efficacy and safety of sunitinib in Chinese patients with imatinib - resistant or - intolerant gastrointestinal stromal tumors ( GISTs ) , and evaluate the impact of genotype on sunitinib efficacy . MATERIALS & METHODS : In a single - arm retrospective study , 55 patients with recurrent or metastatic GISTs who were resistant or intolerant to prior imatinib treatment received sunitinib for at least one treatment cycle . RESULTS : The median progression - free survival was 35 weeks ( 95 % CI : 24 . 6 - 45 . 4 ) in patients who received sunitinib 37 . 5 mg / day as a continuous daily dose versus 30 weeks ( 95 % CI : 12 . 8 - 47 . 2 ) in those who received sunitinib 50 mg / day as a 4 - weeks - on , 2 - weeks - off ( 4 / 2 ) schedule ( p = 0 . 707 ) . The median overall survival of all patients was 86 weeks ( 95 % CI : 75 . 0 - 97 . 0 ) . Patients with P10721 exon 9 mutations had a significantly longer progression - free survival compared with those with P10721 exon 11 mutations and patients with wild - type GISTs ( p = 0 . 022 ) . DB01268 therapy was well tolerated , with most adverse events rated as grade 1 or 2 in severity . The sunitinib 37 . 5 mg / day continuous daily dose schedule was better tolerated by Chinese GIST patients than the 50 mg / day 4 / 2 schedule . CONCLUSION : DB01268 was effective and well tolerated in Chinese patients with imatinib - resistant or - intolerant GISTs . Patients with P10721 exon 9 mutations showed the best efficacy . A 37 . 5 mg / day continuous daily dose sunitinib dosing schedule appears to be the optimal choice for Chinese patients due to a decreased incidence of adverse events .",
"P40763 signaling is induced by intercellular adhesion in squamous cell carcinoma cells . The signal transducer and activator of transcription - 3 ( P40763 ) frequently activated during tumor progression has been linked to enhanced cell growth . In squamous cell carcinoma of the head and neck ( HNSCC ) , P40763 signaling has been shown to inhibit apoptosis and induce a more aggressive phenotype through the activation of specific signaling pathways . In the present study , we have examined the potential mechanism by which cell - cell contact initiates P40763 activation . Using a panel of HNSCC cell lines , Ca (+ 2 )- dependent cell - cell adhesion and adherens junction formation in multicellular aggregates triggered phosphorylation of P40763 - Y705 and P42224 - Y701 . This intercellular adhesion - induced P40763 activation was mediated by JAK and Src signaling and partially by P00533 signaling . In addition , immunolocalization studies revealed initial formation of phosphorylated P40763 - Y705 at nascent P12830 cell junctions with eventual translocation to the nucleus in cell aggregates . Adhesion - mediated P35610 activation in monolayer and cell aggregate cultures required functional P12830 . These results indicate that , in HNSCC cells , cadherin - mediated intercellular adhesion induces P35610 signaling that may modulate cell survival and resistance to apoptosis during tumor progression .",
"Tyrosine kinases as targets in cancer therapy - successes and failures . Protein kinases play a crucial role in signal transduction and also in cellular proliferation , differentiation and various regulatory mechanisms . The inhibition of growth - related kinases , especially tyrosine kinases , might therefore provide new therapies for diseases such as cancer . Due to the enormous progress that has been made in the past few years in the identification of the human genome , in molecular and cell biology technologies , in structural biology and in bioinformatics , the number of receptor and non - receptor tyrosine kinases that have been identified as valuable molecular targets has greatly increased . Currently , more than 20 different tyrosine kinase targets are under evaluation in drug discovery projects in oncology . The progress made in the crystallisation of protein kinases , in most cases complexed with DB00171 - site - directed inhibitors , has confirmed that the ATPbinding domain of tyrosine kinases is an attractive target for rational drug design ; more than 20 DB00171 - competitive , low molecular weight inhibitors are in various phases of clinical evaluation . Meanwhile , clinical proof - of - concept ( POC ) has been achieved with several antibodies and small molecules targeted against tyrosine kinases . With Herceptin , Glivec and ___MASK62___ ( registered in Japan ) , the first kinase drugs have entered the market . This review describes the preclinical and clinical status of low molecular weight drugs targeted against different tyrosine kinases ( e . g . , epidermal growth factor receptor [ P00533 ] , vascular endothelial growth factor receptor [ VEGFR ] , platelet - derived growth factor receptor [ P09619 ] , Kit , Fms - like tyrosine kinase [ Flt ] - 3 ) , briefly describes new targets , and provides a critical analysis of the current situation in the area of tyrosine kinase inhibitors .",
"___MASK46___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK46___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .",
"DB01268 acts primarily on tumor endothelium rather than tumor cells to inhibit the growth of renal cell carcinoma . DB01268 is a broad - spectrum small - molecule inhibitor of receptor tyrosine kinases ( RTK ) that serves as the present standard of care for first - line therapy of advanced clear cell renal cell carcinoma ( ccRCC ) . A full understanding of the targets and mechanism of action of sunitinib in ccRCC treatment remains incomplete . In this study , we evaluated several tumor cell and endothelial targets of sunitinib and investigated which RTK ( s ) may specifically contribute to its therapeutic effects . Microarray expression profiling and Western blot analysis revealed that among known sunitinib targets , only platelet - derived growth factor receptor - beta and vascular endothelial growth factor receptor - 2 ( P35968 ) were overexpressed in ccRCCs relative to normal tissues . DB01268 was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations ( approximately 0 . 1 micromol / L ) that inhibit RTK targets . In contrast , sunitinib inhibited endothelial cell proliferation and motility at the same concentrations by suppressing P35968 signaling . Moreover , whereas sunitinib inhibited the growth of ccRCC xenograft tumors and decreased tumor microvessel density as soon as 12 hours after treatment , sunitinib showed no significant effects on tumor cell proliferation or apoptosis up to 72 hours after treatment . Our findings indicate that sunitinib inhibits ccRCC growth primarily through an antiangiogenic mechanism and not through direct targeting of ccRCC tumor cells .",
"P50281 as a downstream target of P11274 - P00519 / P00519 interactor 1 signaling : polarized distribution and involvement in P11274 - P00519 - stimulated leukemic cell migration .",
"DB01268 : a newly approved small - molecule inhibitor of angiogenesis . The advent of targeted therapies has allowed treatment to be directed at signaling pathways integral to tumor growth and survival . DB01268 ( SU11248 , sunitinib malate ; Pfizer Inc . , New York , NY , USA ) is a novel oral small - molecule multitargeted receptor tyrosine kinase inhibitor that has demonstrated direct antitumor activity and antiangiogenic action . It targets the vascular endothelial growth factor receptor ( VEGFR ) , platelet derived growth factor receptor ( P09619 ) , stem - cell factor receptor and Fms - like tyrosine kinase receptor 3 receptor tyrosine - kinases . In January 2006 , sunitinib malate was granted approval by the U . S . Food and Drug Administration for the treatment of gastrointestinal stromal tumor after disease progression on , or intolerance to , imatinib mesylate , as well as for the treatment of metastatic renal cell cancer . This review will discuss the development of sunitinib , particularly in acute myeloid leukemia , imatinib - resistant gastrointestinal stromal tumors and renal cell cancer . The review will also discuss ongoing trials with sunitinib in other malignancies such as neuroendocrine tumors and breast cancer , as well as its potential future development in combination therapy with other agents and in other malignancies .",
"DB01268 in malignant melanoma : a treatment option only for P10721 - mutated patients ? DB01268 has previously been reported to be potentially effective in the treatment of malignant melanomas expressing c - P10721 . Here we report on the case of a 77 - year - old gentleman affected by a metastatic clear cell carcinoma of the kidney and a metastatic malignant melanoma with liver and lung metastases . Despite the negativity for CD117 and the absence of P10721 amplification or mutations in the melanoma specimen , he achieved a partial response both in the lungs and in the liver while on sunitinib ( 50 mg once / day , 4 weeks on / 2 weeks off ) for the treatment of kidney cancer . To our knowledge , this represents the first evidence of sunitinib activity in P10721 wild - type melanoma . Further studies should be performed to confirm these preliminary data .",
"The retinoid signalling molecule , O95361 , is repressed during squamous cell carcinoma skin carcinogenesis in vivo and reduces skin cancer cell migration in vitro . Retinoid therapy is used for chemo - prevention in immuno - suppressed patients at high risk of developing skin cancer . The retinoid signalling molecule , tripartite motif protein 16 ( O95361 ) , is a regulator of keratinocyte differentiation and a tumour suppressor in retinoid - sensitive neuroblastoma . We sought to determine the role of O95361 in skin squamous cell carcinoma ( SCC ) pathogenesis . We have shown that O95361 expression was markedly reduced during the histological progression from normal skin to actinic keratosis and SCC . SCC cell lines exhibited lower cytoplasmic and nuclear O95361 expression compared with primary human keratinocyte ( PHK ) cells due to reduced O95361 protein stability . Overexpressed O95361 translocated to the nucleus , inducing growth arrest and cell differentiation . In SCC cells , O95361 bound to and down regulated nuclear Q01094 , this is required for cell replication . Retinoid treatment increased nuclear O95361 expression in retinoid - sensitive PHK cells , but not in retinoid - resistant SCC cells . Overexpression of O95361 reduced SCC cell migration , which required the C - terminal P07949 finger protein ( RFP ) - like domain of O95361 . The mesenchymal intermediate filament protein , vimentin , was directly bound and down - regulated by O95361 and was required for O95361 - reduced cell migration . Taken together , our data suggest that loss of O95361 expression plays an important role in the development of cutaneous SCC and is a determinant of retinoid sensitivity .",
"DB01268 malate in solitary fibrous tumor ( P51668 ) . BACKGROUND : To report on sunitinib activity in a retrospective series of 35 solitary fibrous tumor ( P51668 ) treated at a single institution . PATIENTS AND METHODS : From April 2008 , 35 patients with progressive advanced P51668 ( male / female : 20 / 15 ; mean age : 58 years ; meningeal / extrameningeal : 6 / 29 ; locally advanced / metastatic : 15 / 20 ; prior chemotherapy : 25 ) were treated , on an individual use basis , with continuous - dosing sunitinib 37 . 5 mg / day . P09619 ( P09619 ) and vascular endothelial growth factor receptor 2 ( P35968 ) status were assessed by immunohistochemistry and , in a subgroup of patients , by real time PCR . RESULTS : Thirty - one patients were assessable for response by RECIST ( one early death ; three early interruptions ) . Best responses were 2 partial response ( PR ) , 16 stable disease , 13 progressive disease . A < 30 % decrease in size was observed in three patients . Fourteen of 29 patients assessable by Choi criteria had a PR . Median progression - free survival by RECIST was 6 months ( range 1 - 22 ) . In two of six patients , resistance to sunitinib was overcome by increasing sunitinib to 50 mg / day . P09619 and / or P35968 were positive in all cases and not predictive of response ; a less aggressive morphology corresponded to an increased response rate ( 53 % PR by Choi in the malignant P51668 , 20 % PR in the pleomorphic / dedifferentiated P51668 ) . CONCLUSIONS : DB01268 is active in P51668 . Response can be long - lasting .",
"Strategic combination therapy overcomes tyrosine kinase coactivation in adrenocortical carcinoma . BACKGROUND : Coactivation of tyrosine kinase limits the efficacy of tyrosine kinase inhibitors . We hypothesized that a strategic combination therapy could overcome tyrosine kinase coactivation and compensatory oncogenic signaling in patients with adrenocortical carcinoma ( ACC ) . METHODS : We profiled 88 tyrosine kinases before and after treatment with sunitinib in H295R and SW13 ACC cells . The effects of monotherapy and strategic combination regimens were determined by the 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 5 -( 3 - carboxymethoxyphenyl )- 2 -( 4 - sulfophenyl )- 2H - tetrazolium ( ie , MTS ) assay . RESULTS : The minimum inhibitory concentrations ( IC ( min ) ) of sunitinib quenched its primary targets : P36888 , P35968 , and P07949 . In contrast , P29323 , P08631 , Chk2 , P07947 , CREB , MEK , MSK , p38 , P09769 , and P30530 were hyperactivated . Monotherapy with sunitinib or PD98059 at their IC ( min ) reduced proliferation by 23 % and 19 % , respectively , in H295R cells and by 25 % and 24 % , respectively , in SW13 cells . DB01268 and PD98059 in combination decreased proliferation by 68 % and 64 % in H295R and in SW13 cells , respectively ( P < . 05 versus monotherapy ) . The effects of combination treatment exceeded the sum of the effects observed with each individual agent alone . CONCLUSION : We describe the first preclinical model to develop strategic combination therapy to overcome tyrosine kinase coactivation in ACC . Because many tyrosine kinase inhibitors are readily available , this model can be immediately tested in clinical trials for patients with advanced ACC .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK36___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"DB01268 : bridging present and future cancer treatment . Tyrosine kinase receptors ( RTKs ) are a heterogeneous group of transmembrane proteins involved in signal transduction . These receptors are expressed in many different cells and regulate cellular growth , differentiation and angiogenesis . Overexpression and / or the structural alteration of different RTKs classes are generally associated to cancer and , when RTKs - mediated signal transduction pathways are abnormally activated , generate cancer growth , angiogenesis and metastatization . Therapeutic intervention targeting RTKs concerns antagonist drugs as little molecules or monoclonal antibodies . DB01268 malate is a little molecule able to block intracellular tyrosine kinase domain of RTKs , which has both direct anticancer and antiangiogenetic activity . DB01268 targets selectively vascular endothelial growth factor , P10721 , Flt3 and platelet - derived growth factor receptors and the receptor encoded by the ret proto - oncogene . This drug is used in the treatment of gastrointestinal stromal cancer ( GIST ) resistant to imatinib and metastatic renal cell carcinoma ( RCC ) . In this review , we report preclinical data of sunitinib , even about synergism with chemotherapy and radiotherapy , data relative to phase III trials of sunitinib in the treatment of GIST and RCC , and we try to plan what will be future applications of sunitinib in different types of cancer , even in association to chemotherapy , radiotherapy and monoclonal antibodies .",
"DB01268 in metastatic thymic carcinomas : laboratory findings and initial clinical experience . BACKGROUND : Thymic carcinoma ( TC ) is a rare aggressive tumour . Median survival with current treatments is only 2 years . DB01268 is a multi - targeted tyrosine kinase inhibitor that has shown benefit in various other cancers . METHODS : Laboratory analyses of snap - frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases ( RTKs ) in TC samples . On the basis of molecular analyses showing activation of multiple RTKs in their tumour , four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols . RESULTS : RTK analysis in three of the patients showed activation of multiple RTKs , including platelet - derived growth factor - beta and vascular endothelial growth factor 3 . Mutations of P00533 , c - P10721 , P01116 , and P15056 genes were not found . Administration of sunitinib yielded a partial remission ( lasting 2 to 18 + months ) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in DB09150 - PET in another one . The overall survival with sunitinib treatment ranges from 4 to 40 + months . Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re - administration of sunitinib . CONCLUSIONS : DB01268 is an active treatment for metastatic TC . A panel of molecular analyses may be warranted for optimal patient selection .",
"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"Reinvestigation of carrier transport properties in liquid crystalline 2 - phenylbenzothiazole derivatives . We have reinvestigated the charge carrier transport properties in a liquid crystal of 2 -( 4 '- heptyloxyphenyl )- 6 - dodecylthiobenzothiazole ( 7O - P10721 - P28222 ) , for which the electronic conduction was first established in rodlike liquid crystals and for which the highest hole mobility in the smectic A ( SmA ) phase ever achieved was reported . We found that 7O - P10721 - P28222 exhibited three crystal phases , one of which appeared in a limited temperature range of 10 degrees just below the phase transition temperature from the SmA phase . In this crystal phase , nondispersive transient photohole currents were observed in time - of - flight experiments , and its hole mobility was determined to be 8 x 10 (- 3 ) cm ( 2 )/ Vs , slightly higher than that reported previously in the SmA phase . For the SmA phase , however , the hole mobility was 1 x 10 (- 4 ) cm ( 2 )/ Vs . Furthermore , we established the electron transport in the SmA phase of purified 7O - P10721 - P28222 , whose mobility was the same as the hole mobility in that phase . In order to confirm generality of the new findings in 7O - P10721 - P28222 , we investigated the carrier transport properties of its derivative having a short hydrocarbon chain , 2 -( 4 '- heptyloxyphenyl )- 6 - butylthiobenzothiazole ( 7O - P10721 - S4 ) , and obtained comparable results . The present results correct a mistake in the previous report and give an idea of what a typical mobility in the SmA phase is . On the basis of these results , we discuss what determines the charge carrier mobility in smectic mesophases .",
"Ligand - dependent platelet - derived growth factor receptor ( P09619 ) - alpha activation sensitizes rare lung cancer and sarcoma cells to P09619 kinase inhibitors . Platelet - derived growth factor ( PDGF ) receptors ( P09619 ) and their ligands play critical roles in several human malignancies . DB01268 is a clinically approved multitargeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor , c - P10721 , and P09619 , and has shown clinical activity in various solid tumors . Activation of P09619 signaling has been described in gastrointestinal stromal tumors ( P16234 mutations ) as well as in chronic myeloid leukemia ( P11274 - P16234 translocation ) , and sunitinib can yield clinical benefit in both settings . However , the discovery of P09619 activating mutations or gene rearrangements in other tumor types could reveal additional patient populations who might benefit from treatment with anti - P09619 therapies , such as sunitinib . Using a high - throughput cancer cell line screening platform , we found that only 2 of 637 tested human tumor - derived cell lines show significant sensitivity to single - agent sunitinib exposure . These two cell lines [ a non - small - cell lung cancer ( NSCLC ) and a rhabdomyosarcoma ] showed expression of highly phosphorylated P16234 . In the sunitinib - sensitive adenosquamous NSCLC cell line , P16234 expression was associated with focal PFGRA gene amplification , which was similarly detected in a small fraction of squamous cell NSCLC primary tumor specimens . Moreover , in this NSCLC cell line , focal amplification of the gene encoding the P09619 ligand Q9NRA1 was also detected , and silencing P16234 or Q9NRA1 expression by RNA interference inhibited proliferation . A similar codependency on P16234 and Q9NRA1 was observed in the sunitinib - sensitive rhabdomyosarcoma cell line . These findings suggest that , in addition to gastrointestinal stromal tumors , rare tumors that show Q9NRA1 - mediated P16234 activation may also be clinically responsive to pharmacologic P16234 or Q9NRA1 inhibition .",
"Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors . BACKGROUND : Myelosuppression has been observed with several multikinase angiogenesis inhibitors in clinical studies , although the frequency and severity varies among the different agents . Inhibitors targeting vascular endothelial growth factor receptor ( VEGFR ) often inhibit other kinases , which may contribute to their adverse - event profiles . METHODS : Kinase selectivity of pazopanib , sorafenib , and sunitinib was evaluated in a panel of 242 kinases . Cellular potency was measured using autophosphorylation assays . Effect on human bone marrow progenitor growth in the presence of multiple growth factors was evaluated and correlated with the kinase selectivity . RESULTS : DB01268 inhibited more kinases than pazopanib and sorafenib , at potencies within 10 - fold of P35968 . All three compounds potently inhibited P35968 , platelet - derived growth factor receptor - beta and c - Kit , However , pazopanib was less active against Flt - 3 in both kinase and cellular assays . The inhibitory properties of pazopanib , sorafenib , and sunitinib were dependent on the growth factor used to initiate bone marrow colony formation . Addition of stem cell factor and / or Flt - 3 ligand with granulocyte - macrophage colony stimulating factor resulted in significant shifts in potency for sorafenib and sunitinib but less so for pazopanib . CONCLUSION : Activity against c - kit and Flt - 3 by multikinase angiogenesis inhibitors provide a potential explanation for the differences in myelosuppression observed with these agents in patients .",
"Plasma biomarkers correlating with clinical outcome in a phase II study of sorafenib in advanced NSCLC . We investigated the relationship between plasma protein biomarker concentrations and clinical outcomes in 52 patients with relapsed / refractory advanced non - small cell lung cancer ( NSCLC ) treated with 400 ~ mg bid sorafenib in a phase II trial . Blood samples were collected at baseline , on day 15 of cycle 1 ( C1D15 ) , and on day 1 of cycle 3 ( C3D1 ) , and plasma concentrations of total P15692 , P15692 - 165 , soluble ( s ) P35968 , DB00102 , sPDGFR - β , sEGFR , sHER - 2 , uPA , P05121 , Q03405 , P01033 , and circulating Ras P38936 were assayed by ELISA . Elevated baseline P15692 , P15692 - 165 , DB00102 , Ras P38936 , and P01033 concentrations were associated with poorer patient outcomes ( shorter overall survival [ OS ] and / or progression - free survival [ PFS ] ) . During treatment , the mean concentrations of sVEGFR - 2 , DB00102 , sPDGFR - β , P01033 , Q03405 , and P05121 decreased , while the mean sEGFR concentration increased . Increases in P15692 , P15692 - 165 , DB00102 , and P01033 during treatment were associated with better outcomes ( longer OS and / or PFS ) , whereas increases in plasma Ras P38936 during treatment were associated with shorter PFS . The associations between baseline concentrations and / or pharmacodynamic changes in plasma proteins and clinical outcomes in NSCLC patients treated with sorafenib suggest that these biomarkers may have a prognostic role and / or predict the efficacy of sorafenib in patients with NSCLC .",
"Recent advances in the treatment of gastrointestinal stromal tumors . Constitutively activating mutations in the P10721 and platelet - derived growth factor receptor α ( P16234 ) RTKs play a crucial role in the biology of gastrointestinal stromal tumors ( GISTs ) , and this disease has served as an effective model for targeting gain - of - function kinase mutations in cancer . Imatinib has entered the clinical arena in the last decade and substantially improved the outcome in these formerly untreatable cancers . However , most advanced GISTs responding to imatinib progress within 2 - 3 years due to heterogeneous subclones harboring a range of imatinib - resistant secondary P10721 mutations . DB01268 , and more recently , regorafenib , have obtained US Food and Drug Administration approval for the treatment of GISTs after imatinib failure , and thus expanded the treatment options in resistant disease . Within this framework , we present an evaluation of current GIST management , emphasizing the most recent advances in the field together with a discussion on future steps to be taken in refractory disease .",
"Differential radiosensitisation by ZD1839 ( ___MASK62___ ) , a highly selective epidermal growth factor receptor tyrosine kinase inhibitor in two related bladder cancer cell lines . The epidermal growth factor receptor ( P00533 ) is expressed in a wide variety of epithelial tumours including carcinoma of the bladder . Stimulation of the P00533 pathway is blocked by ZD1839 ( ___MASK62___ ) , a highly selective P00533 tyrosine kinase inhibitor . Radical radiotherapy is an established organ sparing treatment option for muscle invasive bladder cancer and this study has explored the possibility for the use of ZD1839 as a radiosensitiser in this scenario . The effect of combination treatment with ZD1839 ( 0 . 01 microM ) and ionising radiation in the established bladder cancer cell lines MGH - U1 and its radiosensitive mutant clone S40b was measured by clonogenic assays . A highly significant radiosensitising effect was seen in both cell lines ( P < 0 . 001 for MGH - U1 and S40b cell lines ) . This effect was independent of the concentration of the drug and the duration of exposure prior to treatment with ionising radiation . Cell cycle kinetics of both cell lines was not significantly altered with ZD1839 ( 0 . 01 microM ) as a single agent . A modest induction of apoptosis was observed with ZD1839 ( 0 . 01 microM ) as a single agent , but a marked induction was observed with the combination treatment of ZD1839 and ionising radiation . These results suggest a potentially important role for ZD1839 in combination with radiotherapy in the treatment of muscle invasive bladder cancer .",
"DB01268 in the treatment of advanced solid tumors . DB01268 is an oral multikinase inhibitor that blocks the vascular endothelial growth factor receptor ( VEGFR ) , platelet - derived growth factor receptor ( P09619 ) alpha and beta , c - kit , and other receptors . These attributes have proven to be efficacious in the treatment of metastatic renal cell carcinoma ( RCC ) , unresectable gastrointestinal stromal tumors ( GIST ) , and well - differentiated advanced pancreatic neuroendocrine tumors ( PNET ) . Though activity has been reported in other tumor types , phase III trials have not yet demonstrated improved survival outcomes in these cancers . Most side effects including hypertension , hand - foot syndrome , and diarrhea are generally well manageable . This review will detail the preclinical data leading up to the results of the pivotal phase III clinical trials that have led to the widespread use of sunitinib in advanced RCC , GIST , and PNET .",
"Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients . PURPOSE : To investigate the angiogenic changes in primary tumor tissue of renal cell carcinoma ( RCC ) patients treated with P15692 - targeted therapy . EXPERIMENTAL DESIGN : Phase II trials of P15692 pathway - targeted therapy given before cytoreductive surgery were carried out with metastatic RCC patients with the primary tumor in situ to investigate the necessity of nephrectomy . Primary tumor tissues were obtained and assessed for angiogenesis parameters . Results were compared with similar analyses on untreated tumors . RESULTS : DB01268 or bevacizumab pretreatment resulted in a significant reduction of microvessel density in the primary tumor . Also , an increase in vascular pericyte coverage was found in sunitinib - pretreated tumors , consistent with efficient angiogenesis inhibition . Expression of several key regulators of angiogenesis was found to be suppressed in pretreated tissues , among which P17948 and P35968 , angiopoietin - 1 and angiopoietin - 2 and platelet - derived growth factor - B . In addition , apoptosis in tumor and endothelial cells was induced . Interestingly , in sunitinib - pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed , which was not the case in bevacizumab - pretreated tumors . A positive correlation with the interval between halting the therapy and surgery was found , suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment . CONCLUSION : This study describes , for the first time , the angiostatic response in human primary renal cancers at the tissue level upon treatment with P15692 - targeted therapy . Discontinuation of treatment with tyrosine kinase inhibitors leads to accelerated endothelial cell proliferation . The results of this study contribute important data to the ongoing discussion on the discontinuation of treatment with kinase inhibitors .",
"A curated database of miRNA mediated feed - forward loops involving MYC as master regulator . BACKGROUND : The MYC transcription factors are known to be involved in the biology of many human cancer types . But little is known about the Myc / microRNAs cooperation in the regulation of genes at the transcriptional and post - transcriptional level . METHODOLOGY / PRINCIPAL FINDINGS : Employing independent databases with experimentally validated data , we identified several mixed microRNA / Transcription Factor Feed - Forward Loops regulated by Myc and characterized completely by experimentally supported regulatory interactions , in human . We then studied the statistical and functional properties of these circuits and discussed in more detail a few interesting examples involving Q01094 , P60484 , P06400 and P15692 . CONCLUSIONS / SIGNIFICANCE : We have assembled and characterized a catalogue of human mixed Transcription Factor / microRNA Feed - Forward Loops , having Myc as master regulator and completely defined by experimentally verified regulatory interactions .",
"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .",
"Induction of high mobility group box 1 release from serotonin - stimulated human umbilical vein endothelial cells . High mobility group box 1 ( P09429 ) is a non - histone nuclear protein which is released from the nucleus of activated macrophages into the extracellular space in response to stimuli such as endotoxin or necrosis . The P09429 functions as a potent proinflammatory cytokine in the extracellular spaces . Recently , P09429 has been implicated in the progression of atherosclerosis . However , the association between P09429 and the development of atherosclerosis is poorly understood . Therefore , we examined whether serotonin ( 5 - HT ) , a key factor involved in the development of atherosclerosis , induced P09429 release in human umbilical vein endothelial cells ( HUVECs ) . We found that 5 - HT induced the release of P09429 but not of P27361 / 2 and JNK from HUVECs via the 5 - HT receptor ( P28222 ) / p38 mitogen - activated protein kinase ( MAPK ) signaling pathway . The p38MAPK inhibitor SB203580 and the P28222 antagonist GR55526 markedly inhibited P09429 release from 5 - HT - stimulated HUVECs . The vascular endothelial growth factor ( P15692 ) derived from activated macrophages in atherosclerotic lesions also plays an important role in the progression of atherosclerosis . We found that P09429 induced P15692 production in macrophage - like RAW264 . 7 cells . P09429 induced the activation of p38MAPK , P27361 / 2 and Akt . The P19957 - kinase inhibitor LY294002 significantly inhibited P15692 production in P09429 - stimulated macrophages , while other kinase inhibitors did not . These results suggest that P09429 release may contribute as a risk factor in the development and progression of atherosclerosis .",
"In vivo antitumor and antimetastatic activity of sunitinib in preclinical neuroblastoma mouse model . Neuroblastoma ( NB ) is one of the most common pediatric solid tumors originating from the neural crest lineage . Despite intensive treatment protocols including megatherapy with hematopoietic stem cell transplantation , the prognosis of NB patients remains poor . More effective therapeutics are required . High vascularity has been described as a feature of aggressive , widely disseminated NB . Our previous work demonstrated the overexpression of vascular endothelial growth factor ( P15692 ) in NB , and we showed that an anti - P15692 receptor ( P35968 ) antibody could induce sustained NB tumor suppression and regression . DB01268 is a kinase inhibitor targeting platelet - derived growth factor receptors and VEGFRs and , therefore , a promising antiangiogenic agent . In this study , we investigated the antitumor activity of sunitinib and its synergistic cytotoxicity with conventional ( cyclophosphamide ) and novel ( rapamycin ) therapies . Both NB cell lines and tumor - initiating cells from patient tumor samples were used in our in vitro and in vivo models for these drug testing . We show that sunitinib inhibits tumor cell proliferation and phosphorylation of VEGFRs . It also inhibits tumor growth , angiogenesis , and metastasis in tumor xenograft models . Low - dose sunitinib ( 20 mg / kg ) demonstrates synergistic cytotoxicity with an P42345 inhibitor , rapamycin , which is more effective than the traditional chemotherapeutic drug , cyclophosphamide . These preclinical studies provide the evidence of antitumor activity of sunitinib both in the early stage of tumor formation and in the progressive metastatic disease . These studies also provide the framework for clinical trial of sunitinib , alone and in combination with conventional and novel therapies to increase efficacy and improve patient outcome in NB .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK3___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK3___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK3___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"17 ___MASK87___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis .",
"Effects of preset sequential administrations of sunitinib and everolimus on tumour differentiation in Caki - 1 renal cell carcinoma . BACKGROUND : DB01268 ( VEGFR / P09619 inhibitor ) and everolimus ( P42345 inhibitor ) are both approved for advanced renal cell carcinoma ( RCC ) as first - line and second - line therapy , respectively . In the clinics , sunitinib treatment is limited by the emergence of acquired resistance , leading to a switch to second - line treatment at progression , often based on everolimus . No data have been yet generated on programmed alternating sequential strategies combining alternative use of sunitinib and everolimus before progression . Such strategy is expected to delay the emergence of acquired resistance and improve tumour control . The aim of our study was to assess the changes in tumours induced by three different sequences administration of sunitinib and everolimus . METHODS : In human Caki - 1 RCC xenograft model , sunitinib was alternated with everolimus every week , every 2 weeks , or every 3 weeks . Effects on necrosis , hypoxia , angiogenesis , and EMT status were assessed by immunohisochemistry and immunofluorescence . RESULTS : DB01268 and everolimus programmed sequential regimens before progression yielded longer median time to tumour progression than sunitinib and everolimus monotherapies . In each group of treatment , tumour growth control was associated with inhibition of P42345 pathway and changes from a mesenchymal towards an epithelial phenotype , with a decrease in vimentin and an increase in P12830 expression . The sequential combinations of these two agents in a RCC mouse clinical trial induced antiangiogenic effects , leading to tumour necrosis . CONCLUSIONS : In summary , our study showed that alternate sequence of sunitinib and everolimus mitigated the development of mesenchymal phenotype compared with sunitinib as single agent .",
"Inhibition of cerebrovascular raf activation attenuates cerebral blood flow and prevents upregulation of contractile receptors after subarachnoid hemorrhage . BACKGROUND : Late cerebral ischemia carries high morbidity and mortality after subarachnoid hemorrhage ( Q53FZ2 ) due to reduced cerebral blood flow ( Q03701 ) and the subsequent cerebral ischemia which is associated with upregulation of contractile receptors in the vascular smooth muscle cells ( SMC ) via activation of mitogen - activated protein kinase ( MAPK ) of the extracellular signal - regulated kinase ( P29323 ) 1 / 2 signal pathway . We hypothesize that Q53FZ2 initiates cerebrovascular P27361 / 2 activation , resulting in receptor upregulation . The raf inhibitor will inhibit the molecular events upstream P27361 / 2 and may provide a therapeutic window for treatment of cerebral ischemia after Q53FZ2 . RESULTS : Here we demonstrate that Q53FZ2 increases the phosphorylation level of P27361 / 2 in cerebral vessels and reduces the neurology score in rats in additional with the Q03701 measured by an autoradiographic method . The intracisternal administration of SB - 386023 - b , a specific inhibitor of raf , given 6 h after Q53FZ2 , aborts the receptor changes and protects the brain from the development of late cerebral ischemia at 48 h . This is accompanied by reduced phosphorylation of P27361 / 2 in cerebrovascular SMC . Q53FZ2 per se enhances contractile responses to endothelin - 1 ( ET - 1 ) , 5 - carboxamidotryptamine ( 5 - CT ) and angiotensin II ( Ang II ) , upregulates ETB , P28222 and AT1 receptor mRNA and protein levels . Treatment with SB - 386023 - b given as late as at 6 h but not at 12 h after the Q53FZ2 significantly decreased the receptor upregulation , the reduction in Q03701 and the neurology score . CONCLUSION : These results provide evidence for a role of the P27361 / 2 pathway in regulation of expression of cerebrovascular SMC receptors . It is suggested that raf inhibition may reduce late cerebral ischemia after Q53FZ2 and provides a realistic time window for therapy .",
"The 4q12 amplicon in malignant peripheral nerve sheath tumors : consequences on gene expression and implications for sunitinib treatment . BACKGROUND : Malignant peripheral nerve sheath tumors ( MPNST ) are highly aggressive tumors which originate from Schwann cells and develop in about 10 % of neurofibromatosis type 1 ( P21359 ) patients . The five year survival rate is poor and more effective therapies are needed . DB01268 is a drug targeting receptor tyrosine kinases ( RTK ) like PDGFRalpha , c - Kit and P35968 . These genes are structurally related and cluster on chromosomal segment 4q12 . METHODOLOGY / PRINCIPAL FINDINGS : Here we characterize this region by multiplex ligation - dependent probe amplification ( MLPA ) in MPNST . Our probe set encompasses the 3 adjacent RTK genes ( P16234 , P10721 , P35968 ) and 6 flanking genes . We found amplification of several genes within this region in a subset of MPNST and MPNST cell lines . Transcript and protein expression of P16234 matched well with its increased copy number suggesting a central role of P16234 within the amplicon . Studying the effect of sunitinib on 5 MPNST cell lines revealed that cell line S462 harboring the 4q12 amplicon was extremely sensitive to the drug with an IC50 below 1 . 0 microM . Moreover , sunitinib induced apoptosis and prevented PDGF - AA induced signaling via PDGFRalpha as determined by western blotting . Co - expression of P15692 and its receptor P35968 ( P35968 ) was present in MPNST cell lines suggesting an autocrine loop . We show that P15692 triggered signal transduction via the MAPK pathway , which could be blocked by sunitinib . CONCLUSIONS / SIGNIFICANCE : Since multiple receptors targeted by sunitinib are expressed or over - expressed by MPNST cells sunitinib appears as an attractive drug for treatment of MPNST patients . Presence of the 4q12 amplicon and subsequent over - expression of P16234 might serve as predictive markers for efficacy of sunitinib .",
"Real - time US versus CT determination of pubic arch interference for brachytherapy . PURPOSE : Part 1 , to determine whether transrectal ultrasonography ( US ) enables accurate determination of pubic arch interference ( P05121 ) for prostate brachytherapy ( P10721 ) ; part 2 , to compare the accuracy of transrectal US with that of computed tomography ( CT ) for P05121 determination ; and part 3 , to determine the cost savings of P05121 determination with transrectal US versus that with CT . MATERIALS AND METHODS : Part 1 : The pubic arch was identified intraoperatively with transrectal US and compared with attempted needle passage ( 14 patients ) . Part 2 : Planning CT with the patient supine was compared with planning transrectal US with patients in the dorsal lithotomy position ( nine patients ) . Part 3 : Cost savings were calculated for P05121 determination with transrectal US versus that with CT ( 32 patients per group ) . RESULTS : Part 1 : Transrectal US accurately showed the pubic arch relative to the prostate . Part 2 : CT resulted in P05121 overestimation by 11 . 8 mm . Part 3 : Cost savings with transrectal US were $ 1 , 465 per patient . CONCLUSION : Transrectal US P05121 determination is easily performed , intraoperatively useful , and accurate . CT can result in P05121 overestimation . Reducing direct CT costs and the indirect costs of unnecessary hormonal therapy for false - positive P05121 will reduce expense and improve patient care . Transrectal US should replace CT for P05121 determination .",
"Combined targeted therapies in non - small cell lung cancer : a winner strategy ? PURPOSE OF REVIEW : Current treatment modalities provide limited improvement in the natural course of lung cancer , and prognosis remains poor . Lung cancer is a malignancy with great molecular heterogeneity . The complexity of the signalling process leading to cancer cell proliferation and to the neoplastic phenotype supports the necessity of interfering at different stages to avoid cancer cell resistance to therapy . RECENT FINDINGS : Use of several agents with multiple growth factor receptor or intracellular targets has shown encouraging results in phase I and II clinical trials in non - small cell lung cancer . DB05294 is a dual epidermal growth factor receptor and vascular endothelial growth factor receptor 2 small - molecule tyrosine kinase inhibitor ; sorafenib is an oral kinase inhibitor of P04049 and is also active against vascular endothelial growth factor receptors 2 and 3 , platelet - derived growth factor receptor beta , and c - P10721 . DB01268 is a vascular endothelial growth factor receptor 1 , 2 , and 3 , c - P10721 , and platelet - derived growth factor receptor alpha and beta tyrosine kinase inhibitor . SUMMARY : Combined use of epidermal growth factor receptor - tyrosine kinase inhibitor erlotinib and the humanized vascular endothelial growth factor receptor monoclonal antibody bevacizumab in advanced , chemotherapy - refractory non - small cell lung cancer has shown promising results ."
] |
[
"___MASK36___",
"___MASK3___",
"___MASK45___",
"___MASK46___",
"___MASK62___",
"___MASK67___",
"___MASK87___",
"___MASK94___",
"___MASK99___"
] |
___MASK3___
|
MH_train_479
|
interacts_with DB01240?
|
[
"The anticoagulant effect of PGI2S and tPA in transgenic umbilical vein endothelial cells is linked to up - regulation of PKA and PKC . The selection of vascular grafts for coronary artery bypass surgery is crucial for a positive outcome . This study aimed to establish a novel line of vascular endothelial cells with a potent anticoagulant effect . A lentiviral vector was used to stably transfect human umbilical vein endothelial cells ( HUVECs ) with PGI2S alone ( HUVEC - PGI2S ) or both PGI2S and tPA ( HUVEC - PGI2S - tPA ) . Both HUVEC - PGI2S and HUVEC - PGI2S - tPA cells over - expressing PGI2S and tPA were compared to mock - transfected cells . The enzyme - linked immuno sorbent assay ( ELISAs ) demonstrated that the anticoagulation components , P01008 and P00747 , were up - regulated and coagulation factor FVIII was down - regulated in both cell lines . QRT - PCR and western blotting demonstrated the vasodilation and platelet disaggregation proteins PKA , PKC , and P43119 were up - regulated in both cell lines , but MAPK expression was not altered in either cell line . However , cell viability and colony formation assays and cell cycle analysis demonstrated that both cell lines had a lower rate of cell growth and induced P55008 phase arrest . HUVEC - PGI2S and HUVEC - PGI2S - tPA cells have a potent anticoagulant effect and their use in vascular heterografts may decrease the risk of thrombosis .",
"Inhibition of myoblast migration by prostacyclin is associated with enhanced cell fusion . Satellite cells are stem cells that are critical for the formation and growth of skeletal muscle during myogenesis . To differentiate and fuse , proliferating satellite cells or myoblasts must migrate and establish stable cell - cell contacts . However , the factors that regulate myoblast migration and fusion are not understood completely . We have identified DB01240 as a novel regulator of myogenesis in vitro . DB01240 is a member of the family of prostaglandins ( PG ) , autocrine / paracrine signaling molecules synthesized via the cyclooxygenase - 1 and - 2 pathways . Primary mouse muscle cells both secrete DB01240 and express the P43119 , IP , at various stages of myogenesis . Using genetic and pharmacological approaches , we show that DB01240 is a negative regulator of myoblast migration that also enhances cell fusion . Thus , DB01240 may act as a \" brake \" on migrating cells to facilitate cell - cell contact and fusion . Together , our results highlight the importance of the balance between positive and negative regulators in cell migration and myogenesis . This work may have implications for migration of other populations of adult stem cells and / or cells that undergo fusion .",
"Altered gene expression of prostacyclin synthase and prostacyclin receptor in the thoracic aorta of spontaneously hypertensive rats . OBJECTIVE : The aim of this study was to evaluate the possible role of prostacyclin ( DB01240 ) in the pathogenesis of hypertension in spontaneously hypertensive rats ( SHR ) . METHODS : Measurement of mRNA and protein levels of PGH synthase ( PGHS ) - 1 , DB01240 synthase and the P43119 , in the thoracic aorta was performed in SHR aged 5 , 10 , 20 , and 40 weeks old and in age - matched normotensive Wistar - Kyoto ( WKY ) rats with a competitive polymerase chain reaction method and immunoblotting . Aortic production of 6 - keto - PGF1 alpha , the main metabolite of DB01240 , was also measured . RESULTS : Compared with age - matched WKY rats , P23219 mRNA and protein levels in the thoracic aorta of SHR increased with age , reaching three - and twofold higher than WKY rats at 40 weeks old , respectively . DB01240 synthase mRNA and protein levels in SHR were significantly higher than in WKY rats at 20 and 40 weeks old . In contrast , P43119 mRNA levels in SHR were consistently lower than in WKY rats at all ages . CONCLUSIONS : These results provide evidence that hypertension elicits alterations in levels of arachidonic acid metabolites , including PGH2 and DB01240 . They also suggest that the decreased expression of P43119 mRNA in prehypertensive SHR could be one of the causes of hypertension in SHR .",
"The ' allosteric modulator ' P35240 - 202676 disrupts G protein - coupled receptor function via sulphydryl - sensitive mechanisms . 1 . Previous studies suggest that the thiadiazole compound P35240 - 202676 ( N -( 2 , 3 - diphenyl - 1 , 2 , 4 - thiadiazol - 5 -( 2H )- ylidene ) methanamine ) acts as an allosteric modulator of a variety of structurally distinct G protein - coupled receptors ( GPCRs ) . It was postulated that P35240 - 202676 would directly bind a structural motif in the receptor molecule common to divergent members of the GPCR family . The molecular mechanisms of such a promiscuous action , however , remain obscure . 2 . To clarify the mechanism of P35240 - 202676 action , we used the functional approach of [ 35S ] GTPgammaS autoradiography with rat brain cryostat sections together with classical membrane [ 35S ] GTPgammaS binding assays to evaluate how the thiadiazole affects G protein activity mediated by various receptors linked to the Gi - family of G proteins . 3 . We found that in the absence of dithiotreitol ( DTT ) , P35240 - 202676 ( 10 (- 7 )- 10 (- 5 ) M ) elicits nonspecific effects in the [ 35S ] GTPgammaS - based G protein activation assays , thereby severely compromising interpretations on the compounds ability to allosterically inhibit receptor - mediated G protein activity . Such a nonspecific behaviour was fully reversed upon addition of DTT ( 1 mM ) , revealing thiol - based mechanism of action . 4 . In routine incubations containing DTT , P35240 - 202676 had no effect on receptor - driven G protein activity , as assessed for adenosine A1 , alpha2 - adrenergic , cannabinoid P21554 , lysophosphatidic acid Q92633 , muscarinic M2 / M4 , purinergic Q9H244 or sphingosine 1 - phosphate receptors , suggesting that the thiadiazole does not act as an allosteric modulator of GPCR function . 5 . 1H NMR analysis indicated that P35240 - 202676 underwent structural changes after incubation with the reducing agent DTT or with brain tissue . 6 . We conclude that P35240 - 202676 modulates GPCRs via thiol modification rather than via true allosteric mechanisms .",
"Thiazolidinedione drugs down - regulate P61073 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor gamma - dependent manner . Peroxisome proliferator activated receptor ( Q07869 ) gamma is a nuclear receptor involved primarily in lipid and glucose metabolism . PPARgamma is also expressed in several cancer types , and has been suggested to play a role in tumor progression . PPARgamma agonists have been shown to reduce the growth of colorectal carcinoma cells in culture and in xenograft models . Furthermore , the PPARgamma agonist thiazolidinedione has been shown to reduce metastasis in a murine model of rectal cancer . Since the chemokine receptor P61073 has emerged as an important player in tumorigenesis , particularly in the process of metastasis , we sought to determine if PPARgamma agonists might act in part by reducing P61073 expression . We found that rosiglitazone , a thiazolidinedione PPARgamma agonist used primarily in the treatment of type 2 diabetes , significantly reduced cell - surface expression of P61073 protein on HT - 29 human colorectal carcinoma cells . This effect occurred at concentrations as low as 1 nM , and was first evident after 8 h of drug exposure . P61073 mRNA was also down - regulated after treatment with rosiglitazone , indicating that the effect occurs at the level of transcription . Four other thiazolidinedione compounds ( ciglitazone , pioglitazone , troglitazone , and MCC555 ) also significantly reduced P61073 expression . To confirm the involvement of PPARgamma in thiazolidinedione - induced P61073 down - regulation , we used PPARgamma antagonists GW9662 and T0070907 , both of which completely blocked the effect of rosiglitazone on P61073 expression . Furthermore , HT - 29 cells in which PPARgamma expression was reduced using shRNA were less responsive to rosiglitazone . In conclusion , we have shown that thiazolidinedione compounds reduce P61073 mRNA and cell - surface protein expression in a PPARgamma - dependent manner .",
"Activation of a TGF - beta - specific multistep gene expression program in mature macrophages requires glucocorticoid - mediated surface expression of TGF - beta receptor II . Alternatively activated ( M2 ) macrophages regulate steady state - , cancer - , and inflammation - related tissue remodeling . They are induced by Th2 - cytokines and glucocorticoids ( GC ) . The responsiveness of mature macrophages to TGF - beta , a cytokine involved in inflammation , cancer , and atherosclerosis , is currently controversial . Recently , we demonstrated that Q9NRM6 is up - regulated in human monocyte - derived macrophages differentiated in the presence of Th2 cytokines P05112 and TGF - beta1 . In this study , we show that mature human macrophages differentiated in the presence of P05112 , and dexamethasone ( M2 ( P05112 / GC ) ) but not M2 ( P05112 ) responds to TGF - beta1 which induced a gene expression program comprising 111 genes including transcriptional / signaling regulators ( Q02535 and Q08116 ) , immune modulators ( P20292 and Q9NRM6 ) and atherosclerosis - related genes ( P20292 , P41146 , P02654 , P02655 , and P02649 ) . Analysis of molecular mechanism underlying GC / TGF - beta cooperation revealed that surface expression of TGF - betaRII was high in M2 ( GC ) and M2 ( P05112 / GC ) , but absent from M2 ( P05112 ) , whereas the expression of TGF - betaRI / II mRNA , TGF - betaRII total protein , and surface expression of TGF - betaRIII were unchanged . GC dexamethasone was essential for increased surface expression of functional TGF - betaRII because its effect was observed also in combination with P35225 , P09603 , and GM - P04141 . Prolonged Q15796 - mediated signaling observed in TGF - beta1 - treated M2 ( P05112 / GC ) was due to insufficient activity of negative feedback mechanism what can be explained by up - regulation of Q96EB6 , a negative regulator of O15105 , and the retention of TGF - betaRII complex on the cell surface . In summary , mature human M2 macrophages made permissive to TGF - beta by GC - induced surface expression of TGF - betaRII activate in response to TGF - beta1 , a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"P43119 up - regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1 / 2 pathway . DB01240 ( P06744 ) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven - transmembrane G protein - coupled receptor ( IP receptor ) . Recent studies have ascertained a role for prostanoid - receptor signaling in angiogenesis . In this study we examined the temporal - spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes . Quantitative RT - PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle . Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity . Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle . To explore the role of the IP receptor in glandular epithelial cells , we used the Ishikawa endometrial epithelial cell line . Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost ( a P06744 analog ) rapidly activated P27361 / 2 signaling and induced the expression of proangiogenic genes , basic fibroblast growth factor , angiopoietin - 1 , and angiopoietin - 2 , in an epidermal growth factor receptor ( P00533 ) - dependent manner . Furthermore , P00533 colocalized with IP receptor in the glandular epithelial compartment . These data suggest that P06744 - IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the P00533 .",
"Cyclooxygenase inhibition abrogates aeroallergen - induced immune tolerance by suppressing prostaglandin I2 receptor signaling . BACKGROUND : The prevalence of allergic diseases has doubled in developed countries in the past several decades . Cyclooxygenase ( P36551 ) - inhibiting drugs augmented allergic diseases in mice by increasing allergic sensitization and memory immune responses . However , whether P36551 inhibition can promote allergic airway diseases by inhibiting immune tolerance is not known . OBJECTIVE : To determine the role of the P36551 pathway and prostaglandin I2 ( DB01240 ) signaling through the P43119 ( IP ) in aeroallergen - induced immune tolerance . METHODS : Wild - type ( WT ) BALB / c mice and IP knockout mice were aerosolized with ovalbumin ( OVA ) to induce immune tolerance prior to immune sensitization with an intraperitoneal injection of OVA / alum . The P36551 inhibitor indomethacin or vehicle was administered in drinking water to inhibit enzyme activity during the sensitization phase . Two weeks after sensitization , the mice were challenged with OVA aerosols . Mouse bronchoalveolar lavage fluid was harvested for cell counts and TH2 cytokine measurements . RESULTS : WT mice treated with indomethacin had greater numbers of total cells , eosinophils , and lymphocytes , and increased P05113 and P35225 protein expression in BAL fluid compared to vehicle - treated mice . Similarly , IP knockout mice had augmented inflammation and TH2 cytokine responses compared to WT mice . In contrast , the DB01240 analog cicaprost attenuated the anti - tolerance effect of P36551 inhibition . CONCLUSION : P36551 inhibition abrogated immune tolerance by suppressing DB01240 IP signaling , suggesting that DB01240 signaling promotes immune tolerance and that clinical use of P36551 - inhibiting drugs may increase the risk of developing allergic diseases .",
"Microarray analyses of the effects of NF - kappaB or PI3K pathway inhibitors on the LPS - induced gene expression profile in RAW264 . 7 cells : synergistic effects of rapamycin on LPS - induced P14780 - overexpression . Lipopolysaccharide ( LPS ) activates a broad range of signalling pathways including mainly NF - kappaB and the MAPK cascade , but recent evidence suggests that LPS stimulation also activates the PI3K pathway . To unravel the specific roles of both pathways in LPS signalling and gene expression profiling , we investigated the effects of different inhibitors of NF - kappaB ( BAY 11 - 7082 ) , PI3K ( wortmannin and LY294002 ) but also of P42345 ( rapamycin ) , a kinase acting downstream of PI3K / Akt , in LPS - stimulated RAW264 . 7 macrophages , analyzing their effects on the LPS - induced gene expression profile using a low density DNA microarray designed to monitor the expression of pro - inflammatory genes . After statistical and hierarchical cluster analyses , we determined five clusters of genes differentially affected by the four inhibitors used . In the fifth cluster corresponding to genes upregulated by LPS and mainly affected by BAY 11 - 7082 , the gene encoding P14780 displayed a particular expression profile , since rapamycin drastically enhanced the LPS - induced upregulation at both the mRNA and protein levels . ___MASK91___ also enhanced the LPS - induced NF - kappaB transactivation as determined by a reporter assay , phosphorylation of the p38 and Erk1 / 2 MAPKs , and counteracted Q07869 activity . These results suggest that P42345 could negatively regulate the effects of LPS on the NF - kappaB and MAPK pathways . We also performed real - time RT - PCR assays on mmp9 expression using rosiglitazone ( agonist of PPARgamma ) , PD98059 ( inhibitor of Erk 1 / 2 ) and SB203580 ( inhibitor of p38 ( MAPK ) ) , that were able to counteract the rapamycin mediated overexpression of mmp9 in response to LPS . Our results suggest a new pathway involving P42345 for regulating specifically mmp9 in LPS - stimulated RAW264 . 7 cells .",
"P12644 modulates fibroblast growth factor - mediated induction of proximal and distal lung differentiation in mouse embryonic tracheal epithelium in mesenchyme - free culture . Lung morphogenesis and differentiation require interaction between the epithelium and mesenchyme , which is mediated by diffusible molecules such as fibroblast growth factors ( FGFs ) , bone morphogenetic protein 4 ( P12644 ) , and Shh . We have used mesenchyme - free culture to study the effects of these molecules on lung epithelial differentiation . We have tested the individual abilities of P05230 , P09038 , P21781 , P31371 , O15520 , and O76093 , as well as P12644 and Shh to promote growth and specify distal lung differentiation in mouse tracheal epithelium . The different FGFs exhibited distinct abilities to induce epithelial growth and the expression of the distal lung epithelial marker , surfactant protein C ( P11686 ) , although all FGFs were able to induce expression of P12644 . Tracheal epithelium treated with O15520 showed little growth and failed to express P11686 as measured by whole - mount in situ hybridization and quantitative real - time polymerase chain reaction . P05230 treatment resulted in the strongest induction of P11686 . Treatment with P12644 inhibited epithelial growth and differentiation and antagonized the stimulatory effects of P05230 . In contrast , inhibition of endogenous P12644 signaling with Q13253 protein did not inhibit growth or expression of P11686 but did increase the expression of the proximal lung markers P11684 and Q92949 . Expression of Shh was not affected by any of the conditions tested . These results suggest that P12644 does not signal epithelial cells to adopt a distal fate but may regulate the expansion of proximal epithelial cells in the lung .",
"Human prostacyclin platelet receptors in diabetes mellitus . Conflicting data have been reported about the impaired sensitivity to the inhibitory effect of prostacyclin ( DB01240 ) in platelets from patients with diabetes . In the present paper we investigated binding of and sensitivity to DB01240 of platelets from insulin dependent ( IDDM ) ( n = 9 ) , non insulin dependent ( NIDDM ) ( n = 8 ) diabetics and two groups of ten healthy subjects of equivalent age in relation to platelet lipidic content . Platelet sensitivity to DB01240 ( DB01240 IC50 ) was found not significantly changed in diabetics as compared to controls ; similarly , no significant differences of the number of high affinity receptors for DB01240 in platelets from patients with IDDM and NIDDM were observed . Platelet sensitivity to DB01240 and DB01240 receptors were found to be significantly related to platelet cholesterol content ( r = 0 . 89 , p less than 0 . 001 and r = - 0 . 80 , p less than 0 . 001 respectively ) . In conclusion platelet P43119 changes are not detectable in diabetics in good metabolic control , but could take place when platelet lipid composition is altered .",
"Pulmonary prostacyclin synthase overexpression in transgenic mice protects against development of hypoxic pulmonary hypertension . Q16647 ( PGIS ) is the final committed enzyme in the metabolic pathway leading to prostacyclin ( DB01240 ) production . Patients with severe pulmonary hypertension have a PGIS deficiency of their precapillary vessels , but the importance of this deficiency for lung vascular remodeling remains unclear . We hypothesized that selective pulmonary overexpression of PGIS may prevent the development of pulmonary hypertension . To study this hypothesis , transgenic mice were created with selective pulmonary PGIS overexpression using a construct of the 3 . 7 - kb human surfactant protein - C ( P11686 ) promoter and the rat PGIS cDNA . Transgenic mice ( Tg + ) and nontransgenic littermates ( Tg - ) were subjected to a simulated altitude of 17 , 000 ft for 5 weeks , and right ventricular systolic pressure ( RVSP ) was measured . Histology was performed on the lungs . The Tg + mice produced 2 - fold more pulmonary 6 - keto prostaglandin F1alpha ( PGF1alpha ) levels than did Tg - mice . After exposure to chronic hypobaric hypoxia , Tg + mice have lower RVSP than do Tg - mice . Histologic examination of the lungs revealed nearly normal arteriolar vessels in the Tg + mice in comparison with vessel wall hypertrophy in the Tg - mice . These studies demonstrate that Tg + mice were protected from the development of pulmonary hypertension after exposure to chronic hypobaric hypoxia . We conclude that PGIS plays a major role in modifying the pulmonary vascular response to chronic hypoxia . This has important implications for the pathogenesis and treatment of severe pulmonary hypertension .",
"Is transforming growth factor - β signaling activated in human hypertrophied prostate treated by 5 - alpha reductase inhibitor ? BACKGROUND AND AIM : It is well known that androgen deprivation relates to penile fibrosis , so we hypothesize that long - term treatment with 5 - alphareductase inhibitors ( 5ARIs ) may increase the risk of fibrosis of prostate . PATIENTS AND METHODS : Thirty - two BPH patients who underwent transurethral resection of the prostate were enrolled . The patients were divided into two groups : group one , 16 patients underwent TURP who had been treated with tamsulosin for 2 years ; group two , 16 patients underwent TURP who had been treated with combination of tamsulosin and dutasteride for at least 1 year . We evaluated the expressions of P29475 , P35228 , P29474 , TGF - β1 , TGF - β2 , phosphorylated - Q15796 / 3 ( p - Q15796 / 3 ) , P12830 , P19022 , and α - smooth muscle actin in the resected prostate tissues by western blotting , and the TGF - β concentration was determined by ELISA kit . RESULTS : The expressions of 3 isoforms of NOS were significantly increased in group 2 except of P29474 in lateral prostate , and the expressions of TGF - β1 , TGF - β2 , and p - Q15796 / 3 increased about 2 - fold compared with group 1 . In group 2 , the P12830 expression decreased while P19022 expression increased significantly . CONCLUSIONS : The overexpression of P29475 may contribute to prostate smooth muscle relaxation ; however , long - time treatment with 5 Q9Y4X5 increases the risk of fibrosis of prostate .",
"Non - prostanoid prostacyclin mimetics . 6 . Derivatives of 2 -[ 3 -[ 2 -( 4 , 5 - Diphenyl - 2 - oxazolyl ) ethyl ] phenoxy ] acetic acid modified beta - to the oxazole ring . 2 -[ 3 -[ 2 -( 4 , 5 - Diphenyl - 2 - oxazolyl ) ethyl ] phenoxy ] acetic acid , 1 , has been described as a non - prostanoid DB01240 mimetic that demonstrates anti - thrombotic properties of long duration in animal models of thrombosis . The effects of substitution and modification of the carbon beta - to the oxazole heterocycle of 1 were examined and equated with the potency of the compounds as inhibitors of ADP - induced human platelet aggregation in vitro . Potency was sensitive to both the size of the substituent and the identity of the beta - atom . The carbamates 13c - e demonstrated IC50 ' s of 0 . 28 - 0 . 36 microM and were significantly more potent than the progenitor 1 , IC50 = 1 . 2 microM . The ethyl carbamate 13c displaced [ 3H ] - iloprost from platelet membranes in a concentration - dependent fashion that was half maximal at 20 nM , which compares with IC50 ' s of 171 nM for 1 and 39 nM or unlabelled iloprost . Carbamate 13c stimulated platelet adenylate cyclase but the maximal effect was less than that observed for DB01240 , identifying 13c as a partial agonist at the platelet P43119 .",
"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK87___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"Estrogen protects the heart from ischemia - reperfusion injury via P35354 - derived DB01240 . There is an accumulating body of data to suggest that estrogen mediates its cardioprotective effects via cyclooxygenase activation and synthesis of prostaglandins ( PG ) , specifically DB01240 . We hypothesized that inhibition of P35354 would prevent estrogen ' s cardioprotective effects after myocardial ischemia - reperfusion . Acute treatment with 17beta - estradiol ( E2 ; 20 microg / rabbit ) increased P35354 protein expression and activity in the myocardium . To determine the effects of P35354 inhibition on infarct size after E2 treatment , New Zealand white rabbits were anesthetized and administered the P35354 inhibitor nimesulide ( 5 mg / kg ) or vehicle intravenously 30 minutes before an intravenous injection of E2 . Thirty minutes after estrogen treatment , the coronary artery was occluded for 30 minutes followed by 4 hours of reperfusion . E2 significantly decreased infarct size as a percent of area at risk when compared to vehicle ( 18 . 9 +/- 3 . 1 versus 47 . 0 +/- 4 . 1 ; P < 0 . 001 ) . Pretreatment with nimesulide nullified the infarct size sparing effect of E2 ( 55 . 8 +/- 5 . 6 ) . Treatment with the P43119 antagonist RO3244794 also abolished the protective effects of E2 ( 45 . 3 +/- 4 . 5 ) . The results indicate that estrogen protects the myocardium from ischemia - reperfusion injury through increased production of P35354 - derived DB01240 . The data indicate that selective P35354 inhibitors might counteract the potential cytoprotective effects of estrogen in premenopausal or postmenopausal women .",
"Altered expression of inflammation - related genes in human carotid atherosclerotic plaques . OBJECTIVE : Inflammation is a pivotal process in atherosclerosis development and progression , but the underlying molecular mechanisms remain largely obscure . We have conducted an extensive expression study of atherosclerotic plaques to identify the inflammatory pathways involved in atherosclerosis . METHODS : We studied 11 human carotid plaques , their respective adjacent regions and 7 control arteries from different subjects . Expression of 92 genes was studied by TaqMan low - density array human inflammation panel . Human aortic endothelial and smooth muscle cells were used for in vitro experiments . RESULTS : The mRNA levels of 44 / 92 genes ( 48 % ) differed significantly between the tissues examined ( 13 up - regulated and 31 down - regulated ) . Dysregulated genes encode molecules belonging to different functional classes although most of them encode enzymes involved in the eicosanoid synthesis pathway . The expression of Q16647 and P43119 genes was decreased in human aortic endothelial and smooth muscle cells stimulated with oxLDL and P01375 - α . CONCLUSIONS : This study not only reveals several dysregulated genes in human lesions but also focuses the role played by the genes involved in the eicosanoid synthesis pathway during atherosclerotic development . The decrease of Q16647 and P43119 expression after oxLDL treatment mirrors the decreased mRNA levels in atherosclerotic lesions versus control arteries , which suggests that oxidation is important for Q16647 and P43119 regulation in human vessel cells during atherosclerosis development .",
"P15692 expression is augmented by hypoxia ‑ induced PGIS in human fibroblasts . Q16647 ( PGIS or Q16647 ) is an enzyme that catalyses the conversion of prostaglandin H2 ( PGH2 ) to prostaglandin I2 ( DB01240 ) . DB01240 promotes cancer growth by activating peroxisome proliferator - activated receptor δ ( PPARδ ) , and increases the expression levels of the pro - angiogenic factor vascular endothelial growth factor ( P15692 ) . We found that the expression of the PGIS gene was enhanced in WI - 38 , TIG - 3 - 20 and HEL human lung fibroblast cells and two cancer cell lines ( NB - 1 and G361 ) under hypoxic conditions . The main localization of PGIS changed from the cytoplasm to the nucleus by hypoxia in WI - 38 cells . The induced PGIS had an enzymatic activity since the intracellular level of 6 - keto - prostaglandin , a useful marker of DB01240 biosynthesis in vivo , was increased with the increasing levels of PGIS . Expression of P15692 was increased in parallel with PGIS induction under hypoxic conditions . PGIS knockdown resulted in the decreased expression of P15692 mRNA . Since P15692 is a known PPARδ target gene , we examined the effects of siRNAs targeting PPARδ on the expression of P15692 under hypoxic conditions . Knockdown of PPARδ suppressed the expression of P15692 under hypoxic conditions in WI - 38 cells . These findings suggest that PGIS is induced by hypoxia and regulates the expression of P15692 in fibroblasts . Fibroblasts in the hypoxic area of tumors may have an important role in tumor growth and angiogenesis .",
"Developmental regulation of prostacyclin synthase and prostacyclin receptors in the ovine uterus and conceptus during the peri - implantation period . This study documents the expression of prostacyclin ( DB01240 ) synthase ( Q16647 ) and DB01240 receptors in the trophoblast and uterus of the ewe at the time of maternal recognition of pregnancy ( i . e . days 7 , 9 , 12 , 14 and 17 ) . The membrane receptor for DB01240 ( P43119 ) and the nuclear receptors , i . e . peroxisome proliferator - activated receptors ( Q07869 ) and their heterodimer partners the retinoid X receptors ( RXR ) , were analysed . In the endometrium , Q16647 transcript and protein were expressed at day 9 of pregnancy and levels declined from days 12 to 17 . Immunohistochemistry and in situ hybridization indicated that Q16647 was mainly located in the luminal epithelium of the endometrium . Endometrial P43119 , Q07869 , P37231 and P48443 expression was regulated during the peri - implantation period whereas Q03181 , P19793 and P28702 were consistently expressed . In the trophoblast , Q16647 transcript levels rose as development progressed and peaked at day 17 . P43119 and Q07869 transcripts peaked before day 12 and then declined and became nearly undetectable by day 17 , whereas Q03181 and P37231 transcript levels rose steadily from days 12 to 17 . Because the PPARs and the RXRs display different expression profiles , we suggest that different heterodimers may form and support distinct functions as development proceeds . Our results also underline the importance of Q16647 and Q03181 in the trophoblast and P43119 in the uterus , suggesting that DB01240 is of both uterine and trophoblastic origin and is involved in a complex signalling pathway at around the time of implantation in the ewe .",
"Identification of the prostacyclin receptor by use of [ 15 - 3H1 ] 19 -( 3 - azidophenyl )- 20 - norisocarbacyclin , an irreversible specific photoaffinity probe . The prostaglandin I ( DB01240 ) receptor of mouse mastocytoma P - 815 cells was characterized by photo - affinity labeling with the stable DB01240 analogue [ 15 - 3H1 ] - 19 -( 3 - azidophenyl )- 20 - norisocarbacyclin ( [ 3H ] APNIC ) used as a potential photoaffinity probe for the receptor . [ 3H ] APNIC bound to the mastocytoma membrane with high affinity and in a saturable manner . Scatchard plot analysis indicated a single binding site with a Kd of 4 . 7 nM and a Bmax of 0 . 58 pmol / mg protein . The binding of [ 3H ] APNIC was dose dependently inhibited by APNIC and iloprost , another stable DB01240 agonist , and to a much lesser extent by DB00917 . The binding of the radioligand showed sensitivity to the guanine nucleotide guanosine 5 '- O -( 3 - thio - triphosphate ) ( GTP gamma S ) . Photolysis of [ 3H ] APNIC - prelabeled membranes resulted in incorporation of radiolabel into a protein of approximately 43 kDa . Photolabeling was inhibited by DB01240 agonists and other prostaglandins with specificity for the P43119 and was modulated by GTP gamma S . A protein of approximately 45 kDa was also labeled by [ 3H ] APNIC in the membrane of porcine platelets , membranes that are known to be abundant in DB01240 receptors . These results demonstrate that [ 3H ] APNIC specifically labels a protein that may represent the P43119 and that this radioprobe will be a useful reagent for further characterization and purification of the P43119 .",
"Recombinational and physical mapping of the locus for primary open - angle glaucoma ( Q99972 ) on chromosome 1q23 - q25 . Primary open - angle glaucoma ( POAG ) is a leading cause of irreversible blindness in industrialized countries . A locus for juvenile - onset POAG , Q99972 , has been mapped to 1q21 - q31 in a 9 - cM interval . With recombinant haplotypes , we have now reduced the Q99972 interval to a maximum of 3 cM , between the D1S452 / NGA1 / D1S210 and NGA5 loci . These loci are 2 . 8 Mb apart on a 4 . 7 - Mb contig that we have completed between the D1S2851 and D1S218 loci and that includes 96 YAC clones and 48 STSs . The new Q99972 interval itself is now covered by 25 YACs , 30 STSs , and 16 restriction enzyme site landmarks . The lack of a NotI site suggests that the region has few CpG islands and a low gene content . This is compatible with its predominant cytogenetic location on the 1q24 G - band . Finally , we have excluded important candidate genes , including genes coding for three ATPases ( P05026 , P23634 , P50993 ) , an ion channel ( VDAC4 ) , antithrombine III ( P01008 ) , and prostaglandin synthase ( P35354 ) . Our results provide a basis to identify the Q99972 gene .",
"Impairment of breast cancer cell invasion by P35354 - specific inhibitor NS398 : roles of P61073 and of uPA system . Inhibition of cyclooxygenase - 2 ( P35354 ) is known to impair cancer cell metastatic behaviour , but the mechanisms involved largely remain elusive . We aimed to analyse whether the antimetastatic effect of P35354 inhibition in breast cancer cells could be explained by variations in the expression levels of chemokine receptor P61073 , vascular endothelium growth factor ( P15692 ) and Q96NZ9 / Q03405 components of the urokinase plasminogen activator system ( Q03405 ) . Breast cancer cell line MDA - MB - 231 was exposed to P35354 - specific inhibitor NS398 . Experimental data were assessed using Matrigel invasion tests , qRT - PCR , ELISA , flow cytometry and MTT test . Exposure to NS398 had no major effect on cell viability , apoptosis or P15692 production . Cell invasion was significantly decreased with reductions ranging from of 3 . 6 % with 10 μM NS398 to 81 . 04 % with 100 μM NS398 . P61073 membrane expression was significantly reduced by 18 % ( P < 0 . 05 ) when cells were treated with 100 μM of NS398 for 72 h . Q96NZ9 mRNA levels were significantly reduced to 78 and 63 % after treatment with 10 μM NS398 for 48 and 72 h , respectively ( P < 0 . 05 ) . Q03405 mRNA levels also decreased with mild NS398 concentrations , reaching the lowest level of 56 % with 50 μM of NS398 for 48 h ( P < 0 . 05 ) . With NS398 higher concentrations , Q03405 and Q96NZ9 expression levels increased . According to our results , impairment of expression of P61073 , Q96NZ9 and Q03405 differentially contribute to the antimetastatic effect of P35354 inhibitors depending on drug concentration .",
"P43119 induces P42224 and P40763 phosphorylations in human erythroleukemia cells : a mechanism requiring PTX - insensitive G proteins , P29323 and JNK . The ability of the human prostacyclin receptor ( hIP ) to regulate the activities of signal transducers and activators of transcription ( STATs ) has not yet been documented . In the present study , we have delineated the mechanism by which hIP induces P40763 phosphorylations in human erythroleukemia ( HEL ) cells . Stimulation of endogenous hIP by its specific agonist , cicaprost , resulted in P40763 Tyr705 and Ser727 phosphorylations in a time - and concentration - dependent manner . Cicaprost - induced P40763 Tyr705 and Ser727 phosphorylations were resistant to pertussis toxin ( PTX ) treatment , suggesting that these responses were mediated through PTX - insensitive G proteins . In addition , extracellular signal - regulated kinase ( P29323 ) and c - Jun N - terminal kinase ( JNK ) , but not p38 MAPK , were shown to be phosphorylated by cicaprost in a time - and concentration - dependent manner via PTX - insensitive G proteins . The levels of the interaction between P40763 , P29323 and JNK were enhanced by cicaprost treatment . The involvement of P04049 , Q02750 / 2 and JNK in cicaprost - induced phosphorylations of P40763 was illustrated by the use of their selective inhibitors . In contrast , p38 MAPK did not appear to be required . Similar observations were obtained with P42224 upon stimulation by cicaprost . Taken together , these results demonstrate for the first time that hIP activation by cicaprost can lead to P42224 and P40763 phosphorylations via signaling pathways involving PTX - insensitive G proteins , P29323 and JNK .",
"[ Moclobemide ( ___MASK35___ ) , the first P21397 - inhibitor : really something new ? ] .",
"Dehydration activates an NF - kappaB - driven , P35354 - dependent survival mechanism in renal medullary interstitial cells . Renal prostaglandin ( PG ) synthesis is mediated by cyclooxygenase - 1 and - 2 ( P23219 and P35354 ) . After dehydration , the maintenance of normal renal function becomes particularly dependent upon PG synthesis . The present studies were designed to examine the potential link between medullary P23219 and P35354 expression in hypertonic stress . In response to water deprivation , P35354 , but not P23219 , mRNA levels increase significantly in the renal medulla , specifically in renal medullary interstitial cells ( RMICs ) . DB09145 deprivation also increases renal NF - kappaB - driven reporter expression in transgenic mice . NF - kappaB activity and P35354 expression could be induced in cultured RMICs with hypertonic sodium chloride and mannitol , but not urea . RMIC P35354 expression was also induced by driving NF - kappaB activation with a constitutively active O15111 alpha ( IKKalpha ) . Conversely , introduction of a dominant - negative IkappaB mutant reduced P35354 expression after hypertonicity or IKKalpha induction . RMICs failed to survive hypertonicity when P35354 was downregulated using a P35354 - selective antisense or blocked with the selective nonsteroidal anti - inflammatory drug ( NSAID ) SC58236 , reagents that did not affect cell survival in isotonic media . In rabbits treated with SC58236 , water deprivation induced apoptosis of medullary interstitial cells in the renal papilla . These results demonstrate that water deprivation and hypertonicity activate NF - kappaB . The consequent increase in P35354 expression favors RMIC survival in hypertonic conditions . Inhibition of RMIC P35354 could contribute to NSAID - induced papillary injury .",
"DB05229 sodium , a stable prostacyclin analogue , elicits dilation of isolated porcine retinal arterioles : roles of P29474 and potassium channels . PURPOSE : DB01240 ( DB01240 ) is usually described as an endoEDRFsthelium - derived relaxing factor , but the vasoreactivity to DB01240 in the retinal arterioles and the underlying mechanisms are not fully understood . We examined the effects of DB01240 on the retinal microcirculation using beraprost sodium ( BPS ) , a stable DB01240 analogue , and the signaling mechanisms involved in this vasomotor activity . METHODS : Porcine retinal arterioles were isolated , cannulated , and pressurized without flow in vitro . Video microscopic techniques recorded the diametric responses to BPS . RESULTS : DB05229 sodium elicited dose - dependent ( 0 . 1 pM - 0 . 1 μM ) vasodilation of the retinal arterioles that was abolished by the P43119 ( IP ) antagonist CAY10441 . DB05229 sodium - induced vasodilation decreased by 50 % after the endothelium was removed and was inhibited by the nitric oxide ( NO ) synthase inhibitor N ( G )- nitro - L - arginine methyl ester ( L - NAME ) comparable with denudation . Inhibition of soluble guanylyl cyclase by 1H - 1 , 2 , 4 - oxadiazolo [ 4 , 3 - a ] quinoxalin - 1 - one ( ODQ ) and blockage of protein kinase A ( PKA ) by Rp - 8 - Br - cAMPS were comparable to L - NAME . DB05229 sodium - induced vasodilation was also inhibited by the nonselective potassium channel inhibitor , tetraethylammonium , and the adenosine triphosphate - sensitive potassium ( KATP ) channel blocker , glibenclamide . Residual vasodilation in the presence of glibenclamide decreased further with subsequent application of ODQ . CONCLUSIONS : DB05229 sodium , a stable DB01240 analogue , causes vasodilation of the retinal arterioles mediated via the IP receptor . The current findings suggest that BPS elicits endothelium - dependent and - independent dilation of the retinal arterioles mediated by NO induced by activation of PKA in the endothelium and the KATP channel activation in the vascular smooth muscle , respectively .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"Identification of antithrombin - modulating genes . Role of O95461 , a gene encoding a bifunctional glycosyltransferase , in the secretion of proteins ? The haemostatic relevance of antithrombin together with the low genetic variability of P01008 , and the high heritability of plasma levels encourage the search for modulating genes . We used a hypothesis - free approach to identify these genes , evaluating associations between plasma antithrombin and 307 , 984 polymorphisms in the GAIT study ( 352 individuals from 21 Spanish families ) . Despite no SNP reaching the genome wide significance threshold , we verified milder positive associations in 307 blood donors from a different cohort . This validation study suggested O95461 , a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin - like linear polysaccharides , as a potential modulator of antithrombin based on the significant association of one SNPs , rs762057 , with anti - FXa activity , particularly after adjustment for age , sex and P01008 rs2227589 genotype , all factors influencing antithrombin levels ( p = 0 . 02 ) . Additional results sustained this association . O95461 silencing inHepG2 and P29320 - EBNA cells did not affect P01008 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention . Milder effects were observed on α1 - antitrypsin , prothrombin and transferrin . Our study suggests O95461 as the first known modifier of plasma antithrombin , and proposes a new role for O95461 in modulating extracellular secretion of certain glycoproteins .",
"___MASK100___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"A surface plasmon resonance - based solution affinity assay for heparan sulfate - binding proteins . A surface plasmon resonance - based solution affinity assay is described for measuring the K ( d ) of binding of heparin / heparan sulfate - binding proteins with a variety of ligands . The assay involves the passage of a pre - equilibrated solution of protein and ligand over a sensor chip onto which heparin has been immobilised . DB01109 sensor chips prepared by four different methods , including biotin - streptavidin affinity capture and direct covalent attachment to the chip surface , were successfully used in the assay and gave similar K ( d ) values . The assay is applicable to a wide variety of heparin / HS - binding proteins of diverse structure and function ( e . g . , P05230 , P09038 , P15692 , P10145 , P80075 , P01008 , P02776 ) and to ligands of varying molecular weight and degree of sulfation ( e . g . , heparin , DB05808 , sucrose octasulfate , naphthalene trisulfonate ) and is thus well suited for the rapid screening of ligands in drug discovery applications .",
"Hypoxia - inducible vascular endothelial growth factor gene therapy using the oxygen - dependent degradation domain in myocardial ischemia . PURPOSE : A hypoxia - inducible P15692 expression system with the oxygen - dependent degradation ( Q8TAX0 ) domain was constructed and tested to be used in gene therapy for ischemic myocardial disease . METHODS : Luciferase and P15692 expression vector systems were constructed with or without the Q8TAX0 domain : pEpo - SV - Luc ( or pEpo - SV - P15692 ) and pEpo - SV - Luc - Q8TAX0 ( or pEpo - SV - P15692 - Q8TAX0 ) . In vitro gene expression efficiency of each vector type was evaluated in P29320 293 cells under both hypoxic and normoxic conditions . The amount of P15692 protein was estimated by ELISA . The P15692 expression vectors with or without the Q8TAX0 domain were injected into ischemic rat myocardium . Fibrosis , neovascularization , and cardiomyocyte apoptosis were assessed using Masson ' s trichrome staining , α - smooth muscle actin ( α - SMA ) immunostaining , and the TUNEL assay , respectively . RESULTS : The plasmid vectors containing Q8TAX0 significantly improved the expression level of P15692 protein in hypoxic conditions . The enhancement of P15692 protein production was attributed to increased protein stability due to oxygen deficiency . In a rat model of myocardial ischemia , the pEpo - SV - P15692 - Q8TAX0 group exhibited less myocardial fibrosis , higher microvessel density , and less cardiomyocyte apoptosis compared to the control groups ( saline and pEpo - SV - P15692 treatments ) . CONCLUSION : An Q8TAX0 - mediated P15692 expression system that facilitates P15692 - production under hypoxia may be useful in the treatment of ischemic heart disease .",
"___MASK6___ block of cloned human T - type voltage - gated calcium channels . ___MASK6___ ( ZNS ) is a multi - target antiepileptic drug reported to be efficient in the treatment of both partial and generalized seizures , with T - type Ca ( 2 +) channel blockade being one of its proposed mechanisms of action . In this study , we systematically investigated electrophysiological effects of ZNS on cloned human Ca ( v ) 3 . 1 - 3 . 3 Ca ( 2 +) channels in a heterologous P29320 - 293 expression system using whole cell patch - clamp technique . Concentration - response studies were performed in the range from 5 microM to 2mM for Ca ( v ) 3 . 2 Ca ( 2 +) channels exhibiting a 15 . 4 - 30 . 8 % reduction of Ca ( 2 +) influx within the maximum therapeutic plasma range ( 50 - 200 microM ZNS ) . The other T - type Ca ( 2 +) channel entities , Ca ( v ) 3 . 1 and Q9P0X4 , were even less sensitive to ZNS . Both voltage - and concentration - dependence of inactivation kinetics remained unchanged for Ca ( v ) 3 . 2 VGCC , whereas Ca ( v ) 3 . 1 and Q9P0X4 exhibited minor , though significant reduction of inactivation - tau . Interestingly , ZNS block of Ca ( v ) 3 . 2 VGCCs was not use - dependent and remained unaffected by changes in the holding potential . Steady - state inactivation studies did not display a significant shift in steady - state availability of Ca ( v ) 3 . 2 channels at 100 microM ZNS ( DeltaV ( 1 / 2 )= 3 . 1mV , p = 0 . 071 ) . Our studies indicate that ZNS is a moderate blocker of human Ca ( v ) 3 T - type Ca ( 2 +) channels with little or no effect on Ca ( v ) 3 . 2 Ca ( 2 +) channel inactivation kinetics , use - and state - dependence of blockade . These results suggest that T - type Ca ( 2 +) channel inhibition only partially contributes to the anti - absence activity of ZNS antiepileptic drug .",
"Evidence for distinct prostaglandin I2 and D2 receptors in human platelets . Incubation of human platelet - rich plasma with prostaglandin I2 ( DB01240 ) , results in a marked increase in adenosine 3 ': 5 '- monophosphate ( DB02527 ) that persists for at least 60 min . The persistent stimulation of DB02527 levels by DB01240 can be rapidly reversed by the addition of either prostaglandin E1 or E2 ( PGE1 , DB00917 ) , but not by prostaglandin D2 ( PGD2 ) . Studies of agonist - specific desensitization of DB02527 accumulation show that PGE1 or DB00917 can desensitize for subsequent PGE or DB01240 activation , and that subthreshold levels of DB01240 desensitize for subsequent PGE1 stimulation . PGD2 desensitizes for consequent PGD2 activation , but not for PGE1 , DB00917 or DB01240 , and PGE compounds and DB01240 do not desensitize for subsequent PGD2 activation . Agonist - specific desensitization for DB01240 is not dependent on DB02527 accumulation , but appears to be a consequence of receptor occupation . Support of the desensitization experiments was obtained through the use of the prostaglandin antagonist N - 0164 [ sodium - p - benzyl - 4 -[- oxo - 2 -( 4 - chlorobenzyl )- 3 - phenyl - propyl ] phenyl phosphonate ) . This compound proved to be a potent antagonist of PGD2 and a weak antagonist of DB01240 - stimulated DB02527 accumulation . These data indicate that human platelets have distinct pharmacological receptors for both DB01240 and PGD2 , and that PGE compounds may actually interact with a P43119 .",
"DB01088 has potent anti - inflammatory properties on human monocyte - derived dendritic cells . BACKGROUND : The stable prostaglandin I2 analogue ( iloprost ) iloprost has been shown to inhibit allergic airway inflammation in mice by modulating the function of myeloid dendritic cells ( DCs ) . OBJECTIVE : The aim of the current study was to investigate the biological activity of iloprost on human monocyte - derived DCs . METHODS : I prostanoid ( IP ) receptor expression was analysed by RT - PCR . Cytokine secretion by DCs and P01730 + T cells was measured by ELISA . The expression of the transcription factor FoxP3 after co - culture of DCs with P01730 + CD45RA + T cells was analysed by flow cytometry . RESULTS : Human monocyte - derived DCs were found to express mRNA specific for the P43119 IP , and stimulation with iloprost resulted in increased cyclic AMP levels in both immature DCs ( iDCs ) and mature DCs ( mDCs ) . Moreover , iloprost dose dependently inhibited the secretion of P01375 , P05231 , P10145 and IL - 12p70 in mDCs , while it enhanced P22301 production . Changes in cytokine secretion were paralleled by an altered T - cell priming capacity of DCs : in co - culture experiments of iloprost - treated mDC and naïve CD45RA + T cells , an induction of regulatory T cells could be observed , as demonstrated by increased intracellular FoxP3 expression and P22301 production . Additionally , iloprost inhibited the MIP - 3beta - induced migration of mDCs . CONCLUSION : In summary , our results provide evidence that iloprost profoundly affects the function of human myeloid DCs . Therefore , iloprost might also be a new therapeutical option for the treatment of asthma in humans .",
"Suppression of NF - kappaB activity by sulfasalazine is mediated by direct inhibition of IkappaB kinases alpha and beta . BACKGROUND & AIMS : Activation of NF - kappaB / Rel has been implicated in the pathogenesis of inflammatory bowel disease ( Q9UKU7 ) . Various drugs used in the treatment of Q9UKU7 , such as glucocorticoids , DB00244 , and sulfasalazine , interfere with NF - kappaB / Rel signaling . The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF - kappaB activation . METHODS : The effects of sulfasalazine and its moieties on NF - kappaB signaling were evaluated using electromobility shift , transfection , and immune complex kinase assays . The direct effect of sulfasalazine on O15111 ( IKK ) activity was investigated using purified recombinant O15111 and - beta proteins . RESULTS : NF - kappaB / Rel activity induced by tumor necrosis factor alpha , 12 - O - tetradecanoylphorbol - 13 - acetate , or overexpression of NF - kappaB - inducing kinase , O15111 , O14920 , or constitutively active O15111 and O14920 mutants was inhibited dose dependently by sulfasalazine . Sulfasalazine inhibited tumor necrosis factor alpha - induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells , as well as the catalytic activity of purified O15111 and O14920 in vitro . In contrast , the moieties of sulfasalazine , DB00244 , and sulfapyridine or ___MASK37___ had no effect . Activation of extracellular signal - related kinase ( P29323 ) 1 and 2 , c - Jun - N - terminal kinase ( JNK ) 1 , and p38 was unaffected by sulfasalazine . The decrease in substrate phosphorylation by O15111 and - beta is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate . CONCLUSIONS : These data identify sulfasalazine as a direct inhibitor of O15111 and - beta by antagonizing adenosine triphosphate binding . The suppression of NF - kappaB activation by inhibition of the IKKs contributes to the well - known anti - inflammatory and immunosuppressive effects of sulfasalazine .",
"DB01240 ( P06744 ) receptor binding and cyclic AMP synthesis activities of PGI1 analogues , SM - 10906 and its methyl ester , SM - 10902 , in mastocytoma P - 815 cells . The prostacyclin I1 ( PGI1 ) analogue , SM - 10906 and its methyl ester , SM - 10902 , have been compared with the DB01240 analogue , iloprost , with respect to binding to the P43119 , stimulation of adenylate cyclase activity and inhibition of thrombin - induced Ca2 + mobilization in mastocytoma P - 815 cells . SM - 10906 displaced [ 3H ] iloprost binding to the membrane fraction , the IC50 value being 100 nM , but showed very low affinity for the prostaglandin E ( PGE ) receptor . SM - 10906 dose - dependently stimulated GTP - dependent adenylate cyclase activity in the membrane fraction , the EC50 value being 35 nM . Furthermore , SM - 10906 prevented a thrombin - induced increase in the intracellular Ca2 + concentration , the IC50 value being 300 nM . These IC50 and EC50 values are much lower than those of SM - 10902 . These results demonstrate that SM - 10906 , a stable PGI1 derivative , is an agonist for the [ 3H ] iloprost - binding ( DB01240 ) receptor , and that it prevents thrombin - induced Ca2 + mobilization through stimulation of the adenylate cyclase system in mastocytoma cells . On the other hand , a methyl ester derivative of PGI1 , SM - 10902 , was inactive in the binding assay , but it seems to be a partial agonist for adenylate cyclase activity [ corrected ] .",
"___MASK15___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients .",
"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK71___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .",
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK34___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK34___ who were treated with a single dose of mifepristone .",
"A lung - specific neo - antigen elicits specific CD8 + T cell tolerance with preserved P01730 + T cell reactivity . Implications for immune - mediated lung disease . The A / Japan / 57 influenza hemagglutinin ( HA ) was expressed in BALB / c mice under the transcriptional control of the surfactant protein C ( P11686 ) promoter , resulting in expression of HA in type II alveolar epithelial cells , as well as low level variable expression in other tissues , including the thymus in some of the founder lines . Transgenic animals were able to recover from infection with A / Japan / 57 influenza , and they were able to mount antibody responses to A / Japan / 57 HA in titers similar to wild type . We therefore tested their P01730 + T lymphocyte responses to HA and found them to be similar to wild type responses . However , CD8 + T cells from A / Japan / 57 - infected transgenic animals were unable to express cytolytic activity against target cells expressing the A / Japan / 57 HA . The CD8 + T cell tolerance was also extremely specific , since transgenics immunized with an influenza strain containing a single amino acid substitution in a dominant HA epitope were able to mount full cytolytic responses to that epitope , but not the wild - type epitope . Adoptive transfer of CD8 + T cell clones into transgenic animals resulted extensive interstitial pneumonitis that was antigen - specific and associated with significant morbidity and mortality . We conclude that a lung - specific transgene may lead to specific CD8 + T cell tolerance , with P01730 + T cell and B cell reactivity to the antigen , and that P01730 + T cell reactivity may remain intact to an antigen expressed in the thymus , even when CD8 + T cell tolerance exists . This observation may have profound implications concerning immune - mediated lung diseases , particularly those mediated by P01730 + T cells .",
"Surfactin exhibits neuroprotective effects by inhibiting amyloid β - mediated microglial activation . Microglial - mediated neuroinflammation and neurotoxicity contribute to the pathogenesis of neurodegenerative diseases including Alzheimer ' s disease ; therefore , control of microglial activation and subsequent suppression of neurotoxic pro - inflammatory molecules could provide a potential therapeutic approach for the treatment of such diseases . In this study , we investigated the effects of surfactin , a surfactant from Bacillus subtilis , on oligomeric amyloid β ( Aβ ) - induced microglial activation and neurotoxicity . Surfactin significantly suppressed expression of P14780 , P35228 and P35354 , as well as production of ROS , NO , DB00917 , P01375 - α , IL - 1β , P05231 and P13500 in Aβ - stimulated BV - 2 microglial cells . Moreover , surfactin markedly inhibited Aβ - induced nuclear translocation and activation of NF - κB as well as phosphorylation of JNK and p38 MAPK . Furthermore , surfactin protected hippocampal HT22 cells from indirect neuronal toxicity mediated by Aβ - treated microglial cells , but had no effect on Aβ - induced direct toxicity to HT22 cells . These results suggest that surfactin impairs the Aβ - induced inflammatory response of microglial cells and confers protection against indirect neurotoxicity to hippocampal cells . Our findings indicate that surfactin may have therapeutic potential for ameliorating Alzheimer ' s disease as well as other neurodegenerative disorders which involve neuroinflammation .",
"High - dose aspirin in dogs increases vascular resistance with limited additional anti - platelet effect when combined with potent Q9H244 inhibition . INTRODUCTION : With the arrival of the potent Q9H244 antagonists , ticagrelor and prasugrel , the need for co - treatment with aspirin in acute coronary syndromes must be re - examined . This study assessed whether high - dose aspirin : a ) provides additional anti - platelet efficacy , assessed in vivo and ex vivo , when combined with Q9H244 inhibition ; and / or b ) has a negative effect on vascular function . MATERIALS AND METHODS : Using an anaesthetized dog model of thrombosis , the effects of aspirin ( 50mg / kg ) in addition to clopidogrel and ticagrelor were evaluated at two levels of Q9H244 inhibition , maximal ( ≥ 96 % ) and sub - maximal ( ~ 80 % ) , as assessed by ex vivo ADP - induced whole blood impedence aggregometry . RESULTS : In the absence of aspirin , maximal and sub - maximal Q9H244 inhibition inhibited arachidonic acid - induced platelet aggregation by approximately 80 % and 24 % , respectively , without affecting platelet TXA2 formation . During maximal Q9H244 inhibition , aspirin provided less additional inhibition of ex vivo arachidonic acid - and collagen - induced platelet aggregation , as compared with sub - maximal Q9H244 inhibition , without additional anti - thrombotic effect in vivo . DB00945 significantly decreased in vivo DB01240 production ( 27 % ) and increased vascular resistance ( 16 % ) , independently of Q9H244 antagonism . CONCLUSION : In the dog , Q9H244 antagonists inhibit TXA2 - mediated platelet - aggregation independently of aspirin . DB00945 provides less additional anti - platelet effects during maximal compared with sub - maximal Q9H244 inhibition but increases vascular resistance .",
"Steatohepatitis in laboratory opossums exhibiting a high lipemic response to dietary cholesterol and fat . Plasma VLDL and LDL cholesterol were markedly elevated ( > 40 - fold ) in high - responding opossums , but moderately elevated ( 6 - fold ) in low - responding opossums after they had consumed a high - cholesterol and high - fat diet for 24 wk . In both high - and low - responding opossums , plasma triglycerides were slightly elevated , threefold and twofold , respectively . Dietary challenge also induced fatty livers in high responders , but not in low responders . We studied the lipid composition , histopathological features , and gene expression patterns of the fatty livers . Free cholesterol ( 2 - fold ) , esterified cholesterol ( 11 - fold ) , and triglycerides ( 2 - fold ) were higher in the livers of high responders than those in low responders , whereas free fatty acid levels were similar . The fatty livers of high responders showed extensive lobular disarray by histology . Inflammatory cells and ballooned hepatocytes were also present , as were perisinusoidal fibrosis and ductular proliferation . In contrast , liver histology was normal in low responders . Hepatic gene expression revealed differences associated with the development of steatohepatitis in high responders . The accumulation of hepatic cholesterol was concomitant with upregulation of the P04035 gene and downregulation of the Q02318 , Q9H221 , and P21439 genes . Genes involved in inflammation ( P01375 , P19838 , and P35354 ) and in oxidative stress ( P13498 and P14598 ) were upregulated . Upregulation of the growth factor genes ( PDGF and P01137 ) and collagen genes ( Col1A1 , Col3A1 , and Col4A1 ) was consistent with fibrosis . Some of the histological characteristics of the fatty livers of high - responding opossums imitate those in the livers of humans with nonalcoholic steatohepatitis .",
"Differential activation of Gi and Gs proteins by E - and I - type prostaglandins in membranes from the human erythroleukaemia cell line , HEL . The group of prostaglandin ( PG ) E2 - and prostacyclin receptors consists of different subtypes , which exhibit different affinities for prostaglandins and synthetic analogues . DB00917 activities the E - type PG receptor subtypes EP1 , EP2 and EP3 , whereas the DB00917 analogue , sulprostone , binds only to the EP1 and EP3 receptor subtypes . The stable DB01240 analogues , iloprost and cicaprost , both activate the P43119 ( IP ) and iloprost , additionally , bind to the EP1 subtype . Using these subtype - selective PG receptor agonists , we studied the interaction of PG receptor subtypes with Gs and Gi - type heterotrimeric guanine nucleotide - binding proteins ( G proteins ) in membranes from the human erythroleukaemia cell line , HEL . Sulprostone stimulated high - affinity GTPase in HEL membranes in a pertussis toxin ( PTX ) - sensitive manner . In contrast , the stimulations induced by DB00917 , iloprost and cicaprost were only partially inhibited by PTX . DB00917 , sulprostone , iloprost and cicaprost stimulated cholera toxin - catalysed ADP - ribosylation as well as labelling with GTP azidoanilide of membrane proteins comigrating with immunologically identified Gi protein alpha subunits . Furthermore , DB00917 , iloprost and cicaprost enhanced GTP azidoanilide - labelling of Gs protein alpha subunits , whereas sulprostone did not . We suggest that in HEL cells ( 1 ) EP1 and EP3 receptor subtypes activate P55008 proteins , that ( 2 ) the EP2 receptor subtype activates Gs proteins and that ( 3 ) the IP receptor activates both Gi and Gs proteins .",
"Normal and perturbed endothelial cells from canine femoral arteries and femoral veins exhibit heterogeneity in hemostatic properties and growth characteristics . BACKGROUND : We sought to examine the heterogeneity of endothelial cells from the same anatomic site but different vascular systems and described P04275 ( P04275 ) release and morphological change in response to injury - associated factor in femoral vessels from canine in vitro . METHODS : Levels of hemostatic factors ( P04275 , plasminogen activator inhibitor type 1 ( P05121 ) , antithrombin III ( P01008 ) , in tissue sections and cultured endothelial cells of canine femoral arteries and canine femoral veins were compared by the immunohistochemistry technique . In addition to comparing cell growth density and cell protein contents , cultured femoral arterial endothelial cells ( FAECs ) and cultured femoral venous endothelial cells ( FVECs ) were incubated with a series concentration of basic fibroblast factor ( P09038 ) ( 1 , 10 , 100 ng / ml ) for up to 48 hours to test the amount of P04275 secretion and morphological change . RESULTS : Both in tissue sections and cultured cells , the levels of P04275 are higher in FVECs than in FAECs . We were unable to differentiate the level of P05121 and P01008 difference between FAECs and FVECs . P09038 ( 10 ng / ml ) significantly increased P04275 secretion from cultured FAECs but not from FVECs . The size of cultured FAECs is smaller than of FVECs ; however , FAECs have higher amounts of protein contents than FVECs . CONCLUSIONS : These comparative studies provide evidence indicating that the characteristics of FVECs differ from those of FAECs . These differences may be indicated heterogeneity with either inherited or acquired thrombotic disease .",
"___MASK71___ enhances the inhibitory effects of a selective AT1 receptor blocker , valsartan , on atherosclerosis . We investigated the effects of a P04035 inhibitor ( statin ) on the inhibitory effects of an angiotensin II type - 1 receptor ( AT1 ) blocker on atherosclerosis and explored cellular mechanisms . We gave apolipoprotein E null mice a high - cholesterol diet for 10 weeks and measured atherosclerotic plaque area and lipid deposition . Neither 1 mg / kg per day of valsartan nor 3 mg / kg per day of fluvastatin had any effect on blood pressure or cholesterol concentration ; however , both drugs decreased plaque area and lipid deposition after 10 weeks . We then reduced the doses of both drugs to 0 . 1 mg / kg per day and 1 mg / kg per day , respectively . At these doses , neither drug had an effect on atherosclerotic lesions . When both drugs were combined at these doses , a significant reduction in atherosclerotic lesions was observed . Similar inhibitory effects of valsartan or fluvastatin on the expressions of nicotinamide - adenine dinucleotide / nicotinamide - adenine dinucleotide phosphate oxidase subunits P13498 and p47phox , production of superoxide anion , the expression of monocyte chemoattractant protein - 1 , and intercellular adhesion molecule - 1 expression were observed . These results suggest that concomitant AT1 receptor and cholesterol biosynthesis blockade , particularly when given concomitantly , blunts oxidative stress and inflammation independent of blood pressure or cholesterol - related effects .",
"Altered expression of beta - catenin , P12830 , cycloxygenase - 2 , and p53 protein by ovine intestinal adenocarcinoma cells . Around 1 . 6 % of sheep in New Zealand develop small - intestinal adenocarcinomas . These neoplasms typically develop widespread metastases . The common development of these neoplasms and their subsequent behavior suggests that sheep could be a useful animal model of human colonic cancer . However , for an animal model of human disease to be relevant , similar genetic mutations should be present . Genetic mutations within human colonic cancers frequently result in expression of cycloxygenase - 2 ( P35354 ) , loss of membranous expression of beta - catenin and P12830 , and accumulation of p53 protein within the neoplastic cells . Immunohistochemistry was used to investigate the presence of these 4 proteins within 26 ovine intestinal adenocarcinomas . Loss of membranous beta - catenin reactivity was observed in 14 of 26 ovine intestinal adenocarcinomas ( 54 % ) . The loss of membranous beta - catenin reactivity was accompanied by cytoplasmic and nuclear reactivity in 2 neoplasms . Loss of P12830 was observed within 8 of 26 neoplasms ( 31 % ) . Neoplastic cell expression of P35354 was observed in 12 of 26 neoplasms ( 46 % ) , whereas cells within 3 of 26 neoplasms ( 11 % ) contained visible p53 protein . In conclusion , all 4 proteins that commonly have altered expression in human colonic cancers were also altered in a proportion of the ovine intestinal adenocarcinomas . These results provide additional evidence that sheep could be useful for the study of human colonic cancer .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"DB01240 - deficient mice develop ischemic renal disorders , including nephrosclerosis and renal infarction . BACKGROUND : DB01240 ( DB01240 ) is a short - lived endogenous inhibitor of platelet aggregation and a potent vasodilator and regulator of the growth of vascular smooth muscle cells . To study the role of DB01240 in the vascular system in vivo , DB01240 - deficient ( PGID ) mice were established by genetic disruption of the DB01240 synthase gene . METHODS AND RESULTS : DB01240 synthase - null mice were generated by replacing the exons of DB01240 synthase gene that encodes for the catalytic site of the enzyme with a neomycin resistance gene . In these mice , DB01240 levels in the plasma , kidneys , and lungs were reduced , whereas thromboxane and prostaglandin E2 levels became elevated . Blood pressure and the amounts of urea nitrogen and creatinine in plasma of the PGID mice were significantly higher than those of wild - type mice ( P < 0 . 05 ) . They developed progressive morphological abnormalities in the kidneys , accompanied by atrophy , surface irregularity , fibrosis , cyst , arterial sclerosis , and hypertrophy of vessel walls . Thickening of the thoracic aortic media and adventitia were observed in aged PGID mice . Importantly , these phenotypes have not been reported in P43119 - deficient mice . CONCLUSIONS : DB01240 deficiency resulted in the development of vascular disorders with the thickening of vascular walls and interstitial fibrosis , especially in mouse kidneys . The findings demonstrated in vivo that DB01240 is important in the homeostasis of blood vessels . Our established PGID mice are useful for studies on the initiation and development of vascular diseases , such as ischemic renal disorders with arterial sclerosis and infarction , and also for studies on the novel signaling pathway of DB01240 .",
"DB01240 - IP signaling and prostaglandin E2 - EP2 / EP4 signaling both mediate joint inflammation in mouse collagen - induced arthritis . Prostaglandin ( PG ) I2 ( prostacyclin [ P06744 ] ) and DB00917 are abundantly present in the synovial fluid of rheumatoid arthritis ( RA ) patients . Although the role of DB00917 in RA has been well studied , how much DB01240 contributes to RA is little known . To examine this issue , we backcrossed mice lacking the P43119 ( IP ) to the DBA / 1J strain and subjected them to collagen - induced arthritis ( CIA ) . IP - deficient ( IP -/- ) mice exhibited significant reduction in arthritic scores compared with wild - type ( WT ) mice , despite anti - collagen antibody production and complement activation similar to WT mice . IP -/- mice also showed significant reduction in contents of proinflammatory cytokines , such as interleukin ( IL ) - 6 in arthritic paws . Consistently , the addition of an IP agonist to cultured synovial fibroblasts significantly enhanced P05231 production and induced expression of other arthritis - related genes . On the other hand , loss or inhibition of each PGE receptor subtype alone did not affect elicitation of inflammation in CIA . However , a partial but significant suppression of CIA was achieved by the combined inhibition of EP2 and EP4 . Our results show significant roles of both DB01240 - IP and DB00917 - EP2 / EP4 signaling in the development of CIA , and suggest that inhibition of DB00917 synthesis alone may not be sufficient for suppression of RA symptoms .",
"___MASK91___ induces Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells promoting a new immunoregulatory pathway . Q8NHJ6 ( high ) Q8N423 ( high ) dendritic cells ( DCs ) may cause anergy in P01730 (+) CD45RO (+) CD25 (+) T cells transforming them into regulatory T cells ( Tregs ) . Here , we tested whether chronic exposure to rapamycin may modulate this immunoregulatory pathway in renal transplant recipients . Forty renal transplant patients with biopsy - proven chronic allograft nephropathy and receiving calcineurin inhibitors were randomly assigned to either calcineurin inhibitor dose reduction or withdrawal with rapamycin introduction . At conversion and 2 years thereafter , we measured the rapamycin effects on circulating DCs ( BDCA1 / Q8WTT0 and Q8NHJ6 / Q8N423 expression ) , P01730 (+)/ CD25 ( high )/ Foxp3 (+) Tregs , CD8 (+)/ P10747 (-) T cells , and the Th1 / Th2 balance in graft biopsies . In rapamycin - treated patients , peripheral Q8WTT0 (+) cells were significantly increased along with Q8NHJ6 / Q8N423 (+) DCs . The number of circulating P01730 (+)/ CD25 ( high )/ Foxp3 (+)/ P16410 (+) Tregs , CD8 (+) P10747 (-) T cells , and P17693 serum levels were higher in the rapamycin - treated group . The number of Q8NHJ6 / Q8N423 (+) Q8WTT0 (+) DC was directly and significantly correlated with circulating Tregs and CD8 (+) P10747 (-) T cells . Q8NHJ6 / Q8N423 expression was increased in kidney biopsies at the end of the study period along with a significant bias toward a Th2 response within the graft only in the rapamycin - treated patients . Thus , rapamycin induces the upregulation of Q8NHJ6 and Q8N423 on the DC surface , and this effect is associated with an increase in the number of Tregs and expansion of the CD8 (+) P10747 (-) T cell population . This suggests that P42345 inhibition may promote a novel immunoregulatory pathway .",
"Decreased susceptibility to renovascular hypertension in mice lacking the prostaglandin I2 receptor IP . Persistent reduction of renal perfusion pressure induces renovascular hypertension by activating the renin - angiotensin - aldosterone system ; however , the sensing mechanism remains elusive . Here we investigated the role of DB01240 in renovascular hypertension in vivo , employing mice lacking the P43119 ( IP -/- mice ) . In WT mice with a two - kidney , one - clip model of renovascular hypertension , the BP was significantly elevated . The increase in BP in IP -/- mice , however , was significantly lower than that in WT mice . Similarly , the increases in plasma renin activity , renal renin mRNA , and plasma aldosterone in response to renal artery stenosis were all significantly lower in IP -/- mice than in WT mice . All these parameters were measured in mice lacking the four DB00917 receptor subtypes individually , and we found that these mice had similar responses to WT mice . DB01240 is produced by P35354 and a selective inhibitor of this enzyme , SC - 58125 , also significantly reduced the increases in plasma renin activity and renin mRNA expression in WT mice with renal artery stenosis , but these effects were absent in IP -/- mice . When the renin - angiotensin - aldosterone system was activated by salt depletion , SC - 58125 blunted the response in WT mice but not in IP -/- mice . These results indicate that DB01240 derived from P35354 plays a critical role in regulating the release of renin and consequently renovascular hypertension in vivo .",
"DB00184 induces cell proliferation , invasion and epithelial - mesenchymal transition in a variety of human cancer cell lines . Cigarette smoking is strongly correlated with the onset of nonsmall cell lung cancer ( NSCLC ) . DB00184 , an active component of cigarettes , has been found to induce proliferation of lung cancer cell lines . In addition , nicotine can induce angiogenesis and confer resistance to apoptosis . All these events are mediated through the nicotinic acetylcholine receptors ( nAChRs ) on lung cancer cells . In this study , we demonstrate that nicotine can promote anchorage - independent growth in NSCLCs . In addition , nicotine also induces morphological changes characteristic of a migratory , invasive phenotype in NSCLCs on collagen gel . These morphological changes were similar to those induced by the promigratory growth factor P15692 . The proinvasive effects of nicotine were mediated by alpha7 - nAChRs on NSCLCs . RT - PCR analysis showed that the alpha7 - nAChRs were also expressed on human breast cancer and pancreatic cancer cell lines . DB00184 was found to promote proliferation and invasion in human breast cancer . The proinvasive effects of nicotine were mediated via a nAChR , Src and calcium - dependent signaling pathway in breast cancer cells . In a similar fashion , nicotine could also induce proliferation and invasion of Aspc1 pancreatic cancer cells . Most importantly , nicotine could induce changes in gene expression consistent with epithelial to mesenchymal transition ( EMT ) , characterized by reduction of epithelial markers like P12830 expression , ZO - 1 staining and concomitant increase in levels of mesenchymal proteins like vimentin and fibronectin in human breast and lung cancer cells . Therefore , it is probable that the ability of nicotine to induce invasion and EMT may contribute to the progression of breast and lung cancers .",
"P35354 - derived prostacyclin modulates vascular remodeling . Suppression of prostacyclin ( DB01240 ) biosynthesis may explain the increased incidence of myocardial infarction and stroke which has been observed in placebo controlled trials of cyclooxygenase ( P36551 ) - 2 inhibitors . Herein , we examine if P35354 - derived DB01240 might condition the response of the vasculature to sustained physiologic stress in experimental models that retain endothelial integrity . Deletion of the P43119 ( IP ) or suppression of DB01240 with the selective P35354 inhibitor , nimesulide , both augment intimal hyperplasia while preserving luminal geometry in mouse models of transplant arteriosclerosis or flow - induced vascular remodeling . Moreover , nimesulide or IP deletion augments the reduction in blood flow caused by common carotid artery ligation in wild - type mice . Generation of both thromboxane ( Tx ) A2 and the isoprostane , 8 , 12 - iso iPF ( 2alpha )- VI , are increased in the setting of flow reduction and the latter increases further on administration of nimesulide . Deletion of the TxA2 receptor ( TP ) reduces the hyperplastic response to nimesulide and carotid ligation , despite further augmentation of TP ligand production . Suppression of P35354 - derived DB01240 or deletion of IP profoundly influences the architectural response of the vasculature to hemodynamic stress . Mechanism based vascular remodeling may interact with a predisposition to hypertension and atherosclerosis in contributing to the gradual transformation of cardiovascular risk during extended periods of treatment with selective inhibitors of P35354 .",
"Effect of prostaglandins and thromboxane A2 on the contractility of rabbit splenic capsular smooth muscle . The effect of various prostaglandins ( PGs ) and a thromboxane A2 ( TXA2 ) - generating system on the contractility of rabbit splenic capsular smooth muscle has been investigated . DB01240 as well as higher concentrations of PGE1 and 5 , 6 beta - dihydro - DB01240 inhibit noradrenaline - induced contractions of the smooth muscle preparation . The TXA2 - generating system and high concentrations of PGD2 , on the other hand , increase the contractions . The results support the concept that the hypothetical P43119 on the smooth muscle of the rabbit splenic capsule resembles , in its specificity , the P43119 on platelets ."
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___MASK87___
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MH_train_480
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interacts_with DB08875?
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[
"Analyses of cross species polymerase chain reaction products to infer the ancestral state of human polymorphisms . In numerous population genetic and disease association studies decisions about the ancestry of polymorphic alleles are often made based on the relative frequency of the alleles in the extant populations with the most frequent allele being deemed as ancestral . However , the frequency of an allele in a population is generally not a perfect indicator of its ancestral status . A more accurate method to assess ancestral / derived status of polymorphic alleles involves identification of shared alleles between species . We used this strategy to examine genomic regions homologous to several human polymorphisms in four species of non - human primates . Cross species polymerase chain reaction ( CS - PCR ) , with primers designed from human sequence , was used to investigate regions of interest . Nineteen polymorphisms at six loci ( P14416 , HOXB @ , PAH , D4S10 , P10745 , and P07949 ) were examined either by restriction fragment length analysis of PCR products ( PCR - RFLP ) or by direct sequencing . At seventeen of the eighteen PCR - RFLPs , non - human primates were monomorphic and identical to each other for either lack of restriction enzyme site or presence of the site . Thus , at these seventeen polymorphic sites the shared alleles are most likely to be the ancestral ones in humans . In several cases we have used sequence data to further demonstrate that the nucleotide at the site of the polymorphism is conserved between species confirming the hypothesis of a single ancestral allele . However , not all human alleles can be simply resolved into ancestral and derived ; sequence data from one PCR - RFLP ( in an intron of the PAH locus ) and a single strand conformational polymorphism ( SSCP ) in the 3 ' untranslated region ( UTR ) of the P14416 gene illustrate this point .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK75___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"Identification of new candidate therapeutic target genes in triple - negative breast cancer . Triple - negative breast cancer ( TNBC ) is a subgroup of breast cancer that is negative for estrogen and progesterone receptor and P04626 protein expression . It is characterized by its aggressive behavior and by the lack of targeted therapies . To identify new therapeutic targets in TNBC , we used real - time quantitative RT - PCR to analyze 63 TNBC samples in terms of their mRNA expression of 26 genes coding for the major proteins currently targeted by drugs used to treat other cancers or undergoing clinical trials in breast cancer . Six of the 26 genes tested ( P15692 , P12931 , P09874 , Q05397 , P04049 , and P22607 ) were significantly upregulated in 13 % to 46 % of the TNBCs . None of the 6 genes was specifically upregulated in the TNBCs compared with 3 other classical breast tumor subtypes . No association was observed between overexpression of these 6 genes ( except for P22607 ) and P42336 mutation status . These results confirm the interest of targeting P15692 and P09874 in ongoing clinical trials in TNBC patients and also identify new target genes ( P12931 , Q05397 , P04049 , and P22607 ) . Clinical trials could be initiated easily with existing drugs . Our results also suggest that these target genes might serve as predictive biomarkers of the TNBC treatment response .",
"Increased expression of hypoxia - inducible factor - 1alpha , p48 , and the Notch signaling cascade during acute pancreatitis in mice . Acute pancreatitis ( AP ) is a complex disease that may be linked to acinar cell apoptosis and inadequate acinar cell replacement . Differentiation of acinar cells is regulated by p48 , a DNA binding subunit of the transcription factor PTF1 , and the Notch signaling pathway . Acinar cell apoptosis is triggered by oxygen deprivation , ie , hypoxia , by activation of hypoxia inducible factor - 1alpha ( HIF - 1alpha ) . The aim of this study was to characterize by Northern blot analyses expression of HIF - 1alpha , HIF - 1alpha - inducible genes ( P11166 , P15692 , p53 ) , p48 , and genes involved in the Notch signaling pathway ( Notch - 1 , Dll1 , P02753 - Jk , DB09106 - 1 ) during cerulein - induced AP in mice . Maximal expression of HIF - 1alpha , HIF - 1alpha - inducible genes , p48 , and Notch signaling genes occurred 8 - 12 hours after induction of AP . Maximal expression of p53 occurred 12 - 48 hours after induction of AP . These findings demonstrate that multiple pancreatic genes are activated acutely during AP that support pancreatic cell replenishment , regulation of expression of acinar cell - specific genes , and apoptosis .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK90___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"Reconstruction and functional analysis of altered molecular pathways in human atherosclerotic arteries . BACKGROUND : Atherosclerosis affects aorta , coronary , carotid , and iliac arteries most frequently than any other body vessel . There may be common molecular pathways sustaining this process . Plaque presence and diffusion is revealed by circulating factors that can mediate systemic reaction leading to plaque rupture and thrombosis . RESULTS : We used DNA microarrays and meta - analysis to study how the presence of calcified plaque modifies human coronary and carotid gene expression . We identified a series of potential human atherogenic genes that are integrated in functional networks involved in atherosclerosis . Caveolae and JAK / P35610 pathways , and P06702 / P05109 interacting proteins are certainly involved in the development of vascular disease . We found that the system of caveolae is directly connected with genes that respond to hormone receptors , and indirectly with the apoptosis pathway . Cytokines , chemokines and growth factors released in the blood flux were investigated in parallel . High levels of RANTES , IL - 1ra , MIP - 1 alpha , MIP - 1 beta , P60568 , P05112 , P05113 , P05231 , P13232 , Q16552 , DB00102 , P15692 and P01579 were found in plasma of atherosclerotic patients and might also be integrated in the molecular networks underlying atherosclerotic modifications of these vessels . CONCLUSION : The pattern of cytokine and P06702 / P05109 up - regulation characterizes atherosclerosis as a proinflammatory disorder . Activation of the JAK / P35610 pathway is confirmed by the up - regulation of P05231 , P42224 , Q00978 and Q13651 genes in coronary and carotid plaques . The functional network constructed in our research is an evidence of the central role of P35610 protein and the caveolae system to contribute to preserve the plaque . Moreover , Cav - 1 is involved in SMC differentiation and dyslipidemia confirming the importance of lipid homeostasis in the atherosclerotic phenotype .",
"Response to DB08875 in patients with P07949 fusion - positive lung adenocarcinomas . The discovery of P07949 fusions in lung cancers has uncovered a new therapeutic target for patients whose tumors harbor these changes . In an unselected population of non - small cell lung carcinomas ( NSCLCs ) , P07949 fusions are present in 1 % to 2 % of cases . This incidence increases substantially , however , in never - smokers with lung adenocarcinomas that lack other known driver oncogenes . Although preclinical data provide experimental support for the use of P07949 inhibitors in the treatment of P07949 fusion - positive tumors , clinical data on response are lacking . We report preliminary data for the first three patients treated with the P07949 inhibitor cabozantinib on a prospective phase II trial for patients with P07949 fusion - positive NSCLCs ( NCT01639508 ) . Confirmed partial responses were observed in 2 patients , including one harboring a novel Q9UPN9 - P07949 fusion . A third patient with a P33176 - P07949 fusion has had prolonged stable disease approaching 8 months ( 31 weeks ) . All three patients remain progression - free on treatment .",
"Endothelial progenitor cells in relation to endothelin - 1 and endothelin receptor blockade : a randomized , controlled trial . AIMS : Endothelial progenitor cells ( EPC ) represent an endogenous repair mechanism involving rendothelialization and neoangiogenesis . Patients with both diabetes and vascular disease have low numbers of circulating EPC . The endothelium - derived peptide , endothelin - 1 ( ET - 1 ) , is increased in patients with type 2 diabetes and vascular complications and has been suggested to contribute to endothelial dysfunction . Therefore , we investigated the relation between EPC and plasma ET - 1 and the effect of dual ET - 1 receptor antagonist treatment . METHODS : In this double blind study patients with type 2 diabetes mellitus and microalbuminuria were randomized to treatment with the dual P25101 / ETB receptor antagonist ___MASK7___ treatment ( 125mg bid ; n = 17 ) or placebo ( n = 19 ) for four weeks . Different EPC subpopulations were enumerated by flow cytometry using triple staining ( P28906 , CD133 , P35968 ) at baseline at the end of treatment . Viability was assessed by 7AAD and Annexin - V - staining . RESULTS : Baseline ET - 1 levels correlated significantly with P02741 levels . Patients with ET - 1 levels above the median value had higher levels of P28906 (+) CD133 (+) and P28906 (+) P35968 (+) EPC . There was no difference in P28906 (+) and P28906 (+) CD133 (+) P35968 (+) cells , markers of EPC apoptosis or circulating markers of endothelial damage between patients with ET - 1 levels below or above the median . Four week treatment with ___MASK7___ did not change EPC levels . CONCLUSION : Among patients with type 2 diabetes and vascular disease , high plasma levels of ET - 1 are associated with higher number of EPC . The recruitment of EPC does not seem to be regulated via ET - 1 receptor activation since treatment with a dual ET - 1 receptor blocker did not affect circulating EPC numbers .",
"Q9BQB6 pharmacogenetics and pharmacoproteomics in patients on warfarin anticoagulant therapy : transthyretin precursor as a potential biomarker . BACKGROUND : Recognizing specific protein changes in response to drug administration in humans has the potential for the development of personalized medicine . Such changes can be identified by pharmacoproteomics approach based on proteomic technologies . It can also be helpful in matching a particular target - based therapy to a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism . ___MASK25___ is a commonly prescribed oral anticoagulant in patients with prosthetic valve disease , venous thromboembolism and stroke . METHODS AND FINDING : We used a combined pharmacogenetics and iTRAQ - coupled LC - MS / MS pharmacoproteomics approach to analyze plasma protein profiles of 53 patients , and identified significantly upregulated level of transthyretin precursor in patients receiving low dose of warfarin but not in those on high dose of warfarin . In addition , real - time RT - PCR , western blotting , human P05231 ELISA assay were done for the results validation . CONCLUSION : This combined pharmacogenomics and pharmacoproteomics approach may be applied for other target - based therapies , in matching a particular marker in a subgroup of patients , in addition to the profile of genetic polymorphism .",
"DB08875 : a MET , P07949 , and P35968 tyrosine kinase inhibitor . DB08875 is a receptor tyrosine kinase inhibitor with activity against MET , P35968 , P36888 , c - P10721 , and P07949 . Activity of cabozantinib toward a broad range of tumor models could be detected in several preclinical studies . Of note , cabozantinib decreases metastasis potential and tumor invasiveness when compared with placebo or agents that target VEGFR and have no activity against MET . Clinical phase I and II studies with cabozantinib have been conducted in various malignancies including medullary thyroid cancer ( P04629 ) , NSCLC , breast , ovarian , pancreatic , and prostate cancer . In P04629 , gain of function mutations of P07949 are central for tumorigenesis . Hereditary forms of P04629 ( MEN II ) are caused by germline mutations of P07949 , in sporadic P04629 in up to 50 % of cases P07949 mutations occur . Additionally , activating molecular changes in VEGFR and MET pathways have also been implicated in P04629 progression . Clinical responses with cabozantinib in P04629 could be observed in early clinical trials , and following confirmation of clinical benefit in a randomized phase III trial , cabozantinib gained FDA approval for first - line treatment of advanced P04629 in 2012 . In prostate cancer models , MET expression increases with androgen ablation and clinical progression of bone and lymph node metastasis . A phase II trial with cabozantinib also showed very promising response rates in patients with metastatic prostate cancer . Therefore , randomized phase III studies are currently ongoing to validate the efficacy of cabozantinib in heavily pretreated prostate cancer patients .",
"Regulation of mammalian cell cycle progression in the regenerating liver . The process of cell division in mammalian cells is orchestrated by cell - cycle - dependent oscillations of cyclin protein levels . P12004 levels are controlled by redundant transcriptional , post - translational and degradation feedback loops . How each of these separate loops contributes to the regulation of the key cell cycle events and to the connection between the P55008 - S transition and the subsequent mitotic events is under investigation . Here , we present an integrated computational model of the mammalian cell cycle based on the sequential activation of cyclins . We validate the model against experimental data on liver cells ( hepatocytes ) , which undergo one or two rounds of synchronous circadian - clock gated cell divisions during liver regeneration , after partial hepatectomy ( PH ) . The model exhibits bandpass filter properties that allow the system to ignore strong but transient , or sustained but weak damages after PH . Bifurcation analysis of the model suggests two different threshold mechanisms for the progression of the cell through mitosis . These results are coherent with the notion that the mitotic exit in mammalian cells is bistable , and suggests that Cdc20 homologue 1 ( Cdh1 ) is an important regulator of mitosis . Regulation by Cdh1 also explains the observed G2 / M phase prolongation after hepatocyte growth factor ( P14210 ) stimulation during S phase .",
"Immunological assessment of cryotherapy in breast cancer patients . BACKGROUND : In murine studies , cryotherapy has induced antitumor immune responses associated with the rejection of tumors . However , the effects of freezing - induced immunomodulation in breast cancer ( BC ) patients remain unclear . MATERIALS AND METHODS : Ten BC patients were prospectively divided into two groups : 1 ) cryotherapy followed by surgical excision and 2 ) surgical excision - alone . The cytokine profiles of plasma and peripheral blood mononuclear cells ( PBMCs ) were analyzed using flow cytometry following in vitro stimulation with the 30 - mer P15941 peptide . RESULTS : No differences in the percentages of interferon - γ ( IFN - γ ) - producing cluster of differentiation ( CD ) 4 (+) or CD8 (+) T cells and the plasma levels of IFN - γ , interleukin - 1β ( IL - 1β ) , P60568 , P05112 , P05113 , P05231 , P10145 , P22301 , IL - 12p70 , tumor necrosis factor - α ( P01375 - α ) and P01375 - β were observed between these 2 groups , and PBMCs were not significantly altered . CONCLUSION : Alternations to the type 1 and 2 helper cytokine profiles were not detected in vitro in BC patients treated with cryotherapy - alone .",
"A novel tumor necrosis factor - responsive transcription factor which recognizes a regulatory element in hemopoietic growth factor genes . A conserved DNA sequence element , termed cytokine 1 ( P04264 ) , is found in the promoter regions of many hemopoietic growth factor ( P14210 ) genes . Mutational analyses and modification interference experiments show that this sequence specifically binds a nuclear transcription factor , NF - GMa , which is a protein with a molecular mass of 43 kilodaltons . It interacts with different affinities with the P04264 - like sequence from a number of P14210 genes , including granulocyte macrophage colony - stimulating factor ( GM - P04141 ) , granulocyte ( G ) - P04141 , interleukin 3 ( P08700 ) , and P05113 . We show here that the level of NF - GMa binding is induced in embryonic fibroblasts by tumor necrosis factor - alpha ( P01375 ) treatment and that the P04264 sequence from the G - P04141 gene is a P01375 - responsive enhancer in these cells . The NF - GMa protein is distinct from another P01375 - responsive transcription factor , NF - kappa B , by several criteria . Firstly , several NF - kappa B - binding sites , although having sequence similarity with the P04264 sequence , can not compete efficiently for NF - GMa binding to P04264 . Secondly , the P04264 sequence from both G - P04141 and GM - P04141 does not respond to phorbol ester treatment as would an NF - kappa B - binding element . These results demonstrate that NF - GMa is a novel transcription factor inducible by P01375 and binds to a common element in P14210 gene promoters .",
"Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population . Blood pressure ( BP ) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions . Standing upright is a recent evolutionary trait , and genetic factors that influence postural adaptations may contribute to BP variability . We studied the effect of posture on the genetics of BP and intermediate BP phenotypes . We included 384 sib - pairs in 64 sib - ships from families ascertained by early - onset hypertension and dyslipidemia . Blood pressure , three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright . The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees . Linkage was conducted on 196 candidate genes by sib - pair analyses , and empirical estimates of significance were obtained . A permutation algorithm was implemented to study the postural effect on linkage . ADRA1A , APO , CAST , Q9Y5Q5 , P34998 , P24530 , P09038 , GC , P17302 , Q92953 , P08254 , P01303 , P08235 , P26678 , P37173 , P25445 , and P34981 showed evidence of linkage with any phenotype in the supine position and not upon standing , whereas P15121 , P16671 , P25101 , P12259 , P14780 , PKD2 , P27169 , P37231 , Q9UBK2 , P17252 , and P07949 were specifically linked to standing phenotypes . Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture . When investigators perform genetic studies exclusively on a single posture , important genetic components of BP are missed . Supine and standing BPs have distinct genetic signatures . Standardized maneuvers influence the results of genetic investigations into BP , thus reflecting its dynamic regulation .",
"Notch4 - induced inhibition of endothelial sprouting requires the ankyrin repeats and involves signaling through P02753 - Jkappa . Notch proteins comprise a family of transmembrane receptors . Ligand activation of Notch releases the intracellular domain of the receptor that translocates to the nucleus and regulates transcription through the DNA - binding protein P02753 - Jkappa . Previously , it has been shown that the Notch4 intracellular region ( N4IC ) can inhibit endothelial sprouting and angiogenesis . Here , N4IC deletion mutants were assessed for their ability to inhibit human microvascular endothelial cell ( HMEC ) sprouting with the use of a quantitative endothelial sprouting assay . Deletion of the ankyrin repeats , but not the RAM ( P02753 - Jkappa associated module ) domain or C - terminal region ( CT ) , abrogated the inhibition of fibroblast growth factor 2 ( P09038 ) - and vascular endothelial growth factor ( P15692 ) - induced sprouting by Notch4 , whereas the ankyrin repeats alone partially blocked sprouting . The ankyrin repeats were also the only domain required for up - regulation of P02753 - Jkappa - dependent gene expression . Interestingly , enforced expression of the ankyrin domain alone was sufficient to up - regulate some , but not all , P02753 - Jkappa - dependent genes . Although N4IC reduced P15692 receptor - 2 ( P35968 ) and vascular endothelial ( VE ) - cadherin expression , neither of these events is necessary and sufficient to explain N4IC - mediated inhibition of sprouting . A constitutively active P02753 - Jkappa mutant significantly inhibited HMEC sprouting but not as strongly as N4IC . Thus , Notch4 - induced inhibition of sprouting requires the ankyrin repeats and appears to involve P02753 - Jkappa - dependent and - independent signaling .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK39___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK25___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .",
"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space .",
"DB08875 ( DB05153 ) , a novel MET and P35968 inhibitor , simultaneously suppresses metastasis , angiogenesis , and tumor growth . The signaling pathway of the receptor tyrosine kinase MET and its ligand hepatocyte growth factor ( P14210 ) is important for cell growth , survival , and motility and is functionally linked to the signaling pathway of P15692 , which is widely recognized as a key effector in angiogenesis and cancer progression . Dysregulation of the MET / P15692 axis is found in a number of human malignancies and has been associated with tumorigenesis . DB08875 ( DB05153 ) is a small - molecule kinase inhibitor with potent activity toward MET and P15692 receptor 2 ( P35968 ) , as well as a number of other receptor tyrosine kinases that have also been implicated in tumor pathobiology , including P07949 , P10721 , P30530 , and P36888 . Treatment with cabozantinib inhibited MET and P35968 phosphorylation in vitro and in tumor models in vivo and led to significant reductions in cell invasion in vitro . In mouse models , cabozantinib dramatically altered tumor pathology , resulting in decreased tumor and endothelial cell proliferation coupled with increased apoptosis and dose - dependent inhibition of tumor growth in breast , lung , and glioma tumor models . Importantly , treatment with cabozantinib did not increase lung tumor burden in an experimental model of metastasis , which has been observed with inhibitors of P15692 signaling that do not target MET . Collectively , these data suggest that cabozantinib is a promising agent for inhibiting tumor angiogenesis and metastasis in cancers with dysregulated MET and VEGFR signaling .",
"Benzyl isothiocyanate suppresses pancreatic tumor angiogenesis and invasion by inhibiting HIF - α / P15692 / Rho - GTPases : pivotal role of P35610 - 3 . Our previous studies have shown that benzyl isothiocyanate ( BITC ) suppresses pancreatic tumor growth by inhibiting P35610 - 3 ; however , the exact mechanism of tumor growth suppression was not clear . Here we evaluated the effects and mechanism of BITC on pancreatic tumor angiogenesis . Our results reveal that BITC significantly inhibits neovasularization on rat aorta and Chicken - Chorioallantoic membrane . Furthermore , BITC blocks the migration and invasion of BxPC - 3 and PanC - 1 pancreatic cancer cells in a dose dependant manner . Moreover , secretion of P15692 and P08253 in normoxic and hypoxic BxPC - 3 and PanC - 1 cells was significantly suppressed by BITC . Both P15692 and P08253 play a critical role in angiogenesis and metastasis . Our results reveal that BITC significantly suppresses the phosphorylation of P35968 ( DB00135 - 1175 ) , and expression of HIF - α . Rho - GTPases , which are regulated by P15692 play a crucial role in pancreatic cancer progression . BITC treatment reduced the expression of RhoC whereas up - regulated the expression of tumor suppressor RhoB . P35610 - 3 over - expression or P05231 treatment significantly induced HIF - 1α and P15692 expression ; however , BITC substantially suppressed P35610 - 3 as well as P35610 - 3 - induced HIF - 1α and P15692 expression . Finally , in vivo tumor growth and matrigel - plug assay show reduced tumor growth and substantial reduction of hemoglobin content in the matrigel plugs and tumors of mice treated orally with 12 µmol BITC , indicating reduced tumor angiogenesis . Immunoblotting of BITC treated tumors show reduced expression of P35610 - 3 phosphorylation ( DB00135 - 705 ) , HIF - α , P35968 , P15692 , P08253 , CD31 and RhoC . Taken together , our results suggest that BITC suppresses pancreatic tumor growth by inhibiting tumor angiogenesis through P35610 - 3 - dependant pathway .",
"Consequences of the Y139F Vkorc1 mutation on resistance to AVKs : in - vivo investigation in a 7th generation of congenic Y139F strain of rats . OBJECTIVES : In humans , warfarin is used as an anticoagulant to reduce the risk of thromboembolic clinical events . ___MASK25___ derivatives are also used as rodenticides in pest control . The gene encoding the protein targeted by anticoagulants is the Vitamin K - 2 , 3 - epoxide reductase subunit 1 ( Q9BQB6 ) . Since its discovery in 2004 , various amino acid and transcription - regulatory altering Q9BQB6 mutations have been identified in patients who required extreme antivitamin K dosages , or wild populations of rodents that were difficult to control with anticoagulant rodenticides . One unresolved question concerns the dependency of the Q9BQB6 on the genetic background in humans and rodents that respond weakly or not at all to anticoagulants . Moreover , an important question requiring further analyses concerns the role of the Vkorc1 gene in mediating resistance to more recently developed warfarin derivatives ( superwarfarins ) . METHODS : In this study , we bred a quasicongenic rat strain by using a wild - caught anticoagulant resistant rat as a donor to introduce the Y > F amino acid change at position 139 in the Vkorc1 into the genetic background of an anticoagulant susceptible Spraque - Dawley recipient strain . RESULTS AND CONCLUSION : In this manuscript we report the prothrombin times measured in the P08709 generation after exposure to chlorophacinone , bromadiolone , difenacoum and difethialone . We observed that the mutation Y139F mediates resistance in an otherwise susceptible genetic background when exposed to chlorophacinone and bromadiolone . However , the physiological response to the super - warfarins , difenacoum and difethialone , may be strongly dependent on other genes located outside the congenic interval ( 28 . 3 cM ) bracketing the Vkorc1 in our P08709 generation congenic strain .",
"Serum levels of antibodies to thyroid peroxidase correlate with quantitative descriptors of thyroid ultrasound images in patients with breast cancer . The aim of the study was to compare the structural changes in ultrasound image of the thyroid tissue in 12 women with breast cancer ( BC ) and 8 women with colorectal cancer ( CC ) . MATLAB software was used to analyse the digitised images . As quantitative descriptors of thyroid ultrasound images ( QDTI ) were used raw grey scale values of individual image pixels ( RAW ) and the optimal one - dimensional discriminative texture features ( F2 , F6 , P08709 ) . The possible relations between QDTI and thyroid laboratory parameters were tested . In the BC group serum levels of antibodies to thyroid peroxidase negatively correlated with feature RAW ( multiple regression , beta coefficient - 0 . 75 , p = 0 . 004 ) and positively with feature F2 ( multiple regression , beta coefficient 1 . 44 , p = 0 . 04 ) . In the BC group RAW negatively correlated with serum levels of tumour marker P15941 ( Pearson ' s correlation coefficient , r =- 0 . 714 , p = 0 . 00917 ) . No such correlations were found in CC group . The correlations between QDTI and serum levels of antibodies to thyroid peroxidase in patients with BC show that the positivity of antibodies to thyroid peroxidase is probably accompanied with structural changes in the thyroid tissue .",
"Pharmacogenetics in chemotherapy of colorectal cancer . Although in recent years , chemotherapeutic options for colorectal carcinoma have expanded , overall response rates are still too low , with high rates of toxicity . Pharmacogenetics aim at predicting both treatment response and adverse effects in individual patients . This review describes the current knowledge of pharmacogenetic markers in the systemic treatment of colorectal cancer . P22309 * 28 leads to reduced conjugation of SN - 38 , the active metabolite of irinotecan , resulting in an increased rate of adverse effects , especially neutropenia . To a lesser extent , increased DB00544 toxicity is predicted by Q12882 * 2A . A variable number of tandem repeats polymorphism in the thymidylate synthase enhancer region , in combination with a single nucleotide polymorphism C > G , may predict poorer response to DB00544 . Efficacy of oxaliplatin is influenced by polymorphisms in components of DNA repair systems , such as P07992 and P18887 . Polymorphic changes in the endothelial growth factor receptor probably predict cetuximab efficacy . Furthermore , the antibody - depended cell - mediated cytotoxic effect of cetuximab may be reduced by polymorphisms in the immunoglobin G fragment C receptors . DB00112 efficacy is suspected to be influenced by polymorphisms in the P15692 gene and the hypoxia inducible factor 1alpha gene . Although the interpretation of pharmacogenetic studies is complicated , results imply a promising way of pretreatment prediction of chemotherapy efficacy and toxicity .",
"Targeting MET and vascular endothelial growth factor receptor signaling in castration - resistant prostate cancer . Effective management of bone metastases in men with castration - resistant prostate cancer ( CRPC ) remains an important unmet medical need . MET and vascular endothelial growth factor receptor ( VEGFR ) are rational targets for intervention in CRPC . Clinical trials involving agents that inhibit one but not both pathways have reported modest activity and no improvement in overall survival . DB08875 is an oral multitargeted tyrosine kinase inhibitor that inhibits both MET and P35968 . A phase II randomized discontinuation study involving subjects with CRPC demonstrated that cabozantinib therapy is associated with improvement in bone scans , bone turnover markers , and pain response , but with significant adverse events leading to dose reduction and treatment discontinuation . Lower doses of cabozantinib retain high levels of activity with less toxicity . Ongoing phase III clinical trials will define the role of cabozantinib in CRPC . We summarize the rationale for targeting MET and VEGFR pathways in CRPC and the clinical data available to date .",
"Targetting esophageal and gastric cancers with monoclonal antibodies . Target therapies and notably monoclonal antibodies are currently being considered for esophageal , gastric , and gastroesophageal junction cancers . P00533 was found to be overexpressed in 60 - 86 % of gastric or gastroesophageal tumors and in 50 - 70 % of esophageal cancers . Cetuximab was shown to be a radiosensitizing agent in the treatment of ENT neoplasia . These results led to several phase II encouraging therapeutic trials evaluating the combination of cetuximab with radiochemotherapy in locally advanced esophageal cancers . Numerous encouraging phase II trials evaluating cetuximab combined with chemotherapy in patients with gastric adenocarcinoma or gastroesophageal junction cancer were reported . These promising results are still to be confirmed by the ongoing phase III trials . Several studies reported P04626 overexpression in gastric cancer ( 7 - 34 % ) , which appeared to be associated with poorer prognosis . ___MASK21___ is a monoclonal antibody directed against the extracellular P04626 domain . The international phase III trial known as ToGA ( ___MASK21___ for Gastric Cancer ) aimed to determine the clinical efficacy and acceptable toxicity profile of trastuzumab in combination with first - line chemotherapy in P04626 - overexpressing gastric or gastroesophageal cancer . Angiogenesis is an essential step in the initial phase of tumorigenesis , and it is normally absent from healthy tissues except for particular physiological situations , such as wound healing . P15692 plays a role in endothelial growth and angiogenesis . DB00112 , a humanized monoclonal anti - P15692 antibody , is currently being studied for gastric cancer . The phase III AVAGAST study , evaluating bevacizumab in association with chemotherapy in advanced gastric adenocarcinoma , did not achieve its primary aim of improved OS in bevacizumab - treated patients .",
"Suppression of proliferation and migration in highly - metastatic lung cancer cells as well as tumor growth by a new synthesized compound TBrC and its molecular mechanisms of action . To develop new anticancer agents has been considered as a useful and necessary strategy to suppress highly - metastatic lung cancer , the leading cause of cancer - related deaths in the world . In this study , we synthesized a new compound ethyl 6 - bromocoumarin - 3 - carboxylyl L - theanine ( TBrC ) and studied the anticancer activity of TBrC and its molecular mechanisms of action . Our results show that TBrC remarkably inhibits the proliferation and migration in highly - metastatic lung cancer cells by inducing apoptosis and cell cycle arrest as well as regulating related protein expressions . Further study indicated that TBrC not only enhances the protein levels of Bax , cytosolic cytochrome c , caspase - 3 and P09874 but also reduces the protein expressions of Bcl - 2 , cyclin D1 , P17948 and NF - κB as well as inhibits the phosphorylation and expressions of P35968 and Akt in the cancer cells . More importantly , TBrC displays strong suppression of highly - metastatic tumor growth and reduces the tumor weight by 61 . 6 % in tumor - bearing mice without toxicity to the mice . Our results suggest that TBrC suppresses the proliferation and migration of lung cancer cells via VEGFR - Akt - NF - κB signaling pathways ; TBrC may have a wide therapeutic and / or adjuvant therapeutic application in the treatment of lung cancer .",
"Targeted therapy in gastric cancer . Gastric cancer is often diagnosed at an advanced stage . Although chemotherapy prolongs survival and improves quality of life , the survival of gastric cancer patients with advanced disease is short . Thanks to recent insights into the molecular pathways involved in gastric carcinogenesis , new targeted treatment options have become available for gastric cancer patients . ___MASK21___ , an antibody targeted to HER - 2 , was shown to improve survival of advanced gastric cancer patients harboring HER - 2 overexpression due to gene amplification in their tumor cells , and is currently also explored in adjuvant and neoadjuvant settings . Another agent with promising results in clinical trials is ramucirumab , an antibody targeting P35968 . No clear survival benefit , however , were experienced with agents targeting P00533 ( cetuximab , panitumumab ) , P15692 ( bevacizumab ) , or P42345 ( everolimus ) . Drugs targeting c - MET / P14210 are currently under investigation in biomarker - selected cohorts , with promising results in early clinical trials . This review will summarize the current status of targeted treatment options in gastric cancer .",
"Adeno - associated virus - mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs . We have previously shown that VEGF165 gene delivery into ischemic skeletal muscle exerts not only proangiogenic , but also remarkable antiapoptotic and proregenerative activity . The aim of this study was to determine whether recombinant adeno - associated virus ( rAAV ) - mediated gene delivery of VEGF165 into cardiac muscle , during acute myocardial infarction , exerts a protective effect to promote long - term functional recovery . Acute infarction of the anterior LV wall was induced in 12 chronically instrumented dogs by permanent occlusion of the LAD coronary artery . Four hours after occlusion , rAAV - VEGF165 or rAAV - LacZ ( n = 6 each ; 5x10 ( 12 ) viral particles per animal ) was directly injected with an echo - guided needle into the dysfunctional cardiac wall . LV and arterial pressure , dP / dtmax , and ejection fraction were not significantly different between the two groups over time . In contrast , in the infarcted region , at four weeks after infarction , fractional shortening was 75 +/- 18 % and - 3 +/- 15 % of baseline and length - pressure area was 54 +/- 15 % and 0 . 8 +/- 15 % of baseline in VEGF165 versus LacZ , respectively ( P < 0 . 05 ) . Histological analysis of the border regions showed a marked increase in the number of alpha - SMA - positive arterioles ( 68 +/- 2 . 8 versus 100 +/- 3 . 8 vessels per microscopic field in LacZ and VEGF165 group , respectively ; P < 0 . 05 ) . In both groups , the receptor P35968 was diffusely expressed on the surviving cardiomyocytes and , consistently , myocardial viability was significantly improved in the VEGF165 - treated group , with several troponin T - expressing cardiomyocytes displaying nuclear positivity for the proliferation marker P12004 . Altogether , our results indicate that VEGF165 gene delivery exerts a marked beneficial action by enhancing both arteriologenesis and cardiomyocyte viability in infarcted myocardium .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK94___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"DB08875 and prostate cancer : inhibiting seed and disrupting soil ? Treatment with cabozantinib , an inhibitor of MET and P35968 signaling , has demonstrated clinical benefit in early trials in men with metastatic prostate cancer . Preclinical evidence suggests that cabozantinib can kill cancer cell seeds while disrupting angiogenesis and stromal cells in the metastatic soil .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Rare mutations in non - small - cell lung cancer . In the last decade , new insights in molecular biology have changed the therapeutic landscape of non - small - cell lung cancer . Since 2004 , when activating mutations of the P00533 were firstly identified , several genetic aberrations have been discovered , mainly in adenocarcinoma . P00533 mutations are a relatively frequent event in non - small - cell lung cancer , generally consisting of exon 19 deletion or exon 21 substitution . In adenocarcinoma , additional rare mutations are detectable in the P00533 gene , as well as in other genes , including Q9UM73 , P08922 , P07949 , P04626 and P15056 . Recent studies in squamous cell carcinoma identified P04637 as the most frequent mutation , followed by additional more rare mutations , including PI3KCA , P60484 , Q16832 and FGFR . The aim of the present review is to analyze the potential prognostic and predictive role of rare mutations .",
"A phase I study of cabozantinib ( DB05153 ) in patients with differentiated thyroid cancer . BACKGROUND : DB08875 targets tyrosine kinases including MET , vascular endothelial growth factor ( P15692 ) receptor 2 , and rearranged during transfection ( P07949 ) . Differentiated thyroid cancer ( DTC ) is a tumor type that may be sensitive to cabozantinib . Therefore , we evaluated cabozantinib in a cohort of heavily pretreated patients with metastatic DTC . METHODS : This single - arm open - label phase I trial assessed the safety , tolerability , and antitumor activity of cabozantinib in DTC patients taking part in a drug - drug interaction study . Adult patients with histologically confirmed metastatic or surgically unresectable DTC ( including papillary , follicular , or Hürthle cell ) were enrolled . Patients received daily oral dosing of 140 mg cabozantinib . Safety was assessed by evaluation of adverse events ( AEs ) , vital signs , electrocardiograms , laboratory tests , and concomitant medications . Tumor response by magnetic resonance imaging or computed tomography scan was investigator assessed using Response Evaluation Criteria In Solid Tumors ( RECIST ) v1 . 0 . RESULTS : The study enrolled 15 patients who had failed standard radioactive iodine therapy . Patients had received a median of two prior systemic agents , and 11 patients ( 73 % ) had previously received at least one P15692 pathway inhibiting therapy . Common AEs included diarrhea , nausea , fatigue , and decreased appetite . Partial response was reported in eight patients ( 53 % ) . Median progression - free survival and median overall survival were not reached . CONCLUSIONS : DB08875 demonstrates a safety profile similar to other multitargeted VEGFR inhibitors in advanced DTC patients . The antitumor activity observed in this study warrants further investigation of cabozantinib in patients with advanced DTC .",
"DB08875 overcomes crizotinib resistance in P08922 fusion - positive cancer . PURPOSE : P08922 rearrangement leads to constitutive P08922 activation with potent transforming activity . In an ongoing phase I trial , the Q9UM73 tyrosine kinase inhibitor ( TKI ) crizotinib shows remarkable initial responses in patients with non - small cell lung cancer ( NSCLC ) harboring P08922 fusions ; however , cancers eventually develop crizotinib resistance due to acquired mutations such as G2032R in P08922 . Thus , understanding the crizotinib - resistance mechanisms in P08922 - rearranged NSCLC and identification of therapeutic strategies to overcome the resistance are required . EXPERIMENTAL DESIGN : The sensitivity of P04233 - P08922 - transformed Ba / P13726 cells to multiple Q9UM73 inhibitors was examined . Acquired P08922 inhibitor - resistant mutations in P04233 - P08922 fusion were screened by N - ethyl - N - nitrosourea mutagenesis with Ba / P13726 cells . To overcome the resistance mutation , we performed high - throughput drug screening with small - molecular inhibitors and anticancer drugs used in clinical practice or being currently tested in clinical trials . The effect of the identified drug was assessed in the P04233 - P08922 - mutant Ba / P13726 cells and crizotinib - resistant patient - derived cancer cells ( MGH047 ) harboring G2032R - mutated P04233 - P08922 . RESULTS : We identified multiple novel crizotinib - resistance mutations in the P08922 kinase domain , including the G2032R mutation . As the result of high - throughput drug screening , we found that the cMET / P07949 / VEGFR inhibitor cabozantinib ( DB05153 ) effectively inhibited the survival of P04233 - P08922 wild - type ( WT ) and resistant mutants harboring Ba / P13726 and MGH047 cells . Furthermore , cabozantinib could overcome all the resistance by all newly identified secondary mutations . CONCLUSIONS : We developed a comprehensive model of acquired resistance to P08922 inhibitors in NSCLC with P08922 rearrangement and identified cabozantinib as a therapeutic strategy to overcome the resistance .",
"Serum hepcidin levels and reticulocyte hemoglobin concentrations as indicators of the iron status of peritoneal dialysis patients . P81172 is the key mediator of renal anemia , and reliable measurement of serum hepcidin levels has been made possible by the ProteinChip system . We therefore investigated the iron status and serum hepcidin levels of peritoneal dialysis ( PD ) patients who had not received frequent doses of an erythrocytosis - stimulating agent ( Q14254 ) and had not received iron therapy . In addition to the usual iron parameters , the iron status of erythrocytes can be determined by measuring reticulocyte hemoglobin ( P07949 - He ) . The mean serum hepcidin level of the PD patients ( n = 52 ) was 80 . 7 ng / mL . Their serum hepcidin levels were significantly positively correlated with their serum ferritin levels and transferrin saturation ( TSAT ) levels , but no correlations were found between their serum hepcidin levels and P07949 - He levels , thereby suggesting that hepcidin has no effect on the iron dynamics of reticulocytes . Since low serum levels of CRP and P05231 , biomarkers of inflammation , were not correlated with the serum hepcidin levels , there is likely to be a threshold for induction of hepcidin expression by inflammation .",
"Antipruritic activity of the kappa - opioid receptor agonist , P04629 - 820 . The effects of the kappa - opioid receptor agonist , P04629 - 820 , (-)- 17 -( cyclopropylmethyl )- 3 , 14beta - dihydroxy - 4 , 5alpha - epoxy - 6beta - [ N - methyl - trans - 3 -( 3 - furyl ) acrylamido ] morphinan hydrochloride , on the itch sensation were compared with those of histamine H1 receptor antagonists , using the mouse pruritogen - induced scratching model . Peroral administration of P04629 - 820 reduced the numbers of DB05875 - or histamine - induced scratches dose dependently . No obvious suppression of the spontaneous locomotor activity was observed at the doses used for the experiments , indicating that the inhibition of scratches was not due to the effect on general behavior . Furthermore , the scratching inhibitory activity of P04629 - 820 was dose dependently antagonized by the specific kappa - opioid receptor antagonist , nor - binaltorphimine , suggesting that the inhibitory activity was mediated via kappa - opioid receptors . P35367 antagonists , chlorpheniramine and ketotifen , did not inhibit DB05875 - induced scratches , or did so only partially . Both antihistamines inhibited the histamine - induced scratches completely . These results suggest that P04629 - 820 has antipruritic activity which is mediated by kappa - opioid receptors , and is effective in both antihistamine - sensitive and - resistant pruritus .",
"DB08875 inhibits prostate cancer growth and prevents tumor - induced bone lesions . PURPOSE : DB08875 , an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor ( MET ) and P15692 receptor 2 ( P35968 ) , induces resolution of bone scan lesions in men with castration - resistant prostate cancer bone metastases . The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect , an indirect effect through modulating bone , or both . EXPERIMENTAL DESIGN : Using human prostate cancer xenograft studies in mice , we determined the impact of cabozantinib on tumor growth in soft tissue and bone . In vitro studies with cabozantinib were performed using ( i ) prostate cancer cell lines to evaluate its impact on cell growth , invasive ability , and MET and ( ii ) osteoblast cell lines to evaluate its impact on viability and differentiation and P35968 . RESULTS : DB08875 inhibited progression of multiple prostate cancer cell lines ( Ace - 1 , C4 - 2B , and LuCaP 35 ) in bone metastatic and soft tissue murine models of prostate cancer , except for PC - 3 prostate cancer cells in which it inhibited only subcutaneous growth . DB08875 directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro . DB08875 had a dose - dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo . It blocked MET and P35968 phosphorylation in prostate cancer cells and osteoblast - like cells , respectively . CONCLUSION : These data indicate that cabozantinib has direct antitumor activity , and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy .",
"Activation and translocation of PKCdelta is necessary for P15692 - induced P29323 activation through P35968 in HEK293T cells . P15692 - P35968 / Flk - 1 signal utilizes the phospholipase C - gamma - protein kinase C ( PKC ) - Raf - MEK - P29323 pathway as the major signaling pathway to induce gene expression and P47712 phosphorylation . However , the spatio - temporal activation of a specific PKC isoform induced by P15692 - P35968 signal has not been clarified . We used HEK293T ( human embryonic kidney ) cells expressing transiently P35968 to examine the activation mechanism of PKC . PKC specific inhibitors and human PKCdelta knock - down using siRNA method showed that PKCdelta played an important role in P15692 - P35968 - induced P29323 activation . P29966 ( P29966 ) translocates from the plasma membrane to the cytoplasm depending upon phosphorylation by PKC . Translocation of P29966 - GFP induced by P15692 - P35968 stimulus was blocked by rottlerin , a PKCdelta specific inhibitor , or human PKCdelta siRNA . P15692 - P35968 stimulation did not induce P29323 phosphorylation in human PKCdelta - knockdown HEK293T cells , but co - expression of rat PKCdelta - GFP recovered the P29323 phosphorylation . Y311 / 332F mutant of rat PKCdelta - GFP which can not be activated by tyrosine - phosphorylation but activated by DAG recovered the P29323 phosphorylation , while C1B - deletion mutant of rat PKCdelta - GFP , which can be activated by tyrosine - phosphorylation but not by DAG , failed to recover the P29323 phosphorylation in human PKCdelta - knockdown HEK293T cell . These results indicate that PKCdelta is involved in P15692 - P35968 - induced P29323 activation via C1B domain .",
"[ Study of the expression of neural stem cell markers in neuroblastoma tumor samples and correlation with prognostic factors ] . INTRODUCTION : The existence of cancer stem cells ( CSC ) in neuroblastoma ( NB ) has been associated with the development of metastasis , resistance to chemotherapy and recurrence . Our objective is to analyze the expression of proliferation and differentiation markers of neural progenitor cells in NB samples , and to correlate this expression with clinical variables such as histology , genetics and response to conventional therapy . MATERIAL AND METHODS : We performed a retrospective - experimental study with neuroblastoma samples obtained from biopsies or tumor resections between 2010 - 2012 in our Hospital . Fluorescence immunohistochemistry was used to analyze the expression of the different markers : P16070 , P04233 , CD133 , tyrosine hydroxylase , endothelin receptors type A ( P25101 ) and B ( ETB ) , p75 , nestina y and Phox2b , all of them related to neural stem cell biology . The level of expression of the markers was then correlated with clinical variables . RESULTS : P48681 expression was positive in 72 . 2 % of samples and P25101 in 66 . 7 % . Q99453 and P04233 expression were lower , being positive in less than 30 % . The markers P16070 , ETB and Q99453 were expressed in more aggressive tumors . P25101 expression correlated significantly with unfavorable histology tumors ( p = 0 . 01 ) , N - myc amplification ( p = 0 . 05 ) and recurrence / progression ( p = 0 . 05 ) . CONCLUSION : The expression of P16070 , ETB and P25101 was associated with more aggressive tumors and poor prognostic factors . These markers are in the membrane of neural stem cells and may be useful to identify and isolate by flow cytometry CSCs of NB for the study of new therapeutic targets .",
"Noncatalytic function of P27361 / 2 can promote Raf / MEK / P29323 - mediated growth arrest signaling . Kinase activity is known as the key biochemical property of MAPKs . Here , we report that P27361 / 2 also utilizes its noncatalytic function to mediate certain signal transductions . Sustained activation of the Raf / MEK / P29323 pathway induces growth arrest , accompanied by changes in cell cycle regulators ( decreased retinoblastoma phosphorylation , Q01094 down - regulation , and / or P38936 ( CIP1 ) up - regulation ) and cell type - specific changes in morphology and expression of c - Myc or P07949 in the human tumor lines LNCaP , U251 , and TT . Ablation of P27361 / 2 by RNA interference abrogated all these effects . However , active site - disabled P29323 mutants ( P27361 - K71R , P28482 - K52R , and P28482 - D147A ) , which competitively inhibit activation of endogenous P27361 / 2 , could not block Raf / MEK - induced growth arrest as well as changes in the cell cycle regulators , although they effectively blocked phosphorylation of the P27361 / 2 catalytic activity readouts , p90 ( RSK ) and ELK1 , as well as the cell type - specific changes . Because this indicated a potential noncatalytic P27361 / 2 function , we generated stable lines of the tumor cells in which both P27361 and P28482 were significantly knocked down , and we further investigated the possibility using rat - derived kinase - deficient P29323 mutants ( P28482 - K52R and P28482 - T183A / Y185F ) that were not targeted by human small hairpin RNA . Indeed , P28482 - K52R selectively restored Raf - induced growth inhibitory signaling in P27361 / 2 - depleted cells , as manifested by regained cellular ability to undergo growth arrest and to control the cell cycle regulators without affecting c - Myc and morphology . However , P28482 - T183A / Y185F was less effective , indicating the requirement of TEY site phosphorylation . Our study suggests that functions of P27361 / 2 other than its \" canonical \" kinase activity are also involved in the pathway - mediated growth arrest signaling .",
"SAR131675 , a potent and selective P35916 - TK inhibitor with antilymphangiogenic , antitumoral , and antimetastatic activities . SAR131675 is a potent and selective P35916 inhibitor . It inhibited P35916 tyrosine kinase activity and P35916 autophosphorylation in P29320 cells with IC ( 50 ) values of 20 and 45 nmol / L , respectively . SAR131675 dose dependently inhibited the proliferation of primary human lymphatic cells , induced by the P35916 ligands P49767 and O43915 , with an IC ( 50 ) of about 20 nmol / L . SAR131675 was found to be highly selective for P35916 versus 107 receptors , enzymes , ion channels , and 65 kinases . However , it was moderately active on P35968 with a P35916 / P35968 ratio of about 10 . SAR131675 had no antiproliferative activity on a panel of 30 tumors and primary cells , further showing its high specificity and indicating that SAR131675 is not a cytotoxic or cytostatic agent . SAR131675 was very well tolerated in mice and showed a potent antitumoral effect in several orthotopic and syngenic models , including mammary 4T1 carcinoma and Q13546 . Tag2 tumors . Interestingly , it significantly reduced lymph node invasion and lung metastasis , showing its antilymphangiogenic activity in vivo . Moreover , treatment of mice before resection of 4T1 primary tumors was sufficient to prevent metastasis . Tumor - associated macrophages ( TAM ) play an important role in tumor growth and metastasis . The expression of P35916 on TAMs has been recently described . F4 / 80 immunostaining clearly showed that SAR131675 significantly reduced TAM infiltration and aggregation in 4T1 tumors . Taken together , SAR131675 is the first highly specific P35916 - TK inhibitor described to date , displaying significant antitumoral and antimetastatic activities in vivo through inhibition of lymphangiogenesis and TAM invasion .",
"Blood flow alterations in TNBS - induced colitis : role of endothelin receptors . OBJECTIVES : The aim of the present study was to investigate the time dependent changes in hemodynamic parameters and to assess the role of endothelin ( ET ) receptors in trinitrobenzene sulfonic acid ( TNBS ) induced colitis . MATERIALS : Inferior mesenteric artery ( IMA ) hemodynamics , myeloperoxidase activity ( P05164 ) and damage scores were measured immediately or 1 , 3 , 5 and 14 days after colitis . TREATMENTS : Another group of rats received a nonselective ET receptor antagonist ___MASK7___ ( 30 mg / kg / day ) , P25101 receptor antagonist BQ485 ( 60 microg / rat / day ) or P24530 receptor antagonist BQ788 ( 60 microg / rat / day ) prior to and on the 1st , 2nd and 3rd days after TNBS administration . RESULTS : IMA flow significantly increased at 90 min followed by a substantial decrease through days 1 - 5 . Tissue P05164 activity and macroscopic damage score increased on 1st day after the induction of colitis and remained elevated 3 , 5 and 14 days following colitis . Treatment with ___MASK7___ or P25101 receptor antagonist largely prevented the colitis - induced reduction in blood flow and tissue injury whereas P24530 receptor antagonist did not attenuate tissue injury or reductions in blood flow . CONCLUSIONS : Our results demonstrate that time - dependent abnormalities occur in IMA hemodynamics following TNBS administration . Our findings also indicate that P25101 receptors but not P24530 receptors play an important role in the colonic inflammation following TNBS administration .",
"Antagonism of endothelin action normalizes altered levels of P15692 and its signaling in the brain of stroke - prone spontaneously hypertensive rat . Stroke - prone spontaneously hypertensive rats ( SHRSP ) often suffer from spontaneous stroke , in part , due to abnormalities in the cerebrovasculature . Here , we investigate the profile of key angiogenic factors and their basic signaling molecules in the brain of SHRSP during the age - dependent stages of hypertension . The profile of P15692 and its receptor , Flk - 1 , was dependent on age and stage of hypertension ( i . e . , down regulated at pre - hypertensive and malignant hypertensive stages , but up regulated at typical hypertensive stage ) , while that of its downstream components , pAkt and P29474 , were down regulated in a time - dependent manner in the frontal cortex of SHRSP compared to age - matched genetic control , normotensive WKY rats . On the other hand , the expression of endothelin - 1 and its type A receptor ( endothelin P25101 receptor ) were up regulated , depending on age and stage of hypertension . In contrast , levels of endothelin type B receptor were down regulated . The regional cerebral blood flow decreased during the development of malignant hypertension . Thus , subsequent experiments were designed to investigate whether endothelin - 1 receptor antagonism , using endothelin - A /- B dual receptor antagonist SB209670 , could normalize the molecular profile of these factors in SHRSP brain . Interestingly , blockage of endothelin - 1 receptor restored to normal , levels of cerebral endothelin - 1 , endothelin P25101 receptor and endothelin ETB receptor ; P15692 and Flk - 1 ; endothelial nitric oxide synthase ( P29474 ) and pAkt , in SHRSP , compared to age - matched WKY . Endothelin receptor blocker might be important to prevent the progression in the defect in P15692 and its angiogenic signaling cascade in the pathogenesis of hypertension - induced vascular remodeling in frontal cortex of SHRSP rats .",
"Profile of cabozantinib and its potential in the treatment of advanced medullary thyroid cancer . Medullary thyroid cancer is an uncommon malignancy for which until recently little effective treatment existed . It is often characterized by mutation and overexpression of the receptor tyrosine kinases P07949 ( rearranged during transfection ) , P35968 ( vascular endothelial growth factor receptor 2 ) and MET ( mesenchymal - epithelial transition factor ) , which make attractive targets for drug development . DB08875 is an orally bioavailable tyrosine kinase inhibitor which blocks MET , VEGRF2 and P07949 , and has shown considerable activity in medullary thyroid cancer in a Phase III trial , including in heavily pretreated patients . Its novel combination of vascular endothelial growth factor and MET inhibition is believed to address the MET escape pathway , which is thought to be the cause of nonsustained tumor responses resulting from inhibition of vascular endothelial growth factor alone .",
"Characterization and binding activity of the chondroitin / dermatan sulfate chain from Endocan , a soluble endothelial proteoglycan . Endocan is a recently identified soluble chondroitin / dermatan sulfate ( CS / DS ) proteoglycan . Synthesized by endothelial cells , it has been found to be over - expressed in the vasculature surrounding a number of tumors , and by promoting growth factor mitogenic activities , hepatocyte growth factor / scatter factor ( P14210 / SF ) in particular , it supports cellular proliferation . In this work , we characterized the glycosaminoglycan ( GAG ) chain of Endocan , purified either from the naturally producing human umbilical vein endothelial cells ( HUVEC ) or from a recombinant over - expression system in human embryonic kidney cells ( P29320 ) . Compositional analysis using different chondroitinases as well as nuclear magnetic resonance studies revealed that the GAG chains from both sources share many characteristics , with the exception of size ( 15 and 40 kDa , respectively , for HUVEC and P29320 - 293 cells ) . The DS - specific , IdoA - containing disaccharides contribute 30 % of the chain ( 15 % of which are 2 - O - sulfated ) and are mostly clustered in tetra - ( 35 % ) , hexa - ( 12 % ) , and octa - ( 5 % ) saccharide domains . Highly sulfated D , E , and B disaccharide units ( HexA2S - GalNAc6S , HexA - GalNAc4S6S , and HexA2S - GalNAc4S ) were also detected in significant amounts in both chains and may account for the P14210 / SF - binding activity of the CS / DS . This work establishes that P29320 - 293 cells can be engineered to provide a valuable source of Endocan with authentic CS / DS chains , enabling the purification of sufficient amounts for structural and / or binding analysis and providing a possible model of Endocan CS / DS chain organization .",
"P01138 - withdrawal induces apoptosis in pancreatic beta cells in vitro . AIMS / HYPOTHESIS : Using primary cultures of human pancreatic islets , purified human pancreatic beta cells and the mouse beta TC6 - P08709 cell line , we analysed the expression of nerve growth factor , ( P01138 / P01138 ) receptors in beta cells . To investigate whether P01138 could sub - serve an autocrine antiapoptotic role in beta cells , we studied the effects of P01138 withdrawal using a neutralizing monoclonal anti - P01138 antibody . METHODS : The expression of P01138 and P01138 receptors ( gp140 ( P04629 ) and p75 ( NTR ) ) were analysed by RT - PCR and immunofluorescence . Pulse - chase experiments and beta cell / PC12 co - cultures were used to investigate P01138 production and secretion from beta cells . Possible apoptosis induced by P01138 withdrawal was monitored by phosphatidylserine translocation , nucleosomal formation , DNA laddering and FACS analysis . Involvement of transcription / translation mechanisms were investigated as well as the gp140 ( P04629 ) required . Finally , signal transduction pathways typically involved in apoptotic mechanisms were analysed by western blot analysis . RESULTS : We show that P01138 and both P01138 receptors , gp140 ( P04629 ) and p75 ( NTR ) are expressed in beta cells where P01138 is produced and secreted in a biologically active form . P01138 - withdrawal induces beta - cell transcription / translation independent apoptosis but mediated by gp140 ( P04629 ) . Analysis of signal transduction pathways revealed that P01138 withdrawal inhibits the P19957 - K , protein kinase B ( AKT ) , Bad survival pathway and activates c - Jun kinase ( JNK ) whereas ERKs and p38 mitogen - activated protein kinase ( MAPK ) are not affected . Moreover , Bcl - XL , but not Bcl - 2 protein expression are reduced . CONCLUSION / INTERPRETATION : We suggest that the integrity of the P01138 / P08138 system and P01138 bioavailability participate in controlling beta - cell survival in culture which represents a key issue for improving possibilities for transplantations in the treatment of diabetes .",
"DB08875 suppresses tumor growth and metastasis in hepatocellular carcinoma by a dual blockade of P35968 and MET . PURPOSE : MET signaling has been suggested a potential role in hepatocellular carcinoma ( HCC ) and associated with prometastasis during antiangiogenesis therapy . We investigated the potential association between MET expression and therapeutic response to sorafenib in patients with HCC . Antitumor effects of cabozantinib , a dual inhibitor of MET and P35968 , were examined in cultured HCC cells as well as in vivo models . EXPERIMENTAL DESIGN : Total MET and phosphorylated MET ( p - MET ) were measured in 29 resected HCC specimens , and correlated with response to sorafenib as postoperative adjuvant therapy . In the second set of experiments using cultured HCC cells , and mouse xenograft and metastatic models , effects of cabozantinib were examined . RESULTS : High level of p - MET in resected HCC specimens was associated with resistance to adjuvant sorafenib therapy . In cultured HCC cells that expressed p - MET , cabozantinib inhibited the activity of MET and its downstream effectors , leading to P55008 - phase arrest . DB08875 inhibited tumor growth in p - MET - positive and p - MET - negative HCC by decreasing angiogenesis , inhibiting proliferation , and promoting apoptosis , but it exhibited more profound efficacy in p - MET - positive HCC xenografts . DB08875 blocked the hepatocyte growth factor ( P14210 ) - stimulated MET pathway and inhibited the migration and invasion of the HCC cells . Notably , cabozantinib reduced the number of metastatic lesions in the lung and liver in the experimental metastatic mouse model . CONCLUSIONS : Patients with HCC with high level of p - MET are associated with resistance to adjuvant sorafenib treatment . The dual blockade of P35968 and MET by cabozantinib has significant antitumor activities in HCC , and the activation of MET in HCC may be a promising efficacy - predicting biomarker . Clin Cancer Res ; 20 ( 11 ) ; 2959 - 70 . © 2014 AACR .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"DB08875 : a review of its use in patients with medullary thyroid cancer . DB08875 ( Cometriq (®) ) is an orally administered small molecule inhibitor of multiple tyrosine kinase receptors , including those involved in the pathogenesis of medullary thyroid cancer ( P04629 ) [ i . e . rearranged during transfection ( P07949 ) , MET and vascular endothelial growth factor receptor ( VEGFR ) - 2 ] . DB08875 is indicated for the treatment of adults with progressive , unresectable locally advanced ( in the EU ) or metastatic ( in the EU and USA ) P04629 . Compared with placebo , cabozantinib significantly prolonged progression - free survival , reflecting a 72 % reduction in the risk of disease progression or death , in patients with unresectable , locally advanced or metastatic P04629 participating in a multinational , phase III study . A significantly higher proportion of patients receiving cabozantinib than those receiving placebo achieved an objective response or disease stabilization ( i . e . a complete or partial response , or stable disease ) . The overall survival benefit with cabozantinib is as yet unclear , with no significant benefit observed in two interim analyses ( one prespecified , and one unplanned and conducted at the request of the US FDA ) . The tolerability profile of oral cabozantinib is typical for a small molecule targeting the VEGFR and other tyrosine kinase - mediated pathways , with adverse events associated with the inhibition of the P15692 pathway ( e . g . gastrointestinal perforation , haemorrhage , hypertension and venous thrombosis ) reported in the phase III study . Treatment - emergent adverse events were generally managed with supportive therapy , dose reductions and / or dose interruptions . Although final overall survival data are awaited , current evidence suggests cabozantinib to be a valuable treatment option for adults with progressive , unresectable locally advanced or metastatic P04629 .",
"Expressed luciferase viability assay ( ELVA ) for the measurement of cell growth and viability . An expressed luciferase viability assay ( ELVA ) has been developed for cell viability and cell number based on detecting the expression of luciferase transfected into the cells . Stable transfectants were produced that expressed luciferase constitutively . Like many endogenous enzymes , luciferase is rapidly degraded following cell death , so that the enzyme can be used as a measure of cell viability . A modified luciferase assay was used in which the reagents were added directly to the cells in a microplate . The main advantages compared to other cell viability assays are the wide dynamic range , high sensitivity , low background , and the absence of any requirement to wash or harvest the cells . Stable transfectants of three factor - dependent cell lines ( B13 , Ba / P13726 and CTLL ) were produced and used in cytokine assays . Three strategies of selection after electroporation were tested : ( 1 ) using a plasmid containing both the genes encoding firefly luciferase and a selectable marker ( neo ) , ( 2 ) cotransfection of a plasmid containing luciferase and a plasmid containing a selectable marker ( puromycin resistance ) , and ( 3 ) cotransfection of a plasmid containing luciferase and a plasmid containing the human IL - 5Ralpha - chain , and selecting in P05113 . This latter strategy produces an P05113 responsive cell line expressing luciferase in a single step without the need for antibiotic selection .",
"A dose - ranging study of cabozantinib in men with castration - resistant prostate cancer and bone metastases . BACKGROUND : DB08875 is an oral MET / P35968 inhibitor . A recent phase II study of cabozantinib ( 100 mg daily ) showed improved bone scans in subjects with metastatic castration - resistant prostate cancer ( mCRPC ) , but adverse events ( AE ) caused frequent dose reductions . This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses . EXPERIMENTAL DESIGN : An adaptive design was used to determine the lowest active daily dose among 60 , 40 , and 20 mg . The primary endpoint was week 6 bone scan response , defined as ≥ 30 % decrease in bone scan lesion area . The secondary endpoint was change in circulating tumor cells ( CTC ) . RESULTS : Among 11 evaluable subjects enrolled at 40 mg , there were 9 partial responses ( PR ) , 1 complete response , and 1 stable disease ( SD ) . Of 10 subjects subsequently enrolled at 20 mg , there were 1 PR , 5 SDs , and 4 with progressive disease . Among 13 subjects enrolled on the 40 mg expansion cohort , there were 6 PRs and 7 SDs . No subjects required dose reduction or treatment interruption at 6 or 12 weeks ; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks . At 40 mg , median treatment duration was 27 weeks . 58 % of subjects with ≥ 5 CTCs / 7 . 5 mL at baseline converted to < 5 . CONCLUSIONS : DB08875 40 mg daily was associated with a high rate of bone scan response . DB08875 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily . These observations informed the design of phase III studies of cabozantinib in mCRPC .",
"Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .",
"DB08875 for the treatment of advanced medullary thyroid cancer . INTRODUCTION : Patients with advanced medullary thyroid cancer ( P04629 ) have poor prognoses and limited treatment options . Improved knowledge about molecular aberrations associated with P04629 and the availability of novel targeted tyrosine kinase inhibitors ( TKIs ) have led to new potential treatment modalities . DB08875 is an oral multitargeted TKI with activity against multiple receptors including P07949 , vascular endothelial growth factor receptor type 2 ( P35968 ) , and MET that has been evaluated in P04629 in the preclinical and clinical arenas . METHODS : This article reviews unmet clinical needs in advanced P04629 . The authors consider novel agents that have been studied in P04629 , with a focus on the investigational agent cabozantinib . Up - to - date clinical data of cabozantinib in P04629 are discussed . RESULTS : Recent clinical evaluation suggests that cabozantinib is the first agent to prolong progression - free survival in patients with progressive P04629 . These findings indicate that cabozantinib may be an effective therapy in advanced P04629 . No improvement in overall survival has been demonstrated but data are not mature . CONCLUSION : DB08875 may be an effective treatment option for patients with advanced P04629 and is worthy of further evaluation .",
"Effects of ellagic Acid on angiogenic factors in prostate cancer cells . BACKGROUND : Several natural antioxidants , including ellagic acid ( EA ) , have been reported to have chemotherapeutic activity in vivo and in vitro settings . Cytochrome P450 ( CYP ) activity and synthesis of both epoxyeicosatrienoic acids ( EETs ) and 20 - hydroxy - 5 , 8 , 11 , 14 - eicosatetraenoic acid ( 20 - HETE ) , together with vascular endothelial growth factor ( P15692 ) and heme oxygenase system ( HO ) have emerged as important modulators of tumor growth and metastasis . METHODS : The anti - angiogenic effects of EA were investigated in the human prostatic cancer cell line LnCap . P09601 , P30519 , P51589 and soluble epoxyde hydrolase ( sEH ) expressions were evaluated by western blotting . Levels of P15692 and osteoprotegerin ( O00300 ) were determined in the culture supernatant using an ELISA assay , while CYP mRNAs were determined by qRT - PCR . RESULTS : EA treatment induced a significant decrease ( p < 0 . 05 ) in P09601 , P30519 and P51589 expression , and in P15692 and O00300 levels . Similarly P51589 , P78329 and CYPA22 mRNAs were significantly ( p < 0 . 05 ) down - regulated by EA treatment . The decrease in P51589 mRNA was associated with an increase in sEH expression . CONCLUSIONS : RESULTS reported in the present study highlighted the ability of EA to modulate a new pathway , in addition to anti - proliferative and pro - differentiation properties , via a mechanism that involves a decrease in eicosanoid synthesis and a down - regulation of the HO system in prostate cancer .",
"DB08875 ( DB05153 ) for the treatment of locally advanced or metastatic progressive medullary thyroid cancer . DB08875 ( DB05153 ) is an oral multiple receptor tyrosine kinase inhibitor manufactured by Exelixis Inc . , CA , USA . It mainly inhibits three tyrosine kinase receptors : MET , P35968 and P07949 . In both preclinical and clinical studies it has been shown to inhibit tumor angiogenesis , invasiveness and metastases . The most frequent side effects are fatigue , diarrhea , decreased appetite , nausea , weight loss and palmar - plantar erythrodysesthesia . A Phase III clinical trial ( EXAM study ) of DB05153 versus placebo in advanced and progressive medullary thyroid cancer showed a 28 versus 0 % overall response rate and a progression - free survival of 11 . 2 versus 4 . 0 months ( hazard ratio : 0 . 28 ; 95 % CI : 0 . 19 - 0 . 40 ; p < 0 . 0001 ) in patients treated with cabozantinib and placebo , respectively . The drug has been approved by the US FDA for the treatment of advanced / progressive metastatic medullary thyroid cancer in the USA . The P15941 is now evaluating its approval in Europe .",
"Liver regeneration induced by a designer human P05231 / sIL - 6R fusion protein reverses severe hepatocellular injury . The cytokine P05231 plays a significant role in liver regeneration in conjunction with additional growth factors ( P14210 , P01375 , and TGF - alpha ) . Many P05231 effects depend on a naturally occurring soluble P05231 receptor ( sIL - 6R ) . Here , the chimeric protein hyper - P05231 , constructed from the human P05231 protein fused to a truncated form of its receptor , was found to have superagonistic P05231 properties , and as such , enhanced liver cell regeneration . Hyper - P05231 reversed the state of hepatotoxicity and enhanced the survival rates of rats suffering from fulminant hepatic failure after D - galactosamine administration . The hyper - P05231 protein has a significant potential for use in the treatment of severe human liver diseases .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK17___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"Glucocorticoid - induced surface expression of annexin 1 blocks beta2 - integrin adhesion of human eosinophils to intercellular adhesion molecule 1 surrogate protein . BACKGROUND : Glucocorticoids attenuate the population of eosinophils and T lymphocytes in asthmatic airways . The decrease in airway eosinophilia is caused both by accelerated cell death and by induction of blockade of integrin adhesion . In this study , we examined the hypothesis that annexin 1 surface expression , which is upregulated by the glucocorticoid receptor , prevents integrin adhesion essential to cell migration by blocking intracellular translocation of cytosolic group IV phospholipase A2 ( P47712 ) . OBJECTIVE : To examine the relationship of the glucocorticoid on annexin 1 expression and the effect of blockade of annexin 1 activity on adhesion of human eosinophils in vitro . To determine the relationship between annexin 1surface expression and nuclear membrane translocation of P47712 . METHODS : Eosinophils isolated from human peripheral blood were pretreated with fluticasone propionate ( FP ) , and beta2 - integrin adhesion was measured after stimulation with P05113 or eotaxin . Effects of FP on P47712 expression , phosphorylation , and translocation were determined . The role of annexin 1 was examined by using annexin 1 blocking antibody and / or mimetic peptides . RESULTS : ___MASK84___ decreased stimulated eosinophil adhesion and caused 4 - fold increase in annexin 1 expression on the plasma membrane . Inhibition of adhesion by FP was blocked with annexin 1 blocking antibody . Annexin 1 N - terminal mimetic peptide also blocked beta2 - integrin adhesion . Translocation of P47712 to the nuclear membrane was significantly blocked by incubation with FP . Blockade was reversed with annexin 1 blocking antibody . CONCLUSION : Blockade of beta2 - integrin adhesion by glucocorticoid is regulated by annexin 1 , which blocks P47712 translocation to nuclear membrane .",
"DB08875 inhibits growth of androgen - sensitive and castration - resistant prostate cancer and affects bone remodeling . DB08875 is an inhibitor of multiple receptor tyrosine kinases , including MET and P35968 . In a phase II clinical trial in advanced prostate cancer ( PCa ) , cabozantinib treatment improved bone scans in 68 % of evaluable patients . Our studies aimed to determine the expression of cabozantinib targets during PCa progression and to evaluate its efficacy in hormone - sensitive and castration - resistant PCa in preclinical models while delineating its effects on tumor and bone . Using immunohistochemistry and tissue microarrays containing normal prostate , primary PCa , and soft tissue and bone metastases , our data show that levels of MET , P - MET , and P35968 are increasing during PCa progression . Our data also show that the expression of cabozantinib targets are particularly pronounced in bone metastases . To evaluate cabozantinib efficacy on PCa growth in the bone environment and in soft tissues we used androgen - sensitive LuCaP 23 . 1 and castration - resistant C4 - 2B PCa tumors . In vivo , cabozantinib inhibited the growth of PCa in bone as well as growth of subcutaneous tumors . Furthermore , cabozantinib treatment attenuated the bone response to the tumor and resulted in increased normal bone volume . In summary , the expression pattern of cabozantinib targets in primary and castration - resistant metastatic PCa , and its efficacy in two different models of PCa suggest that this agent has a strong potential for the effective treatment of PCa at different stages of the disease .",
"DB00107 alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men . DB00107 is a hormone and neurotransmitter found to have anti - inflammatory functions in rodents . Here we used experimental bacterial endotoxinemia to examine the role of exogenous oxytocin administration on innate immune responses in humans . Ten healthy men received , in a randomized , placebo - controlled , crossover design , placebo , oxytocin , LPS , and LPS + oxytocin . DB00107 treatment resulted in a transient or prolonged reduction of endotoxin - induced increases in plasma DB01285 , cortisol , procalcitonin , P01375 , IL - 1 receptor antagonist , P05112 , P05231 , macrophage inflammatory protein - 1alpha , macrophage inflammatory protein - 1beta , monocyte chemoattractant protein - 1 ( P13500 ) , interferon - inducible protein 10 , and P15692 . In vitro , oxytocin had no impact on LPS effects in releasing P01375 , P05231 , and P13500 in monocytes and peripheral blood mononuclear cells from healthy human donors . In summary , oxytocin decreases the neuroendocrine and cytokine activation caused by bacterial endotoxin in men , possibly due to the pharmacological modulation of the cholinergic anti - inflammatory pathway . DB00107 might be a candidate for the therapy of inflammatory diseases and conditions associated with high cytokine and P15692 levels .",
"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK21___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK21___ is also being investigated as part of triplet drug regimens . ___MASK21___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .",
"A new cell culture - based assay quantifies vitamin K 2 , 3 - epoxide reductase complex subunit 1 function and reveals warfarin resistance phenotypes not shown by the dithiothreitol - driven Q9BQB6 assay . BACKGROUND : ___MASK25___ directly inhibits the vitamin K 2 , 3 - epoxide reductase complex subunit 1 ( Q9BQB6 ) enzyme to effect anticoagulation . Q9BQB6 function has historically been assessed in vitro using a dithiothreitol ( DTT ) - driven vitamin K 2 , 3 - epoxide reductase ( Q9BQB6 ) assay . ___MASK25___ inhibits wild - type Q9BQB6 function by the DTT - Q9BQB6 assay . However , Q9BQB6 variants with warfarin resistance - associated missense mutations often show low Q9BQB6 activities and warfarin sensitivity instead of resistance . OBJECTIVES : A cell culture - based , indirect Q9BQB6 assay was developed and characterized that accurately reports warfarin sensitivity or resistance for wild - type and variant Q9BQB6 proteins . METHODS : Human coagulation factor ( F ) IX and Q9BQB6 variants were coexpressed in P29320 293T cells under standardized conditions at various warfarin concentrations . Secreted FIX activity served as surrogate marker to report wild - type and variant Q9BQB6 inhibition by warfarin . RESULTS AND CONCLUSIONS : ___MASK25___ dose - response curves fit to the secreted FIX activity data for coexpressed hVKORC1 wild - type , Val29Leu , Val45Ala and Leu128Arg variants . The corresponding calculated IC50 values were 24 . 7 , 136 . 4 , 152 . 0 and 1226 . 4 nm , respectively . Basal activities in the absence of warfarin for all Q9BQB6 variants were similar to that of wild - type Q9BQB6 . Ranked IC50 values from the cell culture - based assay accurately reflect elevated warfarin dosages for patients with Q9BQB6 missense mutation - associated warfarin resistance ."
] |
[
"___MASK17___",
"___MASK21___",
"___MASK25___",
"___MASK39___",
"___MASK75___",
"___MASK7___",
"___MASK84___",
"___MASK90___",
"___MASK94___"
] |
___MASK7___
|
MH_train_481
|
interacts_with DB00998?
|
[
"5 - hydroxytryptamine stimulates phosphorylation of Q8TCB0 / Q8NFH3 mitogen - activated protein kinase activation in bovine aortic endothelial cell cultures . 5 - Hydroxytryptamine ( 5 - HT ) is sequestered and released by endothelial cells , acts as an endothelial cell mitogen , promotes the release of nitric oxide ( NO ) , and has been associated with the Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) cascade . NO also acts as a cell mitogen and promotes signals that culminate in the phosphorylation of MAPK . The aim of this study was to test whether endothelial 5 - HT receptors stimulate dual ( tyrosyl - and threonyl - ) phosphorylation of MAPK through a mitogen - activated protein kinase kinase - 1 ( MEK - 1 ) and P29474 - dependent pathway in bovine aortic endothelial cells ( BAECs ) . As shown by Western blot analysis , 5 - HT and the P28222 - selective agonist 5 - nonyloxytryptamine ( 5 - NOT ) stimulate time - and concentration - dependent ( 0 . 001 - 10 microM ) phosphorylation of MAPK in these cells . The agonist - stimulated phosphorylation of MAPK was blocked by the 5 - HT1b - receptor antagonist isamoltane ( 0 . 01 - 10 p3M ) and the MEK - 1 inhibitor PD 098059 ( [ 2 -( 2 '- amino - 3 '- methoxy - phenyl )- oxanaphthalen - 4 - one ] ; 0 . 01 - 10 microM ¿ . The P29474 inhibitor L - N ( omega )- iminoethyl - L - ornithine ( L - NIO ; 0 . 01 - 10 microM ) failed to block the 1 microM 5 - NOT - stimulated responses . Our findings suggest that the 5 - HT receptors ( specifically P28222 ) mediate signals to MEK - 1 and subsequently to MAPK through an P29474 - independent pathway in BAECs .",
"MnSOD drives neuroendocrine differentiation , androgen independence , and cell survival in prostate cancer cells . An increase in neuroendocrine ( NE ) cell number has been associated with progression of prostate tumor , one of the most frequent cancers among Western males . We previously reported that mitochondrial manganese superoxide dismutase ( MnSOD ) increases during the NE differentiation process . The goal of this study was to find whether MnSOD up - regulation is enough to induce NE differentiation . Several human prostate cancer LNCaP cell clones stably overexpressing MnSOD were characterized and two were selected ( MnSOD - S4 and MnSOD - P28222 ) . MnSOD overexpression induces NE morphological features as well as coexpression of the NE marker synaptophysin . Both MnSOD clones exhibit lower superoxide levels and higher H ( 2 ) O ( 2 ) levels . MnSOD - overexpressing cells show higher proliferation rates in complete medium , but in steroid - free medium MnSOD - P28222 cells are still capable of proliferation . MnSOD up - regulation decreases androgen receptor and prevents its nuclear translocation . MnSOD also induces up - regulation of Bcl - 2 and prevents docetaxel - , etoposide - , or P01375 - induced cell death . Finally , MnSOD - overexpressing cells enhance growth of androgen - independent PC - 3 cells but reduce growth of androgen - dependent cells . These results indicate that redox modulation caused by MnSOD overexpression explains most NE - like features , including morphological changes , NE marker expression , androgen independence , inhibition of apoptosis , and enhancement of cell growth . Many of these events can be associated with the androgen dependent - independent transition during prostate cancer progression .",
"[ Functional characteristics of calcium - sensitive adenylyl cyclase of ciliate Tetrahymena pyriformis ] . DB01373 - sensitive forms of adenylyl cyclase ( AC ) were revealed in most vertebrates and invertebrates and also in some unicellular organisms , in particular ciliates . We have shown for the first time that calcium cations influence the AC activity of ciliate Tetrahymena pyriformis . These cations at the concentrations of 0 . 2 - 20 microM stimulated the enzyme activity , and maximum of catalytic effect was observed at 2 microM Ca2 + . DB01373 cations at a concentrations of 100 microM or higher inhibited the AC activity . P62158 antagonists W - 5 and W - 7 at the concentrations of 20 - 100 microM inhibited the catalytic effect induced by 5 microM Ca2 + and blocked the effect at higher concentrations of Ca2 + . ___MASK28___ , another calmodulin antagonist , reduced Ca2 +- stimulated AC activity only at the concentrations of 200 - 1000 microM . AC stimulating effects of serotonin , P01133 and DB02527 increased in the presence of 5 microM Ca2 + . AC stimulating effects of P01133 , DB02527 and insulin decreased in the presence of 100 microM Ca2 + , and AC stimulating effect of DB02527 decreased also in the presence of calmodulin antagonists ( 1 mM ) . At the same time , stimulating effect of D - glucose in the presence of Ca2 + and calmodulin antagonists did not change essentially . The data obtained speak in favor of the presence of calcium - sensitive forms of AC in ciliate T . pyriformis which mediate enzyme stimulation by P01133 , DB02527 , insulin , and serotonin .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK55___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK55___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"___MASK57___ induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . ___MASK57___ ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"DB00998 Vernalis . Vanguard ( now Vernalis ) has developed frovatriptan , a selective P28222 / 1D partial agonist licensed from GlaxoSmithKline as a potential treatment for migraine [ 188478 ] , [ 194382 ] , [ 377863 ] .",
"Pharmacokinetic evaluation of frovatriptan . INTRODUCTION : Migraine is the most common painful neurological disorder , affecting 13 % of the general population . Triptans represent a powerful pharmacological tool in acute migraine treatment , however , a significant portion of treated patients can not have access to this class due to possible adverse affects . Today , a total of seven DB00669 molecules are available , representing a commonly prescribed migraine treatment . Although there is a need of extensive use of triptans , only 25 % of migraine patients are using triptans . AREAS COVERED : This review includes triptans and evidence for the use of frovatriptan . A systematic approach is used to discuss the pharmacodynamic and pharmacokinetic aspects of frovatriptan , considering the emerging data on the clinical efficacy of frovatriptan in the treatment of migraine and cluster headaches . The data were obtained by searching the following key words in MEDLINE : pharmacokinetic , pharmacodynamic , triptans , frovatriptan , migraine , menstrual migraine , relatively to the period 1988 - 2011 . EXPERT OPINION : DB00998 has been developed in order to improve safety and efficacy of triptans . It shows a favorable tolerability and efficacy profile , limited to 24 / 48 - h headache recurrence , when compared with other triptans . Preclinical data suggest that the pharmacokinetic profile of frovatriptan may differ from other available triptans . In fact , among triptans , frovatriptan showed the highest potency at the P28222 receptor ( 8 . 2 ) and the longer half - life ( 26 h ) . These parameters determine the clinical properties of frovatriptan ; in particular the lowest rate of headache recurrence in comparison with other triptans .",
"Activation of the JAK / P35610 pathway in vascular smooth muscle by serotonin . Serotonin ( 5 - hydroxytryptamine , 5 - HT ) is a vasoconstrictor and mitogen whose levels are elevated in diabetes . Previous studies have shown the presence of 5 - Q13049 , P41595 , and P28222 receptors in vascular smooth muscle cells ( VSMCs ) . There are currently no data regarding P41595 and P28222 receptor activation of the JAK / P35610 pathway in VSMCs and resultant potential alterations in 5 - HT signaling in diabetes . Therefore , we tested the hypothesis that 5 - HT differentially activates the JAK / P35610 pathway in VSMCs under conditions of normal ( 5 mM ) and high ( 25 mM ) glucose . Treatment of rat VSMCs with 5 - HT ( 10 (- 6 ) M ) resulted in time - dependent activation ( approximately 2 - fold ) of O60674 , P23458 , and P42224 , but not P40763 ( maximal at 5 min , returned to baseline by 30 min ) . The P41595 receptor agonist BW723C86 and the P28222 receptor agonist CGS12066A ( 10 (- 9 )- 10 (- 5 ) M , 5 - min stimulation ) did not activate the JAK / P35610 pathway . Treatment with the 5 - Q13049 receptor antagonist ketanserin ( 10 nM ) inhibited O60674 activation by 5 - HT . Treatment of streptozotocin - induced diabetic rats with ketanserin ( 5 mg . kg - 1 . day - 1 ) reduced activation of O60674 and P42224 but not P40763 in endothelium - denuded thoracic aorta in vivo . 5 - HT ( 10 (- 6 ) M ) treatment resulted in increased cell proliferation and increased DNA synthesis , which were inhibited by the O60674 inhibitor AG490 . Further studies with apocynin , diphenyleneiodonium chloride , catalase , and virally transfected superoxide dismutase had no effect at either glucose concentration on activation of the JAK / P35610 pathway by 5 - HT . Therefore , we conclude that 5 - HT activates O60674 , P23458 , and P42224 via the 5 - Q13049 receptors in a reactive oxygen species - independent manner under both normal and high glucose conditions .",
"Array - comparative genomic hybridization to detect genomewide changes in microdissected primary and metastatic oral squamous cell carcinomas . Oral squamous cell carcinoma ( OSCC ) is a common worldwide malignancy . However , it is unclear what , if any , genomic alterations occur as the disease progresses to invasive and metastatic OSCC . This study used genomewide array - CGH in microdissected specimens to map genetic alterations found in primary OSCC and neck lymph node metastases . We used array - based comparative genomic hybridization ( array - CGH ) to screen genomewide alterations in eight pairs of microdissected tissue samples from primary and metastatic OSCC . In addition , 25 primary and metastatic OSCC tissue pairs were examined with immunohistochemistry for protein expression of the most frequently altered genes . The highest frequencies of gains were detected in P12524 , Q04864 , TERC , P42336 , P10242 , P08183 , P01112 , GARP , P30279 , P07332 , P04626 , P01127 , and Q05066 . The highest frequencies of losses were detected in p44S10 , O15164 , P06858 , Q13126 , P35226 , P11161 , and Q13163 . Genomic alterations in TGFbeta2 , cellular retinoid - binding protein 1 gene ( P09455 ) , P42336 , P28222 , P01112 , P21860 , and O14965 differed significantly between primary OSCC and their metastatic counterparts . Genomic alterations in Q05513 , P00519 , and P08620 were significantly different in patients who died compared with those who survived . Immunohistochemistry confirmed high P42336 immunoreactivity in primary and metastatic OSCC . Higher P08620 immunoreactivity in primary OSCC is associated with a worse prognosis . Loss of P09455 immunoreactivity is evident in primary and metastatic OSCC . Our study suggests that precise genomic profiling can be useful in determining gene number changes in OSCC . As our understanding of these changes grow , this profiling may become a practical tool for clinical evaluation .",
"___MASK15___ , a new P04035 inhibitor , reduces the colonic inflammatory response in dextran sulfate sodium - induced colitis in mice . The aim of the present study was to elucidate the beneficial effects of rosuvastatin , a new P04035 inhibitor , on colonic mucosal damage and on the inflammatory response in a dextran sulfate sodium ( DSS ) colitis model . Acute colitis was induced using 8 % DSS in female BALB / c mice . Colonic mucosal inflammation was evaluated clinically , biochemically , and histologically . Mucosal protein contents and mRNA levels of tumor necrosis factor ( P01375 ) - alpha were determined by immunoassay and real time - PCR . The mRNA levels of endothelial nitric oxide synthase ( P29474 ) were determined by real - time PCR . Disease activity scores in DSS - induced colitis model mice , as determined by weight loss , stool consistency , and blood in stool , were significantly lower in the rosuvastatin - treated mice than in control mice . Shortening of the colon was significantly reversed by rosuvastatin . Increases in tissue - associated myeloperoxidase activity and thiobarbituric acid - reactive substances after DSS administration were both significantly inhibited by treatment with rosuvastatin . ___MASK15___ also inhibited increases in intestinal P01375 protein and mRNA expression after DSS administration , respectively . The mucosal mRNA levels of P29474 were decreased after DSS administration , but preserved in mice treated with rosuvastatin . These results suggest that rosuvastatin prevents the development of DSS - induced colitis in mice via the inhibition of mucosal inflammatory responses associated with the preservation of P29474 transcription .",
"___MASK12___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK12___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK47___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"Involvement of P28222 receptors in DB00669 - induced contractile responses in guinea - pig isolated iliac artery . Using a series of triptans we characterized in vitro the 5 - hydroxytryptamine ( 5 - HT ) receptor that mediates the contraction in guinea - pig iliac arteries moderately precontracted by prostaglandin F2alpha ( PGF2alpha ) . Additionally , we investigated by reverse - transcriptase polymerase chain reaction ( RT - PCR ) which DB00669 - sensitive receptor is present in this tissue . DB00998 , zolmitriptan , rizatriptan , naratriptan , sumatriptan , and almotriptan contracted guinea - pig iliac arteries with pD2 values of 7 . 52 +/- 0 . 04 , 6 . 72 +/- 0 . 03 , 6 . 38 +/- 0 . 06 , 6 . 22 +/- 0 . 05 , 5 . 86 +/- 0 . 05 and 5 . 26 +/- 0 . 04 respectively . For comparison , the pD2 values for 5 - HT and 5 - carboxamidotryptamine ( 5 - CT ) were 7 . 52 +/- 0 . 02 and 7 . 55 +/- 0 . 03 respectively . In contrast to all other triptans tested , the concentration - response curve for eletriptan was biphasic ( first phase : 0 . 01 - 3 microM , pD2 approximately 6 . 6 ; second phase : > or = 10 microM ) . Contractions to 5 - HT , 5 - CT , frovatriptan , zolmitriptan , rizatriptan , naratriptan , sumatriptan , almotriptan , and eletriptan ( first phase ) were antagonized by the P28222 / 1D receptor antagonist GR127935 ( 10 nM ) and the P28222 receptor antagonist SB216641 ( 10 nM ) . RT - PCR studies in guinea - pig iliac arteries showed a strong signal for the P28222 receptor while expression of P28221 and P30939 receptors was not detected in any sample . The present results demonstrate that DB00669 - induced contraction in guinea - pig iliac arteries is mediated by the P28222 receptor . The guinea - pig iliac artery may be used as a convenient in vitro model to study the ( cardio ) vascular side - effect potential of anti - migraine drugs of the DB00669 family .",
"Role of presynaptic serotonergic receptors on the mechanism of action of P08908 and P28222 agonists on masculine sexual behaviour : physiological and pharmacological implications . In order to establish whether the P08908 or the 5HT1B agonists , 8 - OH - DPAT or TFMPP , produce their facilitatory or inhibitory actions on masculine sexual behaviour via a mechanism involving : ( a ) the serotonin synthesis or release ; ( b ) the stimulation of presynaptic receptors , or ( c ) the stimulation of somatodendritic receptors , three series of experiments were performed . The administration of the serotonin synthesis inhibitor , p - chlorophenylalanine ( p - P15085 , 300 mg / kg x 3 days ) , facilitated sexual behaviour but does not interfere neither with the inhibitory nor with the facilitatory effects of TFMPP ( 0 . 5 mg / kg ) or 8 - OH - DPAT ( 0 . 5 mg / kg ) , respectively . The icv or the intraraphé administration of the serotonergic neurotoxin , 5 , 7 - dihydroxytryptamine ( 5 , 7 - DB02901 ) , slightly stimulated masculine sexual behaviour and produced a decrease in serotonin and its metabolite levels . In lesioned animals TFMPP ( 0 . 5 mg / kg ) resulted in an inhibitory effect reflected as a prolongation of the ejaculation latency . The inhibitory effect of this drug on mounting behaviour was not observed in 5 , 7 - DB02901 treated rats . In lesioned animals 8 - OH - DPAT ( 0 . 5 mg / kg ) produced the same facilitatory effect . Present data indicate that serotonergic postsynaptic receptors mediate both the inhibitory and the facilitatory actions of TFMPP or 8 - OH - DPAT in copulation . All data further support the idea that endogenous serotonin acts via the stimulation of P28222 receptors to induce its inhibitory effects on masculine sexual behaviour .",
"Meta - analysis of oral DB00669 therapy for migraine : number needed to treat and relative cost to achieve relief within 2 hours . OBJECTIVE : To determine the cost - effectiveness of the P28222 / 1D agonists , or triptans , in the acute treatment of migraine . METHODS : To determine the cost - effectiveness of the triptans , a meta - analysis was conducted of the efficacy data from 27 oral DB00669 trials , using the endpoint of \" pain - free \" status within 2 hours after initial dosing as the indicator of efficacy . Efficacy data were used to determine the number needed to treat ( Q13423 ) to achieve pain - free status in 1 patient within 2 hours postdose and then applied the per - dose costs for each DB00669 to the Q13423 values . RESULTS : Rizatriptan 10 mg and almotriptan 12 . 5 mg were the most cost - effective of the triptans , costing $ 48 . 34 and $ 48 . 57 US dollars , respectively , to achieve pain - free status in 1 patient within 2 hours postdose . DB00998 2 . 5 mg was the most costly , with a cost - effective ratio of $ 162 . 49 US dollars . All other triptans fell between these extremes : zolmitriptan 5 mg ( $ 65 . 18 US dollars ) , sumatriptan 100 mg ( $ 70 . 83 US dollars ) , sumatriptan 50 mg ( $ 75 . 67 US dollars ) , zolmitriptan 2 . 5 mg ( $ 78 . 74 US dollars ) , and naratriptan 2 . 5 mg ( $ 141 . 43 US dollars ) , in decreasing order of cost - effectiveness . CONCLUSION : Using an Q13423 analysis , the least - costly drugs to achieve migraine cure within 2 hours are rizatriptan 10 mg and almotriptan 12 . 5 mg . From a population health perspective , the lower acquisition cost of almotriptan 12 . 5 mg allows for effective treatment of more patients than rizatriptan 10 mg for no additional medication cost .",
"Deliberate self - harm is associated with allelic variation in the tryptophan hydroxylase gene ( P17752 A779C ) , but not with polymorphisms in five other serotonergic genes . BACKGROUND : There is a heritable component to suicidal behaviour , encouraging the search for the associated risk alleles . Given the putative role of the 5 - HT ( 5 - hydroxytryptamine ; serotonin ) system in suicidal behaviour , serotonergic genes are leading candidates . In particular , several studies have reported an association with variants in the tryptophan hydroxylase ( P17752 ) gene . METHOD : We studied six serotonergic gene polymorphisms in a well - characterized sample of 129 deliberate self - harm subjects and 329 comparison subjects . The polymorphisms were P17752 ( A779C ) , 5 - HT transporter ( 5 - HTT , LPR S / L ) , monoamine oxidase A ( P21397 G941T ) , P28222 receptor ( P28222 G861C ) , 5 - Q13049 receptor ( P28223 T102C ) , and P28335 receptor ( P28335 Cys23Ser ) . Genotyping was done using polymerase chain reaction ( PCR ) - based assays . The primary analyses compared allele and genotype frequencies between cases and controls . There were a limited number of planned secondary analyses within the deliberate self - harm group . RESULTS : The P17752 A779 allele was more common in deliberate self - harm subjects than in controls ( OR 1 . 38 , 95 % CI 1 . 02 - 1 . 88 ; P = 0 . 03 ) . None of the other polymorphisms was associated with deliberate self - harm . Within the deliberate self - harm group there were no associations with impulsivity , suicide risk , lifetime history of depression , or family history of deliberate self - harm . CONCLUSIONS : Our data extend the evidence that allelic variation in the P17752 gene is a risk factor for deliberate self - harm . No evidence was found to implicate the other polymorphisms .",
"DB00998 : a selective type 1B / 1D serotonin receptor agonist for the treatment of migraine headache . DB00998 belongs to an innovative family of compounds aimed at breaking through the long - standing barrier of migraine headache understanding and treatment . While a typology of headaches has been recognized for some time , and a number of therapies have been introduced for reduction of headache pain and duration , the causes of migraine remain a subject of debate . Those prone to attacks continue to endure them and suffer the related symptoms such as nausea and disorientation . DB00998 , like all the triptans , acts by inducing vasoconstriction of the meningeal arteries . It has been shown in pharmacological tests to act selectively as a potent agonist of serotonin P28222 / 1D receptors . DB00998 has been well tolerated in humans and efficacious in reducing headache pain and duration in clinical trials , which have also indicated that dose adjustments for age or gender are not necessary for the drug . Patients have found the use of frovatriptan acceptable over the long - term , and overall a low - incidence of adverse effects has been reported . Though not a prophylactic , frovatriptan has demonstrated the potential to significantly improve the therapeutic approaches to the treatment of migraine .",
"The efficacy and tolerability of frovatriptan and dexketoprofen for the treatment of acute migraine attacks . DB00998 is a DB00669 characterized by a high affinity for P28222 / 1D receptors and a long half - life contributing to a more sustained and prolonged action than other triptans . DB09214 is a nonsteroidal anti - inflammatory drug with a relatively short half - life and rapid onset of action , blocking the action of cyclo - oxygenase , which is involved in prostaglandins ' production , thus reducing inflammation and pain . Both drugs have been successfully employed as monotherapies for the treatment of acute migraine attacks . The combination of these two drugs ( frovatriptan 2 . 5 mg plus dexketoprofen 25 or 37 . 5 mg ) has been tested in migraine sufferers , showing a rapid and good initial efficacy , with 2 - h pain free rates of 51 % , and a high persistence in the 48 - h following the onset of pain : recurrence occurred in only 29 % of attacks and sustained pain free rates were 43 % at 24 - and 33 % at 48 - h .",
"Disabling the mitotic spindle and tumor growth by targeting a cavity - induced allosteric site of survivin . Survivin is a member of the inhibitor of apoptosis protein family and has an essential role in mitosis . Survivin is overexpressed in a large variety of human cancers and represents an attractive target for cancer therapy . P00533 and Her / neu - transformed human tumors in particular exhibit high levels of survivin . The survivin protein forms dimers through a conserved region that is critical for subcellular localization and biological functions of the protein . We identified small molecules that target a specific cavity adjacent to the survivin dimerization surfaces . P28222 , a lead compound identified in the screen , can bind to the survivin protein at the intended target site . Moreover , P28222 alters spindle formation , causing mitotic arrest and cell death , and inhibits tumor growth in vitro and in vivo . Cell death occurs in premetaphase stage following mitotic arrest and is not a consequence of general toxicity . Thus , the study validates a novel therapeutic target site in the survivin protein and provides a promising strategy to develop a new class of therapeutic small molecules for the treatment of human cancers .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"Desmopressin ( ___MASK10___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK10___ ) also has strong vasodilatory effects . ___MASK10___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK10___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK10___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK10___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK10___ - induced vasodilation .",
"DB00998 , a P28222 / 1D receptor agonist for migraine . DB00998 is one of the most recent serotonin receptor agonists to receive FDA , approved labelling for use in the acute management of migraine with or without aura in adults . The mechanism of action of frovatriptan is thought to be similar to that of a serotonin agonist . However , frovatriptan has distinctive pharmacokinetic and pharmacologic properties , chiefly , a high affinity for serotonin receptors 1B and 1D and a long elimination half - life ; frovatriptan was shown to be more selective for cerebral than coronary arteries , a property which makes frovatriptan more favourable in patients at risk of coronary artery disease . Additionally , frovatriptan has a half - life of approximately 25 h , substantially longer than that of any other agent within its class . This property makes frovatriptan suitable for patients who typically suffer migraines of long duration and / or those who suffer migraine recurrence . The efficacy of frovatriptan in the treatment of acute migraine was demonstrated in five double - blind , randomised , placebo - controlled trials . At 2h , headache response rates for frovatriptan 2 . 5 mg ranged from 38 to 40 % compared to 22 - 35 % for placebo . Headache recurrence for frovatriptan 2 . 5 mg at 24h ranged from 9 to 14 % compared with 18 % in placebo subjects . DB00998 has no clinically significant pharmacokinetic interactions with drugs used for migraine prophylaxis or with commonly prescribed medications . Adverse effects of frovatriptan including dizziness , paresthesia , dry mouth , fatigue and flushing were generally mild and well tolerated . Given the fact that patient response to serotonin agonists is individualised , and selecting an effective agent may involve trial and error , frovatriptan is a welcome alternative in the acute management of migraine .",
"___MASK42___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK42___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK42___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK42___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK42___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK24___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK24___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"DB00998 . black triangle DB00998 , a new serotonin receptor agonist developed for the acute treatment of migraine , has high affinity for serotonin P28222 and P28221 receptor subtypes and is a potent stimulator of contraction in human basilar arteries . black triangle A long terminal elimination half - life ( approximately 26 hours ) is a distinctive pharmacokinetic feature of frovatriptan which appears to be independent of dose , age , gender and renal function . black triangle A single oral dose of frovatriptan 2 . 5mg was effective in the acute treatment of migraine providing meaningful relief within 2 hours to approximately twice as many recipients as placebo in clinical trials . black triangle Consistent relief of migraine symptoms was achieved in patients who treated a number of consecutive attacks with frovatriptan and the incidence of 24 - hour migraine recurrence was reduced . black triangle DB00998 was well tolerated in clinical trials , with the overall incidence of adverse events occurring with frovatriptan 2 . 5mg only slightly higher than that reported with placebo . Mild to moderate fatigue , nausea and paraesthesia were the most commonly reported drug - related adverse events .",
"A review of the use of frovatriptan in the treatment of menstrually related migraine . Menstrual migraine ( MM ) is a highly prevalent condition associated with considerable disability . Migraine attacks occur exclusively around the menstrual period in approximately 10 % of women with migraine , that is , pure menstrual migraine , while at least 50 % of them also experience migraine at other times of the month , that is , menstrually related migraine ( MRM ) . The therapeutic approach to patients with MRM is based on treatment of the attack , or prophylactic strategies . Triptans are recommended as first - line treatments for moderate to severe migraine attacks , including MM . DB00998 is one of the newest triptans . Its high affinity for P28222 / 1D receptors and long half - life contribute to its distinctive clinical effect , characterized by a more sustained and prolonged effect than other triptans . Indeed , frovatriptan proved to be effective in treating the acute attack , but was particularly effective in the short - term preventive therapy of MM . In addition , frovatriptan is one of the safest triptans , with the lowest risk of treatment - emergent adverse events . Following extensive evidence from randomized pharmacological trials , frovatriptan has now gained a grade A recommendation from the guidelines for short - term prophylaxis of MM . Recent post - hoc analyses of direct comparative trials also suggest that frovatriptan might have an important role in the acute treatment of MRM . In these studies , frovatriptan showed pain relief and pain - free rates similar to those of zolmitriptan , rizatriptan , and almotriptan , but with significantly lower recurrence rates . More well - designed , randomized , prospective studies , specifically enrolling women with MM , will be needed in the near future to confirm the efficacy of frovatriptan in this migraine subtype .",
"Fluorescence energy transfer analysis of calmodulin - peptide complexes . The interactions between calmodulin and the tryptophan residues of synthetic peptides corresponding to the calmodulin binding domains of skeletal muscle myosin light - chain kinase and the plasma membrane calcium pump were examined . The single tryptophan residue contained in each peptide became relatively immobilized and inaccessible to iodide ion upon binding to calmodulin , indicating that the indole side chain was inserted into a hydrophobic cleft in the surface of calmodulin . Fluorescence energy transfer from peptidyl tryptophan residues to an AEDANS moiety attached to cysteine - 26 of spinach calmodulin was measured . Included in these analyses was a tryptophan - containing peptide analog of the calmodulin binding domain of neuromodulin . These data indicated that the indole ring of each peptide inserted 32 - 35 A away from cysteine - 26 and may therefore interact with the carboxyl - terminal lobe of P62158 in its \" bent \" conformation [ Persechini & Kretsinger ( 1988a ) J . Cardiovasc . Pharmacol . 12 ( Suppl 5 ) , S1 - P28222 ; Ikura et al . ( 1992 ) Science 256 , 632 - 638 ; Vorherr et al . ( 1992 ) Eur . J . Biochem . 204 , 931 - 937 ] . The interchange of tryptophan - 3 and phenylalanine - 21 of the calcium pump peptide increased the efficiency of energy transfer to the AEDANS - moiety approximately 12 - fold , reducing the calculated distance to 20 A . These data suggest that phenylalanine - 21 of the calcium pump peptide interacts with the hydrophobic cleft in the amino - terminal lobe of P62158 .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 ."
] |
[
"___MASK10___",
"___MASK12___",
"___MASK15___",
"___MASK24___",
"___MASK28___",
"___MASK42___",
"___MASK47___",
"___MASK55___",
"___MASK57___"
] |
___MASK28___
|
MH_train_482
|
interacts_with DB00216?
|
[
"DB00216 Pfizer . Pfizer has developed and launched eletriptan , a P28222 / 1D agonist , for the potential treatment of migraine with and without aura . DB00216 has 6 - fold greater affinity for the P28221 receptor than sumatriptan , and a 3 - fold greater affinity for the P28222 receptor [ 249570 ] . DB00216 pharmacology has also been evaluated in vitro in comparison with zolmitriptan ( AstraZeneca plc ) and naratriptan ( GlaxoSmithKline plc ) [ 290116 ] .",
"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .",
"P40189 - linked signal transduction promotes the differentiation and maturation of dendritic cells . In order to explore the role of P40189 - linked signal transduction in the differentiation and maturation of dendritic cells ( DC ) , the mAb , B - P28222 , an agonist of P40189 , was used for the activation of P40189 on DC . The effects of cytokines and of anti - P40189 mAb on the proliferation of DC , and their expression of IL - 12 and P33681 ( P33681 - 1 ) by DC were evaluated . DC differentiating from peripheral blood mononuclear cells did not express the P05231 receptor alpha chain , but expressed P40189 . Anti - P40189 mAb promoted the proliferation of DC , induced by P05112 and granulocyte macrophage colony stimulating factor ( GM - P04141 ) , by up - regulating the GM - P04141 receptor on DC . DC induced by P40189 mAb and cytokines expressed DC - derived CC chemokine , as measured by RT - PCR . Induced DC also stimulated strong proliferation of autologous T cells in mixed lymphocyte reaction since an up - regulated expression of IL - 12 and P33681 ( P33681 - 1 ) was observed in DC activated by anti - P40189 mAb . Thus , P40189 signal transduction is important for the differentiation and maturation of DC .",
"P00734 haplotype associated with kidney stone disease in Northeastern Thai patients . OBJECTIVE : To evaluate genetic variations associated with kidney stone disease in Northeastern Thai patients . METHODS : Altogether , 67 single nucleotide polymorphisms ( SNP ) distributed within 8 candidate genes , namely P04155 , P05109 , P06702 , P80511 , P02760 , P10451 , P07911 , and F2 , which encode stone inhibitor proteins , including trefoil factor 1 , calgranulin ( A , B , and C ) , bikunin , osteopontin , tamm - Horsfall protein , and prothrombin , respectively , were initially genotyped in 112 individuals each and in additional subjects to consist of 164 patients and 216 control subjects in total . RESULTS : We found that minor allele and homozygous genotype frequencies of 8 of 10 SNPs distributed within the F2 gene were significantly higher in the control group than in the patient group . Two F2 haplotypes were found to be dually associated with kidney stone risk , one ( TGCCGCCGCG ) with increased disease risk and the other ( CGTTCCGCTA ) with decreased disease risk . However , these 2 haplotypes were associated with the disease risks in only the female , not the male , group . CONCLUSIONS : The results of our study indicate that genetic variation of F2 is associated with kidney stone risk in Northeastern Thai female patients .",
"Characterization and localization of the rabbit ocular calcitonin gene - related peptide ( P80511 ) - receptor component protein ( RCP ) . PURPOSE : To determine whether the calcitonin gene - related peptide ( P80511 ) receptor component protein ( RCP ) , a novel signal transduction molecule , is required for P80511 signaling in the eye and to determine potential ocular sites of P80511 action . METHODS : The cDNA for the rabbit ocular RCP homologue was cloned using a combination of reverse transcription - polymerase chain reaction ( RT - PCR ) and rapid amplification of cDNA ends ( RACE ) . Function of the rabbit ocular RCP was assessed using a sensitive oocyte - based assay , which utilizes the protein kinase A ( PKA ) - sensitive cystic fibrosis transmembrane conductance regulator ( P13569 ) as a sensor of DB02527 formation . RCP expression in the rabbit eye was localized using immunohistochemistry . RESULTS : A 2063 - bp cDNA for the rabbit ocular RCP was cloned and sequenced . Expression of the rabbit RCP cDNA confers P80511 responsiveness in a sensitive oocyte - based assay . Antisense oligonucleotides made to the ocular RCP abolishes P80511 responsiveness of ciliary body and iris mRNA in the oocyte - P13569 assay . Localization of RCP protein in the rabbit eye using immunohistochemistry demonstrated RCP immunoreactivity in the ciliary body and iris blood vessels , as well as in layers of the ciliary epithelium . CONCLUSIONS : The rabbit ocular RCP appears to be required for signal transduction at ocular P80511 receptors and is localized to sites previously reported to bind P80511 , which affect intraocular pressure and neurogenic inflammation .",
"Candidate gene studies of ADHD : a meta - analytic review . Quantitative genetic studies ( i . e . , twin and adoption studies ) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder ( ADHD ) . Over the past 15 years , considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD . The first aim of the present study was to conduct a comprehensive meta - analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies . The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results . Significant associations were identified for several candidate genes including Q01959 , P21917 , P21918 , P31645 , P28222 , and P60880 . Further , significant heterogeneity was observed for the associations between ADHD and Q01959 , P21917 , P21918 , P09172 , P08913 , P31645 , Q8IWU9 , P21397 , and P60880 , suggesting that future studies should explore potential moderators of these associations ( e . g . , ADHD subtype diagnoses , gender , exposure to environmental risk factors ) . We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD .",
"Efficacy , safety and tolerability of oral eletriptan in the acute treatment of migraine : results of a phase III , multicentre , placebo - controlled study across three attacks . The efficacy , safety and tolerability of the P28222 / D receptor agonist eletriptan ( 40 mg and 80 mg ) in acute treatment of migraine was evaluated in a multinational , randomized , double - blind , parallel - group , placebo - controlled , three - attack study treating 1153 patients . In the initial attack , significantly more eletriptan patients reported headache relief and complete pain relief at 2 h vs . placebo ( 40 mg 62 % and 32 % , 80 mg 65 % and 34 % , placebo 19 % and 3 % ; P < 0 . 0001 ) . Headache relief occurred faster after eletriptan , with more patients at both doses reporting relief 30 min ( P < 0 . 01 ) and 1 h ( P < 0 . 0001 ) after treatment than after placebo . There was a significantly lower recurrence rate with eletriptan 80 mg compared with placebo ( P < 0 . 01 ) . Adverse events for all treatments were generally mild or moderate and self - limiting . DB00216 40 mg and eletriptan 80 mg both appear to be effective and well - tolerated acute migraine treatments .",
"Characterisation of the contractile activity of eletriptan at the canine vascular P28222 receptor . The functional activity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1 H - indole ) at the contractile serotonin ( 5 - hydroxytryptamine ; 5 - HT ) ' 1B - like ' receptor in dog isolated saphenous vein and basilar artery was investigated . DB00216 , like 5 - HT and sumatriptan potently contracted saphenous vein ( pEC50 : 6 . 3 , 6 . 9 and 6 . 1 , respectively ) and basilar artery ( pEC50 7 . 2 , 7 . 5 and 6 . 8 , respectively ) . The maximum responses evoked by eletriptan was , unlike sumatriptan , significantly lower than that to 5 - HT ( intrinsic activity saphenous vein : eletriptan 0 . 57 , 5 - HT 1 . 0 , sumatriptan 0 . 85 ; basilar artery : eletriptan 0 . 77 , 5 - HT 0 . 98 , sumatriptan 0 . 89 ) . Contractions evoked by eletriptan were antagonised by the P28222 / 1D receptor antagonist GR125743 ( N - [ 4 - methoxy - 3 - ( 4 - methyl piperazin - 1 - yl ) phenyl ] - 3 - methyl - 4 -( 4 - pyridyl ) benzamide ) with pA2 values of 9 . 1 in saphenous vein and 9 . 4 in basilar artery . Affinity estimates ( pKA ) for 5 - HT and sumatriptan determined from receptor alkylation studies in saphenous vein were 6 . 6 and 6 . 3 , respectively , compared to the apparent equilibrium dissociation constant ( pKp ) for eletriptan of 6 . 8 . The rank order of relative intrinsic efficacies ( epsilon ) was 5 - HT > sumatriptan > eletriptan . Thus , eletriptan required greater receptor occupancy ( 4 . 4 - fold ) to evoke an equivalent contraction to 5 - HT and sumatriptan in dog isolated saphenous vein . These data demonstrate that eletriptan is a potent partial agonist at the canine vascular P28222 receptor .",
"Serotonergic stimulation of corticotropin - releasing hormone and pro - opiomelanocortin gene expression . The neurotransmitter serotonin ( 5 - HT ) stimulates adrenocorticotropic hormone ( DB01285 ) secretion from the anterior pituitary gland via activation of central 5 - HT1 and 5 - HT2 receptors . The effect of 5 - HT is predominantly indirect and may be mediated via release of hypothalamic corticotropin - releasing hormone ( P06850 ) . We therefore investigated the possible involvement of P06850 in the serotonergic stimulation of DB01285 secretion in male rats . Increased neuronal 5 - HT content induced by systemic administration of the precursor 5 - hydroxytryptophan ( 5 - HTP ) in combination with the 5 - HT reuptake inhibitor fluoxetine raised P06850 mRNA expression in the paraventricular nucleus ( PVN ) by 64 % , increased pro - opiomelanocortin ( P01189 ) mRNA in the anterior pituitary lobe by 17 % and stimulated DB01285 secretion five - fold . Central administration of 5 - HT agonists specific to P08908 , P28222 , 5 - Q13049 or P28335 receptors increased P06850 mRNA in the PVN by 15 - 50 % , P01189 mRNA in the anterior pituitary by 15 - 27 % and DB01285 secretion three - to five - fold , whereas a specific 5 - Q9H205 agonist had no effect . Systemic administration of a specific anti - P06850 antiserum inhibited the DB01285 response to 5 - HTP and fluoxetine and prevented the 5 - HTP and fluoxetine - induced P01189 mRNA response in the anterior pituitary lobe . Central or systemic infusion of 5 - HT increased DB01285 secretion seven - and eight - fold , respectively . Systemic pretreatment with the anti - P06850 antiserum reduced the DB01285 responses to 5 - HT by 80 % and 64 % , respectively . It is concluded that 5 - HT via activation of P08908 , 5 - Q13049 , P28335 and possibly also P28222 receptors increases the synthesis of P06850 in the PVN and P01189 in the anterior pituitary lobe , which results in increased DB01285 secretion . Furthermore , the results indicate that P06850 is an important mediator of the DB01285 response to 5 - HT .",
"Sequence and functional analysis of cloned guinea pig and rat serotonin P28221 receptors : common pharmacological features within the P28221 receptor subfamily . This study was undertaken to investigate the pharmacology of cloned guinea pig and rat 5 - hydroxytryptamine ( serotonin ; 5 - HT ) 1D receptor sites . Guinea pig , rat , and mouse P28221 receptor genes were cloned , and their amino acid sequences were compared with those of the human , dog , and rabbit . The overall amino acid sequence identity between these P28221 receptors is high and varies between 86 and 99 % . The sequence homology is slightly more divergent ( 13 - 27 % ) in the N - terminal extracellular region of these P28221 receptors . Guinea pig and rat P28221 receptors , stably and separately expressed in rat P13671 glial cells , are negatively coupled to cyclic AMP formation upon stimulation with agonists , as previously found for cloned human P28221 receptor sites . The cyclic AMP data show some common pharmacological features for the P28221 receptors of guinea pig , rat , and human : an almost similar rank order of potency for the investigated P28221 receptor agonists , stereoselectivity for the binding affinity and agonist potency of R (+)- 8 - hydroxy - 2 -( di - n - propylamino ) tetralin , and equal P28221 receptor - mediated antagonist potency for methiothepin and the 5 - HT2 receptor antagonists ritanserin and ketanserin . In conclusion , the pharmacology of the cloned P28221 receptor subtype seems , unlike the P28222 receptor subtype , conserved among various mammal species such as the human , guinea pig , and rat .",
"___MASK55___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK81___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 .",
"___MASK66___ consumption is regulated by a human polymorphism in dopamine neurons . Smoking is the most important preventable cause of morbidity and mortality worldwide . Recent genome - wide association studies highlighted a human haplotype on chromosome 15 underlying the risk for tobacco dependence and lung cancer . Several polymorphisms in the P32297 - P30532 - P30926 cluster coding for the nicotinic acetylcholine receptor ( nAChR ) α3 , α5 and β4 subunits were implicated . In mouse models , we define a key role in the control of sensitivity to nicotine for the α5 subunit in dopaminergic ( DAergic ) neurons of the ventral tegmental area ( VTA ) . We first investigated the reinforcing effects of nicotine in drug - naive α5 (-/-) mice using an acute intravenous nicotine self - administration task and ex vivo and in vivo electrophysiological recordings of nicotine - elicited DA cell activation . We designed lentiviral re - expression vectors to achieve targeted re - expression of wild - type or mutant α5 in the VTA , in general , or in DA neurons exclusively . Our results establish a crucial role for α5 *- nAChRs in DAergic neurons . These receptors are key regulators that determine the minimum nicotine dose necessary for DA cell activation and thus nicotine reinforcement . Finally , we demonstrate that a single - nucleotide polymorphism , the non - synonymous α5 variant rs16969968 , frequent in many human populations , exhibits a partial loss of function of the protein in vivo . This leads to increased nicotine consumption in the self - administration paradigm . We thus define a critical link between a human predisposition marker , its expression in DA neurons and nicotine intake .",
"Fluorescence energy transfer analysis of calmodulin - peptide complexes . The interactions between calmodulin and the tryptophan residues of synthetic peptides corresponding to the calmodulin binding domains of skeletal muscle myosin light - chain kinase and the plasma membrane calcium pump were examined . The single tryptophan residue contained in each peptide became relatively immobilized and inaccessible to iodide ion upon binding to calmodulin , indicating that the indole side chain was inserted into a hydrophobic cleft in the surface of calmodulin . Fluorescence energy transfer from peptidyl tryptophan residues to an AEDANS moiety attached to cysteine - 26 of spinach calmodulin was measured . Included in these analyses was a tryptophan - containing peptide analog of the calmodulin binding domain of neuromodulin . These data indicated that the indole ring of each peptide inserted 32 - 35 A away from cysteine - 26 and may therefore interact with the carboxyl - terminal lobe of P62158 in its \" bent \" conformation [ Persechini & Kretsinger ( 1988a ) J . Cardiovasc . Pharmacol . 12 ( Suppl 5 ) , S1 - P28222 ; Ikura et al . ( 1992 ) Science 256 , 632 - 638 ; Vorherr et al . ( 1992 ) Eur . J . Biochem . 204 , 931 - 937 ] . The interchange of tryptophan - 3 and phenylalanine - 21 of the calcium pump peptide increased the efficiency of energy transfer to the AEDANS - moiety approximately 12 - fold , reducing the calculated distance to 20 A . These data suggest that phenylalanine - 21 of the calcium pump peptide interacts with the hydrophobic cleft in the amino - terminal lobe of P62158 .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK12___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"DB09280 - ___MASK68___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"A combination of molecular cytogenetic analyses reveals complex genetic alterations in conventional renal cell carcinoma . Here we report the complex pattern of genomic imbalances and rearrangements in a panel of 19 renal cell carcinoma cell lines detected with molecular cytogenetic analysis . Consistent heterogeneity in chromosome number was found , and most cell lines showed a near - triploid chromosome complement . Several cell lines showed deletions of the P04637 ( alias p53 ) , CDKN2A ( alias p16 ) , and P40337 genes . Multiplex fluorescence in situ hybridization ( M - Q5TCZ1 ) analysis revealed chromosome 3 translocated to several other partners chromosomes , as well as breakage events commonly affecting chromosomes 1 , 5 , 8 , 10 , and 17 . The most common abnormality detected with comparative genomic hybridization ( CGH ) was deletions of chromosome 3p , with loss of the Q9NS23 , P49789 , and p44S10 loci frequently involved . CGH gain of 5q showed overrepresentation of the P18146 and P07333 genes . Recurrent alterations to chromosome 7 included rearrangement of 7q11 and gains of the P00533 , O15164 , and P35250 genes . Several lines exhibited rearrangement of 12q11 approximately q14 and overrepresentation of P11802 and SAS loci . M - Q5TCZ1 revealed several other recurrent translocations , and CGH findings included loss of 9p , 14q , and 18q and gain of 8q , 12 , and 20 . Further genomic microarray changes included loss of Q13126 , IGH @ , P28222 , and Q13485 ( previously Q13485 ) and gains of MYC and P11387 . An excellent correlation was observed between the genomic array and Q5TCZ1 data , demonstrating that this technique is effective and accurate . The aberrations detected here may reflect important pathways in renal cancer pathogenesis .",
"Effects of eletriptan on the peptidergic innervation of the cerebral dura mater and trigeminal ganglion , and on the expression of c - fos and c - jun in the trigeminal complex of the rat in an experimental migraine model . Nociceptive axons and terminals in the supratentorial cerebral dura mater display an intense calcitonin gene - related peptide ( P80511 ) immunoreactivity . In an experimental migraine model , it has been shown that electrical stimulation of the rat trigeminal ganglion induced an increase in the lengths of P80511 - immunoreactive axons , increased size and number of pleomorphic axonal varicosities in the dura mater , and an increased number of c - jun and c - fos protein - expressing nerve cells in the trigeminal complex . We demonstrate the effect of the highly specific and moderately lipophilic serotonin agonist eletriptan ( Pfizer ) which prevents the effects of electrical stimulation in the dura mater . DB00216 also affected the caudal trigeminal complex ; it markedly reduced the numbers of the oncoprotein - expressing cells , mainly after stimulation and to some extent also in nonstimulated animals . DB00216 also affected expression of P80511 in perikarya of trigeminal ganglion cells , insofar as the number of small nerve cells exhibiting a compact P80511 immunoreaction was decreased to one quarter of the original value . In all these respects , eletriptan acted in a similar way to sumatriptan , with the notable exception that eletriptan also blocked the stimulation - induced effects in the nucleus caudalis trigemini and the upper cervical spinal cord ( trigeminal complex ) , whereas sumatriptan did not . It is concluded that eletriptan , acting on perikarya and both the peripheral and the central axon terminals of primary sensory neurons , exerts its antimigraine effect by an agonist action on P28222 / 1D receptors throughout the entire trigeminal system , probably by passing the blood - brain - barrier because of its lipophilic character .",
"[ ___MASK53___ : A new drug of B - cell malignancies ] . ___MASK53___ ( Imbruvica ® ) is a first - in - class , orally administered once - daily , that inhibits B - cell antigen receptor signaling downstream of Bruton ' s tyrosine kinase ( Q06187 ) . ___MASK53___ has been approved in USA in February 2014 and in France in October 2014 for the treatment of patients with relapsed / refractory mantle cell lymphoma ( Q8WXI8 ) or chronic lymphocytic leukaemia ( CLL ) and for the treatment of patients with CLL and a chromosome 17 deletion ( del 17p ) or P04637 mutation . In clinical studies , ibrutinib induced an impressive overall response rate ( 68 % ) in patients with relapsed / refractory Q8WXI8 ( phase II study ) . In CLL , ibrutinib has shown to significantly improve progression - free survival , response rate and overall survival in patients with relapsed / refractory CLL , including in those with del 17p . ___MASK53___ had an acceptable tolerability profile . Less than 10 % of patients discontinued their treatment because of adverse events . Results are pending in other B - cell lymphomas subtypes such as in diffuse large B - cell lymphoma and in follicular lymphoma . An approval extension has already been enregistered for Waldenström disease in USA in January 2015 . Given its efficacy and tolerability , ibrutinib is an emerging treatment option for patients with B - cell malignancies .",
"P01258 gene - related peptide - like immunoreactivity and its relation with neurotensin - and corticotropin - releasing hormone - like immunoreactive neurons in the bed nuclei of the stria terminalis in the rat . The distribution of calcitonin gene - related peptide ( P80511 ) - like immunoreactive ( LI ) nerve cells and terminals ( BST ) was studied in the rat . Only the fusiform nucleus was found to consistently contain P80511 - LI neurons . The CRGP - LI terminals had a wide distribution in the BST , being most numerous in the oval and the fusiform nuclei . In the oval nucleus the P80511 - LI terminals formed characteristic \" baskets . \" Since the oval nucleus was known to be studded with neurotensin ( NT ) - and corticotropin - releasing hormone ( P06850 ) - LI neurons , the relationship of the P80511 - LI nerves to NT - and P06850 - LI neurons was investigated by means of a double immunostaining technique . A part of the P80511 - LI baskets were found to contain NT - or P80511 - LI neurons . The possible involvement of the P80511 / NT or P06850 relationship in reciprocal connection between the BST and the parabrachial nucleus and in cardiovascular regulation is discussed .",
"___MASK59___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK59___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"Characterisation of the 5 - HT receptor binding profile of eletriptan and kinetics of [ 3H ] eletriptan binding at human P28222 and P28221 receptors . The affinity of eletriptan ( ( R ) - 3 -( 1 - methyl - 2 - pyrrolidinylmethyl )- 5 - [ 2 - ( phenylsulphonyl ) ethyl ] - 1H - indole ) for a range of 5 - HT receptors was compared to values obtained for other P28222 / 1D receptor agonists known to be effective in the treatment of migraine . DB00216 , like sumatriptan , zolmitriptan , naratriptan and rizatriptan had highest affinity for the human P28222 , P28221 and putative 5 - ht1f receptor . Kinetic studies comparing the binding of [ 3H ] eletriptan and [ 3H ] sumatriptan to the human recombinant P28222 and P28221 receptors expressed in HeLa cells revealed that both radioligands bound with high specificity ( > 90 % ) and reached equilibrium within 10 - 15 min . However , [ 3H ] eletriptan had over 6 - fold higher affinity than [ 3H ] sumatriptan at the P28221 receptor ( K ( D ) ) : 0 . 92 and 6 . 58 nM , respectively ) and over 3 - fold higher affinity than [ 3H ] sumatriptan at the P28222 receptor ( K ( D ) : 3 . 14 and 11 . 07 nM , respectively ) . Association and dissociation rates for both radioligands could only be accurately determined at the P28221 receptor and then only at 4 degrees C . At this temperature , [ 3H ] eletriptan had a significantly ( P < 0 . 05 ) faster association rate ( K ( on ) 0 . 249 min (- 1 ) nM (- 1 ) ) than [ 3H ] sumatriptan ( K ( on ) 0 . 024 min (- 1 ) nM (- 1 ) ) and a significantly ( P < 0 . 05 ) slower off - rate ( K ( off ) 0 . 027 min (- 1 ) compared to 0 . 037 min (- 1 ) for [ 3H ] sumatriptan ) . These data indicate that eletriptan is a potent ligand at the human P28222 , P28221 , and 5 - ht1f receptors and are consistent with its potent vasoconstrictor activity and use as a drug for the acute treatment of migraine headache .",
"Emergence of motor circuit activity . In the developing nervous system , ordered neuronal activity patterns can occur even in the absence of sensory input and to investigate how these arise , we have used the model system of the embryonic chicken spinal motor circuit , focusing on motor neurons of the lateral motor column ( O15467 ) . At the earliest stages of their molecular differentiation , we can detect differences between medial and lateral O15467 neurons in terms of expression of neurotransmitter receptor subunits , including P30532 , P36544 , Q12879 , P39086 , P08908 and P28222 , as well as the Q9H2X9 transporter . Using patch - clamp recordings we also demonstrate that medial and lateral O15467 motor neurons have subtly different activity patterns that reflect the differential expression of neurotransmitter receptor subunits . Using a combination of patch - clamp recordings in single neurons and calcium - imaging of motor neuron populations , we demonstrate that inhibition of nicotinic , muscarinic or GABA - ergic activity , has profound effects of motor circuit activity during the initial stages of neuromuscular junction formation . Finally , by analysing the activity of large populations of motor neurons at different developmental stages , we show that the asynchronous , disordered neuronal activity that occurs at early stages of circuit formation develops into organised , synchronous activity evident at the stage of O15467 neuron muscle innervation . In light of the considerable diversity of neurotransmitter receptor expression , activity patterns in the O15467 are surprisingly similar between neuronal types , however the emergence of patterned activity , in conjunction with the differential expression of transmitter systems likely leads to the development of near - mature patterns of locomotor activity by perinatal ages .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK15___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"A DNA hypermethylation profile reveals new potential biomarkers for prostate cancer diagnosis and prognosis . BACKGROUND : DNA hypermethylation has emerged as a novel molecular biomarker for the evaluation of prostate cancer diagnosis and prognosis . Defining the specific gene hypermethylation profile for prostate cancer could involve groups of genes that specifically discriminate patients with indolent and aggressive tumors . METHODS : Genome - wide methylation analysis was performed on 83 tumor and 10 normal prostate samples using the GoldenGate Methylation Cancer Panel I ( Illumina , Inc . ) . All clinical stages of disease were considered . RESULTS : We found 41 genes hypermethylated in more than 20 % of the tumors analyzed ( P < 0 . 01 ) . Of these , we newly identified P28161 and P01210 as being genes that are hypermethylated in prostate cancer and that were simultaneously methylated in 40 . 9 % of the tumors analyzed . We also identified panels of genes that are more frequently methylated in tumor samples with clinico - pathological indicators of poor prognosis : a high Gleason score , elevated Ki - 67 , and advanced disease . Of these , we found simultaneous hypermethylation of P13569 and P28222 to be common in patients with a high Gleason score and high Ki - 67 levels ; this might indicate the population at higher risk of therapeutic failure . The DNA hypermethylation profile was associated with cancer - specific mortality ( log - rank test , P = 0 . 007 ) and biochemical recurrence - free survival ( log - rank test , P = 0 . 0008 ) . CONCLUSIONS : Our findings strongly indicate that epigenetic silencing of P28161 and P01210 is a common event in prostate cancer that could be used as a molecular marker for prostate cancer diagnosis . In addition , simultaneous P28222 and P13569 hypermethylation could help discriminate aggressive from indolent prostate tumors .",
"Porcine carotid vascular effects of eletriptan ( UK - 116 , 044 ) : a new P28222 / 1D receptor agonist with anti - migraine activity . It has been suggested that opening of cephalic arteriovenous anastomoses may be involved in the headache phase of migraine . Indeed , a number of acutely acting anti - migraine drugs , including the ergot alkaloids and sumatriptan , constrict porcine carotid arteriovenous anastomoses . In this study , using pentobarbital anaesthetised pigs , we investigated the effects of eletriptan , a close structural analogue of sumatriptan , on the distribution of common carotid artery blood flow into arteriovenous anastomotic and nutrient ( capillary ) fractions . DB00216 ( 10 , 30 , 100 , 300 and 1000 microg kg (- 1 ) , i . v . ) decreased the total carotid blood flow , exclusively by decreasing cephalic arteriovenous anastomotic blood flow ; nutrient blood flow , particularly to the ear , skin and fat , was significantly increased . The doses of eletriptan needed to reduce arteriovenous anastomotic blood flow and conductance by 50 % ( ED50 ) were , respectively , 117 +/- 21 microg kg (- 1 ) ( 251 +/- 45 nmol kg (- 1 ) ) and 184 +/- 42 microg kg (- 1 ) ( 396 +/- 91 nmol kg (- 1 ) ) ; the highest dose caused reductions of 84 +/- 3 % and 77 +/- 4 % , respectively . The eletriptan - induced changes in carotid haemodynamics were clearly attenuated by pretreating the pigs with the selective P28222 / 1D receptor antagonist GR127935 ( 0 . 5 mg kg (- 1 ) ) . On the basis of these results , we conclude that ( 1 ) the eletriptan - induced constriction of cephalic arteriovenous anastomoses as well as the arteriolar dilatation in head tissues is predominantly mediated by P28222 / 1D receptors , and ( 2 ) eletriptan should be effective in aborting migraine headache . Clinical studies have already demonstrated its therapeutic action in migraine patients .",
"Increased expression of receptor for advanced glycation end products by synovial tissue macrophages in rheumatoid arthritis . OBJECTIVE : The accumulation of advanced glycation end products ( AGEs ) , P80511 , and high mobility group box chromosomal protein 1 has been associated with joint inflammation in rheumatoid arthritis ( RA ) . This study was undertaken to determine the induction of the receptor for these proteins , termed receptor for AGEs ( RAGE ) , in synovial tissue ( ST ) macrophages from RA patients . METHODS : RAGE and P34810 expression in ST were determined by 2 - color immunofluorescence labeling . Cell surface and messenger RNA ( mRNA ) expression of RAGE were examined by flow cytometry and reverse transcriptase - polymerase chain reaction ( PCR ) or real - time PCR , respectively . RESULTS : P34810 + lining macrophages , like the vasculature , expressed high levels of RAGE in inflamed ST from RA patients . RAGE mRNA expression was significantly higher in RA ST than in ST from patients with osteoarthritis . RAGE mRNA levels were significantly higher in ST macrophages and normal endothelial cells than in ST P01730 + T cells and synovial fibroblasts stimulated with tumor necrosis factor alpha and interleukin - 1beta ( IL - 1beta ) . Cell surface RAGE was highly induced on normal monocytes after a 24 - hour incubation with a 20 % concentration of RA ST cell culture supernatants . RAGE mRNA expression in adherent monocytes was augmented by various cytokines , most potently by IL - 1beta . CONCLUSION : These results indicate that RAGE overexpression in lining macrophages may be induced , at least in part , by cytokines such as IL - 1 , leading to the amplification of inflammatory responses mediated by RAGE ligands that are abundant in RA joints .",
"Purification and characterization of heterogeneous pluripotent hematopoietic stem cell populations expressing high levels of c - kit receptor . Mouse pluripotent hematopoietic stem cells ( PHSC ) were fractionated based on size and density using counterflow centrifugal elutriation ( CCE ) . These heterogeneous PHSC populations were further enriched by subtraction of cells with lineage - specific markers ( Lin - ) followed by positive sorting for c - kit expression . The cells were characterized for their functional and biochemical properties . We defined a subpopulation of c - kit - positive cells that expressed high numbers of c - kit receptors ( c - kitBR ) . One hundred c - kitBR cells from either low - or higher - density fractions were sufficient to repopulate the lymphohematopoietic system in WBB6F1 - W / Wv ( W / Wv ) recipients , whereas no PHSC were found in cells with low ( c - kitDULL ) or no ( c - kitNEG ) c - kit expression . Lin - c - kitBR cells were separated into RhoDULL and RhoBR subsets based on their ability to efflux rhodamine 123 ( Rho ) . The PHSC were concentrated in Lin - c - kitBR RhoDULL cells and the number of Lin - c - kitBR RhoBR cells correlated directly with the number of day 12 colony - forming unit - spleen ( CFU - P28222 ) in each fraction . We were not able to enrich further for PHSC using monoclonal antibodies to the cell - surface markers AA4 . 1 or P01730 , which have been used by others to isolate PHSC . The small , low - density Lin - c - kitBR subset contained PHSC and few CFU - P28222 . This enabled us to assay PHSC for expression of the flk - 2 gene , which encodes a tyrosine kinase receptor present on fetal liver PHSC . Purified RNA from the low - density Lin - c - kitBR subset did not contain flk - 2 mRNA . We suggest that AA4 . 1 , P01730 and flk - 2 are expressed as stage - specific markers on PHSC in cell cycle .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK43___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK43___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK43___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK43___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK43___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively ."
] |
[
"___MASK12___",
"___MASK15___",
"___MASK43___",
"___MASK53___",
"___MASK55___",
"___MASK59___",
"___MASK66___",
"___MASK68___",
"___MASK81___"
] |
___MASK68___
|
MH_train_483
|
interacts_with DB00624?
|
[
"P10275 targets NFkappaB and TSP1 to suppress prostate tumor growth in vivo . The androgen role in the maintenance of prostate epithelium is subject to conflicting opinions . While androgen ablation drives the regression of normal and cancerous prostate , testosterone may cause both proliferation and apoptosis . Several investigators note decreased proliferation and stronger response to chemotherapy of the prostate cancer cells stably expressing androgen receptor ( AR ) , however no mechanistic explanation was offered . In this paper we demonstrate in vivo anti - tumor effect of the AR on prostate cancer growth and identify its molecular mediators . We analyzed the effect of AR on the tumorigenicity of prostate cancer cells . Unexpectedly , the AR - expressing cells formed tumors in male mice at a much lower rate than the AR - negative controls . Moreover , the AR - expressing tumors showed decreased vascularity and massive apoptosis . AR expression lowered the angiogenic potential of cancer cells , by increasing secretion of an anti - angiogenic protein , thrombospondin - 1 . AR activation caused a decrease in RelA , a subunit of the pro - survival transcription factor NFkappaB , reduced its nuclear localization and transcriptional activity . This , in turn , diminished the expression of its anti - apoptotic targets , Bcl - 2 and P05231 . Increased apoptosis within AR - expressing tumors was likely due to the NFkappaB suppression , since it was restricted to the cells lacking nuclear ( active ) NFkappaB . Thus we for the first time identified combined decrease of NFkappaB and increased TSP1 as molecular events underlying the AR anti - tumor activity in vivo . Our data indicate that intermittent androgen ablation is preferable to continuous withdrawal , a standard treatment for early - stage prostate cancer . ( c ) 2007 Wiley - Liss , Inc .",
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK42___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK42___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"P10275 in nuclei of rat testis . Testis nuclei of hypophysectomized rats selectively accumulate labeled testosterone and 5alpha - dihydrotestosterone following the injection of tritiated testosterone in vivo . DB00624 and 5alpha - dihydrotestosterone are bound to macromolecules in nuclei and can be extracted with 0 . 5 M DB00761 . Accumulation of protein bound radioactive androgens in nuclei of isolated seminiferous tubules is similar to that of whole testis . The relative amounts of testosterone and dihydrotestosterone in purified nuclei were similar to the relative amounts bound to cytoplasmic receptors , suggesting that cytoplasmic androgen - receptor complexes may be transported into the nuclei . Binding of labeled androgen is saturable and inhibited by prior injection of unlabeled testosterone or cyproterone acetate . Nuclear binding sites are destroyed by the proteolytic enzyme pronase , but not by DNase . Like the cytoplasmic androgen - receptor complexes in rat testis , nuclear androgen - protein complexes are heat labile and dissociate slowly at 0 degrees C . androgens fail to accumulate in testis nuclei of the Stanley - Gumbreck androgen insensitive rat , a species lacking cytoplasmic androgen receptors in testis and other androgen target tissues .",
"The androgen axis in recurrent prostate cancer . PURPOSE : Prostate cancer that recurs during androgen deprivation therapy is referred to as androgen - independent . High levels of expression of androgen receptor and androgen receptor - regulated genes in recurrent prostate cancer suggest a role for androgen receptor and its ligands in prostate cancer recurrence . EXPERIMENTAL DESIGN : Recurrent prostate cancer specimens from 22 men whose prostate cancer recurred locally during androgen deprivation therapy and benign prostate specimens from 48 men who had received no prior treatment were studied . P10275 expression was measured using monoclonal antibody and automated digital video image analysis . Tissue androgens were measured using radioimmunoassay . RESULTS : Epithelial nuclei androgen receptor immunostaining in recurrent prostate cancer ( mean optical density , 0 . 284 +/- SD 0 . 115 and percentage positive nuclei , 83 . 7 +/- 11 . 6 ) was similar to benign prostate ( mean optical density , 0 . 315 +/- 0 . 044 and percentage positive nuclei , 77 . 3 +/- 13 . 0 ) . Tissue levels of testosterone were similar in recurrent prostate cancer ( 2 . 78 +/- 2 . 34 pmol / g tissue ) and benign prostate ( 3 . 26 +/- 2 . 66 pmol / g tissue ) . Tissue levels of dihydrotestosterone , dehydroepiandrosterone , and androstenedione were lower ( Wilcoxon , P = 0 . 0000068 , 0 . 00093 , and 0 . 0089 , respectively ) in recurrent prostate cancer than in benign prostate , and mean dihydrotestosterone levels , although reduced , remained 1 . 45 nM . P10275 activation in recurrent prostate cancer was suggested by the androgen - regulated gene product , prostate - specific antigen , at 8 . 80 +/- 10 . 80 nmol / g tissue . CONCLUSIONS : DB00624 and dihydrotestosterone occur in recurrent prostate cancer tissue at levels sufficient to activate androgen receptor . Novel therapies for recurrent prostate cancer should target androgen receptor directly and prevent the formation of androgens within prostate cancer tissue .",
"DB00624 stimulates proliferation and inhibits interleukin - 6 production of normal and hereditary gingival fibromatosis fibroblasts . Hereditary gingival fibromatosis ( P14210 ) is a rare oral condition characterized by a slow and progressive enlargement of the gingiva , involving both the maxilla and mandible . In vitro , P14210 fibroblasts demonstrate a proliferative index significantly higher than fibroblasts from normal gingiva ( NG ) . The objective of this study was to determine the effect of dihydrotestosterone on the proliferation of gingival fibroblasts derived from patients with P14210 ( n = 4 ) and from four healthy individuals . Additionally , we analyzed the effect of dihydrotestosterone on interleukin - 6 ( P05231 ) production and determined the expression levels of androgen receptors in NG and P14210 fibroblasts . Gingival fibroblasts from NG and P14210 were incubated with increasing concentrations of dihydrotestosterone with or without androgen blockers , and cultured for 24 h , and the proliferation index was determined by automated cell counter . P05231 production , in this system , was quantified using a \" capture \" enzyme - linked immunosorbent assay ( ELISA ) . Semi - quantitative reverse transcriptase - polymerase chain reaction ( RT - PCR ) was performed to measure the mRNA expression of androgen receptors . The results indicated that dihydrotestosterone simultaneously downregulates the production of P05231 and upregulates the cell proliferation . DB01216 and cyprosterone acetate , two anti - androgens , partially reversed these effects . P10275 mRNA expression was identified in both NG and P14210 fibroblasts ; however , the levels in NG were higher than those observed in P14210 . These results show that testosterone coordinates the proliferation and production of P05231 of normal and P14210 fibroblasts .",
"___MASK10___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK10___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK10___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK10___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"Increased dihydrotestosterone receptor levels in high - stage renal adenocarcinoma . Primary renal adenocarcinoma tissue , metastatic deposits , and normal kidney parenchyma from 16 patients were assayed for sex hormone receptors by dextran - coated charcoal adsorption and sucrose gradient centrifugation techniques . DB02901 receptors ( P10275 ) were found in all renal carcinomatous tissue ( 20 / 20 ) and in 93 % ( 13 / 14 ) autologous normal kidneys analyzed . DB00624 receptors were found in 84 % ( 16 / 19 ) of tumors and 93 % ( 14 / 15 ) or normal kidneys analyzed . Estrogen receptors in small amounts ( ER ) were detected in only 5 % ( 1 / 19 ) of tumors and in 7 % ( 1 / 15 ) of normal kidneys . Progesterone receptors ( PR ) in low quantities were detected in 30 % ( 6 / 20 ) of renal tumors and in 40 % ( 6 / 15 ) of normal kidneys . P10275 levels in high - stage tumors ( DB00279 , DB00451 ) were significantly elevated over levels in autologous normal kidney , whereas in low - stage tumors localized to the kidney ( T1 and P24752 tumors ) P10275 levels were not significantly different from autologous normal kidney . The mean levels of P10275 in high - stage kidney tumors were significantly elevated over levels in low - stage tumors ( P less than 0 . 001 ) . P10275 estimation in renal neoplasms may help in biologic staging of renal adenocarcinoma and could define a group of patients in whom anti - androgen therapy may be worth a trial .",
"Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1 / 2 pluripotent cells through an androgen receptor - mediated pathway . DB00624 supplementation increases skeletal muscle mass and decreases fat mass ; however , the underlying mechanisms are unknown . We hypothesized that testosterone regulates body composition by promoting the commitment of mesenchymal pluripotent cells into myogenic lineage and inhibiting their differentiation into adipogenic lineage . Mouse C3H 10T1 / 2 pluripotent cells were treated with testosterone ( 0 - 300 nM ) or dihydrotestosterone ( DB02901 , 0 - 30 nM ) for 0 - 14 d , and myogenic conversion was evaluated by immunocytochemical staining for early ( MyoD ) and late ( myosin heavy chain II ; MHC ) myogenic markers and by measurements of MyoD and MHC mRNA and protein . Adipogenic differentiation was assessed by adipocyte counting and by measurements of peroxisomal proliferator - activated receptor gamma 2 ( Q07869 gamma 2 ) mRNA and Q07869 gamma 2 protein and CCAAT / enhancer binding protein alpha . The number of MyoD + myogenic cells and MHC + myotubes and MyoD and MHC mRNA and protein levels increased dose dependently in response to testosterone and DB02901 treatment . Both testosterone and DB02901 decreased the number of adipocytes and down - regulated the expression of Q07869 gamma 2 mRNA and Q07869 gamma 2 protein and CCAAT / enhancer binding protein alpha . P10275 mRNA and protein levels were low at baseline but increased after testosterone or DB02901 treatment . The effects of testosterone and DB02901 on myogenesis and adipogenesis were blocked by bicalutamide . Therefore , testosterone and DB02901 regulate lineage determination in mesenchymal pluripotent cells by promoting their commitment to the myogenic lineage and inhibiting their differentiation into the adipogenic lineage through an androgen receptor - mediated pathway . The observation that differentiation of pluripotent cells is androgen dependent provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass in men .",
"Serum testosterone plays an important role in the metastatic ability of castration resistant prostate cancer . PURPOSE : Prostate cells are dependent on androgens for growth and proliferation . Androgen deprivation therapy is the recommended treatment for advanced / metastatic prostate cancer . Under this therapy , prostate cancer will inevitably progress to castration resistant prostate cancer ( CRPC ) . Despite putative castration resistance , testosterone might still play a crucial role in the progression of CRPC . The goal of this study was to determine the role of testosterone in the formation of metastases of CRPC in both in vitro and in vivo settings . METHODS : In vitro , the effect of testosterone and the non - aromatizable androgen methyltrienolone on migration , invasion and proliferation of a castration - resistant prostate cancer rat cell line ( Dunning R3327 - MATLyLu ) was assessed using a transwell assay and a sulforhodamine B assay and immunohistochemical detection of ki67 . P10275 status was determined using Western blot . In vivo , Copenhagen rats were divided in four groups ( males , females , castrated males and females with testosterone suppletion ) and inoculated with MATLyLu cells . Tumor size was assessed daily . RESULTS : DB00624 increased cell migration and invasion in a concentration - dependent manner in vitro . DB00624 did not affect in vitro cell proliferation . No difference was shown between the effect of testosterone and methyltrienolone . In vivo , in groups with higher levels of circulating testosterone , more rats had ( micro ) metastases compared with groups with low levels of testosterone . No effect was observed on primary tumor size / growth . CONCLUSIONS : Despite assumed castration resistance , progression of prostate cancer is still influenced by androgens . Therefore , continuous suppression of serum testosterone in patients who show disease progression during castration therapy is still warranted .",
"P10275 is responsible for rat organic cation transporter 2 gene regulation but not for rOCT1 and rOCT3 . PURPOSE : Organic cation transporters 1 - 3 ( OCT1 - 3 ; Slc22a1 - 3 ) mediate the membrane transport of organic cations in the kidney . We previously reported that rat ( r ) OCT2 expression in the kidney was regulated by testosterone . In this study , we examined the transcriptional mechanisms underlying the testosterone - dependent regulation of rOCT2 expression . METHODS : Approximately 3000 - bp fragments of the rOCT1 - 3 promoter region were isolated , and promoter activities were measured in the renal epithelial cell line LLC - P30613 with the coexpression of rat androgen receptor . RESULTS : Among reporter constructs tested , only rOCT2 promoter activity was stimulated by testosterone . This stimulation was suppressed by nilutamide , an antiandrogen drug . Reporter assays using deletion constructs and mutational constructs of putative androgen response elements ( ARE ) in the rOCT2 promoter region suggested that two AREs , located at approximately - 3000 and - 1300 , respectively , play an important role in the induction by testosterone . CONCLUSIONS : DB00624 induces the expression of rOCT2 , but not of rOCT1 and rOCT3 , via the AR - mediated transcriptional pathway . This is the first study to address the transcriptional mechanisms of testosterone - dependent gene regulation of the Slc22 family .",
"Constitutive NF - kappaB activation confers interleukin 6 ( P05231 ) independence and resistance to dexamethasone and Janus kinase inhibitor ___MASK10___ in murine plasmacytoma cells . Myeloma cells are dependent on P05231 for their survival and proliferation during the early stages of disease , and independence from P05231 is associated with disease progression . The role of the NF - κB pathway in the P05231 - independent growth of myeloma cells has not been studied . Because human herpesvirus 8 - encoded P13646 selectively activates the NF - κB pathway , we have used it as a molecular tool to examine the ability of the NF - κB pathway to confer P05231 independence on murine plasmacytomas . We demonstrated that ectopic expression of P13646 , but not its NF - κB - defective mutant or a structural homolog , protected plasmacytomas against P05231 withdrawal - induced apoptosis and resulted in emergence of P05231 - independent clones that could proliferate long - term in vitro in the absence of P05231 and form abdominal plasmacytomas with visceral involvement when injected intraperitoneally into syngeneic mice . These P05231 - independent clones were dependent on NF - κB activity for their survival and proliferation but were resistant to dexamethasone and ___MASK10___ , a selective P23458 / 2 inhibitor . Ectopic expression of human T cell leukemia virus 1 - encoded Tax protein , which resembles P13646 in inducing constitutive NF - κB activation , similarly protected plasmacytoma cells against P05231 withdrawal - induced apoptosis . Although P13646 is known to up - regulate P05231 gene expression , its protective effect was not due to induction of endogenous P05231 production but instead was associated with sustained expression of several antiapoptotic members of the Bcl2 family upon P05231 withdrawal . Collectively , these results demonstrate that NF - κB activation can not only promote the emergence of P05231 independence during myeloma progression but can also confer resistance to dexamethasone and ___MASK10___ .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK20___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"Functional analysis of discoidin domain receptor 2 in synovial fibroblasts in rheumatoid arthritis . In order to know whether any protein tyrosine kinase ( PTK ) is involved in the over - proliferation and erosiveness of synovial fibroblasts ( SF ) of rheumatoid arthritis ( RA ) patients , RT - PCR and RNA dot blotting were done to analyse PTKs profile in RA SF . Platelet - derived growth factor receptor A ( P16234 ) , insulin - like growth factor 1 receptor ( IGF - 1R ) , P23458 ( P23458 ) , P29597 , discoidin domain receptor 2 ( Q16832 ) , and Lyn were expressed in SF , and the expression of P16234 , IGF - 1R , and Q16832 in SF of RA were higher than that of osteoarthritis ( OA , as control ) . Immunoblotting and gelatinase zymography showed that Q16832 in RA SF , which still secreted active matrix metalloproteinase 1 ( P03956 ) in vitro , were in active form . Stimulation of collagen II could make NIH - 3T3 cells ( as control ) produce P03956 , which could be inhibited by soluble extracellular part of Q16832 . These results indicated that the over - expression of P03956 in RA SF might be related to the activation of Q16832 , and collagen II , act as Q16832 ligand , might be one of the stimulators of the over - expression of P03956 of RA SF .",
"Broadening of transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model to represent late stage androgen depletion independent cancer . BACKGROUND : The transgenic adenocarcinoma of the mouse prostate ( TRAMP ) model closely mimics PC - progression as it occurs in humans . However , the timing of disease incidence and progression ( especially late stage ) makes it logistically difficult to conduct experiments synchronously and economically . The development and characterization of androgen depletion independent ( ADI ) TRAMP sublines are reported . METHODS : Sublines were derived from androgen - sensitive TRAMP - C1 and TRAMP - P06681 cell lines by androgen deprivation in vitro and in vivo . Epithelial origin ( cytokeratin ) and expression of late stage biomarkers ( P12830 and KAI - 1 ) were evaluated using immunohistochemistry . P10275 ( AR ) status was assessed through quantitative real time PCR , Western blotting , and immunohistochemistry . Coexpression of AR and P12830 was also evaluated . Clonogenicity and invasive potential were measured by soft agar and matrigel invasion assays . Proliferation / survival of sublines in response to androgen was assessed by WST - 1 assay . In vivo growth of subcutaneous tumors was assessed in castrated and sham - castrated C57BL / 6 mice . RESULTS : The sublines were epithelial and displayed ADI in vitro and in vivo . Compared to the parental lines , these showed ( 1 ) significantly faster growth rates in vitro and in vivo independent of androgen depletion , ( 2 ) greater tumorigenic , and invasive potential in vitro . All showed substantial downregulation in expression levels of tumor suppressor , P12830 , and metastatis suppressor , KAI - 1 . Interestingly , the percentage of cells expressing AR with downregulated P12830 was higher in ADI cells , suggesting a possible interaction between the two pathways . CONCLUSIONS : The TRAMP model now encompasses ADI sublines potentially representing different phenotypes with increased tumorigenicity and invasiveness .",
"P10275 - immunoreactive cells in ram hypothalamus : distribution and co - localization patterns with gonadotropin - releasing hormone , somatostatin and tyrosine hydroxylase . DB00624 exerts important feedback effects on the hypothalamus of the ram to influence reproductive functioning . To provide a neuroanatomical basis for understanding this androgen action , the present study has examined androgen receptor ( AR ) immunoreactivity within the hypothalamus and adjacent brain areas of the intact non - breeding season ram . The largest populations of AR - immunoreactive cells were detected in the medial preoptic area , infundibular and premammillary nuclei in addition to the ventromedial nucleus ( VMN ) where cells were found distributed throughout its medial and lateral divisions . Smaller numbers of AR - expressing cells were identified in the bed nucleus of the stria terminalis and anterior hypothalamic area ( DB00551 ) including the paraventricular , but not the supraoptic , nucleus . Double - labelling immunocytochemistry revealed the presence of AR immunoreactivity in only 2 of 460 gonadotropin - releasing hormone ( DB00644 ) neurons . A very small population of TH - immunoreactive cells located in the lateral aspect of the DB00551 was found to contain ARs . Dopaminergic cells elsewhere in the hypothalamus , including the infundibular nucleus , did not display AR immunoreactivity . Nearly 50 % of AR - expressing cells in the lateral VMN were immunoreactive for somatostatin while less than 5 % of periventricular somatostatin neurons displayed AR immunoreactivity . These results show where ARs are expressed in the ram hypothalamus and indicate the neuroanatomical sites at which androgen may act to influence reproductive function . The absence of ARs in the neuroendocrine DB00644 and tuberoinfundibular dopaminergic cells suggests that androgens do not influence the genome of these cells in any direct manner . In contrast , the somatostatin neurons of the VMN appear to be an important target for circulating androgens in the non - breeding season ram .",
"P10275 in human placental villi . In studies with a synthetic androgen , R 1881 , an androgen - binding component was found in the cytosol of human placental villi . Kinetic analysis indicated that the Kd value of this component was 1 . 4 nM at 0 - 4 degrees C and that binding of R 1881 amounted to 277 +/- 73 fmol / mg protein . glycerol density gradient ultracentrifugation showed a peak of binding activity in the 8S region in a medium of low ionic strength , but in the 4 . 5S region in a medium containing 9 . 5 M DB00761 . The R 1881 - binding component was inactivated by mild heat - or trypsin - treatment , but not by treatment with DNase or RNase . Most of the R 1881 - binding activity was sedimented at 20 to 40 % saturation of ammonium sulfate . These findings indicate that the R 1881 - binding component in human placental cytosol is quite similar in its characteristics to androgen receptors , which are present in various androgen - responsive organs . DB00624 was a more potent competitor of R 1881 - binding than DB02901 or cyproterone acetate . Scatchard plots indicated that the binding site of testosterone was identical with that of R 1881 . These findings suggest that the androgen receptor in placental cytosol is specific for testosterone . The Kd value for testosterone was calculated to be 3 . 2 nM .",
"Androgens and metabolic syndrome : lessons from androgen receptor knock out ( ARKO ) mice . DB00624 ( T ) is an important factor for determining body composition in males . Abdominal obesity is inversely correlated with serum T levels in men , leading to greater mortality . Pathologically hypogonadal men also have a significantly higher fat mass , which is reversed by T administration . However , the mechanism for such anti - obesity effect of androgen has not been well clarified . P10275 ( AR ) null male mice revealed late - onset obesity . Male ARKO mice were euphagic compared to the wild - type male controls , but also less dynamic and less oxygen consuming . Transcript profiling indicated that male ARKO mice had lower transcripts for the thermogenetic uncoupling protein 1 ( P25874 ) . We also found enhanced secretion of adiponectin , which is insulin - sensitizing , from adipose tissue in comparison to wild type , which might partly explain why the overall insulin sensitivity of male ARKO mice remained almost intact despite their apparent obesity . In addition , decreased lipolysis rather than increased lipid synthesis was observed , which might also account for the increased adiposity in male ARKO mice . The results revealed that AR plays important roles in male metabolism by affecting the energy balance , and is negative to both adiposity and insulin sensitivity .",
"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .",
"DB00624 potentiates the hypoxic ventilatory response of adult male rats subjected to neonatal stress . Neonatal stress disrupts development of homeostatic systems . During adulthood , male rats subjected to neonatal maternal separation ( Q5H8A3 ) are hypertensive and show a larger hypoxic ventilatory response ( HVR ) , with greater respiratory instability during sleep . Neonatal stress also affects sex hormone secretion ; hypoxia increases circulating testosterone of Q5H8A3 ( but not control ) male rats . Given that these effects of Q5H8A3 are not observed in females , we tested the hypothesis that testosterone elevation is necessary for the stress - related increase of the HVR in adult male rats . Pups subjected to Q5H8A3 were placed in an incubator for 3 h per day from postnatal day 3 to 12 . Control pups remained undisturbed . Rats were reared until adulthood , and the HVR was measured by plethysmography ( fractional inspired O2 = 0 . 12 , for 20 min ) . We used gonadectomy to evaluate the effects of reducing testosterone on the HVR . Gonadectomy had no effect on the HVR of control animals but reduced that of Q5H8A3 animals below control levels . Immunohistochemistry was used to quantify androgen receptors in brainstem areas involved in the HVR . P10275 expression was generally greater in Q5H8A3 rats than in control rats ; the most significant increase was noted in the caudal region of the nucleus tractus solitarii . We conclude that the abnormal regulation of testosterone is important in stress - related augmentation of the HVR . The greater number of androgen receptors within the brainstem may explain why Q5H8A3 rats are more sensitive to testosterone withdrawal . Based on the similarities of the cardiorespiratory phenotype of Q5H8A3 rats and patients suffering from sleep - disordered breathing , these results provide new insight into its pathophysiology , especially sex - based differences in its prevalence .",
"Effects of peroxisome proliferator - activated receptor ligands , bezafibrate and fenofibrate , on adiponectin level . OBJECTIVE : Q15848 is adipose - specific secretory protein and acts as anti - diabetic and anti - atherosclerotic molecule . We previously found peroxisome proliferators response element in adiponectin promoter region , suggesting that peroxisome proliferator - activated receptor ( Q07869 ) ligands elevate adiponectin . Fibrates are known to be PPARalpha ligands and were shown to reduce risks of diabetes and cardiovascular disease . Effect of fibrates on adiponectin has not been clarified , whereas thiazolidinediones enhance adiponectin . Thus , we explored the possibility and mechanism that fibrates enhance adiponectin in humans , mice , and cells . METHODS AND RESULTS : Significant increase of serum adiponectin was observed in bezafibrate - treated subjects compared with placebo group in patients enrolled in The ___MASK61___ Infarction Prevention study . Higher baseline adiponectin levels were strongly associated with reduced risk of new diabetes . Fibrates , bezafibrate and fenofibrate , significantly elevated adiponectin levels in wild - type mice and 3T3 - Q9NUQ9 adipocytes . Such an effect was not observed in PPARalpha - deficient mice and adipocytes . Fibrates activated adiponectin promoter but failed to enhance its activity when the point mutation occurred in peroxisome proliferators response element site and the endogenous PPARalpha was knocked down by PPARalpha - RNAi . CONCLUSIONS : Our results suggest that fibrates enhance adiponectin partly through adipose PPARalpha and measurement of adiponectin might be a useful tool for searching subjects at high risk for diabetes .",
"Pubertal maturation is associated with an increase in the number of androgen receptor - immunoreactive cells in the brains of male ferrets . P10275 - immunoreactive ( AR - IR ) cells were identified in brains of male ferrets before and after the onset of pubertal maturation . There was a greater number of AR - IR cells after the onset of pubertal maturation in some , but not all , brain regions examined . Regions in which the number of AR - IR cells increased included the preoptic area and the amygdala , areas known to be involved in the control of male reproductive behaviors . The mechanisms responsible for the increase in AR - IR cells are unknown , but might be related to the higher circulating levels of testosterone that were present in the older animals . DB00624 may increase androgen receptor ( AR ) immunoreactivity both by concentrating already existing ARs within the nucleus and by stimulating de novo synthesis of receptor protein .",
"Androgen Receptor Enhances p27 Degradation in Prostate Cancer Cells through Rapid and Selective Q53ET0 Activation . P10275 ( AR ) plays a central role in prostate cancer ( PCa ) growth , with androgen deprivation or AR down - regulation causing cell - cycle arrest and accumulation of the p27 cyclin - dependent kinase inhibitor . The molecular basis for this AR regulation of cell - cycle progression remains unclear . Here we demonstrate that androgen can rapidly reduce p27 protein in PCa cells by increasing its proteasome - mediated degradation . This rapid androgen - stimulated p27 degradation was mediated by AKT through the phosphorylation of p27 T157 . Significantly , androgen increased Q53ET0 - mediated AKT S473 phosphorylation without affecting the PDK1 - mediated AKT T308 phosphorylation or Q6UUV9 activity . The Q53ET0 activation was further supported by enhanced P42345 / Q6R327 association and increased phosphorylation of additional Q53ET0 substrates , O00141 and PKCα . The androgen - stimulated nuclear translocation of AR was associated with markedly - increased nuclear Q9BPZ7 , a critical component of Q53ET0 . Finally , the androgen - mediated Q53ET0 / AKT activation targets a subset of AKT substrates including p27 and Q12778 , but not Q96B36 . This study reveals a pathway linking AR to a selective activation of Q53ET0 , the subsequent activation of AKT , and phosphorylation of a discrete set of AKT substrates that regulate cellular proliferation and survival . These findings establish that Q53ET0 can function as a central regulator of growth in response to signals that are distinct from those regulating Q6UUV9 , and support efforts to target Q53ET0 for cancer therapy .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"DB00624 inhibits matrix metalloproteinase - 1 production in human endometrial stromal cells in vitro . P10275 ( AR ) is reported to be expressed in human uterine endometrium , but not much information is available on the role of androgens in human endometrium . The purpose of this study is to investigate the role of androgens in the regulation of matrix metalloproteinase ( MMP ) - 1 , which is one of the important MMPs for menstruation and embryo implantation in human endometrium . Human endometrial stromal cells ( HESCs ) were obtained from human endometrium by enzymatic dissociation method . Purified HESCs were incubated with 17beta - estradiol ( E2 ) , testosterone , or E2 + testosterone . Progestins ( natural progesterone or medroxyprogesterone acetate ) or vehicle ( dimethyl sulfoxide ) were also added to the media instead of testosterone . Furthermore , hydroxyflutamide ( FLU ), a specific AR antagonist , was also supplemented to cultured media . The amounts of P03956 in cultured media and in HESC lysates were examined by ELISA measurements and western blotting analysis respectively . The expression of ARmRNA in HESCs RNA was analyzed by RT - PCR . DB00624 significantly inhibited P03956 in both cultured media and cell lysates in a dose - dependent manner . Progestins also inhibited P03956 . Furthermore , FLU completely recovered the decrease of P03956 induced by testosterone . ARmRNA was detected in all HESCs RNA . The present study demonstrated that the secretion and production of P03956 in HESCs in vitro were inhibited by testosterone through androgen receptors in a manner similar to that seen for progesterone . These findings indicate that androgen may play an important role in morphological and functional changes of human endometrium .",
"P10275 dependent and independent activities of testosterone on hepatic microsomal drug metabolism . Administration of testosterone for 6 days to intact female and castrate male BALB / cJ mice stimulated hepatic microsomal ethylmorphine N - demethylase activity and cytochrome P - 450 content by 50 - 75 % . DB00624 also stimulated hepatic microsomal NADPH - oxidase activity , but to a lesser degree . To probe the mechanism of this effect of androgens , two antiandrogens ( cyproterone acetate and flutamide ) were employed . Since cyproterone acetate was a potent stimulator of hepatic microsomal ethylmorphine N - demethylase activity and cytochrome P - 450 content , no antiandrogenic activity of this steroid could be detected . By contrast , flutamide alone had little effect on either ethylmorphine N - demethylase activity or cytochrome P - 450 content . However , this drug effectively blocked the stimulatory effects of testosterone on ethylmorphine N - demethylase activity and cytochrome P - 450 content but not on NADPH - oxidase activity . This effect was not species specific , since flutamide also prevented androgen stimulation of ethylmorphine metabolism in adult castrate and prepubertal male Fisher rats . The testosterone - induced increase of hepatic weight and microsomal protein content was not affected by the administration of flutamide . The observations are consistent with the hypothesis that androgens have two distinct effects on the liver . First , testosterone may act as a general , nonspecific stimulant of liver weight and microsomal protein content which is independent of the androgen receptor . Secondly , testosterone action in the liver may be expressed via an androgen - specific or androgen receptor - dependent mechanism which controls , in part , the cytochrome P - 450 - dependent demethylase system .",
"P10275 signaling induced by supraphysiological doses of dihydrotestosterone in human peripheral blood lymphocytes . Anabolic androgenic steroids , a class of steroid hormones related to testosterone , are natural ligands of androgen receptor ( AR ) , a member of the nuclear receptor superfamily of ligand - activated transcription factors . AR binds specific DNA elements , known as androgen - response elements . DB00624 , the main male sexual hormone , binds AR directly and indirectly , through conversion into dihydrotestosterone ( DB02901 ) , its more active metabolite . Anabolic androgenic steroids are frequently detected in the urine of doped athletes ; their consumption is also growing among sport amateurs and adolescents . The effects of androgens can differ depending on the target cells and / or tissues . To gain insight into transcription activation mechanisms of AR , we investigated AR protein signaling in human peripheral blood lymphocytes treated with supraphysiological doses of DB02901 . We performed a comparative proteomic analysis and we identified about 30 differentially expressed proteins . At least five species contained a consensus androgen - response elements sequence in the promoter region of related coding genes . The analysis also revealed that high doses of DB02901 activate the drug detoxification process , could stimulate an increase in cell motility and exert a prosurvival effect rather than an apoptotic one .",
"Altered levels of angiopoietin 1 and tie 2 are associated with androgen - regulated vascular regression and growth in the ventral prostate in adult mice and rats . The involution of the rat ventral prostate gland after castration could be caused by primary changes in the vasculature . To explore the mechanisms , we studied the effects of castration and testosterone treatment on the vasculature in the ventral prostate in adult rats and mice . P10275 expression , vascular morphology , and the expression of angiopoietin ( ang ) 1 and 2 and their receptor tie 2 were examined 1 , 3 , and 7 d after castration and after testosterone treatment of castrated animals using stereological methods , immunohistochemistry , laser capture microdissection , and Western blotting . One day after castration , the percentage of blood vessels covered with smooth muscle actin , endothelial cell proliferation , and vascular volume had decreased , whereas endothelial cell apoptosis had increased . Simultaneously , ang 1 and tie 2 protein levels decreased . Nuclear expression of androgen receptor was observed not only in glandular and stroma smooth muscle cells but also in the mural cells of prostate arteries and veins and was markedly down - regulated already 1 d after castration . DB00624 administration of castrated mice and rats reversed all the observed effects . At the mRNA level , tie 2 was exclusively , but ang 1 predominantly , expressed in the stroma , compared with the epithelial compartment . Local delivery of soluble tie 2 during testosterone - stimulated growth , inhibited vascular maturation and increased vascular volume and leukocyte infiltration compared with controls . We conclude that androgens may regulate the prostate vasculature by direct effects on mural vascular cells and by influencing the secretion of the angiopoietins , in above all , the stroma cells .",
"P10275 in Sertoli cells is not required for testosterone - induced suppression of spermatogenesis , but contributes to Sertoli cell organization in Utp14b jsd mice . DB00624 acting through the androgen receptor ( AR ) maintains the arrest of spermatogonial differentiation in juvenile spermatogonial depletion ( jsd mutation in the Utp14b gene ) mutant adult male mice . It is not known which of the somatic cell types expressing AR mediates this inhibition . To determine whether Sertoli cells are responsible , we selectively eliminated AR in Sertoli cells in jsd mice containing a floxed - Ar gene and an anti - Müllerian hormone - Cre transgene . In these Sertoli AR - knockout ( SCARKO ) - jsd mice , spermatogonial differentiation did not recover . However , the normal organization of Sertoli cell nuclei was drastically disrupted in SCARKO - jsd mice compared with SCARKO or jsd mice . In addition , the extent of ectoplasmic specializations was reduced ; tight junctions were not found ; vinculin , an anchoring protein found in ectoplasmic specializations , became uniformly distributed in the cytoplasm ; and the adult Sertoli cells showed excess heterochromatin subjacent to their nuclear envelope . Despite the abnormalities in Sertoli cells in SCARKO - jsd mice , global suppression of testosterone action and levels was still effective in restoring the differentiated germ cells , and this was accompanied by an improved arrangement of Sertoli cell nuclei . We conclude that Sertoli cells are not targets for the testosterone - mediated inhibition of spermatogonial differentiation in jsd mice , and that both AR in Sertoli cells and the presence of differentiated germ cells contribute to maintaining the organization of Sertoli cells within the seminiferous tubules .",
"P10275 ( CAG ) n polymorphism and androgen levels in women with systemic lupus erythematosus and healthy controls . Systemic lupus erythematosus ( SLE ) is an autoimmune disorder that affects mainly females . Therefore , interrelations between the reproductive and immune system have been assumed . Considering the complex influence of hormones and receptors , we aimed to investigate the influence of androgens and androgen receptor ( AR ) polymorphism in women with SLE . One hundred and sixteen patients and 44 healthy women were investigated . DB00624 , sex hormone - binding globulin ( P04278 ) , dehydroepiandrosterone - sulphate ( DHEAS ) concentrations and AR ( CAG ) n polymorphism were determined . SLE patients had significantly lower levels of total and free testosterone and DHEAS in comparison with the controls . No differences in the CAG repeat length between the groups were established . Women with two alleles carrying more than 22 CAG repeats had significantly higher levels of P04278 ( 101 . 51 ± 61 . 81 vs . 69 . 22 ± 45 . 93 nmol / l , p = 0 . 015 ) and DHEAS ( 3 . 11 ± 2 . 65 vs . 2 . 11 ± 3 . 06 μmol / l , p = 0 . 007 ) and a tendency to higher testosterone concentrations ( 2 . 35 ± 2 . 10 vs . 1 . 71 ± 1 . 70 nmol / l , p = 0 . 056 ) in comparison with other women . The CAG repeat length in the relatively longer ( CAG ) n allele was inversely related to the Systemic Lupus International Collaborating Clinics / P10323 index ( r = - 0 . 258 , p = 0 . 009 ) . In conclusion , the androgen receptor ( CAG ) n polymorphism is not related to the development of SLE , but it could modulate the severity of the lupus chronic damages as well as the androgen levels in women .",
"P10275 in human skin cytosol . Human skin , an accessible tissue , is an androgen target organ . We have measured the androgen - binding capacity of human skin cytosol using either 5 alpha [ 3H ] dihydrotestosterone ( [ 3H ] DB02901 ) or [ 3H ] methyltrienolone ( [ 3H ] R - 1881 ) as ligand . Samples were incubated for 20 h at 0 C , and dextran - coated charcoal was used to separate bound from free steroids . The androgen receptor has a high affinity for both ligands ( 0 . 23 +/- 0 . 04 nM for [ 3H ] DB02901 ; 0 . 32 +/- 0 . 16 nM for [ 3H ] R - 1881 ) . DB00624 , cyproterone acetate , and , to a lesser extent , estradiol also bind this protein . Progesterone displaces R - 1881 from its binding sites , whereas its 5 alpha - reduced metabolite somewhat inhibits DB02901 binding . The highest binding capacity is measured in cytosol of skin from external genitalia ( 129 . 14 +/- 58 . 0 fmol / g skin ; n = 34 ) ; it is lower in pubic skin ( 21 . 8 +/- 13 fmol / g skin ; n = 6 ) . There is no variation as a function of age or sex in genital skin ; the higher concentrations observed in the cytosol of pubic skin of women compared to that of men are probably related to lower levels of endogenous steroids . Whereas most patients with the complete form of the testicular feminization syndrome do not have detectable concentrations of androgen receptor , one patient with apparent complete clinical androgen insensitivity had a normal androgen - binding capacity . The parity of values in genital skin from men and women , the absence of variation with age , and the presence of a cytosolic androgen receptor in some androgen - insensitive patients suggest that the androgen receptor in human skin cytosol is not regulated by androgens .",
"Androgen receptors . DB00624 and its active metabolite dihydrotestosterone exert their influence on target cells through a specific intracellular protein receptor . Structural abnormalities of this receptor lead to a diminished androgen action within the cell and result in the syndrome of androgen insensitivity . Androgen insensitivity is classified on the basis of whether the insensitivity is complete or partial and whether the androgen receptor is normally present ( AR (+) ) , absent ( AR (-) ) or diminished ( AR (+/-) ) . All patients with androgen insensitivity have normal or high plasma levels of testosterone and elevated serum LH . Patients with complete androgen insensitivity are phenotypically female . The clinical presentation of partial androgen insensitivity is variable , ranging from a minimal amount of virilization to a completely masculine appearance . All patients described with a syndrome of androgen insensitivity are infertile . The influence of androgen receptor function in the pathogenesis of benign prostatic hypertrophy is being investigated . P10275 content is also being studied as a possible marker of responsiveness to hormonal therapy in prostatic carcinoma .",
"P10275 is essential for sexual differentiation of responses to olfactory cues in mice . During sexual differentiation males and females are exposed to different levels of testosterone , which promotes sex differences in the adult brain and in behavior . DB00624 can act after aromatization or reduction via a number of steroid hormone receptors . Here we provide new evidence that the androgen receptor ( AR ) is essential for sexual differentiation in mice . We used mice carrying the testicular feminization ( Tfm ) mutation of the AR . Adult Tfm males , wild - type male and female littermates were gonadectomized and given subcutaneous estradiol implants . In all sexually dimorphic traits , Tfm males had responses equivalent to females and different from males . In simultaneous choice tests , males spent significantly more time investigating female - soiled bedding , whereas females and Tfm males preferred to investigate male - soiled bedding . Tfm males and females did not have a partner preference in tests with awake stimulus animals , whereas males showed a preference for females over males . Exposure to male - soiled , but not clean , bedding produced a significant increase in c - Fos - immunoreactive cells in the medial preoptic area and bed nucleus of the stria terminalis in Tfm males and females , no increase was noted in males . Masculine sexual behavior ( mounting and thrusting ) was not sexually dimorphic , and all groups displayed these behaviors . Our results support data collected in humans suggesting a role for the androgen receptor in sexual differentiation of social preferences and neural responses to pheromones .",
"The effectiveness of lurasidone as an adjunct to lithium or divalproex in the treatment of bipolar disorder . The majority of patients with bipolar disorder spend a lot of time in depressive episodes that impose a great burden on patients , caregivers , and society and accounts for the largest part of the morbidity - mortality of the illness . ___MASK1___ is an atypical antipsychotic with a potent binding affinity as antagonist for D2 , 5 - Q13049 , P34969 , and partial agonist at P08908 receptors . Affinity for other receptors as H1 and muscarinic were negligible . ___MASK1___ was approved in 2010 for the treatment of schizophrenia and recently , 2013 , for bipolar depression in monotherapy and an adjunct to lithium or valproate . Clinical trials have established that lurasidone adjuvant to lithium or valproate has more efficacy than the placebo and is associated with minimal weight gain and no clinically meaningful alterations in glucose , lipids , or the QT interval . Additional studies are desirable to know the clinical profile of lurasidone in long - term treatment , in patients with bipolar II disorders , and versus other antipsychotic agents .",
"In utero and lactational exposure to 2 , 3 , 7 , 8 - tetrachlorodibenzo - p - dioxin alters postnatal development of seminal vesicle epithelium . 2 , 3 , 7 , 8 - Tetrachlorodibenzo - p - dioxin ( TCDD ) has been shown to alter male reproductive development of laboratory animals through in utero and lactational exposure . As a result of exposure , the accessory glands of the male reproductive tract , including the seminal vesicle , are decreased in size as determined by total weight of the tissue . Analysis of seminal vesicle weights over time suggests that the changes may be transient . Administration of 1 . 0 microg / kg TCDD during gestation caused a significant decrease in seminal vesicle weights of offspring 8 - 11 months of age . We examined the effects of TCDD on seminal vesicles from rats exposed in utero and lactationally . Pregnant Long Evans rats were gavaged on gestation day 15 with 1 . 0 microg / kg TCDD in corn oil . Male pups were euthanized and necropsied on postnatal days ( P01160 ) 15 , 25 , 32 , 49 , 63 , and 120 . Seminal vesicles were weighed and then fixed in 10 % neutral buffered formalin and processed for microscopic examination . Seminal vesicle weights were not significantly decreased until P01160 32 . P10275 mRNA expression in P01160 25 seminal vesicles was not different from control . In the present study , TCDD exposure decreased seminal vesicle epithelial branching and differentiation . Control epithelial cells had tall columnar morphology with relatively abundant cytoplasm , whereas TCDD - treated cells had rounded nuclei and less cytoplasm . In addition , immunolocalization of proliferating nuclear antigen was confined to undifferentiated basal epithelial cells of controls but was found in both basal and luminal cells of the treated seminal vesicle . Results indicate that the TCDD - induced impaired growth of the rat seminal vesicles is associated with a dramatic decrease in the development of the epithelium .",
"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .",
"p62 links β - adrenergic input to mitochondrial function and thermogenesis . The scaffold protein p62 ( sequestosome 1 ; Q13501 ) is an emerging key molecular link among the metabolic , immune , and proliferative processes of the cell . Here , we report that adipocyte - specific , but not CNS - , liver - , muscle - , or myeloid - specific p62 - deficient mice are obese and exhibit a decreased metabolic rate caused by impaired nonshivering thermogenesis . Our results show that p62 regulates energy metabolism via control of mitochondrial function in brown adipose tissue ( Q14032 ) . Accordingly , adipocyte - specific p62 deficiency led to impaired mitochondrial function , causing Q14032 to become unresponsive to β - adrenergic stimuli . Ablation of p62 leads to decreased activation of p38 targets , affecting signaling molecules that control mitochondrial function , such as P15336 , CREB , PGC1α , Q92813 , NRF1 , CYTC , P35354 , ATP5β , and P25874 . p62 ablation in HIB1B and Q14032 primary cells demonstrated that p62 controls thermogenesis in a cell - autonomous manner , independently of brown adipocyte development or differentiation . Together , our data identify p62 as a novel regulator of mitochondrial function and brown fat thermogenesis .",
"P06401 level as a predictor of response to megestrol acetate in advanced breast cancer : a retrospective study . ___MASK16___ ( 160 mg / day ) produced a response rate of 44 % in a retrospective series of 39 evaluable patients with advanced breast cancer . The estrogen - receptor ( ER ) level was greater than 10 fmols / mg of protein in 28 patients , and the progesterone - receptor ( PR ) level was greater than 10 fmols / mg of protein in 26 patients . ER and PR levels , age , and disease - free interval were analyzed for their relationship to response . The PR was the single best predictor of response to megestrol acetate ; the addition of ER added 2 % to the predictive accuracy rate of PR alone .",
"P10275 promotes the migration and invasion of upper urinary tract urothelial carcinoma cells through the upregulation of P14780 and P35354 . Dysregulated androgen receptor ( AR ) signaling is implicated in several types of tumor , including carcinomas of the prostate , breast , liver and bladder . However , the contribution of AR to the progression of upper urinary tract urothelial carcinomas ( UUTUC ) has not been fully investigated . In the present study , we demonstrated that the AR is involved in the metastasis and invasiveness of UUTUC cells . We investigated the role of the AR in UUTUC by using UUTUC - derived BFTC 909 cells . The overexpression of AR promotes the migration and invasion of BFTC 909 cells . Expression of migration / invasion - related genes was increased in BFTC 909 cells overexpressing AR determined by qPCR and western blot analyses . The results showed that AR - enhanced migration and invasion of UUTUC cells are linked to the upregulation of the matrix - degrading enzyme P14780 and cyclooxygenase ( P36551 ) - 2 . Subsequently , the blocking of P14780 and P35354 signaling by inhibitors suppressed AR - enhanced cell migration and invasion . The results of the present study provide evidence for the first time of the role of AR in the motility and invasion of UUT cancer cells and support the hypothesis that the AR may play a critical role in the establishment of the invasive phenotype in urothelial neoplasia of UUT . Thus , the AR may also serve as a novel biomarker and potential therapeutic target for UUT cancer .",
"D - DB00128 implication in the modulation of frog brain sex steroid levels . There is evidence that D - aspartate ( D - DB00128 ) modulates sex hormone levels in frog testis by regulating the activity of P450 aromatase ( P450 aro ) , the key enzyme which converts DB00624 ( T ) in 17ß - Estradiol ( E2 ) . Here we report , for the first time , that there is a direct correlation among brain levels of D - DB00128 , P450 aro , E2 and Estradiol Receptor ( ERα ) in the male frogs during the reproductive as well as the post - reproductive phases of the breeding cycle , with highest levels being observed in the post - reproductive period . D - DB00128 i . p . administration to frogs ready for reproduction , induced an increase of brain P450 aro protein expression with concomitant enhancement of both E2 levels and ERα expression ; at the same time , brain T levels and P10275 expression decreased . In contrast , in the post - reproductive frogs , D - DB00128 treatment did not modify any of these parameters . Taken together , these results imply that the regulation of P450 aro expression by D - DB00128 could be an important step in the control of E2 levels in the frog brain .",
"Androgen action . Androgens are important for male sex development and physiology . Their actions are mediated by the androgen receptor ( AR ) , a ligand - dependent nuclear transcription factor . The activity of the AR is controlled at multiple stages due to ligand binding and induced structural changes assisted by the foldosome , compartmentalization , recruitment of coregulators , posttranslational modifications and chromatin remodeling , leading to subsequent transcription of androgen - responsive target genes . Beside these short - term androgen actions , there is phenomenological and experimental evidence of long - term androgen programming in mammals and in the human during sensitive programming time windows , both pre - and postnatally . At the molecular level , research into androgen insensitivity syndrome has unmasked androgen programming at the transcriptome level , in genital fibroblasts and peripheral blood mononuclear cells , and at the epigenome level . Androgens are crucial for male sex development and physiology during embryogenesis , at puberty and in adult life . DB00624 and its more potent metabolite , dihydrotestosterone , which is converted from testosterone within the target cell by 5α - reductase II , are the main androgens involved in male sex differentiation . Androgen action is mediated by a single AR . The AR belongs to the nuclear receptor 3 group C , composed of the glucocorticoid receptor ( P04150 ) , mineralocorticoid receptor ( P08235 ) , progesterone receptor ( P06401 ) and AR ( P10275 ) , and acts as a ligand - dependent transcription factor .",
"___MASK23___ induces surfactant lipid accumulation and lung inflammation in mice . Interstitial lung disease ( ILD ) is a well - known adverse effect of mammalian target of rapamycin ( P42345 ) inhibitors . However , it remains unknown how lung toxicities are induced by P42345 inhibitors . Here , we constructed a mouse model of P42345 inhibitor - induced ILD using temsirolimus and examined the pathogenesis of the disease . Male ICR mice were treated with an intraperitoneal injection of different doses of temsirolimus ( 3 or 30 mg · kg (- 1 )· wk (- 1 ) ) or vehicle . ___MASK23___ treatment increased capillary - alveolar permeability and induced neutrophil infiltration and fibrinous exudate into the alveolar space , indicating alveolar epithelial and / or endothelial injury . It also induced macrophage depletion and the accumulation of excessive surfactant phospholipids and cholesterols . Alveolar macrophage depletion is thought to cause surfactant lipid accumulation . To further examine whether temsirolimus has cytotoxic and / or cytostatic effects on alveolar macrophages and alveolar epithelial cells , we performed in vitro experiments . ___MASK23___ inhibited cell proliferation and viability in both alveolar macrophage and alveolar epithelial cells . ___MASK23___ treatment caused some signs of pulmonary inflammation , including upregulated expression of several proinflammatory cytokines in both bronchoalveolar lavage cells and lung homogenates , and an increase in lymphocytes in the bronchoalveolar lavage fluid . These findings indicate that temsirolimus has the potential to induce alveolar epithelial injury and to deplete alveolar macrophages followed by surfactant lipid accumulation , resulting in pulmonary inflammation . This is the first study to focus on the pathogenesis of P42345 inhibitor - induced ILD using an animal model .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Protection of lung epithelial cells from protease - mediated injury by trappin - 2 A62L , an engineered inhibitor of neutrophil serine proteases . Neutrophil serine proteases ( NSPs ) , including elastase , proteinase 3 and cathepsin G , play critical roles in the pathogenesis of chronic inflammatory lung diseases . The release of excess NSPs leads to the destruction of lung tissue and an overexuberant , sustained inflammatory response . Antiproteases could be valuable tools for controlling these NSP - mediated inflammatory events . We have examined the capacity of trappin - 2 A62L , a potent engineered inhibitor of all three NSPs , to protect human lung A549 epithelial cells from the deleterious effects of NSPs . Trappin - 2 A62L , significantly inhibited the detachment of A549 cells and the degradation of the tight - junction proteins , P12830 , β - catenin and ZO - 1 , induced by each individual NSP and by activated neutrophils . Trappin - 2 A62L also decreased the release of the pro - inflammatory cytokines P05231 and P10145 from A549 cells that had been stimulated with elastase or LPS . Trappin - 2 A62D / M63L , a trappin - 2 variant that has no antiprotease activity , has similar properties , suggesting that the anti - inflammatory action of trappin - 2 is independent of its antiprotease activity . Interestingly , we present evidence that trappin - 2 A62L , as well as wild - type trappin - 2 , enter A549 cells and move rapidly to the cytoplasm and nucleus , where they are likely to exert their anti - inflammatory effects . We have also demonstrated that trappin - 2 A62L inhibits the early apoptosis of A549 cells mediated by NSPs . Thus , our data indicate that trappin - 2 A62L is a powerful anti - protease and anti - inflammatory agent that could be used to develop a treatment for patients with inflammatory lung diseases .",
"Recent androgen receptor antagonists in prostate cancer . P10275 has been shown to promote prostate cell growth and carcinogenesis of prostate cancer by up - regulating its target genes . DB00624 and dihydrotestosterone are two major hormones which bind to and activate androgen receptor . Targeting both the androgen receptor and the enzymes catalyzing the biosynthesis of testosterone and dihydrotestosterone has been shown to be clinically beneficial in the treatment of prostate cancer . Prostate cancer can become castration - resistant after long term treatment with chemo drugs , so efforts in finding compounds with improved efficiency to castration - resistant prostate cancer are urgently needed . In this review we summarized the studies on recent progress in the development of small molecular AR antagonists for the treatment of prostate cancer .",
"P10275 is widely expressed in bovine placentomes and up - regulated during differentiation of bovine trophoblast giant cells . OBJECTIVES : In cattle no biological role has been definitely identified for placental estrogens and progesterone . However , in the bovine trophoblast androgens may also be produced and have local effects . Thus , the aims of this study were to identify androgen receptor ( AR ) expressing cells and to monitor testosterone tissue concentrations in bovine placentomes throughout gestation . METHODS : Placental AR expression was characterized at the mRNA and protein level applying conventional and real - time RT - qPCR , western blot and immunohistochemistry . DB00624 was measured by radioimmunoassay . RESULTS : AR - mRNA was qualitatively detected from day 50 of gestation until term . Mean relative gene expression levels were constant between day 100 and late gestation . A slight non - significant increase was observed in the prepartal period . With immunohistochemistry distinct nuclear signals were predominantly observed in invasive trophoblast giant cells ( P21980 ) from day 80 until term . In mature P21980 of the trophoblast , immature P21980 and uninucleated trophoblast cells , stromal cells of the chorionic villi , caruncular epithelial and stromal cells immunoreactive score values were low at early and midgestation but increased significantly ( p < 0 . 01 ) during late gestation and remained high until parturition . With western blot in placentomal tissue a specific band of approximately 110 kDa was detected as it was the case in epididymis used as a positive control . DB00624 concentrations increased from 0 . 70 ± 0 . 29 pmol / g wet tissue between days 60 - 220 to 4 . 22 ± 1 . 29 pmol / g during late gestation ( p < 0 . 001 ) . DISCUSSION : The results are consistent with androgens as active products of bovine placental steroidogenesis . The substantial up - regulation of AR expression during P21980 differentiation suggests that androgens may be related to this process .",
"Gene expression in sexually dimorphic muscles in sheep . DB00624 is known to act differentially on skeletal muscle from different regions of the body . Two genes likely to mediate the testosterone effect are insulin - like growth factor I ( P05019 ) , an important growth regulator acting in an autocrine and paracrine way , and androgen receptor ( AR ) , because receptor density could account for differential muscle growth . Another muscle - specific gene that may play a role in differential muscle growth is myostatin , a member of the transforming growth factor - beta superfamily , shown to be a negative regulator of skeletal muscle mass . The objective of this study was to quantify and compare the steady state expression of these three genes in two different skeletal muscles in sheep . Eleven Dorset rams were slaughtered after reaching puberty and total RNA was extracted from samples of semitendinosus and splenius muscles . P05019 mRNA was measured using a competitive reverse - transcription - polymerase chain reaction . P10275 and myostatin mRNA were measured by a ribonuclease protection assay ( RPA ) with standard curves . The means ( attomoles / microg RNA ) for splenius and semitendinosus muscles were 1 . 39 and 1 . 02 ( SE = 0 . 14 ) , 4 . 05 and 2 . 96 ( SE = 0 . 24 ) , and 4 . 30 and 3 . 85 ( SE = 0 . 37 ) for P05019 , AR , and myostatin , respectively . The difference between the two muscles was significant for P05019 and AR mRNA levels with higher levels in the splenius but not significant for myostatin . Our results show that locally produced P05019 and the regulation of AR expression may be important for sexually dimorphic muscle growth patterns .",
"Axotomy transiently down - regulates androgen receptors in motoneurons of the spinal nucleus of the bulbocavernosus . DB00624 is an important trophic factor for motoneurons in the spinal nucleus of the bulbocavernosus ( SNB ) , and SNB motoneurons are more responsive to testosterone than are other motoneurons . Axonal injury during early postnatal life prevents the normal development of steroid - sensitivity by adult SNB motoneurons . Axonal injury also causes changes in the expression by motoneurons of a wide range of proteins , including the up - regulation of trophic factor receptors . We have used a polyclonal antibody ( PG - 21 ; G . S . Prins ) to study the expression of androgen receptors in SNB motoneurons after axonal injury . PG - 21 labeled motoneuronal nuclei in the lower lumbar spinal cord of rats in a pattern that matched autoradiographic reports of androgen accumulation in this region of the nervous system . A population of numerous , small cells located dorsal to the central canal also showed evidence of androgen receptor expression . Cutting the axons of SNB motoneurons in adulthood or in development caused a decrease in androgen receptor immunoreactivity in SNB motoneurons . This is the first report that a trophic factor receptor in motoneurons is down - regulated after axonal injury , and is interesting in light of reports that testosterone treatment can facilitate motoneuronal regeneration after nerve cut . P10275 levels subsequently returned to normal , regardless of the age at axotomy , providing no evidence for a lasting effect of developmental axotomy on androgen receptor levels in SNB motoneurons . Thus , axotomy - induced down - regulation of androgen receptors does not underlie the inability of SNB motoneurons to respond to androgen treatment several months after pudendal nerve cut in development .",
"Pomegranate extract induces apoptosis in human prostate cancer cells by modulation of the IGF - IGFBP axis . The IGF axis is critical for the regulation of apoptosis in many human cancer cell lines . Recently , potent anti - tumorigenic effects of pomegranate juice and extracts have been reported . Consequently , pomegranate has potential not only as a treatment but also as a preventative measure against certain types of cancer , including prostate . In this study , we investigated the relationship between pomegranate - induced apoptosis in human prostate cancer cells and the IGF / IGFBP system . Treatment of LAPC4 prostate cancer cells with 10microg / ml POMx , a highly potent pomegranate extract prepared from skin and arils minus seeds and standardized to ellagitannin content ( 37 % punicalagins by HPLC ) , resulted in inhibition of cell proliferation and induction of apoptosis . Interestingly , co - treatment with POMx and P17936 revealed synergistic stimulation of apoptosis and additive inhibition of cell growth . Western blot analysis revealed that treatment with POMx or POMx / P17936 combination resulted in increased JNK phosphorylation , and decreased Akt and P42345 activation , consistent with a growth inhibitory , pro - apoptotic function . We also investigated the relationship between DB01277 and pomegranate - induced apoptosis in 22RV1 prostate cancer cells . Co - treatment with 100ng / ml DB01277 completely blocked apoptosis induction by POMx . In contrast , P05019 failed to inhibit POMx - induced apoptosis in R (-) cells , suggesting the importance of IGF - IR . POMx - treatment decreased Igf1 mRNA expression in a dose - dependent manner indicating that its actions also involve tumor - specific suppression of DB01277 . These studies revealed novel interactions between the IGF system and pomegranate - induced apoptosis .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK75___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"The androgen receptor : a mediator of diverse responses . Androgens mediate a number of diverse responses through the androgen receptor , a 110 kD ligand - activated nuclear receptor . P10275 expression , which is found in a variety of tissues , changes throughout development , aging , and malignant transformation . The androgen receptor can be activated by two ligands , testosterone and dihydrotestosterone , which bind to the androgen receptor with different affinities . This difference in binding affinity results in different levels of activation of the androgen receptor by the two ligands . The androgen receptor acts as a transcriptional modifier of a variety of genes by binding to an androgen response element . The ability to confer androgen specific actions by the androgen response element may depend on other cell - specific transcription factors and cis - acting DNA elements in close proximity to it . DB00624 and dihydrotestosterone appear to act upon an identical nuclear receptor . However , in certain instances , they mediate different physiologic responses . For example , dihydrotestosterone , but not testosterone , is capable of mediating full sexual development of the male external genitalia . In some cases , the androgen receptor may induce opposite physiologic responses in similar tissue types depending on their location . For example , in male pattern baldness , activated androgen receptors may suppress the growth of distinct hair follicle populations through initiating stromal - epithelial actions , whereas other hair follicles continue to proliferate . In other cases , altered androgen receptor activity due to its mutation or altered expression may lead to pathology such as recurrence of prostate cancer due to development of androgen independence allowing tumor cell proliferation under androgen deprivation .",
"Chemical ablation of androgen receptor in prostate cancer cells by the histone deacetylase inhibitor LAQ824 . P10275 plays a critical role in the development of primary as well as advanced hormone - refractory prostate cancer . Therefore , ablation of androgen receptor from prostate cancer cells is an interesting concept for developing a new therapy not only for androgen - dependent prostate cancer but also for metastatic hormone - refractory prostate cancer , for which there is no effective treatment available . We report here that LAQ824 , a cinnamyl hydroxamatic acid histone deacetylase inhibitor currently in human clinical trials , effectively depleted androgen receptor in prostate cancer cells at nanomolar concentrations . LAQ824 seemed capable of depleting both the mutant and wild - type androgen receptors in either androgen - dependent and androgen - independent prostate cancer cells . Although LAQ824 may exert its effect through multiple mechanisms , several lines of evidence suggest that inactivation of the heat shock protein - 90 ( Hsp90 ) molecular chaperone is involved in LAQ824 - induced androgen receptor depletion . Besides androgen receptor , LAQ824 reduced the level of Hsp90 client proteins HER - 2 ( ErbB2 ) , Akt / P31749 , and P04049 in LNCaP cells . Another Hsp90 inhibitor , 17 - allyamino - 17 - demethoxygeldanamycin ( 17 - P29372 ) , also induced androgen receptor diminution . LAQ824 induced Hsp90 acetylation in LNCaP cells , which resulted in inhibition of its DB00171 - binding activity , dissociation of Hsp90 - androgen receptor complex , and proteasome - mediated degradation of androgen receptor . Consequently , LAQ824 blocked androgen - induced prostate - specific antigen production in LNCaP cells . LAQ824 effectively inhibited cell proliferation and induced apoptosis of these prostate cancer cells . These results reveal that LAQ824 is a potent agent for depletion of androgen receptor and a potential new drug for prostate cancer .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"[ Monoamine imbalance of the central nervous system in a case of Shy - Drager syndrome with recurrent attacks of a neuroleptic malignant syndrome ] . A 79 - year - old male suffering from Shy - Drager syndrome was treated with a daily dosage of 300 mg of L - threo - 3 , 4 - dihydroxyphenylserine ( DB06262 ) . He developed a neuroleptic malignant syndrome ( Q5H8A3 ) like state 1 month after teh initiation of DB06262 therapy . And recurrent attacks of Q5H8A3 occurred subsequently despite discontinuation of DB06262 administration . We measured homovanillic acid ( HVA ) , 3 methoxy 4 hydroxyphenylethylenglycol ( MHPG ) , and 5 - hydroxyindoleacetic acid ( 5 - HIAA ) in this corrected brospinal fluid ( P04141 ) , both during his 2 attacks of Q5H8A3 and after recovery . The HVA and 5 HIAA levels after recovery were low compared with those in age - matched normal controls . However , his levels in the active phase were not different from those after recovery . In contrast , MHPG levels were elevated and his HVA / MHPG ratios decreased in the active phase compared with those in the recovery phase . The results indicate that his symptoms of Q5H8A3 are attributed to the imbalance between dopamine and noradrenalin rather than the dopamine receptor blockade in the central nervous system . We suggest further evaluations of P04141 monoamine metabolites in similar cases to determine the pathogenesis of Q5H8A3 .",
"P10275 - dependent transactivation of growth arrest - specific gene 6 mediates inhibitory effects of testosterone on vascular calcification . Recent epidemiological studies have found that androgen deficiency is associated with a higher incidence of cardiovascular disease in men . However , little is known about the mechanism underlying the cardioprotective effects of androgens . Here we show the inhibitory effects of testosterone on vascular calcification and a critical role of androgen receptor ( AR ) - dependent transactivation of growth arrest - specific gene 6 ( Gas6 ) , a key regulator of inorganic phosphate ( P ( i ) ) - induced calcification of vascular smooth muscle cells ( VSMC ) . DB00624 and nonaromatizable androgen dihydrotestosterone inhibited P ( i )- induced calcification of human aortic VSMC in a concentration - dependent manner . Androgen inhibited P ( i )- induced VSMC apoptosis , an essential process for VSMC calcification . The effects on VSMC calcification were mediated by restoration of P ( i )- induced down - regulation of Gas6 expression and a subsequent reduction of Akt phosphorylation . These effects of androgen were blocked by an AR antagonist , flutamide , but not by an estrogen receptor antagonist , DB00947 . We then explored the mechanistic role of the AR in Gas6 expression and found an abundant expression of AR predominantly in the nucleus of VSMC and two consensus ARE sequences in the Gas6 promoter region . DB02901 stimulated Gas6 promoter activity , and this effect was abrogated by flutamide and by AR siRNA . Site - specific mutation revealed that the proximal ARE was essential for androgen - dependent transactivation of Gas6 . Furthermore , chromatin immunoprecipitation assays demonstrated ligand - dependent binding of the AR to the proximal ARE of Gas6 . These results indicate that AR signaling directly regulates Gas6 transcription , which leads to inhibition of vascular calcification , and provides a mechanistic insight into the cardioprotective action of androgens .",
"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( DB02901 ) in castrated male and female mice subjected to DB02901 replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by DB02901 in mice CPs .",
"DB00624 and androgen receptor in human nephrolithiasis . PURPOSE : We investigated the relationship of kidney calculi with plasma free and total testosterone , and androgen receptor up - regulation in the kidneys of men with nephrolithiasis . MATERIALS AND METHODS : Male patients with kidney stone and healthy men were included in the study . Blood was collected in a tube containing 2 % heparin in the morning . Total and free serum testosterone was measured by enzyme linked immunosorbent assay . All patients underwent percutaneous nephrostolithotomy . At the end of the procedure ultrasound guided puncture biopsy was done to acquire kidney tissue . Normal kidney tissue obtained at autopsy served as the control . P10275 was detected in kidney tissue by immunohistochemistry . Stone composition was analyzed in each patient . RESULTS : The study included 37 male patients 22 to 39 years old and 31 healthy men 24 to 37 years old . All calculi were composed of calcium oxalate monohydrate or calcium oxalate dihydrate and a few also contained protein or uric acid . Mean ± SD serum total and free testosterone was 13 . 29 ± 4 . 79 ng / ml and 63 . 23 ± 28 . 58 pg / ml in patients , and 7 . 30 ± 0 . 82 ng / ml and 35 . 59 ± 24 . 91 pg / ml in healthy men , respectively ( each p < 0 . 001 ) . Immunohistochemistry revealed androgen receptor up - regulation in the kidneys of patients with nephrolithiasis . CONCLUSIONS : Our data suggest the important role of enhanced androgen signaling in human nephrolithiasis .",
"Sex steroid regulation of chin - marking behavior in male New Zealand rabbits . Chin - marking behavior ( chinning ) was evaluated daily in nine intact adult male rabbits . All subjects ( Ss ) displayed chinning ( mean of means +/- SE = 61 +/- 7 marks / 10 min ) but the frequency of this behavior varied largely across them ( range of mean chinning frequency = 19 - 84 marks / 10 min ) . Chinning frequency showed abrupt variations at intervals of 2 - 3 days , but periodogram analysis did not reveal the existence of an endogenous rhythm in this behavior . Castration significantly decreased ( mean of means +/- SE = 29 +/- 9 marks / 10 min ; p < 0 . 01 ) . but did not suppress chinning . DB00624 propionate ( TP ; 1 mg / day for 16 days ) restored chinning in castrated Ss to slightly below precastration levels ( mean +/- S . E . V 53 +/- 13 marks / 10 min ) . The daily administration of 1 microgram estradiol benzoate ( EB ) plus 1 mg dihydrotestosterone propionate ( DHTP ) stimulated chinning within 2 days ( mean increase = 147 % ; p < 0 . 005 ) . DHTP ( 1 mg / day ) given alone stimulated chinning only after 11 days of treatment ( mean increase = 475 % ; p < 0 . 01 ) . At higher doses , both DHTP ( 10 mg / day ) and EB ( 10 or 50 micrograms / day ) stimulated chinning by 450 % , 80 % , and 100 % , respectively , over baseline values . Results indicate that chinning largely depends on testicular steroids . P10275 occupation by T or DB02901 , which is enhanced by E , optimally activates chinning .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK98___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"Regulation of androgen receptor mRNA in rat Sertoli and peritubular cells . Regulation of 9 . 5 - kb androgen receptor mRNA concentrations in Sertoli and peritubular cells from 20 - day - old rats was studied by Northern blot analysis . Treatment of cells in vitro for 1 - 7 days with 300 ng / ml DB00094 increased androgen receptor mRNA up to 4 - fold in Sertoli cells but not in peritubular cells . DB00624 ( 100 ng / ml ) had no effect or slightly decreased androgen receptor mRNA in Sertoli and peritubular cells . P10275 mRNA concentrations in Sertoli and peritubular cells from rats killed 15 days after hypophysectomy were elevated 4 - 5 - fold over those in cells from intact rats . The androgen receptor mRNA concentration was decreased in both Sertoli and peritubular cells isolated from hypophysectomized animals treated with 500 micrograms / day testosterone propionate in vivo and subsequently with 100 ng / ml testosterone in vitro . DB00094 treatment ( 100 micrograms / day in vivo , followed by 300 ng / ml in vitro ) did not increase androgen receptor mRNA over that in cells from hypophysectomized controls but rather decreased its concentration to varying degrees in Sertoli and peritubular cells . The rise in androgen receptor mRNA in both Sertoli and peritubular cells isolated from hypophysectomized animals is attributable , at least in part , to the absence of the inhibitory influence of testosterone . Other data in the literature suggest positive regulation of Sertoli cell androgen receptor protein by DB00094 and androgens . Consequently , complex mechanisms involving transcriptional , translational , and post - translational regulation probably control androgen receptor concentrations in the cells of the rat seminiferous tubule .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males ."
] |
[
"___MASK10___",
"___MASK16___",
"___MASK1___",
"___MASK20___",
"___MASK23___",
"___MASK42___",
"___MASK61___",
"___MASK75___",
"___MASK98___"
] |
___MASK98___
|
MH_train_484
|
interacts_with DB00814?
|
[
"Antiinflammatory and neurological activity of pyrithione and related sulfur - containing pyridine N - oxides from Persian shallot ( Allium stipitatum ) . ETHNOPHARMACOLOGICAL RELEVANCE : Persian shallot ( Allium stipitatum ) is a bulbous plant native to Turkey , Iran and Central Asia . It is frequently used in folk medicine for the treatment of a variety of disorders , including inflammation and stress . Antiinflammatory and neurological activities of pyrithione and four related sulfur - containing pyridine N - oxides which are prominent constituents of Allium stipitatum were tested . METHODS : The antiinflammatory activity was tested by the ability of the compounds to inhibit cyclooxygenase ( P23219 and P35354 ) , whereas the neurological activities were evaluated by assessing the compounds ability to inhibit monoamine oxidase - A ( P21397 ) and acetylcholinesterase ( P22303 ) . The compounds ׳ affinity for the serotonin transport protein ( P31645 ) and the GABAA - benzodiazepine receptor were also investigated . RESULTS : 2 -[( Methylthio ) methyldithio ] pyridine N - oxide showed very high antiinflammatory effects which are comparable with those of common pharmaceuticals ( IC₅₀ of 7 . 8 and 15 . 4 µM for P23219 and P35354 , respectively ) . On the other hand , neurological activities of the compounds were rather modest . Some compounds moderately inhibited P22303 ( IC₅₀ of 104 - 1041 µM ) and P21397 ( IC₅₀ of 98 - 241 µM ) and exhibited an affinity for the P31645 and GABAA - benzodiazepine receptor . CONCLUSIONS : Our findings may help to rationalize the wide use of Persian shallot for the treatment of inflammatory disorders .",
"Systems pharmacology assessment of the 5 - fluorouracil pathway . AIM : To assess the impact of the 5 - fluorouracil ( DB00544 ) drug - pathway genes on cytotoxicity , and determine whether loss - of - function analyses coupled with functional assays can help prioritize pharmacogenomic candidate genes . MATERIALS & METHODS : Dose - response experiments were used to quantify the phenotype of sensitivity to DB00544 following the specific knockdown of genes selected from the DB00544 PharmGKB drug pathway in three human colorectal cell lines . Changes in sensitivity were considered significant if the IC ( 50 ) for shRNA - exposed cells were three standard deviations outside the mean IC ( 50 ) for control - treated cells . RESULTS : Of the 24 genes analyzed , 13 produced significant changes on the phenotype of sensitivity to DB00544 ( P00374 , Q14117 , P23919 , P33316 , Q05932 , Q92820 , P15531 , Q8TCD5 , P23921 , P04818 , Q9BZX2 , P13051 and P11172 ) . CONCLUSION : The RNAi screening strategy enabled prioritization of the genes from the DB00544 drug pathway . Further validation of the genes credentialed in this study should include gene activity or expression and mutation analyses of clinical samples .",
"P35354 induction and prostaglandin E2 accumulation in squamous cell carcinoma as a consequence of epidermal growth factor receptor activation by imatinib mesylate . Imatinib mesylate is a novel anti - tumor agent useful in the clinical management of chronic myelogenous leukemia and gastrointestinal stromal tumors with minimal toxicity relative to other forms of cancer therapy . Its clinical activity and minimal toxicity are related to specific inhibition of cellular targets including P11274 - P00519 , platelet - derived growth factor receptor and c - kit kinases , resulting in the collapse of downstream signaling cascades important for transformation . In some patients , unexpected toxicities arise that are not associated with inhibition of any known cellular imatinib target . In this report , we investigated the effects of imatinib on squamous carcinoma cell signaling . Imatinib induced expression of P35354 in a dose - dependent manner with concomitant accumulation of prostaglandin E2 . P35354 induction by imatinib was initiated through epidermal growth factor ( P01133 ) receptor kinase activation and downstream signaling through mitogenic - activated protein kinase . P35354 induction by imatinib was blocked by Q02750 or P01133 receptor inhibition . Imatinib did not activate stressor cytokine - signaling pathways ( p38 kinase , nuclear factor - kB nuclear translocation ) or affect P23219 expression . Imatinib failed to activate P01133 receptor signals in other tumor types , suggesting that P35354 induction in imatinib - treated cells is mediated through release of autocrine factors expressed or activated in squamous tumors . P35354 induction by imatinib in squamous tumors derived from the head and neck region is unique with respect to other target - specific agents and may represent one of the unintended toxic effects of imatinib described in some patients .",
"Effect of cyclooxygenase inhibitors on the P06850 - induced pituitary - adrenocortical activity during crowding stress . The aim of the present study was to determine the effect of social stress and significance of prostaglandins ( PG ) generated by constitutive and inducible cyclooxygenase ( P23219 and P35354 ) in the stimulation of hypothalamic - pituitary - adrenal ( Q9Y251 ) axis by corticotropin releasing hormone ( P06850 ) under basal and social crowding stress conditions . The stressed rats were crowded in groups of 24 to a cage for 3 or 7 days , whereas the control animals were haused in groups of 7 to a cage of the same size . The activity of Q9Y251 axis was determined by measuring plasma DB01285 and serum corticosterone levels 1 h after i . p . P06850 administration . Inhibitors of P23219 , piroxicam ( 0 . 2 , 2 . 0 , and 5 . 0 mg / kg ) , and P35354 , compound NS - 398 ( 0 . 2 and 2 . 0 mg / kg ) , were administered i . p . 15 min prior to P06850 ( 0 . 1 microg / kg i . p . ) to control or crowded rats . The obtained results indicate that social stress for 3 and 7 days markedly intensifies the stimulatory action of P06850 on DB01285 secretion . Neither piroxicam nor NS - 398 induce any significant effect on the P06850 - elicited DB01285 and corticosterone secretion in non - stressed or crowded rats . Therefore , PG generated by P23219 or P35354 do not participate to a significant extent in the stimulation of Q9Y251 axis by P06850 under either basal conditions or during crowding stress . These results also indicate that the stimulatory action of P06850 on DB01285 secretion is not only completely resistant to desensitization but is sensitized during social crowding stress . The results contrast with a significant involvement of PG in the vasopressin - induced stimulation of Q9Y251 response during crowding stress .",
"Signaling pathways mediating induction of the early response genes prostaglandin G / H synthase - 2 and egr - 1 by serotonin via 5 - Q13049 receptors . Signaling pathways responsible for serotonin ( 5 - HT ) - mediated induction of early response genes prostaglandin G / H synthase - 2 ( P35354 , cyclooxygenase - 2 ) and egr - 1 were investigated in rat mesangial cells . Gene induction by 5 - HT was dependent on 5 - Q13049 receptors that were pertussis toxin insensitive indicating coupling to a G - protein of the Gq family . Binding of 5 - HT to this receptor activates phosphatidylinositol - specific phospholipase C ( P98160 ) and release of Ca2 + from internal stores , but this activation was not related to P35354 mRNA expression . Similarly , P19957 kinase was not involved in 5 - HT signaling . Instead , inhibition of phosphatidylcholine - specific P98160 interfered with P35354 and egr - 1 mRNA induction , suggesting this enzyme as a link between 5 - Q13049 receptors and protein kinase C , an essential part of 5 - HT - mediated signaling . The Q96HU1 kinase pathway was identified as common signaling pathway of 5 - HT or phorbol ester - induced gene expression . Increase of intracellular DB02527 by forskolin or dibutyryl DB02527 did not induce P35354 or egr - 1 mRNA expression by itself , but strongly inhibited 5 - HT - mediated mRNA induction . P35354 mRNA and protein induction by 5 - HT was also abolished by chelation of Ca2 + ions by EGTA , suggesting involvement of Ca2 +- dependent enzymes . In contrast , egr - 1 mRNA expression was superinduced in the presence of EGTA . Induction of Egr - 1 protein was not changed by EGTA hinting to Ca2 +- sensitive posttranscriptional steps . Activation of the Gq - coupled 5 - Q13049 receptor thus leads to the expression of the early response genes P35354 and egr - 1 , using common as well as differing signaling elements that allow differential regulation of the expression of these genes that are functionally related to renal hemodynamics and proliferation of mesangial cells , respectively .",
"[ ___MASK57___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK57___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .",
"DB00945 antagonizes the cytotoxic effect of methotrexate in lung cancer cells . DB00563 ( MTX ) has been widely used for the treatment of cancer and rheumatoid arthritis ( RA ) . DB00945 ( ASA ) is a non - selective cyclooxygenase ( P36551 ) inhibitor that contributes to the treatment of inflammatory conditions such as RA . It has been observed that the antitumor effect of ASA can be attributed to inhibition of cell cycle progression , induction of apoptosis and inhibition of angiogenesis . In the present study , we revealed that the treatment with a combination of MTX and ASA resulted in antagonism of the cytotoxic effect as demonstrated by P50991 and colony formation assays . ASA alleviated the MTX - mediated S phase accumulation and recovered the P55008 phase . MTX - mediated accumulation of the S phase marker cyclin A was also alleviated by ASA . Notably , FAS protein levels were upregulated by MTX in A549 cells . The antagonism of MTX efficacy caused by ASA was accompanied by altered expression of caspase - 3 , Bcl - 2 and FAS but not dihydrofolate reductase ( P00374 ) . This suggests that the alteration of caspase - 3 , Bcl - 2 and FAS was involved in the antagonism between ASA and MTX . Exogenously added folic acid reversed the MTX - mediated P00374 inhibition following either MTX or MTX + ASA treatments . Most importantly , we demonstrated for the first time that the commonly used non - steroidal anti - inflammatory drug for headache ASA and possibly other P23219 / 2 inhibitors can produce a strong antagonistic effect on the growth inhibition of lung cancer cells when administered in combination with MTX . The clinical implication of our finding is obvious , i . e . , the clinical efficacy of MTX therapy can be compromised by ASA and their concomitant use should be avoided .",
"Quantum mechanics - based properties for 3D - QSAR . We have used a set of four local properties based on semiempirical molecular orbital calculations ( electron density ( ρ ) , hydrogen bond donor field ( HDF ) , hydrogen bond acceptor field ( P00748 ) , and molecular lipophilicity potential ( MLP ) ) for 3D - QSAR studies to overcome the limitations of the current force field - based molecular interaction fields ( MIFs ) . These properties can be calculated rapidly and are thus amenable to high - throughput industrial applications . Their statistical performance was compared with that of conventional 3D - QSAR approaches using nine data sets ( angiotensin converting enzyme inhibitors ( P12821 ) , acetylcholinesterase inhibitors ( AchE ) , benzodiazepine receptor ligands ( BZR ) , cyclooxygenase - 2 inhibitors ( P35354 ) , dihydrofolate reductase inhibitors ( P00374 ) , glycogen phosphorylase b inhibitors ( GPB ) , thermolysin inhibitors ( THER ) , thrombin inhibitors ( THR ) , and serine protease factor Xa inhibitors ( fXa ) ) . The 3D - QSAR models generated were tested thoroughly for robustness and predictive ability . The average performance of the quantum mechanical molecular interaction field ( QM - MIF ) models for the nine data sets is better than that of the conventional force field - based MIFs . In the individual data sets , the QM - MIF models always perform better than , or as well as , the conventional approaches . It is particularly encouraging that the relative performance of the QM - MIF models improves in the external validation . In addition , the models generated showed statistical stability with respect to model building procedure variations such as grid spacing size and grid orientation . QM - MIF contour maps reproduce the features important for ligand binding for the example data set ( factor Xa inhibitors ) , demonstrating the intuitive chemical interpretability of QM - MIFs .",
"[ Drugs stimulating insulin release . Importance of their use for improving glycemia , safety and quality of life in diabetes mellitus type 2 ] . Etiopathogenesis of diabetes mellitus is bipolar . On one hand there occurs impairment in beta - cell function caused by genetic factors or abnormal development during fetal period . On the other hand defects of peripheral insulin action are also of significant importance . The bipolarity is also expressed by changing relationship between genetic and environmental factors . P01308 release is connected with closing DB00171 - dependent kalium channel , a structure closely connected with sulfonylurea receptors . Several receptors may be distinguished : Q09428 in Langerhans isles and SUR2 in heart ( SUR2A ) and vessel smoot muscles ( SUR2B ) . In the treatment of insulin release disorders sulfonylureas are still of significant importance though repaglinid and phenyloalanine derivates also have some clinical importance . Within sulfonylurea derivates there have been developed some preparations of slow drug release ( ___MASK41___ GITS , Diaprel MR ) . One daily dose of ___MASK41___ GITS and lower tendency to hypoglycaemia favour acceptation of the therapy by the patients what is also important for their quality of life . Quality of life is now regarded as important as obtaining good indices of diabetes control .",
"[ Meloxicam ( DB00814 ) : a review of its pharmacological and clinical profile ] . Meloxicam ( DB00814 ) is a new nonsteroidal anti - inflammatory drug ( NSAID ) derived from enolic acid , exhibiting selectivity for cyclooxygenase ( P36551 ) - 2 over P23219 . Meloxicam has shown potent anti - inflammatory and analgesic activity together with low gastrointestinal toxicity in animal models . It is a potent inhibitor not only of acute exudation in adjuvant arthritis in the rat , but also of bone and cartilage destruction . The therapeutic range of meloxicam in the rat , with regard to inhibition of adjuvant arthritis , was several times greater than that of other NSAIDs . Meloxicam in therapeutic doses was found to have no effect on bleeding time or platelet aggregation in healthy volunteers . In clinical studies , meloxicam has shown reliable efficacy against rheumatoid arthritis , osteoarthritis , lumbago ( low back pain ) , scapulohumeral periarthritis , and neck - shoulder - arm syndrome with low gastrointestinal toxicity .",
"Nuclear factor kappa B inhibition improves conductance artery function in type 2 diabetic mice . BACKGROUND : We previously reported that enhanced nuclear factor kappa B ( NFκB ) activity is responsible for resistance arteries dysfunction in type 2 diabetic mice . METHODS : In this study , we aimed to determine whether augmented NFκB activity also impairs conductance artery ( thoracic aorta ) function in type 2 diabetic mice . We treated type 2 diabetic ( db (-) / db (-) ) and control ( db (-) / db (+) ) mice with two NFκB inhibitors ( dehydroxymethylepoxyquinomicin , 6 mg / kg , twice a week and IKK - NBD peptide , 500 µg / kg / day ) for 4 weeks . RESULTS : As expected , the NFκB inhibition did not affect blood glucose level and body weight . Thoracic aorta vascular endothelium - dependent relaxation ( EDR ) , determined by the wire myograph , was impaired in diabetic mice compared with control and was significantly improved after NFκB inhibition . Interestingly , thoracic EDR was also rescued in db (-) / db (- p50NFκB -/-) and db (-) / db (- P09874 -/-) double knockout mice compared with db (-) / db (-) mice . Similarly , the acute in vitro down regulation of NFκB - p65 using p65 shRNA lentiviral particles in arteries from db (-) / db (-) mice also improved thoracic aorta EDR . Western blot analysis showed that the p65NFκB phosphorylation , cleaved P09874 and P35354 expression were increased in thoracic aorta from diabetic mice , which were restored after NFκB inhibition and in db (-) / db (- p - 50NFκB -/-) and db (-) / db (- P09874 -/-) mice . CONCLUSIONS : The present results indicate that in male type 2 diabetic mice , the augmented NFκB activity also impairs conductance artery function through P09874 and P35354 - dependent mechanisms .",
"___MASK79___ binding to human and rat dopamine and 5 - HT receptors . ___MASK79___ ( ___MASK79___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK79___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK79___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK79___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"Poly ( ADP - ribose ) polymerase - 1 is a nuclear epigenetic regulator of mitochondrial DNA repair and transcription . Poly ( ADP - ribose ) polymerase - 1 ( P09874 ) is a NAD - consuming enzyme with an emerging key role in epigenetic regulation of gene transcription . Although P09874 expression is characteristically restricted to the nucleus , a few studies report the mitochondrial localization of the enzyme and its ability to regulate organelle functioning . Here , we show that , despite exclusive nuclear localization of P09874 , mitochondrial homeostasis is compromised in cell lines exposed to P09874 pharmacological inhibitors or small interfering RNA . P09874 suppression reduces integrity of mitochondrial DNA ( mtDNA ) , as well as expression of mitochondria - encoded respiratory complex subunits P23219 , P35354 , and ND - 2 . Accordingly , P09874 localizes at promoters of nuclear genes encoding both the mtDNA repair proteins P13051 , P12882 , and P27695 and the mtDNA transcription factors Q8WVM0 and Q9H5Q4 . It is noteworthy that poly ( ADP - ribosyl ) ation is required for nuclear gene expression of these mitochondrial proteins . Consistent with these findings , P09874 suppression impairs mitochondrial DB00171 production . Our results indicate that P09874 plays a central role in mitochondrial homeostasis by epigenetically regulating nuclear genes involved in mtDNA repair and transcription . These data might have important implications in pharmacology of P09874 inhibitors as well as clinical oncology and aging .",
"Poly ( DB02059 ) polymerase - 1 signalling of the DNA damage induced by P11387 poison in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Glioblastomas are widely characterised by the mutation of the p53 gene and p53 disruption sensitizes glioblastoma cells to P11387 ( TOPO I ) inhibitor - mediated apoptosis . We investigated the effects of combined treatments with the P11387 inhibitor ___MASK90___ and the poly ( DB02059 ) polymerase - 1 inhibitor DB02690 in D54 ( p53wt ) and U251 ( p53mut ) glioblastoma cell lines . Analysis of cell growth and cell cycle kinetics showed a synergistic anti - proliferative effect of 10 nM TPT and 10 microM DB02690 and a G2 / M block of the cell cycle . We also evaluated , the influence of TPT +/- DB02690 treatment on P09874 and p53 activity . We got evidences of a TPT - dependent increase of P09874 auto - modification level in both the cells . Moreover , in the D54 ( p53wt ) cells we found that in co - treatments DB02690 incremented the TPT - dependent stimulation of p53 transcriptional activity and increased the P38936 nuclear amount . Conversely , in U251 ( p53mut ) cells we found that DB02690 incremented the TPT - dependent apoptosis characterised by P09874 proteolysis . Our findings suggest that the modulation of P09874 can be considered a strategy in the potentiation of the chemotherapeutic action of TOPO I poisons in glioblastoma cells apart from their p53 status .",
"DB00171 - sensitive potassium channels ( K ( DB00171 ) ) in retina : a key role for delayed ischemic tolerance . The objectives of the present study were to determine the localization of K ( DB00171 ) channels in normal retina and to evaluate their potential roles in ischemic preconditioning ( IPC ) in a rat model of ischemia induced by increased intraocular pressure ( IOP ) . Brown Norway rats were subjected to sublethal 3 - , lethal 20 - and 40 - min ischemia and the functional recovery was evaluated using electroretinography . The time interval between ischemic insults ranged from 1 to 72 h . The effects of K ( DB00171 ) channel blockade on IPC protection were studied by treatment with 0 . 01 % glipizide . IPC was mimicked by injection of K ( DB00171 ) channel openers of 0 . 01 % (-) cromakalim or 0 . 01 % P1060 72 h before 20 - min ischemia . Co - expression of K ( DB00171 ) channel subunits Kir6 . 2 / Q09428 was observed in the retinal pigment epithelium , inner segments of photoreceptors , outer plexiform and ganglion cell layers and at the border of the inner nuclear layer . In contrast to a 20 - or 40 - min ischemia , a 3 - min ischemia induced no alteration of the electroretinogram ( ERG ) and constituted the preconditioning stimulus . An ischemic challenge of 40 min in preconditioned rats induced impairment of retinal function . However , animals preconditioned 24 , 48 and 72 h before 20 - min ischemia had a significant improvement of the ERG . (-) Cromakalim and P1060 mimicked the effect of IPC . ___MASK41___ significantly suppressed the protective effects of preconditioning . In conclusion , activation of K ( DB00171 ) channels plays an important role in the mechanism of preconditioning by enhancing the resistance of the retina against a severe ischemic insult .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK82___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK82___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"___MASK97___ and the novel multireceptor ligand somatostatin receptor agonist pasireotide ( DB06663 ) block the adrenalectomy - induced increase in mitotic activity in male rat anterior pituitary . The novel somatostatin receptor agonist pasireotide binds with high affinity to somatostatin receptors P30872 , 2 , 3 , and 5 . Acting principally through the latter , it inhibits basal and P06850 - stimulated DB01285 secretion from the AtT20 corticotroph cell line and DB01285 release from a proportion of human corticotroph adenomas both in vitro and in vivo . Data supporting an additional antiproliferative effect has led to pasireotide being explored as a potential therapy for patients with Cushing ' s disease . We have compared the effects of pasireotide and octreotide on adrenalectomy - induced mitotic and apoptotic activity in the male rat anterior pituitary . Adrenalectomized rats were treated with daily sc injections of vehicle , pasireotide , or octreotide . Changes in proliferation and apoptosis were determined 2 - 6 d postoperatively . DB06663 and octreotide had no effect on baseline pituitary cell turnover and no measurable effects on apoptosis . However , the wave of increased mitotic activity normally seen in the pituitary after adrenalectomy was completely abolished . Nevertheless , pasireotide and octreotide did not diminish the increase in DB01285 - immunopositive cell index after adrenalectomy , indicating that cell division and differentiation of hormonally null cells in the pituitary are under independent control . In conclusion , basal cell turnover in the pituitary is not inhibited by pasireotide or octreotide . Bilateral adrenalectomy stimulates differentiation of preexisting null cells into DB01285 - positive cells . Cell division after bilateral adrenalectomy occurs in a specific subpopulation of hormonally null cells that are equally sensitive to the antiproliferative effects of pasireotide and octreotide , implicating P30874 receptors in this antimitotic response .",
"DB00472 induces preventive and complex effects against colon cancer development in epithelial and stromal areas in rats . DB00472 ( FLX ) is a drug commonly used as antidepressant . However , its effects on tumorigenesis remain controversial . Aiming to evaluate the effects of FLX treatment on early malignant changes , we analyzed serotonin ( 5 - HT ) metabolism and recognition , aberrant crypt foci ( Q9NQ94 ) , proliferative process , microvessels , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase - 2 ( P35354 ) expression in colon tissue . Male Wistar rats received a daily FLX - gavage ( 30mgkg (- 1 ) ) and , a single dose of 1 , 2 dimethylhydrazine ( Q03001 ; i . p . , 125mgkg (- 1 ) ) . After 6 weeks of FLX - treatment , our results revealed that FLX and nor - fluoxetine ( N - FLX ) are present in colon tissue , which was related to significant increase in serotonin ( 5 - HT ) levels ( P < 0 . 05 ) possibly through a blockade in P31645 mRNA ( serotonin reuptake transporter ; P < 0 . 05 ) resulting in lower 5 - hydroxyindoleacetic acid ( 5 - HIAA ) levels ( P < 0 . 01 ) and , P28335 receptor mRNA expressions . FLX - treatment decreased dysplastic Q9NQ94 development ( P < 0 . 01 ) and proliferative process ( P < 0 . 001 ) in epithelia . We observed a significant decrease in the development of malignant microvessels ( P < 0 . 05 ) , P15692 ( P < 0 . 001 ) , and P35354 expression ( P < 0 . 01 ) . These findings suggest that FLX may have oncostatic effects on carcinogenic colon tissue , probably due to its modulatory activity on 5 - HT metabolism and / or its ability to reduce colonic malignant events .",
"miRNA signature and Dicer requirement during human endometrial stromal decidualization in vitro . Decidualization is a morphological and biochemical transformation of endometrial stromal fibroblast into differentiated decidual cells , which is critical for embryo implantation and pregnancy establishment . The complex regulatory networks have been elucidated at both the transcriptome and the proteome levels , however very little is known about the post - transcriptional regulation of this process . miRNAs regulate multiple physiological pathways and their de - regulation is associated with human disorders including gynaecological conditions such as endometriosis and preeclampsia . In this study we profile the miRNAs expression throughout human endometrial stromal ( hESCs ) decidualization and analyze the requirement of the miRNA biogenesis enzyme Dicer during this process . A total of 26 miRNAs were upregulated and 17 miRNAs downregulated in decidualized hESCs compared to non - decidualized hESCs . Three miRNAs families , miR - 181 , miR - 183 and miR - 200 , are down - regulated during the decidualization process . Using miRNAs target prediction algorithms we have identified the potential targets and pathways regulated by these miRNAs . The knockdown of Dicer has a minor effect on hESCs during in vitro decidualization . We have analyzed a battery of decidualization markers such as cell morphology , P01236 , P08833 , P55773 and P35625 secretion as well as P31260 , P35354 , SP1 , C / EBPß and Q12778 expression in decidualized hESCs with decreased Dicer function . We found decreased levels of P31260 and altered intracellular organization of actin filaments in Dicer knockdown decidualized hESCs compared to control . Our results provide the miRNA signature of hESC during the decidualization process in vitro . We also provide the first functional characterization of Dicer during human endometrial decidualization although surprisingly we found that Dicer plays a minor role regulating this process suggesting that alternative biogenesis miRNAs pathways must be involved in human endometrial decidualization .",
"The P28335 receptor agonist lorcaserin reduces nicotine self - administration , discrimination , and reinstatement : relationship to feeding behavior and impulse control . ___MASK53___ ( ( 1R ) - 8 - chloro - 1 - methyl - 2 , 3 , 4 , 5 - tetrahydro - 1H - 3 - benzazepine HCl ) is a selective 5 - HT ( 2C ) receptor agonist with clinical efficacy in phase - III obesity trials . Based on evidence that this drug class also affects behaviors motivated by drug reinforcement , we compared the effect of lorcaserin on behavior maintained by food and nicotine reinforcement , as well as the stimulant and discriminative stimulus properties of nicotine in the rat . Acutely administered lorcaserin ( 0 . 3 - 3 mg / kg , subcutaneous ( SC ) ) dose dependently reduced feeding induced by 22 - h food deprivation or palatability . Effects up to 1 mg / kg were consistent with a specific effect on feeding motivation . ___MASK53___ ( 0 . 6 - 1 mg / kg , SC ) reduced operant responding for food on progressive and fixed ratio schedules of reinforcement . In this dose range lorcaserin also reversed the motor stimulant effect of nicotine , reduced intravenous self - administration of nicotine , and attenuated the nicotine cue in rats trained to discriminate nicotine from saline . ___MASK53___ also reduced the reinstatement of nicotine - seeking behavior elicited by a compound cue comprising a nicotine prime and conditioned stimulus previously paired with nicotine reinforcement . ___MASK53___ did not reinstate nicotine - seeking behavior or substitute for a nicotine cue . Finally , lorcaserin ( 0 . 3 - 1 mg / kg ) reduced nicotine - induced increases in anticipatory responding , a measure of impulsive action , in rats performing the five - choice serial reaction time task . Importantly , these results indicate that lorcaserin , and likely other selective 5 - HT ( 2C ) receptor agonists , similarly affect both food - and nicotine - motivated behaviors , and nicotine - induced impulsivity . Collectively , these findings highlight a therapeutic potential for 5 - HT ( 2C ) agonists such as lorcaserin beyond obesity into addictive behaviors , such as nicotine dependence .",
"Therapeutic targeting of CPT - 11 induced diarrhea : a case for prophylaxis . CPT - 11 ( irinotecan ) , a P11387 inhibitor is one of the main treatments for colorectal cancer . The main dose limiting toxicities are neutropenia and late onset diarrhea . Though neutropenia is manageable , CPT - 11 induced diarrhea is frequently severe , resulting in hospitalizations , dose reductions or omissions leading to ineffective treatment administration . Many potential agents have been tested in preclinical and clinical studies to prevent or ameliorate CPT - 11 induced late onset diarrhea . It is predicted that prophylaxis of CPT - 11 induced diarrhea will reduce sub - therapeutic dosing as well as hospitalizations and will eventually lead to dose escalations resulting in better response rates . This article reviews various experimental agents and strategies employed to prevent this debilitating toxicity . Covered topics include schedule / dose modification , intestinal alkalization , structural / chemical modification , genetic testing , anti - diarrheal therapies , transporter ( P08183 , Q92887 , Q96JK2 ) inhibitors , enzyme ( β - glucuronidase , P22309 , P08684 , carboxylesterase , P35354 ) inducers and inhibitors , probiotics , antibiotics , adsorbing agents , cytokine and growth factor activators and inhibitors and other miscellaneous agents .",
"Gene - environment interactions in parkinsonism and Parkinson ' s disease : the Geoparkinson study . OBJECTIVES : To investigate associations of Parkinson ' s disease ( PD ) and parkinsonian syndromes with polymorphic genes that influence metabolism of either foreign chemical substances or dopamine and to seek evidence of gene - environment interaction effects that modify risk . METHODS : A case - control study of 959 prevalent cases of parkinsonism ( 767 with PD ) and 1989 controls across five European centres . Occupational hygienists estimated the average annual intensity of exposure to solvents , pesticides and metals , ( iron , copper , manganese ) , blind to disease status . P10635 , P27169 , P09488 , P30711 , P21266 , P09211 , P15559 , Q16678 , P21397 , P27338 , SOD 2 , P07099 , Q01959 , P14416 and NAT2 were genotyped . Results were analysed using multiple logistic regression adjusting for key confounders . RESULTS : There was a modest but significant association between P21397 polymorphism in males and disease risk ( G vs T , OR 1 . 30 , 95 % CI 1 . 02 to 1 . 66 , adjusted ) . The majority of gene - environment analyses did not show significant interaction effects . There were possible interaction effects between P09488 null genotype and solvent exposure ( which were stronger when limited to PD cases only ) . CONCLUSIONS : Many small studies have reported associations between genetic polymorphisms and PD . Fewer have examined gene - environment interactions . This large study was sufficiently powered to examine these aspects . P09488 null subjects heavily exposed to solvents appear to be at increased risk of PD . There was insufficient evidence that the other gene - environment combinations investigated modified disease risk , suggesting they contribute little to the burden of PD .",
"Dopamine receptors and psychiatric drug treatment . The established antipsychotic drugs act mainly by antagonizing dopamine mediated synaptic transmission in the brain . Increase in the rate of production of dopamine metabolites as well as the firing rate of dopamine - containing neurons can be interpreted as compensatory responses to an interruption of synaptic transmission at dopamine nerve terminals . The demonstration of involvement of limbic and cortical mechanisms in the antipsychotic activity of neuroleptic drugs is far more difficult than the involvement of nigro - striatal and tubero - infundibular mechanisms in the neurological and neuroendocrine effects of these drugs . Application of radioreceptor techniques to dopamine research has supported the findings obtained by other neuropsychopharmacological research techniques , providing more direct evidence of dopamine receptor blockade by neuroleptic drugs . Further research is needed especially in studying the nature of the time - dependent adaptive changes at the receptor sites as well as the differences between the different dopamine projections and neural systems in the brain . The different subtypes of dopamine receptors in the brain , currently called D1 and D2 dopamine receptors , seem to be parallel , although in many respects independently - acting regulatory systems . P14416 - selective antagonists such as sulpiride seem to cause selective D2 receptor up - regulation . P01236 secretion seems to be regulated by D2 dopamine receptors . The exact physiological role of D1 dopamine receptors as well as the clinical consequences of selective D1 antagonism is not known . ___MASK57___ and clozapine are examples of atypical neuroleptic compounds that have quite different profile of action , the former having strong and selective antidopaminergic action , the latter combining a number of non - dopaminergic mechanisms with rather slight effects on dopamine receptors . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Acetylbritannilactone suppresses lipopolysaccharide - induced vascular smooth muscle cell inflammatory response . To investigate the mechanism of action by which a new anti - inflammatory active compound , 1 - O - acetylbritannilactone ( P00519 ) isolated from Inula britannica - F . , inhibits inflammatory responses in vascular smooth muscle cells ( VSMCs ) . Enzyme immunoassay was used to measure the levels of prostandin E ( 2 ) ( PGE ( 2 ) ) production . Immunocytochemistry staining and Western blot analysis were performed to detect the nuclear translocation of nuclear factor - kappaB ( NF - kappaB ) p65 and the expression of IkappaB - alpha , pIkappaB - alpha and cyclooxygenase - 2 ( P35354 ) . Electrophoretic mobility shift assays ( EMSA ) were used to detect DNA - binding activity of NF - kappaB in VSMCs . P00519 ( 5 , 10 , 20 micrommol / l ) had several concentration - dependent effects , including inhibition of lipopolysaccharide ( LPS ) - induced PGE ( 2 ) production and P35354 expression , and blockade of NF - kappaB activation and translocation . These effects were owing to reductions in IkappaB - alpha phosphorylation and degradation induced by LPS . In addition , P00519 directly inhibited the binding of active NF - kappaB to specific DNA cis - element . These results indicate that P00519 is a potent inhibitor of LPS - stimulated VSMC inflammatory responses through blockade of NF - kappaB activity and inhibition of inflammatory gene P35354 expression .",
"Association between severe toxicity of nilotinib and P22309 polymorphisms in Japanese patients with chronic myelogenous leukemia . BACKGROUND : ___MASK96___ is a P11274 - P00519 kinase inhibitor approved for the treatment of Philadelphia chromosome - positive chronic myelogenous leukemia ( CML ) . The P22309 ( P22309 ) polymorphism P22309 * 28 ( * 28 ) /* 28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib . Beside * 28 , P22309 * 6 ( * 6 ) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan , metabolized by P22309 . We retrospectively investigated the association between severe toxicity of nilotinib and P22309 polymorphisms ( * 6 and * 28 ) in Japanese patients with CML . PATIENTS AND METHODS : Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of P22309 polymorphisms with severe nilotinib - related toxicity . Genotyping analyses were determined for * 6 and * 28 . RESULTS : All 3 patients with the * 6 /* 6 or * 6 /* 28 genotype had severe toxicity , including QT interval prolongation ( grade 3 ) , elevated lipase levels ( grade 3 ) plus hyperbilirubinemia ( grade 2 ) , and anemia ( grade 3 ) plus hepatic cyst hemorrhage ( grade 2 ) in 1 patient each . Among the 5 patients with the * 6 /* 1 or * 1 /* 1 genotype , 1 had elevated lipase levels ( grade 3 ) and another had severe pain in the lower extremities ( grade 3 ) . CONCLUSION : These findings suggest that P22309 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients .",
"Cellular distribution and contribution of cyclooxygenase P35354 to diabetogenesis in NOD mouse . Unlike most other mammalian cells , beta - cells of Langerhans constitutively express cyclooxygenase ( P36551 ) - 2 rather than P23219 . P35354 is also constitutively expressed in type 1 diabetes ( T1D ) patients ' periphery blood monocytes and macrophage . To understand the role of P35354 in the beta - cell , we investigated P35354 expression in beta - cells and islet infiltrates of NOD and BALB / c mice using fluorescence immunohistochemistry and cytochemical confocal microscopy and Western blotting . Immunostaining showed that P35354 is expressed in islet - infiltrating macrophages , and that the expression of insulin and P35354 disappeared concomitantly from the beta - cells when NOD mice progressed toward overt diabetes . Also cultured P01308 - 1E cells coexpressed insulin and P35354 but clearly in different subcellular compartments . Treatment with celecoxib increased insulin release from these cells in a dose - dependent manner in glucose concentrations ranging from 5 to 17 mM . Excessive P35354 expression by the islet - infiltrating macrophages may contribute to the beta - cell death during insulitis . The effects of celecoxib on P01308 - 1E cells suggest that PGE ( 2 ) and other downstream products of P35354 may contribute to the regulation of insulin release from the beta - cells .",
"Role of P34969 receptors in the inhibition of the vasodepressor sensory CGRPergic outflow in pithed rats . The role of calcitonin gene - related peptide ( P80511 ) in the modulation of vascular tone has been widely documented . Indeed , electrical stimulation of the perivascular sensory outflow in pithed rats induces vasodepressor responses by activation of P80511 receptors . This study investigated the role of P34969 receptors in the inhibition of the rat vasodepressor sensory outflow . Male Wistar pithed rats were pretreated with i . v . continuous infusions of hexamethonium and methoxamine , followed by physiological saline or AS - 19 ( a P34969 receptor agonist ) . Then , electrical stimulation of the spinal cord resulted in frequency - dependent decreases in DBP . The infusions of AS - 19 , as compared to those of saline , inhibited the vasodepressor responses induced by electrical stimulation without affecting those to i . v . bolus injections of exogenous α - P80511 . This inhibition by AS - 19 was abolished by the antagonists pimozide ( P34969 ) or sulfisoxazole ( P25101 ) , but not by indomethacin ( P23219 / 2 ) or losartan ( AT1 ) , at doses that did not affect per se the electrically - induced vasodepressor responses . Interestingly , glibenclamide ( an DB00171 - dependent K (+) channel blocker ) attenuated these vasodepressor responses . The present results suggest that AS - 19 - induced inhibition of the rat vasodepressor sensory CGRPergic outflow is mainly mediated by P34969 receptors via endothelin release , with the possible involvement of DB00171 - dependent K (+) channels .",
"Meloxicam . Meloxicam ( DB00814 trade mark , Boehringer Ingelheim ) is a relatively new oral non - steroidal anti - inflammatory drug ( NSAID ) approved for the treatment of osteoarthritis in the US . It has also been evaluated for the treatment of rheumatoid arthritis , ankylosing spondylitis and acute ' rheumatic ' pain . Meloxicam has been shown to be P35354 preferential , particularly at its lowest therapeutic dose , and is anti - inflammatory by inhibiting prostanoid synthesis in inflammatory cells . Since it is P35354 preferential , it would be expected to have less gastrointestinal toxicity than non - selective NSAIDs . In clinical trials of meloxicam in osteoarthritis , it was found to be as effective as piroxicam , diclofenac and naproxen with less clinical gastrointestinal symptoms and less perforations , obstructions and bleeds by meta - analysis . Adverse events , including peripheral oedema and hypertension , occurred at a similar rate as with traditional NSAIDs .",
"5 - Q9H205 - and P28335 - antagonist properties of cyamemazine : significance for its clinical anxiolytic activity . RATIONALE : DB09000 is a neuroleptic compound which possesses anxiolytic properties in humans . On the other hand , 5 - Q9H205 - and P28335 - receptors have been implicated in anxiety disorders and a previous binding study has shown that cyamemazine possesses high affinity for both serotonin receptor types . OBJECTIVE : The present study was undertaken to establish whether cyamemazine antagonizes 5 - Q9H205 - and / or P28335 - mediated responses , and whether it compares with reference compounds . METHODS : DB09000 was tested for its ability to antagonize : ( i ) 5 - Q9H205 - dependent contraction of the isolated guinea - pig ileum and bradycardic responses in the rat and ( ii ) P28335 - dependent phospholipase C ( P98160 ) stimulation in rat brain membranes . RESULTS : In isolated guinea - pig ileum , cyamemazine potently and competitively antagonized 5 - HT - dependent contractions ( pA2 = 7 . 52 +/- 0 . 08 ; n = 5 ) . In this test , cyamemazine was 5 - 7 times more potent ( pIC50 = 6 . 75 +/- 0 . 13 ) than tropisetron ( pIC50 = 6 . 02 +/- 0 . 04 ) . In rats , cyamemazine i . v . antagonized 5 - HT - dependent bradycardic responses with ID50 % = 3 . 2 +/- 1 . 5 mg / kg ( n = 4 ) . Finally , in rat brain membranes cyamemazine antagonized P28335 - dependent P98160 stimulation with Ki = 424 nM ( mianserin exhibits a Ki = 113 nM ) . CONCLUSIONS : DB09000 behaves as an antagonist at both 5 - Q9H205 - and P28335 - receptors , which compares well with reference compounds . These 5 - Q9H205 - and P28335 - antagonistic actions of cyamemazine can be involved , at least in part , in its beneficial therapeutic actions in anxiety disorders .",
"Regulation of P01160 secretion from isolated atria by prostaglandins and cyclooxygenase - 2 . Cyclooxygenase ( P36551 ) is a key enzyme regulating the production of various prostaglandins ( PGs ) from arachidonic acid . Angiotensin II has been reported to be an important inflammatory mediator , which increases P35354 . The aim of this study was to determine the role of various PGs and P35354 in the regulation of atrial natriuretic peptide ( P01160 ) secretion . PGF2alpha and PGD2 caused dose - dependent increases in P01160 release and intra - atrial pressure . The potency for the stimulation of P01160 secretion by PGF2alpha was higher than that by PGD2 . In contrast , DB00917 , DB01240 , PGJ2 , and thromboxane A2 did not show any significant effects . The increases in intra - atrial pressure and P01160 secretion induced by PGF2alpha and PGD2 were significantly attenuated by the pretreatment with an inhibitor of PGF2alpha receptor . By the pretreatment with an inhibitor for phospholipase C ( P98160 ) , inositol 3 - phosphate ( IP3 ) receptor , protein kinase C ( PKC ) , or myosin light chain kinase ( MLCK ) , PGF2alpha - mediated increase in P01160 secretion and positive inotropy were attenuated . Inhibitor for P23219 or P35354 did not cause any significant effects on atrial parameters . In hypertrophied rat atria , PGF2alpha - induced positive inotropy and P01160 secretion were markedly attenuated whereas P35354 inhibitor stimulated P01160 secretion . The expression of P35354 increased and the expression of PGF2alpha receptor mRNA decreased in hypertrophied rat atria . These results suggest that PGF2alpha increased the P01160 secretion and positive inotropy through P98160 - IP3 - PKC - MLCK pathway , and the modulation of P01160 secretion by P35354 inhibitor and PGF2alpha may partly relate to the development of renal hypertension .",
"[ Innate resistance to thymidylate synthase inhibition after 5 - fluorouracil treatment -- a rationale of combined use of cisplatin and its optimal administration dose ] . We examined the changes of the number of ___MASK44___ MP binding sites of thymidylate thynthase ( TS - BS ) in Yoshida sarcoma after administration of DB00544 to the tumor bearing rats . We also investigated the optimal dose of DB00515 for the increase of intracellular folate level . In the group received consecutive 7 - days administration of DB09327 ( U - 7 group ) , total TS - BS was significantly increased compared with non - treatment group and the group received only DB09327 ( U - 1 group ) . For free TS - BS , however , there was no difference despite of DB09327 administration . P04818 inhibition rate ( TSIR ) was , therefore , significantly high in U - 7 group compared with U - 1 group . It seemed necessary to take some counter measure for the induction of TS in the tumor tissue when DB00544 chemotherapy was performed . The optimal dose of DB00515 as a modulator of DB00544 was 1 mg / kg in rat when it was estimated from the changes of intracellular folate levels after administration , which was less than the dose to reveal its own anticancer effect ."
] |
[
"___MASK41___",
"___MASK44___",
"___MASK53___",
"___MASK57___",
"___MASK79___",
"___MASK82___",
"___MASK90___",
"___MASK96___",
"___MASK97___"
] |
___MASK44___
|
MH_train_485
|
interacts_with DB00065?
|
[
"DB00065 acts directly on human osteoclast precursors and enhances osteoclast formation induced by receptor activator of nuclear factor kappaB ligand in vitro . DB00065 is known to protect against the development of joint destruction . In the present study , we sought to determine whether DB00065 acts directly on human osteoclast precursors and influences monocyte - osteoclast differentiation induced by receptor activator of nuclear factor kappaB ligand ( O14788 ) in vitro . Peripheral blood mononuclear cells ( PBMCs ) isolated from rheumatoid arthritis ( RA ) patients and normal controls were cultured in the presence of O14788 and macrophage colony stimulating factor . DB00065 , antihuman tumor necrosis factor alpha ( TNFalpha ) , antihuman P01375 soluble receptor p55 ( TNFR p55 ) , and antihuman P01375 soluble receptor p75 ( TNFR p75 ) antibodies were added . Osteoclast formation was determined by assessing the number of tartrate - resistant acid phosphatase ( TRAP ) staining cells and the extent of lacunar resorption . Addition of DB00065 resulted in a marked increase in the number of TRAP - positive multinucleated cells ( TRAP (+) MNCs ) and in the extent of lacunar resorption compared with the control cultures . Antihuman TNFalpha antibody showed the same effect ; however , the addition of neither TNFR p55 nor TNFR p75 antibody affected the extent of TRAP (+) MNCs and lacunar resorption . Our results suggest that infliximab acts directly on early osteoclast precursors , and stimulates osteoclast formation and lacunar resorption induced by O14788 in vitro .",
"DB00065 in relapsing polychondritis . Relapsing polychondritis ( RP ) is a rare systemic disease of unknown etiology , characterized by recurrent inflammation of cartilaginous structures and other connective tissues , including the ears , nose , joints , respiratory tract , and others . Due to the presence of typical signs and symptoms , biopsy is seldom necessary . Treatment includes corticosteroids , occasionally associated with immunosuppressive agents , but refractory cases are described . Recent reports suggest that anti - P01375 agents , such as infliximab , may be of value in patients who do not respond to conventional therapy , but experience with this treatment is scarce . In this paper , the authors report the case of a patient with RP refractory to combined treatment with corticosteroids and immunosuppressive agents , who showed a good response to infliximab .",
"Selecting appropriate anti - P01375 agents in inflammatory bowel disease . DB00065 was the first anti - P01375 agent to be approved by the US FDA for the treatment of Crohn ' s disease ( CD ) in 1998 . In the past 10 years , two other agents , adalimumab and certolizumab pegol , have also been approved for the treatment of CD . In the absence of head - to - head comparisons , the efficacy of these agents appear to be similar for the treatment of luminal CD . There are also prospective , randomized , controlled data to support the use of infliximab for the treatment of fistulizing CD and ulcerative colitis , and supportive post hoc data for the use of adalimumab and certolizumab pegol for the treatment of fistulizing CD . Practical matters , such as patient preference regarding the mode of administration , approval by third - party payers and residual patient cost , may actually play a larger role in choosing a particular anti - P01375 agent , as efficacy and safety issues are similar for all three . Unfortunately , many patients do not respond , lose response or develop intolerance to anti - P01375 treatment . Thus , new therapies are needed . DB00108 , the first biologic that is not an anti - P01375 agent , was FDA - approved in January 2008 for the treatment of CD patients who have failed conventional treatment , including anti - P01375 therapy . As we continue to learn more about the pathogenesis of inflammatory bowel disease , novel targets for drug therapy are being developed .",
"Spinal epidural abscess associated with infliximab treatment for psoriatic arthritis . Case report . P01375 - alpha inhibitors are used to treat numerous chronic inflammatory and rheumatological diseases , such as Crohn disease , rheumatoid arthritis , and psoriatic arthritis . Because the mechanism of these inhibitors is to decrease the body ' s inflammatory response , the primary complication of treatment is infection . The authors present the first case of a spinal epidural abscess in a patient receiving long - term infliximab therapy for severe psoriatic arthritis . DB00065 and its side - effect profile are discussed , along with other associated complications .",
"[ Efficacy and security of tumor necrosis factor antagonists in the treatment of rheumatoid arthritis ] . In the last decade , tumor necrosis factor ( P01375 ) antagonists had supposed an important therapeutic advance in the treatment of patients with rheumatoid arthritis ( RA ) in both early and established RA . Three agents currently available -- infliximab , etanercept , and adalimumab -- have been designed to modify the biologic effects of P01375 . DB00065 and adalimumab are monoclonal antibodies , whereas etanercept is a soluble protein , with different pharmacokinetic and pharmacodynamic properties , conditioning some possible adverse effects . Although comparative studies are not available , the 3 drugs have demonstrated efficacy and security , with a better quality of life of patients with RA . DB00065 , etanercept and adalimumab have been proved alone and in combination with methotrexate , with a better therapeutic , clinical , radiological and functional response in the group under combined therapy . Both clinical trials and post - market experience have demonstrated the security of these drugs , minimizing the risks with an adequate selection of patients .",
"Advances in the treatment of Kawasaki disease . PURPOSE OF REVIEW : Intravenous immunoglobulin ( IVIG ) and aspirin is the standard initial therapy in the treatment of Kawasaki disease . Some patients have persistent or recrudescent fever despite this therapy . Although there is no conclusive body of evidence defining the best second and third - line therapies for Kawasaki patients , there have been several recent studies published describing the results of these therapies . RECENT FINDINGS : This review summarizes the current recommendations for the initial therapy and describes the second and third - line therapies studied in Japan and the United States . A recent study in a Japanese population of Kawasaki disease patients at high risk for IVIG resistance found that the group receiving steroids , in addition to IVIG and aspirin , had fewer coronary artery abnormalities than the group receiving IVIG and aspirin alone . Small studies of etanercept and infliximab have showed these P01375 blockers to be well tolerated and effective in the resolution of fever . SUMMARY : Although most practitioners in the USA use IVIG as a second - line therapy for those Kawasaki disease patients who have persistent or recrudescent fever , promising new therapies are under study . DB00065 and steroids are currently the two agents that have been most studied . However , larger studies and studies in genetically diverse populations are needed .",
"Treatment of inflammatory bowel disease : a review of medical therapy . Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) are chronic inflammatory diseases of the gastrointestinal tract . While a cure remains elusive , both can be treated with medications that induce and maintain remission . With the recent advent of therapies that inhibit tumor necrosis factor ( P01375 ) alpha the overlap in medical therapies for UC and CD has become greater . Although DB00244 agents have been a mainstay in the treatment of both CD and UC , the data for their efficacy in patients with CD , particularly as maintenance therapy , are equivocal . Antibiotics may have a limited role in the treatment of colonic CD . Steroids continue to be the first choice to treat active disease not responsive to other more conservative therapy ; non - systemic steroids such as oral and rectal budesonide for ileal and right - sided CD and distal UC respectively are also effective in mild - moderate disease . 6 - mercaptopurine ( DB01033 ) and its prodrug azathioprine are steroid - sparing immunomodulators effective in the maintenance of remission of both CD and UC , while methotrexate may be used in both induction and maintenance of CD . DB00065 and adalimumab are anti - P01375 agents approved in the US and Europe for the treatment of Crohn ' s disease , and infliximab is also approved for the treatment of UC .",
"Pharmacological properties of thalidomide and its analogues . Thalidomide and its immunomodulatory imide drugs ( IMiDs ) analogues DB00480 ( DB00480 , DB00480 ) and CC - 4047 ( Actimid , ___MASK55___ ) have been used as anti - inflammatory and anticancerous drugs in the recent years . Thalidomide and IMiDs inhibit the cytokines tumour necrosis factor - alpha ( P01375 ) , interleukins ( IL ) 1 - beta , 6 , 12 , and granulocyte macrophage - colony stimulating factor ( GM - P04141 ) . They also costimulate primary human T , NKT and NK lymphocytes inducing their proliferation , cytokine production , and cytotoxic activity . On the other hand , the compounds are anti - angiogenic , anti - proliferative , and pro - apoptotic . Thalidomide analogues have been used as inhibitors of alpha glucosidase and could be potential drugs for diabetes treatment . In this review , we explore the current trend of the different structures , the new patents , and the possible new applications in different pathologies .",
"Augmentation by citalopram of risperidone - induced monoamine release in rat prefrontal cortex . RATIONALE : A typical antipsychotics ( APDs ) , e . g . olanzapine and risperidone , have been reported to be effective adjunctive treatment for depression if selective serotonin ( 5 - HT ) reuptake inhibitors ( SSRIs ) alone are ineffective . OBJECTIVES AND METHODS : We utilized microdialysis in awake , freely moving rats to study the effect of risperidone in combination with citalopram , an SSRI , on extracellular 5 - HT , dopamine ( DA ) , and norepinephrine ( NE ) efflux in rat medial prefrontal cortex ( mPFC ) . RESULTS : ___MASK34___ ( 1 . 0 mg / kg , s . c . ) , given alone , significantly increased 5 - HT , DA , and NE concentrations in the mPFC . DB00215 ( 10 mg / kg , s . c . ) , by itself , produced a significant increase in 5 - HT levels only . The combination of risperidone and citalopram produced significantly greater increases in efflux of both DA and NE than risperidone alone . However , the effect of this combination on extracellular 5 - HT concentrations was not significantly different than that of citalopram alone . The augmentation of DA and NE efflux induced by risperidone plus citalopram could be partially blocked by the selective P08908 antagonist , WAY 100635 ( 0 . 2 mg / kg , s . c . ) . CONCLUSIONS : The results suggest that the ability of atypical APDs to augment the therapeutic efficacy of SSRIs in major depression and treatment - resistant depression may be due , at least in part , to potentiation of SSRI - induced increases in cortical DA and NE . The contributions of P08908 receptor stimulation and 5 - Q13049 and alpha2 adrenergic receptor antagonism to this augmentation are discussed .",
"Anti - P01375 immunotherapy is associated with increased gingival inflammation without clinical attachment loss in subjects with rheumatoid arthritis . BACKGROUND : Because periodontitis presents many similarities with rheumatoid arthritis ( RA ) with regard to tumor necrosis factor - alpha ( P01375 ) - induced bone resorption , the benefits of P01375 blockade in RA prompted us to determine its efficacy in treating coexisting periodontitis . METHODS : Periodontal status was evaluated in 40 subjects with RA who were divided into two groups : Group I contained 20 subjects who had received infliximab every 6 weeks for > or = 22 months at the time of periodontal evaluation . The 20 subjects in group II were evaluated before their first infusion with infliximab . Nine subjects in group II had periodontitis . These subjects were reevaluated after they received nine infusions of infliximab . RESULTS : DB00065 tended to aggravate gingival inflammation as indicated by differences in the modified gingival and papillary bleeding indices between subjects in groups I and II with coexisting periodontitis before and after treatment . DB00563 had no effect on periodontal status . Although the plaque index revealed that bacterial infection persisted , the probing depth was equal in groups I and II and equivalent before and after treatment in subjects with periodontitis , whereas attachment loss was decreased after infliximab treatment . CONCLUSIONS : Inflammation and destruction constitute two interrelated yet separate components of periodontitis in patients with RA . Therefore , P01375 blockade could be beneficial in the treatment of periodontitis .",
"[ The immune status changes in patients with inflammatory bowel disease under the influence of mesenchymal stromal cells and infliximab therapy ] . Out of 28 patients with inflammatory bowel disease in 11 ( 39 . 3 % ) revealed the presence of autoantibodies to gastric parietal cells . Appointment of O60682 and infliximab did not lead to a reduction in antibody levels , in fact , in 6 ( 21 . 4 % ) patients had a further increase in the content of mentioned autoantibodies . Identification of autoantibodies to gastric parietal cells is considered as adherence to Q9UKU7 autoimmune gastritis ( formation of a systemic process ) that requires use of corticosteroids . Transplantation of mesenchymal stromal cells in Q9UKU7 reduces enhanced circulation of autoantibodies against antigens of neutrophils cytoplasmic structures , thereby reducing the severity of autoimmune reactions . Transplantation of MSCs reduces autoaggression in patients with ulcerative colitis , reducing the autoreactive clone of B lymphocytes ( P15391 + P06127 + ) . Analysis effectiveness of the therapy . Transplantation of MSCs in Q9UKU7 has a systemic immunoregulatory effect : on the one hand , stimulates oppressed cytokine synthesis , on the other -- reduses the intensity of the autoimmune reactions and activity of pathological processes . DB00065 selectively blocks P01375 , without affecting other proinflammatory cytokines .",
"DB00065 : lack of efficacy on perforating complications in Crohn ' s disease . BACKGROUND : DB00065 ( Remicade ) , a chimeric monoclonal antibody against tumor necrosis factor alpha ( P01375 ) , has emerged as promising therapeutic option in perianal fistulizing Crohn ' s disease ( CD ) . However , little knowledge exists about its use for the treatment of internal fistulas in CD . We present our experience with infliximab in this situation . METHODS : Four patients with CD who had internal fistulas ( Case 1 : entero - enteral and entero - abdominal ; Case 2 : entero - enteral ; Case 3 : entero - enteral and parastomal ; Case 4 : entero - vesical ) were treated with 3 infusions of infliximab ( 5 mg / kg body weight ) with intervals of 2 and 4 weeks . In addition , 3 patients had strictures and 2 patients had perianal fistulas . RESULTS : After the three infusions of infliximab ( 5 mg / kg body weight ) , internal fistulas remained unchanged in all patients . The perianal fistulas present in 2 cases were healed . Administration of infliximab was safe and well tolerated in all cases . CONCLUSION : Treatment with 3 infusions of infliximab ( 5 mg / kg body weight ) led to healing of only the perianal fistulas , whereas the internal fistulas were not influenced . We conclude that in these 4 cases , infliximab was well tolerated but not effective for the management of internal fistulas and was no alternative for surgery .",
"Redo Ileal pouch - anal anastomosis combined with anti - P01375 - α maintenance therapy for Crohn ' s disease with pelvic fistula : report of two cases . Pouch failure has been reported to occur after ileal pouch - anal anastomosis for Crohn ' s disease . We report two cases of patients with Crohn ' s disease , who underwent redo ileal pouch - anal anastomosis ( redo - IPAA ) combined with anti - P01375 - α maintenance therapy , with good functional results . The first patient , a man with presumed ulcerative colitis , suffered pelvic fistula recurrence and anastomotic dehiscence . He underwent redo - IPAA , at which time longitudinal ulcers were found . DB00065 was started 4 days postoperatively and continued . The second patient , a woman treated for ulcerative colitis , underwent laparoscopic IPAA 8 years later . After the development of a pelvic fistula , twisted mesentery of the ileal pouch was found intraoperatively and Crohn ' s disease was diagnosed . DB00051 therapy resulted in fistula closure . Redo - IPAA was performed to normalize the twisted mesentery of the ileal pouch . No complications have been observed in either patient , both of whom have experienced good functional results after closure of the covering stomas .",
"DB03419 incorporation into genomic DNA does not predict toxicity caused by chemotherapeutic inhibition of thymidylate synthase . P04818 ( TS ) is an important target of several chemotherapeutic agents , including DB00544 and raltitrexed ( ___MASK93___ ) . During TS inhibition , TTP levels decrease with a subsequent increase in dUTP . DB03419 incorporated into the genome is removed by base excision repair ( BER ) . Thus , BER initiated by uracil DNA glycosylase ( P13051 ) activity has been hypothesized to influence the toxicity induced by TS inhibitors . In this study we created a human cell line expressing the Ugi protein inhibitor of P13051 family of UDGs , which reduces cellular P13051 activity by at least 45 - fold . Genomic uracil incorporation was directly measured by mass spectrometry following treatment with TS inhibitors . Genomic uracil levels were increased over 4 - fold following TS inhibition in the Ugi - expressing cells , but did not detectably increase in P13051 proficient cells . Despite the difference in genomic uracil levels , there was no difference in toxicity between the P13051 proficient and P13051 - inhibited cells to folate or nucleotide - based inhibitors of TS . Cell cycle analysis showed that P13051 proficient and P13051 - inhibited cells arrested in early S - phase and resumed replication progression during recovery from RTX treatment almost identically . The induction of gamma - P16104 was measured following TS inhibition as a measure of whether uracil excision promoted DNA double strand break formation during S - phase arrest . Although gamma - P16104 was detectable following TS inhibition , there was no difference between P13051 proficient and P13051 - inhibited cells . We therefore conclude that uracil excision initiated by P13051 does not adequately explain the toxicity caused by TS inhibition in this model .",
"Genetic polymorphisms of tumour necrosis factor receptor superfamily 1A and 1B affect responses to infliximab in Japanese patients with Crohn ' s disease . BACKGROUND : Tumour necrosis factor alpha is the key inflammatory cytokine involved in the pathogenesis of Crohn ' s disease . DB00065 , a chimaeric monoclonal antibody of tumour necrosis factor - alpha is successfully used for the treatment of Crohn ' s disease , although the response to infliximab therapy differs among patients . The genetic background of the individual may partially explain the differences of the responsiveness . AIM : To investigate whether the polymorphisms in these genes are associated with the response to infliximab treatment as tumour necrosis factor - alpha exerts its biological activity through P01375 receptor superfamily 1A and 1B . METHODS : Eighty Crohn ' s disease patients were enrolled in the study and classified into responder and nonresponder according to the efficacy of infliximab treatment . Single nucleotide polymorphisms of P01375 receptor superfamily 1A ( rs767455 and rs4149570 ) and P01375 receptor superfamily 1B ( rs1061622 , rs1061624 and rs3397 ) were determined . RESULTS : The minor allele carrier of rs767455 showed a significant association with a lack of efficacy compared to the major genotype ( OR = 0 . 26 ; 95 % CI : 0 . 08 - 0 . 91 ) . A P01375 receptor superfamily 1B haplotype inferred by rs1061624 and rs3397 also showed significant differences in the distribution between responder and nonresponder ( P = 0 . 01 ) . CONCLUSION : These results suggest that tumour necrosis factor receptor genotypes may be involved in the different responses to infliximab in Japanese patients with Crohn ' s disease .",
"Screening of 134 single nucleotide polymorphisms ( SNPs ) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes . More than 120 published reports have described associations between single nucleotide polymorphisms ( SNPs ) and type 2 diabetes . However , multiple studies of the same variant have often been discordant . From a literature search , we identified previously reported type 2 diabetes - associated SNPs . We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium ( r ( 2 ) > 0 . 8 ) with another typed SNP . Of the 114 SNPs examined , we followed up the 20 most significant SNPs ( P < 0 . 10 ) on an additional 384 case subjects and 366 control subjects from a population - based study in Finland . In the combined data , we replicated association ( P < 0 . 05 ) for 12 SNPs : P37231 Pro12Ala and His447 , Q14654 Glu23Lys and rs5210 , P01375 - 857 , P11168 Ile110Thr , P20823 / TCF1 rs2701175 and GE117881_360 , P35558 - 232 , Q13562 Thr45Ala , P05231 - 598 , and P22413 Lys121Gln . The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association ( P = 0 . 012 ) . We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample ( P = 0 . 03 ) , although we also replicated 4 of 58 SNPs from genes that had only one previous report of association .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK28___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"Experiences with a long - term treatment of a massive gluteal acne inversa with infliximab in Crohn ' s disease . BACKGROUND : In 40 % of all cases of Crohn ' s disease fistulas emerge during the course of disease . Nevertheless , acne inversa has to be taken into account as an infrequent differential diagnosis . DB00065 as an antibody against the pro - inflammatory mediator P01375 is active in cases of acute Crohn ' s disease , concomitant fistulas and cutaneous manifestations . CASE REPORT : We report on the case of a 54 - year - old patient suffering for five years from a severe suppurative fistuling cutaneous disease concomitant to Crohn ' s disease . At the start of treatment the histological findings of a specimen presented chronically fibrosing lymphoplasmacellular dermatitis with both a very high number of plasma cells and a burrow - like fistula system . Due to superinfection the treatment was at first based on the administration of intravenous and oral doses of antibiotic agents , followed by a treatment course of 14 months with methotrexate and seven applications of infliximab . During the Crohn ' s disease , which was accompanied by persisting concomitant discomforts , an extensive surgical sanitation of the fistulous tracts was performed . Acne inversa was diagnosed in the subsequent histological analysis of the operative specimen . CONCLUSIONS : Acne inversa is a very rare cutaneous disease . Several case reports describe the successful treatment of acne inversa concomitant to Crohn ' s disease using anti - P01375 - antibodies . The long - term course of the case presented here shows that the non - response to infliximab might be caused by both the long duration and the distinct grade of seriousness of the acne inversa .",
"DB00065 in ulcerative colitis . DB00065 , a monoclonal anti - P01375 antibody , is commonly used for treatment of moderate to severe Crohn ' s disease ( CD ) . Its role in the treatment for ulcerative colitis ( UC ) remains controversial . We review the role of P01375 in the pathogenesis of UC and describe the randomized , double - blind , placebo - controlled trials and systematic reviews that assess the efficacy of infliximab in the treatment of moderate to severe UC .",
"The link between unpredictable chronic mild stress model for depression and vascular inflammation ? Inflammation has been suggested to be associated with stress - induced depression and cardiovascular dysfunction . P01375 alpha ( P01375 - α ) is a major cytokine in the activation of neuroendocrine , immune , and behavioral responses . In this study , we investigated the effects of infliximab ( a P01375 - α inhibitor ) on endothelium - dependent vascular reactivity , systemic blood pressure , and endothelial nitric oxide synthase ( P29474 ) immunoreactivity in the unpredictable chronic mild stress ( UCMS ) model of depression in rats . There was no significant change between all groups in the systemic blood pressure . In UCMS , endothelium - dependent relaxation of the smooth muscle in response to carbachol was significantly decreased with 50 % maximal response ( E max ) and pD2 values compared with the controls . DB00065 was able to reverse this UCMS effect . Relaxation in response to the nitric oxide ( NO ) donor sodium nitroprusside and papaverine and DB00761 - induced contractile responses was similar between groups . In UCMS , decreased expression of P29474 was detected . Moreover , there was no significant change in UCMS + infliximab group with respect to control rats . Our results suggest that tumor necrosis factor - alpha ( P01375 - α ) could be a major mediator of vascular dysfunction associated with UCMS , leading to decreased expression of P29474 .",
"Linkage assignment of eleven genes to the porcine genome . We report comparative linkage mapping of eleven genes in the swine genome by RFLP analysis . These genes include : Acid phosphatase type 5 ( P13686 ) , Cholecystokinin Type B Receptor ( P32239 ) , Antibiotic Peptide ( P49913 ) , P01308 - like Growth Factor 1 Receptor ( P08069 ) , Integrin Alpha M ( P11215 ) , Integrin Beta 2 ( ITGbeta2 ) , Opioid Receptor Mu - 1 ( P35372 ) , Pro - hormone Converter ( PC1 / 3 ) , DB00162 Binding Q12988 ( P10745 ) , Ribosomal DNA ( RNR1 ) , and Zona Pellucida Glycoprotein 1 ( P60852 ) . The P32239 and ITGbeta2 loci define the ends of the linkage groups on Chromosomes ( Chro ) ( SSC ) 9p and 13qter , respectively .",
"DB00065 for the therapy of chronic sarcoidosis , Baughman RP , Drent M , Kavuru M et al . : DB00065 therapy in patients with chronic sarcoidosis and pulmonary involvement . Am . J . Respir . Crit . Care Med . ( 2006 ) 174 ( 7 ): 795 - 802 . Sarcoidosis is an inflammatory multiorgan disease in which the lungs are the most commonly affected . It can also involve the skin , lupus pernio being a common form of chronic cutaneous sarcoidosis . The histopathologically specific lesion is represented by non - caseating granulomas occurring in the involved organs , with P01375 playing a role in granuloma generation . Several therapies are available , with corticosteroids representing the conventional therapy given as topic or systemic formulations . Anti - P01375 therapies ( such as etanercept or infliximab ) have been assessed so far , the latter most commonly in refractory sarcoidosis . The discussed study evaluates the safety and efficacy of infliximab in chronic sarcoidosis with pulmonary manifestations .",
"Niacin reduces plasma P11597 levels by diminishing liver macrophage content in P11597 transgenic mice . The anti - dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of P11597 . Since liver macrophages contribute to hepatic P11597 expression , we investigated the role of macrophages in the P11597 - lowering effect of niacin in mice . In vitro studies showed that niacin does not directly attenuate P11597 expression in macrophages . Treatment of normolipidemic human P11597 transgenic mice , fed a Western - type diet with niacin for 4 weeks , significantly reduced the hepatic cholesterol concentration ( - 20 % ) , hepatic P11597 gene expression ( - 20 % ) , and plasma P11597 mass ( - 30 % ) . Concomitantly , niacin decreased the hepatic expression of P34810 ( - 44 % ) and P45844 ( - 32 % ) , both of which are specific markers for the hepatic macrophage content . The decrease in hepatic P11597 expression was significantly correlated with the reduction of hepatic macrophage markers . Furthermore , niacin attenuated atherogenic diet - induced inflammation in liver , as evident from decreased expression of P01375 ( - 43 % ) . Niacin similarly decreased the macrophage markers and absolute macrophage content in hyperlipidemic P02649 * 3 - Leiden . P11597 transgenic mice on a Western - type diet . In conclusion , niacin decreases hepatic P11597 expression and plasma P11597 mass by attenuating liver inflammation and macrophage content in response to its primary lipid - lowering effect , rather than by attenuating the macrophage P11597 expression level .",
"Is there a benefit from the concomitant use of immunosupression with anti - P01375 in Crohn ' s disease ; heads or tails ? Over the last some years the increasing knowledge on the pathogenesis of Crohn ' s disease led to the development of a number of biological agents targeting specific molecules involved in gut inflammation , first of all P01375 and its receptors . DB00065 , adalimumab and certolizumab have been successful in inducing and maintaining remission in Crohn ' s disease at both short and long term . This was recently confirmed by a Cochrane meta - analysis and also open label extension follow - up and cohort studies . Emerging new data however indicate that combination therapy with infliximab - azathioprine appears to have added benefit in inducing steroid - free remission and mucosal healing than either infliximab or azathioprine alone in azathioprine - naïve patients with early disease . Similarly the combination of steroids induction and infliximab was efficacious in luminal Crohn ' s disease . In contrast , there seems to be no synergism between methotrexate and infliximab . It is also less clear whether it is beneficial to use short or long - term infliximab - azathioprine combination in patients who previously failed therapy with azathioprine . In contrast , combination may potentially be associated with increased risk for infection and cancer . In case control - studies , especially the combination of steroids and anti - P01375 and older age increased the risk for infectious complications , while scattered case reports point to the potentially increased risk of a rare form of non - Hodgkin ' s lymphoma ( Hepatosplenic T cell lymphoma ) with the use of azathioprine - anti - P01375 combination . The aim of this review is to summarize the benefits and risks for the use combination therapy with P01375 inhibitors in the treatment of Crohn ' s disease .",
"High - dose infliximab prophylaxis in endotoxin - induced uveitis . PURPOSE : The aim of this study to analyze the preventive effect of high - dose infliximab in endotoxin - induced uveitis ( EIU ) in rabbits . METHODS : An experimental study was conducted on 64 rabbits . Salmonella typhimurium lipopolysaccharide endotoxin was intravitreally injected . DB00065 was intravenously ( i . v . ) injected 24 h before the intravitreal injection ( 20 mg / kg ) . The animals were randomly assigned to five groups : group A , saline intravitreal injection ; group B , DB00065 i . v . group C , infliximab + saline ; group D , intravitreal endotoxin and group E , infliximab i . v . + intravitreal endotoxin . With two masked observers , a microscopic examination of aqueous humor ( cells , tumor necrosis factor [ P01375 ] alpha ) and aqueous protein level were performed 24 h after an endotoxin injection and 48 h after an infliximab infusion . RESULTS : DB00065 treatment , at a dose of 20 mg / kg , significantly improved all the parameters . Inflammatory cell infiltration was significantly reduced in the iris , ciliary body , and anterior chamber ( U Mann - Whitney test , P = 0 . 01 ) . Associated with a lower level of P01375 and protein exudate in aqueous humor ( U Mann - Whitney test , P = 0 . 01 ) . CONCLUSIONS : DB00065 , at a dose of 20 mg / kg , is effective in the prophylaxis of the EIU .",
"Treatment with infliximab : Implications in oral surgery ? A case report . DB00065 is a tumour necrosis factor - alpha ( P01375 ) inhibitor ( neutralising antibody ) , which is increasingly being used as an immunosuppressant to manage inflammatory conditions including rheumatoid arthritis , ankylosing spondylitis and Crohn ' s disease . Its side effects include diabetes mellitus , an increased incidence of lymphoma and greater susceptibility to infections such as pulmonary tuberculosis . In patients on infliximab , the oral cavity may act as a bacterial reservoir leading to unwanted local or systemic complications . To date no report describes the potential implication / s of infliximab in patients having oral surgery . This case report may be the first in the English language to report the development of mandibular osteomyelitis after surgical extraction in a patient on infliximab .",
"Earlobe sarcoidosis . BACKGROUND : DB00065 , a P01375 blocking agent , is an upcoming therapeutic option for cases of refractory sarcoidosis . In pulmonary sarcoidosis , changes imaged by DB09150 - PET during infliximab treatment in sarcoidosis patients correlate with signs of clinical improvement . DESIGN : Case - report . RESULTS AND CONCLUSIONS : A patient with severe earlobe sarcoidosis , treated with infliximab , is presented . This case shows that even relatively small extrapulmonary localisations of sarcoidosis can be visualised by DB09150 - PET , and that a decrease of DB09150 - uptake correlates well with clinical improvement on infliximab treatment .",
"[ Proteomic analysis of changes in the serum protein profile by anti - P01375 therapy ] . We analyzed the alternation in serum protein by infliximab therapy using proteomics - based technique . More than 50 gel spots were seen to increase or decrease in correlation with clinical improvements of rheumatoid arthritis ( RA ) . Spots of interest were identified by two dimensional electrophoresis and mass spectrometry . DB00065 therapy reduced the inflammatory proteins such as P02741 , serum amyloid protein A , serum amyloid protein P , and alpha1 - acid glycoprotein , while the therapy increased Apo A - I , retinol - binding protein , vitamin D - binding protein , and gelsolin . This suggested that infliximab therapy shifted the inflammatory status of serum protein profile of RA patients to normal and modified the extracellular actin - scavenging system as well as vitamin and lipid profile .",
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK70___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .",
"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK67___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK67___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .",
"Anti - inflammatory effects of pravastatin on Helicobacter pylori - induced gastritis in mice . ___MASK96___ , an P04035 inhibitor , exerts anti - inflammatory effects via several mechanisms including induction of endothelial nitric oxide synthase ( P29474 ) . We investigated the effect of pravastatin on Helicobacter pylori - induced gastritis in mice . Mice with or without H . pylori infection received intraperitoneal pravastatin daily for 1 week . Expression of P29474 mRNA and tumor necrosis factor - alpha mRNA and myeloperoxidase activity in gastric tissue was determined . P05164 activity was reduced in a dose - dependent manner by pravastatin , with activity inhibited by 53 . 5 and 73 . 7 % at doses of 0 . 3 and 1 mg / kg , respectively . At a dose of 1 mg / kg , pravastatin reduced the level of tumor necrosis factor - alpha mRNA by 52 . 7 % , while it did not affect P29474 expression . ___MASK96___ had no effects on these inflammatory parameters in uninfected mice . ___MASK96___ did not affect the viability of H . pylori . In conclusion , pravastatin exerts an anti - inflammatory effect on H . pylori - induced gastritis in mice without affecting P29474 expression .",
"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .",
"Effect of infliximab on the healing of intestinal anastomosis . An experimental study in rats . BACKGROUND AND AIM : DB00065 is effective in the induction and maintenance of remission in Crohn ' s disease . Whether , the perioperative administration of anti - P01375 compromises intestinal healing leading to anastomotic failure and increased risk of postoperative complications , remains controversial . The aim of the study was to evaluate the effect of DB00065 on intestinal anastomosis healing . METHODS : Fifty six wistar rats were divided into 4 groups : ( a ) 20 rats were subjected to excision of part of the terminal ileum followed by anastomosis which was evaluated on the 3rd or 7th postoperative day ; ( b ) 20 rats received DB00065 and thereafter , the same surgical protocol as group ( a ) was followed ; ( c ) 8 rats received DB00065 and served as relative control group ; and ( d ) 8 served as absolute control group . Bursting pressure was used for testing intestinal healing . Additionally , the anastomoses were examined macroscopically , histologically and immunohistochemically for TGFb1 , P03956 , P08253 and Collagen V . The results were confirmed by Western blot analysis . RESULTS : There were no significant differences in bursting pressures and septic intra - abdominal events among non - DB00065 ( a ) and DB00065 - treated ( b ) groups . DB00065 - treated ( b ) group showed mild to moderate inflammation , whereas the non - DB00065 ( a ) group exhibited severe inflammation . Expression of TGFb1 , P08253 and collagen V was significantly higher in the DB00065 - treated ( b ) group . CONCLUSION : DB00065 seems to influence intestinal healing in terms of less inflammatory activity and higher tissue remodeling activity .",
"Chronic P01375 - α neutralization does not improve insulin resistance or endothelial function in \" healthy \" men with metabolic syndrome . The possible contribution of tumor necrosis factor - α ( P01375 - α ) to the development of obesity - associated insulin resistance in humans is still controversial . Our study investigated the effect of P01375 - α neutralization on insulin resistance in healthy , obese and insulin resistant men . We performed a prospective , randomized , double - blind placebo - controlled trial in nine young , healthy obese male subjects with metabolic syndrome and insulin resistance . Volunteers received three infusions ( wks 0 , 2 and 6 ) of infliximab or placebo . P01308 resistance was measured at baseline and after 70 d by homeostatic model assessment ( HOMA ) index as well as by minimal model analysis of an intravenous glucose tolerance test . Endothelial function was accessed before and after intervention by flow mediated dilation . DB00065 improved the inflammatory status as indicated by reduced high sensitivity P02741 ( hsCRP ) and fibrinogen levels ( 2 . 77 ± 0 . 6 to 1 . 8 ± 0 . 5 μg / L , and 3 . 42 ± 0 . 18 to 3 . 18 ± 0 . 28 g / L ; ( day 0 and day 70 , P = 0 . 020 and 0 . 037 respectively ) , but did not improve insulin resistance ( HOMA index and intravenous glucose - tolerance test [ ivGGT ] ) or endothelial function . Despite improvements in inflammatory status , chronic P01375 - α neutralization does not improve insulin resistance or endothelial function in seemingly healthy , but obese , insulin - resistant volunteers . This study severely questions the proposal that P01375 - α is a causative link between adiposity and insulin resistance .",
"Mechanisms for cytotoxic effects of anti - tumor necrosis factor agents on transmembrane tumor necrosis factor alpha - expressing cells : comparison among infliximab , etanercept , and adalimumab . OBJECTIVE : Three anti - tumor necrosis factor alpha ( anti - TNFalpha ) agents have been proved to be effective for rheumatoid arthritis ( RA ) and other inflammatory disorders . DB00065 and adalimumab have been generated as anti - TNFalpha monoclonal antibodies , while etanercept is engineered from human type II P01375 receptors . In spite of all 3 agents ' equal efficacy for RA , both infliximab and adalimumab are effective for other diseases such as Crohn ' s disease and Wegener ' s granulomatosis , while etanercept is not . We undertook this study to understand the different clinical effects of these anti - TNFalpha agents by analyzing their biologic activities on transmembrane TNFalpha . METHODS : Jurkat T cells stably expressing an uncleavable form of transmembrane TNFalpha were used for the following studies : 1 ) flow cytometric analysis of binding activities of anti - P01375 agents to cell surface transmembrane TNFalpha , 2 ) complement - dependent cytotoxicity ( CDC ) , 3 ) antibody - dependent cell - mediated cytotoxicity ( ADCC ) by using peripheral blood mononuclear cells , and 4 ) outside - to - inside ( reverse ) signal transduction through transmembrane TNFalpha estimated by apoptosis and cell cycle analysis using flow cytometry . RESULTS : All of the anti - TNFalpha agents bound to transmembrane TNFalpha . DB00065 and adalimumab exerted almost equal CDC activities , while etanercept showed considerably lower activity . ADCC activities were almost equal among these 3 agents . DB00051 and infliximab induced apoptosis and cell cycle arrest in transmembrane TNFalpha - expressing Jurkat T cells , reflecting an outside - to - inside signal transduction through transmembrane TNFalpha . CONCLUSION : Three different anti - P01375 agents showed different biologic effects on transmembrane TNFalpha . This finding suggests that CDC and outside - to - inside signals by anti - TNFalpha antibodies may explain the successful clinical efficacy of adalimumab and infliximab in Crohn ' s disease and Wegener ' s granulomatosis .",
"Treatment of immune - mediated extraintestinal manifestations of inflammatory bowel disease with infliximab . The introduction of infliximab into clinical practice is one of the most significant advances in the care of patients who have Q9UKU7 . DB00065 has become an important part of the medical armamentarium to treat extraintestinal manifestations that often are refractory to other medications and are a significant cause of morbidity in these patients . Two other P01375 inhibitors recently have demonstrated efficacy in CD : certolizumab pegol and adalimumab . The Food and Drug Administration has approved adalimumab for use in RA . One predicts that these agents also may have activity in the extraintestinal manifestation for Q9UKU7 . To determine whether future biologics are effective in the EIM of Q9UKU7 , one may need to look no further than the vast clinical trial experience in primary chronic inflammatory diseases of the joints and skin : RA and psoriasis . For example , the Food and DRug Administration recently has approved an anti - B - cell therapy , rituximab , and a T - cell costimulation modulator , abatacept , for use in RA . It certainly will be of interest to determine whether these biologic agents demonstrate efficacy in the intestinal and EIM of Q9UKU7 .",
"P01375 alpha antibody ( infliximab ) therapy profoundly down - regulates the inflammation in Crohn ' s ileocolitis . BACKGROUND & AIMS : Anti - tumor necrosis factor alpha monoclonal antibody treatment ( infliximab ) reduces clinical signs and symptoms in patients with Crohn ' s disease . The effects of infliximab on mucosal histopathologic abnormalities in Crohn ' s ileocolitis were studied . METHODS : Thirteen patients with steroid - refractory Crohn ' s disease were treated with a single infusion of infliximab ( 5 - 20 mg / kg ) , and 5 were treated with placebo . Ileal and colonic biopsy specimens of all patients were collected before and 4 weeks after therapy . Severity of inflammation was assessed by a histological score . Immunohistochemical stainings with antibodies against HLA - DR , P34810 , tumor necrosis factor alpha , intercellular adhesion molecule 1 , lymphocyte function - associated antigen , P01730 , CD8 , and interleukin 4 were performed . RESULTS : Total histological activity score was reduced significantly in both ileitis and colitis after infliximab . This is caused by a virtual disappearance of the neutrophils and a reduction of mononuclear cells . Mucosal architecture returned to normal in 4 patients at 4 weeks . The number of lamina propria mononuclear cells decreased because of a global reduction of P01730 (+) and CD8 (+) T lymphocytes and P34810 (+) monocytes . Aberrant colonic epithelial HLA - DR expression completely disappeared . The percentage of intercellular adhesion molecule 1 and lymphocyte function - associated antigen 1 - expressing and interleukin 4 - and tumor necrosis factor - positive lamina propria mononuclear cells sharply decreased . CONCLUSIONS : DB00065 dramatically decreases histological disease activity in Crohn ' s ileocolitis . Signs of active inflammation nearly disappear accompanied by a profound down - regulation of mucosal inflammatory mediators .",
"Differential effect of DB03932 , pravastatin , and fluvastatin on production of Q14116 and expression of P05362 and P25942 in human monocytes . A novel , proinflammatory cytokine , interleukin ( IL ) - 18 production was detected in the medium of human monocytes treated with 3 - hydroxy - 3 - methylglutaryl coenzyme - A ( HMG - DB01992 ) reductase inhibitors , pravastatin , and fluvastatin ( 0 . 1 and 1 muM ) but not with the statin - derived lymphocyte function - associated antigen - 1 ( LFA - 1 ) inhibitor DB03932 , which did not inhibit P04035 . ___MASK96___ and fluvastatin also induced the production of Q14116 , tumor necrosis factor alpha ( P01375 ) and interferon - gamma ( P01579 ) in human peripheral blood mononuclear cells ( PBMC ) in contrast to DB03932 . Q14116 production by PBMC is located upstream of the cytokine cascade activated by these statins . The Q14116 - induced cytokine production was demonstrated to be dependent on adhesion molecule expression on monocytes . In the absence and presence of lower concentrations ( 0 . 1 and 1 ng / ml ) of Q14116 , pravastatin and fluvastatin inhibited the expression of intercellular adhesion molecule ( ICAM ) - 1 and induced the expression of P25942 , whereas DB03932 had no effect . In the presence of higher concentrations ( 5 , 10 , and 100 ng / ml ) of Q14116 , pravastatin , fluvastatin , and DB03932 similarly inhibited the expression of P05362 and P25942 as well as the production of IL - 12 , P01375 , and P01579 in PBMC . The effects of pravastatin and fluvastatin but not DB03932 were abolished by the addition of mevalonate , indicating the involvement of P04035 in the action of pravastatin and fluvastatin . Thus , the effects of DB03932 were distinct from those of pravastatin and fluvastatin in the presence of lower concentrations of Q14116 . It was concluded that DB03932 has the inhibitory effect on an Q14116 - initiated immune response without any activation on monocytes .",
"DB00065 monotherapy for refractory psoriasis : preliminary results . Tumour necrosis factor ( P01375 ) - alpha plays an important role in the pathogenesis of psoriasis . DB00065 is an anti - P01375 chimeric monoclonal antibody , which is licensed for the treatment of rheumatoid arthritis and Crohn ' s disease . Some reports have shown the efficacy of infliximab , either in monotherapy or in combination with methotrexate , for the treatment of psoriatic arthropathy and psoriasis . The efficacy and tolerability of infliximab monotherapy was evaluated in 29 patients with moderate to severe psoriasis , unresponsive to conventional treatments . Fourteen patients suffered from concomitant arthropathy . Patients received intravenous infliximab , 5mg / kg , at weeks 0 , 2 , and 6 . After this 3 - dose - induction regimen , patients were followed - up at monthly intervals and retreated with a single - dose infusion in case of relapse of signs and symptoms . Clinical assessment was performed using the psoriasis area and severity index ( PASI ) to monitor psoriasis activity ; pruritus and joint pain were assessed on a scale of 0 to 3 . A marked improvement of skin lesions and subjective symptoms was noted in the majority of patients ; an excellent reduction of PASI score ( > or = 75 % ) was observed in 13 . 8 % of cases at week 2 , 71 . 4 % at week 6 and 78 . 6 % at week 10 . During the follow - up period , some patients maintained satisfactory clinical results without requiring any additional infusions . In general , skin lesions showed a trend towards a more prolonged and sustained improvement as compared with subjective symptoms . Treatment was well tolerated and no serious adverse events occurred .",
"Clinical use and mechanisms of infliximab treatment on inflammatory bowel disease : a recent update . The pathogenesis and treatment of inflammatory bowel disease ( Q9UKU7 ) have been recently advanced , while it is still challenged with high morbidity and poor prognosis . DB00065 , a monoclonal antibody of tumor necrosis factor ( P01375 ) , has emerged as an efficient treatment with many clinical benefits such as quick disease activity reduction and Q9UKU7 patient life quality improvement . However , the biological effects of infliximab on Q9UKU7 need to be elucidated . This paper reviewed the clinical use and recently advanced biological action of infliximab on Q9UKU7 . By forming the stable complex with the soluble or the membrane form of P01375 in fluid environment or on cell surface of immune cell , fibroblast , endothelium , and epithelium , infliximab quenches P01375 activity and performs the important biological actions which lead to amelioration and remission of immune responses . The mechanisms of infliximab treatment for Q9UKU7 were intensively discussed . The recent advances on two topics including predictors and side effects of infliximab treatment were also reviewed .",
"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK22___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .",
"DB00065 treatment reduces the serum levels of interleukin - 23 in patients with rheumatoid arthritis . In this study , we investigated the effect of the antitumor necrosis factor alpha ( anti - P01375 ) antibody , infliximab , combined with methotrexate ( MTX ) and MTX alone on the serum levels of interleukin ( IL ) - 23 and Q16552 in rheumatoid arthritis ( RA ) patients . DB00065 combined with MTX was administered to 26 patients with RA ( infliximab group ) , and MTX alone was given to 20 patients with RA ( MTX group ) . We evaluated clinical and laboratory parameters , including the Disease Activity Scores of 28 joints ( DAS28 ) and serum levels of IL - 23 and Q16552 at baseline and at 14 and 30 weeks after the initial treatment with these drugs . Single regression analysis was performed between the levels of serum IL - 23 and other clinical and laboratory parameters at baseline before the initial treatment with infliximab or MTX . A significant reduction of DAS28 scores was observed in both the infliximab and the MTX group at 14 and 30 weeks after the initial treatment . A significant decrease in serum levels of IL - 23 was observed in the infliximab group but not in the MTX group at 14 and 30 weeks after the initial treatment . Serum Q16552 levels did not show a significant change during the follow - up period . At baseline , before the initial treatment with infliximab or MTX , serum IL - 23 levels showed a significant correlation with DAS28 and the number of swollen joints . This study indicated that the reduction of serum IL - 23 levels in RA patients was a novel action of infliximab .",
"[ The effect of blocking P01375 in patients with cancer - related cachexia and anorexia ] . Cancer - related cachexia and anorexia are present in more than 80 % of patients with malignancies . The pathophysiology is not fully known and during the past several years major attention was attributed to the function of secreted cytokines , such as P01375 , as a fundamental part of the process . In the attempt to prevent the weight loss , which in many cases causes the patients ' death , many studies have been conducted where the effect of the cytokine P01375 was blocked . This article presents two different studies from the past several years where the effect was inhibited by two different methods : one by the monoclonal antibody DB00065 and the other by blocking the P01375 receptor with DB00005 . Both were double - blinded and the patients were randomly divided into arms , with the control group treated with placebo . In both groups , primary and secondary outcomes were defined , however , in the end , no statistical significance was achieved . In conclusion , cancer - related cachexia and anorexia are not the result of one cytokine by itself and blocking it causes only a minimal change without any statistical significance in cancer patients . It is reasonable to assume that the body adaptation to the tumor , which results in cachexia , is due to several mediators working together rather than a single major mediator .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Experimental autoimmune encephalomyelitis in the Wistar rat : dependence of MBP - specific T cell responsiveness on P33681 costimulation . Experimental autoimmune encephalomyelitis ( EAE ) is an animal model of human multiple sclerosis that requires the activation of autoreactive T cells for the expression of pathology . EAE has been most frequently studied in the Lewis rat model as well as in several murine models of EAE including the PLJ and B10PL strains . In the present study we describe a novel model of EAE induced in the Wistar rat strain by immunization with guinea pig spinal cord antigens and pertussis toxin ( PT ) . T cell responses were induced to myelin basic protein . Autoreactive T cells could be totally blocked by the in vitro treatment with ___MASK97___ , a protein that blocks the costimulation of autoreactive T cells . The addition of P60568 could reverse the inhibition seen in vitro with ___MASK97___ . The effects of inhibition of P33681 costimulation were also examined by an analysis of cytokine responses and P60568 receptor on T cells . ___MASK97___ treatment in vitro reduced the expression of P60568 receptor on T cells , enhanced T cell apoptosis and decreased the synthesis of P60568 , P01579 and P01375 . ___MASK97___ treatment had no effect on P22301 synthesis by T cells , a cytokine implicated in the functions of regulatory T cell subsets . Overall , our studies support the rationale of P33681 blocking therapies as a potential treatment for models of multiple sclerosis . The induction of EAE in the Wistar rat provides yet another novel model in which to examine the regulation of T cell autoimmunity .",
"P05362 - independent lymphocyte transmigration across high endothelium : differential up - regulation by interferon gamma , tumor necrosis factor - alpha and interleukin 1 beta . The adhesion of lymphocytes to cytokine - treated high endothelium was studied using cultured high endothelial cells ( O14777 ) . Pretreatment of the O14777 layer with a variety of cytokines caused up - regulation of lymphocyte adhesion with the effects ordered interferon gamma ( P01579 ) greater than tumor necrosis factor - alpha ( P01375 ) greater than or equal to interleukin 1 beta ( IL 1 beta ) . Increased lymphocyte adhesion was found to be independent of P05362 as expression by O14777 was not increased by cytokines and antibodies against P05362 did not block adhesion . The peptide CS1 and anti - beta 1 integrin subunit antibodies , however , caused partial inhibition of lymphocyte adhesion thus indicating a role for fibronectin on O14777 and alpha 4 beta 1 on lymphocytes . Study of the kinetics of lymphocyte adhesion showed that the effects of P01579 and P01375 were persistent and remained detectable 2 . 5 h after removal of the cytokines whereas the effects of IL 1 beta were transient and were not sustained beyond 1 h . All of the cytokines used caused transient increases in the number of surface - bound lymphocytes with P01579 greater than P01375 greater than or equal to IL 1 beta , however , the most dramatic effect was on the transmigration of lymphocytes across the O14777 . Both P01579 and P01375 caused sustained increased transmigration with P01579 having the greater effect . IL 1 beta had little effect on transmigration . This model demonstrates that the binding and transmigration of lymphocytes across O14777 can be differentially regulated by the actions of individual cytokines . These results support the concept that locally produced cytokines regulate O14777 function within the lymph node .",
"The role of pharmacogenomics in the prediction of efficacy of anti - P01375 therapy in patients with Crohn ' s disease . P01375 plays a central role in the pathophysiology of Crohn ' s disease . DB00065 , a chimeric monoclonal antibody against P01375 , has been shown to be effective and well - tolerated in several large placebo - controlled trials and has become a common treatment for Crohn ' s disease . The blockade of P01375 through the infusion of infliximab is characterized by high clinical efficacy and rapid onset of action . A single infusion of infliximab results in a remission rate of 30 - 40 % . Lack of response appears to be a stable trait even after repeated infusions , suggesting that it might be genetically determined . Mutations in the P01375 gene have been extensively studied as predictors of response with various results . Polymorphisms in the P01375 receptors P19438 and P01375 - R2 have been found not to be associated with treatment response . Similarly , the three mutations in the Q9HC29 gene , which are independently associated with susceptibility to Crohn ' s disease , have also been found not to be associated with treatment response .",
"Severe gram positive bacterial infection in an ulcerative colitis patient treated with DB00065 . Tumour necrosis factor - alpha ( P01375 - α ) inhibitors represent an important treatment advance for a number of inflammatory conditions , including inflammatory bowel disease . Since their introduction in 1999 , it has become clear that some biological therapies may be associated with an increased risk for bacterial infections . Herein we present the first case of septic arthritis and spine empyema , caused by S . aureus , in a 63 year - old patient with ulcerative colitis , who was under treatment with DB00065 and with 40mg per day of prednisolone .",
"DB00065 dependency in children with Crohn ' s disease . BACKGROUND : Recently , infliximab dependency has been described . AIM : To assess frequency of ID in 82 consecutive Crohn ' s disease children treated with infliximab 2000 - 2006 and to describe clinical and genetic predictors of long - term infliximab response . METHODS : A phenotype model of infliximab dependency was used to assess treatment response : ' immediate outcome ' ( 30 days after infliximab start ) -- complete / partial / no response . ' Long - term outcome ' : ( i ) prolonged response : maintenance of complete / partial response ; ( ii ) infliximab dependency : relapse < or = 90 days after intended infliximab cessation requiring repeated infusions to regain complete / partial response or need of infliximab > 12 months to sustain response . Polymorphisms P01375 - 308 A > G , P01375 - 857 C > T , Casp9 93 C > T , P48023 - 844 C > T , P01374 252 C > T and Q9HC29 ( R702W , G908R , 1007fs ) were analysed . RESULTS : Ninety - four per cent of children obtained complete / partial response . In long - term outcome , 22 % maintained prolonged response , 12 % had no response , while 66 % became infliximab dependent . Perianal disease and no previous surgery were associated with infliximab dependency ( OR 5 . 34 , 95 % CI : 1 . 24 - 22 . 55 ; OR 6 . 7 , 95 % CI : 1 . 67 - 26 . 61 ) . No association was found with studied polymorphisms . The cumulative probability of surgery 50 months after starting infliximab was 10 % in infliximab dependency , 30 % in prolonged responders and 70 % in nonresponders ( P = 0 . 0002 ) . CONCLUSIONS : Sixty - six per cent of children became infliximab dependent . Perianal disease and no surgery prior to infliximab were associated with infliximab dependency phenotype .",
"Anti - P01375 therapy for polymyalgia rheumatica : report of 99 cases and review of the literature . The objective of this study was to analyze the clinical , laboratorial , and therapeutical response of polymyalgia rheumatica ( PMR ) to anti - tumor necrosis factor ( anti - P01375 ) treatment . We systematically searched English articles on the subjects of PMR who were treated with P01375 blockers in Pubmed from 1994 to 2010 . In addition , we reported on two patients with PMR who were treated by the Rheumatology Division of the Hospital das Clínicas da Faculdade de Medicina da Universidade in São Paulo , Brazil . Ninety - nine cases of patients with PMR treated with anti - P01375 were reviewed . The age of these patients ranged from 63 to 84 years , and 70 . 7 % of them were female . Disease duration varied from 10 . 5 weeks to 95 months , and time of follow - up varied from 2 weeks to 21 months . DB00065 was the anti - P01375 of choice in three studies , while etanercept was in five . Time to response varied from 2 to 8 weeks . After anti - P01375 treatment , prednisone reduction was observed in all studies . Clinical improvement was found in 7 / 7 studies , and laboratory improvement of at least 50 % of inflammatory markers was observed in 6 / 7 studies . This study demonstrated a good clinical and laboratory response to anti - P01375 therapy in patients with PMR , with or without glucocorticoid .",
"DB00065 therapy in pediatric Takayasu ' s arteritis : report of two cases . Takayasu arteritis ( TA ) is a chronic vasculitis of unknown etiology . Experience with anti - tumor necrosis factor alpha ( anti - P01375 ) agents in difficult - to - treat patients with TA is limited and refers to adult patients . Here , we present two cases of pediatric TA treated with infliximab , in which clinical remission was observed . Anti - P01375 treatment represents a useful therapy in pediatric Takayasu arteritis too , especially to avoid the risk of long - term corticosteroids toxicity .",
"[ DB00065 in the treatment of rheumatoid arthritis ] . DB00065 is a chimeric monoclonal antibody capable of neutralizing human P01375 alpha . A number of clinical trials for the treatment of rheumatoid arthritis ( RA ) with infliximab indicated that P01375 alpha blockade was effective and well tolerated with the excellent results occurring at 3 and 10 mg / kg in combination with methotrexate . Treatment of RA patients with the combination of infliximab and methotrexate also prevented radiographic evidence of progression of joint damage . If the clinical efficacy is sustained and the safety is confirmed over the long term , infliximab may become an essential agent of choice for the treatment of RA .",
"[ DB00065 therapy for three adolescent patients with refractory Takayasu ' s arteritis ] . Takayasu ' s arteritis ( TA ) is a chronic idiopathic inflammatory disease affecting primarily aorta and its proximal branches . Pediatric patients with TA tend to have more severe clinical course and be refractory to conventional treatments compared with adults . Corticosteroids are major treatment of TA , however , high dose is required to get remission . Particularly , adolescent patients are usually suffering from side - effects of excessive dose of corticosteroids . Immunosuppressants are added expecting the corticosteroid sparing agents . However , some patients , such as HLA - B52 positive , tend to be registant to these conventional treatments . Recently , several reports showed the efficacy of DB00065 , anti - tumor necrosis factor ( P01375 ) alpha monoclonal antibody , for adult patients with refractory TA . We described three cases of adolescents with TA treated with DB00065 . It was initially effective in all three patients . However , serious infusion reaction occurred in one of them during 11 ( th ) times of DB00065 infusion and she discontinued the therapy . Other two patients showed good response in initial phase , but clinical manifestations and laboratory findings became worse after several months . In these patients with secondary failure to DB00065 , increased dosage and shortening the interval of infusions provided effectiveness again . DB00065 would be a good choice for adolescent patients with TA refractory to conventional treatments . However , we should carefully monitor safety and efficacy of this agent considering its peculiarity .",
"Mycoepoxydiene , a fungal polyketide inhibits MCF - 7 cells through simultaneously targeting p53 and NF - κB pathways . Mycoepoxydiene ( Q9UQD0 ) is a cytotoxic polyketide that is isolated from the marine fungal strain Diaporthe sp . HLY - 1 , which is associated with mangroves ; however , the mechanism of action of Q9UQD0 remains unknown . Here , we report the molecular mechanisms of apoptosis activation and growth inhibition induced by Q9UQD0 in MCF - 7 cells . The present results show that Q9UQD0 induces DNA damage through the production of reactive oxygen species ( ROS ) , which resulted in the phosphorylation of P16104 and the activation of the Q13315 kinase ( Q13315 ) and p53 signaling pathways . In addition , Q9UQD0 increases the accumulation of IκBα and enhances the association between IKKγ and Hsp27 via the activation of Hsp27 , which eventually resulted in the inhibition of P01375 - α - induced NF - κB transactivation . Therefore , we conclude that Q9UQD0 inhibits MCF - 7 cells by simultaneously activating p53 to induce apoptosis and suppressing NF - κB to disrupt cell proliferation . Because small molecules having both of these effects are rare , further exploration of Q9UQD0 as an antitumor lead compound is needed .",
"Mechanisms of action of infliximab in inflammatory bowel disease : an anti - inflammatory multitasker . The pro - inflammatory cytokine tumor necrosis factor - alpha ( P01375 ) plays a central role in mucosal inflammation and is a key mediator in the inflammatory cascade in both Crohn ' s disease ( CD ) and ulcerative colitis ( UC ) . DB00065 , a monoclonal antibody against P01375 has been proved highly effective in the clinical management of both forms of Q9UKU7 . Aim of this paper is to review the mechanisms of action of infliximab in Q9UKU7 .",
"Interstitial pneumonitis associated with infliximab therapy without methotrexate treatment . P01375 ( P01375 ) - α inhibitors are increasingly being used to treat rheumatoid arthritis . DB00065 ( P27352 ) is a P01375 - α inhibitor that is usually used in combination with methotrexate ( MTX ) . Interstitial lung disease ( ILD ) during combination therapy has been attributed to MTX rather than P27352 . However , P27352 - associated ILD without combination with MTX has recently been reported . We describe herein a case of severe ILD secondary to P27352 without MTX therapy .",
"DB00065 in two patients with juvenile ankylosing spondylitis . DB00065 , a monoclonal chimeric anti - tumor necrosis factor alpha ( anti - P01375 ) antibody , was tried in two patients suffering from severe refractory juvenile ankylosing spondylarthritis with disease duration of more than 10 years . To assess the response , validated clinical activity parameters were monitored prospectively . In both patients , treatment with infliximab at a dosage of 5 mg / kg body weight already led to considerable improvement with loss of joint pain the day after it was given . Bath Ankylosing Spondylitis Functional Index scores decreased from 5 . 8 to 0 and 7 . 2 to 1 . 0 and the Bath Ankylosing Spondylitis Disease Activity Index from 2 . 6 to 1 . 4 and 9 . 0 to 1 . 0 . In one patient , the response to a single infusion continued for more than 8 months . Because of a recurrence of symptoms in intervals of 2 months , the fourth infusion has now been given to the second patient , resulting in immediate clinical response . No side effects have been noted . DB00065 seems to be a promising agent for treatment of active and refractory juvenile ankylosing spondylitis . Controlled studies and long - term observations are warranted .",
"[ Inhibitors of tumour necrosis factor - alpha for the treatment of arthritis and uveitis in childhood ] . BACKGROUND : Chronic uveitis in childhood is a common complication of juvenile idiopathic arthritis ( JIA ) that frequently leads to loss of vision . Besides from corticosteroids and immunosuppressive drugs , Tumour necrosis factor - alpha ( P01375 ) inhibitors are used frequently . MATERIALS AND METHODS : The literature published before September 2006 was evaluated for the usefulness of P01375 inhibitors ( etanercept , infliximab , adalimumab ) for the treatment of JIA - associated uveitis . RESULTS : P01375 inhibitors are effective drugs for the treatment of chronic uveitis in childhood . The response rate of uveitis in childhood to etanercept was approximately 50 % . However , disease recurrence , first manifestations of uveitis and new complications occurred during the treatment . DB00065 and adalimumab appear to be more effective for the treatment of uveitis in childhood than etanercept . CONCLUSIONS : The therapy with P01375 inhibitors is expensive and increases the long - term risk for secondary diseases , such as tuberculosis and probably malignant lymphoma . Their use should be restricted to uveitis patients not responding to corticosteroids and at least one of established immunosuppressive drugs ."
] |
[
"___MASK22___",
"___MASK28___",
"___MASK34___",
"___MASK55___",
"___MASK67___",
"___MASK70___",
"___MASK93___",
"___MASK96___",
"___MASK97___"
] |
___MASK97___
|
MH_train_486
|
interacts_with DB09029?
|
[
"Cyclophosphamide and other new agents for the treatment of severe aplastic anemia . Severe aplastic anemia ( P0DJI8 ) has a poor prognosis in the absence of treatment . Current accepted therapeutic strategies include allogeneic stem - cell transplantation and immunosuppression , both resulting in long - term survival in the majority of patients . Although human leukocyte antigen ( HLA ) - matched sibling stem - cell transplantation is highly effective , the 25 % probability of finding a suitable sibling donor within a family renders this approach available to only a minority of patients . Transplantation using HLA - matched , unrelated donors carries a high risk of treatment failure along with considerable toxicity . While combined immunosuppression with both antithymocyte globulin ( ATG ) and cyclosporine A ( Q13216 ) produces hematologic improvement in most patients , relapse is common . Late evolution of aplastic anemia to other serious hematologic disorders , including paroxysmal nocturnal hemoglobinuria ( PNH ) , myelodysplasia , and acute leukemia , is also a significant problem following treatment with ATG / Q13216 . Recently , results of immunosuppression in P0DJI8 with another potent immunosuppressive agent , cyclophosphamide , were reported in a small number of patients . The overall response rate was similar to that seen with ATG / Q13216 , but relapse and late clonal disease were not observed during a long period of follow - up . A larger randomized trial comparing sustained hematologic response rates to either conventional immunosuppression with ATG / Q13216 or high - dose cyclophosphamide and Q13216 is now underway ; secondary end points include response duration , event - free survival , and overall survival . Additionally , a number of protocols designed to test the efficacy of alternative immunosuppressive or immunomodulatory agents are being developed .",
"Molecular and biologic characterization of a newly established Philadelphia - positive acute lymphoblastic leukemia cell line ( Z - 33 ) with an autocrine response to GM - P04141 . We have recently established a new Philadelphia chromosome ( Ph1 ) - positive acute lymphoblastic leukemia ( ALL ) cell line , designated Z - 33 . This line has Q401N2 morphology , ultrastructural characteristics of lymphoblasts and typical B lineage surface markers identical to those observed in the Ph1 - positive ALL patient from whom the line was derived . In addition , a rearranged immunoglobulin heavy - chain gene ( JH ) band was found in Z - 33 cells by Southern blot analysis , confirming B cell clonality . Cytogenetic analysis of the cell line revealed t ( 9 ; 22 )( q34 ; q11 . 2 ) . Polymerase chain reaction ( PCR ) - amplified cDNA from Z - 33 cells demonstrated an e1 - az P11274 - P00519 junction , and the p190BCR - P00519 protein was detected in them by the immune complex kinase assay . Z - 33 cells produce interleukin ( IL ) - 1 beta , P05231 , granulocyte colony - stimulating factor ( DB00099 ) , granulocyte - macrophage P04141 ( GM - P04141 ) , tumor necrosis factor ( P01375 ) - alpha , and transforming growth factor ( TGF ) - beta , Neither P01584 , DB00099 , P01375 , nor their corresponding antibodies affected the cell line ' s growth . In contrast , anti - GM - P04141 neutralizing antibodies suppressed Z - 33 colony formation , and GM - P04141 stimulated it in a dose - dependent fashion . In addition , receptor studies with biotinylated GM - P04141 demonstrated specific binding to Z - 33 cells , indicating that the cells express GM - P04141 receptors . Taken together , our data suggest that the Ph1 - positive Z - 33 ALL cells produce GM - P04141 , express GM - P04141 receptors , and show an autocrine proliferative response to this cytokine .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"The influence of non - HLA gene polymorphisms and interactions on disease risk in a Western Australian multiple sclerosis cohort . Non - Human Leukocyte Antigen ( HLA ) genes have concomitant , although modest , effects on multiple sclerosis ( MS ) susceptibility ; however findings have varied in different populations . Here we present the results of an association study of 16 single nucleotide polymorphisms ( SNPs ) in 10 non - HLA genes ( P16871 , P01589 , CLEC - 16A , P29597 , P19256 , Q13568 , P40763 , P16410 , P02649 , P05362 ) in a Western Australian cohort of 350 MS patients and 498 population control subjects . Our results indicate that in this population , SNPs in P16871 , P29597 , Q13568 and P02649 have modifying effects on MS susceptibility . We also found evidence of interactive protective effects between polymorphisms in the P16871 / P19256 , CLEC - 16A / P16410 , and P29597 / Q13568 genes , which in some instances are restricted within HLA - or gender - defined groups .",
"Aripiprazole : a novel atypical antipsychotic drug with a uniquely robust pharmacology . Aripiprazole ( ___MASK58___ ) is an atypical antipsychotic drug that has been recently introduced for clinical use in the treatment of schizophrenia . Aripiprazole has a unique pharmacologic profile that includes partial agonism at several G - protein coupled receptors ( GPCRs ) [ especially dopamine ( D2 ) and P08908 ] and antagonistic action at others ( especially 5 - Q13049 ) . Clinical trials indicate that aripiprazole is effective in treating the positive and negative symptoms of schizophrenia . In short - term studies rapid onset of action ( within one week ) has been demonstrated . Preliminary data indicate that aripiprazole may also be effective in the treatment of manic symptoms of bipolar disorder . At recommended doses , aripiprazole appears to be safe and well tolerated in most adult patients with schizophrenia and schizoaffective disorder . There is only limited information available on the use of aripiprazole in children and adolescents , and pilot data suggest that a revised dosing strategy , based on weight , is indicated in this population . In the long - term studies , the use of aripiprazole was associated with continued efficacy , good compliance and increased time - to - relapse . Aripiprazole represents the first functionally selective atypical antipsychotic drug .",
"Bacterial translocation in cirrhotic rats stimulates P29474 - derived NO production and impairs mesenteric vascular contractility . DB00435 ( NO ) has been implicated in the arterial vasodilation and associated vascular hyporesponsiveness to vasoconstrictors observed in liver cirrhosis . Bacteria , potent activators of NO and P01375 synthesis , are found in the mesenteric lymph nodes ( MLNs ) of ascitic cirrhotic rats . Here , we investigated the impact of bacterial translocation ( BT ) to MLNs on P01375 production , vascular NO release , and contractility in the mesenteric vasculature of ascitic cirrhotic rats . Vascular response to the alpha - adrenoagonist methoxamine , which is diminished in the superior mesenteric arterial beds of cirrhotic rats , is further blunted in the presence of BT . BT promoted vascular NO release in cirrhotic rats , an effect that depended on pressure - induced shear stress and was blocked by the NO inhibitor N ( omega )- nitro - L - arginine . Removing the endothelium had the same effect . Endothelial NO synthase ( P29474 ) , but not the inducible isoform ( P35228 ) , was present in mesenteric vasculature of cirrhotic rats with and without BT , and its expression was enhanced compared with controls . P01375 was induced in MLNs by BT and accumulated in parallel in the serum . This P01375 production was associated with elevated levels of tetrahydrobiopterin ( BH ( 4 ) ) , a P01375 - stimulated cofactor and enhancer of P29474 - derived NO biosynthesis and NOS activity in mesenteric vasculature . These findings establish a link between BT to MLNs and increased P01375 production and elevated BH ( 4 ) levels enhancing P29474 - derived NO overproduction , further impairing contractility in the cirrhotic mesenteric vasculature .",
"A novel mutation in P30518 causing congenital nephrogenic diabetes insipidus with complete resistance to antidiuretic hormone . A 6 - month - old male infant presented with failure to thrive . Hypernatraemia and elevated serum osmolality in the presence of low urine sodium and osmolality led to the diagnosis of diabetes insipidus . Administration of ___MASK89___ ( dDAVP ) neither decreased urine volume nor increased urine osmolality indicating congenital nephrogenic diabetes insipidus . Molecular analysis in the arginine - vasopressin receptor - 2 gene ( P30518 ) located on chromosome Xq28 demonstrated a novel 5 - base pair deletion ( c . 962 - 966delACCCC ; g . 1429 - 1433delACCCC ) leading to a shift of the reading frame ( p . Asn321fs ) and a premature termination codon implying an absent or non - functional protein . Treatment with hydrochlorothiazide , amiloride and indomethacin led to a favourable clinical course .",
"___MASK99___ reduces infection and inflammation in acute Pseudomonas aeruginosa pneumonia . The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia . This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P . aeruginosa lung infection . Q96RD7 ( Px1 ) channels mediate the activation of caspase - 1 and release of IL - 1β induced by Q99572 receptor activation . The approved drug probenecid is an inhibitor of Px1 and DB00171 release . In this study , we demonstrate that probenecid reduces infection and inflammation in acute P . aeruginosa pneumonia . Treatment of mice prior to infection with P . aeruginosa resulted in an enhanced clearance of P . aeruginosa and reduced levels of inflammatory mediators , such as IL - 1β . In addition , probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell - derived macrophages upon bacterial infection but not in human bronchial epithelial cells . Thus , Px1 blockade via probenecid treatment may be a therapeutic option in P . aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation .",
"Synergism between bosutinib ( ___MASK48___ ) and the Chk1 inhibitor ( PF - 00477736 ) in highly imatinib - resistant P11274 / ABL ⁺ leukemia cells . Interactions between the dual P11274 / P00519 and Src inhibitor bosutinib and the Chk1 inhibitor PF - 00477736 were examined in P11274 / P00519 (+) leukemia cells , particularly imatinib - resistant cells , including those with the T315I mutation . Bosutinib blocked PF - 00477736 - induced P27361 / 2 activation and sharply increased apoptosis in association with Mcl - 1 inhibition , p34 ( cdc2 ) dephosphorylation , BimEL up - regulation , and DNA damage in imatinib - resistant CML or Ph (+) ALL cell lines . Inhibition of Src or Q02750 by shRNA significantly enhanced PF - 0047736 lethality . Bosutinib / PF - 00477736 co - treatment also potentiated cell death in P28906 (+) CML patient samples , including dasatinib - resistant blast crisis cells exhibiting both T315I and E355G mutations , but was minimally toxic to normal P28906 (+) cells . Finally , combined in vivo treatment significantly suppressed BaF3 / T315I tumor growth and prolonged survival in an allogeneic mouse model . Together , these findings suggest that this targeted combination strategy warrants attention in IM - resistant CML or Ph (+) ALL .",
"Desmopressin ( ___MASK89___ ) induces NO production in human endothelial cells via V2 receptor - and DB02527 - mediated signaling . The hemostatic agent desmopressin ( ___MASK89___ ) also has strong vasodilatory effects . ___MASK89___ is a selective agonist for the vasopressin V2 receptor ( P30518 ) , which is coupled to DB02527 - dependent signaling . ___MASK89___ - induced vasodilation may be due to endothelial NO synthase ( P29474 ) activation . This hypothesis implies DB02527 - mediated P29474 activation . It also implies wide extrarenal , endothelial P30518 expression . We show that in human umbilical vein endothelial cells ( HUVECs ) the DB02527 - raising agents forskolin and epinephrine increase NO production , as measured by a l - NMMA - inhibitable rise in cellular cGMP content . They also increase P29474 enzymatic activity , in a partly calcium - independent manner . DB02527 - mediated P29474 activation is associated with phosphorylation of residue Ser1177 , in a phosphatidyl inositol 3 - kinase ( PI3K ) - independent manner . HUVECs do not express P30518 . However , after heterologous P30518 expression , ___MASK89___ induces DB02527 - dependent P29474 activation via Ser1177 phosphorylation . We have previously found P30518 expression in cultured lung endothelial cells . By real time quantitative RT - PCR , we now find a wide P30518 distribution notably in heart , lung and skeletal muscle . These results indicate that ___MASK89___ and other DB02527 - raising agents can activate P29474 via PI3K - independent Ser1177 phosphorylation in human endothelial cells . This mechanism most likely accounts for ___MASK89___ - induced vasodilation .",
"Novel real - time polymerase chain reaction assay for simultaneous detection of recurrent fusion genes in acute myeloid leukemia . The recent World Health Organization classification recognizes different subtypes of acute myeloid leukemia ( AML ) according to the presence of several recurrent genetic abnormalities . Detection of these abnormalities and other molecular changes is of increasing interest because it contributes to a refined diagnosis and prognostic assessment in AML and enables monitoring of minimal residual disease . These genetic abnormalities can be detected using single RT - PCR , although the screening is still labor intensive and costly . We have developed a novel real - time RT - PCR assay to simultaneously detect 15 AML - associated rearrangements that is a simple and easily applicable method for use in clinical diagnostic laboratories . This method showed 100 % specificity and sensitivity ( 95 % confidence interval , 91 % to 100 % and 92 % to 100 % , respectively ) . The procedure was validated in a series of 105 patients with AML . The method confirmed all translocations detected using standard cytogenetics and fluorescence in situ hybridization and some additional undetected rearrangements . Two patients demonstrated two molecular rearrangements simultaneously , with P11274 - P00519 implicated in both , in addition to Q01196 - MECOM in one patient and P29590 - P10276 in another . In conclusion , this novel real - time RT - PCR assay for simultaneous detection of multiple AML - associated fusion genes is a versatile and sensitive method for reliable screening of recurrent rearrangements in AML .",
"Serotonin receptor activation leads to neurite outgrowth and neuronal survival . Serotonin 5 - HT1 receptors are implicated in anxiety and depression . These receptors belong to the family A of G - protein - coupled receptors and couple to inhibitory G - proteins . Recent studies show that chronic activation of P08908 receptors leads to proliferation of hippocampal neurons suggesting that neurogenesis contributes to the effects of antidepressants . However , the molecular mechanisms and pathways involved are not understood . We used Neuro 2A cells transfected with P08908 receptors and SK - N - SH cells endogenously expressing the receptor to examine the effect of receptor activation on neuronal survival and neurite outgrowth . We find that receptor activation leads to increased neurite outgrowth that can be blocked by the receptor selective antagonist and by treatment with pertussis toxin or lactacystin implicating inhibitory G - proteins and proteasomal degradation in this process . Interestingly , the small G - protein Rap and the transcription factor P35610 - 3 are also involved since reducing the levels of Rap1 ( using small interfering RNA ) or P35610 - 3 ( using dominant negative P40763 ) significantly blocks P08908 - receptor - mediated neurite outgrowth . The observed increase in the phosphorylation of Src and P35610 - 3 , at sites leading to their activation , further supports a crucial role for these proteins in neurite outgrowth . We also find that prolonged activation of endogenous P08908 receptors leads to increased cell survival even under starving conditions ; this is completely blocked by co - treatment with the antagonist . Taken together , these findings indicate that activation of the P08908 receptor leads to a number of neurotropic events by activating a series of signal transduction molecules leading to long - term changes required for neurogenesis .",
"Lung carcinogenesis from chronic obstructive pulmonary disease : characteristics of lung cancer from P48444 and contribution of signal transducers and lung stem cells in the inflammatory microenvironment . Chronic obstructive pulmonary disease ( P48444 ) and lung cancer are closely related . The annual incidence of lung cancer arising from P48444 has been reported to be 0 . 8 - 1 . 7 % . Treatment of lung cancer from P48444 is very difficult due to low cardiopulmonary function , rapid tumor growth , and resistance to molecularly targeted therapies . Chronic inflammation caused by toxic gases can induce P48444 and lung cancer . Carcinogenesis in the inflammatory microenvironment occurs during cycles of tissue injury and repair . Cellular damage can induce induction of necrotic cell death and loss of tissue integrity . Quiescent normal stem cells or differentiated progenitor cells are introduced to repair injured tissues . However , inflammatory mediators may promote the growth of bronchioalveolar stem cells , and activation of NF - κB and signal transducer and activator of transcription 3 ( P40763 ) play crucial roles in the development of lung cancer from P48444 . Many of the protumorgenic effects of NF - κB and P40763 activation in immune cells are mediated through paracrine signaling . NF - κB and P40763 also contribute to epithelial - mesenchymal transition . To improve lung cancer treatment outcomes , lung cancer from P48444 must be overcome . In this article , we review the characteristics of lung cancer from P48444 and the mechanisms of carcinogenesis in the inflammatory microenvironment . We also propose the necessity of identifying the mechanisms underlying progression of P48444 to lung cancer , and comment on the clinical implications with respect to lung cancer prevention , screening , and therapy .",
"Influence of a 3 - day regimen of azithromycin on the disposition kinetics of cyclosporine A in stable renal transplant patients . Some macrolide antibiotics have been shown to produce significant drug - drug interactions through the inhibition of cytochrome P450 ( CYP ) enzymes . In renal transplant patients these interactions pose potentially serious problems for the safe administration of cyclosporine A ( Q13216 ) , a substrate of P08684 . The effects of azithromycin on Q13216 disposition kinetics were evaluated in eight stable renal transplant patients . Patients had been stabilized on individualized doses of Q13216 which remained unchanged throughout the study . ___MASK47___ was administered for 3 days . Baseline measurements of Q13216 disposition kinetics were taken prior to azithromycin treatment ( study day 2 ) and after 3 days ( study day 5 ) of azithromycin treatment ( 500mg / day , orally ) . The key parameters of interest were the area under the Q13216 blood concentration versus time curve ( AUC ) measured for 24h after the morning dose of Q13216 on both days 2 and 5 , and the C ( max ) values of Q13216 . The geometric mean ratios ( GMRs ) of those parameters ( day 5 / day 2 ) and their 90 % confidence intervals ( 90 % CI ) were 107 ( 98 , 116 ) and 119 ( 104 , 136 ) , respectively . The 7 % increase in exposure level and 19 % increase in peak plasma concentration are not likely to be clinically significant . It is concluded that azithromycin ( 500mg / dayx3 days ) does not alter the disposition kinetics of Q13216 in a clinically significant way , and that Q13216 dosage adjustments are not warranted in renal transplant patients taking these two drugs together .",
"Is phentermine an inhibitor of monoamine oxidase ? A critical appraisal . ___MASK24___ produces a spectrum of concentration - dependent biochemical effects . It interacts with NE transporters at 0 . 1 microM , DA transporters at about 1 microM , 5 - HT transporters at 15 microM and P21397 at about 100 microM . When administered at typical anorectic doses , phentermine primarily interacts with DA and NE transporters and does not produce biochemical or neurochemical effects which would occur if it were inhibiting P21397 . Some other explanation other than MAO inhibition must be sought to explain how oral phentermine increases platelet 5 - HT , since platelet P27338 does not metabolize platelet 5 - HT , and since amphetamine - type drugs are even weaker inhibitors of P27338 than P21397 . Clinical studies in humans have shown that amphetamine , which is a more potent inhibitor of P21397 than phentermine , does not inhibit P21397 at therapeutic doses . Neither phentermine alone , fluoxetine alone or their combined use have been associated with cardiac valvulopathy , and clinical experience has shown their combined use to be free of significant adverse effects . Viewed collectively , there appears to be no data to support the hypothesis that phentermine inhibits MAO at typical therapeutic doses .",
"The cleaved cytoplasmic tail of polycystin - 1 regulates Src - dependent P40763 activation . P98161 ( PC1 ) mutations result in proliferative renal cyst growth and progression to renal failure in autosomal dominant polycystic kidney disease ( ADPKD ) . The transcription factor P40763 ( signal transducer and activator of transcription 3 ) was shown to be activated in cyst - lining cells in ADPKD and Q15139 mouse models and may drive renal cyst growth , but the mechanisms leading to persistent P40763 activation are unknown . A proteolytic fragment of PC1 corresponding to the cytoplasmic tail , PC1 - p30 , is overexpressed in ADPKD . Here , we show that PC1 - p30 interacts with the nonreceptor tyrosine kinase Src , resulting in Src - dependent activation of P40763 by tyrosine phosphorylation . The PC1 - p30 - mediated activation of Src / P40763 was independent of JAK family kinases and insensitive to the P40763 inhibitor suppressor of cytokine signaling 3 . Signaling by the P01133 receptor ( P00533 ) or DB02527 amplified the activation of Src / P40763 by PC1 - p30 . Expression of PC1 - p30 changed the cellular response to DB02527 signaling . In the absence of PC1 - p30 , DB02527 dampened P00533 - or P05231 - dependent activation of P40763 ; in the presence of PC1 - p30 , DB02527 amplified Src - dependent activation of P40763 . In the polycystic kidney ( PCK ) rat model , activation of P40763 in renal cystic cells depended on vasopressin receptor 2 ( P30518 ) signaling , which increased DB02527 levels . Genetic inhibition of vasopressin expression or treatment with a pharmacologic P30518 inhibitor strongly suppressed P40763 activation and reduced renal cyst growth . These results suggest that PC1 , via its cleaved cytoplasmic tail , integrates signaling inputs from P00533 and DB02527 , resulting in Src - dependent activation of P40763 and a proliferative response .",
"Identification of the fused bicyclic 4 - amino - 2 - phenylpyrimidine derivatives as novel and potent DB05876 inhibitors . 2 - Phenyl - 4 - piperidinyl - 6 , 7 - dihydrothieno [ 3 , 4 - d ] pyrimidine derivative ( 2 ) was found to be a new DB05876 inhibitor with moderate Q07343 activity ( IC50 = 150 nM ) . A number of derivatives with a variety of 4 - amino substituents and fused bicyclic pyrimidines were synthesized . Among these , 5 , 5 - dioxo - 7 , 8 - dihydro - 6H - thiopyrano [ 3 , 2 - d ] pyrimidine derivative ( 18 ) showed potent Q07343 inhibitory activity ( IC50 = 25 nM ) . Finally , N - propylacetamide derivative ( 31b ) was determined as a potent inhibitor for both Q07343 ( IC50 = 7 . 5 nM ) and P01375 - α production in mouse splenocytes ( IC50 = 9 . 8 nM ) and showed good in vivo anti - inflammatory activity in the LPS - induced lung inflammation model in mice ( ID50 = 18 mg / kg ) . The binding mode of the new inhibitor ( 31e ) in the catalytic site of Q07343 is presented based on an X - ray crystal structure of the ligand - enzyme complex .",
"Inhibition of Q16552 as a pharmacological approach for Q9UKU7 . Several experimental approaches have been utilized , in order to critically examine the roles of Q16552 family members in intestinal inflammation . These approaches have included : ( 1 ) the use of Q16552 and Q96PD4 - deficient mice , ( 2 ) specific antibodies directed against Q16552 , ( 3 ) an Q16552 vaccine , ( 4 ) methods to block the Q16552 receptor and ( 5 ) small - molecule inhibitors of Q16552 . Previous studies found somewhat conflicting results in preclinical models of Inflammatory Bowel Disease ( Q9UKU7 ) , using specific strains of Q16552 - deficient mice . This paper will review the preclinical results using various pharmacological approaches [ specific Q16552 antibodies , an Q16552 receptor fusion protein , IL - 12 / IL - 23 p40 subunit and Q16552 vaccine approaches , as well as a small molecule inhibitor ( Vidofludimus ) ] to inhibit Q16552 in animal models of Q9UKU7 . Recent clinical results in patients with Q9UKU7 will also be discussed for DB09029 ( an Q16552 antibody ) , Brodalumab ( an Q16552 receptor antibody ) and two small - molecule drugs ( Vidofludimus and DB08895 ) , which inhibit Q16552 as part of their overall pharmacological profiles . This review paper will also discuss some pharmacological lessons learned from the preclinical and clinical studies with anti - Q16552 drugs , as related to drug pharmacodynamics , Q16552 receptor subtypes and other pertinent factors . Finally , future pharmacological approaches of interest will be discussed , such as : ( 1 ) Retinoic acid receptor - related orphan nuclear receptor gamma t ( Rorγt ) antagonists , ( 2 ) P10276 ( RARα ) antagonists , ( 3 ) Pim - 1 kinase inhibitors and ( 4 ) Dual small - molecule inhibitors of NF - κB and P40763 , like synthetic triterpenoids .",
"A negative feedback loop mediated by P40763 limits human Th17 responses . The transcription factor P40763 is critically required for the differentiation of Th17 cells , a T cell subset involved in various chronic inflammatory diseases . In this article , we report that P40763 also drives a negative - feedback loop that limits the formation of Q16552 - producing T cells within a memory population . By activating human memory P01730 (+) CD45RO (+) T cells at a high density ( HiD ) or a low density ( LoD ) in the presence of the pro - Th17 cytokines IL - 1β , IL - 23 , and TGF - β , we observed that the numbers of Th17 cells were significantly higher under LoD conditions . Assessment of P40763 phosphorylation revealed a more rapid and stronger P40763 activation in HiD cells than in LoD cells . Transient inhibition of active P40763 in HiD cultures significantly enhanced Th17 cell numbers . Expression of the P40763 - regulated ectonucleotidase P49961 , which catalyzes DB00171 hydrolysis , was higher in HiD , than in LoD , cell cultures . Interestingly , inhibition of P49961 ectonucleotidase activity enhanced Th17 responses under HiD conditions . Conversely , blocking the DB00171 receptor Q99572 reduced Th17 responses in LoD cultures . These data suggest that P40763 negatively regulates Th17 cells by limiting the availability of DB00171 . This negative - feedback loop may provide a safety mechanism to limit tissue damage by Th17 cells during chronic inflammation . Furthermore , our results have relevance for the design of novel immunotherapeutics that target the P40763 - signaling pathway , because inhibition of this pathway may enhance , rather than suppress , memory Th17 responses .",
"DAPk1 inhibits NF - κB activation through P01375 - α and P27352 - γ - induced apoptosis . Recent studies have shown DAPk as a molecular modulator induced by the second messenger , responsible for controlling cell destiny decisions , but the detailed mechanism mediating the role of DAPk1 during cell death is still not fully understood . In this present report , we attempted to characterize the effects of P01375 - α and P27352 - γ on DAPk1 in human ovarian carcinoma cell lines , OVCAR - 3 . Both P01375 - α and P27352 - γ significantly induce DAPk1 levels in a time - dependent manner . At the same time , they both arrested cell cycle progression in the G ( 0 )- G ( 1 ) and G2 / M phase , down - regulated cyclin D1 , P11802 and NF - κB expression , while also up - regulating p27 and p16 expression . Subsequently , the efficacy of the combined treatment with DAPk1 was investigated . In the presence of DAPk1 , P01375 - α or P27352 - γ - induced apoptosis was additively increased , while P01375 - α or P27352 - γ - induced NF - κB activity was inhibited . Conversely , P01375 - α or P27352 - γ - dependent NF - κB activity was further enhanced by the inhibition of DAPk1 with its specific siRNA . The activity of NF - κB was dependent on the level of DAPk1 , indicating the requirement of DAPk1 for the activation of NF - κB . Low levels of DAPk1 expression were frequently observed in different human patient ' s tissue and cancer cell lines compared to normal samples . In addition , over - expression of DAPk1 from either P01375 - α or P27352 - γ - treatment cells suppressed the anti - apoptosis protein P98170 as well as P35354 and P05362 , more than control . Taken together , our data findings suggest that DAPk1 can mediate the pro - apoptotic activity of P01375 - α and P27352 - γ via the NF - κB signaling pathways .",
"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .",
"Interaction of murine peritoneal leukocytes and mesothelial cells : in vitro model system to survey cellular events on serosal membranes during inflammation . All serosal cavities including peritoneum are lined with a simple squamous mesothelium . Primary culture of murine mesothelial cells has been established to study their cellular interactions with peritoneal leukocytes . The mesothelial character was determined by the cytokeratin and vimentin expression . The mesothelial cells expressed P05362 and P16070 molecules . The expression of P05362 , but not P16070 , was significantly enhanced by the treatment with P01375 ( 100 U / ml ) . We have also investigated possible influence of transforming growth factors , TGF - alpha ( 20 ng / ml ) and TGF - beta ( 2 ng / ml ) , and epidermal growth factor ( 20 ng / ml ) . These factors were not found to modulate P05362 or P16070 expression in vitro . During coculture experiments unstimulated mesothelial cells were almost nonadherent for both resident and elicited peritoneal mononuclear leukocytes for several hours . P01375 or P01133 pretreatment of mesothelial cells greatly enhanced their adhesive affinity to peritoneal mononuclear leukocytes , while TGF - beta pretreatment even reduced the low basal adhesion . Prolonged coculture for 3 weeks resulted in remarkable proliferation and differentiation of both resident and elicited monocytes / macrophages on the mesothelial surface . The stimulation of mesothelial cell culture with P01133 resulted in the macrophage colony - stimulating activity ( M - Q13216 ) production . M - Q13216 was mainly due to P09603 as confirmed with anti P09603 monoclonal antibody ; the residual M - Q13216 was not formed by GM - P04141 . After several passages the mesothelial cells started to produce M - Q13216 spontaneously .",
"The potential role of PD0332991 ( ___MASK13___ ) in the treatment of multiple myeloma . INTRODUCTION : Multiple myeloma ( MM ) remains an incurable malignancy indicating a need for continued investigation of novel therapies . Recent studies have highlighted the role of cyclin - dependent kinases ( CDK ) in the pathogenesis of MM . PD0332991 ( ___MASK13___ ) is an orally bioavailable , highly selective inhibitor of the P11802 / 6 - cyclin complex and downstream retinoblastoma protein ( Rb ) activation pathway that induces cell cycle arrest in the P55008 phase . AREAS COVERED : In this review , the authors summarize the role of the P11802 / 6 signaling pathway in MM . They also summarize the development of PD0332991 as a specific inhibitor of P11802 / 6 , and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM . EXPERT OPINION : While PD0332991 is essentially cytostatic , inducing prolonged P55008 arrest , it enhances the cytotoxic effect of other agents effective in MM , including bortezomib and lenalidomide , as confirmed in early phase clinical trials . However , with a plethora of other drugs of different classes being tested in MM , further development of PD0332991 will depend on defining the most efficacious combination with least toxicity . An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM . The next few years are likely to better define the place of PD0332991 in the treatment of MM .",
"Not all monoclonals are created equal - lessons from failed drug trials in Crohn ' s disease . The recent success of the anti - integrin antibody DB09033 can barely conceal the fact that the biologics armamentarium in Crohn ' s disease has barely evolved beyond P01375 blockers so far . This contrasts with other immune - related diseases considered mechanistically and genetically closely related , such as psoriasis and rheumatoid arthritis , where approved biologics target a variety of independent biological mechanisms . Several pharmacological assets that entered clinical development have proven ineffective , or less effective than originally anticipated . While blockade of Q16552 and its receptor via DB09029 and Brodalumab , respectively , worsened Crohn ' s disease , the beneficial effect of IL - 12 / 23 p40 blockade via Ustekinumab appeared confined to a subpopulation of Crohn ' s disease patients who have previously failed on P01375 blockers . Clinical development of the IFNγ blocker DB05111 was stopped despite demonstrating some clinical benefit , while the T cell co - stimulation blocker DB01281 did not exhibit any hint towards efficacy in Crohn ' s disease . Here I review results from these individual development programmes , and also reflect on the lack of efficacy of the P01375 blocker DB00005 . I will discuss aspects of individual trials that might have confounded their interpretation and highlight the evolution in primary and secondary endpoints that have contributed to increasing robustness of results obtained in recent years . Finally , I suggest that mechanistic studies in murine genetic models combined with exploratory immunological studies incorporated in early drug development may represent the key for identifying the next generation of successful pharmacological targets in Crohn ' s disease .",
"Prasugrel : a new antiplatelet drug for the prevention and treatment of cardiovascular disease . Prasugrel , trade name ___MASK77___ , is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration . It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine . Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic Q9H244 receptor on the platelet surface . Prasugrel has been shown to be a potent antiplatelet agent with a faster , more consistent , and greater inhibition of platelet aggregation compared with clopidogrel . It is debatable , however , how effectively these pharmacologic benefits will translate to clinical benefits . The results of the large TRITON - TIMI 38 trial , which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents , demonstrated a significant reduction in ischemic events , including stent thrombosis , with prasugrel , but with an increased risk of major bleeding . The exact role of prasugrel in the management of ischemic heart disease is still being defined , but the risk : benefit ratio will likely play a major role in directing the best place for therapy with this new agent .",
"Novel path to P05231 trans - signaling through thrombin - induced soluble P05231 receptor release by platelets . Interleukin ( IL ) - 6 is a multifunctional cytokine with a critical role in inflammatory , immunoregulatory and haemopoietic responses . Its receptor consists of an ubiquitously expressed membrane transducing element ( P40189 ) and of the specific element P08887 ( P08887 ) , present only on hepatocytes and some leukocyte subsets . P08887 also exists as soluble protein ( sIL - 6R ) that , in the presence of P05231 , forms a complex able to bind P40189 and , thanks to the mechanism called trans - signaling , transduces P05231 effect through tyrosine phosphorylation and activation of the signal transducer and transcription activator ( P35610 ) - 3 . The aim of this study was to analyze the bidirectional relationships between platelet aggregation and P05231 - dependent effects . While platelets do not produce P05231 , we found that resting platelets express P40189 , but not P08887 , on their membranes . Upon activation by thrombin or calcium ionophore A23187 , but not by ADP , the P08887 is released in soluble form , while cangrelor , the specific inhibitor of Q9H244 receptor , can partially inhibit sIL - 6R release . This sIL - 6R is biologically active and , in the presence of P05231 , can trigger P05231 trans - signaling , inducing an autocrine activation loop ( as measured by an increase in P08887 and P40189 content ) and P40763 phosphorylation . On the other hand , P05231 trans - signaling has no effect on platelet degranulation or aggregation by itself , nor on thrombin - induced platelet aggregation . Our data add an important piece to the puzzle of thrombosis and inflammation : in the presence of P05231 , which can be produced by stressed endothelial cells , the platelet - derived P05231 trans - signaling could be crucial for the evolution of inflammation within a damaged vessel .",
"Q99572 receptor - dependent intestinal afferent hypersensitivity in a mouse model of postinfectious irritable bowel syndrome . The DB00171 - gated P2X ( 7 ) receptor ( P2X ( 7 ) R ) was shown to be an important mediator of inflammation and inflammatory pain through its regulation of IL - 1β processing and release . Trichinella spiralis - infected mice develop a postinflammatory visceral hypersensitivity that is reminiscent of the clinical features associated with postinfectious irritable bowel syndrome . In this study , we used P2X ( 7 ) R knockout mice ( P2X ( 7 ) R (-/-) ) to investigate the role of P2X ( 7 ) R activation in the in vivo production of IL - 1β and the development of postinflammatory visceral hypersensitivity in the T . spiralis - infected mouse . During acute nematode infection , IL - 1β - containing cells and P2X ( 7 ) R expression were increased in the jejunum of wild - type ( WT ) mice . Peritoneal and serum IL - 1β levels were also increased , which was indicative of elevated IL - 1β release . However , in the P2X ( 7 ) R (-/-) animals , we found that infection had no effect upon intracellular , plasma , or peritoneal IL - 1β levels . Conversely , infection augmented peritoneal P01375 - α levels in both WT and P2X ( 7 ) R (-/-) animals . Infection was also associated with a P2X ( 7 ) R - dependent increase in extracellular peritoneal lactate dehydrogenase , and it triggered immunological changes in both strains . Jejunal afferent fiber mechanosensitivity was assessed in uninfected and postinfected WT and P2X ( 7 ) R (-/-) animals . Postinfected WT animals developed an augmented afferent fiber response to mechanical stimuli ; however , this did not develop in postinfected P2X ( 7 ) R (-/-) animals . Therefore , our results demonstrated that P2X ( 7 ) Rs play a pivotal role in intestinal inflammation and are a trigger for the development of visceral hypersensitivity .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"Hedyotis diffusa Willd inhibits colorectal cancer growth in vivo via inhibition of P40763 signaling pathway . Signal Transducer and Activator of Transcription 3 ( P40763 ) , a common oncogenic mediator , is constitutively activated in many types of human cancers ; therefore it is a major focus in the development of novel anti - cancer agents . Hedyotis diffusa Willd has been used as a major component in several Chinese medicine formulas for the clinical treatment of colorectal cancer ( CRC ) . However , the precise mechanism of its anti - tumor activity remains largely unclear . Using a CRC mouse xenograft model , in the present study we evaluated the effect of the ethanol extract of Hedyotis diffusa Willd ( EEHDW ) on tumor growth in vivo and investigated the underlying molecular mechanisms . We found that EEHDW reduced tumor volume and tumor weight , but had no effect on body weight gain in CRC mice , demonstrating that EEHDW can inhibit CRC growth in vivo without apparent adverse effect . In addition , EEHDW treatment suppressed P40763 phosphorylation in tumor tissues , which in turn resulted in the promotion of cancer cell apoptosis and inhibition of proliferation . Moreover , EEHDW treatment altered the expression pattern of several important target genes of the P40763 signaling pathway , i . e . , decreased expression of P12004 D1 , P11802 and Bcl - 2 as well as up - regulated P38936 and Bax . These results suggest that suppression of the P40763 pathway might be one of the mechanisms by which EEHDW treats colorectal cancer .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"[ New therapeutic strategy for autoimmune and chronic inflammatory disease based on clinical results using P05231 blocking therapy with a humanized anti - P05231 receptor antibody ] . Remarkable clinical effects were observed by P05231 blockage with a humanized anti P05231 receptor antibody in patients with Castleman ' s disease , rheumatoid arthritis , and juvenile inflammatory arthritis . This evidence suggests that the hyper - function of P05231 is an essential key cytokine in the pathogenesis of the above diseases , in which many cytokines , chemokines , and inflammatory molecules are activated . We found , for example , P01375 blocking therapy showed a reduction of acute phase proteins , such as CRP and P0DJI8 , however , the P05231 blockade induced not only reduction but also normalization of CRP and P0DJI8 serum levels . To elucidate this in vivo phenomenon , we analyzed the expression of cytokine inducing CRP and P0DJI8 mRNA with the intracellular signal transduction mechanism in vitro . The results , indicated that the P05231 signal was essential though the activation of P40763 for the induction and augmentation of CRP or P0DJI8 by the associated stimulation with P01375 or IL - 1 . Recently , it is now known that P05231 is a regulatory molecule in the induction of Th17 cells with TGF - beta . Therefore , P05231 blockage may potentially improve autoimmune diseases , beginning with the pathogenic initiation phase . We believe that unknown pathogenic inflammatory phenomena can be clarified using this analytical strategy and cytokine blocking therapy . Furthermore , in the future we hope to induce complete remission of autoimmune diseases by using cytokine blockage freely .",
"Cross - talk between PKA - Cβ and p65 mediates synergistic induction of Q07343 by roflumilast and NTHi . Phosphodiesterase 4B ( Q07343 ) plays a key role in regulating inflammation . ___MASK20___ , a phosphodiesterase ( PDE ) 4 - selective inhibitor , has recently been approved for treating severe chronic obstructive pulmonary disease ( P48444 ) patients with exacerbation . However , there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the possible contribution of Q07343 up - regulation , which could be counterproductive for suppressing inflammation . Thus , understanding how Q07343 is up - regulated in the context of the complex pathogenesis and medications of P48444 may help improve the efficacy and possibly ameliorate the tolerance of roflumilast . Here we show that roflumilast synergizes with nontypeable Haemophilus influenzae ( NTHi ) , a major bacterial cause of P48444 exacerbation , to up - regulate PDE4B2 expression in human airway epithelial cells in vitro and in vivo . Up - regulated PDE4B2 contributes to the induction of certain important chemokines in both enzymatic activity - dependent and activity - independent manners . We also found that protein kinase A catalytic subunit β ( PKA - Cβ ) and nuclear factor - κB ( NF - κB ) p65 subunit were required for the synergistic induction of PDE4B2 . PKA - Cβ phosphorylates p65 in a DB02527 - dependent manner . Moreover , Ser276 of p65 is critical for mediating the PKA - Cβ - induced p65 phosphorylation and the synergistic induction of PDE4B2 . Collectively , our data unveil a previously unidentified mechanism underlying synergistic up - regulation of PDE4B2 via a cross - talk between PKA - Cβ and p65 and may help develop new therapeutic strategies to improve the efficacy of DB05876 inhibitor ."
] |
[
"___MASK13___",
"___MASK20___",
"___MASK24___",
"___MASK47___",
"___MASK48___",
"___MASK58___",
"___MASK77___",
"___MASK89___",
"___MASK99___"
] |
___MASK20___
|
MH_train_487
|
interacts_with DB00159?
|
[
"Genotype frequencies of 50 polymorphisms for 241 Japanese non - cancer patients . This paper lists the genotype frequencies of 50 polymorphisms of 37 genes ( P05091 , P07550 , P13945 , P21964 , P16671 , P25025 , P24385 , P35354 , P11509 , P05093 , P11511 , IGF1 , IL - 1A , IL - 1B , IL - 1RN , IL - 1R1 , P05231 , P10145 , P22301 , P41159 , Le , L - myc , P05164 , Q99707 , P42898 , P21397 , P15559 , O15527 , p53 , p73 , Se , P31213 , TGF - B , P01375 - A , P01375 - B , P18074 , and P18887 ) and 6 sets of combined genotype frequencies for 241 non - cancer Japanese outpatients . Though the genotype frequencies of 25 polymorphisms have already been reported in our previous papers , 15 polymorphisms ( P16671 A52C , P25025 C785T , P24385 G870A , IGF1 C / T at intron 2 and G2502T , IL - 1A 46 - bp VNTR , IL - 1R1 C - 116T , P05231 Ins / Del 17C , P10145 A - 278T and C74T , IL - 10 T - 819C , P41159 A - 2548G , P31213 2 - bp VNTR , P18074 Lys751Gln , and P18887 Arg399Gln ) and six sets of combined genotype frequencies ( IL - 1B C - 31T and IL - 1A C - 889T , IL - 1B C - 31T and IL - 1RN 86 - bp VNTR , IL - 1B C - 31T and IL - 1R1 C - 116T , P01375 - A G - 308A and P01375 - B A252G , P31213 Val89Leu and 2 - bp VNTR , and P18887 Arg399Gln and P18074 Lys751Gln ) were reported in this paper for the first time for Japanese . Although microarray technology will produce this kind of information in near future , this is the first document that reports the genotype / allele frequencies among Japanese for an archival purpose .",
"Basal cell carcinoma and variants in genes coding for immune response , DNA repair , folate and iron metabolism . Basal cell carcinoma ( BCC ) is one of the most common neoplasms in the world and its incidence has been increasing worldwide in recent years . BCCs are caused by an interplay between genetic and environment factors . We conducted a case - control association study in BCC patients and controls from Sweden and Finland . Fifteen single nucleotide polymorphisms ( SNPs ) , P05231 - 174G / C , - 634G / C , and - 597G / A ; P22301 - 1082G / A and - 592C / A ; IL - 1beta - 511C / T ; NBS1 exon 5 Glu185Gln ; Q01831 exon 15 Lys939Gln ; P18074 exon 23 Lys751Gln ; P18887 exon 10 Arg399Gln ; O43542 exon 7 Thr241Met ; cyclin D1 exon 4 G870A ; P42898 exon 4 Ala222Val and exon 7 Glu429Ala ; Q30201 exon 4 C282Y were performed by Pyrosequencing and RFLP techniques . Most of the genotype distributions were in accordance with the Hardy - Weinberg equilibrium ( HWE ) , except for P22301 - 1082G / A , where cases with BCC showed a significant deviation from HWE ( P = 0 . 04 ) . Linkage disequilibrium was observed between the - 174 and - 597 alleles in the P05231 gene in the present populations . No difference between BCC and controls appeared in any of the SNPs analyzed . Only the combined distributions of TT / AA genotypes in P42898 exon 4 ( C / T ) and exon 7 ( A / C ) showed slight increase in BCC compared to controls ( P < 0 . 07 , OR : 1 . 94 ; 95 % CI : 0 . 96 - 3 . 89 ) .",
"Identification of Reverb ( alpha ) as a novel ROR ( alpha ) target gene . The nuclear receptor superfamily comprises a large number of ligand - activated transcription factors that are involved in numerous biological processes such as cell proliferation , differentiation , and homeostasis . ROR ( alpha ) ( P35398 ) and Reverb ( alpha ) ( P20393 ) are two members of this family whose biological functions are largely unknown . In addition , no ligand has been yet identified for these two receptors ; therefore , they are referred as orphan receptors . Here , we show that ROR ( alpha ) and Reverb ( alpha ) are expressed with a similar tissue distribution and are both induced during the differentiation of rat Q9BTT4 myoblastic cells . Ectopic expression of ROR ( alpha ) 1 in Q9BTT4 cells significantly induces Reverb ( alpha ) expression as demonstrated by Northern blot analysis . Using reverse transcription - PCR to analyze Reverb ( alpha ) gene expression from staggerer mice , we found that there was a significant reduction of Reverb ( alpha ) mRNA in the skeletal muscle comparing it with the wild - type mice , which suggests that ROR ( alpha ) is involved in the regulation of Reverb ( alpha ) gene expression . Transient transfection assays using the Reverb ( alpha ) promoter demonstrate that ROR ( alpha ) regulates the Reverb ( alpha ) gene at the transcriptional level . Furthermore , mutagenesis experiments indicate that ROR ( alpha ) regulates Reverb ( alpha ) transcription via a monomeric ROR response element located in the Reverb ( alpha ) gene promoter . Electrophoretic mobility shift assays show that ROR ( alpha ) binds strongly to this site in a specific - manner . Finally , overexpression of Q9Y3R0 / Q06418 - 2 , but not Q15788 , potentiates ROR ( alpha )- stimulated Reverb ( alpha ) promoter activity in transient transfection experiments . Together , our results identify Reverb ( alpha ) as a novel target gene for ROR ( alpha ) .",
"DB00159 modulates DB00091 - induced proinflammatory cytokine over - expression in osteoblastic cells in vitro . Several adverse outcomes are reported in subjects undergoing long term DB00091 ( DB00091 ) treatment . Severe osteopenia has been described in clinical and experimental reports , while beneficial effects of n - 3 polyunsaturated fatty acids ( PUFAs ) on bone metabolism are recognized . In the present study we investigated the effects of n - 3 versus n - 6 PUFAs on osteoblastic cells treated with DB00091 , evaluating the expression of interleukin ( IL ) - 1 & # 223 ; , interleukin - 6 ( P05231 ) , inducible nitric oxide synthase ( P35228 ) , and cyclooxygenase - 2 ( P35354 ) in two different experimental protocols and the production of P05231 , IL - 1 & # 223 ; , and tumor necrosis factor alpha ( TNFalpha ) in cells challenged simultaneously with DB00091 and eicosapentaenoic acid ( EPA ) for 48h . IL - 1 & # 223 ; and P05231 up - regulation , induced by DB00091 , was counteracted by the addition of EPA in both protocols ; on the contrary , arachidonic acid ( AA ) magnified DB00091 the effects . P35354 and P35228 levels were not modified by DB00091 treatment . These in vitro results , that substantiate clinical reports of DB00091 - induced osteopenia , demonstrate a beneficial effect of EPA on DB00091 - altered cytokine profile , opening new perspectives in the non - pharmacological management of adverse outcomes in DB00091 - treated patients .",
"Glucocorticoid - independent repression of tumor necrosis factor ( P01375 ) alpha - stimulated interleukin ( IL ) - 6 expression by the glucocorticoid receptor : a potential mechanism for protection against an excessive inflammatory response . TNFα signaling and cytokine levels play a crucial role in cervical immunity and the host response to infections . We investigated the role of liganded and unliganded glucocorticoid receptor ( GR ) in P05231 and P10145 gene regulation in response to TNFα in the End1 / E6E7 immortalized human endocervical epithelial cell line . In the absence of glucocorticoids , both decreasing GR protein levels by an siRNA strategy and results with the GR antagonist DB00834 suggest a role for the unliganded GR in reduction of TNFα - induced P05231 and P10145 mRNA levels in End1 / E6E7 cells . Moreover , GR - dependent repression of endogenous P05231 mRNA as well as a minimal P05231 promoter - reporter gene is also demonstrated in COS - 1 cells in the absence of GR ligand , suggesting a transcriptional mechanism that is not cell - specific . TNFα induced recruitment of both the unliganded GR and GR - interacting protein type 1 ( Q9Y3R0 ) to the P05231 promoter . This , together with Q9Y3R0 overexpression studies , suggests a function for Q9Y3R0 as a GR co - repressor in this context . TNFα was shown to induce phosphorylation of the unliganded human GR at DB00133 - 226 but not DB00133 - 211 , unlike dexamethasone , which induced hyperphosphorylation at both serine residues . DB00133 - 226 is shown to be required for the ligand - independent GR - mediated repression of P05231 in response to TNFα . Taken together , these results support a model whereby the unliganded GR attenuates TNFα - stimulated P05231 transcription by a mechanism involving selective phosphorylation and recruitment of the unliganded GR and Q9Y3R0 to the P05231 promoter . These findings suggest the presence of a novel autoregulatory mechanism that may prevent overproduction of P05231 in the endocervix , possibly protecting against negative effects of excessive inflammation .",
"Adipose tissue dysfunction in nascent metabolic syndrome . The metabolic syndrome ( MetS ) confers an increased risk for both type 2 diabetes mellitus ( T2DM ) and cardiovascular disease ( CVD ) . Moreover , studies on adipose tissue biology in nascent MetS uncomplicated by T2DM and / or CVD are scanty . Recently , we demonstrated that adipose tissue dysregulation and aberrant adipokine secretion contribute towards the syndrome ' s low - grade chronic proinflammatory state and insulin resistance . Specifically , we have made the novel observation that subcutaneous adipose tissue ( P21673 ) in subjects with nascent MetS has increased macrophage recruitment with cardinal crown - like structures . We have also shown that subjects with nascent MetS have increased the levels of P21673 - secreted adipokines ( IL - 1 , P05231 , P10145 , leptin , P02753 - 4 , CRP , P0DJI8 , P05121 , P13500 , and chemerin ) and plasma adipokines ( IL - 1 , P05231 , leptin , P02753 - 4 , CRP , P0DJI8 , and chemerin ) , as well as decreased levels of plasma adiponectin and both plasma and P21673 omentin - 1 . The majority of these abnormalities persisted following correction for increased adiposity . Our data , as well as data from other investigators , thus , highlight the importance of subcutaneous adipose tissue dysfunction in subjects with MetS and its contribution to the proinflammatory state and insulin resistance . This adipokine profile may contribute to increased insulin resistance and low - grade inflammation , promoting the increased risk of T2DM and CVD .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK33___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"Peroxisome - proliferator activator receptor - gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion . The aim of this study was to investigate whether peroxisome proliferator - activated receptor ( Q07869 ) - gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well - established in vitro model of the early endometriotic lesion . The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study . EM42 cells , LP9 cells or both were treated with the P37231 agonist ciglitazone ( CTZ ) at varying concentrations ( 10 , 20 and 40 microM ) x 48 h with subsequent co - culture of EM42 and LP9 cells . The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control ( EM42 and LP9 cells co - cultured without prior treatment with CTZ ) . Next , attachment of CTZ - treated and untreated EM42 cells to hyaluronic acid ( HA ) , a cell adhesion molecule ( P62158 ) on peritoneal mesothelial cells , were assessed . Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ , treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27 % ( P < 0 . 01 ) . Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37 % ( P < 0 . 01 ) . Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66 % ( P = 0 . 056 ) . CTZ did not decrease invasion of EM42 cells through the LP9 monolayer . CTZ may inhibit EM42 cell proliferation . In conclusion , CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion .",
"Studies on induction of lamotrigine metabolism in transgenic UGT1 mice . A transgenic ' knock - in ' mouse model expressing a human UGT1 locus ( P01266 - UGT1 ) was recently developed and validated . Although these animals express mouse P22309 proteins , P22310 is a pseudo - gene in mice . Therefore , P01266 - UGT1 mice serve as a ' humanized ' P22310 animal model . Lamotrigine ( LTG ) is primarily metabolized to its N - glucuronide ( LTGG ) by hUGT1A4 . This investigation aimed at examining the impact of pregnane X receptor ( O75469 ) , constitutive androstane receptor ( CAR ) and peroxisome proliferator - activated receptor ( Q07869 ) activators on LTG glucuronidation in vivo and in vitro . P01266 - UGT1 mice were administered the inducers phenobarbital ( CAR ) , pregnenolone - 16alpha - carbonitrile ( O75469 ) , WY - 14643 ( Q07869 ) , ciglitazone ( P37231 ) , or L - 165041 ( Q03181 ) , once daily for 3 or 4 days . Thereafter , LTG was administered orally and blood samples were collected over 24 h . LTG was measured in blood and formation of LTGG was measured in pooled microsomes made from the livers of treated animals . A three - fold increase in in vivo LTG clearance was seen after phenobarbital administration . In microsomes prepared from phenobarbital - treated P01266 - UGT1 animals , 13 - fold higher CL ( int ) ( Vmax / K ( m ) ) value was observed as compared with the untreated transgenic mice . A trend toward induction of catalytic activity in vitro and in vivo was also observed following pregnenolone - 16alpha - carbonitrile and WY - 14643 treatment . This study demonstrates the successful application of P01266 - UGT1 mice as a novel tool to study the impact of induction and regulation on metabolism of P22310 substrates .",
"Anti - inflammatory activity of Taraxacum officinale . Taraxacum officinale has been widely used as a folkloric medicine for the treatment of diverse diseases . The dried plant was extracted with 70 % ethanol to generate its ethanol extract ( TEE ) . For some experiments , ethyl acetate ( EA ) , n - butanol ( BuOH ) and aqueous ( Aq ) fractions were prepared in succession from TEE . TEE showed a scavenging activity in the 1 , 1 - diphenyl - 2 - picrylhydrazyl ( DPPH ) assay , a diminishing effect on intracellular reactive oxygen species ( ROS ) level , and an anti - angiogenic activity in the chicken chorioallantoic ( P62158 ) assay . In the carrageenan - induced air pouch model , TEE inhibited production of exudate , and significantly diminished nitric oxide ( NO ) and leukocyte levels in the exudate . It also possessed an inhibitory effect on acetic acid - induced vascular permeability and caused a dose - dependent inhibition on acetic acid - induced abdominal writhing in mice . Suppressive effects of TEE on the production of NO and expression of inducible nitric oxide synthase ( P35228 ) and cyclooxygenase - 2 ( P35354 ) in lipopolysaccharide ( LPS ) - stimulated macrophages were also assessed . Among the fractions , the n - butanol fraction ( BuOH ) was identified to be most effective in the P62158 assay . Collectively , Taraxacum officinale contains anti - angiogenic , anti - inflammatory and anti - nociceptive activities through its inhibition of NO production and P35354 expression and / or its antioxidative activity .",
"15 - Deoxy - delta 12 , 14 - prostaglandin J2 inhibits the expression of granulocyte - macrophage colony - stimulating factor in endothelial cells stimulated with lipopolysaccharide . P04141 ( GM - P04141 ) , one of major hematopoietic growth factors , activates mature leukocytes . GM - P04141 is produced by endothelial cells stimulated with lipopolysaccharide ( LPS ) , and the LPS - induced GM - P04141 production may play an important role in the activation of neutrophils on the endothelial surface . 15 - Deoxy - delta 12 , 14 - prostaglandin J2 ( 15d - PGJ2 ) is a ligand for peroxisome proliferator - activated receptor - gamma ( P37231 ) and modulates inflammatory reactions by regulating the expression of various genes . We studied the effect of 15d - PGJ2 on the LPS - induced GM - P04141 expression in endothelial cells . Human umbilical vein endothelial cells ( HUVEC ) were cultured and the expressions of GM - P04141 mRNA and protein were analyzed by reverse transcription - polymerase chain reaction and enzyme - linked immunosorbent assay , respectively . 15d - PGJ2 inhibited the LPS - induced GM - P04141 expression in a concentration - dependent manner ; but ciglitazone , another agonist for P37231 , had no effect . This suggests that 15d - PGJ2 inhibits GM - P04141 expression through a mechanism unrelated to P37231 . 15d - PGJ2 induced , by itself , the expression of interleukin - 8 , a potent proinflammatory chemokine , in HUVEC . 15d - PGJ2 may regulate inflammatory reactions by controlling the balance of various cytokines .",
"Can a cocktail designed for phenotyping pharmacokinetics and metabolism enzymes in human be used efficiently in rat ? We recently designed the CIME cocktail consisting of 10 drugs to assess the activity of the major human CYPs ( P05177 , P10632 , P11712 , P33261 , P10635 and CYP3A ) , a phase II enzyme ( P22309 / 6 / 9 ) , two drug transporters ( P - gp and Q9Y6L6 ) and a component of the renal function ( Videau et al . 2010 ) . The present work aimed at studying the usefulness of the CIME cocktail in the rat . The CIME cocktail was given per os to three male and three female rats , or incubated with rat liver microsomes . Parent substrates and metabolites were quantified by LC - MS / MS in plasma , urine and hepatic microsomal media , and phenotyping index were subsequently calculated . The CIME cocktail could therefore be used in the rat to phenotype rapidly and simultaneously CYP3A1 / 2 with omeprazole / omeprazole - sulfone , midazolam / 1 '- hydroxymidazolam or 4 - hydroxymidazolam and / or dextromethorphan / 3 - methoxymorphinan , CYP2C6 / 11 with tolbutamide / 4 - hydroxytolbutamide , CYP2D1 / 2 with omeprazole / 5 - hydroxyomeprazole or dextromethorphan / dextrorphan , and P19224 / 7 with acetaminophen / acetaminophen - glucuronide . Our results confirmed also several known gender differences and brought new information on the urinary excretion of rosuvastatin . However , the major rat CYPs , CYP2C11 and CYP2C12 , are not specifically assessed . An optimized version of the CIME cocktail should therefore be designed and would be of major importance to more largely phenotype Q09013 enzymes in rats to study Q09013 variability factors such as disease , age , or to exposure to inductors or inhibitors .",
"Tumor cell - derived prostaglandin E2 inhibits monocyte function by interfering with P51681 and Mac - 1 . The cyclooxygenases ( P36551 ) - 1 and P35354 are key enzymes in the conversion of arachidonic acid to prostaglandins and other eicosanoids . Whereas P23219 is expressed ubiquitously , P35354 is an immediate - early gene often associated with malignant transformation , and a role for the P36551 enzymes in tumor initiation and promotion is discussed . Nonsteroidal anti - inflammatory drugs ( NSAIDs ) like aspirin and indomethacin that block P23219 and - 2 have been shown to have beneficial effects for tumor patients . Therefore , these compounds have gained interest also among oncologists . However , the molecular mechanism by which NSAIDs inhibit carcinogenesis is not clearly understood . The prostaglandin - dependent and - independent effect may both account for their antineoplastic action . We show here that tumor cells derived from different tumors regularly produce prostaglandin E ( 2 ) ( PGE ( 2 ) ) interfering with the function of monocytes . In particular , PGE ( 2 ) inhibits the potential of monocytes to migrate in the direction of a chemotactic stimulus and to adhere to endothelial cell . This inhibition is most probably due to a modulation of the chemokine receptor P51681 and the beta2 - integrin Mac - 1 . Both down - regulation of P51681 and reduced expression of Mac - 1 may diminish the potential of peripheral blood monocytes to leave blood vessels and invade target tissues . Since both dysfunctions can be restored with NSAIDs , our findings help to explain the molecular chemopreventive action of NSAIDs on tumor formation and progression .",
"Characterization of plant P18887 and its interaction with proliferating cell nuclear antigen . In plants , there are no P06746 ( Pol beta ) and P49916 ( Lig3 ) genes . Thus , the plant short - patch base excision repair ( short - patch BER ) pathway must differ considerably from that in mammals . We characterized the rice ( Oryza Sativa L . cv . Nipponbare ) homologue of the mammalian X - ray repair cross complementing 1 ( P18887 ) , a well - known BER protein . The plant P18887 lacks the N - terminal domain ( NTD ) which is required for Pol beta binding and is essential for mammalian cell survival . The recombinant rice P18887 ( OsXRCC1 ) protein binds single - stranded DNA ( ssDNA ) as well as double - stranded DNA ( dsDNA ) and also interacts with rice proliferating cell nuclear antigen ( OsPCNA ) in a pull - down assay . Through immunoprecipitation , we demonstrated that OsXRCC1 forms a complex with P12004 in vivo . OsXRCC1 mRNA was expressed in all rice organs and was induced by application of bleomycin , but not of MMS , H ( 2 ) O ( 2 ) or UV - B . ___MASK10___ also increased the fraction of OsXRCC1 associated with chromatin . These results suggest that OsXRCC1 contributes to DNA repair pathways that differ from the mammalian BER system .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK39___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK39___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"___MASK94___ - induced apoptosis is specifically enhanced by expression of the sulfonylurea receptor isoform Q09428 but not by expression of SUR2B or the mutant Q09428 ( M1289T ) . Q09428 ( Q09428 ) is the regulatory subunit of the pancreatic DB00171 - sensitive K + channel ( K ( DB00171 ) channel ) , which is essential for triggering insulin secretion via membrane depolarization . Sulfonylureas , such as glibenclamide and tolbutamide , act as K ( DB00171 ) channel blockers and are widely used in diabetes treatment . These antidiabetic substances are known to induce apoptosis in pancreatic beta - cells or beta - cell lines under certain conditions . However , the precise molecular mechanisms of this sulfonylurea - induced apoptosis are still unidentified . To investigate the role of Q09428 in apoptosis induction , we tested the effect of glibenclamide on recombinant human embryonic kidney 293 cells expressing either Q09428 , the smooth muscular isoform SUR2B , or the mutant Q09428 ( M1289T ) at which a single amino acid in transmembrane helix 17 ( TM17 ) was exchanged by the corresponding amino acid of SUR2 . By analyzing cell detachment , nuclear condensation , DNA fragmentation , and caspase - 3 - like activity , we observed a Q09428 - specific enhancement of glibenclamide - induced apoptosis that was not seen in SUR2B , Q09428 ( M1289T ) , or control cells . Coexpression with the pore - forming Kir6 . 2 subunit did not significantly alter the apoptotic effect of glibenclamide on Q09428 cells . In conclusion , expression of Q09428 , but not of SUR2B or Q09428 ( M1289T ) , renders cells more susceptible to glibenclamide - induced apoptosis . Therefore , Q09428 as a pancreatic protein could be involved in specific variation of beta - cell mass and might also contribute to the regulation of insulin secretion at this level . According to our results , TM17 is essentially involved in Q09428 - mediated apoptosis . This effect does not require the presence of functional Kir6 . 2 - containing K ( DB00171 ) channels , which points to additional , so far unknown functions of Q09428 .",
"Oral keratinocytes support non - replicative infection and transfer of harbored HIV - 1 to permissive cells . BACKGROUND : Oral keratinocytes on the mucosal surface are frequently exposed to HIV - 1 through contact with infected sexual partners or nursing mothers . To determine the plausibility that oral keratinocytes are primary targets of HIV - 1 , we tested the hypothesis that HIV - 1 infects oral keratinocytes in a restricted manner . RESULTS : To study the fate of HIV - 1 , immortalized oral keratinocytes ( OKF6 / O14746 - 2 ; O14746 - 2 cells ) were characterized for the fate of HIV - specific RNA and DNA . At 6 h post inoculation with X4 or R5 - tropic HIV - 1 , HIV - 1gag RNA was detected maximally within O14746 - 2 cells . Reverse transcriptase activity in O14746 - 2 cells was confirmed by VSV - G - mediated infection with HIV - NL4 - 3Deltaenv - EGFP . ___MASK88___ inhibited EGFP expression in a dose - dependent manner , suggesting that viral replication can be supported if receptors are bypassed . Within 3 h post inoculation , integrated HIV - 1 DNA was detected in O14746 - 2 cell nuclei and persisted after subculture . Multiply spliced and unspliced HIV - 1 mRNAs were not detectable up to 72 h post inoculation , suggesting that HIV replication may abort and that infection is non - productive . Within 48 h post inoculation , however , virus harbored by P01730 negative O14746 - 2 cells trans infected co - cultured peripheral blood mononuclear cells ( PBMCs ) or MOLT4 cells ( P01730 + P51681 + ) by direct cell - to - cell transfer or by releasing low levels of infectious virions . Primary tonsil epithelial cells also trans infected HIV - 1 to permissive cells in a donor - specific manner . CONCLUSION : Oral keratinocytes appear , therefore , to support stable non - replicative integration , while harboring and transmitting infectious X4 - or R5 - tropic HIV - 1 to permissive cells for up to 48 h .",
"Salacia oblonga extract increases glucose transporter 4 - mediated glucose uptake in Q9BTT4 rat myotubes : role of mangiferin . BACKGROUND AND AIMS : To evaluate if the antidiabetic properties of Salacia oblonga extract are mediated not only by inhibiting intestinal alpha - glycosidases but also by enhancing glucose transport in muscle and adipose cells . METHODS : S . oblonga extract effects on 2 - deoxy - D - glucose uptake were assayed in muscle Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the amount and translocation of glucose transporters were assayed . A fractionation of the extract was carried out to identify the active compounds . Furthermore , we analyzed the phosphorylation status of key components of signaling pathways that are involved in the molecular mechanisms regulating glucose uptake . RESULTS : S . oblonga extract increased 2 - deoxy - D - glucose uptake by 50 % in Q9BTT4 - myotubes and 3T3 - adipocytes . In Q9BTT4 - myotubes , the extract increased up to a 100 % the P14672 content , activating P14672 promoter transcription and its translocation to the plasma membrane . Mangiferin was identified as the bioactive compound . Furthermore , mangiferin effects were concomitant with the phosphorylation of DB00131 - activated protein kinase without the activation of P31749 / Akt . The effect of mangiferin on 2 - deoxy - D - glucose uptake was blocked by GW9662 , an irreversible P37231 antagonist . CONCLUSIONS : S . oblonga extract and mangiferin may exert their antidiabetic effect by increasing P14672 expression and translocation in muscle cells . These effects are probably mediated through two independent pathways that are related to DB00131 - activated protein kinase and P37231 .",
"A structural and in vitro characterization of asoprisnil : a selective progesterone receptor modulator . Selective progesterone receptor modulators ( SPRMs ) have been suggested as therapeutic agents for treatment of gynecological disorders . One such SPRM , asoprisnil , was recently in clinical trials for treatment of uterine fibroids and endometriosis . We present the crystal structures of progesterone receptor ( PR ) ligand binding domain complexed with asoprisnil and the corepressors nuclear receptor corepressor ( NCoR ) and Q9Y618 . This is the first report of steroid nuclear receptor crystal structures with ligand and corepressors . These structures show PR in a different conformation than PR complexed with progesterone ( P4 ) . We profiled asoprisnil in PR - dependent assays to understand further the PR - mediated mechanism of action . We confirmed previous findings that asoprisnil demonstrated antagonism , but not agonism , in a PR - B transfection assay and the T47D breast cancer cell alkaline phosphatase activity assay . Asoprisnil , but not DB00834 , weakly recruited the coactivators Q15788 and Q9Y6Q9 . However , asoprisnil strongly recruited the corepressor NCoR in a manner similar to DB00834 . Unlike DB00834 , NCoR binding to asoprisnil - bound PR could be displaced with equal affinity by NCoR or Q15596 peptides . We further showed that it weakly activated T47D cell gene expression of Sgk - 1 and O60437 and antagonized P4 - induced expression of both genes . In rat leiomyoma ELT3 cells , asoprisnil demonstrated partial P4 - like inhibition of cyclooxygenase ( P36551 ) enzymatic activity and P35354 gene expression . In the rat uterotrophic assay , asoprisnil demonstrated no P4 - like ability to oppose estrogen . Our data suggest that asoprisnil differentially recruits coactivators and corepressors compared to DB00834 or P4 , and this specific cofactor interaction profile is apparently insufficient to oppose estrogenic activity in rat uterus .",
"ω - 3 fatty acid eicosapentaenoic acid attenuates P25189 +- induced neurodegeneration in fully differentiated human SH - SY5Y and primary mesencephalic cells . DB00159 ( EPA ) , a neuroactive omega - 3 fatty acid , has been demonstrated to exert neuroprotective effects in experimental models of Parkinson ' s disease ( PD ) , but the cellular mechanisms of protection are unknown . Here , we studied the effects of EPA in fully differentiated human SH - SY5Y cells and primary mesencephalic neurons treated with P25189 (+) . In both in - vitro models of PD , EPA attenuated an P25189 (+) - induced reduction in cell viability . EPA also prevented the presence of electron - dense cytoplasmic inclusions in SH - SY5Y cells . Then , possible mechanisms of the neuroprotection were studied . In primary neurons , EPA attenuated an P25189 (+) - induced increase in Tyrosine - related kinase B ( TrkB ) receptors . In SH - SY5Y cells , EPA down - regulated reactive oxygen species and nitric oxide . This antioxidant effect of EPA may have been mediated by its inhibition of neuronal NADPH oxidase and cyclo - oxygenase - 2 ( P35354 ) , as P25189 (+) increased the expression of these enzymes . Furthermore , EPA prevented an increase in cytosolic phospholipase A2 ( P47712 ) , an enzyme linked with P35354 in the potentially pro - inflammatory arachidonic acid cascade . Lastly , EPA attenuated an increase in the bax : bcl - 2 ratio , and cytochrome c release . However , EPA did not prevent mitochondrial enlargement or a decrease in mitochondrial membrane potential . This study demonstrated cellular mechanisms by which EPA provided neuroprotective effects in experimental PD .",
"Chromosomal changes in high - and low - invasive mouse lung adenocarcinoma cell strains derived from early passage mouse lung adenocarcinoma cell strains . The incidence of adenocarcinoma of the lung is increasing in the United States , however , the difficulties in obtaining lung cancer families and representative samples of early to late stages of the disease have lead to the study of mouse models for lung cancer . We used Spectral Karyotyping ( Q06418 ) , mapping with fluorescently labeled genomic clones ( Q5TCZ1 ) , comparative genomic hybridization ( CGH ) arrays , gene expression arrays , Western immunoblot and real time polymerase chain reaction ( PCR ) to analyze nine pairs of high - invasive and low - invasive tumor cell strains derived from early passage mouse lung adenocarcinoma cells to detect molecular changes associated with tumor invasion . The duplication of chromosomes 1 and 15 and deletion of chromosome 8 were significantly associated with a high - invasive phenotype . The duplication of chromosome 1 at band C4 and E1 / 2 - H1 were the most significant chromosomal changes in the high - invasive cell strains . Mapping with Q5TCZ1 and CGH array further narrowed the minimum region of duplication of chromosome 1 to 71 - 82 centimorgans ( cM ) . Expression array analysis and confirmation by real time PCR demonstrated increased expression of P35354 , Q15631 ( TB - P02753 ) , O43781 , Q9H1E3 and Tubulin - alpha4 genes in the high - invasive cell strains . Elevated expression and copy number of these genes , which are involved in inflammation , cell movement , proliferation , inhibition of apoptosis and telomere elongation , were associated with an invasive phenotype . Similar linkage groups are altered in invasive human lung adenocarcinoma , implying that the mouse is a valid genetic model for the study of the progression of human lung adenocarcinoma .",
"Therapy with a synthetic retinoid -- ( Ro 10 - 1670 ) etretin -- increases the cellular retinoic acid - binding protein in nonlesional psoriatic skin . Cellular retinol ( P09455 ) - and retinoic acid ( CRABP ) - binding proteins were determined in samples of lesional and nonlesional skin of psoriatic patients , before and during oral administration of a synthetic retinoid , ___MASK65___ ( Ro 10 - 1670 ) . A 200 % increase in CRABP levels , measured by the ability of the protein to bind retinoic acid , was observed in the normal skin during treatment . The P09455 levels were not altered during therapy . The results show that P09455 and CRABP are independently regulated in human skin and suggest that synthetic retinoids may exert their pharmacologic effects by interfering with the regulation of natural retinoic acid receptors .",
"DB00159 inhibits prostaglandin D2 generation by inhibiting cyclo - oxygenase - 2 in cultured human mast cells . BACKGROUND : DB00159 ( EPA ) is catalysed by cyclo - oxygenase ( P36551 ) , as is arachidonic acid , and is a competitive inhibitor of arachidonate metabolism . OBJECTIVES : We examined the effect of EPA on prostaglandin ( PG ) D2 generation in the cultured human mast cells with IgE - anti - IgE challenge incubation . METHODS : Cultured human mast cells were incubated with EPA ( 1 micromol / L ) for 20 h , then challenged with anti - IgE incubation after treatment with IgE . At the same time , P36551 inhibitors were tested to identify P23219 and P35354 activity . PGD2 synthetic activity was also assayed in a cell - free homogenate of cultured mast cells with P36551 inhibitors and EPA . DB11320 in the culture medium and in cells was assayed with the HPLC - fluorescent method . PGD2 and PGD3 were assayed with gas chromatography - mass spectrometry and the stable isotope dilution method . RESULTS : Although EPA incubation did not affect histamine release by cultured human mast cells in response to IgE - anti - IgE challenge incubation , it did decrease PGD2 generation by inhibiting the P35354 pathway . In contrast , in the cell - free homogenate of cultured human mast cells , EPA inhibited both P23219 and P35354 activities . CONCLUSION : Pre - incubation with EPA primarily affects the P35354 pathway in cultured human mast cells and reduces PGD2 generation in response to IgE - anti - IgE challenge incubation . These findings suggest that P23219 and P35354 have different substrate flow systems in mast cells . They also suggest that endogenous EPA diet supplementation would reduce PGD2 production and could serve as an anti - inflammatory substrate in human mast cells .",
"Regulatory regions of growth - related genes can activate an exogenous gene of the alpha - fetoprotein promoter to a comparable degree in human hepatocellular carcinoma cells . We examined the transcriptional activation by the regulatory regions of the midkine ( MK ) , survivin ( Q09428 ) , cyclooxygenase - 2 ( P35354 ) , telomerase reverse transcriptase ( O14746 ) and alpha - fetoprotein ( AFP ) genes in human hepatocellular carcinoma cells . Luciferase assays showed that the Q09428 regulatory region exhibited the greatest activity and that the MK regulatory region activated the reporter gene better than the enhancer - linked AFP promoter even in high - AFP - producing cells . The P35354 and O14746 regulatory regions also activated the reporter gene better than the AFP enhancer / promoter in intermediate - AFP - producing cells . Combination of the regulatory regions arranged in tandem modulated their transcriptional activities , depending on the arrangement of the promoters and cells examined . These data suggested that the regulatory regions of the growth - related genes could be useful to activate a therapeutic gene in hepatocellular carcinoma cells irrespective of the amounts of AFP production but combinatory use of the promoter regions could not always contribute to enhanced activity .",
"Creating a genotype - based dosing algorithm for acenocoumarol steady dose . ___MASK33___ is a commonly prescribed anticoagulant drug for the prophylaxis and treatment of venous and arterial thromboembolic disorders in several countries . In counterpart of warfarin , there is scarce information about pharmacogenetic algorithms for steady acenocoumarol dose estimation . The aim of this study was to develop an algorithm of prediction for acenocoumarol . The algorithm was created using the data from 973 retrospectively selected anticoagulated patients and was validated in a second independent cohort adding up to 2 , 683 patients . The best regression model to predict stable dosage in the Primary Cohort included clinical factors ( age and body mass index , BSA ) and genetic variants ( Q9BQB6 , P11712 * and P78329 polymorphisms ) and explained up to 50 % of stable dose . In the validation study the clinical algorithm yielded an adjusted R² = 0 . 15 ( estimation ´ s standard error = 4 . 5 ) and the genetic approach improved the dose forecast up to 30 % ( estimation ´ s standard error = 4 . 6 ) . Again , the best model combined clinical and genetic factors ( R² = 0 . 48 ; estimation ´ s standard error = 4 ) which provided the best results of doses estimates within 20 % of the real dose in patients taking lower ( ≤ 7 mg / week ) or higher ( ≥ 25 mg / week ) acenocoumarol doses . In conclusion , we developed a prediction algorithm using clinical data and three polymorphisms in Q9BQB6 , P11712 * and P78329 genes that provided a steady acenocoumarol dose for about 50 % of patients in the Validation Cohort . Such algorithm was especially useful to patients who need higher or lower acenocoumarol doses , those patients with higher time required until their stabilisation and are more prone to suffer a treatment derived complication .",
"Cytochromes P450 are differently expressed in normal and varicose human saphenous veins : linkage with varicosis . The expression of cytochrome P450 ( CYP ) enzymes and cyclo - oxygenases ( P36551 ) was investigated in human saphenous veins by reverse transcription - polymerase chain reaction analysis . Non - varicose veins were obtained from patients undergoing aortocoronary bypass grafting , whereas varicose veins were obtained from patients undergoing stripping removal of varicose saphenous veins . In non - varicose veins , Q16678 , CYP2C , P05181 and Q02928 were detected , whereas P51589 , P20815 , P23219 and P35354 were detected almost exclusively in varicose veins . P78329 was not detectable . Except for Q02928 , the levels of individual CYP mRNA were higher in varicose veins than in control veins . Smooth muscle cell volume , determined by a colour image - analysis system , was increased approximately 1 . 5 - fold in varicose veins . Because CYPs and COXs produce various vasoactive compounds , increased expression of these enzymes could be involved in the impairment of vascular tone and may contribute to varicose pathology . Then , CYP or P36551 modulators may be potentially active in the treatment of chronic venous insufficiency .",
"Effects of external calcium on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . DB01373 is a known signalling molecule in eukaryotic cells and plays a central role in the regulation of many cellular processes . In the following study , we report on the effect of external calcium treatments on the biotransformation of DB06749 to ginsenoside Rd by Paecilomyces bainier 229 - 7 . We observed that the intracellular calcium content of P . bainier 229 - 7 mycelia was increased in response to exposure to high external Ca ( 2 +) concentrations . Both ginsenoside Rd biotransformation and β - glucosidase activity were both found to be dependent on the external calcium concentration . At an optimal Ca ( 2 +) concentration of 45 mM , maximal ginsenoside Rd bioconversion rate of 92 . 44 % was observed and maximal β - glucosidase activity of 0 . 1778 U was reached in a 72 - h biotransformation . The Ca ( 2 +) channel blocker Verapamil blocked the trans - membrane influx of calcium and decreased ginsenoside Rd biotransformatiom . In addition , β - glucosidase activity and ginsenoside Rd content decreased by 36 . 0 and 29 . 2 % respectively after a 72 - h incubation in the presence of 0 . 05 mM P62158 ( P62158 ) antagonist ___MASK8___ . These results suggest that both Ca ( 2 +) channels and P62158 are involved in ginsenoside Rd biotransformation via regulation of β - glucosidase activity . This is the first report regarding the effects of calcium signal transduction on biotransformation and enzyme activity in fungi .",
"Crosstalk between circulating peroxisome proliferator - activated receptor gamma , adipokines and metabolic syndrome in obese subjects . BACKGROUND : P37231 ( PPARγ ) has direct and indirect function in adipokines production process . We aimed to assess the possible influence of circulating PPARγ on relative risk of metabolic syndrome and also examine the association between circulating PPARγ and adipokines levels among obese subjects . METHODS : A total of 96 obese subjects ( body mass index ( BMI ) ≥ 30 ) were included in the current cross - sectional study . We assessed the body composition with the use of Body Composition Analyzer BC - 418MA - Tanita . The MetS ( metabolic syndrome ) was defined based on the National DB04540 Education Program Adult Treatment Panel III . All baseline blood samples were obtained following an overnight fasting . Serum concentrations of adipokines including DB00162 binding protein 4 ( P02753 ) , omentin - 1 , vaspin , progranulin , nesfatin - 1 and circulating PPARγ was measured with the use of an enzyme - linked immunosorbent assay method . Statistical analyses were performed using software package used for statistical analysis ( SPSS ) . RESULTS : We found main association between circulating PPARγ and body composition in obese population . The risk of metabolic syndrome in subjects with higher concentration of PPARγ was 1 . 9 fold in compared with lower concentration of PPARγ after adjustment for age , sex and BMI . There was significant association between PPARγ and adipokines , specially nesfatin - 1 and progranulin . Defined adipokines pattern among participants demonstrated the markedly higher concentration of vaspin , P02753 and nesfatin - 1 in participants with MetS compared to non - MetS subjects . CONCLUSIONS : It appears all of studied adipokines might have association with PPARγ level and might simultaneously be involve in some common pathway to make susceptible obese subjects for MetS .",
"Protective effects of metallothionein on isoniazid and rifampicin - induced hepatotoxicity in mice . Isoniazid ( ___MASK76___ ) and DB01045 ( RFP ) are widely used in the world for the treatment of tuberculosis , but the hepatotoxicity is a major concern during clinical therapy . Previous studies showed that these drugs induced oxidative stress in liver , and several antioxidants abated this effect . Metallothionein ( MT ) , a member of cysteine - rich protein , has been proposed as a potent antioxidant . This study attempts to determine whether endogenous expression of MT protects against ___MASK76___ and RFP - induced hepatic oxidative stress in mice . Wild type ( MT +/+ ) and MT - null ( MT -/- ) mice were treated intragastrically with ___MASK76___ ( 150 mg / kg ) , RFP ( 300 mg / kg ) , or the combination ( 150 mg / kg ___MASK76___ + 300 mg / kg RFP ) for 21 days . The results showed that MT -/- mice were more sensitive than MT +/+ mice to ___MASK76___ and RFP - induced hepatic injuries as evidenced by hepatic histopathological alterations , increased serum Q9NRA2 levels and liver index , and hepatic oxidative stress as evidenced by the increase of MDA production and the change of liver antioxidant status . Furthermore , ___MASK76___ increased the protein expression of hepatic P05181 and ___MASK76___ / RFP ( alone or in combination ) decreased the expression of hepatic P05177 . These findings clearly demonstrate that basal MT provides protection against ___MASK76___ and RFP - induced toxicity in hepatocytes . The P05181 and P05177 were involved in the pathogenesis of ___MASK76___ and RFP - induced hepatotoxicity .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Mutation of the calmodulin binding motif IQ of the L - type Ca ( v ) 1 . 2 Ca2 + channel to EQ induces dilated cardiomyopathy and death . Cardiac excitation - contraction coupling ( EC coupling ) links the electrical excitation of the cell membrane to the mechanical contractile machinery of the heart . DB01373 channels are major players of EC coupling and are regulated by voltage and Ca ( 2 +)/ calmodulin ( P62158 ) . P62158 binds to the IQ motif located in the C terminus of the Ca ( v ) 1 . 2 channel and induces Ca ( 2 +)- dependent inactivation ( CDI ) and facilitation ( P05231 ) . Mutation of DB00167 to DB00142 ( Ile1624Glu ) in the IQ motif abolished regulation of the channel by CDI and P05231 . Here , we addressed the physiological consequences of such a mutation in the heart . Murine hearts expressing the Ca ( v ) 1 . 2 ( I1624E ) mutation were generated in adult heterozygous mice through inactivation of the floxed WT Ca ( v ) 1 . 2 ( Q401N2 ) allele by tamoxifen - induced cardiac - specific activation of the MerCreMer Cre recombinase . Within 10 days after the first tamoxifen injection these mice developed dilated cardiomyopathy ( DCM ) accompanied by apoptosis of cardiac myocytes ( CM ) and fibrosis . In Ca ( v ) 1 . 2 ( I1624E ) hearts , the activity of phospho - P62158 kinase II and phospho - MAPK was increased . CMs expressed reduced levels of Ca ( v ) 1 . 2 ( I1624E ) channel protein and I ( Ca ) . The Ca ( v ) 1 . 2 ( I1624E ) channel showed \" CDI \" kinetics . Despite a lower sarcoplasmic reticulum Ca ( 2 +) content , cellular contractility and global Ca ( 2 +) transients remained unchanged because the EC coupling gain was up - regulated by an increased neuroendocrine activity . Treatment of mice with metoprolol and captopril reduced DCM in Ca ( v ) 1 . 2 ( I1624E ) hearts at day 10 . We conclude that mutation of the IQ motif to IE leads to dilated cardiomyopathy and death .",
"P37231 ( PPARgamma ) and immunoregulation : enhancement of regulatory T cells through PPARgamma - dependent and - independent mechanisms . Peroxisome proliferator - activated receptor ( Q07869 ) gamma is a nuclear hormone receptor primarily characterized for its effect on insulin metabolism . PPARgamma ligands , used to treat human type 2 diabetes , also down - regulate most immune system cells including APCs and pathogenic T cells . These effects putatively underlie the efficacy of PPARgamma ligands in treating animal models of autoimmunity , leading to projections of therapeutic potential in human autoimmunity . However , the relationship between PPARgamma ligands and P01730 + CD25 + regulatory T cells ( Tregs ) has not been examined . Specifically , no studies have examined the role of Tregs in mediating the in vivo immunoregulatory effects of PPARgamma ligands , and there have been no investigations of the use of PPARgamma ligands to treat autoimmunity in the absence of Tregs . We now characterize the novel relationship between ciglitazone , a thiazolidinedione class of PPARgamma ligand , and both murine natural Tregs ( nTregs ) and inducible Tregs ( iTregs ) . In vitro , ciglitazone significantly enhances generation of iTregs in a PPARgamma - independent manner . Surprisingly , and contrary to the current paradigm , we find that , in a model of graft - vs - host disease , the immunotherapeutic effect of ciglitazone requires the presence of nTregs that express PPARgamma . Overall , our results indicate that , unlike its down - regulatory effect on other cells of the immune system , ciglitazone has an enhancing effect on both iTregs and nTregs , and this finding may have important implications for using PPARgamma ligands in treating human autoimmune disease .",
"Omega - 3 polyunsaturated fatty acids and inflammatory processes : nutrition or pharmacology ? DB00159 ( EPA ) and docosahexaenoic acid ( DB01708 ) are n - 3 fatty acids found in oily fish and fish oil supplements . These fatty acids are able to inhibit partly a number of aspects of inflammation including leucocyte chemotaxis , adhesion molecule expression and leucocyte - endothelial adhesive interactions , production of eicosanoids like prostaglandins and leukotrienes from the n - 6 fatty acid arachidonic acid , production of inflammatory cytokines and T cell reactivity . In parallel , EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonioc acid and EPA and DB01708 give rise to anti - inflammatory and inflammation resolving resolvins and protectins . Mechanisms underlying the anti - inflammatory actions of n - 3 fatty acids include altered cell membrane phospholipid fatty acid composition , disruption of lipid rafts , inhibition of activation of the pro - inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes , activation of the anti - inflammatory transcription factor P37231 ( i . e . peroxisome proliferator activated receptor γ ) and binding to the G protein coupled receptor Q5NUL3 . These mechanisms are interlinked . In adult humans , an EPA plus DB01708 intake greater than 2 g day ⁻ ¹ seems to be required to elicit anti - inflammatory actions , but few dose finding studies have been performed . Animal models demonstrate benefit from n - 3 fatty acids in rheumatoid arthritis ( RA ) , inflammatory bowel disease ( Q9UKU7 ) and asthma . Clinical trials of fish oil in patients with RA demonstrate benefit supported by meta - analyses of the data . Clinical trails of fish oil in patients with Q9UKU7 and asthma are inconsistent with no overall clear evidence of efficacy .",
"Red meat and poultry , cooking practices , genetic susceptibility and risk of prostate cancer : results from a multiethnic case - control study . Red meat , processed and unprocessed , has been considered a potential prostate cancer ( DB11245 ) risk factor ; epidemiological evidence , however , is inconclusive . An association between meat intake and DB11245 may be due to potent chemical carcinogens that are generated when meats are cooked at high temperatures . We investigated the association between red meat and poultry intake and localized and advanced DB11245 taking into account cooking practices and polymorphisms in enzymes that metabolize carcinogens that accumulate in cooked meats . We analyzed data for 1096 controls , 717 localized and 1140 advanced cases from the California Collaborative Prostate Cancer Study , a multiethnic , population - based case - control study . We examined nutrient density - adjusted intake of red meat and poultry and tested for effect modification by 12 SNPs and 2 copy number variants in 10 carcinogen metabolism genes : P09211 , P35354 , P05177 , P05181 , P07099 , Q16678 , P19224 , NAT2 , P09488 and P30711 . We observed a positive association between risk of advanced DB11245 and high intake of red meat cooked at high temperatures ( trend P = 0 . 026 ) , cooked by pan - frying ( trend P = 0 . 035 ) , and cooked until well - done ( trend P = 0 . 013 ) . An inverse association was observed for baked poultry and advanced DB11245 risk ( trend P = 0 . 023 ) . A gene - by - diet interaction was observed between an SNP in the P35354 gene and the estimated levels of meat mutagens ( interaction P = 0 . 008 ) . Our results support a role for carcinogens that accumulate in meats cooked at high temperatures as potential DB11245 risk factors , and may support a role for heterocyclic amines ( HCAs ) in DB11245 etiology .",
"Gamma tocopherol upregulates the expression of 15 - S - HETE and induces growth arrest through a Q07869 gamma - dependent mechanism in PC - 3 human prostate cancer cells . Chronic inflammation and dietary fat consumption correlates with an increase in prostate cancer . Our previous studies in the colon have demonstrated that gamma - tocopherol treatment could upregulate the expression of peroxisome proliferator - activated preceptors ( Q07869 ) gamma , a nuclear receptor involved in fatty acid metabolism as well modulation of cell proliferation and differentiation . In this study , we explored the possibility that gamma - tocopherol could induce growth arrest in PC - 3 prostate cancer cells through the regulation of fatty acid metabolism . Growth arrest ( 40 % ) and Q07869 gamma mRNA and protein upregulation was achieved with gamma - tocopherol within 6 h . gamma - Tocopherol - mediated growth arrest was demonstrated to be Q07869 gamma dependent using the agonist GW9662 and a Q07869 gamma dominant negative vector . gamma - tocopherol was shown not to be a direct Q07869 gamma ligand , but rather 15 - S - HETE ( an endogenous Q07869 gamma ligand ) was upregulated by gamma - tocopherol treatment . 15 - Lipoxygenase - 2 , a tumor suppressor and the enzyme that converts arachidonic acid to 15 - S - HETE , was upregulated at 3 h following gamma - tocopherol treatment . Expression of proteins downstream of the Q07869 gamma pathway were examined . P12004 D1 , cyclin D3 , bcl - 2 , and NFkappa B proteins were found to be downregulated following gamma - tocopherol treatment . These data demonstrate that the growth arrest mediated by gamma - tocopherol follows a P37231 - dependent mechanism .",
"Neem leaf glycoprotein suppresses regulatory T cell mediated suppression of monocyte / macrophage functions . We have shown that neem leaf glycoprotein ( NLGP ) inhibits the regulatory T cell ( Tregs ) induced suppression of tumoricidal functions of P08571 (+) P34810 (+) monocyte / macrophages ( MO / Mφ ) from human peripheral blood . Cytotoxic efficacy of MO / Mφ toward macrophage sensitive cells , U937 , is decreased in presence of Tregs ( induced ) , however , it was increased further by supplementation of NLGP in culture . Associated Treg mediated inhibition of perforin / granzyme B expression and nitric oxide release from MO / Mφ was normalized by NLGP . Altered status of signature cytokines , like , IL - 12 , P22301 , P05231 , TNFα from MO / Mφ under influence of Tregs is also rectified by NLGP . Tregs significantly enhanced the expression of altered marker , mannose receptor ( CD206 ) on P34810 (+) cells that was downregulated upon NLGP exposure . In addition to tumoricidal functions , antigen presenting ability of MO / Mφ is hampered by Treg induced downregulation of P33681 , P42081 and HLA - DB01048 . NLGP upregulated these molecules in MO / Mφ even in the presence of Tregs . Treg mediated inhibition of MO / Mφ chemotaxis in contact dependent manner was also normalized partially by NLGP , where participation of P51681 was documented . Overall results suggest that Treg influenced pro - tumor MO / Mφ functions are rectified in a significant extent by NLGP to create an anti - tumor immune environment .",
"Effect of canagliflozin on renal threshold for glucose , glycemia , and body weight in normal and diabetic animal models . BACKGROUND : ___MASK27___ is a sodium glucose co - transporter ( SGLT ) 2 inhibitor in clinical development for the treatment of type 2 diabetes mellitus ( T2DM ) . METHODS : ( 14 ) C - alpha - methylglucoside uptake in Chinese hamster ovary - K cells expressing human , rat , or mouse SGLT2 or P13866 ; ( 3 ) H - 2 - deoxy - d - glucose uptake in Q9BTT4 myoblasts ; and 2 - electrode voltage clamp recording of oocytes expressing human SGLT3 were analyzed . Graded glucose infusions were performed to determine rate of urinary glucose excretion ( UGE ) at different blood glucose ( BG ) concentrations and the renal threshold for glucose excretion ( RT ( G ) ) in vehicle or canagliflozin - treated Zucker diabetic fatty ( ZDF ) rats . This study aimed to characterize the pharmacodynamic effects of canagliflozin in vitro and in preclinical models of T2DM and obesity . RESULTS : Treatment with canagliflozin 1 mg / kg lowered RT ( G ) from 415 ± 12 mg / dl to 94 ± 10 mg / dl in ZDF rats while maintaining a threshold relationship between BG and UGE with virtually no UGE observed when BG was below RT ( G ) . ___MASK27___ dose - dependently decreased BG concentrations in db / db mice treated acutely . In ZDF rats treated for 4 weeks , canagliflozin decreased glycated hemoglobin ( HbA1c ) and improved measures of insulin secretion . In obese animal models , canagliflozin increased UGE and decreased BG , body weight gain , epididymal fat , liver weight , and the respiratory exchange ratio . CONCLUSIONS : ___MASK27___ lowered RT ( G ) and increased UGE , improved glycemic control and beta - cell function in rodent models of T2DM , and reduced body weight gain in rodent models of obesity .",
"Expression of cytosolic retinoid - binding protein genes in human skin biopsies and cultured keratinocytes and fibroblasts . Using reverse transcription coupled to polymerase chain reaction we have studied the mRNA expression of serum retinol - binding protein and cytosolic receptors for retinol and retinoic acid in skin biopsies , and in cultured epidermal keratinocytes and dermal fibroblasts . Transcripts for cellular retinol - binding protein ( P09455 ) I and cellular retinoic - acid - binding protein ( CRABP ) I were found in normal skin , keratinocytes , and fibroblasts . CRABP II transcripts were detected in skin and keratinocytes . A decreased mRNA expression of CRABP I and an increased mRNA expression of CRABP II were found in lesional psoriatic skin compared with uninvolved skin . mRNA transcripts for serum retinol - binding protein ( s - P02753 ) were detected in all tissues and cells . The biological importance of s - P02753 expression in keratinocytes and fibroblasts is not known , but hypothetically this protein may be involved in the intracellular shuttling of retinol and retinoic acid , or in the retransportation of cellular retinoids into the extracellular space ."
] |
[
"___MASK10___",
"___MASK27___",
"___MASK33___",
"___MASK39___",
"___MASK65___",
"___MASK76___",
"___MASK88___",
"___MASK8___",
"___MASK94___"
] |
___MASK33___
|
MH_train_488
|
interacts_with DB00153?
|
[
"Angiotensin - converting - enzyme inhibitors suppress synthesis of tumour necrosis factor and interleukin 1 by human peripheral blood mononuclear cells . Administration of angiotensin - converting - enzyme ( P12821 ) inhibitors reduce vascular proliferation following endothelial injury as well as progression of renal disease in various animal models . These effects might be due to interference with cytokines such as interleukin 1 ( IL - 1 ) or tumour necrosis factor alpha ( P01375 ) since they have been implicated in regulating the effects of vascular cell growth factors such as fibroblast - and platelet - derived growth factors . We investigated the in vitro synthesis of IL - 1 and P01375 from human peripheral blood mononuclear cells ( PBMC ) in the presence of various P12821 - inhibitors . ___MASK60___ dose - dependently suppressed the P01584 - induced synthesis of P01375 by 74 % ( P < 0 . 01 ) and the P01584 - induced synthesis of P01583 by 60 % ( P < 0 . 01 ) . Cytokine synthesis induced by lipopolysaccharide was less affected . At concentrations suppressing P01375 and IL - 1 , captopril did not reduce the synthesis of complement P01024 in the same cells . Enalapril and cilazapril also suppressed cytokine - induced cytokine synthesis . Ramipril , lisinopril , perindopril and spirapril had no significant effect on P01375 synthesis suggesting that the effect was not related specifically to the inhibition of P12821 . Accumulation of mRNA for IL - 1 and P01375 were not affected by captopril , suggesting a posttranscriptional effect . We conclude that certain P12821 - inhibitors suppress IL - 1 and P01375 synthesis at a posttranscriptional level and might therefore influence cytokine - mediated cell growth .",
"Genetic factors influencing outcome from neurotrauma . PURPOSE OF REVIEW : Clinical outcome after neurotrauma is considerably variable and can only partly be explained by known prognostic factors . There is converging evidence from genetic research that a number of genetic variants may contribute to this variability . This review provides recent data from human studies , published in the previous year , on genetic factors influencing outcome after neurotrauma . The bibliographic databases MEDLINE , EMBASE and PsycINFO were searched to identify relevant studies . RECENT FINDINGS : Genetic susceptibility to various aspects of clinical outcome after neurotrauma was reported in recent clinical studies . Genetic loci investigated include polymorphisms in P02649 , P21397 , P23560 , NOS3 , P05231 , P12036 , P31645 , P21964 , P48454 and Q8IX03 genes . The importance of these findings and future directions are discussed . SUMMARY : Recent genetic studies have revealed emerging aspects and extended the existing knowledge regarding the pathogenesis of neurotrauma and the genetic influence on phenotypic diversity . A better understanding of the underlying biological pathways and molecular mechanisms of an individual ' s response to neurotrauma may hold the promise of novel treatment strategies and improved clinical outcome .",
"MicroRNA - 21 targets the vitamin D - dependent antimicrobial pathway in leprosy . Leprosy provides a model to investigate mechanisms of immune regulation in humans , given that the disease forms a spectrum of clinical presentations that correlate with host immune responses . Here we identified 13 miRNAs that were differentially expressed in the lesions of subjects with progressive lepromatous ( L - lep ) versus the self - limited tuberculoid ( T - lep ) disease . Bioinformatic analysis revealed a significant enrichment of L - lep - specific miRNAs that preferentially target key immune genes downregulated in L - lep versus T - lep lesions . The most differentially expressed miRNA in L - lep lesions , hsa - mir - 21 , was upregulated in Mycobacterium leprae - infected monocytes . By directly downregulating O60603 / 1 heterodimer ( O60603 / 1 ) - induced O15528 and P01584 expression as well as indirectly upregulating interleukin - 10 ( P22301 ) , hsa - mir - 21 inhibited expression of the genes encoding two vitamin D - dependent antimicrobial peptides , CAMP and O15263 . Conversely , knockdown of hsa - mir - 21 in M . leprae - infected monocytes enhanced expression of CAMP and O15263 and restored O60603 / 1 - mediated antimicrobial activity against M . leprae . Therefore , the ability of M . leprae to upregulate hsa - mir - 21 targets multiple genes associated with the immunologically localized disease form , providing an effective mechanism to escape from the vitamin D - dependent antimicrobial pathway .",
"Pituitary - adrenal axis regulation in P06850 - deficient mice . P06850 ( P06850 ) - deficient ( knockout ( KO ) ) mice demonstrate severely impaired adrenal responses to restraint , ether , and fasting , and lack the normal diurnal glucocorticoid ( GC ) rhythm . Here , we summarize recent studies determining the role of P06850 in augmenting plasma adrenocorticotrophic hormone ( ___MASK20___ ) concentration after glucocorticoid withdrawal and pituitary - adrenal axis stimulation in the context of inflammation . Even though GC insufficient , basal pituitary proopiomelanocortin ( P01189 ) mRNA , ___MASK20___ peptide content within the pituitary , and plasma ___MASK20___ concentrations are not elevated in P06850 KO mice . P01189 mRNA content in P06850 KO mice increases following adrenalectomy , and this increase is reversed by GC , but not aldosterone , replacement . In marked contrast to the increase in P01189 mRNA , plasma ___MASK20___ does not increase in the P06850 KO mice following adrenalectomy . Administration of P06850 to adrenalectomized P06850 KO mice results in acute , robust ___MASK20___ secretion . Thus , loss of GC feedback can increase P01189 gene expression in the pituitary , but P06850 action is essential for increased secretion of ___MASK20___ into the circulation . While GC secretion is impaired in P06850 KO mice after most stimuli , we have found near - normal GC responses to inflammation and systemic immune challenge . Studies in mice with P06850 and P05231 deficiency reveal that P05231 is essential for activation of the pituitary - adrenal axis during inflammatory and other stressors in the absence of P06850 .",
"Relative Expression of Vitamin D Hydroxylases , O15528 and Q07973 , and of P35354 and Heterogeneity of Human Colorectal Cancer in Relation to Age , Gender , Tumor Location , and Malignancy : Results from Factor and Cluster Analysis . Previous studies on the significance of vitamin D insufficiency and chronic inflammation in colorectal cancer development clearly indicated that maintenance of cellular homeostasis in the large intestinal epithelium requires balanced interaction of 1 , 25 -( OH ) 2D3 and prostaglandin cellular signaling networks . The present study addresses the question how colorectal cancer pathogenesis depends on alterations of activities of vitamin D hydroxylases , i . e . , O15528 - encoded 25 - hydroxyvitamin D - 1a - hydroxylase and Q07973 - encoded 25 - hydroxyvitamin D - 24 - hydroxylase , and inflammation - induced cyclooxygenase - 2 ( P35354 ) . Data from 105 cancer patients on O15528 , P11473 , Q07973 , and P35354 mRNA expression in relation to tumor grade , anatomical location , gender and age were fit into a multivariate model of exploratory factor analysis . Nearly identical results were obtained by the principal factor and the maximum likelihood method , and these were confirmed by hierarchical cluster analysis : Within the eight mutually dependent variables studied four independent constellations were found that identify different features of colorectal cancer pathogenesis : ( i ) Escape of P35354 activity from restraints by the O15528 / P11473 system can initiate cancer growth anywhere in the colorectum regardless of age and gender ; ( ii ) variations in P35354 expression are mainly responsible for differences in cancer incidence in relation to tumor location ; ( iii ) advancing age has a strong gender - specific influence on cancer incidence ; ( iv ) progression from well differentiated to undifferentiated cancer is solely associated with a rise in Q07973 expression .",
"Expression of vitamin D receptor and metabolizing enzymes in multiple sclerosis - affected brain tissue . Vitamin D deficiency has been implicated as a risk factor for multiple sclerosis ( MS ) , but how vitamin D metabolism affects MS pathophysiology is not understood . We studied the expression of vitamin D receptor ( P11473 ) and related enzymes , including 1 , 25 ( OH )( 2 ) D - 24 - hydroxylase ( Q07973 ; Q07973 ) and 25 ( OH ) D - 1α - hydroxylase ( O15528 ) , in CNS tissues of 39 MS patients and 20 controls and in primary human glial cells in vitro . In control and MS normal - appearing white matter ( NAWM ) , nuclear P11473 immunostaining was observed in oligodendrocyte - like cells , human leukocyte antigen ( HLA ) - positive microglia , and glial fibrillary acidic protein - positive astrocytes . There was a 2 - fold increase in P11473 transcripts in MS NAWM versus control white matter ( p = 0 . 03 ) . In chronic active MS lesions , HLA - positive microglia / macrophages showed nuclear P11473 staining ; astrocytes showed nuclear and cytoplasmic P11473 staining . Staining for Q07973 was restricted to astrocytes . P11473 and O15528 mRNA expressions were increased in active MS lesions versus NAWM ( p < 0 . 01 , p = 0 . 04 , respectively ) . In primary human astrocytes in vitro , the active form of vitamin D , 1 , 25 ( OH )( 2 ) D ( 3 ) , induced upregulation of P11473 and Q07973 . P01375 and interferon - γ upregulated O15528 mRNA in primary human microglia and astrocytes . Increased P11473 expression in MS NAWM and inflammatory cytokine - induced amplified expression of P11473 and O15528 in chronic active MS lesions suggest increased sensitivity to vitamin D in NAWM and a possible endogenous role for vitamin D metabolism in the suppression of active MS lesions .",
"A case study of acenocoumarol sensitivity and genotype - phenotype discordancy explained by combinations of polymorphisms in Q9BQB6 and P11712 . To determine the cause of a genotype - phenotype discordancy for acenocoumarol sensitivity . Methods A patient , highly sensitive to acenocoumarol , and previously determined to carry only a single P11712 * 3 allele , was genotyped for additional functionally defective alleles in the P11712 and Q9BQB6 genes . Family members were also analyzed to trace the pedigree . Results The acenocoumarol - sensitive patient was found to possess , in addition to P11712 * 3 allele , a P11712 * 11 allele and the Q9BQB6 AA diplotype which were all traced back through the parental lines . Conclusions ___MASK49___ sensitivity in this subject is the consequence of inheritance of multiple functionally defective alleles in both the P11712 and Q9BQB6 genes . The study provides additional data in support of diminished P11712 activity due to the presence of the rare * 11 allele .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"___MASK9___ , a low - molecular - weight heparin , promotes angiogenesis mediated by heparin - binding P15692 in vivo . Tumors are angiogenesis dependent and vascular endothelial growth factor - A ( P15692 ) , a heparin - binding protein , is a key angiogenic factor . As chemotherapy and co - treatment with anticoagulant low - molecular - weight heparin ( LMWH ) are common in cancer patients , we investigated whether angiogenesis in vivo mediated by P15692 is modulated by metronomic - type treatment with : ( i ) the LMWH dalteparin ; ( ii ) low - dosage cytostatic epirubicin ; or ( iii ) a combination of these two drugs . Using the quantitative rat mesentery angiogenesis assay , in which angiogenesis was induced by intraperitoneal injection of very low doses of P15692 , dalteparin sodium ( Fragmin (®) ) and epirubicin ( Farmorubicin (®) ) were administered separately or in combination by continuous subcutaneous infusion at a constant rate for 14 consecutive days . ___MASK9___ was administered at 27 , 80 , or 240 IU / kg / day , i . e . , doses that reflect the clinical usage of this drug , while epirubicin was given at the well - tolerated dosage of 0 . 4 mg / kg / day . While dalteparin significantly stimulated angiogenesis in an inversely dose - dependent manner , epirubicin did not significantly affect angiogenesis . However , concurrent treatment with dalteparin and epirubicin significantly inhibited angiogenesis . The effect of dalteparin is the first demonstration of a proangiogenic effect of any LMWH in vivo . The fact that co - treatment with dalteparin and epirubicin significantly inhibited angiogenesis suggests a complex drug effect .",
"Nongenomic , glucocorticoid receptor - mediated regulation of serotonin transporter cell surface expression in embryonic stem cell derived serotonergic neurons . Depressive disorders have been linked to the combined dysregulation of the hypothalamus - pituitary - adrenal ( Q9Y251 ) - axis and the serotonergic system . The Q9Y251 - axis and serotonergic ( 5 - HT ) neurons exert reciprocal regulatory actions . It has been reported that glucocorticoid - glucocorticoid receptor ( GR ) signaling influences serotonin transporter ( 5 - HTT ) transcription but data also points to the fact that 5 - HTT expression is regulated nongenomically via redistribution of 5 - HTT from the cell surface into intracellular compartments . In order to analyze the acute effects of glucocorticoids on 5 - HTT cell surface localization we differentiated serotonergic neurons from mouse embryonic stem ( ES ) cells derived from the C57BL / 6N blastocysts . These postmitotic 5 - HT neurons express all relevant serotonergic markers following the application of a growth factor - based differentiation protocol . Increasing concentrations of the GR agonist dexamethasone ( ___MASK31___ ) resulted in enhanced , dose - dependent 5 - HTT cell surface localization in the presence of the protein synthesis inhibitor cycloheximide already 1h after incubation . Inhibition of GR function by the specific GR - antagonist mifepristone abolished the increase in 5 - HTT cell surface localization . Hence , our data account for a nongenomic upregulation of 5 - HTT cell surface expression by glucocorticoid - GR interaction which likely constitutes a rapid physiological response to increased levels of glucocorticoids as seen during stress . Taken together , we provide a cellular model to analyze and dissect glucocorticoid - P31645 interactions on a molecular level that corresponds to in vivo animal models using C57BL / 6N mice .",
"Clot penetration and retention by plasminogen activators promote fibrinolysis . P00750 ( tPA ) remains the sole thrombolytic approved by the FDA for the treatment of pulmonary embolism ( PE ). tPA has not been replaced by third generation plasminogen activators , e . g . DB00015 ( Ret ) and ___MASK77___ ( TNK ) that circulate with longer life - spans and in theory should have more extended potency in vivo . One reason for this paradox is the inability to assign units of activity to plasminogen activators based on specific biologically relevant standards , which impairs objective comparison . Here , we compare clot permeation , retention and fibrinolytic activities of tPA , TNK and Ret in vitro and clot composition over time with outcome in a mouse model of disseminated pulmonary microembolism ( ME ) . When clots were incubated in the continuous presence of drug , tPA , TNK and Ret lysed fibrin clots identically in the absence of PA inhibitor - 1 ( e . g . P05121 ) . Ret , which has lower fibrin affinity and greater susceptibility to inhibition by P05121 than tPA , was less effective in lysing plasma clots , while TNK was less effective when the fibrin content of the clots was enhanced . However , when clots were afforded only brief exposure to drug , as occurs in vivo , Ret showed more extensive clot permeation , greater retention and lysis than tPA or TNK . These results were reproduced in vivo in a mouse model of ME . These studies indicate the need for more relevant tests of plasminogen activator activity in vitro and in vivo and they show that clot permeation and retention are important potential predictors of clinical utility .",
"Effects of 25 - hydroxyvitamin D3 and 1 , 25 - dihydroxyvitamin D3 on cytokine production by human decidual cells . The active form of vitamin D , 1 , 25 - dihydroxyvitamin D ( 3 ) ( 1 , 25 [ OH ]( 2 ) D ( 3 ) ) is a potent immunomodulatory seco - steroid . We have demonstrated that several components of vitamin D metabolism and signaling are strongly expressed in human uterine decidua from first trimester pregnancies , suggesting that locally produced 1 , 25 ( OH )( 2 ) D ( 3 ) may exert immunosuppressive effects during early stages of gestation . To investigate this further , we used primary cultures of human decidual cells from first and third trimester pregnancies to demonstrate expression and activity of the enzyme that catalyzes synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) , 1alpha - hydroxylase ( O15528 ) . Synthesis of 1 , 25 ( OH )( 2 ) D ( 3 ) was higher in first trimester decidual cells ( 41 +/- 11 . 8 fmoles / h / mg protein ) than in third trimester cells ( 8 +/- 4 . 4 fmoles / h / mg protein ; P < 0 . 05 ) . Purification of decidual cells followed by quantitative RT - PCR analysis showed that O15528 was expressed by both CD10 (+ VE ) stromal - enriched and CD10 (- VE ) stromal - depleted cells , with higher levels of mRNA in first trimester pregnancies . Expression of O15528 correlated with O00206 and P14902 . Functional responses to 1 , 25 ( OH )( 2 ) D ( 3 ) were studied using CD56 (+ VE ) natural killer ( NK ) cells isolated from first trimester decidua . Decidual NK cells treated with 1 , 25 ( OH )( 2 ) D ( 3 ) or precursor 25 - hydroxyvitamin D ( 3 ) ( 25OHD ( 3 ) ) for 28 h showed decreased synthesis of cytokines , such as granulocyte - macrophage colony stimulating factor 2 ( P04141 ) , tumor necrosis factor , and interleukin 6 , but increased expression of mRNA for the antimicrobial peptide cathelicidin antimicrobial peptide . These data indicate that human decidual cells are able to synthesize active 1 , 25 ( OH )( 2 ) D ( 3 ) , particularly in early gestation , and this may act in an autocrine / paracrine fashion to regulate both acquired and innate immune responses at the fetal - maternal interface .",
"___MASK29___ transdermal system : in the treatment of major depressive disorder . The monamine oxidase ( MAO ) inhibitor selegiline is selective for P27338 at the low oral dosages used in the treatment of Parkinson ' s disease . However , P21397 is also inhibited at the high oral dosages needed to effectively treat depression ( not an approved indication ) , necessitating a tyramine - restricted diet . The selegiline transdermal system was designed to deliver antidepressant drug concentrations to the CNS , without substantially impairing small intestine P21397 activity . At the target dose of 6 mg / 24 hours , tyramine dietary restrictions are not needed . Short - term treatment with fixed ( 6 mg / 24 hours ) or flexible ( 6 , 9 or 12 mg / 24 hours ) doses of selegiline transdermal system was superior to placebo on most measures of antidepressant activity in 6 - or 8 - week , randomised , double - blind , multicentre studies in adult outpatients with major depressive disorder ( MDD ) . Likewise , long - term treatment with a fixed dose of selegiline transdermal system 6 mg / 24 hours was superior to placebo as maintenance therapy in a 52 - week , randomised , double - blind , multicentre , relapse - prevention trial in patients with MDD . ___MASK29___ transdermal system therapy was generally well tolerated in placebo - controlled studies ; application site reactions , mostly of mild to moderate severity , were the most commonly reported adverse events . The incidence of sexual adverse effects and weight gain was low and similar to that with placebo .",
"The immunological effects of electrolyzed reduced water on the Echinostoma hortense infection in C57BL / 6 mice . Electrolyzed reduced water ( ERW ) is widely used for drinking by people in Asia . The purpose of this study was to examine the immunological effect of ERW on the immunity of animals by supplying ERW to C57BL / 6 mice infected with Echinostoma hortense metacercariae . In the non - infected groups , interleukin ( IL ) - 4 ( p < 0 . 001 ) , P05113 , P22301 , IL - 1beta , tumor necrosis factor ( P01375 ) - alpha and immunoglobulin ( Ig ) A expression of the group fed ERW ( ERW group ) increased in small intestine compared with the normal control group . In the case of infected groups , the group fed ERW ( ERW + E . hortense group ) showed the result that P05112 , P05113 , P22301 and Ig A expression increased , but IL - 1beta and P01375 ( p < 0 . 001 ) decreased , and the number of goblet cells ( p < 0 . 001 ) and helix pomatia agglutinin ( Q9Y251 ) positive cells increased compared with the group without feeding ERW . However , adult worm recovery rate was markedly increased ( p < 0 . 05 ) . On the other hand , the expression of all the cytokines except P22301 in spleen was mildly increased but not significant statistically , and there was no significant difference in the numerical changes of white blood cell ( WBC ) . These results indicate that feeding ERW may have influence on the local immune response ( Th - 1 type cytokines such as IL - 1beta , P01375 ) in the small intestine but not on the systemic immune response .",
"Vitamin D metabolism , mechanism of action , and clinical applications . DB00169 is made in the skin from 7 - dehydrocholesterol under the influence of UV light . DB00153 ( ergocalciferol ) is derived from the plant sterol ergosterol . Vitamin D is metabolized first to 25 hydroxyvitamin D ( 25OHD ) , then to the hormonal form 1 , 25 - dihydroxyvitamin D ( 1 , 25 ( OH ) 2D ) . Q6VVX0 is the most important 25 - hydroxylase ; O15528 is the key 1 - hydroxylase . Both 25OHD and 1 , 25 ( OH ) 2D are catabolized by Q07973 . 1 , 25 ( OH ) 2D is the ligand for the vitamin D receptor ( P11473 ) , a transcription factor , binding to sites in the DNA called vitamin D response elements ( VDREs ) . There are thousands of these binding sites regulating hundreds of genes in a cell - specific fashion . P11473 - regulated transcription is dependent on comodulators , the profile of which is also cell specific . Analogs of 1 , 25 ( OH ) 2D are being developed to target specific diseases with minimal side effects . This review will examine these different aspects of vitamin D metabolism , mechanism of action , and clinical application .",
"Increase in proinflammatory cytokines in peripheral blood without haemostatic changes after LPS inhalation . INTRODUCTION : Bronchoalveolar fibrin deposition is a characteristic of various lung disorders including acute lung injury , acute respiratory distress syndrome and sepsis . It is secondary to the activation of coagulation and inhibition of fibrinolysis in the alveolar space , and can be stimulated by lipopolysaccharide ( LPS ) inhalation . The aim of this study was to determine the relation between compartmental stress in the lung and systemic response after LPS inhalation by measuring haemostatic parameters . PATIENTS AND METHODS : 12 healthy subjects underwent a bronchial challenge test with LPS ; sequential dosages were performed for 5 biological markers ( P05231 ( P05231 ) , C - Reactive Protein ( CRP ) , P00734 Fragments 1 and 2 ( F 1 + 2 ) , cortisol and P00747 Activator Inhibitor 1 ( P05121 ) before endotoxin inhalation and 2 , 4 , 6 , 8 and 24 hours afterwards . RESULTS : P05231 and CRP levels in the peripheral blood were higher after LPS inhalation ; there was no activation of coagulation and no increase in P05121 level . CONCLUSION : This study confirms that despite systemic release of proinflammatory cytokines , LPS inhalation does not induce systemic haemostatic response to LPS challenge .",
"P18509 , interleukin - 6 and glucocorticoids regulate the release of vascular endothelial growth factor in pituitary folliculostellate cells . There is increasing evidence that hormones play an important role in the control of endothelial cell function and growth by regulating the production of vascular endothelial growth factor ( P15692 ) . P15692 regulates vascular permeability and represents the most powerful growth factor for endothelial cells . In the normal anterior pituitary , P15692 has been detected only in folliculostellate ( FS ) cells . In the present study , the regulation of the release of P15692 from FS - like mouse TtT / GF cells , and from FS cells of rat pituitary monolayer cell cultures was investigated using a specific P15692 ELISA . Basal release of P15692 was demonstrated in cultures of both TtT / GF cells and rat pituitary cells . Interestingly , the P15692 secretion was stimulated by both forms of pituitary adenylate cyclase - activating polypeptide ( PACAP - 38 and PACAP - 27 ) , indicating that this hypothalamic peptide regulates endothelial cell function and growth within the pituitary . P15692 secretion was also stimulated by interleukin - 6 ( P05231 ) whereas basal , P05231 - and PACAP - stimulated secretion was inhibited by the synthetic glucocorticoid dexamethasone . The inhibitory action of dexamethasone was reversed by the glucocorticoid receptor antagonist DB00834 , suggesting that in FS cells functional glucocorticoid receptors mediate the inhibitory action of glucocorticoids on the P15692 secretion . The endocrine and auto -/ paracrine control of P15692 production in pituitary FS cells by PACAP , P05231 and glucocorticoids may play an important role both in angiogenesis and vascular permeability regulation within the pituitary under physiological and pathophysiological conditions .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"Vitamin D and the regulation of placental inflammation . The vitamin D - activating enzyme 1α - hydroxylase ( O15528 ) and vitamin D receptor ( P11473 ) support anti - inflammatory responses to vitamin D in many tissues . Given the high basal expression of O15528 and P11473 in trophoblastic cells from the placenta , we hypothesized that anti - inflammatory effects of vitamin D may be particularly important in this organ . Pregnant wild type ( WT ) mice i . p . injected with LPS showed elevated expression of mouse Cyp27b1 ( 4 - fold ) and P11473 ( 6 - fold ) . Similar results were also obtained after ex vivo treatment of WT placentas with LPS . To assess the functional impact of this , we carried out ex vivo studies using placentas -/- for fetal ( trophoblastic ) Cyp27b1 or P11473 . Vehicle - treated -/- placentas showed increased expression of IFN - γ and decreased expression of P22301 relative to +/+ placentas . LPS - treated -/- placentas showed increased expression of O60603 , IFN - γ , and P05231 . Array analyses identified other inflammatory factors that are dysregulated in Cyp27b1 (-/-) versus Cyp27b1 (+/+) placentas after LPS challenge . Data highlighted enhanced expression of P05112 , P40933 , and Q14116 , as well as several chemokines and their receptors , in Cyp27b1 (-/-) placentas . Similar results for P05231 expression were observed with placentas -/- for trophoblastic P11473 . Finally , ex vivo treatment of WT placentas with the substrate for Cyp27b1 , 25 - hydroxyvitamin D ( 3 ) , suppressed LPS - induced expression of P05231 and the chemokine Ccl11 . These data indicate that fetal ( trophoblastic ) vitamin D plays a pivotal role in controlling placental inflammation . In humans , this may be a key factor in placental responses to infection and associated adverse outcomes of pregnancy .",
"[ Prominent features of management strategies in acute coronary syndromes with the new oral antiplatelet agents ] . The novel oral Q9H244 inhibitors ( prasugrel and ticagrelor ) have been incorporated into the recently updated acute coronary syndrome ( ACS ) guidelines , as an adjunct antiplatelet treatment to aspirin . The studies involving the use of new oral antiplatelet agents that are more potent , predictable and faster platelet inhibitors than clopidogrel have demonstrated superiority with respect to the primary composite endpoint ( cardiovascular death , non - lethal myocardial infarction , stroke ) for both prasugrel and ticagrelor compared to clopidogrel . The subgroup analysis of the relevant studies showed that these new agents differ in their level of efficacy in different ACS patient subgroups : ( 1 ) Mortality was reduced with ticagrelor ; ( 2 ) ___MASK45___ is especially more effective in intermediate - and high - risk non - ST elevation ACS patients in whom early invasive strategy is selected ; ( 3 ) Prasugrel should be especially preferred in patients with acute ST elevation myocardial infarction undergoing percutaneous coronary intervention ( P05154 ) after diagnostic angiography ; and ( 4 ) Prasugrel is more effective in diabetic patients . While clopidogrel is recommended for ACS patients who are followed with a non - invasive strategy or who have not undergone percutaneous revascularization , it is the last line choice or an alternative to the Q9H244 inhibitor therapy for patients undergoing invasive strategy .",
"Celecoxib with chemotherapy in colorectal cancer . P35354 ( P35354 ) is the enzyme that normally synthesizes prostaglandins during an inflammatory response . Many primary and metastatic cancers express P35354 , and its presence is correlated with tumor angiogenesis , more invasive tumor phenotype , resistance to apoptosis , and systemic immunosuppression . The expression of P35354 is associated with a worse prognosis . Inhibition of prostaglandin synthesis may be beneficial in human malignancy . Regular consumption of nonsteroidal anti - inflammatory drugs ( NSAIDs ) decreases the incidence of , and mortality rate resulting from , a number of types of gastrointestinal cancers . Premalignant colonic lesions regress following the administration of nonspecific P36551 inhibitors , such as sulindac ( ___MASK26___ ) . Advanced solid tumor patients treated with indomethacin ( DB00328 ) survive twice as long as do such patients who receive supportive care alone . The U . S . Food and Drug Administration has approved specific P35354 inhibitors for the treatment of arthritis , pain , and familial adenomatous polyposis . Preclinical studies show that these drugs block angiogenesis , suppress solid tumor metastases , and slow the growth of implanted gastrointestinal cancer cell lines . The P35354 inhibitors have safely and effectively been combined with chemotherapeutic agents in experimental studies . Ongoing clinical trials are currently assessing the potential therapeutic role of P35354 inhibitors in both prevention and treatment of a diverse range of human cancers ."
] |
[
"___MASK20___",
"___MASK26___",
"___MASK29___",
"___MASK31___",
"___MASK45___",
"___MASK49___",
"___MASK60___",
"___MASK77___",
"___MASK9___"
] |
___MASK49___
|
MH_train_489
|
interacts_with DB05294?
|
[
"Endogenous concentrations of ouabain act as a cofactor to stimulate fluid secretion and cyst growth of in vitro ADPKD models via DB02527 and P00533 - Src - MEK pathways . In autosomal - dominant polycystic kidney disease ( ADPKD ) , renal cysts develop by aberrant epithelial cell proliferation and transepithelial fluid secretion . We previously showed that ouabain increases proliferation of cultured human ADPKD cells via stimulation of the P01133 receptor ( P00533 ) - Src - MEK / P29323 signaling pathway . We examined whether ouabain affects fluid secretion and in vitro cyst growth of human ADPKD cell monolayers , ADPKD cell microcysts cultured in a three - dimensional collagen matrix , and metanephric organ cultures from Pkd1 ( m1Bei ) mice . Physiological concentrations of ouabain alone did not affect net transepithelial basal - to - apical fluid transport in ADPKD monolayers or growth of cultured ADPKD microcysts . In contrast , in the presence of forskolin or 8 - bromo - DB02527 , ouabain significantly enhanced ADPKD fluid secretion and microcyst expansion . Ouabain exerted this effect by enhancing DB02527 - dependent Cl (-) secretion via the P13569 . Similarly , ouabain accelerated DB02527 - dependent cyst enlargement in Pkd1 ( m1Bei ) mice metanephroi , with a more prominent response in homozygous than heterozygous mice . Ouabain had no effect on fluid secretion and cystogenesis of normal human kidney cells and caused only slight cystic dilations in wild - type mouse kidneys . The effects of ouabain in ADPKD cells and Pkd1 ( m1Bei ) metanephroi were prevented by inhibitors of P00533 ( AG1478 ) , Src ( Q99463 ) , and MEK ( U0126 ) . Together , our results show that ouabain , used in physiological concentrations , has synergistic effects on DB02527 - mediated fluid secretion and cyst growth , via activation of the P00533 - Src - MEK pathway . These data provide important evidence for the role of ouabain as an endogenous hormone that exacerbates ADPKD cyst progression .",
"A randomized phase II efficacy and safety study of vandetanib ( DB05294 ) in combination with bicalutamide versus bicalutamide alone in patients with chemotherapy naïve castration - resistant prostate cancer . PURPOSE : To investigate the efficacy and safety of combining vandetanib , an orally available multi - targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptor - 2 ( P35968 ) and epidermal growth factor receptor ( P00533 ) , with bicalutamide in patients with metastatic castration - resistant prostate cancer ( mCRPC ) . METHODS : This was an open - label , randomized phase II multi - center study . Eligible patients had rising PSA on androgen deprivation therapy , minimal symptoms and were chemotherapy - naïve . Protocol therapy was either vandetanib 300 mg oral daily plus bicalutamide 50 mg oral daily ( Arm A ) or bicalutamide 50 mg oral daily alone ( Arm B ) with cross - over to vandetanib monotherapy at progression . The primary endpoint was PSA response ( ≥ 50 % decline from baseline ) . RESULTS : Thirty - nine patients were recruited , 19 in Arm A and 20 in Arm B . PSA response was comparable in Arm A and Arm B ( 18 vs . 19 % ) . Time to PSA progression was 3 . 16 months ( 95 % confidence interval ( CI ) : 1 . 09 , not reached ( NR ) ) for Arm A and 3 . 09 months ( 95 % CI : 1 . 22 , NR ) for Arm B . Treatment discontinuation due to adverse events was more common in Arm A compared to Arm B ( 42 vs . 5 % ; p = 0 . 019 ) . Treatment with vandetanib was associated with a reduction in soluble P35968 levels after two cycles but an increase in plasma P15692 levels . CONCLUSION : The combination of vandetanib and bicalutamide was associated with considerable toxicity and did not have superior efficacy over bicalutamide alone . Further evaluation of this combination is not warranted in mCRPC .",
"Implantation of P15692 transfected preadipocytes improves vascularization of fibrin implants on the cylinder chorioallantoic membrane ( P62158 ) model . The successful substitution or augmentation of soft tissues by implantation of three dimensional cell constructs , consisting of human preadipocytes and fibrin glue as a carrier matrix , requires a rapid and homogeneous vascularization of the whole implant in order to provide a sufficient blood supply of centrally situated cells . Previous investigations have shown that under in vivo conditions primary human preadipocytes induce vascularization of fibrin matrices by secretion of several growth factors , such as P15692 and P09038 . The current study investigates whether vascularization of implants can be improved by transplantation of preadipocytes following transfection with a P15692 - vector . Transfection was performed by electroporation with an pCMX - GFP and pCMX - VEGF165 vector . Transfection efficiency ( GFP expression ) and P15692 expression were determined in vitro by FACS analysis and P15692 immunoassay , respectively . In vivo investigations to determine the vascularization of the implants were performed on the cylinder chorioallantoic membrane ( P62158 ) . Four million P15692 transfected cells were transferred within a fibrin matrix onto the P62158 on the 7 ( th ) day of incubation and after 8 days the vascularization of the implant was histologically examined and evaluated by means of a computer - assisted image analysis program . Transfection of preadipocytes with the GFP vector by electroporation yielded transfection efficiencies between 12 % and 41 % of surviving cells . Results of the P15692 immunoassay demonstrated that P15692 expression was significantly higher following transfection . Investigations on the P62158 outlined a significantly higher rate of vascularization in the transfected vs . control population . Our investigations demonstrate that primary human preadipocytes can be successfully transfected by electroporation with a P15692 vector . The enhanced P15692 expression on transfected cells results in an increase of vascularization of the cell constructs on the P62158 .",
"Combined vascular endothelial growth factor receptor and epidermal growth factor receptor ( P00533 ) blockade inhibits tumor growth in xenograft models of P00533 inhibitor resistance . PURPOSE : The epidermal growth factor receptor ( P00533 ) tyrosine kinase inhibitors ( TKI ) gefitinib and erlotinib benefit some non - small cell lung cancer ( NSCLC ) patients , but most do not respond ( primary resistance ) and those who initially respond eventually progress ( acquired resistance ) . P00533 TKI resistance is not completely understood and has been associated with certain P00533 and K - DB01367 mutations and MET amplification . EXPERIMENTAL DESIGN : We hypothesized that dual inhibition of the vascular endothelial growth factor ( P15692 ) and P00533 pathways may overcome primary and acquired resistance . We investigated the P15692 receptor / P00533 TKI vandetanib , and the combination of bevacizumab and erlotinib in vivo using xenograft models of P00533 TKI sensitivity , primary resistance , and three models of acquired resistance , including models with mutated K - DB01367 and secondary P00533 T790M mutation . RESULTS : DB05294 , gefitinib , and erlotinib had similar profiles of in vitro activity and caused sustained tumor regressions in vivo in the sensitive HCC827 model . In all four resistant models , vandetanib and bevacizumab / erlotinib were significantly more effective than erlotinib or gefitinib alone . Erlotinib resistance was associated with a rise in both host and tumor - derived P15692 but not P00533 secondary mutations in the P01116 mutant - bearing A549 xenografts . Dual inhibition reduced tumor endothelial proliferation compared with P15692 or P00533 blockade alone , suggesting that the enhanced activity of dual inhibition is due at least in part to antiendothelial effects . CONCLUSION : These studies suggest that erlotinib resistance may be associated with a rise in both tumor cell and host stromal P15692 and that combined blockade of the VEGFR and P00533 pathways can abrogate primary or acquired resistance to P00533 TKIs . This approach merits further evaluation in NSCLC patients .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Q8NFH3 / Q8TCB0 mitogen - activated protein kinases inhibit atrial natriuretic peptide mRNA transcription in P40189 - mediated hypertrophic ventricular myocytes . OBJECTIVE : To understand the role of P01160 mRNA transcription regulation in P40189 - mediated cardiomyocyte hypertrophy , and the involved mitogen - activated protein kinase kinase ( MEK ) - extracellular signal - regulated kinase ( P29323 , also called Q8NFH3 / Q8TCB0 MAPK ) signaling pathway . METHODS : Isolated neonatal ventricular myocytes were treated with different concentrations of Q16619 ( 10 (- 9 ) , 10 (- 8 ) and 10 (- 7 ) mol / L ) . MTT was used to analyze the viability and RT - PCR was used to detect P01160 mRNA levels in cardiomyocyte . To inhibit Q8NFH3 / Q8TCB0 MAPK activity in hypertrophic cardiomyocytes , the cells were pretreated with a specific Q02750 inhibitor . RESULTS : Q16619 significantly induced P01160 mRNA expression and the viability of cardiomyocytes in a dose - and time - dependent manner . Furthermore , blocking Q8NFH3 / Q8TCB0 MAPK activity by the special Q02750 inhibitor upregulated the P01160 mRNA . CONCLUSIONS : Q8NFH3 / Q8TCB0 MAPK have an important role in suppressing P01160 mRNA transcription and cell activity in P40189 - mediated hypertrophic ventricular myocytes .",
"Activation of alternative pathways of angiogenesis and involvement of stem cells following anti - angiogenesis treatment in glioma . Malignant gliomas are hypervascular tumors that are highly resistant to all the currently available multimodal treatments . Therefore , anti - angiogenic therapies targeting P15692 or P15692 receptors ( VEGFRs ) were designed and thought to be an effective tool for controlling the growth of malignant gliomas . However , recent results of early clinical trials using humanized monoclonal antibodies against P15692 ( DB00112 ) , as well as small - molecule tyrosine kinase inhibitors that target different P15692 receptors ( VEGFRs ) ( DB04879 , DB05294 , DB01268 , DB00398 , etc ) alone or in combination with other therapeutic agents demonstrated differing outcomes , with the majority of reports indicating that glioma developed resistance to the employed anti - angiogenic treatments . It has been noted that continued anti - angiogenic therapy targeting only the P15692 - VEGFR system might affect pro - angiogenic factors other than P15692 , such as basic fibroblast growth factor ( P09038 ) , stromal derived factor 1 ( P48061 ) and Tie - 2 . These factors may in turn stimulate angiogenesis by mobilizing bone marrow derived precursor cells , such as endothelial progenitor cells ( EPCs ) , which are known to promote angiogenesis and vasculogenesis . In this short review , the current antiangiogenic treatments , possible mechanisms of activation of alternative pathways of angiogenesis , and possible involvement of bone marrow derived progenitor cells in the failure of anti - angiogenic treatments are discussed .",
"DB05294 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model . Angiogenesis inhibitors have been used to treat some cancers , but the therapeutic potential of these agents for gastric cancer has remained unclear . To investigate their therapeutic potential , we examined the effect of DB05294 , an agent that selectively targets vascular endothelial growth factor receptor - 2 ( P35968 ; P35968 ) tyrosine kinase and epidermal growth factor receptor ( P00533 ) tyrosine kinase , in a highly metastatic orthotopic model using an undifferentiated gastric cancer cell line , 58As1 . DB05294 ( 100 mg / kg / day , p . o . , 2 weeks ) significantly inhibited tumor growth ( p < 0 . 05 vs . control ) and reduced tumor dissemination into the peritoneal cavity ( p < 0 . 05 vs . control ) . In addition , to identify putative tumor biomarkers that would reflect the effects of DB05294 treatment in clinical settings , we examined the gene expression profiles of implanted gastric tumors treated with DB05294 in vivo . Twenty - eight candidate genes were identified , including P17936 , P35318 , Q9BY76 , O00469 , Q99576 , Q92597 , P09104 , Q9Y5L2 and O60238 , which are known to be hypoxia - inducible genes . These genes and gene products may be useful biomarkers for monitoring the effects of DB05294 treatment . DB05294 also improved the survival of mice with implanted another undifferentiated gastric cancer cell line , 44As3 . In conclusion , our results suggest that DB05294 may have clinical activity against gastric cancer , particularly undifferentiated gastric cancer with peritoneal dissemination . We also identified putative biomarkers for monitoring the pharmacodynamic effects of DB05294 by gene expression profiling .",
"DB05294 for the treatment of medullary thyroid cancer . DB05294 ( DB05294 , Caprelsa , AstraZeneca ) , an oral small - molecule tyrosine kinase inhibitor ( TKI ) that targets the rearranged during transfection receptor ( P07949 ) , P15692 receptor ( P35968 - 3 ) , and P01133 receptor ( P00533 ) , is the first systemic therapy approved by the U . S . Food and Drug Administration ( FDA ) for the treatment of symptomatic or progressive advanced medullary thyroid cancer ( P04629 ) . In a randomized phase III trial of patients with unresectable , locally advanced , or metastatic P04629 , vandetanib improved progression - free survival compared with placebo [ HR , 0 . 46 ; 95 % confidence interval ( CI ) , 0 . 31 - 0 . 69 ; P < 0 . 001 ] . However , the benefits in delaying disease progression need to be balanced against the associated and potentially serious toxicities , including diarrhea , hypertension , and QTc prolongation . Here , we review the clinical development of vandetanib leading to its integration into the current treatment paradigm and highlight the ongoing and future challenges in TKI use in P04629 .",
"Investigation of two dosing schedules of vandetanib ( DB05294 ) , an inhibitor of vascular endothelial growth factor receptor and epidermal growth factor receptor signaling , in combination with irinotecan in a human colon cancer xenograft model . PURPOSE : This in vivo study was designed to determine the optimal doses and schedules of vandetanib , a dual epidermal growth factor receptor ( P00533 ) - vascular endothelial growth factor receptor tyrosine kinase inhibitor , in combination with irinotecan in a murine xenograft model of human colon cancer . EXPERIMENTAL DESIGN : HT - 29 tumor - bearing nude mice were treated with two doses of vandetanib ( 12 . 5 and 25 mg / kg / d ) with or without irinotecan ( 100 mg / kg ) using either sequential or concurrent schedules for 30 days . Tumor size was measured using standard variables , whereas the antiangiogenic response was evaluated using dynamic contrast - enhanced magnetic resonance imaging . Additionally , effects on P00533 - dependent signal transduction pathways and proliferation were assessed using immunohistochemistry . These pharmacodynamic end points were then evaluated for associations with antitumor efficacy and / or to plasma / tumor concentrations of vandetanib . RESULTS : The greatest antitumor efficacy was observed in the groups receiving the highest dose of vandetanib given continuously ( concurrent schedule ) , alone or in combination with irinotecan . These dosing schedules resulted in significant effects on tumor vasculature , with decreased volume transfer constants , area under the curve , and permeability surface factor as well as increased gadolinium clearance after 30 days of treatment . In addition , these groups showed the greatest inhibition of P00533 signaling . Interestingly , tumor concentrations of vandetanib were increased by irinotecan in the concurrent schedule , possibly due to decreased tumor perfusion in this group . CONCLUSIONS : These data suggest that higher , sustained concentrations of vandetanib ( versus intermittent ) , alone and in combination with irinotecan , result in optimal antitumor efficacy in this model and may have implications for the design of future clinical studies with this drug .",
"Enhancement of cytotoxicity of natural product drugs against multidrug resistant variant cell lines of human head and neck squamous cell carcinoma and breast carcinoma by tesmilifene . N , N - diethyl - 2 -[ 4 -( phenylmethyl ) phenoxyl ] ethanamine ( tesmilifene ) , a tamoxifen derivative with antihistamine activity , greatly enhanced the survival of doxorubicin - treated , advanced stage breast cancer patients in a phase III trial . However , the molecular basis of tesmilifene action is not firmly established . The effects of tesmilifene on activity of several anticancer drugs was investigated using human head and neck squamous cell carcinoma ( HNSCC ) and breast carcinoma cell lines as a model system . Multidrug resistant ( MDR ) variants of an HNSCC cell line , HN - 5a / V15e , and a breast carcinoma cell line , MCF - 7 / V25a , both highly overexpressed mdr1 ( P08183 ) mRNA and the proteins P - glycoprotein and glutathione transferase - pi . Drug sensitivities were measured by a vital stain after 4 days of continuous exposure to anticancer drug in the absence and presence of tesmilifene at a concentration that alone had no antiproliferative effect . ___MASK30___ had minimal effect on drug cytotoxicity against the parental cell lines . However , the same tesmilifene treatment enhanced cytotoxicity of docetaxel , paclitaxel , epirubicin , doxorubicin , and vinorelbine against both MDR cell lines by up to 50 % . Flow cytometric measurement of annexin V / propidium iodide staining demonstrated that tesmilifene increased the killing of HN - 5a / V15e cells caused by docetaxel after 24 and 48h exposure . ___MASK30___ increased accumulation of radiolabelled vincristine in HN - 5a / V15e cells , over 4h , by up to 100 % . The results suggest that tesmilifene might be effective in the treatment of tumors that are resistant to natural product drugs . The mechanism of enhancement appears to be related to expression of an ABC pump - dependent , MDR phenotype .",
"Local immunotherapy of glioma patients with a combination of 2 bispecific antibody fragments and resting autologous lymphocytes : evidence for in situ t - cell activation and therapeutic efficacy . After adoptive transfer of pre - activated lymphocytes into the operation cavity of glioma patients , tumor regression and improved survival have been reported in some patients . Results were most impressive when bispecific antibodies with tumor x CD3 specificity were also applied . In this study , we attempted to avoid time - consuming pre - activation procedures for adoptively transferred cells by using a combination of bispecific antibodies directed to the P01133 receptor ( P00533 ) on tumor cells and to CD3 and P10747 on T cells . Eleven patients with high - grade malignant glioma received 3 injections of 2 bispecific antibody fragments ( P00533 x CD3 and P00533 x P10747 ) together with freshly isolated autologous lymphocytes via an Ommaya reservoir . Intracavitary fluid aspirated during immunotherapy was examined for markers of T - cell activation . Increased levels of soluble P60568 receptor and P01375 were detected in the intracavitary fluid of all patients tested . Two of the 11 treated patients experienced a beneficial response to therapy as defined by a transient contrast enhancement in subsequent Q9BWK5 scans and prolonged survival . Side effects were transient and consisted of fever , nausea , headache and aggravation of pre - existing neurologic deficits . These adverse effects were most likely due to the antibody construct containing anti - CD3 specificity . Two patients developed cerebral edema and required steroid treatment .",
"Genetic and epigenetic markers in the evaluation of pancreatic masses . BACKGROUND : Methylation markers have shown promise in the early diagnosis of pancreatic carcinoma . The aim of this study was to assess the diagnostic utility of hypermethylation status of candidate genes in combination with P01116 mutation detection in the evaluation of pancreatic masses . EXPERIMENTAL DESIGN : Sixty - one fine needle aspirates of pancreatic masses ( 43 pancreatic adenocarcinomas and 18 chronic pancreatitis ) were studied . Methylation status of P25021 , Q05925 , P09486 , P55290 and P25054 were analysed using melting curve analysis after DNA bisulfite treatment . P01116 mutations were also analysed . RESULTS : The methylation panel had a sensitivity of 73 % ( 27 of 37 , CI 95 % 56 to 86 % ) and a specificity of 100 % whenever two or more promoters were found hypermethylated . P01116 mutations showed a sensitivity of 77 % ( 33 of 43 , CI 95 % 62 to 88 % ) and a specificity of 100 % . Both molecular analyses added useful information to cytology by increasing the number of informative cases . When genetic and epigenetic analyses were combined sensitivity was 84 % ( 36 of 43 CI 95 % 69 to 93 % ) maintaining a 100 % specificity . CONCLUSIONS : Analysis of hypermethylation status of a panel of genes and P01116 mutation detection offer a similar diagnostic yield in the evaluation of pancreatic masses . The combined molecular analysis increases the number of informative cases without diminishing specificity .",
"DB05294 alters the protein pattern in malignant glioma and normal brain in the BT4C rat glioma model . The treatment of glioblastoma is unsatisfactory . Improved understanding of the biological effects of treatment , together with development of new tools to predict outcome of the initiated treatment are therefore of great need . DB05294 ( DB05294 ) is mainly a vascular endothelial growth factor ( P15692 ) and epidermal growth factor ( P01133 ) receptor tyrosine kinase inhibitor . This study investigated the pattern of protein expression in brain tumor and normal brain tissue , following treatment with vandetanib in a rat glioma model . BT4C - cells were stereotactically implanted into the brain of BD IX rats . The rats were divided into three different experiments . The treatment schedule for experiments one and two consisted of daily , oral doses of vandetanib from day 6 until day 12 or 20 after implantation , respectively . In the third experiment , each animal received a single dose of vandetanib on day 19 after implantation and was then sacrificed 2 , 8 or 24 h thereafter . The protein expression profiles were analyzed by SELDI - TOF - MS and evaluated with multivariate statistical methods . Following treatment with vandetanib , we found significantly altered protein expression pattern in malignant glioma and normal brain . Analyzing protein spectra is an interesting option to assess biological effects induced in brain tissue by signal transduction inhibitors such as vandetanib .",
"Modeling the neurovascular niche : murine strain differences mimic the range of responses to chronic hypoxia in the premature newborn . Preterm birth results in significant cognitive and motor disabilities , but recent evidence suggests that there is variable recovery over time . One possibility that may explain this variable recovery entails variable neurogenic responses in the subventricular zone ( SVZ ) following the period of chronic hypoxia experienced by these neonates . In this report , we have characterized the responses to chronic hypoxia of two mouse strains that represent a wide range of susceptibility to chronic hypoxia . We determined that C57BL / 6 pups and neural progenitor cells ( NPCs ) derived from them exhibit a blunted response to hypoxic insult compared with CD - 1 pups and NPCs . Specifically , C57BL / 6 pups and NPCs exhibited blunted in vivo and in vitro proliferative and increased apoptotic responses to hypoxic insult . Additionally , C57BL / 6 NPCs exhibited lower baseline levels and hypoxia - induced levels of selected transcription factors , growth factors , and receptors ( including HIF - 1alpha , Q9GZT9 , P23560 , P15692 , P48061 , TrkB , Nrp - 1 , P61073 , and NO ) that determine , in part , the responsiveness to chronic hypoxic insult compared with CD - 1 pups and NPCs , providing insight into this important and timely problem in perinatology .",
"P00533 gene expression in avian epiphyseal growth - plate cartilage cells : effect of serum , parathyroid hormone and atrial natriuretic peptide . Avian chondrocytes and fibroblasts , derived from epiphyseal growth - plate and skin , respectively , were cultured in vitro . In chondrocytes , epidermal growth factor ( P01133 ) caused a dose - dependent stimulation of proliferation . P01133 receptor mRNA was not detected with the v - erb B probe in chondrocytes cultured in the presence of 5 % fetal calf serum ( FCS ) . In the absence of FCS in the medium , a time - dependent increase in the level of P01133 receptor mRNA was observed . Parallel changes were also observed in the level of P01133 receptor , as demonstrated by immunofluorescence using antibodies directed against avian P01133 receptor . In avian fibroblasts , P01133 receptor mRNA and P01133 receptor levels were not affected by FCS . Furthermore , FCS did not affect the level of thyroid hormone receptor mRNA ( using v - erb A as a probe ) in either chondrocytes or fibroblasts . Parathyroid hormone ( PTH ) , which acts as a mitogen in avian chondrocytes attenuated -- whereas atrial natriuretic peptide ( P01160 ) , a suppressor of chondrocyte proliferation , enhanced -- P01133 receptor mRNA . The present results show that avian growth - plate chondrocytes respond to P01133 and bear P01133 receptors . The levels of P01133 mRNA and P01133 receptor are inversely related to cell proliferation . The results also support previous suggestions that PTH and P01160 play important roles in chondrocyte proliferation , possibly through their effect on the synthesis of the P01133 receptor .",
"Influence of immunomodulatory drugs on the cytotoxicity induced by monoclonal antibody 17 - 1A and interleukin - 2 . Patients treated with monoclonal antibodies and cytokines for cancer receive often co - medication , which may influence treatment efficacy . Therefore , we investigated with a flowcytometric cytotoxicity assay the effect of several immunomodulatory drugs on antibody dependent cellular cytotoxicity ( ADCC ) , interleukin - 2 ( P60568 ) induced cytotoxicity and P60568 - induced - ADCC . We found that dexamethasone markedly inhibited the P60568 induced cytotoxicity and the P60568 - induced - ADCC . ___MASK93___ , a P46098 serotonin receptor antagonist augmented significantly ADCC . Clemastine , a histamine type - 2 receptor antagonist augmented the P60568 - induced - ADCC . The P01375 antagonist thalidomide suppressed ADCC whereas pentoxifylline proved to be ineffective . Other tested drugs namely ibuprofen and indomethacin , both prostaglandin E2 antagonists , cimetidine a histamine type - 2 receptor antagonist , the opioid pethidine , prostaglandin E2 and histamine exerted minor effects or had no influence on the tested parameters . We conclude that glucocorticosteroids should be avoided with monoclonal antibody and cytokine treatment . According to our in vitro data the other drugs tested did not have a negative impact on cellular cytotoxicity and ADCC .",
"P00533 inhibitors in development for the treatment of non - small cell lung cancer . The epidermal growth factor receptor ( P00533 ) inhibitors erlotinib , gefitinib , and cetuximab have undergone extensive clinical testing and have established clinical activity in non - small cell lung cancer and other types of solid tumors . A number of newer inhibitors are currently in clinical development with different spectra of activity or mechanisms of receptor inhibition . These include monoclonal antibodies , such as panitumumab and matuzumab ; dual inhibitors of P00533 and vascular endothelial growth factor receptor , such as DB05294 and AEE788 ; inhibitors of multiple P00533 family members , such as lapatinib ; and irreversible inhibitors , such as canertinib and HKI272 . Preclinical studies suggest that several of these agents may have activity in tumors refractory to erlotinib or gefitinib . Among these agents , DB05294 has undergone the most extensive clinical testing . The antitumor activity of DB05294 in these two randomized phase II clinical trials in patients with non - small cell lung cancer was felt to be sufficiently promising to warrant phase III clinical testing . Several of the other P00533 inhibitors are also undergoing advanced clinical testing , either alone or in combination with other agents . P00533 has now been validated as a clinically relevant target , and several different types of agents inhibiting this receptor are currently in development . Future research will be needed to elucidate the role of these agents in patients with P00533 inhibitor - naive and P00533 inhibitor - refractory disease , to define the molecular characteristics that predict response , and to determine whether these drugs should be used in combination with other targeted agents or chemotherapy .",
"DB05294 is effective in P00533 - mutant lung cancer cells with P60484 deficiency . The effectiveness of vandetanib , an agent that targets P07949 , VEGFR and P00533 signaling , against P00533 - mutant lung cancer cells with P60484 loss was investigated . Two P00533 mutant non - small cell lung cancer ( NSCLC ) cell lines , PC - 9 ( P60484 wild type ) and NCI - H1650 ( P60484 null ) , were used . We transfected an intact P60484 gene into H1650 cells and knocked down P60484 expression in PC - 9 cells using shRNA . The effectiveness of gefitinib and vandetanib was assessed using a xenograft model . While PC - 9 cells were more resistant to vandetanib than gefitinib , H1650 cells were more sensitive to vandetanib than gefitinib . Both gefitinib and vandetanib suppressed the activation of P00533 and MAPK in H1650 cells , although phosphorylated AKT levels were not affected . In an H1650 cell xenograft model , vandetanib was also more effective than gefitinib . Although P60484 - transfected H1650 cells did not show restoration of sensitivity to gefitinib in vitro , the xenograft tumors responded to gefitinib and vandetanib . Knockdown of P60484 in PC - 9 cells caused resistance to gefitinib . In conclusion , vandetanib might be effective in NSCLC with P00533 mutations that lack P60484 expression . The contribution of P60484 absence to vandetanib activity in NSCLC cells harboring P00533 mutations should be further examined .",
"P15692 - associated tyrosine kinase inhibition increases the tumor response to single and fractionated dose radiotherapy . PURPOSE : In this study , the efficacy of combining DB05294 ( DB05294 ) , a vascular endothelial growth factor ( P15692 ) receptor 2 - associated tyrosine kinase inhibitor currently undergoing Phase II clinical trial evaluation , with single and fractionated dose radiation exposures was examined in a human colorectal carcinoma model ( HT29 ) . METHODS AND MATERIALS : HT29 xenograft - bearing mice were treated with either single - dose ( 10 Gy ) or multifraction ( 2 Gy / day for 2 weeks ) radiotherapy alone or in conjunction with a 2 - week course of DB05294 ( 25 mg / kg ) . In the single - dose investigation , DB05294 treatment followed radiotherapy , whereas in the fractionated dose studies the antiangiogenic therapy was given before , after , or concurrent with the radiation . Tumor response was determined by tumor growth delay . RESULTS : DB05294 increased the response of HT29 xenografts to both single and fractionated dose radiotherapy . In the fractionation studies sequencing of therapies had little impact on treatment outcomes ; the time for the median tumors in each of the treatment groups to grow to five times the starting size was 53 , 53 . 5 , and 49 days , respectively . CONCLUSIONS : These studies indicate that DB05294 , when used in conjunction with radiation therapy , has a clear therapeutic advantage , providing a rationale for considering the combination of this agent with radiotherapy in the clinic .",
"Identification of a lung adenocarcinoma cell line with Q16204 - P07949 fusion gene and the effect of P07949 inhibitors in vitro and in vivo . Rearrangements of the proto - oncogene P07949 are newly identified potential driver mutations in lung adenocarcinoma ( LAD ) . However , the absence of cell lines harboring P07949 fusion genes has hampered the investigation of the biological relevance of P07949 and the development of P07949 - targeted therapy . Thus , we aimed to identify a P07949 fusion positive LAD cell line . Eleven LAD cell lines were screened for P07949 fusion transcripts by reverse transcription - polymerase chain reaction . The biological relevance of the Q16204 - P07949 gene products was assessed by cell growth , survival and phosphorylation of P27361 / 2 and AKT with or without the suppression of P07949 expression using RNA interference . The efficacy of P07949 inhibitors was evaluated in vitro using a culture system and in an in vivo xenograft model . Expression of the Q16204 - P07949 fusion gene in LC - 2 / ad cells was demonstrated by the mRNA and protein levels , and the genomic break - point was confirmed by genomic DNA sequencing . Mutations in P01116 and P00533 were not observed in the LC - 2 / ad cells . Q16204 - P07949 was constitutively active , and the introduction of a siRNA targeting the P07949 3 ' region decreased cell proliferation by downregulating P07949 and P27361 / 2 phosphorylation . Moreover , treatment with P07949 - inhibitors , including vandetanib , reduced cell viability , which was accompanied by the downregulation of the AKT and P27361 / 2 signaling pathways . DB05294 exhibited anti - tumor effects in the xenograft model . Endogenously expressing Q16204 - P07949 contributed to cell growth . The inhibition of kinase activity could be an effective treatment strategy for LAD . LC - 2 / ad is a useful model for developing fusion P07949 - targeted therapy .",
"Effective dasatinib uptake may occur without human organic cation transporter 1 ( O15245 ) : implications for the treatment of imatinib - resistant chronic myeloid leukemia . We have previously shown that imatinib uptake into chronic myeloid leukemia ( CML ) cells is dependent on human organic cation transporter 1 ( O15245 ; O15245 ) , and that low O15245 expression is an important determinant of clinical outcome to imatinib treatment . We hypothesized that dasatinib might be transported differently than imatinib , possibly accounting for its favorable effects in imatinib - resistant patients . ( 14 ) C - dasatinib uptake was greater in KCL22 - transfected cells with pcDNA3 - O15245 plasmid ( high O15245 - expressing cells ) than in control cells ( P = . 02 ) . However , hOCT inhibitors did not decrease dasatinib uptake into either control or primary cells , in contrast to their block on imatinib uptake . Dasa - tinib decreased the level of phosphorylated CrkL to 49 . 9 % in control and 40 . 3 % in high O15245 - expressing cells . Dasa - tinib efflux was investigated in confluent P08183 - transfected MDCKII cell monolayers . Both dasatinib and imatinib were transported from the basal to the apical layer , indicating that they were transported by P08183 , which was confirmed using the P08183 inhibitor PSC833 ( P = . 001 and P < . 001 , respectively ) . Compared with imatinib , dasatinib achieved superior intracellular levels and P11274 - P00519 suppression even in cells with low or blocked O15245 . Efflux of dasatinib and imatinib appear similar via P08183 . Dasatinib may therefore offer an advantage over imatinib in patients with low O15245 expression .",
"A transgenic platform for testing drugs intended for reversal of cardiac remodeling identifies a novel 11βHSD1 inhibitor rescuing hypertrophy independently of re - vascularization . RATIONALE : Rescuing adverse myocardial remodeling is an unmet clinical goal and , correspondingly , pharmacological means for its intended reversal are urgently needed . OBJECTIVES : To harness a newly - developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling . METHODS AND RESULTS : A P15692 - based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure . Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy , enlarged LV size and improve cardiac function was monitored . Arguing for clinical relevance of the experimental system , clinically - used drugs operating on the P00797 - Angiotensin - DB04630 - System ( RAAS ) , namely , the P12821 inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling . Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point - of - no - return . Similarly , the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature . Extending the arsenal of remodeling - reversing drugs to pathways other than RAAS , a specific inhibitor of 11β - hydroxy - steroid dehydrogenase type 1 ( 11β HSD1 ) , a key enzyme required for generating active glucocorticoids , fully rescued myocardial hypertrophy . This was associated with mitigating the hypertrophy - associated gene signature , including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization - induced reversal . CONCLUSIONS : A system was developed suitable for identifying novel remodeling - reversing drugs operating in different pathways and for gaining insights into their mechanisms of action , exemplified here by uncoupling their vascular affects .",
"DB05294 , a multitargeted inhibitor for receptor tyrosine kinases , suppresses growth of gliomas expressing an epidermal growth factor receptor mutant , EGFRvIII , in the brain . P00533 ( P00533 ) vIII is a mutated P00533 that is frequently overexpressed in glioblastomas and implicated in response to receptor tyrosine kinase inhibitors . In this study , we investigate the effect of DB05294 ( ZACTIMA , vandetanib ) , a dual inhibitor for vascular endothelial growth factor receptor 2 and P00533 on growth and angiogenesis of gliomas expressing EGFRvIII . We used two glioma xenograft models , U87MG cells overexpressing EGFRvIII and short - term cultured primary glioma GBM8 cells with EGFRvIII . DB05294 inhibited tumor growth and angiogenesis and induced cell apoptosis in various brain gliomas . Moreover , significant inhibition of EGFRvIII - expressing U87MG and GBM8 gliomas was observed compared with their controls . Magnetic resonance imaging analysis using the apparent diffusion coefficient and three - dimensional P24752 * weighed measurements validated DB05294 inhibition on tumor growth and angiogenesis in EGFRvIII - expressing GBM8 gliomas . Mechanistically , DB05294 shows better inhibition of cell growth and survival of U87MG / EGFRvIII , GBM6 , and GBM8 cells that express EGFRvIII than U87MG or GBM14 cells that have nondetectable EGFRvIII through attenuation of activated phosphorylation of signal transducer and activator of transcription 3 , Akt , and Bcl - X ( L ) expression . Albeit in lesser extent , DB05294 also displays suppressions of U87MG / P00533 and GBM12 cells that overexpress wild - type P00533 . Additionally , DB05294 inhibits activation of extracellular signal - regulated kinase 1 / 2 in both types of cells , and expression of a constitutively active phosphoinositide 3 - kinases partially rescued DB05294 inhibition in U87MG / EGFRvIII cells . Taken together , these data show that DB05294 significantly inhibited growth and angiogenesis of gliomas expressing EGFRvIII by specifically blocking EGFRvIII - activated signaling mediators , suggesting a potential application of DB05294 in treatments for glioblastomas that overexpress EGFRvIII . Mol Cancer Ther ; 9 ( 4 ) ; 929 - 41 . ( c ) 2010 AACR .",
"Personalized medicine and pharmacogenetic biomarkers : progress in molecular oncology testing . In the field of oncology , clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood . Progress in biomarker technology , coupled with the companion clinical diagnostic laboratory tests , continue to advance this field , where individualized and customized treatment appropriate for each individual patient define the standard of care . Here , we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing : P15056 V600E for vemurafenib in melanoma ; Q9HC35 - Q9UM73 for crizotinib and P00533 for erlotinib and gefitinib in non - small - cell lung cancer ; P01116 against the use of cetuximab and panitumumab in colorectal cancer ; P04626 ( P04626 / neu ) for trastuzumab in breast cancer ; P11274 - P00519 for tyrosine kinase inhibitors in chronic myeloid leukemia ; and P29590 / RARα for all - trans - retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia .",
"Prolonged exposure of colon cancer cells to the epidermal growth factor receptor inhibitor gefitinib ( DB00317 ( TM ) ) and to the antiangiogenic agent DB05294 : Cytotoxic and biomolecular effects . AIM : To analyze the biological effects of prolonged in vitro exposure of HT - 29 and LoVo colon cancer cell lines to gefitinib ( DB00317 ) , an inhibitor of epidermal growth factor receptor ( P00533 ) activity , and DB05294 , an inhibitor of both P35968 and P00533 activities . METHODS : Cells were treated with each drug for up to 2 wk using either a continuous or an intermittent ( 4 d of drug exposure followed by 3 d of washout each week ) schedule . RESULTS : In both cell types , prolonged exposure ( up to 14 d ) to gefitinib or DB05294 produced a similar inhibition of cell growth that was persistent and independent of the treatment schedule . The effects on cell growth were associated with a pronounced inhibition of p - P00533 and / or p - P35968 expression . Treatment with gefitinib or DB05294 also inhibited the expression of P00533 downstream signal molecules , p - Erk1 / 2 and p - Akt , although the magnitude of these effects varied between treatments and cell lines . Furthermore , expression of the drug resistance - related protein Q9UNQ0 was shown to significantly increase after 14 d of continuous exposure to the two drugs . CONCLUSION : We conclude that long - term exposure of colon cancer cells to gefitinib and DB05294 does not modify their cytotoxic effects but it might have an effect on sensitivity to classical cytotoxic drugs .",
"DB05294 , an inhibitor of VEGFR and P00533 tyrosine kinase activity in combination with radiotherapy . Radiation enhances both epithelial growth factor receptor ( P00533 ) and vascular endothelial growth factor ( P15692 ) expression , which are a part of key pathways for tumor progression . Some tumors may not respond well to P00533 inhibitors alone or may develop resistance to P00533 inhibitors . Therefore , drug therapy targeted to P15692 receptors and EGFRs , when combined with radiotherapy ( RT ) , may improve tumor control and provide wider applicability . This article focuses on DB05294 , an inhibitor of P00533 and P15692 receptor signaling in combination with RT . We discuss preclinical and clinical studies with RT and inhibitors of P15692 or P00533 signaling first . We then address issues associated with DB05294 pharmacokinetic dosing , and scheduling when combined with RT . We also discuss DB05294 in the context of anti - P00533 therapy resistance . Dual inhibition of P00533 and P15692 receptor signaling pathways shows promise in enhancing RT efficacy .",
"Vascular endothelial growth factor receptor tyrosine kinase inhibitors vandetanib ( DB05294 ) and DB04849 in lung cancer . Vascular endothelial growth factor ( P15692 ) is a rational target for advanced non - small cell lung cancer ( NSCLC ) , a hypothesis validated by the recent Eastern Cooperative Oncology Group E4599 trial showing that the addition of the P15692 monoclonal antibody bevacizumab to chemotherapy prolongs overall survival . Several new tyrosine kinase inhibitors targeting the P15692 pathway are currently in advanced clinical development for NSCLC and offer several possible advantages compared with monoclonal antibodies , including oral administration , more flexible dosing , a broader spectrum of target inhibition , and different toxicity profiles . Among these agents , vandetanib ( DB05294 ) , an inhibitor of the P15692 receptor ( VEGFR ) - 2 and epidermal growth factor receptor tyrosine kinase , has been the most extensively studied . In a randomized phase II study of patients with platinum - refractory NSCLC , including squamous histology , vandetanib prolonged progression - free survival compared with gefitinib . In another phase II trial , an improvement in progression - free survival was observed for vandetanib in combination with docetaxel compared with docetaxel alone . DB04849 is an inhibitor of P17948 , P35968 , and P35916 and other tyrosine kinases that has shown clinical activity in NSCLC in combination with carboplatin and paclitaxel . Several phase III trials are under way testing these agents either as monotherapy or in combination with chemotherapy in patients with lung cancer . Early results with these agents , and others being tested , raise the possibility that there will eventually be multiple P15692 - targeted therapies available in the clinic that can potentially benefit a broader range of patients with advanced - stage NSCLC .",
"Treatment of cardiovascular dysfunction associated with the metabolic syndrome and type 2 diabetes . Our previous studies have shown vascular dysfunction in small coronary and mesenteric arteries in Zucker obese rats , a model of the metabolic syndrome , and Zucker Diabetic Fatty ( ZDF ) rats , a model of type 2 diabetes . Because of their lipid lowering action and antioxidant activity , we predicted that treatment with ___MASK89___ , an P04035 inhibitor ( statin ) or Enalapril , an angiotensin converting enzyme ( P12821 ) inhibitor would improve vascular dysfunction associated with the metabolic syndrome and type 2 diabetes . METHODS : 20 - week - old Zucker obese and 16 - week - old ZDF rats were treated with ___MASK89___ ( 25 mg / kg / day ) or Enalapril ( 20 mg / kg / day ) for 12 weeks . We examined metabolic parameters , indices of oxidative stress and vascular dysfunction in ventricular and mesenteric small arteries ( 75 - 175 microm intraluminal diameter ) from lean , Zucker obese and ZDF rats ( untreated and treated ) . RESULTS : Endothelial dependent responses were attenuated in coronary vessels from Zucker obese and ZDF rats compared to responses from lean rats . Both drugs improved metabolic parameters , oxidative stress , and vascular dysfunction in Zucker obese rats , however , only partial improvement was observed in ZDF rats , suggesting more aggressive treatment is needed when hyperglycemia is involved . CONCLUSION : Vascular dysfunction is improved when Zucker obese and , to a lesser degree , when ZDF rats were treated with ___MASK89___ or Enalapril .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK76___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"Synergistic proapoptotic effects of the two tyrosine kinase inhibitors pazopanib and lapatinib on multiple carcinoma cell lines . ___MASK100___ and lapatinib are two tyrosine kinase inhibitors that have been designed to inhibit the P15692 tyrosine kinase receptors 1 , 2 and 3 ( pazopanib ) , and the P00533 and P04626 receptors in a dual manner ( lapatinib ) . ___MASK100___ has also been reported to mediate inhibitory effect on a selected panel of additional tyrosine kinases such as P09619 and c - kit . Here , we report that pazopanib and lapatinib act synergistically to induce apoptosis of A549 non - small - cell lung cancer cells . Systematic assessment of the kinome revealed that both pazopanib and lapatinib inhibited dozens of different tyrosine kinases and that their combination could suppress the activity of some tyrosine kinases ( such as c - DB00134 ) that were not or only partially affected by either of the two agents alone . We also found that pazopanib and lapatinib induced selective changes in the transcriptome of A549 cells , some of which were specific for the combination of both agents . Analysis of a panel of unrelated human carcinoma cell lines revealed a signature of 52 genes whose up - or downregulation reflected the combined action of pazopanib and lapatinib . Indeed , pazopanib and lapatinib exerted synergistic cytotoxic effects on several distinct non - small - cell lung cancer cells as well as on unrelated carcinomas . Altogether , these results support the contention that combinations of tyrosine kinase inhibitors should be evaluated for synergistic antitumor effects . Such combinations may lead to a ' collapse ' of pro - survival signal transduction pathways that leads to apoptotic cell death .",
"Current status of vandetanib ( DB05294 ) in the treatment of non - small cell lung cancer . DB05294 ( DB05294 ) is an oral small molecule inhibitor of multiple intracellular receptor kinases , including the vascular endothelial growth factor receptor ( VEGFR ) - 2 and epidermal growth factor receptor ( P00533 ) . Both VEGFR and P00533 pathways have emerged as instrumental in the growth and metastasis of multiple malignancies , including non - small cell lung cancer ( NSCLC ) . Indeed , inhibitors of each pathway have been approved by the US Food and Drug Administration for use in advanced NSCLC . As there is considerable cross talk between these pathways , dual inhibition with such agents has become an attractive strategy , with encouraging Phase II clinical trial data to date . The convenience of one oral agent targeting both pathways is clear , and clinical trials have established the maximum tolerated daily dose of vandetanib , with data from randomized Phase III trials emerging . This report will review completed and ongoing NSCLC clinical trials evaluating vandetanib , and speculate on the future of this agent in NSCLC .",
"Tyrosine kinase inhibitors of vascular endothelial growth factor receptors in clinical trials : current status and future directions . Angiogenesis plays a central role in the process of tumor growth and metastatic dissemination . The vascular endothelial growth factor ( P15692 ) family of peptide growth factors and receptors are key regulators of this process . Agents directed either against P15692 or P15692 receptors ( VEGFRs ) have been developed . The tyrosine kinase inhibitors of VEGFRs are low - molecular - weight , DB00171 - mimetic proteins that bind to the DB00171 - binding catalytic site of the tyrosine kinase domain of VEG - FRs , resulting in blockade of intracellular signaling . Several of these agents are currently in different phases of clinical development . Large randomized phase III trials have demonstrated the efficacy of sunitinib and sorafenib in the treatment of patients affected by gastrointestinal stromal tumors and renal cancer refractory to standard therapies , respectively . Positive results also have been reported with the combination of DB05294 and chemotherapy in previously treated non - small cell lung cancer patients . For other agents , such as vatalanib , contrasting outcomes in metastatic colorectal cancer patients have been reported : the final results of these trials are expected in 2006 . However , several key questions remain to be addressed , regarding the choice of an adequate dose or schedule , the presence of \" off - target \" effects , the safety of long - term administration , and the research of new clinical end points or methodological approaches for the optimal clinical development of these agents .",
"DB05294 restores head and neck squamous cell carcinoma cells ' sensitivity to cisplatin and radiation in vivo and in vitro . PURPOSE : We investigated whether vandetanib , an inhibitor of the tyrosine kinase activities of vascular endothelial growth factor receptor - 2 ( P35968 ) , epidermal growth factor receptor ( P00533 ) , and rearranged during transfection ( P07949 ) , could augment the antitumor activity of radiation with or without cisplatin in preclinical in vitro and in vivo models of human head and neck squamous cell carcinoma ( HNSCC ) . EXPERIMENTAL DESIGN : P48449 - 19 and P0CJ72 HNSCC cells that were cisplatin and radioresistant were treated with vandetanib , cisplatin , and radiation alone or in combination in vitro and in vivo using an orthotopic nude mouse model . Treatment effects were assessed using clonogenic survival assay , tumor volume , bioluminescence imaging , tumor growth delay , survival , microvessel density , tumor and endothelial cell apoptosis , and P00533 and Akt phosphorylation data . RESULTS : DB05294 plus cisplatin radiosensitized HNSCC cells in vitro and in vivo . The combination treatment with vandetanib , cisplatin , and radiation was superior to the rest of treatments ( including the double combinations ) in antitumoral effects , prolonging survival , decreasing cervical lymph node metastases in vivo . It also increased both tumor and tumor - associated endothelial cell apoptosis and decreased microvessel density in vivo . An analysis of tumor growth delay data revealed that vandetanib plus cisplatin enhanced radioresponse in vivo . All vandetanib - containing treatments inhibited P00533 and Akt phosphorylation in vitro and in vivo . CONCLUSION : The addition of vandetanib to combination therapy with cisplatin and radiation was able to effectively overcome cisplatin and radioresistance in in vitro and in vivo models of HNSCC . Further study of this regimen in clinical trials may be warranted .",
"Contrast - enhanced Ultrasound Imaging of Antiangiogenic Tumor Therapy . BACKGROUND / AIM : Anti - angiogenic treatment is a promising strategy for cancer therapy and is currently evaluated in clinical trials . The aim of the present study was to further investigate the effects of an anti - angiogenic therapy , inhibiting vascular endothelial growth factor ( P15692 ) and endothelial growth factor ( P01133 ) using a tyrosine kinase inhibitor for blocking tumor angiogenesis and tumor progression in vivo . MATERIALS AND METHODS : Experiments were performed using C57 / Bl6 mice ( 25 ± 5 g of body weight ( b . w . ) ) implanted with subcutaneous Lewis lung carcinoma ( LLC - 1 ) . From day 7 till 21 after tumor cell implantation , animals ( n = 7 per group ) were treated by monotherapy using DB05294 ( 50 mg / kg b . w . per os ( p . o . ) ) daily . A control group received only the solvent polysorbate 80 . Using contrast enhanced ultrasound ( CE - US ) parameters of intra - tumoral microcirculation animals were examined 24 h after the last application of DB05294 . Moreover , subcutaneous tumor growth was measured over the whole therapy period . Finally , histological analyses were performed to analyze the functional vessel density in the tumor tissue . RESULTS : DB05294 reduced tumor growth of LLC - 1 in C57 / Bl6 mice significantly . A significant difference of maximal signal intensity ( ΔSImax ) and area below the intensity time curve ( AUC ) after antiangiogenic therapy was recorded in the tumor center by CE - US . Vessel density after hematoxyline and eosin , as well as CD31 , staining showed no significant difference in both groups . CONCLUSION : Anti - angiogenic effects can be quantitatively demonstrated using CE - US imaging , which represents the spreading of efficient vessels in the tumor tissue , especially in the tumor center .",
"DB05294 and indwelling pleural catheter for non - small - cell lung cancer with recurrent malignant pleural effusion . INTRODUCTION / BACKGROUND : Non - small - cell lung cancer patients with malignant pleural effusion have a poor overall median survival ( 4 . 3 months ) . P15692 is a key regulator of pleural effusion production . It is unknown if pharmacological inhibition of P15692 signaling modifies the disease course of non - small - cell lung cancer patients with recurrent malignant pleural effusion . We report the final results of a single - arm phase II clinical trial of the P15692 receptor inhibitor , vandetanib , combined with intrapleural catheter placement in patients with non - small - cell lung cancer and recurrent malignant pleural effusion , to determine whether vandetanib reduces time to pleurodesis . PATIENTS AND METHODS : Non - small - cell lung cancer patients with proven metastatic disease to the pleural space using pleural fluid cytology or pleural biopsy who required intrapleural catheter placement were eligible for enrollment . On the same day of the intrapleural catheter insertion , the patients were started on a daily oral dose of 300 mg vandetanib , for a maximum of 10 weeks . The primary end point was time to pleurodesis , with response rate as the secondary end point . Exploratory analyses included measurement of pleural fluid cytokines and angiogenic factors before and during therapy . RESULTS : Twenty eligible patients were included in the trial . Eleven patients completed 10 weeks of treatment . Median time to pleurodesis was 35 days ( 95 % confidence interval , 15 - not applicable ) . Median time to pleurodesis in the historical cohort was 63 days ( 95 % confidence interval , 45 - 86 ) when adjusted for Eastern Cooperative Oncology Group performance status ≤ 2 . CONCLUSION : DB05294 therapy was well tolerated ; however , it did not significantly reduce time to pleurodesis .",
"Inhibition of P35968 prevents DMBA - induced mammary tumor formation . Preinvasive mammary pathologies in humans and rat chemical carcinogenesis model systems have an increased microvascular density relative to normal tissue . This suggests the possibility of preventing invasive breast cancer by inhibiting angiogenesis . Vascular endothelial cell growth factor ( P15692 ) is a potent angiogenic growth factor , commonly involved in tumor - induced angiogenesis . Here , we show that both P15692 and P35968 expression increase with histological progression to invasive disease in the rat 7 , 12 - dimethylbenz [ a ] anthracene ( DMBA ) model . Other P15692 receptors , P17948 , neuropilin 1 and neuropilin 2 , are constitutively expressed throughout progression . To examine whether P15692 signaling is functionally relevant to tumor - induced endothelial tubule formation in vitro and for tumor formation in vivo , we utilized the P35968 inhibitor , DB05294 . In vitro endothelial cell tubulogenesis induced by isolated mammary organoids or carcinoma in situ from DMBA - treated rats is inhibited by DB05294 , in a dose - dependent fashion . The administration of DB05294 to DMBA - treated rats inhibits the formation of atypical ductal hyperplasia and carcinoma in situ by greater than 95 % ( P < 0 . 05 ) , when administered 1 week or 6 weeks post - DMBA initiation . Invasive disease was absent in all DB05294 cohorts . These data support the hypothesis that progression of DMBA - induced preinvasive mammary pathologies to palpable disease requires angiogenesis via a P15692 - dependent mechanism .",
"DB01645 potentiates the P01160 effect on a K (+)- conductance in P29320 - 293 cells . P29320 - 293 cells are known to reflect many features of the late distal tubule . Furthermore , they have the ability to release urodilatin , the structural analog to P01160 . RT - PCR was performed to test for the expression of natriuretic peptide receptors . While the mRNA for the human P01160 receptor ( P16066 , P16066 ) could be amplified , the P09543 - specific receptor P20594 ( P20594 ) and the receptor specific for guanylins , P25092 , could not be detected . In patch clamp experiments the effects of P01160 ( 10 nM ) on membrane voltage ( V ( m ) ) were monitored and P29320 - 293 cells depolarized by 2 . 3 +/- 0 . 5 mV ( n = 14 ) . In the presence of the P01133 receptor blocker genistein ( 10 microM ) the effect of P01160 was increased by 65 % to 3 . 9 +/- 0 . 8 mV ( n = 14 ) . After removal of genistein the P01160 - mediated depolarization further increased by 147 % to 5 . 7 +/- 1 . 0 mV ( n = 14 ) . P01160 given repetitively without genistein had no increasing depolarizing effect in P29320 - 293 cells with time . The P01160 effect could be fully blocked by 1 mM Ba ( 2 +) and by 1 microM of the specific PKG inhibitor KT5823 indicating that P01160 inhibits a K (+)- conductance via a cGMP - dependent protein kinase . DB01645 itself hyperpolarized the membrane voltage of P29320 - 293 cells by - 3 . 9 +/- 0 . 6 mV ( n = 11 ) and this effect could also be fully blocked by Ba ( 2 +) ( - 0 . 3 +/- 0 . 1 mV , n = 5 ) , indicating that genistein activates a K (+)- conductance which contributes significantly to the membrane potential of P29320 - 293 cells .",
"Effects of cytokines on P15692 expression and secretion by human first trimester trophoblast cell line . PROBLEM : The mechanism through which vascular endothelial growth factor ( P15692 ) regulation occurs at the feto - maternal interface is poorly understood . The aim of this study was to investigate the effects of various cytokines on P15692 expression and secretion by trophoblast cells . METHOD OF STUDY : We investigated the effects of cytokines on P15692 expression in human first trimester trophoblast cell line by analyzing P15692 messenger RNA ( mRNA ) by reverse transcription - polymerase chain reaction and P15692 protein secretion by enzyme linked immunosorbent assay . RESULTS : The trophoblast cells expressed P15692 mRNA constitutively and the main subtypes were identified as VEGF121 and VEGF165 . When cultured in the presence of interferon ( IFN ) - gamma , interleukin ( IL ) - 1beta , tumor necrosis factor ( P01375 ) - alpha , P60568 , or P22301 , P15692 mRNA expression was found to be significantly increased by IL - 1beta , P01579 and P01375 but to be unaffected by P60568 and P22301 . Moreover , P15692 secretion was most significantly increased by P01579 treatment . CONCLUSION : These results suggest that IL - 1beta , P01579 , and P01375 may regulate the production of P15692 in early gestational trophoblasts .",
"Tyrosine phosphorylation of Q92835 promotes its proteasomal degradation . OBJECTIVE : The activity of the SH2 - containing - phosphatidylinositol - 5 '- phosphatase ( Q92835 , also known as Q92835 ) , a critical hematopoietic - restricted negative regulator of the P19957 kinase ( PI3K ) pathway , is regulated in large part via its protein levels . We sought to determine the mechanism ( s ) involved in its downregulation by P11274 - P00519 and by interleukin ( IL ) - 4 . MATERIALS AND METHODS : We used Ba / P13726 ( Q92817 - tetOFF ) cells to study the downregulation of Q92835 by P11274 - P00519 and bone marrow - derived macrophages to study Q92835 ' s downregulation by P05112 . RESULTS : We show herein that P11274 - P00519 downregulates Q92835 , but not O15357 or P60484 , and this can be blocked with the Src kinase inhibitor Q99463 , which inhibits the tyrosine phosphorylation of Q92835 , or with the proteasomal inhibitor MG - 132 . We also show , using anti - Q92835 immunoprecipitates , that c - Cbl and Cbl - b are associated with Q92835 and that P11274 - P00519 induces Q92835 ' s polyubiquitination . This ubiquitination can be blocked with Q99463 , consistent with the tyrosine phosphorylation of Q92835 acting as a signal for its ubiquitination . In bone marrow - derived macrophages , P05112 also leads to the proteasomal degradation of Q92835 but , unlike in Ba / P13726 ( Q92817 - tetOFF ) cells , O15357 is also proteasomally degraded and the degradation of both inositol phosphatases can be prevented with Q99463 or MG - 132 . CONCLUSION : Our results suggest that Q92835 protein levels can be reduced via P11274 - P00519 and / or Src family member - induced tyrosine phosphorylation of Q92835 because this triggers its polyubiquitination and degradation within the proteasome .",
"Evaluation of antileukaemic effects of rapamycin in patients with imatinib - resistant chronic myeloid leukaemia . BACKGROUND : Recent data suggest that the mammalian target of rapamycin ( P42345 ) is involved in the regulation of growth of neoplastic cells in chronic myeloid leukaemia ( CML ) . PATIENTS AND METHODS : We treated six patients with imatinib - resistant CML in haematological relapse ( leukocytes > 20 , 000 microL (- 1 ) ) with rapamycin at 2 mg per os daily for 14 consecutive days , with dose - adjustment allowed to reach a target rapamycin serum concentration of 10 - 20 pg mL (- 1 ) . RESULTS : A major leukocyte response with decrease to less than 10 , 000 microL (- 1 ) was obtained in two patients , and a minor transient response was seen in two other patients . In responding patients , we also observed a decrease in vascular endothelial growth factor ( P15692 ) mRNA levels in circulating leukaemic cells . Side effects during rapamycin treatment were mild in most patients . In one patient , pneumonia developed . DB00877 was also found to counteract growth of CML cells in vitro as determined by ( 3 ) H - thymidine incorporation . Moreover , rapamycin inhibited the growth of Ba / P13726 cells exhibiting various imatinib - resistant mutants of P11274 / P00519 , including the T315I variant that exhibits resistance against most currently available P11274 / P00519 kinase inhibitors . CONCLUSIONS : DB00877 shows antileukaemic effects in imatinib - resistant CML in vitro and in vivo . Larger trials with rapamycin or rapamycin - derivatives in combination with other targeted drugs are warranted to further determine clinical efficacy in CML .",
"Differential effects of vascular endothelial growth factor receptor - 2 inhibitor DB05294 on circulating endothelial progenitors and mature circulating endothelial cells : implications for use as a surrogate marker of antiangiogenic activity . PURPOSE : Circulating endothelial cells ( CEC ) comprise at least two distinct populations : bone marrow - derived circulating endothelial progenitors ( CEP ) and mature CECs derived from existing vasculature . We hypothesized that antiangiogenic agents may have differential effects on CEPs and mature CECs and that these changes may serve as a marker of biological activity . EXPERIMENTAL DESIGN : The effect of angiogenesis inhibitors on CECs was evaluated by flow cytometry after vascular endothelial growth factor ( P15692 ) - induced mobilization and in mice bearing Lewis lung carcinoma ( LLC ) . Tumor angiogenesis was evaluated in parallel by immunohistochemistry . RESULTS : In nontumor - bearing mice , P15692 administration increased both mature CECs and CEPs . This increase was inhibited by the P15692 receptor 2 inhibitor DB05294 as well as the P15692 inhibitor - soluble Flt - 1 . DB05294 had no significant effect on CECs in the absence of exogenous P15692 stimulation . In contrast , LLC - bearing mice had an increase in mature CECs but not CEPs after 3 days of treatment with DB05294 . The increase in mature CECs was dose - dependent , accompanied by a decrease in tumor microvessel density , and preceded reduction in tumor volume . Treatment of LLC - bearing mice with the vascular targeting agent ZD6126 also increased mature CECs . CONCLUSIONS : P15692 inhibitors can have differential effects on mature CECs and CEPs , and agents inhibiting tumor angiogenesis may cause a concomitant increase in mature CECs . This increase occurs in tumor - bearing but not in nontumor - bearing mice , suggesting that tumor endothelium is a potential source of mature CECs . Therefore , assessing both mature CECs and CEPs may provide insights into the mechanism of antiangiogenic agents and serve as an early surrogate marker of biological activity .",
"DB05294 improves anti - tumor effects of L19mTNFalpha in xenograft models of esophageal cancer . PURPOSE : Targeting the tumor vasculature by vascular disrupting agents ( VDAs ) has shown therapeutic activity in mouse models . In most cases , however , VDA efficacy is substantially compromised by the inability of these drugs to completely kill tumor cells located at the periphery of the tumor mass . In this study , we investigated anti - tumor effects of L19mTNFα , a fusion protein composed of Q9Y2K2 ( scFv ) , specific for the angiogenesis - associated ED - B containing fibronectin isoform , and murine TNFα , in xenograft models of esophageal cancer . EXPERIMENTAL DESIGN : We evaluated ED - B expression in esophageal cancer samples . Subsequently , we generated subcutaneous xenografts from primary tumors , treated them with the L19mTNFα scFv , and determined effects on tumor vasculature , viability and proliferation , and P15692 expression and infiltration by hematopoietic cells . To overcome tumor resistance , L19mTNFα scFv was combined with vandetanib , a tyrosine kinase inhibitor of P15692 receptor , epidermal growth factor receptor , and P07949 signaling . RESULTS : ED - B was broadly expressed by esophageal cancer cell lines , as well as xenografts and primary surgical samples of esophageal cancer . Administration of L19mTNFα acutely damaged tumor vasculature and increased necrosis , indicating a VDA - like activity of this immunoconjugate . This event was followed , however , by rapid tumor growth recovery associated with increased expression of P15692 and recruitment of CD11b + Gr1 + myeloid cells into tumors . Combination of L19mTNFα with vandetanib severely impaired vascular functions in tumors , leading to a reduction of cell proliferation and increased necrosis , without apparent signs of toxicity . CONCLUSION : These findings indicate that a combination of vascular damaging agents with anti - angiogenic drugs could represent a promising therapeutic strategy for esophageal cancer .",
"Genetic mechanism of aspirin - induced urticaria / angioedema . PURPOSE OF REVIEW : DB00945 - induced urticaria / angioedema is a major aspirin - related hypersensitivity often associated with aspirin - intolerant asthma . Genetic studies on aspirin - intolerant asthma have shown chronic overproduction of cysteinyl leukotrienes . The genetic analysis of aspirin - induced urticaria / angioedema is limited , however . RECENT FINDINGS : A recent study on HLA genotypes has suggested that the HLA alleles DRB11302 and DQB10609 may be genetic markers for aspirin - induced urticaria / angioedema . A polymorphism study that examined nine single - nucleotide polymorphisms of five leukotriene - related genes [ P09917 ( encoding P09917 ) , P20292 ( P09917 - activating protein ) , P35354 ( cyclooxygenase 2 ) , Q16873 ( leukotriene C4 synthase ) , and Q9Y271 ( cysteinyl leukotriene receptor 1 ) ] found that promoter polymorphisms of P09917 ( - 1708A > G ) and Q9Y271 ( - 634C > T ) were significantly different between aspirin - intolerant asthma and aspirin - induced urticaria / angioedema , suggesting different contributions to the lipoxygenase pathway . A second polymorphism study , conducted on histamine - related genes , did not find any significant associations with aspirin - induced urticaria / angioedema for the genes P50135 ( encoding histamine N - methyltransferase ) , P35367 or P25021 ( encoding histamine receptor types 1 and 2 respectively ) , or the gene encoding high - affinity IgE receptor Ibeta ( FcepsilonRIbeta ) ; however , the FcepsilonRIalpha gene promoter polymorphism was significantly associated with aspirin - induced urticaria / angioedema . This finding has been supported by in vitro functional studies . SUMMARY : The HLA alleles DRB11302 and DQB10609 , and the P09917 and FcepsilonRIalpha promoter polymorphisms , may contribute to the pathogenesis of aspirin - induced urticaria / angioedema . Further investigation to identify candidate genetic markers would help to elucidate the pathogenic mechanism of this condition .",
"Administration of P15692 receptor tyrosine kinase inhibitor increases P15692 production causing angiogenesis in human small - cell lung cancer xenografts . Angiogenesis is mediated mainly by vascular endothelial growth factor ( P15692 ) , and P15692 causes rapid growth in cancers , including human small - cell lung cancer ( SCLC ) . The anti - angiogenic strategy of treating cancer using P15692 receptor ( VEGFR ) inhibition is currently of great interest . We tested the effects of the P35968 tyrosine kinase inhibitor ( TKI ) vandetanib on the proliferation of two kinds of SCLC cell lines : SBC - 1 cells , with detectable P35968 expression and MS - 1 - L cells , without detectable P35968 expression . To evaluate the anti - tumor and anti - angiogenic effects of vandetanib in vivo , we grafted SBC - 1 and MS - 1 - L cells into mice . After a 3 - week treatment , we measured the tumor size and histologically evaluated necrosis and apoptosis using H & E and TUNEL staining , respectively . The microvessels in the xenografts were also quantified by immunostaining of CD31 . DB05294 did not affect the proliferation of SBC - 1 cells , but stimulated the growth of MS - 1 - L cells . In the SCLC xenograft model , vandetanib inhibited growth and tumor angiogenesis in a dose - dependent manner in SBC - 1 xenografts . DB05294 inhibited the growth of MS - 1 - L xenografts at a low dose ( < 12 . 5 mg / kg / day ) , but it did not affect tumor size or change microvessel counts at a higher dose . Interestingly , secretion of P15692 increased significantly in the MS - 1 - L cell line in the presence of a high dose of vandetanib in vitro . The effects of vandetanib on tumor angiogenesis were different in SBC - 1 and MS - 1 - L cell lines . Production of angiogenic factors such as P15692 by the tumor potentially stimulates tumor angiogenesis and results in the acquisition of resistance to VEGFR TKI .",
"Antitumor effects of DB05294 on head and neck squamous cell carcinoma . Angiogenesis is required for tumor growth and metastasis and , therefore , represents a target for cancer treatment . While many factors have been implicated in promoting angiogenesis , vascular endothelial growth factor ( P15692 ) plays a key role in tumor angiogenesis . DB05294 is a potent P15692 receptor - 2 ( P35968 ) tyrosine kinase inhibitor which also has activity against the epidermal growth factor receptor ( P00533 ) tyrosine kinase . The purpose of this study was to investigate the sensitivity of head and neck squamous cell carcinoma ( HNSCC ) cell lines to DB05294 , and to evaluate its antitumor efficacy on HNSCC xenografts . This is the first demonstration of antitumor effects of DB05294 on HNSCC . In vitro DB05294 displayed antiproliferative effects on HNSCC cells and inhibition of P35968 and P00533 pathways . In vivo DB05294 displayed antitumor activity , induced apoptosis and antiangiogenic activity on nude mice bearing an established xenograft of YCU - H891 cells . These results suggest that DB05294 has the potential to inhibit two key pathways in tumor growth via inhibition of P15692 - dependent tumor angiogenesis and via inhibition of P00533 - dependent tumor cell proliferation .",
"Use of dynamic contrast - enhanced Q9BWK5 to evaluate acute treatment with DB05294 , a P15692 signalling inhibitor , in PC - 3 prostate tumours . Dynamic contrast - enhanced magnetic resonance imaging ( DCE - Q9BWK5 ) , using gadopentetate dimeglumine , was used to monitor acute effects on tumour vascular permeability following inhibition of vascular endothelial growth factor - A ( P15692 ) signal transduction . Mice bearing PC - 3 human prostate adenocarcinoma xenografts were treated with DB05294 , a P15692 receptor - 2 ( P35968 ) tyrosine kinase inhibitor . The pharmacokinetic parameter K ( trans ) was obtained , which reflects vascular permeability and perfusion . Mice were imaged immediately before , and following , acute treatment with DB05294 ( 12 . 5 - 100 mg x kg (- 1 ) orally ) . Whole tumours were analysed to obtain mean K ( trans ) values , and a histogram approach was used to examine intratumour heterogeneity . Reproducibility of K ( trans ) measurements gave inter - and intra - animal coefficients of variation of 40 and 18 % , respectively . Dose - related reductions in K ( trans ) were evident following acute DB05294 treatment . A K ( trans ) reduction of approximately 30 % ( P < 0 . 001 ) was evident with 50 and 100 mg x kg (- 1 ) DB05294 , a reduction of 12 . 5 % ( P < 0 . 05 ) at 25 mg x kg (- 1 ) , and a reduction that did not reach statistical significance at 12 . 5 mg kg (- 1 ) . A correlation between this dose response and the growth inhibitory effect of DB05294 following chronic treatment was also observed . The histogram analysis of the data indicated that DB05294 - induced a K ( trans ) reduction in both the most enhancing rim and the core of PC - 3 tumours . Dynamic contrast - enhanced magnetic resonance imaging may have a role in assessing the acute effects of P15692 signalling inhibition , in clinical dose - ranging studies .",
"Modulatory effects of heparin and short - length oligosaccharides of heparin on the metastasis and growth of LMD MDA - MB 231 breast cancer cells in vivo . Expression of the chemokine receptor P61073 allows breast cancer cells to migrate towards specific metastatic target sites which constitutively express P48061 . In this study , we determined whether this interaction could be disrupted using short - chain length heparin oligosaccharides . Radioligand competition binding assays were performed using a range of heparin oligosaccharides to compete with polymeric heparin or heparan sulphate binding to I ( 125 ) P48061 . DB01109 dodecasaccharides were found to be the minimal chain length required to efficiently bind P48061 ( 71 % inhibition ; P < 0 . 001 ) . These oligosaccharides also significantly inhibited P48061 - induced migration of P61073 - expressing LMD MDA - MB 231 breast cancer cells . In addition , heparin dodecasaccharides were found to have less anticoagulant activity than either a smaller quantity of polymeric heparin or a similar amount of the low molecular weight heparin pharmaceutical product , ___MASK47___ . When given subcutaneously in a SCID mouse model of human breast cancer , heparin dodecasaccharides had no effect on the number of lung metastases , but did however inhibit ( P < 0 . 05 ) tumour growth ( lesion area ) compared to control groups . In contrast , polymeric heparin significantly inhibited both the number ( P < 0 . 001 ) and area of metastases , suggesting a differing mechanism for the action of polymeric and heparin - derived oligosaccharides in the inhibition of tumour growth and metastases .",
"Targeting angiogenesis : a review of angiogenesis inhibitors in the treatment of lung cancer . It has now been almost 30 years since Dr J . Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer ; however , it is only recently that anti - angiogenesis agents have entered the clinical setting . The search for novel therapies is particularly important in lung cancer , where the majority of patients succumb to their disease despite aggressive treatments . Several classes of agents now exist that target the different steps involved in angiogenesis . These include drugs inhibiting matrix breakdown , the matrix metalloproteinase inhibitors ( MMPIs ) , such as marimastat , prinomastat , BMS275291 , BAY12 - 9566 , and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor ( P15692 ) and its receptor ( VEGFR ) including rhuMAb P15692 , SU5416 , SU6668 , DB05294 , CP - 547 , 632 and ZD4190 . Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin , angiostatin and interferons . There has also been renewed interest in thalidomide . Drugs such as squalamine , celecoxib , ZD6126 , TNP - 470 and those targeting the integrins are also being evaluated in lung cancer . Despite early enthusiasm for many of these agents , Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue . It is hoped that as our understanding of the complex process of angiogenesis increases , so will our ability to design more effective targeted therapies .",
"DB09280 - ___MASK28___ in Patients with Cystic Fibrosis Homozygous for Phe508del P13569 .",
"___MASK3___ enhances antigen - specific IgE and Th2 cytokine production . BACKGROUND : Treatment with anti - ulcer drugs has been shown to enhance IgE production against food antigens . However , little is known about the immunological effects of cimetidine , a histamine receptor type 2 ( P25021 ) antagonist that is widely used as an anti - ulcer drug , in allergy . Therefore , the present study investigated the role of cimetidine in Th2 immune responses in mice . METHODS : BALB / c mice were immunized intraperitoneally with ovalbumin ( OVA ) with and without cimetidine . The levels of cytokines in supernatants of spleen cells cultured in the presence of OVA for 4 days and the levels of total and OVA - specific IgG ( 1 ) , IgG ( 2a ) and / or IgE in sera from these mice were determined by ELISA . RESULTS : Administration of cimetidine to OVA - sensitized BALB / c mice promoted Th2 cytokine secretion by OVA - stimulated spleen cells in vitro and increased serum levels of OVA - specific IgE , IgG ( 1 ) and IgG ( 2a ) . CONCLUSIONS : These results indicate that cimetidine can enhance Th2 responses , suggesting that cimetidine may contribute to IgE production in allergies .",
"The tyrosine kinase inhibitor DB05294 blocks proliferation of P07949 mutant medullary thyroid carcinoma cells . Oncogenic conversion of the P07949 tyrosine kinase is a frequent feature of medullary thyroid carcinoma ( P04629 ) . DB05294 ( vandetanib ) is an DB00171 - competitive inhibitor of P07949 , epidermal growth factor receptor ( P00533 ) , and vascular endothelial growth factor receptors kinases . In this study , we have studied DB05294 mechanism of action in TT and MZ - CRC - 1 human P04629 cell lines , carrying cysteine 634 to tryptophan ( C634W ) and methionine 918 to threonine ( M918T ) P07949 mutation respectively . DB05294 blunted P04629 cell proliferation and P07949 , Shc and Q8TCB0 / Q8NFH3 mitogen - activated protein kinase ( MAPK ) phosphorylation . Single receptor knockdown by RNA interference showed that P04629 cells depended on P07949 for proliferation . Adoptive expression of the DB05294 - resistant V804M P07949 mutant rescued proliferation of TT cells under DB05294 treatment , showing that P07949 is a key DB05294 target in these P04629 cells . Upon P07949 inhibition , adoptive stimulation of P00533 partially rescued TT cell proliferation , MAPK signaling , and expression of cell - cycle - related genes . This suggests that simultaneous inhibition of P07949 and P00533 by DB05294 may overcome the risk of P04629 cells to escape from P07949 blockade through compensatory over - activation of P00533 .",
"Identification of a variant in P35968 associated with serum P35968 and pharmacodynamics of ___MASK100___ . PURPOSE : P15692 receptor ( VEGFR ) kinases are important drug targets in oncology that affect function of systemic endothelial cells . To discover genetic markers that affect VEGFR inhibitor pharmacodynamics , we performed a genome - wide association study of serum soluble vascular P35968 concentrations [ sVEGFR2 ] , a pharmacodynamic biomarker for P35968 inhibitors . EXPERIMENTAL DESIGN : We conducted a genome - wide association study ( GWAS ) of [ sVEGFR2 ] in 736 healthy Old Order Amish volunteers . Gene variants identified from the GWAS were genotyped serially in a cohort of 128 patients with advanced solid tumor with baseline [ sVEGFR2 ] measurements , and in 121 patients with renal carcinoma with [ sVEGFR2 ] measured before and during pazopanib therapy . RESULTS : rs34231037 ( C482R ) in P35968 , the gene encoding sVEGFR2 was found to be highly associated with [ sVEGFR2 ] , explaining 23 % of the variance ( P = 2 . 7 × 10 (- 37 ) ) . Association of rs34231037 with [ sVEGFR2 ] was replicated in 128 patients with cancer with comparable effect size ( P = 0 . 025 ) . Furthermore , rs34231037 was a significant predictor of changes in [ sVEGFR2 ] in response to pazopanib ( P = 0 . 01 ) . CONCLUSION : Our findings suggest that genome - wide analysis of phenotypes in healthy populations can expedite identification of candidate pharmacogenetic markers . Genotyping for germline variants in P35968 may have clinical utility in identifying patients with cancer with unusual sensitivity to effects of P35968 kinase inhibitors .",
"Targeted molecular therapy of head and neck squamous cell carcinoma with the tyrosine kinase inhibitor vandetanib in a mouse model . BACKGROUND : We investigated the effects of vandetanib , an inhibitor of vascular endothelial growth factor receptor 2 ( P35968 ) and epidermal growth factor receptor ( P00533 ) , alone and in combination with paclitaxel in an orthotopic mouse model of human head and neck squamous cell carcinoma ( HNSCC ) . METHODS : The in vitro effects of vandetanib ( ZACTIMA ) were assessed in 2 HNSCC cell lines on cell growth , apoptosis , receptor and downstream signaling molecule expression , and phosphorylation levels . We assessed in vivo effects of vandetanib and / or paclitaxel by measuring tumor cell apoptosis , endothelial cell apoptosis , microvessel density , tumor size , and animal survival . RESULTS : In vitro , vandetanib inhibited the phosphorylation of P00533 and its downstream targets in HNSCC cells and inhibited proliferation and induced apoptosis of HNSCC cells and extended survival and inhibited tumor growth in nude mice orthotopically injected with human HNSCC . CONCLUSION : DB05294 has the potential to be a novel molecular targeted therapy for HNSCC .",
"Potent antitumor efficacy of interleukin - 18 delivered by conditionally replicative adenovirus vector in renal cell carcinoma - bearing nude mice via inhibition of angiogenesis . It has been demonstrated that interleukin 18 ( Q14116 ) exerts antitumor activity . In this study , we investigated whether oncolytic adenovirus - mediated gene transfer of Q14116 could induce strong antitumor activity . A tumor - selective replicating adenovirus expressing Q14116 ( ZD55 - Q14116 ) was constructed by insertion of an Q14116 expression cassette into the ZD55 vector , which is based on deletion of the adenoviral E1B 55 - kDa gene . ZD55 - Q14116 could express substantially more Q14116 than Ad - Q14116 because of replication of the vector . It has been shown that ZD55 - Q14116 exerted a strong cytopathic effect and significant apoptosis in renal cell carcinoma . ZD55 - Q14116 significantly decreased P15692 and P28906 expression in the tumor cells . Treatment of established tumors with ZD55 - Q14116 showed much stronger antitumor activity than that induced by ZD55 - EGFP or Ad - Q14116 . These data indicated that oncolytic adenovirus expressing Q14116 could exert potential antitumor activity via inhibition of angiogenesis and offer a novel approach to cancer therapy .",
"Targeted therapy against VEGFR and P00533 with DB05294 enhances the therapeutic efficacy of irradiation in an orthotopic model of human non - small - cell lung cancer . PURPOSE : Conventional therapies for patients with lung cancer have reached a therapeutic plateau . We therefore evaluated the feasibility of combined vascular endothelial growth factor ( P15692 ) receptor 2 ( P35968 ) and epidermal growth factor ( P01133 ) receptor ( P00533 ) targeting with radiation therapy in an orthotopic model that closely recapitulates the clinical presentation of human lung cancer . METHODS AND MATERIALS : Effects of irradiation and / or DB05294 , a small - molecule inhibitor of P35968 and P00533 tyrosine kinases , were studied in vitro for human lung adenocarcinoma cells by using proliferation and clonogenic assays . The feasibility of combining DB05294 with radiation therapy was then evaluated in an orthotopic model of human lung adenocarcinoma . Lung tumor burden and spread within the thorax were assessed , and tumor and adjacent tissues were analyzed by means of immunohistochemical staining for multiple parameters , including CD31 , P15692 , P35968 , P01133 , P00533 , matrix metalloproteinase - 2 and - 9 , and basic fibroblast growth factor . RESULTS : DB05294 enhanced the radioresponse of NCI - H441 human lung adenocarcinoma cells by a factor of 1 . 37 and markedly inhibited sublethal damage repair . In vivo , the combined blockade of P35968 and P00533 by DB05294 blocked pleural effusion formation and angiogenesis and enhanced the antivascular and antitumor effects of radiation therapy in the orthotopic human lung cancer model and was superior to chemoradiotherapy . CONCLUSIONS : When radiation therapy is combined with P35968 and P00533 blockade , significant enhancement of antiangiogenic , antivascular , and antitumor effects are seen in an orthotopic model of lung cancer . These data provide support for clinical trials of biologically targeted and conventional therapies for human lung cancer .",
"Tyrosine kinase blockers : new hope for successful cancer therapy . Tyrosine kinases ( TKs ) are attractive targets for cancer therapy , as quite often their abnormal signaling has been linked with tumor development and growth . Constitutive activated TKs stimulate multiple signaling pathways responsible for DNA repair , apoptosis , and cell proliferation . During the last few years , thorough analysis of the mechanism underlying tyrosine kinase ' s activity led to novel cancer therapy using TKs blockers . These drugs are remarkably effective in the treatment of various human tumors including head and neck , gastric , prostate and breast cancer and leukemias . The most successful example of kinase blockers is Imatinib ( Imatinib mesylate , Gleevec , STI571 ) , the inhibitor of Bcr / Abl oncoprotein , which has become a first - line therapy for chronic myelogenous leukemia . The introduction of STI571 for the treatment of leukemia in clinical oncology has had a dramatic impact on how this disease is currently managed . Others kinase inhibitors used recently in cancer therapy include Dasatinib ( BMS - 354825 ) specific for P00519 non - receptor cytoplasmic kinase , Gefitinib ( DB00317 ) , Erlotinib ( DB00530 , Tarceva ) and DB01268 ( SU 11248 , Sutent ) specific for P15692 receptor kinase , AMN107 ( DB04868 ) and INNO - 406 ( NS - 187 ) specific for c - P10721 kinase . The following TK blockers for treatment of various human tumors are in clinical development : DB01259 ( DB01259 ditosylate , DB01259 , GW - 572016 ) , Canertinib ( DB05424 ) , DB05294 ( DB05294 ) , DB04879 ( PTK787 / ZK 222584 ) , DB00398 ( Bay 43 - 9006 , Nexavar ) , and Leflunomide ( SU101 , DB01097 ) . Herein , we discuss the chemistry , biological activity and clinical potential of new drugs with tyrosine kinase blockers for cancer treatment .",
"___MASK3___ induces interleukin - 18 production through H2 - agonist activity in monocytes . The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients ' prognosis by the histamine receptor type 2 ( P25021 ) antagonist cimetidine . This agent , but not the P25021 antagonists ranitidine and famotidine , induced the production of an antitumor cytokine , interleukin ( IL ) - 18 , by human monocytes and dendritic cells ( DC ) . In fact , ranitidine and famotidine antagonized cimetidine - induced Q14116 production . ___MASK3___ induced the activation of caspase - 1 , which is reported to modify immature Q14116 to mature / active Q14116 , and the elevation of intracellular DB02527 , leading to the activation of protein kinase A ( PKA ) . The PKA inhibitor H89 abolished the Q14116 production induced by cimetidine . Moreover , the effects of cimetidine on Q14116 production were reproduced in peripheral blood mononuclear cells from wild - type mice , but not in those from P25021 knockout mice . In conclusion , cimetidine , a partial agonist for P25021 , has a pharmacological profile different from ranitidine and famotidine , possibly contributing to its antitumor activity on gastrointestinal cancers .",
"DB05294 -- clinical experience to date . DB05294 selectively targets two key pathways in tumour growth by inhibiting vascular endothelial growth factor ( P15692 ) - dependent tumour angiogenesis and epidermal growth factor ( P01133 ) - dependent tumour cell proliferation and survival . Phase I clinical evaluation has shown DB05294 to be generally well tolerated , with a pharmacokinetic profile appropriate for once - daily oral dosing . Phase II evaluation of DB05294 at doses of 100 - 300 mg is ongoing in a range of patient types in single and combination regimens . These include three randomised studies of patients with non - small - cell lung cancer . In one of these trials , the efficacy of DB05294 monotherapy is being compared with that of the P01133 receptor tyrosine kinase inhibitor gefitinib ( DB00317 ) in previously treated patients . In the other two trials , the efficacy of DB05294 in combination with certain standard chemotherapy regimens is being compared with that of standard chemotherapy alone : one with carboplatin and paclitaxel in previously untreated patients , and the second with docetaxel in patients who progressed after platinum - containing therapy . The advent of novel molecular - targeted agents such as DB05294 has necessitated a re - evaluation of conventional cancer study design in order to optimise appraisal of this new generation of anticancer agents . The specific considerations of the DB05294 clinical programme are discussed .",
"Antitumor activity of DB05294 , a vascular endothelial growth factor - 2 and epidermal growth factor receptor small molecule tyrosine kinase inhibitor , in combination with SC - 236 , a cyclooxygenase - 2 inhibitor . PURPOSE : The epidermal growth factor receptor ( P00533 ) autocrine pathway plays an important role in cancer cell growth . Vascular endothelial growth factor ( P15692 ) is a key regulator of tumor - induced endothelial cell proliferation and vascular permeability . Enhanced cyclooxygenase - 2 ( P35354 ) expression has been linked to cancer cell proliferation , P00533 activation , P15692 secretion , and tumor - induced angiogenesis . DB05294 is an orally available , small molecule , dual P15692 receptor - 2 ( P35968 ) and P00533 tyrosine kinase inhibitor . We investigated the activity of DB05294 in combination with SC - 236 , a selective P35354 inhibitor , to determine the antitumor activity of the simultaneous blockade of P00533 , P35354 , and P15692 functions . EXPERIMENTAL DESIGN : The antitumor activity in vitro and in vivo of DB05294 and / or SC - 236 was tested in human cancer cell lines with a functional P00533 autocrine pathway . RESULTS : The combination of DB05294 and SC - 236 determined supra - additive growth inhibition in all cancer cell lines tested . In nude mice bearing established human colon ( GEO ) or lung adenocarcinoma ( A549 ) cancer xenografts and treated with DB05294 and / or SC - 236 for 3 weeks , a reversible tumor growth inhibition was seen with each agent , whereas a more prolonged growth inhibition that lasted for 3 to 5 weeks following the end of treatment resulted from the combination of the two agents . A long - term , 10 - week treatment with DB05294 plus SC - 236 resulted in sustained tumor growth inhibition in all mice with tumor eradication in 3 of 10 GEO tumor - bearing mice and in 4 of 10 A549 tumor - bearing mice . CONCLUSIONS : This study provides a rationale for evaluating the simultaneous blockade of P00533 , P35354 , and P15692 signaling as cancer therapy in a clinical setting .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"Inhibition of the liver expression of arylalkylamine N - acetyltransferase increases the expression of angiogenic factors in cholangiocytes . BACKGROUND AND AIMS : Reduction of biliary serotonin N - acetyltransferase ( Q16613 ) expression and melatonin administration / secretion in cholangiocytes increases biliary proliferation and the expression of SR , P13569 and Cl (-)/ HCO3 ( - ) P04920 . The balance between biliary proliferation / damage is regulated by several autocrine neuroendocrine factors including vascular endothelial growth factor - A / C ( P15692 / C ) . VEGFs are secreted by several epithelia , where they modulate cell growth by autocrine and paracrine mechanisms . No data exists regarding the effect of Q16613 modulation on the expressions of VEGFs by cholangiocytes . METHODS : In this study , we evaluated the effect of local modulation of biliary Q16613 expression on the cholangiocytes synthesis of P15692 / C . RESULTS : The decrease in Q16613 expression and subsequent lower melatonin secretion by cholangiocytes was associated with increased expression of P15692 / C . Overexpression of Q16613 in cholangiocyte lines decreased the expression of P15692 / C . CONCLUSIONS : Modulation of melatonin synthesis may affect the expression of P15692 / C by cholangiocytes and may modulate the hepatic microvascularization through the regulation of P15692 / C expression regulating biliary functions .",
"Stage - dependent inhibition of Plasmodium falciparum by potent Ca2 + and calmodulin modulators . The effects of Ca2 + channel blockers , verapamil , nicardipine and diltiazem , and of potent calmodulin ( P62158 ) inhibitors , trifluoperazine ( Q9HCM9 ) , calmidazolium , W - 7 and W - 5 , on Plasmodium falciparum in culture were examined . Among Ca2 + blockers , nicardipine was the most potent with the 50 % inhibitory concentration ( IC50 ) of 4 . 3 microM at 72 h after culture . Parasites were more sensitive to calmidazolium and W - 7 with IC50 of 3 . 4 and 4 . 5 microM , respectively , than to Q9HCM9 and W - 5 . All Ca2 + blockers and P62158 inhibitors suppressed parasite development at later stages . ___MASK6___ , diltiazem , calmidazolium and W - 5 also retarded parasite development at earlier stages and / or subsequent growth following pretreatment . Verapamil , nicardipine , Q9HCM9 and calmidazolium reduced erythrocyte invasion by merozoites . Fluorescence microscopy with the cationic fluorescent dye rhodamine 123 revealed that nicardipine , Q9HCM9 and calmidazolium depolarized both the plasma membrane and mitochondrial membrane potentials of the parasite . It is therefore considered that although all Ca2 + and P62158 antagonists tested here influence parasite development at later stages , they are multifunctional , having effects not directly associated with Ca2 + channels or P62158 ."
] |
[
"___MASK100___",
"___MASK28___",
"___MASK30___",
"___MASK3___",
"___MASK47___",
"___MASK6___",
"___MASK76___",
"___MASK89___",
"___MASK93___"
] |
___MASK100___
|
MH_train_490
|
interacts_with DB06681?
|
[
"Suppressing T cell motility induced by anti - P16410 monotherapy improves antitumor effects . A promising strategy for cancer immunotherapy is to disrupt key pathways regulating immune tolerance , such as cytotoxic T lymphocyte - associated protein 4 ( P16410 ) . However , the determinants of response to anti - P16410 mAb treatment remain incompletely understood . In murine models , anti - P16410 mAbs alone fail to induce effective immune responses to poorly immunogenic tumors but are successful when combined with additional interventions , including local ionizing radiation ( IR ) therapy . We employed an established model based on control of a mouse carcinoma cell line to study endogenous tumor - infiltrating CD8 + T lymphocytes ( TILs ) following treatment with the anti - P16410 mAb 9H10 . Alone , 9H10 monotherapy reversed the arrest of TILs with carcinoma cells in vivo . In contrast , the combination of 9H10 and IR restored MHC class I - dependent arrest . After implantation , the carcinoma cells had reduced expression of retinoic acid early inducible - 1 ( RAE - 1 ) , a ligand for natural killer cell group 2D ( P26718 ) receptor . We found that RAE - 1 expression was induced by IR in vivo and that anti - P26718 mAb blocked the Q15399 arrest induced by IR / 9H10 combination therapy . These results demonstrate that anti - P16410 mAb therapy induces motility of Q15399 and that P26718 ligation offsets this effect to enhance TILs arrest and antitumor activity .",
"DB11320 reduces susceptibility to natural killer cells via down - regulation of P26718 ligands on human monocytic leukaemia THP - 1 cells . Natural killer ( NK ) group 2D ( P26718 ) is a key activating receptor expressed on NK cells , whose interaction with ligands on target cells plays an important role in tumorigenesis . However , the effect of histamine on P26718 ligands on tumour cells is unclear . Here we showed that human monocytic leukaemia THP - 1 cells constitutively express MHC class I - related chain A ( Q29983 ) and Q9BZM6 on their surface , and incubation with histamine reduced the expression in a dose - dependent and time - dependent manner as assessed by flow cytometry . Interferon - γ augmented the surface expression of the P26718 ligands , and this augmentation was significantly attenuated by histamine . The histamine H1 receptor ( P35367 ) agonist 2 - pyridylethylamine and P25021 agonist dimaprit down - regulated the expression of P26718 ligands , and activation of P35367 and P25021 signalling by A23187 and forskolin , respectively , had the same effect , indicating that the histamine - induced down - regulation of P26718 ligands is mediated by P35367 and P25021 . Quantitative reverse transcription - PCR showed that mRNA levels of the P26718 ligands and relevant microRNAs were not significantly changed by histamine . DB11320 down - regulated the surface expression of endoplasmic reticulum protein 5 , and inhibition of matrix metalloproteinases did not impair this down - regulation , indicating that proteolytic shedding was not involved . Instead , pharmacological inhibition of protein transport and proteasome abrogated it , and histamine enhanced ubiquitination of Q29983 . Furthermore , histamine treatment significantly reduced susceptibility to NK cell - mediated cytotoxicity . These results suggest that histamine down - regulates P26718 ligands through the activation of an P35367 - and P25021 - mediated ubiquitin - proteasome pathway and consequently reduces susceptibility to NK cells .",
"Haemostasis unbalance in Pugh - scored liver cirrhosis : characteristic changes of plasma levels of protein C versus protein S . Liver cirrhosis leads to a protido - synthetic impairment that alters the levels of blood clotting factors and haemostasis . The aim of this study was to assess the alterations of haemostatic parameters in the evolution of liver cirrhosis scored according to Child ' s classification , with Pugh ' s modifications . Thirty - seven patients suffering from alcoholic and non - alcoholic liver cirrhosis , representing stages A5 , A6 , P33681 , B8 and Q99622 , were tested for the main blood clotting parameters , i . e . prothrombin time , factor VII , partial activated thromboplastin time , fibrinogen , plasminogen , alpha 2 - antiplasmin and physiological inhibitors [ antithrombin III ( P01008 ) , protein C ( PC ) , protein S ( PS ) ] . No variations were observed between substages A5 and A6 in any of the parameters , except for coagulation inhibitor levels . Most parameters showed a progressive decrease in stages B and C of the disease . The most significant alterations were found in the physiological coagulation inhibitors , with a sharper decrease in PC and AT III level and a lesser decrease in the level of PS through stages A5 and B8 : this evidence could assume an important biological and diagnostic significance .",
"The regulation of rotenone - induced inflammatory factor production by DB00171 - sensitive potassium channel expressed in BV - 2 cells . Our previous studies have demonstrated that activating DB00171 - sensitive potassium channel ( K ( DB00171 ) channel ) , not only improved Parkinsonian behavior and neurochemical symptoms , but also reduced P35228 activity and mRNA levels in striatum and nigra of rotenone rat model of Parkinson ' s disease ( PD ) . In this study , it was first shown that the subunits of K ( DB00171 ) channels are expressed in BV - 2 cells , and then it was investigated whether K ( DB00171 ) channel was involved in regulating inflammatory factor production from BV - 2 cells activated by rotenone . It was found that K ( DB00171 ) channel was expressed in BV - 2 cell and formed by the combination of Kir 6 . 1 and Q09428 2A / 2B . K ( DB00171 ) channel openers ( KCOs ) including pinacidil , diazoxide and iptakalim ( Ipt ) exerted beneficial effects on rotenone - induced morphological alterations of BV - 2 cells , decreased tumor necrosis factor alpha ( P01375 ) production and the expression and activity of inducible isoform of nitric oxide synthase ( P35228 ) . Either glibenclamide or 5 - hydroxydecanoate acid ( a selective mitochondrial K ( DB00171 ) channel blocker ) could abolish the effects of KCOs , suggesting that K ( DB00171 ) channels , especially mitochondrial DB00171 - sensitive potassium channels ( mitoK ( DB00171 ) channels ) , played a crucial role in preventing the activation of BV - 2 cells , and subsequently the production of a variety of proinflammatory factors . Therefore , activation of K ( DB00171 ) channel might be a new therapeutic strategy for treating neuroinflammatory and neurodegenerative disorders .",
"Viral - induced P10747 loss evokes costimulation independent alloimmunity . BACKGROUND : DB06681 , a P33681 - specific fusion protein , blocks P10747 - P33681 costimulation and prevents kidney allograft rejection . However , it is ineffective in a sizable minority of patients . Although T - cell receptor and P10747 engagement are known to initiate T - cell activation , many human antigen - experienced T - cells lose P10747 , and can be activated independent of P10747 signals . We posit that these cells are central drivers of costimulation blockade resistant rejection ( CoBRR ) and propose that CoBRR might relate to an accumulation of P10747 (-) T - cells resulting from viral antigen exposure . MATERIALS AND METHODS : We infected C57BL / 6 mice with polyomavirus ( a BK virus analog ) , murine cytomegalovirus ( a human cytomegalovirus analog ) , and gammaherpesvirus ( HV68 ; an Epstein - Barr virus analog ) and assessed for P10747 expression relative to mock infection controls . We then used mixed lymphocyte reaction ( P08235 ) assays to assess the alloreactive response of these mice against major histocompatibility complex - mismatched cells . RESULTS : We demonstrated that infection with polyomavirus , murine CMV , and HV68 can induce P10747 downregulation in mice . We showed that these analogs of clinically relevant human viruses enable lymphocytes from infected mice to launch an anamnestic , costimulation blockade resistant , alloreactive response against major histocompatibility complex - mismatched cells without prior alloantigen exposure . Further analysis revealed that gammherpesvirus - induced oligoclonal T - cell expansion is required for the increased alloreactivity . CONCLUSIONS : Virus exposure results in reduced T - cell expression of P10747 , the target of costimulation blockade therapy . These viruses also contribute to increased alloreactivity . Thus , P10747 downregulation after viral infection may play a seminal role in driving CoBRR .",
"Molecular targets and regulators of cardiac hypertrophy . Cardiac hypertrophy is one of the main ways in which cardiomyocytes respond to mechanical and neurohormonal stimuli . It enables myocytes to increase their work output , which improves cardiac pump function . Although cardiac hypertrophy may initially represent an adaptive response of the myocardium , ultimately , it often progresses to ventricular dilatation and heart failure which is one of the leading causes of mortality in the western world . A number of signaling modulators that influence gene expression , apoptosis , cytokine release and growth factor signaling , etc . are known to regulate heart . By using genetic and cellular models of cardiac hypertrophy it has been proved that pathological hypertrophy can be prevented or reversed . This finding has promoted an enormous drive to identify novel and specific regulators of hypertrophy . In this review , we have discussed the various molecular signal transduction pathways and the regulators of hypertrophic response which includes calcineurin , cGMP , NFAT , natriuretic peptides , histone deacetylase , P05231 cytokine family , Gq / P49842 signaling , PI3K , MAPK pathways , Na / H exchanger , DB01367 , polypeptide growth factors , P01160 , NO , P01375 , Q07869 and JAK / P35610 pathway , microRNA , Cardiac angiogenesis and gene mutations in adult heart . Augmented knowledge of these signaling pathways and their interactions may potentially be translated into pharmacological therapies for the treatment of various cardiac diseases that are adversely affected by hypertrophy . The purpose of this review is to provide the current knowledge about the molecular pathogenesis of cardiac hypertrophy , with special emphasis on novel researches and investigations .",
"Human umbilical cord Wharton ' s jelly stem cells : immune property genes assay and effect of transplantation on the immune cells of heart failure patients . Stem cells derived from umbilical cord Wharton ' s jelly ( WJSCs ) are not immunogenic and have immunosuppressive effects . To evaluate the related mechanisms and the effect of transplantation on body immune cells , we examined immune property genes expression in WJSCs and levels of T - lymphocytes subgroups and immunoglobulins ( Ig ) in heart failure ( HF ) patients with and without WJSCs transplantation . WJSCs express immune tolerance genes P13747 , P17693 and P30511 and immunomodulation genes P15692 , TGFβ1 , P14210 , P09601 , IL1β , P05231 , P15018 , LGALS - 1 / 3 / 8 , P23219 / 2 and PTGE , while they do not express immune response - related genes HLA - DR , HLA - DQ , HLA - DP , P33681 , P42081 , P25942 and P29965 . No obvious changes of T - lymphocytes subgroups and plasma IgG / IgM were observed in HF patients with WJSCs transplantation . Our results suggest that the immune properties of WJSCs are due to the expression of immune avoidance and immunomodulation genes in the absence of immune response - related genes . WJSCs are secure in immunological aspects when used as seed cells for cardiac repair .",
"Differential inhibition of autoreactive memory - and alloreactive naive T cell responses by soluble cytotoxic T lymphocyte antigen 4 ( sCTLA4 ) , DB01281 and DB06681 . Cytotoxic T lymphocyte antigen 4 ( P16410 ) is a potent inhibitory co - stimulatory molecule believed to be involved in type 1 diabetes and other autoimmune diseases . An association has been reported of both mRNA expression and serum levels of the soluble splice variant of P16410 ( sCTLA4 ) with type 1 diabetes . Furthermore , recombinant fusion proteins DB01281 and DB06681 have been proposed as therapies for type 1 diabetes . We studied the role of ( s ) P16410 in islet autoimmunity . Binding capacity of the proteins to antigen - presenting cells was determined by flow cytometry in competition and binding assays . Functionality of sCTLA4 as well as the therapeutic inhibitory fusion proteins DB01281 and DB06681 was measured in a dose - response lymphocyte stimulation test , using a panel of diabetes - associated T cell clones reactive to islet autoantigens . As controls , mixed lymphocyte reactions ( P08235 ) were performed to assess functionality of these proteins in a primary alloreactive setting . All three P16410 molecules were able to bind to antigen - presenting cells and inhibit the expression of P33681 / P42081 . sCTLA4 was able to suppress proliferation of different committed autoreactive T cell clones in a dose - dependent manner , whereas DB01281 and DB06681 were not . Conversely , DB01281 and DB06681 , rather than sCTLA4 , were able to suppress naive alloreactive proliferation in a P08235 . Our results indicate a differential role for sCTLA4 , DB01281 and DB06681 proteins in memory versus primary immune responses with implications for efficacy in intervention therapy .",
"DB06681 and sirolimus prolong nonhuman primate renal allograft survival without a requirement for memory T cell depletion . DB06681 is an inhibitor of P10747 / P33681 costimulation that is clinically indicated as a calcineurin inhibitor ( CNI ) alternative in combination with mycophenolate mofetil and steroids after renal transplantation . We sought to develop a clinically translatable , nonlymphocyte depleting , belatacept - based regimen that could obviate the need for both CNIs and steroids . Thus , based on murine data showing synergy between costimulation blockade and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched renal allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on costimulation blockade - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . DB06681 and sirolimus therapy successfully prevented rejection in all animals . Tolerance was not induced , as animals rejected after withdrawal of therapy . The regimen did not deplete T cells . Alefecept did not add a survival benefit to the optimized belatacept and sirolimus regimen , despite causing an intended depletion of memory T cells , and caused a marked reduction in regulatory T cells . Furthermore , alefacept - treated animals had a significantly increased incidence of CMV reactivation , suggesting that this combination overly compromised protective immunity . These data support belatacept and sirolimus as a clinically translatable , nondepleting , CNI - free , steroid - sparing immunomodulatory regimen that promotes sustained rejection - free allograft survival after renal transplantation .",
"Linkage of protein kinase C - beta activation and intracellular interleukin - 2 accumulation in human naive P01730 T cells . A critical role for protein kinase C ( PKC ) in signal transduction events has been well established . Moreover , studies of regulation in PKC levels suggest participation in mediating long - term cellular functions . Protein kinase C - beta ( P05771 ) has been reported to be involved in interleukin - 2 ( P60568 ) synthesis in T lymphocytes . In this study , the role of P05771 in intracellular accumulation of P60568 was investigated using specific inhibitors . Preincubation with two different PKC inhibitors , one specific for classical isotypes ( alpha and beta I ) Go6976 , and one which inhibits both classical and non - classical isotypes , GF109203X , caused a complete block in cytoplasmic P60568 accumulation when naive P01730 T cells were stimulated in the presence of P06729 + P10747 + phorbol myristate acetate ( PMA ) . In contrast , preincubation with up to 1000 ng / ml of cyclosporin A ( DB00091 ) resulted in a reduction in the intracellular P60568 detected , as observed by a decrease in the proportion of positive cells as well as a fall in the mean fluorescence intensity ( MFI ) . DB00091 did not influence P05771 translocation . Flow cytometric assessments of P05771 and its isoforms beta I and beta II correlated with Western blotting analysis and these results were further supported by the use of P05771 - positive ( HUT 78 ) and - negative ( BW5147 ) T - cell lines . Using the specific inhibitors , Go6976 and GF109203X , the findings in this study suggest that activation and translocation of P05771 is critical for accumulation of intracellular P60568 . The influence of DB00091 in reducing but not blocking P60568 synthesis is discussed . PMA - induced down - regulation of the P01730 antigen was observed in the presence of Go6976 and but not GF109203X , suggesting regulation by non - classical PKC isoforms .",
"P52333 activity is necessary for phosphorylation of cytosolic phospholipase A2 and prostaglandin E2 synthesis by macrophages infected with Francisella tularensis live vaccine strain . Francisella tularensis , the causative agent of tularemia , modulates the host immune response to gain a survival advantage within the host . One mechanism of immune evasion is the ability of F . tularensis to induce the synthesis of the small lipid mediator prostaglandin E2 ( DB00917 ) , which alters the host T cell response making the host more susceptible to Francisella growth . DB00917 is synthesized by a tightly regulated biosynthetic pathway following stimulation . The synthesis of DB00917 begins with the liberation of arachidonic acid ( AA ) from membrane phospholipids by cytosolic phospholipase A2 ( P47712 ) . AA is subsequently converted to the unstable intermediate PGH2 by cyclooxygenase - 2 ( P35354 ) , and PGH2 undergoes an isomerization reaction to generate DB00917 . Our objective was to identify F . tularensis - activated host signaling pathways that regulate the activity of the enzymes in the DB00917 - biosynthetic pathway . In this study , we show that P47712 , p38 mitogen - activated protein kinase ( MAPK ) , and P52333 ( P52333 ) signaling are necessary for F . tularensis - induced DB00917 production . Inhibition of P52333 activity reduced the phosphorylation of P47712 and P35354 protein levels . In addition , P52333 regulates P47712 phosphorylation independent of transcription . Moreover , p38 MAPK activity is required for F . tularensis - induced P35354 protein synthesis , but not for the phosphorylation of P47712 . This research highlights a unique signaling axis in which P52333 and p38 MAPK regulate the activity of multiple enzymes of the DB00917 - biosynthetic pathway in macrophages infected with F . tularensis .",
"DB06681 : a new era of immunosuppression ? Q8N1N2 T - cell activation in alloimmunity requires the engagement of several costimulatory molecules . P16410 - Ig and its commercially available fusion proteins , belatacept and abatacept , are used to block P33681 / 86 and promote T - cell tolerance . DB06681 , a higher binding affinity molecule , is currently approved for clinical use in renal transplantation . The results of two Phase III clinical trials showed a similar patient / graft survival , with better renal function at a 3 - year follow - up compared with conventional immunosuppression . There was a higher risk of early rejection and post - transplant lymphoproliferative disorder , especially with EBV - negative patients receiving kidneys from EBV - positive donors . DB06681 - treated groups had a better cardiovascular and metabolic profile . The authors review both preclinical and human studies of P16410 - Igs .",
"Safety and immunogenicity of a V3 loop synthetic peptide conjugated to purified protein derivative in HIV - seronegative volunteers . OBJECTIVES : To develop a peptide - based model for a preventive vaccine for HIV - 1 infection . DESIGN : Phase I trial in HIV - 1 - seronegative volunteers . PARTICIPANTS : Adult healthy subjects HIV - 1 - antibody - seronegative in an enzyme - linked immunosorbent assay , screened for tuberculin [ purified protein derivative ( PPD ) ] reactivity with 2 tuberculin units PPD - administered intradermally . INTERVENTIONS : Submicrogram doses of a PPD conjugate with a peptide of the primary neutralizing domain ( P01160 ) of HIV - 1MN ( PPD - MN - P01160 ) were administered intradermally to tuberculin skin - test - positive and - negative volunteers . RESULTS : Antibodies to the MN - P01160 were measured after two immunizations in 10 out of 11 PPD skin - test - positive volunteers . After the fourth immunization high - affinity antibodies were detected , which persisted for over 1 year . High titers of MN - P01160 - specific immunoglobulin ( Ig ) G and IgA were detected in the serum and saliva of all volunteers tested . Serum antibodies were cross - reactive with P01160 peptide from some other HIV - 1 strains but neutralized only the HIV - 1MN prototype . Human leukocyte antigen ( HLA ) - P33681 - restricted MN - P01160 - specific cytotoxic T lymphocytes ( CTL ) were also detected . CONCLUSIONS : The PPD - MN - P01160 vaccine at submicrogram doses is safe and immunogenic in PPD skin - test - positive healthy adult volunteers . Long lasting humoral immune responses in the serum and saliva were possibly accompanied by HLA - P33681 - restricted CTL responses . This is a vaccine prototype that can be rapidly and inexpensively modified to include other peptide epitopes . It is especially suitable for use in a worldwide multibillion Bacillus Calmette - Guérin ( BCG ) - primed or tuberculosis - exposed population at risk for HIV - 1 infection .",
"[ Use of new non - nephrotoxic immunosuppressive drugs in kidney transplantation , especially after ischemia - reperfusion injury ] . Medium - and long - term renal graft survival depends on 4 main factors : the quality of the harvested graft , ischemia - reperfusion injury during harvesting and re - implantation , rejection , and the nephrotoxicity of certain drugs ( especially immunosuppressants ) used in this setting . The most nephrotoxic immunosuppressive drugs are the anticalcineurins ( cyclosporine A and tacrolimus ) , a class discovered in the late 1970s and currently representing a basic component of all immunosuppressive protocols for solid organ graft recipients . The renal tubular and vascular toxicity of anticalcineurins is due to their immunosuppressive mechanism : they block the calcineurin pathway and thereby prevent transmission of the first signal from the T cell receptor to the nucleus , which normally triggers cytokine synthesis , New non - nephrotoxic immunosuppressants are therefore needed , especially for grafts of poor quality or subject to severe ischemia - reperfusion injury . Attention is turning to \" old \" molecules such as anti - thymocyte globulins , but exciting new immunosuppressants are now appearing . DB00092 is a fusion protein that binds to the immunological synapse - associated molecule P06729 , which normally interacts with LFA - 3 . DB06681 , another fusion protein , blocks the T cell second signal CD 28 - P33681 . 1 / P33681 . 2 . Finally , new chemical agents are being developed , such as sautrasporine , a tyrosine kinase inhibitor , and tofacitinib , a Jak inhibitor .",
"Costimulatory blockade with belatacept in clinical and experimental transplantation - a review . BACKGROUND : Current maintenance immunosuppression agents have been critical to the improved graft and patient survival rates in solid organ transplantation observed over the past decade . However , long - term follow - up has revealed that these agents are associated with troublesome side effects and chronic toxicity , contributing to graft loss and death . OBJECTIVES : Costimulation blockade has long been recognized as an important target for immunomodulation in solid organ transplantation . DB06681 , a high - affinity chimeric fusion protein that binds to P33681 / P42081 on antigen - presenting cells , has shown great promise in renal transplantation and is now in Phase III trials . METHODS : This review explores the development and efficacy of belatacept , compared with currently approved immunosuppressive agents used in transplantation . RESULTS : DB06681 seems to be an effective alternative to current maintenance immunosuppressive therapies , with no apparent end organ toxicity and a minimal side - effect profile . This agent works best when used in combination with therapies that target different pathways of T - cell activation , but the optimal regimen has not yet been identified . Data generated in ongoing clinical trials will be essential in validating previous studies and for further development of belatacept - based combinatorial strategies .",
"Maximizing clinical benefit with trastuzumab . To optimize patient management in breast cancer a number of factors are considered , including hormone receptor and P04626 status . A feasible approach for women with less aggressive , estrogen receptor / P04626 - positive metastatic breast cancer is to consider trastuzumab ( Herceptin ; F . Hoffmann - La Roche , Basel , Switzerland ) combined with endocrine therapy . Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors . In patients with aggressive P04626 - positive metastatic breast cancer , trastuzumab / chemotherapy combination regimens are warranted . When administered first line in combination with a taxane , trastuzumab improves all clinical outcome parameters , including survival , in such patients . ___MASK100___ adds little to the toxicity profile of taxanes , and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone . There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single - agent activity in breast cancer , including capecitabine ( DB01101 ; F . Hoffmann - La Roche ) , gemcitabine , and vinorelbine . ___MASK100___ is also being investigated as part of triplet drug regimens . ___MASK100___ has good single - agent activity in first - line therapy . This is of relevance to women with P04626 - positive disease who are not suitable for , or do not wish to receive , cytotoxic chemotherapy . The benefits noted with trastuzumab - containing regimens were documented in clinical trials where trastuzumab was given until disease progression . A further rationale exists to continue trastuzumab beyond progression . Data from retrospective reviews indicate that this strategy is feasible .",
"___MASK88___ , a selective oral vasopressin V2 receptor antagonist , ameliorates podocyte injury in puromycin aminonucleoside nephrotic rats . BACKGROUND : Proteinuria caused by glomerular disease is characterized by podocyte injury . P30518 antagonists are effective in reducing albuminuria , although their actions on glomerular podocytes have not been explored . The objective of this study was to evaluate the effects of tolvaptan , a selective oral V2 receptor antagonist , on podocytes in a puromycin aminonucleoside ( PAN ) - induced nephrosis rat model . METHODS : Rats were allocated to a control , PAN nephrosis , or tolvaptan - treated PAN nephrosis group ( n = 9 per group ) . Urinary protein excretion and serum levels of total protein , albumin , creatinine , and total cholesterol were measured on day 10 . The influence of tolvaptan on podocytes was examined in renal tissues by immunofluorescence and electron microscopy . RESULTS : PAN induced massive proteinuria and serum creatinine elevation on day 10 , both of which were significantly ameliorated by tolvaptan . Immunofluorescence studies of the podocyte - associated proteins nephrin and podocin revealed granular staining patterns in PAN nephrosis rats . In tolvaptan - treated rats , nephrin and podocin expressions retained their normal linear pattern . Electron microscopy showed foot process effacement was ameliorated in tolvaptan - treated rats . CONCLUSIONS : ___MASK88___ is protective against podocyte damage and proteinuria in PAN nephrosis . This study indicates that tolvaptan exerts a renoprotective effect by affecting podocyte morphology and probably function in PAN nephrosis . ___MASK88___ is a promising pharmacological tool in the treatment of renal edema .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen DB00977 ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( ___MASK20___ ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and ___MASK20___ . EE and Q03001 increased ER - labelled neurons in the ARC and ___MASK20___ . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the ___MASK20___ in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"Neonatal estrogen exposure disrupts uterine development in the postnatal sheep . Postnatal development of the ovine uterus between birth and postnatal day ( P01160 ) 56 involves budding differentiation of the endometrial glandular epithelium from the luminal epithelium ( LE ) followed by extensive coiling and branching morphogenesis of the tubular glands . To determine the short - and long - term effects of estrogen on neonatal ovine uterine development after P01160 14 , neonatal sheep were randomly assigned at birth ( P01160 0 ) to be treated daily with estradiol - 17beta benzoate ( EB ; 0 , 0 . 01 , 0 . 1 , 1 , or 10 microg / kg body weight . d ) during one of two developmental periods ( P01160 14 - 27 or 42 - 55 ) . All ewes were hemiovariohysterectomized at the end of EB treatment on either P01160 28 or 56 , and the remaining uterine horn and ovary removed on P01160 112 . Immediate responses to EB treatment included dose - and age - dependent increases in uterine wet weight , thickness of the endometrium , myometrium , and LE , but decreases in endometrial glands on P01160 28 and 56 . Transient exposure to EB decreased gland number and thickness of the endometrium and LE on P01160 112 but did not affect extrauterine reproductive tract structures . The mechanism of estrogen inhibition of uterine development did not involve effects on cell proliferation . Real - time PCR analyses found that EB exposure disrupted normal patterns of growth factor ( P05019 , P01344 , fibroblast growth factor - 7 , fibroblast growth factor - 10 , and hepatocyte growth factor ) and receptor mRNA expression in the uterus . Transient exposure of the neonatal ewe to estrogens during critical periods specifically alters growth factor networks that perturb normal development of the uterus , leading to permanent alterations in uterine structure and function .",
"DB01645 enhancement of respiratory allergen trimellitic anhydride - induced IgE production by adult B6C3F1 mice following in utero and postnatal exposure . The objective of the present study was to determine if exposure to the phytoestrogen genistein ( GEN ) during immune development had any effects on the production of IgE by adult mice following dermal treatment with trimellitic anhydride ( TMA ) , a respiratory allergen . B6C3F1 mice were exposed to GEN either by feeding at 500 ppm or by gavage ( 20 mg / kg ) for varied periods from gestation day ( GD ) 14 to postnatal day ( P01160 ) 84 . In utero exposure to GEN by feeding increased the production of IgE at P01160 84 in male mice but not in female mice . In male mice , continuous exposure to GEN postnatally diminished the in utero exposure - induced enhancement in serum total IgE production . However , continuous exposure to GEN from GD 14 to P01160 84 was required to increase serum total IgE production in female mice . In utero exposure to GEN by gavage increased the production of IgE at P01160 84 in female mice but not in male mice when the mice were maintained on the NIH - 07 rodent diet in which a medium level of phytoestrogens was present . The enhancement in IgE production after GEN exposure in females but not in males was associated with decreases in the percentages of P01730 (+) CD25 (+) T suppressor cells , and increases in the natural killer ( NK ) cell activity , the basal splenocyte proliferation , the expression of P42081 by B cells , and the production of P60568 and P05112 . Overall , the results demonstrated that GEN differentially modulated the developing immune system in male and female mice , and that more IgE was produced upon exposure to TMA in the adult .",
"Role of histamine receptors in the effects of histamine on the production of reactive oxygen species by whole blood phagocytes . AIMS : The diverse physiological functions of histamine are mediated through distinct histamine receptors . In this study we investigated the role of P25021 and Q9H3N8 in the effects of histamine on the production of reactive oxygen species by phagocytes in whole blood . MAIN METHODS : Changes in reactive oxygen species ( ROS ) production by whole blood phagocytes after treatment with histamine , Q9H3N8 agonists ( 4 - methylhistamine , VUF8430 ) , P25021 agonist ( dimaprit ) and their combinations with Q9H3N8 antagonist ( JNJ10191584 ) and P25021 antagonist ( ranitidine ) were determined using the chemiluminescence ( CL ) assay . To exclude the direct scavenging effects of the studied compounds on the CL response , the antioxidant properties of all compounds were measured using several methods ( TRAP , ORAC , and luminol - HRP - H2O2 based CL ) . KEY FINDINGS : DB11320 , 4 - methylhistamine , VUF8430 and dimaprit inhibited the spontaneous and OZP - activated whole blood CL in a dose - dependent manner . On the other hand , only VUF8430 was able to inhibit PMA - activated whole blood CL . ___MASK84___ , but not JNJ10191584 , completely reduced the effects of histamine , 4 - methylhistamine and dimaprit . The direct scavenging ability of tested compounds was negligible . SIGNIFICANCE : Our results demonstrate that the inhibitory effects of histamine on ROS production in whole blood phagocytes were caused by P25021 . Our results also suggest that Q9H3N8 agonists in concentrations higher than 10 (- 6 ) M may also influence ROS production via binding to P25021 .",
"Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II - dependent thrombin inhibitors : importance of heparin cofactor II . DB01109 ( HEP ) prevents thrombus formation ( TF ) and thrombus growth ( TG ) , by accelerating thrombin ( THR ) inhibition by antithrombin III ( P01008 ) . Recent studies suggest that dermatan sulphate which catalyzes thrombin inhibition by heparin cofactor II ( HCII ) , can inhibit TF and TG as effectively as HEP . This study compared the antithrombotic effects of HEP and another agent , ___MASK7___ ( SLX ) which catalyzes thrombin inhibition by P01008 and HCII simultaneously . TF was induced in rabbit jugular veins , using the stasis / hypercoagulation model . TG was measured as the accretion of 125I - fibrin onto existing thrombi in rabbit jugular veins . HEP and SLX inhibited TF when given in doses of 10 and 5 anti - thrombin U / kg , respectively . SLX ( 16 anti - thrombin U / kg or 260 micrograms / kg ) was more effective than HEP ( 120 anti - thrombin U / kg or 800 micrograms / kg ) in preventing TG when administered either as a bolus or by continuous infusion . These data suggest that agents which accelerate THR inhibition by both P01008 and HCII simultaneously , can inhibit TF and TG with less systemic anticoagulation than comparable antithrombotic doses of HEP .",
"Expression of cyclooxygenase - 2 in urinary bladder in rats with cyclophosphamide - induced cystitis . These studies examined the expression of cyclooxygenase - 2 ( P35354 ) expression in the urothelium and suburothelial space and detrusor from rats treated with cyclophosphamide ( CYP ) to induce acute ( 4 h ) , intermediate ( 48 h ) , or chronic ( 10 - day ) cystitis . Western blot analysis and immunohistochemistry were used to demonstrate P35354 expression . In whole mount preparations of urinary bladder , nerve fibers in the suburothelial plexus , and inflammatory cell infiltrates were characterized for P35354 expression after CYP - induced cystitis . P35354 expression significantly ( P < or = 0 . 01 ) increased in the urothelium + suburothelium and detrusor smooth muscle with acute , intermediate , and chronic ( 10 - day ) CYP - induced cystitis , but expression in urothelium + suburothelium was significantly greater . CYP - induced upregulation of P35354 showed by immunostaining in the urothelium + suburothelium was similar to that observed with Western blot analysis and also demonstrated P35354 inflammatory cell infiltrates ( P42081 + ) and nerve fibers ( A6NDG6 + ) in the suburothelial plexus . Although P35354 expression was significantly ( P < or = 0 . 01 ) increased in detrusor smooth muscle , immunohistochemistry failed to demonstrate an obvious change in P35354 - immunoreactivity ( IR ) in detrusor muscle , but P35354 inflammatory infiltrates were present throughout the detrusor . P35354 - IR nerve fibers exhibited increased density in the suburothelial plexus with acute or chronic CYP - induced cystitis . P35354 - IR macrophages ( P42081 + ) were present throughout the urinary bladder with acute and chronic CYP - induced cystitis . These studies demonstrate cellular targets in the urinary bladder where P35354 inhibitors may act .",
"Human Lung Mast Cell Products Regulate Airway Smooth Muscle P02778 Levels . In asthma , the airway smooth muscle ( P17405 ) produces P02778 which may attract P49682 (+) mast / T cells to it . Our aim was to investigate the effects of mast cell products on P17405 cell P02778 production . P17405 cells from people with and without asthma were stimulated with IL - 1 β , P01375 - α , and / or IFN γ and treated with histamine ( 1 - 100 μ M ) ± chlorpheniramine ( P35367 antagonist ; 1 μ M ) or ranitidine ( P25021 antagonist ; 50 μ M ) or tryptase ( 1 nM ) ± leupeptin ( serine protease inhibitor ; 50 μ M ) , heat - inactivated tryptase , or vehicle for 4 h or 24 h . Human lung mast cells ( MC ) were isolated and activated with IgE / anti - IgE and supernatants were collected after 2 h or 24 h . The supernatants were added to P17405 cells for 48 h and P17405 cell P02778 production detected using ELISA ( protein ) and real - time PCR ( mRNA ) . DB11320 reduced IL - 1 β / P01375 - α - induced P02778 protein , but not mRNA , levels independent of H1 and H2 receptor activation , whereas tryptase and MC 2 h supernatants reduced all cytokine - induced P02778 . Tryptase also reduced P02778 levels in a cell - free system . Leupeptin inhibited the effects of tryptase and MC 2 h supernatants . MC 24 h supernatants contained P01375 - α and amplified IFN γ - induced P17405 cell P02778 production . This is the first evidence that MC can regulate P17405 cell P02778 production and its degradation . Thus MC may regulate airway myositis in asthma .",
"Co - signals in organ transplantation . PURPOSE OF REVIEW : The nonimmune effects of currently used immunosuppressive drugs result in a high incidence of late graft loss due to nephrotoxicity and death . As an immune - specific alternative to conventional immunosuppressants , new biotechnology tools can be used to block the costimulation signal of T - cell activation . RECENT FINDINGS : Many experimental studies , particularly preclinical studies in nonhuman primates , have focused on blocking ' classical ' P33681 / P10747 and P25942 / P29965 pathways , which are critical in primary T - cell activation , but also on new P33681 / P10747 and P01375 / P01375 - R pathways families of costimulatory molecules that can deliver positive or negative costimulation signals to regulate the alloimmune response . SUMMARY : DB06681 is a new fusion protein derived from P16410 - Ig that can be used to prevent acute rejection in renal transplantation instead of calcineurin inhibitors . DB06681 can also prevent acute rejection efficiently in humans and , more interestingly , can improve renal function and cardiovascular risk factors in this population .",
"DB11320 H3 receptors aggravate cerebral ischaemic injury by histamine - independent mechanisms . The role of the histamine H3 receptor ( Q9Y5N1 ) in cerebral ischaemia / reperfusion ( I / R ) injury remains unknown . Here we show that Q9Y5N1 expression is upregulated after I / R in two mouse models . Q9Y5N1 antagonists and Q9Y5N1 knockout attenuate I / R injury , which is reversed by an Q9Y5N1 - selective agonist . Interestingly , P35367 and P25021 antagonists , a histidine decarboxylase ( HDC ) inhibitor and HDC knockout all fail to compromise the protection by Q9Y5N1 blockade . Q9Y5N1 blockade inhibits P42345 phosphorylation and reinforces autophagy . The neuroprotection by Q9Y5N1 antagonism is reversed by 3 - methyladenine and siRNA for Atg7 , and is diminished in Atg5 ⁻/⁻ mouse embryonic fibroblasts . Furthermore , the peptide Tat - Q9Y5N1 ( CT414 - 436 ) , which blocks Q9Y696 binding with H3Rs , or siRNA for Q9Y696 , further increases I / R - induced autophagy and protects against I / R injury . Therefore , Q9Y5N1 promotes I / R injury while its antagonism protects against ischaemic injury via histamine - independent mechanisms that involve suppressing Q9Y5N1 / Q9Y696 binding - activated autophagy , suggesting that Q9Y5N1 inhibition is a therapeutic target for cerebral ischaemia .",
"P25942 activation induces p53 - dependent vascular endothelial growth factor secretion in human multiple myeloma cells . It was previously demonstrated that p53 status in human multiple myeloma ( MM ) cells regulates distinct cell cycle responses to P25942 activation . In this study , the production of vascular endothelial growth factor ( P15692 ) and migration in MM cells triggered by P25942 activation was examined , and the influence of p53 status in regulating this process was determined . Two human MM cell lines that express wild - type p53 at permissive ( 28 degrees C ) and mutant p53 at restrictive ( 37 degrees C ) temperatures were used as a model system . P25942 activation induces a 4 - fold ( RPMI 8226 ) and a 6 - fold ( SV ) increase in P15692 transcripts , respectively , under restrictive , but not permissive , temperatures . P15692 expression is significantly induced after P25942 activation in patient MM cells expressing mutant p53 . Increased P15692 transcripts result in increased protein and secretion levels , as evidenced by immunoblotting and enzyme - linked immunosorbent assay . In a double - chamber transmigration assay , P25942 activation of MM cells induced a 3 - fold ( RPMI 8226 ) and a 5 - fold ( SV ) increase in migration under restrictive , but not permissive , conditions . A 2 - to 8 - fold induction in migration of patient MM cells expressing mutant p53 was similarly observed . Transduction of MM cells with a luciferase reporter under the control of a human P15692 promoter further indicated that P25942 - induced P15692 expression was mediated through a transcriptional control mechanism . Finally , adenovirus - mediated wild - type p53 overexpression down - regulated P25942 - induced P15692 expression and transmigration in MM cells expressing mutant p53 . These studies demonstrate that P25942 induces P15692 secretion and MM cell migration , suggesting a role for P25942 in regulating MM homing and angiogenesis .",
"Mesenchymal stem cells control alloreactive CD8 (+) P10747 (-) T cells . P10747 / P33681 co - stimulation blockade with belatacept prevents alloreactivity in kidney transplant patients . However , cells lacking P10747 are not susceptible to belatacept treatment . As CD8 (+) P10747 (-) T - cells have cytotoxic and pathogenic properties , we investigated whether DB05914 ( O60682 ) are effective in controlling these cells . In mixed lymphocyte reactions ( P08235 ) , O60682 and belatacept inhibited peripheral blood mononuclear cell ( PBMC ) proliferation in a dose - dependent manner . O60682 at O60682 / effector cell ratios of 1 : 160 and 1 : 2 · 5 reduced proliferation by 38 · 8 and 92 · 2 % , respectively . DB06681 concentrations of 0 · 1 μg / ml and 10 μg / ml suppressed proliferation by 20 · 7 and 80 · 6 % , respectively . Both treatments in combination did not inhibit each other ' s function . Allostimulated CD8 (+) P10747 (-) T cells were able to proliferate and expressed the cytolytic and cytotoxic effector molecules granzyme B , interferon ( IFN ) - γ and tumour necrosis factor ( P01375 ) - α . While belatacept did not affect the proliferation of CD8 (+) P10747 (-) T cells , O60682 reduced the percentage of P10747 (-) T cells in the proliferating CD8 (+) T cell fraction by 45 · 9 % ( P = 0 · 009 ) . CD8 (+) P10747 (-) T cells as effector cells in P08235 in the presence of P01730 (+) T cell help gained P10747 expression , an effect independent of O60682 . In contrast , allostimulated P10747 (+) T cells did not lose P10747 expression in P08235 - O60682 co - culture , suggesting that O60682 control pre - existing P10747 (-) T cells and not newly induced P10747 (-) T cells . In conclusion , alloreactive CD8 (+) P10747 (-) T cells that remain unaffected by belatacept treatment are inhibited by O60682 . This study indicates the potential of an O60682 - belatacept combination therapy to control alloreactivity .",
"Challenges and opportunities in targeting the costimulation pathway in solid organ transplantation . Signaling through the costimulatory pathway is critical in the regulation of T cell activation . DB01281 , a selective costimulatory antagonist FDA approved for the treatment of moderate to severe rheumatoid arthritis , binds to P33681 and P42081 on antigen presenting cells , blocking the interaction with P10747 on T cells . DB06681 , a second generation P16410 - Ig with 2 amino acid substitutions , has shown considerable promise in clinical transplantation as part of a maintenance immunosuppression regimen . This review will summarize the role of costimulation in T cell activation , detail the development of costimulation antagonists and highlight the pertinent clinical trials completed and ongoing utilizing belatacept as part of an immunosuppressive regimen in organ transplantation .",
"Generation and Molecular Mapping of a Sequence Characterized Amplified Region Marker Linked with the Bct Gene for Resistance to Beet curly top virus in Common Bean . ABSTRACT A random amplified polymorphic DNA ( RAPD ) marker directly linked ( 0 . 0 cM ) with a resistance gene was identified in a snap bean recombinant inbred population ( Moncayo x Primo ) consisting of 94 F ( 5 : 7 ) recombinant inbred lines that had uniform segregation for disease reaction to Beet curly top virus ( BCTV ) across three field locations . Resistance was conditioned by a single dominant allele tentatively designated Bct . Seven hundred and fifty decamer primers were screened to obtain the linked RAPD marker that was then converted to a sequence characterized amplified region ( P62701 ) marker SAS8 . 1550 . The P62701 mapped within a cluster of resistance genes on linkage group P33681 of the core map . A survey of 103 BCTV - resistant and - susceptible snap and dry bean genotypes was conducted using SAS8 . 1550 . Results showed that the P62701 would be highly useful for marker - assisted selection of Bct in snap and dry bean originating from the Andean gene pool . Marker - assisted selection for Bct will expedite the development of BCTV - resistant cultivars and minimize the need for cumbersome pathogen tests .",
"Five - year safety and efficacy of belatacept in renal transplantation . DB06681 is a first - in - class co - stimulation blocker in development for primary maintenance immunosuppression . A Phase II study comparing belatacept with cyclosporine ( DB00091 ) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured Q92565 at 1 year for belatacept , but the incidence of posttransplantation lymphoproliferative disorder was higher . Here , we present the results for the extension of this trial , which aimed to assess long - term safety and efficacy of belatacept . Seventy - eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving DB00091 completed the long - term extension period . Q92565 remained stable in patients who were receiving belatacept for 5 years , and the incidences of death / graft loss or acute rejection were low . The frequencies of serious infections were 16 % for belatacept and 27 % for DB00091 , and neoplasms occurred in 12 % of each group . No patients who were treated with belatacept and one patient who was treated with DB00091 developed posttransplantation lymphoproliferative disorder during the follow - up period . Serious gastrointestinal disorders occurred more frequently with belatacept ( 12 % belatacept versus 8 % DB00091 ) , and serious cardiac disorders occurred more frequently with DB00091 ( 2 % belatacept versus 12 % DB00091 ) . Pharmacokinetic analyses showed consistent exposure to belatacept over time . P42081 receptor saturation was higher in patients who were receiving belatacept every 4 weeks ( 74 % ) compared with every 8 weeks ( 56 % ) . In conclusion , this study demonstrated high patient persistence with intravenous belatacept , stable renal function , predictable pharmacokinetics , and good safety with belatacept over 5 years .",
"Rational development of DB06681 ( belatacept ) , a high - affinity variant of P16410 - Ig with potent immunosuppressive properties . Current success in organ transplantation is dependent upon the use of calcineurin - inhibitor - based immunosuppressive regimens . Unfortunately , current immunotherapy targets molecules with ubiquitous expression resulting in devastating non - immune side effects . T - cell costimulation has been identified as a new potential immunosuppressive target . The best characterized pathway includes P10747 , its homologue P16410 and their ligands P33681 and P42081 . While an immunoglobulin fusion protein construct of P16410 suppressed rejection in rodents , it lacked efficacy in primate transplant models . In an attempt to increase the biologic potency of the parent molecule a novel , modified version of P16410 - Ig , DB06681 ( belatacept ) , was constructed . Two amino acid substitutions ( L104E and A29Y ) gave rise to slower dissociation rates for both P42081 and P33681 . The increased avidity resulted in a 10 - fold increase in potency in vitro and significant prolongation of renal allograft survival in a pre - clinical primate model . The use of immunoselective biologics may provide effective maintenance immunosuppression while avoiding the collateral toxicities associated with conventional immunsuppressants .",
"T - cell phenotype in protocol renal biopsy from transplant recipients treated with belatacept - mediated co - stimulatory blockade . BACKGROUND : DB06681 is thought to disrupt the interaction between P33681 / 86 and P10747 , thus preventing T - cell activation by blocking the co - stimulatory second signal . However , the consequences on the T - cell profile in human renal transplant cases have not been determined . METHODS : In this study , we analysed intra - graft levels of the mRNAs for Treg ( Q9BZS1 ) , cytotoxic CD8 T cells ( P10144 ) , Th1 ( INFγ , Tbet ) , Th2 ( P23771 ) and Th17 ( RORγt and Q16552 ) in protocol biopsies obtained 12 months after renal transplantation in recipients treated with DB06681 or calcineurin inhibitor ( CNI ) . RESULTS : Only the intra - graft abundance of Q9BZS1 mRNA was significantly lower ( P < 0 . 001 ) in the DB06681 group than the CNI group . Conclusions . These results are in agreement with in vitro data suggesting that P10747 is a major co - stimulatory signal of both Tregs development and peripheral homeostasis but contrast with clinical trials showing a better 1 - year graft function and a lower incidence of chronic allograft nephropathy in patients receiving DB06681 than patients treated with CNI . They suggest that immune benefits induced by DB06681 are not mediated by Treg expansion and that Q9BZS1 is not by itself a prognostic marker of long - term graft function in a non - inflammatory context . These results have to be , however , considered as preliminary since the size of our study population is limited .",
"Biomedical nanoparticles modulate specific P01730 + T cell stimulation by inhibition of antigen processing in dendritic cells . Understanding how nanoparticles may affect immune responses is an essential prerequisite to developing novel clinical applications . To investigate nanoparticle - dependent outcomes on immune responses , dendritic cells ( DCs ) were treated with model biomedical poly ( vinylalcohol )- coated super - paramagnetic iron oxide nanoparticles ( P32926 - SPIONs ) . P32926 - SPIONs uptake by human monocyte - derived DCs ( MDDCs ) was analyzed by flow cytometry ( FACS ) and advanced imaging techniques . Viability , activation , function , and stimulatory capacity of MDDCs were assessed by FACS and an in vitro P01730 + T cell assay . P32926 - SPION uptake was dose - dependent , decreased by lipopolysaccharide ( LPS ) - induced MDDC maturation at higher particle concentrations , and was inhibited by cytochalasin D pre - treatment . P32926 - SPIONs did not alter surface marker expression ( P33681 , Q01151 , P42081 , myeloid / plasmacytoid DC markers ) or antigen - uptake , but decreased the capacity of MDDCs to process antigen , stimulate P01730 + T cells , and induce cytokines . The decreased antigen processing and P01730 + T cell stimulation capability of MDDCs following P32926 - SPION treatment suggests that MDDCs may revert to a more functionally immature state following particle exposure .",
"Costimulation blockade in autoimmunity and transplantation . Signaling through the costimulation receptors is a critical pathway in the regulation of T - cell activation . The selective costimulation inhibitor abatacept ( cytotoxic T lymphocyte - associated antigen 4 - Ig ) binds to P33681 and P42081 on antigen - presenting cells , blocking interaction with P10747 on T cells , and is approved for the treatment of moderate to severe rheumatoid arthritis . DB06681 ( DB06681 ) , currently enrolling phase III trials in renal transplantation , was rationally designed from abatacept to bind with more avidity to P42081 , providing the more potent immunosuppressive properties required for immunosuppression in transplantation . This review describes the relevant preclinical studies and summarizes recent clinical findings on these 2 molecules in autoimmune diseases and organ transplantation . Although both inhibit the P10747 costimulatory pathway , they are tailored for specific disease states -- abatacept for autoimmune diseases and belatacept for transplantation .",
"Technology evaluation : DB06681 , Bristol - Myers Squibb . Bristol - Myers Squibb is developing belatacept , a soluble fusion protein of the P33681 - binding domain of P16410 with amino acid changes A29Y and L104E and an Ig tail , which inhibits lymphocyte co - stimulation through P10747 , for the potential treatment of solid organ transplant rejection . DB06681 is currently undergoing phase III clinical trials .",
"Protective effect of treatment with low - dose gliclazide in a model of middle cerebral artery occlusion and reperfusion in rats . The aim of this study was to explore the expression of sulfonylurea receptor 1 ( Q09428 ) , the regulatory subunit of the NCCa - DB00171 channel , and to investigate the protective effects of gliclazide following middle cerebral artery occlusion ( MCAO ) / reperfusion in male Wistar rats . Adult rats underwent 2h of the left MCAO using the intraluminal thread technique before reperfusion . The core areas of the infarct at different reperfusion time points were examined for the mRNA level and protein expression of Q09428 using reverse transcription - polymerase chain reaction ( RT - PCR ) and western blotting respectively . ___MASK63___ was administered intravenously into the right jugular vein for 12h simultaneously with the reperfusion . The number of apoptotic cells was determined using the TUNEL assay . The neurological functional deficits were evaluated using Bederson ׳ s test , and the cerebral infarction volume was visualized with TTC staining . We found up - regulation of Q09428 mRNA and protein levels in ischemic infarct tissues after reperfusion following MCAO , and Q09428 mRNA and protein were maximally upregulated 8 - 12h after a 2 - hour ischemia . The treatment with low - dose of gliclazide reduced the total number of TUNEL - positive cells , the neurological functional deficits and the brain infarct volume . These results suggest that the Q09428 - regulated NCCa - DB00171 channel may be associated with MCAO / reperfusion injury and the infarct - reducing effects of intravenous treatment with gliclazide may be due , in part , to the blocked upregulation of Q09428 expression , the decreased infarct size and the reduced apoptosis in the ischemia - reperfusion brain .",
"DB06681 and sirolimus prolong nonhuman primate islet allograft survival : adverse consequences of concomitant alefacept therapy . Calcineurin inhibitors ( CNI ) and steroids are known to promote insulin resistance , and their avoidance after islet transplantation is preferred from a metabolic standpoint . DB06681 , a P33681 - specific mediator of costimulation blockade ( CoB ) , is clinically indicated as a CNI alternative in renal transplantation , and we have endeavored to develop a clinically translatable , belatacept - based regimen that could obviate the need for both CNIs and steroids . Based on the known synergy between CoB and P42345 inhibition , we studied rhesus monkeys undergoing MHC - mismatched islet allotransplants treated with belatacept and the P42345 inhibitor , sirolimus . To extend prior work on CoB - resistant rejection , some animals also received P06729 blockade with alefacept ( P19256 - Ig ) . Nine rhesus macaques were rendered diabetic with streptozotocin and underwent islet allotransplantation . All received belatacept and sirolimus ; six also received alefacept . DB06681 and sirolimus significantly prolonged rejection - free graft survival ( median 225 days compared to 8 days in controls receiving basiliximab and sirolimus ; p = 0 . 022 ) . The addition of alefacept provided no additional survival benefit , but was associated with Cytomegalovirus reactivation in four of six animals . No recipients produced donor - specific alloantibodies . The combination of belatacept and sirolimus successfully prevents islet allograft survival in rhesus monkeys , but induction with alefacept provides no survival benefit and increases the risk of viral reactivation .",
"Enhanced goblet cell hyperplasia in HDC knockout mice with allergic airway inflammation . BACKGROUND : DB11320 is known to have immunoregulatory roles in allergic reactions through histamine receptor 1 ( P35367 ) , P25021 , Q9Y5N1 and Q9H3N8 . However , its role in goblet cell hyperplasia in the airways of asthma patients is yet to be clarified . OBJECTIVE : This study was designed to examine the role of histamine in goblet cell hyperplasia using histamine - deficient mice ( Hdc -/- mice ) with allergic airway inflammation . METHODS : Wild - type and Hdc -/- C57BL / 6 mice were sensitized with ovalbumin ( OVA ) . After a 2 - week exposure to OVA , goblet cell hyperplasia was evaluated . Cell differentials and cytokines in BALF were analyzed . The mRNA levels of P98088 and Gob - 5 gene were determined quantitatively . RESULTS : The number of eosinophils in BALF increased in both the sensitized wild - type mice and Hdc -/- mice with OVA inhalation . In addition , the numbers of alveolar macrophages and lymphocytes in BALF increased significantly in the sensitized Hdc -/- mice with OVA inhalation compared to the wild - type mice under the same conditions . The concentrations of P05112 ( P05112 ) , P05113 , P35225 , Interferon - gamma ( P01579 ) , tumor necrosis factor - alpha ( P01375 ) and P60568 in the BALF all increased significantly in both groups compared to those exposed to saline . In particular , the concentration of P01375 in the Hdc -/- mice exposed to OVA was significantly higher than that in the wild - type mice under the same conditions . The mRNA levels of Gob - 5 and P98088 , and the ratio of the goblet cells in the airway epithelium significantly increased in Hdc -/- mice exposed to OVA compared to wild - type mice . CONCLUSIONS : These results suggested that histamine may play a regulatory role in goblet cell hyperplasia in allergic airway inflammation .",
"Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing P04626 . In an attempt to treat cancer patients with P04626 overexpressing tumors , we developed a chimeric antigen receptor ( CAR ) based on the widely used humanized monoclonal antibody ( mAb ) ___MASK100___ ( Herceptin ) . An optimized CAR vector containing P10747 , 4 - 1BB , and CD3zeta signaling moieties was assembled in a gamma - retroviral vector and used to transduce autologous peripheral blood lymphocytes ( PBLs ) from a patient with colon cancer metastatic to the lungs and liver , refractory to multiple standard treatments . The gene transfer efficiency into autologous T cells was 79 % CAR (+) in CD3 (+) cells and these cells demonstrated high - specific reactivity in in vitro coculture assays . Following completion of nonmyeloablative conditioning , the patient received 10 ( 10 ) cells intravenously . Within 15 minutes after cell infusion the patient experienced respiratory distress , and displayed a dramatic pulmonary infiltrate on chest X - ray . She was intubated and despite intensive medical intervention the patient died 5 days after treatment . Serum samples after cell infusion showed marked increases in interferon - gamma ( P01579 ) , granulocyte macrophage - colony stimulating factor ( GM - P04141 ) , tumor necrosis factor - alpha ( P01375 ) , interleukin - 6 ( P05231 ) , and P22301 , consistent with a cytokine storm . We speculate that the large number of administered cells localized to the lung immediately following infusion and were triggered to release cytokine by the recognition of low levels of P04626 on lung epithelial cells .",
"Selective measurement of white matter and gray matter diffusion trace values in normal human brain . The trace of the diffusion tensor ( or simply the trace ) is diagnostically valuable for detecting acute ischemic lesions . A number of studies indicate that the trace of human gray matter ( GM ) and white matter ( WM ) are quite similar . This is somewhat surprising considering the different cellular environments of GM and WM . It is possible that partial volume averaging ( P32926 ) effects between GM and WM , inherent in many of the ultrafast imaging sequences used for diffusion measurements , are responsible for this observation . In order to minimize P32926 effects , the trace values of GM and WM have been selectively measured by implementing double inversion recovery ( P30518 ) echo planar imaging ( P10646 ) pulse sequences . Results on six normal volunteers indicate that the trace values of WM and GM are not statistically different .",
"[ Role of neurokinin - 1 receptor in lung injury in rats with acute necrotizing pancreatitis ] . OBJECTIVE : To investigate the expression of neurokinin - 1 receptor ( P25103 ) in the lung tissue , and the relationship between expression of P25103 and lung injury in rats with acute necrotizing pancreatitis ( P01160 ) . METHODS : One hundred and twenty adult Sprague - Dawley rats were randomly divided into P01160 and control groups . Animals in group P01160 were induced by the retrograde intraductal infusion of 5 % sodium taurocholate ( 0 . 1 ml / kg ) , and animals in normal control group received laparotomy only . The accumulation of polymorphonuclear leukocytes in lung tissues was measured with myeloperoxidase ( P05164 ) assay . Lung endothelial barrier destruction was measured by lung capillary permeability ( LCP ) . Reverse transcription polymerase chain reaction ( RT - PCR ) was used to determine the mRNA expression of P25103 , western blot analysis was used to determine P25103 protein expression levels , and immunohistochemistry was used to localize expression site of P25103 . RESULTS : P25103 mRNA level was enhanced in the lung of P01160 compared with normal control group . Western blot analysis showed overexpression of P25103 protein level exited in P01160 group . Statistical analysis revealed correlation between P25103 mRNA and P05164 ( r = 0 . 83 , P < 0 . 01 ) and LCP ( r = 0 . 79 , P < 0 . 01 ) respectively . With immunohistochemistry staining , moderate to strong P25103 immunoreactivity was localized to alveolar membrane , I epithelium , II epithelium and polymorphonuclear leukocytes in the lung of P01160 . CONCLUSION : In P01160 , overexpression of P25103 contributes to disturbance of neuropeptides loop , resulting in aggregation of neutrophilic granulocyte and promoting deterioration of lung injury .",
"A P04035 inhibitor possesses a potent anti - atherosclerotic effect other than serum lipid lowering effects -- the relevance of endothelial nitric oxide synthase and superoxide anion scavenging action . We have determined whether the anti - atherosclerotic effect of a 3 - hydroxy - 3 - methyl - glutaryl - DB01992 ( HMG - DB01992 ) reductase inhibitor ( fluvastatin ) is mediated through nitric oxide ( NO ) as well as affecting plasma lipids . NO related vascular responses , endothelial nitric oxide synthase ( P29474 ) mRNA and superoxide anion ( O ( 2 )(-) ) release were examined in vascular walls of oophorectomized female rabbits fed 0 . 5 % cholesterol chow for 12 weeks with or without fluvastatin ( 2 mg / kg per day ) . Serum lipid profile was not different between two groups . NO dependent responses stimulated by acetylcholine and calcium ionophore A23187 and tone related basal NO response induced by N ( G )- monomethyl - L - arginine acetate ( L - Q13145 ) ; nitric oxide synthase inhibitor were all improved by fluvastatin treatment . Endothelium independent vasorelaxation induced by nitroglycerin was not different between the two groups of rabbits ' arteries . ___MASK69___ treatment increased cyclic GMP concentration in aorta of rabbits . P29474 mRNA expression and O ( 2 )(-) release were measured in aorta using competitive reverse transcription - polymerase chain reaction ( RT - PCR ) and with lucigenin analogue , 2 - methyl - 3 , 7 - dihydroimidazol [ 1 , 2 - a ] pyrazine - 3 - one ( MCLA ) chemiluminescence methods . P29474 mRNA in the endothelial cells of aorta was significantly up - regulated and O ( 2 )(-) production was significantly reduced in fluvastatin treated rabbit aorta . Anti - macrophage staining area , but not anti - smooth muscle cell derived actin stained area in the aorta was also reduced by fluvastatin treatment . Conclusion , fluvastatin , a P04035 inhibitor , retards the initiation of atherosclerosis formation through the improvement of NO bioavailability by both up - regulation of P29474 mRNA and decrease of O ( 2 )(-) production in vascular endothelial cells , and this means that part of the anti - atherosclerotic effect of fluvastatin may be due to nonlipid factors .",
"Synergistic activity of ixabepilone plus other anticancer agents : preclinical and clinical evidence . DB04845 demonstrates marked synergistic activity in combination with capecitabine , which served as the rationale for the evaluation of this combination in the clinic . DB04845 plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer ( MBC ) progressing after treatment with an anthracycline and a taxane ; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy . An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab , bevacizumab , brivanib , and cetuximab ; with immune - modulating agents such as anti - P16410 antibody ; and with other chemotherapy drugs such as irinotecan and epirubicin . Notably , experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab - paclitaxel combined with bevacizumab . These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in P04626 - positive breast cancer ; with bevacizumab in breast cancer , endometrial cancer , renal cancer , and non - small cell lung cancer ( NSCLC ) ; with cetuximab in breast cancer , NSCLC , and pancreatic cancer ; and with brivanib , dasatinib , sorafinib , sunitinib , or vorinostat in MBC . Preliminary results from several of these trials suggest that ixabepilone - based combinations have promising anticancer activity .",
"Electrostatic modeling of peptides derived from the V3 - loop of HIV - 1 gp120 : implications of the interaction with chemokine receptor P51681 . Infection of P01730 + T cells by macrophage - tropic HIV - 1 strains involves interaction of viral gp120 with the host cell chemokine receptor P51681 . The principle neutralizing determinant ( P01160 ) of the V3 - loop of the HIV - 1 gp120 was investigated for its interaction with P51681 by computational modeling methods at atomic resolution and electrostatic calculations to complement experimental findings . The study focused on the recognition step and examined possible peptide - peptide interactions between various P01160 - derived peptides from the V3 - loop and the N - terminal ( Nt ) domain of P51681 . These recognition interactions are possible because of the complementary character of the spatial distribution of the predominantly positive electrostatic potentials of the P01160 - derived peptides and the predominantly negative electrostatic potential of the CCR5Nt domain . The CCR5Nt appears more amenable to interaction with the V3 peptides , than the other P51681 extracellular domains ( ECL ) , because of its length and the domination of its negative electrostatic potential . On the contrary , ECL2 possesses a predominantly positive electrostatic potential . There are positive patches in Nt and negative patches in ECL2 , which , following the non - specific recognition of the V3 - loop by P51681 and with the expected local structural rearrangements to facilitate specific binding , may be contributing to the stabilization of the complex . A sequential two - step specific binding , involving different extracellular domains , is conceivable . Although the electrostatic potentials may play a role in a V3 - P51681 interaction , a more specific model can not be derived in the absence of a three - dimensional structure of a gp120 / P01730 / P51681 complex .",
"What ' s in the pipeline ? New immunosuppressive drugs in transplantation . In the pipeline , there are a number of novel immunosuppressive drugs in preclinical development or in early clinical trials . The major target of new agents are cell - surface molecules important in immune cell interactions ( especially the costimulatory pathway ) , signaling pathways that activate T cells , T - cell proliferation and trafficking and recruitment of immune cells responsible for rejection . The most promising biologic agents include a humanized anti - CD11a ( anti - LFA1 ) , humanized anti - P33681 . 1 / P33681 . 2 , a second - generation DB01281 ( DB06681 ) and a humanized antibody to anti - P08575 RB . Inhibitors of T - cell activation and signaling are still in preclinical development . The most interesting inhibitors of T - cell proliferation include inhibitors of the Janus protein tyrosine kinase , P52333 , and FK778 , a leflunomide analog . Chemokines play an important role in rejection by virtue of their critical role as regulator of trafficking and activation of lymphocytes . Early trials of FTY720 , a synthetic small molecule with functional homology to sphingosine - 1 phosphate leading to lymphocyte sequestration , appear very promising ; however , enthusiasm for this drug is mitigated by its potential cardiac side - effects . Antagonists to several chemokine receptors , including P32246 , P49682 and P51681 , have been shown to be effective in experimental transplantation and are likely to be considered for clinical development .",
"Introduction to the use of belatacept : a fusion protein for the prevention of posttransplant kidney rejection . The development of new immunosuppressive drugs for kidney transplantation resulted both in better short - term outcomes and in decreased metabolic , cardiovascular , and nephrotoxicity risk . DB06681 belongs to a new class of immunosuppressive drugs that selectively inhibits T - cell activation by preventing P10747 activation and by binding its ligands P33681 - 1 and P33681 - 2 . The result is an inactivation of costimulatory pathways . A comparative analysis of the BENEFIT and BENEFIT - EXT datasets showed belatacept regimens resulted in better cardiovascular and metabolic risk profiles than did cyclosporin A ( DB00091 ) regimens : belatacept likewise outperformed DB00091 in terms of lower blood pressure and serum lipids and less new onset diabetes after transplantation . About 20 % of belatacept - treated patients developed adverse effects which included anemia , pyrexia , neutropenia , diarrhea , urinary tract infection , headache , and peripheral edema . At present , belatacept does not seem to predispose patients to a higher rate of infection than DB00091 maintenance immunosuppression . The risk of posttransplant lymphoproliferative diseases was higher in Epstein - Barr virus ( EBV ) - seronegative patients than in EBV - seropositive patients , but the risk may be reduced by use of a less intensive regimen and avoidance of EBV - negative patients and of patients whose pretransplant EBV serology is unknown . DB06681 provides a new option for immunosuppressive therapy in kidney transplantation , but needs further evaluation in terms of the late effects that may derive from prolonged blockage of the costimulatory system and the induction of tolerance status .",
"Chronic induction . What ' s new in the pipeline . Induction therapy with biological agents was introduced the in the 1970s and the rationale , concepts and approach have remained almost unchanged for 30 years . However , the novel biological agents being developed for induction therapy are being designed for chronic rather than short - term therapy with several objectives : reduce dependence on toxic and nephrotoxic agents , improve outcome and ultimately facilitate the emergence of tolerance . The biological agents include efalizumab , a humanized anti - CD11a ( anti - LFA1 ) , anti - CD154 , anti - P25942 , a number of agents targeting P40933 and its receptor , and costimulation blockade with humanized antibodies to P33681 / P42081 and the fusion receptor protein DB06681 , a second generation DB01281 . The past decade has witnessed an unprecedented number of small molecules / oral drugs that have been developed and approved for renal transplantation ; the next decade , however , may witness the emergence of a new class of biological induction agents that may displace some of the currently used drugs .",
"___MASK69___ inhibits growth and alters the malignant phenotype of the P13671 glioma cell line . BACKGROUND : ___MASK69___ is a member of the family of P04035 inhibitors ( statins ) extensively used in medical practice . Increasing evidence suggests that fluvastatin may be implicated in suppression of cancer growth and development . The aim of the present study was to investigate the anti - cancer potential of fluvastatin in P13671 rat malignant glioma cells . METHODS : First , the effects of fluvastatin on cell viability ( MTT assay ) , proliferation ( BrdU assay ) , cell morphology , and cytoskeleton were examined . Subsequently , its effect on extracellular signal regulated kinase 1 and 2 ( P27361 / 2 ) and P45983 and 2 ( JNK 1 / 2 ) expression was estimated by Western blot . Finally , the influence of fluvastatin on cell migration and production of P14780 and P15692 was determined using a wound - healing assay and ELISA test , respectively . RESULTS : The results obtained showed that fluvastatin had a remarkable inhibitory and cytotoxic effect on tumor P13671 cells ( IC ( 50 ) = 8 . 6 μM , 48 h ) , but did not inhibit the growth of normal neuronal cells . The concentrations from 1 to 10 μM induced marked morphologic alterations typical for apoptosis including shrinkage of cytoplasm , chromatin condensation , and nucleus breakdown . CONCLUSION : The inhibitory effects of fluvastatin on cell proliferation seemed to be associated with decreased p - P27361 / 2 expression , upregulation of p - P45983 / 2 , and reduction in the P14780 and P15692 concentrations in culture media . The high anticancer ( antiproliferative , proapoptotic , antiinvasive ) activity of fluvastatin and lack of its toxicity against normal cells indicate a potential use of this statin in the treatment of malignant glioma .",
"[ Use of P30518 - PCR for elaboration of molecular markers of intraspecies bacterial groups as exemplified by Bacillus thuringiensis ] . A recently developed PCR - fingerprinting method , the so - called P30518 ( diverged inverted repeats ) - PCR , was used for quick search for molecular markers of Bacillus thuringiensis subspecies carrying the cry1 genes . The analysis of the fingerprints obtained by this method made it possible to reveal PCR fragments characteristic of the subspecies that produce proteins toxic for insects of the order Lepidoptera . Cloning and sequencing of these fragments allowed systems of P62701 ( sequence characterized amplified region ) primers to be designed , which are specific to the above group of B . thuringiensis strains . Comparison of the specific fragments with sequences available in the GenBank database revealed their homology with the rpoC gene family and the adjacent spacer region , suggesting chromosomal localization of these markers . This increases the reliability of the designed system of P62701 primers , because plasmids may be lost or transferred by transformation between closely related strains . It was demonstrated that the P30518 - PCR method allows markers to be developed that are linked to diagnostic genotypic and phenotypic characteristics of bacteria .",
"Signalling pathways involved in retinal endothelial cell proliferation induced by advanced glycation end products : inhibitory effect of gliclazide . AIM : We have previously demonstrated that advanced glycation end products ( AGEs ) stimulate bovine retinal endothelial cell ( BREC ) proliferation through induction of vascular endothelial growth factor ( P15692 ) production by these cells . We have also shown that gliclazide , a sulfonylurea which decreases oxidative stress , inhibits this effect . The aim of the present study was to characterize the signalling pathways involved in P51606 - induced BREC proliferation and P15692 production and mediating the inhibitory effect of gliclazide on these biological events . METHODS : BRECs were treated or not treated with AGEs in the presence or absence of gliclazide , antioxidants , protein kinase C ( PKC ) , mitogen - activated protein kinase ( MAPK ) or nuclear factor - kappaB ( NF - kappaB ) inhibitors . BREC proliferation was assessed by measuring [ 3H ] - thymidine incorporation into DNA . Activation of PKC , MAPK and NF - kappaB signal transduction pathways and determination of P15692 expression were assessed by Western blot analysis using specific antibodies . MAPK activity was also determined by an in vitro kinase assay . RESULTS : Treatment of BRECs with AGEs significantly increased cell proliferation and P15692 expression . AGEs induced P05771 translocation , extracellular signal - regulated protein kinase 1 / 2 and NF - kappaB activation in these cells . Pharmacological inhibition of these signalling pathways abolished P51606 effects on cell proliferation and P15692 expression . Exposure of BRECs to gliclazide or antioxidants such as vitamin E or N - acetyl - l - cysteine resulted in a significant decrease in P51606 - induced activation of PKC - , MAPK - and NF - kappaB - signalling pathways . CONCLUSIONS : Our results demonstrate the involvement of PKC , MAPK and NF - kappaB in P51606 - induced BREC proliferation and P15692 expression . ___MASK63___ inhibits BREC proliferation by interfering with these intracellular signal transduction pathways .",
"Advances in immunosuppression for kidney transplantation : new strategies for preserving kidney function and reducing cardiovascular risk . The development of new immunosuppressants for renal transplantation is aimed not only at improving & nbsp ; short - term outcomes , but also at achieving better safety , cardiovascular , and metabolic profiles and at decreasing & nbsp ; nephrotoxicity . DB06681 is a fusion protein that inhibits T cell activation by binding to P33681 and P42081 antigens . Clinical trials , particularly the BENEFIT and BENEFIT - EXT studies , have shown that belatacept preserves function and structure in renal grafts . The effects of belatacept provide long - term , sustained results , and the safety and efficacy of this drug have been demonstrated in cases of renal transplantation from expanded criteria donors . Compared to calcineurin inhibitors , belatacept is associated with a lower incidence of chronic allograft nephropathy and a more favourable cardiovascular and metabolic profile .",
"P40933 augments antitumoral activity of an ErbB2 / P04626 cancer vaccine targeted to professional antigen - presenting cells . Targeted delivery of tumor - associated antigens to professional antigen - presenting cells ( P25054 ) is being explored as a strategy to enhance the antitumoral activity of cancer vaccines . Here , we generated a cell - based system for continuous in vivo production of a P16410 - ErbB2 fusion protein as a therapeutic vaccine . The chimeric P16410 - ErbB2 molecule contains the extracellular domain of P16410 for specific targeting to costimulatory P33681 molecules on the surface of P25054 , genetically fused to residues 1 - 222 of human ErbB2 ( P04626 ) as an antigenic determinant . In wild - type BALB / c mice , inoculation of syngeneic epithelial cells continuously secreting the P16410 - ErbB2 fusion vaccine in the vicinity of subcutaneously growing ErbB2 - expressing renal cell carcinomas resulted in the rejection of established tumors , accompanied by the induction of ErbB2 - specific antibodies and cytotoxic T cells . In contrast , treatment with P16410 - ErbB2 vaccine - secreting producer cells alone was insufficient to induce tumor rejection in ErbB2 - transgenic WAP - Her - 2 F1 mice , which are characterized by pronounced immunological tolerance to the human self - antigen . When P16410 - ErbB2 producer cells were modified to additionally secrete interleukin ( IL ) - 15 , antigen - specific antitumoral activity of the vaccine in WAP - Her - 2 F1 mice was restored , documented by an increase in survival , and marked inhibition of the growth of established ErbB2 - expressing , but not antigen - negative tumors . Our results demonstrate that continuous in vivo expression of an P25054 - targeted ErbB2 fusion protein results in antigen - specific immune responses and antitumoral activity in tumor - bearing hosts , which is augmented by the pleiotropic cytokine P40933 . This provides a rationale for further development of this approach for specific cancer immunotherapy .",
"Pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept in adult kidney transplant recipients . BACKGROUND AND OBJECTIVES : DB06681 is a first - in - class , selective co - stimulation blocker recently approved for the prophylaxis of organ rejection in adult kidney transplant recipients . The objective of this study was to report the pharmacokinetics , pharmacodynamics , and immunogenicity of belatacept . METHODS : The pharmacokinetics , pharmacodynamics ( P42081 receptor occupancy ) , and immunogenicity of belatacept were studied in de novo adult kidney transplant recipients in phase II and III clinical studies . RESULTS : Following multiple doses of 5 or 10 mg / kg , the geometric mean ( percentage coefficient of variation ) maximum serum concentration and area under the serum concentration - time curve over one dosing interval of belatacept were 136 ( 20 % ) and 238 ( 27 % ) μg / mL , and 13 , 587 ( 27 % ) and 21 , 241 ( 35 % ) μg · h / mL , respectively . The median belatacept elimination half - life was 8 - 9 days . DB06681 exhibited concentration - dependent binding to P42081 receptors . The pre - dose P42081 receptor occupancy by belatacept decreased from 94 to 65 % between day 5 and 1 year post - transplant , with corresponding pre - dose trough serum concentrations of belatacept decreasing from ~ 35 to 4 μg / mL during this period . The cumulative incidence of developing anti - belatacept antibodies was 5 . 3 % up to 3 years post - transplant and had no impact on belatacept exposure . CONCLUSIONS : DB06681 in adult kidney transplant demonstrated linear pharmacokinetics with low variability , concentration - dependent pharmacodynamics , and a low incidence of anti - drug antibodies .",
"Dietary phytochemicals alter epigenetic events and signaling pathways for inhibition of metastasis cascade : phytoblockers of metastasis cascade . Cancer metastasis is a multistep process in which a cancer cell spreads from the site of the primary lesion , passes through the circulatory system , and establishes a secondary tumor at a new nonadjacent organ or part . Inhibition of cancer progression by dietary phytochemicals ( DPs ) offers significant promise for reducing the incidence and mortality of cancer . Consumption of DPs in the diet has been linked to a decrease in the rate of metastatic cancer in a number of preclinical animal models and human epidemiological studies . DPs have been reported to modulate the numerous biological events including epigenetic events ( noncoding micro - RNAs , histone modification , and DNA methylation ) and multiple signaling transduction pathways ( Wnt / β - catenin , Notch , Sonic hedgehog , P35354 , P00533 , MAPK - P29323 , JAK - P35610 , Akt / PI3K / P42345 , NF - κB , AP - 1 , etc . ) , which can play a key role in regulation of metastasis cascade . Extensive studies have also been performed to determine the molecular mechanisms underlying antimetastatic activity of DPs , with results indicating that these DPs have significant inhibitory activity at nearly every step of the metastatic cascade . DPs have anticancer effects by inducing apoptosis and by inhibiting cell growth , migration , invasion , and angiogenesis . Growing evidence has also shown that these natural agents potentiate the efficacy of chemotherapy and radiotherapy through the regulation of multiple signaling pathways . In this review , we discuss the variety of molecular mechanisms by which DPs regulate metastatic cascade and highlight the potentials of these DPs as promising therapeutic inhibitors of cancer .",
"P45983 , but not P45984 , is required in two mechanistically distinct models of inflammatory arthritis . The roles of the c - Jun N - terminal kinases ( JNKs ) in inflammatory arthritis have been investigated ; however , the roles of each isotype ( ie , P45983 and P45984 ) in rheumatoid arthritis and conclusions about whether inhibition of one or both is necessary for amelioration of disease are unclear . By using P45983 - or P45984 - deficient mice in the collagen - induced arthritis and the KRN T - cell receptor transgenic mouse on C57BL / 6 nonobese diabetic ( K / BxN ) serum transfer arthritis models , we demonstrate that P45983 deficiency results in protection from arthritis , as judged by clinical score and histological evaluation in both models of inflammatory arthritis . In contrast , abrogation of P45984 exacerbates disease . In collagen - induced arthritis , the distinct roles of the JNK isotypes can , at least in part , be explained by altered regulation of P42081 expression in P45983 - or P45984 - deficient macrophages in response to microbial products , thereby affecting T - cell - mediated immunity . The protection from K / BxN serum - induced arthritis in Jnk1 (-/-) mice can also be explained by inept macrophage function because adoptive transfer of wild - type macrophages to Jnk1 (-/-) mice restored disease susceptibility . Thus , our results provide a possible explanation for the modest therapeutic effects of broad JNK inhibitors and suggest that future therapies should selectively target the P45983 isoform .",
"Gateways to clinical trials . Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses . The data in the following tables has been retrieved from the Clinical Studies knowledge area of Prous Science Integrity , the drug discovery and development portal , http :// integrity . prous . com . This issue focuses on the following selection of drugs : 2F5 , 2G12 , abetimus sodium , ABI - 007 , adalimumab , adefovir dipivoxil , DB05387 , alefacept , altropane , aminolevulinic acid hydrochloride , aminolevulinic acid methyl ester , aminopterin , anakinra , aprinocarsen sodium , atazanavir , atlizumab , atomoxetine hydrochloride ; P33681 - 1 vaccine , bevacizumab , DB04851 dicitrate , BMS - 188667 , brasofensine sulfate , bryostatin 1 ; cantuzumab mertansine , Q99698 - 828 , cinacalcet hydrochloride , cipamfylline , creatine , CVT - 3146 ; darbepoetin alfa , DITPA , drotrecogin alfa ( activated ) , duloxetine hydrochloride ; edatrexate , efalizumab , ENMD - 0997 , epoetin , erlosamide , esomeprazole magnesium , etiprednol dicloacetate , etoricoxib , everolimus , ezetimibe ; fampridine , fenretinide , FTY - 720 ; P05019 / P17936 , IL - 1 cytokine trap , ilodecakin , interferon beta , ISIS - 104838 , ISIS - 2503 , ISIS - 5132 , ivabradine hydrochloride ; lafutidine , lanthanum carbonate , l - DB00125 hydrochloride , DB06681 , lerdelimumab , levetiracetam , levobupivacaine hydrochloride , levosimendan , lopinavir ; melagatran , mibefradil hydrochloride , miglustat , morphine - 6 - glucuronide ; nesiritide ; omalizumab , omapatrilat ; p24 - VLP , parecoxib sodium , peginterferon alfa - 2a , peginterferon alfa - 2b , pegsunercept , pitavastatin calcium , plevitrexed , prasterone , pregabalin , PRO - 2000 , prucalopride ; rapacuronium bromide , rebimastat , RGA - 0853 , rubitecan , ruboxistaurin mesilate hydrate , RWJ - 67657 ; S - 16020 - 2 , sarizotan , SLV - 306 , stiripentol ; DB05809 , tenecteplase , teriparatide , tezacitabine , tipifarnib , trabectedin , troglitazone ; valdecoxib , vardenafil ; Z - 338 , ziconotide .",
"Activation of c - Jun - N - terminal - kinase is crucial for the induction of a cell cycle arrest in human colon carcinoma cells caused by flurbiprofen enantiomers . The unselective cyclooxygenase ( P36551 ) inhibitor ___MASK91___ and its - in terms of P36551 - inhibition - \" inactive \" enantiomer R - flurbiprofen have been previously found to inhibit tumor development and growth in various animal models . The underlying mechanisms are unknown . Here , we show that both R - and ___MASK91___ reduce survival of three colon cancer cell lines , which differ in the expression of P35354 ( HCT - 15 , no P35354 ; Caco - 2 , inducible P35354 ; and HT - 29 , constitutive P35354 ) . The IC50 for S - and R - flurbiprofen ranged from 250 to 450 microM . Both flurbiprofen enantiomers induced apoptosis in all three cell lines as indicated by DNA - and PARP - cleavage . In addition , R - and ___MASK91___ caused a P55008 - cell cycle block . The latter was associated with an activation of c - Jun N - terminal kinase ( JNK ) , an increase of the DNA binding activity of the transcription factor AP - 1 and down - regulation of cyclin D1 expression . Western blot analysis , as well as supershift experiments , revealed that the AP - 1 activation was associated with a change of AP - 1 composition toward an increase of JunB . The JNK inhibitor SP600125 antagonized R - and ___MASK91___ - induced AP - 1 DNA binding , suppression of cyclin D1 expression , and the P55008 - cell cycle block . However , JNK inhibition had no effect on flurbiprofen - induced apoptosis . Hence , the cell cycle arrest is obviously mediated , at least in part , through JNK - activation , whereas R - and ___MASK91___ - induced apoptosis is largely independent of JNK . Although in vitro effects of R - and ___MASK91___ were indistinguishable , only R - flurbiprofen inhibited HCT - 15 tumor growth in nude mice , suggesting the involvement of additional in vivo targets , which are differently affected by R - and ___MASK91___ .",
"Efficacy and safety of repeated dosing of netupitant , a neurokinin - 1 receptor antagonist , in treating overactive bladder . AIM : NK - 1 receptors in sensory nerves , the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity . This study was designed to assess the efficacy and safety of a new P25103 antagonist , netupitant , in patients with OAB . METHODS : This was a phase II , multicenter , double - blind study in which adults with OAB symptoms > 6 months were randomized to receive 1 of 3 doses of netupitant ( 50 , 100 , 200 mg ) or placebo once daily for 8 weeks . The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8 . Urinary incontinence , urge urinary incontinence ( UUI ) , and urgency episodes were also assessed . RESULTS : The primary efficacy endpoint was similar in the treatment groups ( - 13 . 85 for placebo to - 16 . 17 in the netupitant 200 mg group ) with no statistically significant differences between netupitant and placebo . The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group . ___MASK77___ was well tolerated with most treatment emergent adverse events ( AEs ) being mild . While the overall incidence of AEs increased with netupitant dose , there was no evidence for this dose dependency based on relationship to treatment , intensity , or time to onset . CONCLUSIONS : The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms , despite a trend favoring netupitant 100 mg . There were no safety concerns with daily administration of netupitant over 8 weeks .",
"Production and characterization of DB06681 , a variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin , in Pichia pastoris . Blocking the P10747 / P33681 costimulatory pathway is a promising strategy in the treatment of graft rejection , graft - versus - host disease and autoimmune diseases . DB06681 , a high - affinity variant of cytotoxic T - lymphocyte antigen 4 - immunoglobulin ( DB01281 ) , is a more potent inhibitor of the interaction between P10747 and P33681 than is DB01281 . In a previous study , DB06681 was produced in a mammalian cell system , which is time - consuming and expensive . To obtain DB06681 more efficiently and cost effectively , we attempted to produce DB06681 using a Pichia pastoris expression system . The gene encoding DB06681 , with an additional 6 - DB00117 tag at the N - terminus , was cloned into the yeast vector pPIC9K and expressed in the P . pastoris strain GS115 . Under the optimized induction conditions for protein expression ( inoculum density , OD ( 600 ) = 80 ; methanol concentration added daily , 1 . 0 - 3 . 0 % ; induction time point , 72 - 96 h ; culture medium pH = 6 . 0 ) , the yield of purified DB06681 was approximately 30 mg l (- 1 ) by one - step Ni - agarose affinity chromatography . Q96IV0 F treatment showed the purified DB06681 to be post - translational modified by N - linked glycosylation . In biological function assays , DB06681 expressed in P . pastoris demonstrated specific binding to P33681 - 1 / P33681 - 2 - positive Raji cells and also suppressed lymphocyte proliferation in a dose - dependent manner . These results suggest that DB06681 produced in P . pastoris is biologically active and will be useful for experimental therapy on immunotherapy for transplant rejection and autoimmune diseases .",
"Polymorphisms of genes related to endothelial cells are associated with primary biliary cirrhosis patients of Cretan origin . BACKGROUND : Primary biliary cirrhosis ( P10515 ) is an organ specific autoimmune disease of still unidentified genetic etiology . We have shown that endothelins ( ETs ) , produced by the liver endothelial cells are increased in P10515 and may play a major pathogenetic role . AIMS : To study gene polymorphisms related to the endothelial cells ( P29474 , P10153 - 1 genes ) and , to investigate whether the previously reported association of P16410 gene polymorphisms is replicated in a genetically homogeneous Greek population . PATIENTS AND METHODS : Genomic DNA was extracted from 100 P10515 patients ( 83 females , 93 % AMA + , 74 / 100 Ludwig stage I - II ) and 158 healthy controls . P29474 , P16410 and ET1 polymorphisms were determined by PCR - RFLPs analysis . RESULTS : Both P29474 intron4 VNTR and P29474 exon7 G894T SNP were significantly associated with increased risk in P10515 . P10153 - 11 rs2071942 \" A \" and rs5370 \" T \" alleles appeared a tendency for association with disease progression . No association was found between P10515 and the P16410 SNPs analyzed . CONCLUSIONS : We demonstrated that P29474 , a gene related to the liver endothelium function is associated with P10515 . Contrarily , the important in adaptive immunity gene P16410 was not associated with the disease in the homogeneous population analyzed . These results are compatible partially with our previous hypothesis that defects of the liver endothelial system , leading to endothelin overproduction , may be a fundamental early pathogenetic mechanism in P10515 ."
] |
[
"___MASK100___",
"___MASK20___",
"___MASK63___",
"___MASK69___",
"___MASK77___",
"___MASK7___",
"___MASK84___",
"___MASK88___",
"___MASK91___"
] |
___MASK100___
|
MH_train_491
|
interacts_with DB06674?
|
[
"Stimulation of epithelial repair is a likely mechanism for the action of mifepristone in reducing duration of bleeding in users of progestogen - only contraceptives . Many women using progestogen ( P ) - only contraceptives experience uterine bleeding problems . In clinical trials , a single low dose of mifepristone , given to ___MASK54___ users at the beginning of a bleeding episode reduced the number of bleeding days by approximately 50 % compared with controls . In this study , a single dose of mifepristone was administered to etonogestrel ( P17813 ) - exposed pseudo - pregnant mice , 5 days after artificial decidualization was induced when the endometrium showed signs of bleeding . Control mice received vehicle alone . Mice were culled 12 - , 18 - , 24 - and 48 - h post - treatment . In the continued presence of P17813 , a single dose of mifepristone stimulated tissue breakdown followed by very rapid repair : most treated tissues were fully restored to the pre - decidualized state by 48 h post - treatment . During repair , proliferating cells ( Ki67 immunostained ) were localized to a band of cells around the basal area in breaking down tissues and to the repairing luminal epithelium and glands . P06401 - positive cells were largely localized to the basal area of the breaking down tissue in treated mice compared with decidual cells in controls . Oestrogen receptor - positive cells were observed in the repairing luminal epithelium and glands compared with the decidua and the basal region in control tissues . It is concluded that mifepristone treatment stimulates rapid restoration of luminal epithelial integrity : such action may be a key event in reducing the number of bleeding days observed in women using ___MASK54___ who were treated with a single dose of mifepristone .",
"Apoptosis and the FLIP and NF - kappa B proteins as pharmacodynamic criteria for biosimilar P01375 antagonists . Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale . The imminent expiration of the patents on reference biological products which block the cytokine P01375 - α ( tumor necrosis factor - α ) raises the possibility of bringing so - called biosimilars to the market ( similar to the biologicals of reference products ) . This occurrence is inevitable , but criteria to adequately evaluate these medications are now needed . Even among controversy , there is a demand from publications correlating the pro - apoptotic mechanism of the original P01375 - α antagonists ( etanercept , infliximab , adalimumab , DB06674 , and certolizumab pegol ) in the treatment of rheumatoid arthritis and other diseases . In this article , the authors discuss the possibility of utilizing the pro - apoptotic effect correlated with the regulation of the anti - apoptotic proteins FLIP and NF - κB as new criteria for analyzing the pharmacodynamics of possible biosimilar P01375 - α antagonists which should be submitted to regulatory agencies for evaluation .",
"anti - P01375 agents as therapeutic choice in immune - mediated inflammatory diseases : focus on adalimumab . The complex pathogenesis of immune - mediated inflammatory diseases ( IMIDs ) has been extensively investigated and dysregulation of cytokines , such as tumour necrosis factor ( P01375 ) has been shown to play a dominant role in the pathogenesis of various IMIDs , such as rheumatoid arthritis , ankylosing spondylitis , Crohn ' s disease , ulcerative colitis , psoriasis and psoriatic arthritis . The subsequent development of biological agents capable of blocking P01375 has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with P01375 having a predominant role . Five P01375 inhibitors have currently been approved for treatment of one or more IMIDs ; these include infliximab , etanercept , adalimumab , DB06674 and certolizumab pegol . Given the similarities in the pathogenic background of IMIDs , one could expect that anti - P01375 agents be similarly effective and with comparable tolerability profiles ; however , this may not be the case . Structural and pharmacological differences among the anti - P01375 drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs , together with differences in potency , therapeutic dose ranges , dosing regimens , administration routes , and propensity for immunogenicity . Among the five P01375 inhibitors approved for treatment of IMIDs , adalimumab has the widest range of indications . Data from controlled clinical trials of adalimumab , showing its excellent efficacy and tolerability in a wide range of indications , are supported by real - world long - term data from observational studies , which confirm the value of adalimumab as a suitable choice in the management of IMIDs .",
"New biologic therapeutics for ulcerative colitis and Crohn ' s disease . INTRODUCTION : Some inflammatory bowel disease ( Q9UKU7 ) patients especially those with refractory Crohn ' s disease ( CD ) or relapsing ulcerative colitis ( UC ) do not respond to current therapies . The newly introduced biological drugs have got some interest due to their specificity and selectivity in modulation of inflammatory elements . AREAS COVERED : In 46 included randomized , placebo - controlled clinical trials , the efficacy and safety of different biologic drugs have been evaluated in moderately to severely active CD or UC patients . Current investigated drugs include new anti - P01375 drugs ( adalimumab , certolizumab pegol , etanercept , onercept and DB06674 ) , anti - P11836 ( rituximab ) , T - cell inhibitors ( abatacept ) and anti - α4 integrins ( natalizumab and vedolizumab ) . DB00051 , certolizumab , and DB06674 showed significant efficacy in induction of remission and maintenance in CD and UC patients with a rate of adverse events similar to placebo in the major trials . DB00108 and vedolizumab were effective in the treatment of moderately to severely active CD and UC patients . However , vedolizumab caused less adverse effects than natalizumab . onercept , etanercept , rituximab and abatacept were all well tolerated but were not effective in CD or UC patients . EXPERT OPINION : Anti - P01375 drugs , except for onercept and etanercept , and anti - α4 integrins exhibit beneficial therapeutic effects . Although they were all well tolerated , the incidence of progressive multifocal leukoencephalopathy associated with natalizumab should not be missed .",
"An update on anti - P01375 agents in ulcerative colitis . Anti - tumor necrosis factor - α agents are key therapeutic options for the treatment of ulcerative colitis . Their efficacy and safety have been shown in large randomized controlled trials . The key evidence gained from these trials of infliximab , adalimumab , and DB06674 is reviewed along with their effect on mucosal healing and long - term outcomes . Also reviewed are methods for optimizing their effectiveness , including therapeutic drug monitoring and treat - to - target strategies . Finally , remaining unresolved questions regarding their role and effectiveness are considered including how these may be addressed in future clinical trials .",
"Safety of anti - tumour necrosis factor agents in patients with chronic hepatitis C infection : a systematic review . OBJECTIVES : To identify all of the patients affected by chronic hepatitis C infection treated with P01375 - α blockers ( adalimumab , certolizumab pegol , etanercept , DB06674 and infliximab ) in order to evaluate the safety profile . METHODS : A systematic review of the literature from January 1990 to October 2010 . RESULTS : In total , 37 publications with data on 153 patients who were treated with anti - P01375 - α agents in the setting of HCV infection were found . The mean anti - P01375 - α treatment duration was 11 . 9 months . Ninety - one patients had RA , 22 had psoriasis , 6 had Crohn ' s disease and 14 patients had other chronic inflammatory diseases . To date , etanercept is the biological agent that has been most extensively used in the patients with HCV infection , with only one definitely confirmed case of HCV hepatitis worsening and five suspected cases ( elevation of transaminases not associated with an increase in the HCV viral load and vice versa ) in 110 treated patients . Treatment with this agent resulted in stable levels of liver transaminases and a stable viral load in 74 patients , with an improvement in HCV chronic liver disease in combination with IFN - ribavirin therapy in 29 patients . CONCLUSIONS : The safety profile of anti - P01375 - α agents in the setting of HCV infection seems to be acceptable , even if differences in the hepatotoxic profile are apparent between different agents . In the absence of long - term and large , controlled clinical trials a definitive statement on the safety of anti - P01375 - α therapies in the setting of chronic HCV infection can not be made .",
"P01375 inhibitors in asthma and P48444 : we must not throw the baby out with the bath water . P01375 ( P01375 ) - alpha , a pleiotropic cytokine that exerts a variety of effects , such as growth promotion , growth inhibition , angiogenesis , cytotoxicity , inflammation , and immunomodulation , has been implicated in several inflammatory conditions . It plays a significant role in many inflammatory diseases of lungs . Given that there is significant literature supporting the pathobiologic role of P01375 in asthma , mainly in severe refractory asthma , and P48444 , P01375 inhibitors ( infliximab , DB06674 and etanercept ) are now regarded as the potential new medications in asthma and P48444 management . The studies reported in literature indicate that P01375 inhibitors are effective in a relatively small subgroup of patients with severe asthma , possibly defined by an increased P01375 axis , but they seem to be ineffective in P48444 , although an observational study demonstrated that P01375 inhibitors were associated with a reduction in the rate of P48444 hospitalisation among patients with P48444 receiving these agents to treat their rheumatoid arthritis . These findings require a smart approach because there is still good reason to target P01375 , perhaps in a more carefully selected patient group . P01375 treatment should , therefore , not be thrown out , or abandoned . Indeed , since severe asthma and P48444 are heterogeneous diseases that have characteristics that occur with different phenotypes that remained poorly characterized and little known about the underlying pathobiology contributing to them , it is likely that definition of these phenotypes and choice of the right outcome measure will allow us to understand which kind of patients can benefit from P01375 inhibitors .",
"P01375 - alpha and X - linked adrenoleukodystrophy . The two most common forms of X - linked adrenoleukodystrophy ( X - P33897 ) , the childhood cerebral form ( CCER ) and the adult form , adrenomyeloneuropathy ( Q9BXJ7 ) , arise from the same mutations in the X - P33897 gene at Xq28 . These two forms are distinguished by the degree of cerebral inflammation . Segregation analysis suggests that an autosomal modifying gene may be a major determinant of phenotype in X - P33897 . Thus , a modifying gene could be involved in initiating or promoting the inflammatory response . In this study we detected a difference in tumor necrosis factor - alpha ( P01375 ) bioactivity , but not P01375 protein levels , in serum from some advanced CCER patients . Early - stage CCER patients and Q9BXJ7 patients were in the normal range . Allelic differences in P01375 or levels of soluble P01375 receptor did not account for bioactivity differences or phenotypic heterogeneity in X - P33897 .",
"Pharmacology of P01375 blockade in rheumatoid arthritis and other chronic inflammatory diseases . P01375 - alpha ( P01375 ) has been unequivocally validated as a therapeutic target in a number of immune - mediated inflammatory disorders ( IMIDs ) . There is now increasing choice of biologic agents within the class all of which successfully neutralize sTNF . But approaches to P01375 inhibition differ and currently include mAbs ( infliximab , adalimumab , and DB06674 ) , either chimeric or human in sequence , a PEGylated Fab ' fragment ( certolizumab ) , and an IgG1 - P20333 fusion protein ( etanercept ) . It is emerging that the pharmacological properties of these three anti - P01375 subtypes differ with respect to Fc function , binding of tmTNF and the possible consequences of this , as well as the ability to form complexes . The mode of administration of each agent , clearance and the local tissue concentrations achieved may also confer unique characteristics of relevance with respect to efficacy and safety .",
"Aspects of P01375 inhibitor therapy in rheumatoid arthritis . Treatment outcomes in rheumatoid arthritis ( RA ) have improved considerably with the use of biological therapies . Since the discovery of the role of tumor necrosis factor ( P01375 ) alpha in the pathogenesis of the disease , three P01375 inhibitors , infliximab , etanercept and adalimumab , have become widely used for the treatment of RA . More recently , two newer P01375 inhibitors - certolizumab pegol and DB06674 - have become available , increasing the armamentarium of therapy . With improved therapies , treatment strategies have also changed , with the aims now being to achieve and maintain remission . This article addresses some of these aspects of treating RA , reviewing the studies on these two newer P01375 inhibitors , certolizumab pegol and DB06674 , and those addressing the induction of remission or low disease activity with P01375 inhibitors and maintenance with less intensive treatment .",
"Current , new and future biological agents on the horizon for the treatment of inflammatory bowel diseases . Biological agents for inflammatory bowel diseases ( Q9UKU7 ) targeting tumor necrosis factor ( P01375 ) have changed the way to treat Q9UKU7 refractory to standard medications and allowed us to reach new therapeutic goals such as mucosal healing and deep remission . A better understanding of the components of the pathological processes that are a hallmark of Q9UKU7 has led to the development of a new family of biological agents in Crohn ' s disease and ulcerative colitis . Biosimilars , which are copy versions of currently licensed biological agents , will be soon available . The biosimilar of infliximab is as effective and as safe as its originator in rheumatologic conditions , while a new anti - P01375 agent , namely DB06674 , has been recently approved for refractory ulcerative colitis . Beyond P01375 blockers , anti - adhesion molecules appear to be a potent drug class for Q9UKU7 . DB09033 was recently approved for both Crohn ' s disease and ulcerative colitis . Numerous other compounds are in the pipeline . Ustekinumab looks very promising for Crohn ' s disease . O15105 antisense oligonucleotide might enrich our armamentarium if preliminary data are confirmed in upcoming clinical trials . Herein , we review the efficacy and safety of new and emerging biological agents that are currently investigated in Q9UKU7 clinical trials .",
"Effects of phenytoin , ketamine , and atropine methyl nitrate in preventing neuromuscular toxicity of acetylcholinesterase inhibitors soman and diisopropylphosphorofluoridate . Toxic manifestations of acetylcholinesterase inhibitors ( P22303 - I ) include muscle twitching and muscle fiber necrosis , in addition to muscarinic manifestations of acetylcholine excess . The P22303 - Is pinacolyl methylphosphonofluoridate ( soman ) or diisopropylphosphorofluoridate ( ___MASK91___ ) were administered to rats to produce spontaneous muscle fiber discharges . Soman produced discharges that arose primarily from the central nervous system ( CNS ) , while those due to ___MASK91___ were generated from the peripheral nerves as well as the CNS . Three drugs were tested for their potential to reduce muscle fiber discharges : atropine methyl nitrate ( Q9BXJ7 ) , ketamine , and phenytoin . DB01221 caused a significant decrease in discharges of CNS origin , while Q9BXJ7 and phenytoin had no effect . For muscle fiber discharges of peripheral origin , all three drugs produced a significant drop in muscle fiber discharges , but phenytoin showed slightly more efficacy than the others . P22303 - I - induced muscle hyperactivity arises from actions on the CNS and on the peripheral nerve in varying proportions for different P22303 - Is . Treatment for the toxicity of P22303 - Is on muscle may be accomplished by administering drugs with distinctive pharmacological actions at target sites in the CNS and peripheral nervous system ( PNS ) where P22303 - Is exert their effects . By attenuating the effects of P22303 - Is at specific CNS or PNS sites , the neuromuscular toxicity can be reduced in a manner specific to the characteristic sites of toxicity of each P22303 - I .",
"Update on biologic therapies in ankylosing spondylitis : a literature review . AIM : The present paper aims to review the recent advances in diagnosis and management of ankylosing spondylitis ( AS ) . METHOD : Medline and abstracts submitted to the recent European League Against Rheumatism ( EULAR ) congress were searched to obtain quality - controlled information on the management of AS . RESULTS : The use of magnetic resonance imaging ( Q9BWK5 ) allows the diagnosis of AS to be made in the pre - radiographic stage . The Assessment in Spondylarthritis International Society recommendations for the management of AS have been modified so that patients with non - radiographic spondyloarthritis ( SpA ) can now be considered for biological therapy . The ' older ' anti - tumour necrosis factor ( P01375 ) continued to be effective in longer - term studies . Studies with longer duration of follow - up have shown that some patients with pre - radiographic SpA entered into prolonged drug - free remission . It is likely that in the foreseeable future , more AS patients will be treated with biological therapies at an earlier stage of the disease . New biologic therapies , DB06674 and secukinumab , are looking promising in improving the signs and symptoms of AS , at least in the short - term . CONCLUSION : Longer - term studies of AS patients treated with infliximab , etanercept and adalimumab continued to show a good clinical response . There is a need for more long - term studies to examine the longitudinal efficacy of DB06674 and secukinumab in AS .",
"Safety issues and concerns of new immunomodulators in rheumatology . INTRODUCTION : The development of biologic therapies has been an enormous leap in the management of patients with rheumatoid and psoriatic arthritis . Since the first anti - P01375 - α therapies , numerous molecules have been identified as targets of immunomodulatory therapies , such as IL - 1 ( anakinra , canakinumab ) , P05231 ( tocilizumab ) , P11836 (+) B cells ( rituximab ) , P16410 ( abatacept ) and two additional anti - P01375 - α therapies ( certolizumab pegol , DB06674 ) . AREAS COVERED : In the present review , we will describe the safety issues related to the immunosuppressive action of these biologic drugs that are mainly represented by infection and malignancy . The risk of infection should be identified before initiating a biologic treatment and markers checked over time , in particular for tuberculosis and hepatitis B and C viruses . Other infections ( bacterial , viral , parasitic ; opportunistic ; surgery - related ) and safety issues may require temporary interruption of the treatment until complete resolution . No significantly increased risk of malignancy , both hematological and solid , has been associated with the use of biologic agents . In all cases , it is difficult to dissect the risks related to biologics from those related to baseline treatments . EXPERT OPINION : Detailed medical history and laboratory screening should be performed before starting biologic therapies . Clinicians should be aware of the different safety profiles associated with different molecules and they should follow up data coming out of the existing registries for biologics in regard to new or old side effects .",
"___MASK71___ -- an anti - Q9Y275 human monoclonal antibody for rheumatoid arthritis . INTRODUCTION : Q9Y275 ( Q9Y275 ) is a major regulatory factor that controls the development and survival of B cells . Elevated serum levels of Q9Y275 have been associated with rheumatoid arthritis ( RA ) . ___MASK71___ is a fully human monoclonal antibody that inhibits Q9Y275 and it is being developed for the treatment of RA . This review aims to summarize up - to - date pharmacological and clinical data of belimumab in the treatment of RA . AREAS COVERED : A literature search was performed on PubMed using keywords , including belimumab , LymphoStat - B , benlysta , Q9Y275 inhibitor , rheumatoid arthritis and autoimmune disease . References of relevant studies were searched by hand . Abstracts of international conferences up to October 2012 were also included . ___MASK71___ was well tolerated in the treatment of RA over 24 weeks . It significantly increased American College of Rheumatology ( P10323 ) 20 responses at week 24 , especially in patients with high disease activity , positive rheumatoid factor , no anti - P01375 treatment experience and those who had failed methotrexate therapy . However , belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA . EXPERT OPINION : These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials . Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA .",
"Round window membrane permeability to DB06674 in guinea pigs : a pilot study . OBJECTIVES / HYPOTHESIS : Autoimmune inner ear disorder is one of a few types of sensorineural hearing loss that is treatable and potentially reversible . Treatment involves oral steroids and methotrexate . Other treatment modalities have been tried with variable success . All such treatments are systemic , with inherent side effects limiting their effectiveness . Recently , tumor necrosis factor ( P01375 ) - α blockers have been suggested as a modality of treatment . The objective of this study was to assess the round window membrane permeability to DB06674 , a P01375 - α blocker . This study is the first to look at the feasibility of local DB06674 delivery into the inner ear , which may allow for targeted immune modulation of autoimmune inner ear disorders without the consequences of systemic treatment . STUDY DESIGN : This is a single - blinded , placebo - controlled , pilot study using guinea pigs to assess round window membrane permeability to DB06674 . METHODS : Golimumab was instilled into the guinea pigs ' middle ear . Inner ear fluid was sampled through the round window membrane after approximately 30 minutes of drug exposure . Golimumab presence in the inner ear was assessed by enzyme - linked immunosorbent assay in both drug - treated and control ears . RESULTS : Higher concentrations of DB06674 were detected in the inner ear fluid samples of DB06674 - exposed ears than in the control ears . The difference was statistically significant ( P < . 001 ) . CONCLUSIONS : Golimumab crosses the round window membrane and is detected in measurable concentrations in the inner ear fluid after 30 minutes of exposure to the membrane . Further studies are needed to learn its pharmacokinetics and the time needed to reach optimal concentration in the inner ear . LEVEL OF EVIDENCE : NA . Laryngoscope , 123 : 2840 - 2844 , 2013 .",
"Modulation of cytokine release from human monocytes by drugs used in the therapy of inflammatory bowel diseases . BACKGROUND : Cytokines produced in the gut mucosa play an important role in the pathogenesis of inflammatory bowel diseases ( Q9UKU7 ) . To determine whether drugs used in the treatment of these diseases modulate cytokine synthesis , we investigated their effects on endotoxin - induced tumour necrosis factor ( P01375 ) - alpha , interleukin ( IL ) - 1 beta and P05231 release by elutriation - purified human monocytes in vitro . METHODS : Drugs tested were dexamethasone , DB00244 , sulphapyridine and zileuton ( a P09917 inhibitor ) . Monocytes were isolated and stimulated with endotoxin , and P01375 , IL - 1 and P05231 levels were determined using an enzyme - linked immunosorbent assay . RESULTS : Monocyte stimulation with endotoxin resulted in an average P01375 release of 2464 +/- 64 pg / 10 ( 6 ) cells , IL - 1 release of 616 +/- 47 pg / 10 ( 6 ) cells and P05231 release of 2259 +/- 148 pg / 10 ( 6 ) cells . Addition of dexamethasone resulted in a reduction of P01375 , IL - 1 and P05231 release to below background levels . DB00891 significantly reduced P01375 and induced IL - 1 release in a dose - dependent fashion , but had no significant effect on P05231 release . 5 - ___MASK73___ did not modulate P05231 synthesis , but significantly reduced IL - 1 and enhanced P01375 synthesis . Zileuton reduced P01375 and P05231 release , but enhanced IL - 1 release . CONCLUSION : We conclude that these anti - inflammatory drugs are able to modulate cytokine release by human monocytes . Further studies are needed to determine whether these effects are related to their therapeutic efficacy in Q9UKU7 .",
"The antibody response against human and chimeric anti - P01375 therapeutic antibodies primarily targets the P01375 binding region . BACKGROUND : In a subset of patients , anti tumour necrosis factor ( P01375 ) therapeutic antibodies are immunogenic , resulting in the formation of antidrug antibodies ( ADAs ) . Neutralising ADAs compete with P01375 for its binding site and reduces the effective serum concentration , causing clinical non - response . It is however unknown to which extent ADAs are neutralising . OBJECTIVES : To study which proportion of antibodies to human ( ised ) anti - P01375 ( adalimumab , DB06674 , certolizumab ) as well as chimeric anti - P01375 ( infliximab ) is neutralising . METHODS : Neutralising capacity of ADAs was assessed using a P01375 competition assay in P00813 - positive sera of patients treated with adalimumab ( n = 21 ) , DB06674 ( n = 4 ) , certolizumab ( n = 9 ) or infliximab ( n = 34 ) sent in to our diagnostic department . RESULTS : In 34 sera with ADAs to adalimumab , DB06674 or certolizumab , > 97 % of the antibodies were neutralising . In 34 sera with ADAs to infliximab > 90 % of the antibodies were neutralising . Further characterisation of the broader antibody response to infliximab revealed that non - neutralising antibodies to infliximab do not target murine domains , but may bind infliximab - unique domains not involved in P01375 binding ( located outside the paratope ) . CONCLUSIONS : Our study shows that ADAs to human ( ised ) as well as chimeric anti - P01375 therapeutic antibodies are largely neutralising . This highly restricted P00813 response suggests an immunodominant role for the paratope of anti - P01375 therapeutics .",
"Clinically relevant advances in rheumatoid arthritis therapy . Owing to the success of biologics in the treatment of rheumatoid arthritis ( RA ) , several novel drugs have been introduced in the therapeutic armamentarium , although not all of them have been approved in all countries worldwide . Among the drugs are tumour necrosis factor ( P01375 ) inhibitors such as certolizumab pegol and DB06674 ( the latter of which was the first P01375 blocker shown to be effective in patients who had been unsuccessfully treated with other P01375 blockers and which can be applied only once a month ) , and the interleukin - 6 receptor antagonist tocilizumab , which not only opens up a completely new field of anti - inflammatory modulation of RA pathophysiology , but also highlights the challenge of novel potential side effects . Moreover , aside from clinical studies showing efficacy in the inhibition of osteoclast activation by the anti - O14788 ( receptor activator of nuclear factor - kappa B ligand ) antibody denosumab , an improved form of steroid application known as slow - release ' tempus tablet ' for treatment of RA and several developments in the small - molecule area have been addressed by clinical trials .",
"Combination systemic therapies in psoriatic arthritis . Psoriatic arthritis ( PsA ) is a chronic , progressive , and debilitating disorder . When monotherapy fails , combination therapy is necessary for the long - term management of these patients . There is currently no review on this subject , and the purpose of this study was to investigate and describe the current literature on combination therapy in PsA . A PubMed MeSH search was performed for psoriatic arthritis and combination therapy , which yielded at total of 83 articles . After excluding reviews and commentaries , and pursuing relevant citations , a total of 21 articles on the subject were found : one study of NSAIDs and methotrexate , three studies of cyclosporine and methotrexate , three studies of non - P01375 biologic inhibitors ( alefacept , ustekinumab ) and methotrexate , and 14 studies of anti - P01375 - inhibitors ( etanercept , adalimumab , infliximab , DB06674 ) and methotrexate . The combination of cyclosporine and methotrexate reduces the dosages and also the side effects of each agent , allowing better disease control with less toxicity . DB00563 in combination with biologic agents , either non - P01375 inhibitors or anti - P01375 inhibitors , may have a role in decreasing side effects , but it does not appear to improve clinical symptoms beyond those attained by biologic monotherapy .",
"Emerging drugs for the treatment of axial and peripheral spondyloarthritis . INTRODUCTION : The topic under discussion is of strong relevance to the field of spondyloarthritis ( SpA ) because , in addition to established biological , there are new promising compounds . The reason for the review is to put all available data together to allow for an overview on recent developments and to especially inform readers about emerging drugs , biologics and small molecules in the field of SpA . AREAS COVERED : This review on new therapies in axial and peripheral SpA comprising psoriatic arthritis ( PsA ) shows , that , in addition to the established anti - P01375 agents infliximab , etanercept , adalimumab , DB06674 , certolizumab and the first biosimilar approved in the EU , there are at least two emerging biologics in the field of SpA : ustekinumab , a compound targeting IL12 / IL - 23 via the p40 subunit of both cytokines works for psoriasis and PsA and probably also for Crohn ' s disease , and the anti - Q16552 antibody secukinumab which has also been shown to work in psoriasis , both compounds seem to also work in ankylosing spondylitis . In addition , the potential of two small molecules , apremilast a phoshodiesterase4 inhibitor and tofacitinib , a januskinase inhibitor is discussed . EXPERT OPINION : Since , in contrast to rheumatoid arthritis , the therapeutic array in SpA is currently limited to P01375 - blockers , and since there is still an unmet need because some patients do not respond to anti - P01375 therapy at all or they loose response , new agents with a different mechanism of action are eagerly awaited .",
"Selective P01375 - α inhibitor - induced injection site reactions . INTRODUCTION : During the last decade , many new biological immune modulators entered the market as new therapeutic principles . P01375 - α is a pro - inflammatory cytokine known to a have a key role in the pathogenic mechanisms of various immune - mediated or inflammatory diseases . P01375 - α blockers have demonstrated efficacy in large , randomized controlled clinical trials either as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs . AREAS COVERED : Although generally well tolerated and safe , potential adverse events may be associated with P01375 - α inhibitor treatment . The authors will briefly review the potential adverse drug reactions and the immunological mechanisms of injection site reactions ( ISRs ) in patients treated with etanercept and adalimumab . EXPERT OPINION : Patients treated with P01375 - α inhibitors can develop ISR around the sites of injections . ' Type IV delayed type reaction ' or ' recall ISRs ' . Eosinophilic cellulitis or ' Wells syndrome ' , ' type III ' and ' type I ' reactions are reported . Long - term studies are necessary to determine the durability of response and the real risk of ISRs with DB06674 and certolizumab pegol . Further studies are also necessary to evaluate the immunogenicity of these drugs .",
"P01375 inhibitors - state of knowledge . P01375 ( P01375 ) is considered a major proinflammatory cytokine , affecting various aspects of the immune reaction . All five P01375 inhibitors currently available on the market ( i . e . , etanercept , infliximab , adalimumab , certolizumab and DB06674 ) are top sellers , although indicated only in autoimmune diseases , including rheumatoid arthritis , Crohn ' s disease and psoriasis . This article briefly discusses the background and place for P01375 inhibitors in modern therapy . The main safety aspects of P01375 inhibitor administration are described in particular , with special consideration of the available meta - analyses . Finally , perspectives on the next - generation P01375 inhibitors and their use in the clinic are given .",
"Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens . Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens ( NAc ) . In the past , different techniques have targeted dopamine levels in the NAc to establish a basal concentration . In this study , we used in vivo fast scan cyclic voltammetry ( FSCV ) in the NAc of awake , freely moving rats . The experiments were primarily designed to capture changes in dopamine caused by phasic firing - that is , the measurement of dopamine ' transients ' . These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc . A series of experiments were designed to probe regulation of extracellular dopamine . DB00281 was infused into the ventral tegmental area , the site of dopamine cell bodies , to arrest neuronal firing . While there was virtually no instantaneous change in dopamine concentration , longer sampling revealed a decrease in dopamine transients and a time - averaged decrease in the extracellular level . Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc . To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter ( Q05940 ) inhibitor , tetrabenazine , to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals . ___MASK93___ almost abolished phasic dopamine release but increased extracellular dopamine to ∼ 500 nM , presumably by inducing reverse transport by dopamine transporter ( Q01959 ) . Taken together , data presented here show that average extracellular dopamine in the NAc is low ( 20 - 30 nM ) and largely arises from phasic dopamine transients .",
"Subacute lupus erythematosus during treatment with DB06674 for seronegative rheumatoid arthritis . We report on a 52 - year - old woman with a history of severe seronegative rheumatoid arthritis . Several conventional therapies and biological therapy with etanercept and infliximab had been unsuccessful . In 2010 she was given DB06674 subcutaneously at a monthly dose of 50 mg . She had a negative Q14201 titre . After 16 months of uninterrupted therapy and sustained response , she developed skin lesions on the upper trunk , back and upper extremities , which worsened on exposure to the sun . The skin biopsy was compatible with subacute lupus erythematosus . Laboratory findings included an Q14201 titre 1 : 640 , negative anti - Ro / SSA and anti - DNA antibodies . Topical corticosteroid therapy proved inadequate . The patient ' s condition improved only after discontinuation of DB06674 . The causal relationship between subacute cutaneous lupus erythematosus and DB06674 is not dose - related and occurs with some delay ( a typical feature of immunological adverse reactions ) . The association is likely , but not confirmed ( because re - challenge was not performed ) . However , a clear improvement was noted after withdrawal . Based on this case , we hypothesized the aetiological role of DB06674 - associated immunogenicity . P01375 - α antagonist - induced lupus - like syndrome ( TAILS ) is a well - known side effect of this class of substances . The British Society of Rheumatology recommends discontinuation of the causal anti - P01375 - α treatment in patients with TAILS .",
"Tailored therapy for severe asthma . Patients with severe asthma or P48444 have often a suboptimal symptom control due to inadequate treatment . A better understanding of pathogenetic mechanisms , phenotypes , endotypes and the new technologies available in the fields of molecular biology and immunogenetics have made it possible to synthesize specific monoclonal antibodies virtually able to interact with any target antigen , or to open a way for new therapeutic target options . At the moment , the only biologic drug available in clinical practice is omalizumab . To overcome the limits of omalizumab , the research has focused on new monoclonal antibodies presenting higher avidity for IgE ( e . g . ligelizumab and lumiximab ) and ability to interact also with low affinity IgE receptor ( FcϵRII ) . At present , many new biological drugs with different mechanisms of action and targets are matter of research . It is very important to identify the asthmatic phenotype in order to select the most appropriate drug for the individual patient . The most promising agents are targeted against cytokines of Th2 pattern and related receptors , such as P60568 ( daclizumab ) and P35225 ( lebrikizumab ) or P05113 in patients with hypereosinophilia ( mepolizumab , reslizumab and benralizumab ) . Other interesting drugs have as a target P01375 - α or its soluble receptor ( infliximab , DB06674 and etanercept ) or IL - 1 ( canakinumab ) , a cytokine with an important systemic proinflammatory action . Finally , the discovery of increased levels of C5a in the airways of asthmatic patients has led to the synthesis of a specific monoclonal antibody ( eculizumab ) . Further help should come from the identification of biomarkers that can guide in choosing the best treatment for the individual patient , such as IgE for omalizumab or periostin for lebrikizumab .",
"Treatment of ulcerative colitis . PURPOSE OF REVIEW : Ulcerative colitis is a chronic inflammatory disease of the colon of unknown cause that is characterized by alternating intervals of active and inactive disease in 80 - 90 % of patients . The primary goal of treatment is to induce and maintain remission using therapy tailored to the individual patient . The purpose of this review was to describe the management of ulcerative colitis with emphasis on the use of anti - tumor necrosis factor ( P01375 ) agents . RECENT FINDINGS : Recent research has shown that new anti - P01375 agents , adalimumab ( P00813 ) and DB06674 , are effective in induction of remission and maintenance of remission in patients with extensive ulcerative colitis . In a recent study , infliximab was found to have comparable efficacy to cyclosporine in treatment of acute severe refractory to corticosteroids ulcerative colitis . SUMMARY : Anti - P01375 therapy should be initiated in patients with acute severe refractory to corticosteroids ulcerative colitis and in patients with moderate - to - severe ulcerative colitis who are not responsive to conventional treatment with aminosalicylates , corticosteroids and immune modulators . Alternatives to infliximab are P00813 and DB06674 . Future research is needed to further assess the long - term efficacy and safety of P00813 and DB06674 in ulcerative colitis .",
"Pharmacogenetics and future therapeutic scenarios : what affects the prediction of response to treatment with etanercept ? There are five tumor necrosis factor alpha ( P01375 - α ) inhibitors available for clinical use that have demonstrated efficacy as monotherapy or in combination with other anti - inflammatory or disease - modifying anti - rheumatic drugs ( DMARDs ) in the treatment of immune - mediated diseases . These include the anti - P01375 - α monoclonal antibodies infliximab , adalimumab , DB06674 , and certolizumab pegol , and the fusion protein , etanercept . The use of pharmacogenetic testing has the potential to increase drug efficiency by identifying genetic factors responsible for a lack of response to , or toxicities from , P01375 - α inhibitors , and could be used to individualize therapy . Several studies have reported associations between genetic polymorphisms and the response to etanercept , but most are small and insufficiently powered to detect effect , and markers tend to be more prognostic than predictive of therapeutic response . Limitations of pharmacogenetic studies include the use of single nucleotide polymorphisms ( SNPs ) , genes in linkage with other loci , interaction of environmental factors , and cohort heterogeneity , all of which can complicate the relationship between genetic polymorphisms and treatment response . Further studies are needed for pharmacogenetics to become a routine part of daily clinical therapeutic practice .",
"P01375 inhibitors in psoriasis : an update . Three inhibitors of tumor necrosis factor ( P01375 ) currently are approved for the treatment of psoriasis : etanercept , infliximab , and adalimumab . The other two P01375 inhibitors , DB06674 and certolizumab pegol , have shown efficacy against plaque psoriasis in clinical trials of psoriatic arthritis ( PsA ) . This article reviews the most recent evidence on the efficacy and safety of the P01375 inhibitors in psoriasis , with special attention to preventing and managing immunogenicity .",
"Screening of 134 single nucleotide polymorphisms ( SNPs ) previously associated with type 2 diabetes replicates association with 12 SNPs in nine genes . More than 120 published reports have described associations between single nucleotide polymorphisms ( SNPs ) and type 2 diabetes . However , multiple studies of the same variant have often been discordant . From a literature search , we identified previously reported type 2 diabetes - associated SNPs . We initially genotyped 134 SNPs on 786 index case subjects from type 2 diabetes families and 617 control subjects with normal glucose tolerance from Finland and excluded from analysis 20 SNPs in strong linkage disequilibrium ( r ( 2 ) > 0 . 8 ) with another typed SNP . Of the 114 SNPs examined , we followed up the 20 most significant SNPs ( P < 0 . 10 ) on an additional 384 case subjects and 366 control subjects from a population - based study in Finland . In the combined data , we replicated association ( P < 0 . 05 ) for 12 SNPs : P37231 Pro12Ala and His447 , Q14654 Glu23Lys and rs5210 , P01375 - 857 , P11168 Ile110Thr , P20823 / TCF1 rs2701175 and GE117881_360 , P35558 - 232 , Q13562 Thr45Ala , P05231 - 598 , and P22413 Lys121Gln . The replication of 12 SNPs of 114 tested was significantly greater than expected by chance under the null hypothesis of no association ( P = 0 . 012 ) . We observed that SNPs from genes that had three or more previous reports of association were significantly more likely to be replicated in our sample ( P = 0 . 03 ) , although we also replicated 4 of 58 SNPs from genes that had only one previous report of association .",
"Long term efficacy and safety of etanercept in the treatment of psoriasis and psoriatic arthritis . Psoriasis is a chronic , immune - mediated inflammatory disease affecting both the skin and joints . Approximately 20 % of patients suffer a moderate to severe form of skin disease and up to 30 % have joint involvement . Standard therapies for psoriasis include topical medications , phototherapy , and both oral systemic and biological therapies whereas therapies for psoriatic arthritis include nonsteroidal anti - inflammatory drugs followed by disease modifying antirheumatic drugs and / or tumor necrosis factor ( P01375 ) - α inhibitors and interleukin - 12 / 23p40 inhibitors . Treatment of both diseases is typically driven by disease severity . In the past decade , major advances in the understanding of the immunopathogenesis of psoriasis and psoriatic arthritis have led to the development of numerous biological therapies , which have revolutionized the treatment for moderate to severe plaque psoriasis and psoriatic arthritis . Anti - P01375 - α agents are currently considered as first line biological therapies for the treatment of moderate to severe psoriasis and psoriatic arthritis . Currently approved anti - P01375 - α agents include etanercept , adalimumab , and infliximab for psoriasis and psoriatic arthritis as well as DB06674 and certolizumab for psoriatic arthritis . In this article , we aim to evaluate the long term safety and efficacy of etanercept in psoriasis and psoriatic arthritis .",
"Optimizing outcomes in rheumatoid arthritis patients with inadequate responses to disease - modifying anti - rheumatic drugs . Conventional DMARDs such as MTX are the mainstay of treatment for patients with RA . However , failure to achieve adequate disease control in many patients , even with combination therapy , has spurred the development of agents that target various immune mediators involved in the disease process . In the past decade , biologic agents have proved viable as alternative or add - on therapy to DMARDs in patients whose disease is inadequately controlled . Well - controlled clinical trials have evaluated the effects of these agents not only on disease activity , but also on inhibition of structural change and improvement in physical function . This article reviews phase 3 clinical trial results on biologic agents that inhibit T - and B - cell activation ( abatacept and rituximab , respectively ) , inflammatory cytokines such as P01375 - α ( adalimumab , etanercept , infliximab , DB06674 and certolizumab ) and P05231 ( tocilizumab ) . Although data comparing the efficacy of the various biologic agents are limited , the availability of biologic therapies with differing mechanisms of action expands therapeutic options for patients whose disease is inadequately controlled with DMARDs and allows for greater individualization of treatment .",
"Psoriasiform exfoliative erythroderma induced by DB06674 . Golimumab is a fully human anti - tumour necrosis factor ( P01375 ) - α monoclonal antibody approved for use in the treatment of active rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis . Psoriasis induced by treatment with anti - P01375 drugs is well documented , but to our knowledge , the development of clinical features of psoriasiform exfoliative erythroderma during treatment with DB06674 has not been previously described .",
"Golimumab and immunogenicity ? 2010 and beyond . Immunogenicity is a frequent adverse event observed with biological agents ' therapy . Challenges of management in patients with rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis treated with DB06674 , an anti - P01375 blocker , include limited generation of antibodies like anti - nuclear , anti - DB06674 , and anti - double stranded DNA antibodies . We conducted here a meta - analysis study in order to evaluate and compare the newly generated antibody levels after DB06674 therapy . The examination of original clinical trials revealed that their levels were neither higher nor significant . Moreover , no evident associations between the induced - antibodies and lupus - like syndromes and / or infusion site reaction were reported . The reduced patients cohort and the absence of systematic newly generated antibodies follow - up might be implicated in the difficulty to evaluate their risk in delaying diseases therapy , and / or predicting for their worse prognosis . Hence , further studies are required to ascertain the real impact of the induced antibodies after DB06674 ' s therapy .",
"Gender difference in the activity but not expression of estrogen receptors alpha and beta in human lung adenocarcinoma cells . The higher frequency of lung adenocarcinoma in women smokers than in men smokers suggests a role for gender - dependent factors in the etiology of lung cancer . We evaluated estrogen receptor ( ER ) alpha and beta expression and activity in human lung adenocarcinoma cell lines and normal lung fibroblasts . Q8N1N2 - length ERalpha and ERbeta proteins were expressed in all cell lines with higher ERbeta than ERalpha . Although estradiol ( E ( 2 ) ) binding was similar , E ( 2 ) stimulated proliferation only in cells from females , and this response was inhibited by anti - estrogens 4 - hydroxytamoxifen ( DB04468 ) and DB00947 . In contrast , E ( 2 ) did not stimulate replication of lung adenocarcinoma cells from males and DB04468 or ICI did not block cell proliferation . Similarly , transcription of an estrogen response element - driven reporter gene was stimulated by E ( 2 ) in lung adenocarcinoma cells from females , but not males . P06401 ( PR ) expression was increased by E ( 2 ) in two out of five adenocarcinoma cell lines from females , but none from males . E ( 2 ) decreased P12830 protein expression in some of the cell lines from females , as it did in MCF - 7 breast cancer cells , but not in the cell lines from males . Thus , ERalpha and ERbeta expression does not correlate with the effect of ER ligands on cellular activities in lung adenocarcinoma cells . On the other hand , coactivator Q15648 expression was higher in lung adenocarcinoma cells from females versus males and higher in adenocarcinoma cells than in normal human bronchial epithelial cells . Q15648 and other ER coregulators may contribute to differences in estrogen responsiveness between lung adenocarcinoma cells in females and males .",
"Anti - P01375 agents in familial Mediterranean fever : report of three cases and review of the literature . Familial Mediterranean fever ( FMF ) is an autoinflammatory disease characterized by recurrent fever , peritonitis / pleuritis , or arthritis attacks . Patients may have FMF - associated mutations of pyrin . The role of biologics such as anti - tumor necrosis factor ( P01375 ) agents ( infliximab , etanercept , adalimumab , DB06674 ) and anakinra , canakinumab , or rilonacept in the treatment of FMF needs to be clarified . Herein we present reports of three patients ( all were positive for HLA Q8TCY5 ) with typical spondylitis associated with FMF who were successfully managed with anti - P01375 agents , along with a literature review . The patients were a 37 - year - old man with concomitant Crohn ' s disease and amyloidosis who was treated with infliximab ( P27352 , 5 mg / kg for 3 years ) and switched to adalimumab ( P00813 ) , and two female patients ( a 24 - year - old and a 31 - year - old ) with FMF who developed severe spondylitis and who were also treated with P00813 . Anti - P01375 agents can control FMF attacks quite effectively and they reveal a promising role in the treatment of FMF - associated amyloidosis and spondylitis .",
"Concomitant loss of p120 - catenin and β - catenin membrane expression and oral carcinoma progression with P12830 reduction . The binding of p120 - catenin and β - catenin to the cytoplasmic domain of P12830 establishes epithelial cell - cell adhesion . Reduction and loss of catenin expression degrades P12830 - mediated carcinoma cell - cell adhesion and causes carcinomas to progress into aggressive states . Since both catenins are differentially regulated and play distinct roles when they dissociate from P12830 , evaluation of their expression , subcellular localization and the correlation with P12830 expression are important subjects . However , the same analyses are not readily performed on squamous cell carcinomas in which P12830 expression determines the disease progression . In the present study , we examined expression and subcellular localization of p120 - catenin and β - catenin in oral carcinomas ( n = 67 ) and its implications in the carcinoma progression and P12830 expression using immunohitochemistry . At the invasive front , catenin - membrane - positive carcinoma cells were decreased in the dedifferentiated ( p120 - catenin , P < 0 . 05 ; β - catenin , P < 0 . 05 ) and invasive carcinomas ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 05 ) and with the P12830 staining ( p120 - catenin , P < 0 . 01 ; β - catenin , P < 0 . 01 ) . Carcinoma cells with β - catenin cytoplasmic and / or nuclear staining were increased at the invasive front compared to the center of tumors ( P < 0 . 01 ) . Although the p120 - catenin isoform shift from three to one associates with carcinoma progression , it was not observed after TGF - β , P01133 or P01375 - α treatments . The total amount of p120 - catenin expression was decreased upon co - treatment of TGF - β with P01133 or P01375 - α . The above data indicate that catenin membrane staining is a primary determinant for P12830 - mediated cell - cell adhesion and progression of oral carcinomas . Furthermore , it suggests that loss of p120 - catenin expression and cytoplasmic localization of β - catenin fine - tune the carcinoma progression .",
"Golimumab . Inflammatory rheumatism : just another P01375 alpha antagonist , no advantage . In the absence of head - to - head comparisons with other P01375 alpha antagonists , which are perfectly feasible , there is no firm evidence that DB06674 has a better risk - benefit balance than other immunosuppressants .",
"Tumour necrosis factor α antagonists in the treatment of rheumatoid arthritis : an immunological perspective . Rheumatoid arthritis ( RA ) is one of the most prevalent autoimmune conditions , affecting approximately 1 % of the adult population . It is associated with decreased quality of life and considerable morbidity and mortality . Various inflammatory cells , including macrophages , neutrophils , mast cells , natural killer cells , B and T cells and stromal cells play key pathophysiological roles in joint inflammation and RA progression . Several cytokines , including interleukin ( IL ) - 1α and / or IL - 1β , and tumour necrosis factor ( P01375 ) - α , are involved at each stage of RA pathogenesis ; namely , by augmenting autoimmunity , sustaining long - term inflammatory synovitis and promoting joint damage . Different cell types are involved in RA pathogenesis through upregulation of several cytokine and soluble pro - inflammatory mediators . As early as the late 1980s , P01375 had been identified as a potential target in RA . Five anti - P01375 drugs , infliximab , adalimumab , certolizumab pegol , etanercept and DB06674 , are now approved for the treatment of RA in various countries . All are bivalent monoclonal antibodies , with the exception of the monovalent certolizumab and etanercept , which is an engineered dimeric receptor . Although all react with and neutralise soluble P01375 in vitro , structural differences in the molecules may contribute to differences in their therapeutic effects and the occurrence of side effects . Pegylated certolizumab permits once - monthly dosing . Other mechanisms of action proposed to be important for the efficacy of anti - P01375 agents are as follows : induction of apoptosis of both monocytes and T cells ; neutralization of membrane P01375 ; antibody - dependent cell - mediated and complement - dependent cytotoxicity ; and reverse signaling via membrane P01375 .",
"Golimumab for severe asthma . BACKGROUND : In severe asthma anti - P01375 therapies might be effective in improving disease control based on preclinical results and on clinical short - term data . However , the long - term efficacy and safety is not known . OBJECTIVE : To discuss the data on DB06674 , an anti - P01375 monoclonal antibody currently used in various forms of arthritis , evaluated as an add - on anti - inflammatory therapy in severe asthma . METHODS / RESULTS : Critical appraisal of the efficacy and safety clinical data . Golimumab was not found to be generally efficacious and demonstrated an unfavourable risk - benefit ratio , but in some asthma subsets its better therapeutic effects might support its use provided the long - term safety is acceptable . CONCLUSIONS : Although at first sight the safety and efficacy data of long - term use of DB06674 in severe asthma might be unsupportive , in some disease subsets it might be really effective .",
"[ Fully human anti P01375 monoclonal antibodies ( adalimumab , DB06674 ) ] . A number of studies have emphasized the critical role of P01375 in the pathogenesis of rheumatoid arthritis ( RA ) . New therapeutics called \" bilologicals \" have been recently admitted for treatment of RA , including infliximab and etanercept , also in Japan . Of note , fully human anti - P01375 a monoclonal antibodies , adalimumab and DB06674 , have been developed to overcome several major problems resulting from the chimeric natures of infliximab . The efficacy and safety of adalimumab have been demonstrated in several clinical trials , as highlighted in this review . Thus , adalimumab has already been approved for treatment of RA in the United States and European Union . The clinical trials of another fully human anti - P01375 monoclonal antibody DB06674 are now under way .",
"Characterization of the aggregation responses of camel platelets . BACKGROUND : Despite evidence of active hemostasis , camel platelets barely respond to common aggregating agents at standard doses used for human platelet aggregation . OBJECTIVES : The purpose of the study was to find out whether camel platelets can be activated by high doses or combinations of aggregation agonists , and to characterize the receptor that mediates the aggregation response to adenosine diphosphate ( ADP ) , the most potent agonist for camel platelets known so far . METHODS : Aggregation studies were performed with platelet - rich plasma ( PRP ) in response to multiple doses or combinations of ADP , epinephrine ( P08473 ) , collagen , and arachidonic acid ( AA ) . Aggregation responses to ADP were performed before and after the addition of the ADP receptor ( Q9H244 ) antagonist ___MASK3___ . RESULTS : Camel platelets responded to ADP at doses higher than the standard dose for human platelets , and to combinations of P08473 and other agonists , while no aggregation was elicited with P08473 or AA alone . ___MASK3___ blocked the ADP - induced aggregation responses in a dose - dependent fashion in vitro . CONCLUSIONS : Camel platelet aggregation can be activated by increasing the dose of some agonists such as ADP , but not AA or P08473 . Irreversible aggregation of camel platelets could also be triggered by a combination of P08473 and ADP , and collagen and AA . Inhibition with clopidogrel suggests that camel platelets express the ADP receptor , Q9H244 . Understanding platelet function in camels will add to the understanding of platelet function in health and disease .",
"Golimumab in patients affected by moderate to severe psoriatic arthritis : an open - label study in thirty - two patients previously treated with other biologics . BACKGROUND : Clinical trials have demonstrated the efficacy of DB06674 ( GLB ) in improving the signs and symptoms of psoriatic arthritis ( PsA ) . OBJECTIVE : The aim of this study was to evaluate the efficacy of GLB in monotherapy in patients affected by PsA with cutaneous involvement unresponsive to other anti - tumor necrosis factor - α ( P01375 - α ) agents . METHODS : This study included 32 patients treated with GLB as monotherapy , at a dosage of 50 mg , subcutaneously , every 4 weeks . Patients were divided into 3 groups ( A , B , and C ) according to their number of previous anti - P01375 - α treatments ( 1 , 2 , or 3 ) . Clinical and laboratory evaluations were performed at weeks 0 , 12 , and 24 . RESULTS : All patients showed significant improvement of their clinical , inflammatory , and quality of life indexes . CONCLUSION : Data suggest that GLB can be successful and safe in patients affected by PsA with skin involvement previously treated with other anti - P01375 - α agents .",
"Golimumab : clinical update on its use for ulcerative colitis . Monoclonal antibodies directed against tumor necrosis factor alpha ( anti - P01375 - α agents ) have dramatically changed the therapeutical approach to inflammatory bowel diseases , such as Crohn ' s disease and ulcerative colitis . A new anti - P01375 drug , DB06674 , has recently been approved for patients with moderate to severe ulcerative colitis . Its efficacy has been demonstrated by preclinical and clinical studies and the drug showed an efficacy and safety profile in line with the other anti - P01375 agents , such as infliximab and adalimumab . This review gives an overview on DB06674 in the treatment of moderate to severe ulcerative colitis .",
"Golimumab : a new anti - P01375 agent for rheumatoid arthritis , psoriatic arthritis and ankylosing spondylitis . Rheumatoid arthritis ( RA ) is a chronic inflammatory systemic disease characterized by symmetric arthritis leading to progressive erosion of cartilage and bone . Psoriatic arthritis and ankylosing spondylitis are also inflammatory arthritides that belong to the spondyloarthritides . Disease - modifying anti - rheumatic drugs and biologic therapies including anti - P01375 agents are used in their treatment . The P01375 antagonists have shown rapid and sustained therapeutic responses . However , a substantial number of patients fail to respond to anti - P01375 agents or experience side effects . Golimumab is a human monoclonal antibody to P01375 - α requiring less frequent administration compared with current anti - P01375 products . Various trials have shown promising results in terms of efficacy and safety in methotrexate - naive and - resistant patients with RA as well as in patients previously treated with other anti - P01375 agents . The efficacy of DB06674 has also been demonstrated in patients with psoriatic arthritis and ankylosing spondylitis .",
"The effect of neutralizing antibodies on the sustainable efficacy of biologic therapies : what ' s in it for African and Middle Eastern rheumatologists . Over the last decade , biologic therapeutic proteins have advanced the treatment of diseases such as rheumatoid arthritis ( RA ) . Therapeutic antibodies such as infliximab , adalimumab , rituximab , tocilizumab , DB06674 , certolizumab pegol , the receptor construct etanercept , and abatacept , an anticluster of differentiation ( CD ) 80 / anti - P42081 fusion protein , are used as treatment for RA and ankylosing spondylitis ( AS ) . DB00065 , adalimumab , DB06674 , certolizumab pegol , and etanercept are inhibitors of tumor necrosis factor ( P01375 ) , a key regulator of inflammation . Left untreated , progression of rheumatic diseases due to inflammation can lead to irreversible joint damage and serious disability . One limitation for the use of therapeutic antibodies is immunogenicity , the induction of antibodies by the adaptive immune system in response to foreign substances . The development of antidrug antibodies ( ADAs ) has a varying impact on the clinical efficacy of biologic agents for the treatment of RA and AS , depending on whether the ADAs are neutralizing or non - neutralizing . Studies have indicated that neutralizing ADAs are associated with a reduced efficacy , decreased drug survival , increased instances of dose escalation , and adverse events . Comparison studies of anti - P01375 biologics have demonstrated that each drug has a different sustained efficacy profile depending on immunogenicity . The purpose of this review is to provide rheumatologists with information regarding the effect of neutralizing antibodies on the sustainable efficacy of anti - P01375 biologic therapies . This information will be of value to practicing rheumatologists in Africa and the Middle East who should take into account the potential for changes in the efficacy and safety of biologic therapies and closely monitor patients under their care .",
"Advances in the management of psoriatic arthritis . Psoriatic arthritis ( PsA ) , which affects musculoskeletal structures , skin and nails , is a heterogeneous chronic inflammatory disease with a wide clinical spectrum and variable course . Patients with PsA are more likely than healthy individuals to have metabolic syndrome or cardiovascular disease . To include these comorbidities , ' psoriatic disease ' has been suggested as an umbrella term . The management of PsA has changed tremendously over the past decade owing to early diagnosis and improvement in treatment strategies , including , early referral from dermatologists and primary - care physicians to rheumatologists , early initiation of therapy , treating to the target of remission or low disease activity , and advances in pharmacological therapy . Outcome assessment is also improving , because of validated instruments for clinical disease manifestations . The commercialization of P01375 blockers , including adalimumab , etanercept , DB06674 and infliximab , is representative of a revolution in the treatment of PsA . A new anti - P01375 agent , certolizumab pegol , and a fully human monoclonal antibody against IL - 12 and IL - 23 , ustekinumab , are approved for the treatment of active PsA . The efficacy of ustekinumab suggests that inhibiting the type 17 T helper pathway might be an alternative to blocking P01375 . PsA management must now use improved measures to predict patient outcomes and define remission , and develop better - targeted therapies .",
"Current and emerging biologics for ulcerative colitis . Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy . Hence , different biological agents that target specific immunological pathways are be - ing investigated for treating ulcerative colitis . Anti - tumor necrosis factor ( P01375 ) agents were the first biologics to be used for treating inflammatory bowel disease . For example , infliximab and adalimumab , which are anti - P01375 agents , are be - ing used for treating ulcerative colitis . Recently , DB06674 , another anti - P01375 agent , and vedolizumab , an anti - adhesion therapy , have been approved for ulcerative colitis by the U . S . Food and Drug Administration . In addition , new medications such as tofacitinib , a Janus kinase inhibitor , and etrolizumab , another anti - adhesion therapy , are emerging as therapeutic agents . Therefore , there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage .",
"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .",
"Role of DB06674 , a P01375 inhibitor , in the treatment of the psoriatic arthritis . Psoriatic arthritis ( PsA ) is an inflammatory arthritis that affects many psoriasis patients and can often have a debilitating disease progression . Golimumab is a new tumor necrosis factor ( P01375 ) antagonist recently approved by the FDA for controlling signs and symptoms of psoriatic arthritis . In a Phase III clinical trial in patients with PsA , patients receiving DB06674 showed significant improvement in the signs and symptoms of disease . It was usually well tolerated , but adverse events generally occurred more in patients receiving DB06674 compared to placebo . Golimumab has also recently shown efficacy in slowing structural damage in PsA . This new biologic therapy provides physicians with another option in the treatment of this inflammatory arthritis while offering patients certain advantages over other P01375 antagonists .",
"Modeling of Q14654 and inhibition mechanism of the natural ligand , ellagic acid , using molecular docking . Diabetes mellitus is a disorder in which blood sugar ( glucose ) levels are abnormally high because the body does not produce enough insulin to meet its needs . Post - prandial hyperglycemia ( PPHG ) is an independent risk factor for the development of macro vascular complications . It is now recognized that normalizing post - prandial blood glucose is more difficult than normalizing fasting glucose . DB01345 channels are the most widely distributed type of ion channel and are found in virtually all living organisms . The function of KATP channels is best understood in pancreatic beta cells , the membrane potential of which is responsive to external glucose concentration . Beta cells show a remarkably complex electrical bursting behavior in response to an increase in glucose level . DB00731 and ___MASK43___ are a class of insulin secretagog agents that lowers blood glucose levels by stimulating insulin secretion from the pancreas . These compounds interact with the DB00171 - sensitive potassium ( K + DB00171 ) channel in pancreatic beta cells . However , the side effects of these drugs overpass their uses , and the need to identify compounds with less adverse effects is exigent . In our research study , we used the natural compound ellagic acid , which is an already proven anti - carcinogen , anti - mutagen , and anticancer initiator , for its anti - diabetic activity in comparison to the two commercial drugs ( DB00731 and ___MASK43___ ) . The drugs and the compounds were docked to the DB00171 - dependent potassium channel and their energy value showed that the compound had higher binding value than the commercial drugs . Then an ADME / Tox analysis for the compound was carried out which showed that ellagic can be a possible lead molecule .",
"Current evidence in the field of the management with P01375 - α inhibitors in psoriatic arthritis and concomitant hepatitis C virus infection . INTRODUCTION : Psoriatic arthritis ( PsA ) is a chronic inflammatory condition involving the spine , enthesis and peripheral joints , which is associated with psoriasis . PsA therapy varies from use of NSAIDs to disease - modifying anti - rheumatic agents ( DMARDs ) . However , their use can represent a limitation in patients with concomitant hepatitis C virus ( HCV ) infection . In the last few decades , anti - P01375 - α therapy has opened new horizons in the treatment of PsA . Hence , the purpose of this review is to explore the efficacy and safety of anti - P01375 - α agents in PsA and concomitant HCV infection . AREAS COVERED : We reviewed the available medical literature to find all cases of PsA and concomitant HCV infection treated with P01375 - α inhibitors . We found a total of 38 cases of patients with PsA and concomitant HCV infection in therapy with anti - P01375 - α agents . EXPERT OPINION : The available literature , summarized in this review , still remains very limited . Data suggest that therapy with the anti - P01375 - α agents , mainly etanercept and adalimumab , at least with short - term use , would appear efficacious and reasonably safe in the management of PsA patients with concomitant HCV infection . With regard to infliximab , efficacy and safety have been scarcely explored , whereas in the case of DB06674 and certolizumab no report was found , may be due to their recent introduction on the market .",
"P35372 and P20813 gene variants as risk factors in methadone - related deaths . ___MASK20___ is a medication valued for its effectiveness in the treatment of heroin addiction ; however , many fatal poisonings associated with its use have been reported over the years . We have examined the association between P20813 and micro - opioid receptor ( P35372 ) gene variations and apparent susceptibility to methadone poisoning . Genomic DNA was extracted from postmortem whole blood of 40 individuals whose deaths were attributed to methadone poisoning . The presence of P20813 * 4 ,* 9 , and * 6 alleles and the P35372 A118G variant was determined by SNP genotyping . P20813 * 4 , * 9 , and * 6 alleles were found to be associated with higher postmortem methadone concentrations in blood ( P < or = 0 . 05 ) . P35372 A118G was also associated with higher postmortem methadone concentrations in blood but not to a level of statistical significance ( P = 0 . 39 ) . In these methadone - related deaths , P35372 118GA was associated with higher postmortem benzodiazepine concentrations ( P = 0 . 04 ) , a finding not associated with morphine - related deaths . The risk of a methadone - related fatality during treatment may be evaluated in part by screening for P20813 * 6 and A118G .",
"Catecholamine - producing cells in the synovial tissue during arthritis : modulation of sympathetic neurotransmitters as new therapeutic target . BACKGROUND : The proinflammatory and anti - inflammatory role of the sympathetic nervous system in early and late inflammation is an unresolved paradox . A drastic loss of sympathetic nerve fibres in the synovial tissue of patients with rheumatoid arthritis ( RA ) has previously been demonstrated . The presence of tyrosine hydroxylase ( TH ) - positive cells in RA and osteoarthritis ( OA ) has been determined , but the role of these cells in inflammation is still unclear . OBJECTIVE : To characterise TH - positive cells in inflamed RA and OA synovial tissue and to study their role in inflammation . METHODS : Synovial samples were obtained from 32 patients with OA and 19 patients with RA and from 10 control patients . Synovial tissue samples were used for immunofluorescence staining . Synovial cells were isolated by tissue digestion and immediately used for cell culture . For in vivo experiments , collagen type - II arthritis in DBA / 1J mice was induced . RESULTS : TH + cells were present only in inflamed tissue and not in controls . Catecholamine - storing vesicles and vesicular monoamine transporter 2 ( Q05940 ) were identified in the synovial tissue . Experimental increase of cytoplasmic catecholamines by Q05940 blockade strongly reduced tumour necrosis factor ( P01375 ) independently of canonical extracellular β - adrenergic signalling . In addition , Q05940 blockade increased cyclic AMP ( DB02527 ) and DB02527 responsive element binding protein , responsible for P01375 inhibition . In vivo , appearance of Q05940 positive cells was confirmed . Q05940 blockade ameliorated inflammation also in vivo . CONCLUSIONS : This study demonstrates that local catecholamine - producing cells start to replace sympathetic nerve fibres around the onset of disease , and modulation of locally produced catecholamines has strong anti - inflammatory effects in vivo and in vitro .",
"Targeting tumor necrosis factor alpha in psoriasis and psoriatic arthritis . BACKGROUND : Psoriasis is an immune - mediated chronic inflammatory disease triggered and maintained by inflammatory mediators , including P01375 . OBJECTIVE / METHODS : To summarize the role of anti - P01375 agents psoriasis therapy , focusing on the mechanisms and biological pathways involved , by reviewing relevant literature . RESULTS / CONCLUSIONS : The three P01375 antagonists currently available ( etanercept , infliximab and adalimumab ) are effective in the therapy of psoriasis and psoriatic arthritis . DB08904 and DB06674 are P01375 inhibitors not approved for therapy of psoriasis yet . In addition to neutralizing soluble P01375 , P01375 blockers bind to membrane P01375 and change the behavior of P01375 - expressing cells , resulting in hastened cell cycle arrest and apoptosis , and suppression of cytokine production . P01375 blockers may also affect adaptive immune responses by reducing T helper cell ( Th ) 1 and Th17 responses , and favoring the development of T - regulatory cells . P01375 antagonists can regulate differentiation and activation of osteoclasts , thus reducing bone destruction in psoriatic arthritis . Anti - P01375 agents differ in their pharmacokinetics and pharmacodinamic properties , which is reflected in their therapeutic and safety profiles . The safety of P01375 antagonists has been established , and patient selection and monitoring allow risk minimization .",
"Efficacy of antitumor necrosis factor ( α ) agents on patients with ankylosing spondylitis . OBJECTIVES : This study was designed to investigate the efficacy of antitumor necrosis factor ( P01375 )( a ) agents ( etanercept , infliximab , DB06674 or adalimumab ) in ankylosing spondylitis ( AS ) . METHODS : A literature search was done using PubMed , Embaseand Cochrane databases . The reference section of all primary studies was inspected for additional references , and only those reporting the results of a randomized - controlled trial comparing etanercept , infliximab or adalimumab with placebo for patients with AS were included in this analysis . RESULTS : Eleven trials with 1851 patients were included . Compared with placebo , anti - P01375 ( α ) agents was associated with significantly higher rates of Assessment in Ankylosing Spondylitis ( ASAS ) 20 responders ( risk ratio [ RR ] : 2 . 45 , 95 % confidence interval [ CI ] : 2 . 13 - 2 . 82 ; P < 0 . 00001 ) , ASAS 50 responders ( RR : 3 . 77 , 95 % CI : 2 . 87 - 4 . 95 ; P < 0 . 00001 ) , ASAS 70 responders ( RR : 3 . 25 , 95 % CI : 1 . 97 - 5 . 35 ; P < 0 . 00001 ) and patients with partial remission ( RR : 5 . 39 , 95 % CI : 3 . 25 - 8 . 93 ; P < 0 . 00001 ) . In addition , there were more patients with at least 50 % improvement in the Bath Ankylosing Spondylitis Disease Activity Index score in the experimental groups ( RR : 3 . 07 , 95 % CI : 2 . 44 - 3 . 86 ; P < 0 . 00001 ) . Most adverse events in both treatment groups were mild or moderate in severity . CONCLUSIONS : Anti - P01375 ( a ) agents is an effective and well - tolerated treatment for reducing clinical symptoms of AS .",
"Two cases of Takayasu ' s arteritis occurring under anti - P01375 therapy . Takayasu ' s arteritis is a granulomatous , large vessel vasculitis that affects the aorta , its major branches and the pulmonary arteries . Compelling evidence exists to support the notion that Takayasu ' s arteritis is a T - cell mediated process and that tumor necrosis factor alpha ( TNFa ) is an important factor in the pathogenesis of this disease . Moreover , encouraging results from recent studies support the use of anti - TNFa therapy for relapsing or resistant cases of Takayasu ' s arteritis . Here , however , we describe the case of two patients : one with seropositive rheumatoid arthritis , the other with HLA - Q8TCY5 negative spondylarthropathy , who developed Takayasu ' s arteritis during treatment with TNFa inhibitors ( adalimumab and DB06674 respectively ) . This is the first report of Takayasu ' s arteritis in rheumatic patients under TNFa blocking agents which suggests the presence of different pathogenetic mechanism in a subgroup of patients with Takayasu ' s arteritis , as well as a potential role of TNFa blockers as triggers of this disease in some cases .",
"___MASK77___ sulfate inhibits P01375 and P01579 - induced production of P05362 in human retinal pigment epithelial cells in vitro . PURPOSE : ___MASK77___ sulfate ( GS ) is a naturally occurring sugar that possesses some immunosuppressive effects in vitro and in vivo , but its mechanism is unknown . We investigated whether GS could modulate the proinflammatory cytokine - induced expression of the gene for intercellular adhesion molecule ( ICAM ) - 1 , an inflammatory protein in human retinal pigment epithelial ( Q96AT9 ) cells . METHODS : ARPE - 19 cells were used as a model to determine the effects of GS on the expression of the P05362 gene upregulated by P01375 or P01579 , by Western blot analysis and semiquantitative reverse transcription polymerase chain reaction ( RT - PCR ) . The activation and nuclear translocation of the nuclear factors NF - kappaB and P42224 were evaluated by immunocytochemistry , Western blot analysis , and electrophoretic mobility shift assay ( EMSA ) . RESULTS : Both P01375 and P01579 increased the expression of P05362 at the mRNA and protein levels in a time - and dose - dependent manner in ARPE - 19 cells . GS effectively downregulated the P01375 - or P01579 - induced expression of P05362 in the protein and mRNA level in a dose - dependent manner . GS further inhibited the nuclear translocation of p65 proteins in P01375 and phosphorylated P42224 in P01579 - stimulated ARPE - 19 cells . CONCLUSIONS : GS inhibits the expression of the P05362 gene in ARPE - 19 cell stimulated with P01375 or P01579 through blockade of NF - kappaB subunit p65 and nuclear translocation of P42224 . This study has demonstrated a potentially important property of GS in reducing P05362 mediated inflammatory mechanisms in the eye .",
"Immunogenicity of anti - P01375 biologic therapies for rheumatoid arthritis . Currently , five anti - P01375 biologic agents are approved for the treatment of rheumatoid arthritis ( RA ) : adalimumab , infliximab , etanercept , DB06674 and certolizumab pegol . Formation of anti - drug antibodies ( P00813 ) has been associated with all five agents . In the case of adalimumab and infliximab , immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response , but for the other three agents , data on immunogenicity are scarce , suggesting that further research would be valuable . Low P00813 levels might not influence the efficacy of anti - P01375 therapy , whereas high P00813 levels impair treatment efficacy by considerably reducing unbound drug levels . Immunogenicity is not only an issue in patients treated with anti - P01375 biologic agents ; the immunogenicity of other therapeutic proteins , such as factor VIII and interferons , is well known and has been investigated for many years . The results of such studies suggest that investigations to determine the optimal treatment regimen ( drug dosing , treatment schedule and co - medication ) required to minimize the likelihood of P00813 formation might be an effective and practical way to deal with the immunogenicity of anti - P01375 biologic agents for RA .",
"DB00173 nucleotides inhibit cytokine generation by human mast cells through a Gs - coupled receptor . DB00171 and ADP activate functionally distinct G protein - coupled purinergic ( P2Y ) receptors . We determined the expression and function of adenine nucleotide - specific P2Y receptors on cord blood - derived human mast cells ( hMCs ) . Human MCs expressed mRNA encoding the ADP - specific P47900 , Q9H244 , and Q9BPV8 receptors ; the DB00171 / UTP - specific P41231 receptor ; and the DB00171 - selective Q96G91 receptor . ADP ( 0 . 05 - 50 muM ) induced calcium flux that was completely blocked by a P47900 receptor - selective antagonist and was not cross - desensitized by DB00171 . Low doses of ADP induced strong phosphorylation of P29323 and p38 MAPKs ; higher doses stimulated eicosanoid production and exocytosis . Although MAPK phosphorylation was blocked by a combination of P47900 - and Q9H244 - selective antagonists , neither interfered with secretion responses . Unexpectedly , both ADP and DB00171 inhibited the generation of P01375 in response to the O60603 ligand , peptidoglycan , and blocked the production of P01375 , P10145 , and MIP - 1beta in response to leukotriene D ( 4 ) . These effects were mimicked by two DB00171 analogues , adenosine 5 '- O -( 3 - thiotriphosphate ) and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate ( BzATP ) , but not by adenosine . ADP , DB00171 , adenosine 5 '- O -( 3 - thiotriphosphate ) , and 2 ', 3 '- O -( 4 - benzoyl - benzoyl ) adenosine 5 '- triphosphate each induced DB02527 accumulation , stimulated the phosphorylation of CREB , and up - regulated the expression of inducible DB02527 early repressor , a CREB - dependent inhibitor of cytokine transcription . Human MCs thus express several ADP - selective P2Y receptors and at least one G ( s )- coupled ADP / DB00171 receptor . Nucleotides could therefore contribute to MC - dependent microvascular leakage in atherosclerosis , tissue injury , and innate immunity while simultaneously limiting the extent of subsequent inflammation by attenuating the generation of inducible cytokines by MCs .",
"Novel P01375 antagonists for the treatment of rheumatoid arthritis . IMPORTANCE OF THE FIELD : P01375 antagonists have become an integral part of the standard of care for patients with rheumatoid arthritis ( RA ) . Two additional P01375 antagonists have recently been approved in the US for this indication , and clinicians will need to understand the data on the efficacy and safety of these agents in order to properly place them into the clinical treatment algorithm . AREAS COVERED IN THIS REVIEW : This review covers the published clinical trial data on the use of certolizumab and DB06674 for RA . The literature search included manuscripts published through September 2009 and abstracts from major meetings ( P10323 and EULAR ) in 2007 - 2009 . WHAT THE READER WILL GAIN : This paper will review the efficacy and safety of DB06674 and certolizumab in the treatment of RA at various stages of disease . Use of these agents will be described in the context of other available alternatives , including other P01375 antagonists and other biologic therapies . TAKE HOME MESSAGE : Certolizumab and DB06674 have comparable efficacy and safety profiles compared with previously approved P01375 antagonists . These two agents have several unique theoretical benefits when compared to existing agents , but the available published data do not suggest a clear clinical advantage at this time ."
] |
[
"___MASK20___",
"___MASK3___",
"___MASK43___",
"___MASK54___",
"___MASK71___",
"___MASK73___",
"___MASK77___",
"___MASK91___",
"___MASK93___"
] |
___MASK71___
|
MH_train_492
|
interacts_with DB01276?
|
[
"P09936 inhibition involved in CREB dephosphorylation in hippocampal slices . Ubiquitin C - terminal hydrolase Q9NUQ9 ( P09936 ) is abundantly expressed in the brain and is critical for the normal function of synapses . DB02527 response element binding protein ( CREB ) is a transcription factor which initiates the expression of proteins that related to the regulation of synaptic plasticity and memory function . Studies have shown that P09936 can influence the expression and activity of CREB , but the underlying mechanisms remain unclear . In this study , we used P09936 inhibitor LDN to treat mice hippocampal slices and found that P09936 inhibition caused the dephosphorylation of CREB at Ser133 site . Meanwhile , hyperphosphorylation of microtubule - associated protein tau ; increased expression of synaptic protein components of P78352 and synapsin - 1 , and decreased activity of tyrosine kinase Fyn were observed after P09936 inhibition . Moreover , all these alternations have an influence on the normal function of N - methyl - D - aspartate ( DB01221 ) receptor Q13224 subunit which is likely to result in the dephosphorylation of CREB . We also found that LDN treatment mediated protein kinase A ( PKA ) deactivation was involved in the dephosphorylation of CREB . Thus , our study introduces a novel possible mechanism for elaborating the effects of P09936 inhibition on the CREB activity and the implicated signaling pathways .",
"Inhibition of noradrenaline release via presynaptic P28222 receptors of the rat vena cava . In the rat inferior vena cava preincubated with 3H - noradrenaline , the effects of nine serotonin ( 5 - HT ) receptor agonists and of eight antagonists ( including two beta - adrenoceptor blocking agents ) on the electrically evoked 3H overflow were determined . 1 . 5 - HT , 5 - carboxamido - tryptamine , 5 - methoxy - 3 ( 1 , 2 , 3 , 6 - tetrahydropyridine - 4 - yl )- 1H - indole ( RU 24969 ) , 5 - methoxytryptamine , N , N - dimethyl - 5HT , tryptamine and 5 - aminotryptamine inhibited the evoked 3H overflow . The potencies of these agonists in inhibiting overflow were significantly correlated with their affinities for P28222 binding sites , but not with their affinities for P08908 , P28335 or 5 - HT2 binding sites . 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) , a P08908 receptor agonist , and ipsapirone , a partial agonist at these receptors , did not inhibit overflow . 2 . Cyanopindolol facilitated the evoked 3H overflow , an effect which was abolished by propranolol . The maximum inhibition of overflow obtainable with 5 - HT was diminished by cyanopindolol . 3 . The concentration - response curve for 5 - HT was shifted to the right by metitepine , metergoline , quipazine , 6 - chloro - 2 -( 1 - piperazinyl ) pyrazine ( MK 212 ) and propranolol which , given alone , did not affect 3H overflow . The apparent pA2 values of these antagonists tended to be correlated with their affinities for P28222 ( but not P08908 , P28335 or 5 - HT2 ) binding sites . Ketanserin , a 5 - HT2 receptor antagonist , and spiperone , which blocks 5 - HT2 and P08908 but not P28222 or P28335 receptors , failed to antagonize the effect of 5 - HT . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"Suppressive effects of glucagon - like peptide - 1 on interferon - gamma - induced nitric oxide production in insulin - producing cells is mediated by inhibition of tumor necrosis factor - alpha production . During the development of Type 1 diabetes , inflammatory cytokines are known to induce the expression of inducible nitric oxide synthase ( P35228 ) in pancreatic islets , and subsequent production of nitric oxide ( NO ) contributes to beta cell destruction . Glucagon - like peptide - 1 ( P0C6A0 ) has been shown to reduce cytokine - induced apoptosis of beta cells . In this study , we investigated whether P0C6A0 affects cytokine - induced NO production , resulting in the inhibition of beta - cell apoptosis . We treated MIN6N8a mouse beta cells with interferon ( IFN ) - gamma in the presence or absence of P0C6A0 and found that P01579 treatment induced P35228 mRNA expression and NO production , which was significantly inhibited by treatment with P0C6A0 . Blocking of P43220 signaling via the cyclic AMP and phosphatidylinositol 3 - kinase pathway did not directly affect the suppressive effect of P0C6A0 on IFN - gamma - induced P35228 mRNA expression . Further studies revealed that P01579 induced the expression of P01375 mRNA and protein , which synergistically induced NO production , and P0C6A0 treatment inhibited this induction of P01375 . To examine whether the reduction of P01375 by P0C6A0 treatment plays a role in suppressing NO production , we treated MIN6N8a cells with P01579 in the presence of anti - P01375 neutralizing antibody and found that NO production was reduced . In addition , treatment of mouse islets with P0C6A0 inhibited the expression of P35228 and TNFmRNA . These results suggest that P0C6A0 inhibits P01579 - induced NO production by suppression of P01375 production .",
"The contribution of serotonin P28335 and melanocortin - 4 receptors to the satiety signaling of glucagon - like peptide 1 and liraglutide , a glucagon - like peptide 1 receptor agonist , in mice . Glucagon - like peptide 1 ( P0C6A0 ) , an insulinotropic gastrointestinal peptide produced mainly from intestinal endocrine L - cells , and liraglutide , a P43220 ( P43220 ) agonist , induce satiety . The serotonin P28335 receptor ( 5 - HT2CR ) and melanoroctin - 4 receptor ( P32245 ) are involved in the regulation of food intake . Here we show that systemic administration of P0C6A0 ( 50 and 200μg / kg ) - induced anorexia was blunted in mice with a 5HT2CR null mutation , and was attenuated in mice with a heterozygous P32245 mutation . On the other hand , systemic administration of liraglutide ( 50 and 100μg / kg ) suppressed food intake in mice lacking 5 - HT2CR , mice with a heterozygous mutation of P32245 and wild - type mice matched for age . Moreover , once - daily consecutive intraperitoneal administration of liraglutide ( 100μg / kg ) over 3days significantly suppressed daily food intake and body weight in mice with a heterozygous mutation of P32245 as well as wild - type mice . These findings suggest that P0C6A0 and liraglutide induce anorexia via different central pathways .",
"___MASK13___ is a suppressor of apoptosis in bovine corpus luteum . Glucocorticoid ( GC ) acts as a modulator of physiological functions in several organs . In the present study , we examined whether GC suppresses luteolysis in bovine corpus luteum ( CL ) . ___MASK13___ ( an active GC ) reduced the mRNA expression of caspase 8 ( Q14790 ) and caspase 3 ( P42574 ) and reduced the enzymatic activity of P42574 and cell death induced by tumor necrosis factor ( P01375 ) and interferon gamma ( P01579 ) in cultured bovine luteal cells . mRNAs and proteins of GC receptor ( P04150 ) , 11beta - hydroxysteroid dehydrogenase type 1 ( P28845 ) , and P80365 were expressed in CL throughout the estrous cycle . Moreover , the protein expression and the enzymatic activity of P28845 were high at the early and the midluteal stages compared to the regressed luteal stage . These results suggest that cortisol suppresses P01375 - P01579 - induced apoptosis in vitro by reducing apoptosis signals via Q14790 and P42574 in bovine CL and that the local increase in cortisol production resulting from increased P28845 at the early and midluteal stages helps to maintain CL function by suppressing apoptosis of luteal cells .",
"Increased plasma adiponectin concentrations are associated with microangiopathy in type 1 diabetic subjects . AIMS / HYPOTHESIS : P01308 resistance is related to an increased risk of diabetic retinopathy and nephropathy in type 1 diabetes . Patients with insulin resistance and / or macrovascular disease have abnormally low levels of adiponectin . The aim of this study was to investigate the relationships between adiponectin and renal and retinal diabetic complications in type 1 diabetic patients . METHODS : In this 6 - year prospective follow - up observational study , we evaluated the severity of retinopathy at baseline and determined the incident risk of microalbuminuria in 126 normoalbuminuric patients with type 1 diabetes . Each patient was age - and sex - matched to two non - diabetic control subjects . RESULTS : Plasma adiponectin concentrations were significantly higher in diabetic subjects than in control subjects ( p < 0 . 0001 ) . The adiponectin concentration was significantly higher in patients with severe diabetic retinopathy than in those without ( Q04695 +/- 14 . 0 vs 29 . 0 +/- 13 . 0 microg / ml , p = 0 . 0005 ) . The 18 patients who developed persistent microalbuminuria had higher adiponectin concentrations than the other patients ( 35 . 8 +/- 14 . 5 vs 30 . 6 +/- 13 . 7 microg / ml ) . Increased adiponectin concentrations were independently associated with the occurrence of microalbuminuria ( p = 0 . 0158 ) after adjustment for baseline urinary albumin concentration ( p = 0 . 004 ) , sex ( p = 0 . 0054 ) , blood pressure ( NS ) and metabolic control ( NS ) . CONCLUSIONS / INTERPRETATION : The elevated adiponectin concentrations observed in subjects with microvascular disease may indicate an altered regulation of this adipocytokine in patients with complications associated with type 1 diabetes .",
"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .",
"Exendin - 4 attenuates lipopolysaccharides induced inflammatory response but does not protects H9c2 cells from apoptosis . BACKGROUND : Glucagon - like peptide - 1 ( P0C6A0 ) and its analogues are reported to exert wide - ranging cardiovascular actions in preclinical and clinical studies . We thus investigated whether the P43220 agonist , exendin - 4 , has inhibitory effects on LPS - stimulated inflammatory response in cardiomyoblasts . METHODS : H9c2 cardiomyoblasts were exposed to LPS and treated with exendin - 4 . Expressions of proinflammatory mediators were assessed using quantitative real - time PCR . Nuclear localization of NF - κB was examined using immunoblotting . mRNA expression of inducible nitric oxide synthase ( P35228 ) and nitric oxide ( NO ) production were evaluated by q PCR and NO assay . Furthermore , anti - apoptotic effect of exendin - 4 in LPS - stimulated H9c2 cells was determined using qPCR and immunoblot . RESULTS : Exposure to LPS increased mRNA expressions of P01375 - α , P35354 and P14780 in H9c2 cells . It also caused increases in P35228 mRNA expression and NF - κB nuclear translocation . Exendin - 4 dose - dependently downregulated mRNA levels of P01375 - α , P35354 and P14780 in LPS - stimulated H9c2 cells . It also reduced NF - κB nuclear translocation . Treatment with exendin - 4 showed no effect on LPS - induced apoptosis in H9c2 cells . CONCLUSIONS : Exendin - 4 exerts an effect on cardiomyoblast exposed to LPS by inhibiting mRNA expression of inflammatory mediators and suppressing NF - κB activation . These effects are consistent with some of the observed anti - inflammatory properties of exendin - 4 , as well as its beneficial actions on the cardiovascular system .",
"___MASK66___ ' s anti - inflammatory effects require glucosamine 6 - O - sulfation and are mediated by blockade of L - and P - selectins . ___MASK66___ has been used clinically as an anticoagulant and antithrombotic agent for over 60 years . Here we show that the potent anti - inflammatory property of heparin results primarily from blockade of P16109 and P14151 . ___MASK66___ and chemically modified analogs were tested as inhibitors of selectin binding to immobilized sialyl Lewis ( X ) and of cell adhesion to immobilized selectins or thrombin - activated endothelial cells . Compared with unfractionated heparin , the modified heparinoids had inhibitory activity in this general order : over - O - sulfated heparin > heparin > 2 - O , 3 - O - desulfated > or = N - desulfated / N - acetylated heparin > or = carboxyl - reduced heparin > or = N -, 2 - O , 3 - O - desulfated heparin >> 6 - O - desulfated heparin . The heparinoids also showed similar differences in their ability to inhibit thioglycollate - induced peritonitis and oxazolone - induced delayed - type hypersensitivity . Mice deficient in P - or L - selectins showed impaired inflammation , which could be further reduced by heparin . However , heparin had no additional effect in mice deficient in both P - and L - selectins . We conclude that ( a ) heparin ' s anti - inflammatory effects are mainly mediated by blocking P - and P14151 - initiated cell adhesion ; ( b ) the sulfate groups at P13671 on the glucosamine residues play a critical role in selectin inhibition ; and ( c ) some non - anticoagulant forms of heparin retain anti - inflammatory activity . Such analogs may prove useful as therapeutically effective inhibitors of inflammation .",
"The development of DB01276 ( exenatide ) from the venom of the Gila monster as an anti - diabetic agent . The development of DB01276 ( synthetic exendin - 4 ; exenatide ) as a treatment of diabetes arose from two , parallel lines of investigation . The development of the ' incretin concept ' which hypothesised that hormones from the gut contributed to the insulin secretion in response to meals , led to the identification of glucagon - like peptide 1 ( P0C6A0 ) as an important ' incretin ' hormone . P0C6A0 not only increases insulin secretion but increases β - cell proliferation and survival , suppresses glucagon secretion , delays gastric emptying and suppresses appetite , all of these actions contributing to a potential anti - diabetic effect . However , P0C6A0 has a very short half due to its rapid breakdown by dipeptidyl peptidase IV and ectopeptidases . A systematic investigation of the composition and activity of venom from the Gila monster , Heloderma suspectum , led to the isolation of a 39 - amino acid peptide , designated exendin - 4 , showing 53 % structural homology with P0C6A0 ( 7 - 36 ) . Exendin - 4 mimicked P0C6A0 through stimulating the P43220 . The much greater stability of exendin - 4 led to its experimental and clinical evaluation as an anti - diabetic agent and its introduction to the market in 2005 .",
"Exenatide twice daily : a review of its use in the management of patients with type 2 diabetes mellitus . Exenatide , administered subcutaneously twice daily ( DB01276 (®) ) , is a synthetic version of the natural peptide exendin - 4 , which is a glucagon - like peptide - 1 ( P0C6A0 ) receptor agonist ( incretin mimetic ) . Exenatide binds to the P43220 with the same affinity as P0C6A0 , but has a much longer half - life , since it is not degraded by the enzyme dipeptidyl peptidase - 4 . Exenatide twice daily enhances glucose - dependent insulin secretion , suppresses inappropriately elevated glucagon secretion , slows gastric emptying and reduces caloric intake . In well - designed clinical trials , adjunctive subcutaneous exenatide 5 or 10 μg twice daily for 16 - 52 weeks significantly and dose - dependently improved glycaemic control and reduced mean body weight compared with placebo in patients with type 2 diabetes inadequately controlled with oral antihyperglycaemic drugs ( OADs ) and / or basal insulin . The improvements in glycaemic control and reductions in body weight were stably maintained during long - term therapy ( up to 3 . 5 years ) . The efficacy of adjunctive exenatide twice daily was generally similar to that of basal , prandial or biphasic insulin , sulfonylureas , rosiglitazone and lixisenatide , and less than that of liraglutide , taspoglutide or exenatide once weekly with respect to reductions in glycated haemoglobin . Exenatide twice daily was generally well tolerated ; mild to moderate nausea and vomiting , which decreased with time on therapy , were the most common adverse events . In patients not receiving concomitant sulfonylureas or insulin , the incidence of hypoglycaemia was low ; when it did occur , it was generally mild in severity . Thus , adjunctive exenatide twice daily is a valuable option in the treatment of type 2 diabetes inadequately controlled with OADs and / or basal insulin .",
"Cannabinoid , melanocortin and opioid receptor expression on P21728 and P14416 subpopulations in rat striatum . The striatum harbors two neuronal populations that enable action selection . One population represents the striatonigral pathway , expresses the dopamine receptor D1 ( P21728 ) and promotes the execution of motor programs , while the other population represents the striatopallidal pathway , expresses the dopamine receptor D2 ( P14416 ) and suppresses voluntary activity . The two populations integrate distinct sensorimotor , cognitive , and emotional information streams and their combined activity enables the selection of adaptive behaviors . Characterization of these populations is critical to the understanding of their role in action selection , because it aids the identification of the molecular mechanisms that separate them . To that end , we used fluorescent in situ hybridization to quantify the percentage of striatal cells that ( co ) express dopaminergic receptors and receptors of the cannabinoid , melanocortin or opioid neurotransmitters systems . Our main findings are that the cannabinoid 1 receptor is equally expressed on both populations with a gradient from dorsal to ventral striatum , that the opioid receptors have a preference for expression with either the P21728 or P14416 and that the melanocortin 4 receptor ( P32245 ) is predominantly expressed in ventral parts of the striatum . In addition , we find that the level of P32245 expression determines its localization to either the P21728 or the P14416 population . Thereby , we provide insight into the sensitivity of the two dopaminoceptive populations to these neurotransmitters and progress the understanding of the mechanisms that enable action selection .",
"P04818 genotype - directed chemotherapy for patients with gastric and gastroesophageal junction cancers . BACKGROUND : Retrospective studies indicate associations between TSER ( thymidylate synthase enhancer region ) genotypes and clinical outcomes in patients receiving ___MASK75___ based chemotherapy , but well - controlled prospective validation has been lacking . METHODS : In this phase II study ( NCT00515216 registered through ClinicalTrials . gov , http :// clinicaltrials . gov / show / NCT00515216 ) , patients with \" good risk \" TSER genotypes ( at least one TSER * 2 allele ) were treated with FOLFOX chemotherapy to determine whether prospective patient selection can improve overall response rates ( ORR ) in patients with gastric and gastroesophageal junction ( GEJ ) cancers , compared with historical outcomes in unselected patients ( estimated 43 % ) . RESULTS : The ORR in genotype - selected patients was Q04695 % ( 9 partial responses out of 23 evaluable patients , 95 % CI , 22 . 2 to 59 . 2 ) , not achieving the primary objective of improving ORR . An encouraging disease control rate ( DCR , consisting of partial responses and stable diseases ) of 95 . 7 % was noted and patients with homozygous TSER * 2 genotype showed better tumor response . CONCLUSIONS : In this first prospective , multi - institutional study in patients with gastric or GEJ cancers , selecting patients with at least one TSER * 2 allele did not improve the ORR but led to an encouraging DCR . Further studies are needed to investigate the utility of selecting patients homozygous for the TSER * 2 allele and additional genomic markers in improving clinical outcomes for patients with gastric and GEJ cancers . TRIAL REGISTRATION : ClinicalTrials . gov NCT00515216 .",
"[ Effect of the monophase oral contraceptive combination with 20 ug ethinyl estradiol / 150 ug desogestrel on haemostasis ] . The authors examined the changes in the haemostasis during the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel at 35 women , a basic group , who used the oral contraceptive in the duration of 12 months and a control group ( n = 35 ) , who do not use the pills . We found statistically significant increase of Antithrombin III ( P01008 ) ( p < 0 . 011 ) , Cofactor II of ___MASK66___ ( HCII ) ( p < 0 . 001 ) , the activity of plasminogen ( p < 0 . 026 ) and beta2 - antiplasmin ( 0 . 026 ) , significant decrease of P02810 ( PrC ) ( p < 0 . 0001 ) and of total Protein S ( TPrS ) ( p < 0 . 03 ) in the basic group in comparision with the control one . We do not observe significant changes in the rest of the haemostatic variables between the two groups . During the use of the oral contraceptive combination with 20 microg ethynil estradiol / 150 microg desogestrel the changes in the system of the natural inhibitors are balanced by these in the system of fibrinolysis .",
"Genome - wide expression patterns associated with oncogenesis and sarcomatous transdifferentation of cholangiocarcinoma . BACKGROUND : The molecular mechanisms of CC ( cholangiocarcinoma ) oncogenesis and progression are poorly understood . This study aimed to determine the genome - wide expression of genes related to CC oncogenesis and sarcomatous transdifferentiation . METHODS : Genes that were differentially expressed between CC cell lines or tissues and cultured normal biliary epithelial ( NBE ) cells were identified using DNA microarray technology . Expressions were validated in human CC tissues and cells . RESULTS : Using unsupervised hierarchical clustering analysis of the cell line and tissue samples , we identified a set of 342 commonly regulated ( > 2 - fold change ) genes . Of these , 53 , including tumor - related genes , were upregulated , and 289 , including tumor suppressor genes , were downregulated ( < 0 . 5 fold change ) . Expression of P10451 , P52799 , Q14209 , P78415 , O95997 , PPARγ , Q04695 , P09936 , Q16270 and P09486 proteins was immunohistochemically verified in human and hamster CC tissues . Additional unsupervised hierarchical clustering analysis of sarcomatoid CC cells compared to three adenocarcinomatous CC cell lines revealed 292 differentially upregulated genes ( > 4 - fold change ) , and 267 differentially downregulated genes ( < 0 . 25 fold change ) . The expression of 12 proteins was validated in the CC cell lines by immunoblot analysis and immunohistochemical staining . Of the proteins analyzed , we found upregulation of the expression of the epithelial - mesenchymal transition ( EMT ) - related proteins P08670 and Q15672 , and restoration of the methylation - silenced proteins P07195 , Q12983 , P09936 , and P47972 during sarcomatoid transdifferentiation of CC . CONCLUSION : The deregulation of oncogenes , tumor suppressor genes , and methylation - related genes may be useful in identifying molecular targets for CC diagnosis and prognosis .",
"Adipose tissue tumor necrosis factor and interleukin - 6 expression in human obesity and insulin resistance . Adipose tissue expresses tumor necrosis factor ( P01375 ) and interleukin ( IL ) - 6 , which may cause obesity - related insulin resistance . We measured P01375 and P05231 expression in the adipose tissue of 50 lean and obese subjects without diabetes . P01308 sensitivity ( S ( I ) ) was determined by an intravenous glucose tolerance test with minimal - model analysis . When lean [ body mass index ( BMI ) < 25 kg / m ( 2 ) ] and obese ( BMI 30 - 40 kg / m ( 2 ) ) subjects were compared , there was a 7 . 5 - fold increase in P01375 secretion ( P < 0 . 05 ) from adipose tissue , and the P01375 secretion was inversely related to S ( I ) ( r = - 0 . 42 , P < 0 . 02 ) . P05231 was abundantly expressed by adipose tissue . In contrast to P01375 , plasma ( rather than adipose ) P05231 demonstrated the strongest relationship with obesity and insulin resistance . Plasma P05231 was significantly higher in obese subjects and demonstrated a highly significant inverse relationship with S ( I ) ( r = - 0 . 71 , P < 0 . 001 ) . To separate the effects of BMI from S ( I ) , subjects who were discordant for S ( I ) were matched for BMI , age , and gender . By use of this approach , subjects with low S ( I ) demonstrated a 3 . 0 - fold increased level of P01375 secretion from adipose tissue and a 2 . 3 - fold higher plasma P05231 level ( P < 0 . 05 ) compared with matched subjects with a high S ( I ) . Plasma P05231 was significantly associated with plasma nonesterified fatty acid levels ( r = 0 . 49 , P < 0 . 002 ) . Thus the local expression of P01375 and plasma P05231 are higher in subjects with obesity - related insulin resistance .",
"Glucagon - like peptide - 1 ( 1 - 37 ) inhibits chemokine - induced migration of human P01730 - positive lymphocytes . The present study examined the effect of P0C6A0 ( 1 - 37 ) on chemokine - induced P01730 - positive lymphocyte migration as an early and critical step in atherogenesis . Pretreatment with P0C6A0 ( 1 - 37 ) reduced the SDF - induced migration of isolated human P01730 - positive lymphocytes in a concentration - dependent manner . Similar effects were seen when RANTES was used as a chemokine . P0C6A0 ( 1 - 37 ) ' s effect on P01730 - positive lymphocyte migration was mediated through an early inhibition of chemokine - induced P19957 kinase activity . Downstream , P0C6A0 ( 1 - 37 ) inhibited SDF - induced phosphorylation of MLC and cofilin and limited f - actin formation as well as P32942 translocation . Furthermore , exendin - 4 inhibited SDF - induced migration of P01730 - positive lymphocytes similarly to P0C6A0 ( 1 - 37 ) , and transfection of these cells with P43220 siRNA abolished P0C6A0 ( 1 - 37 ) ' s action on chemokine - induced P32942 translocation , suggesting an effect mediated via the P43220 . Thus , P0C6A0 ( 1 - 37 ) inhibits chemokine - induced P01730 - positive lymphocyte migration by inhibition of the P19957 - kinase pathway and via the P43220 . This effect provides a potential novel mechanism for how P0C6A0 ( 1 - 37 ) may modulate vascular disease .",
"[ DB01276 : first once weekly P43220 agonist ( exenatide P10586 ) ] . DB01276 is a new galenic formulation ( long - acting release ) of exenatide , the first agonist of Glucagon - Like Peptide - 1 ( P0C6A0 ) receptors having been commercialized for the management of type 2 diabetes . The microsphere technology permits a prolonged absorption of exenatide from the subcutaneous depot , which allows one injection per week instead of two injections per day with the initial formulation of exenatide ( DB01276 ) . The clinical development programme DURATION showed that exenatide 2 mg once weekly more markedly reduces glycated haemoglobin ( HbA ( 1c ) ) , with a similar weight loss but a better digestive tolerance profile ( less nausea and vomiting after treatment initiation ) , compared with the twice daily 10 microg exenatide . When compared to other glucose - lowering agents , once weekly exenatide is more efficacious than sitagliptin , pioglitazone or basal insulin ( glargine or detemir ) , with the advantage of producing weight loss and lowering arterial blood pressure . It does not induce hypoglycaemia and does not necessarily require home blood glucose monitoring , two advantages compared with insulin therapy . DB01276 is currently only reimbursed in Belgium after failure of and in addition to metformin - sulfonylurea combination .",
"Selected P21554 polymorphisms and hyperandrogenemia as well as fat mass and fat distribution in women with polycystic ovary syndrome . The endocannabinoid system is postulated to play an important role in the etiology of obesity , insulin resistance , fat distribution and metabolic disorders . P01308 resistance associated with abdominal obesity plays a leading role in the etiology of hyperandrogenism and other clinical features of the polycystic ovary syndrome ( PCOS ) . A total of 174 women 16 - 38 years old , diagnosed with PCOS according to the Rotterdam criteria are recruited . Control group consisted of 125 healthy women 18 - 45 years old . Medical history , physical examination , anthropometric parameters and metabolic parameters were carried out . Six P21554 gene polymorphisms were diagnosed . We observed a significantly three times higher risk of GG genotype in the polymorphism rs12720071 in women with PCOS versus the control group ( p = 0 . 0344 , OR = 3 . 01 ) . A similar , significant 8 - fold higher risk ( p = 0 . 0176 , OR = 8 . 81 ) was demonstrated for genotype CC polymorphism rs806368 associated with PCOS . We observed a 3 . 6 - fold increased risk of hyperandrogenemia ( free androgen index - FAI > 7 ) in patients with GG genotype in the rs12720071 polymorphism and AA genotype in the polymorphism rs1049353 ( OR = 2 . 7 ) . Our study may indicate a role of the endocannabinoid system in the occurrence of a specific hyperandrogenemia phenotype of PCOS .",
"The interaction of thymidylate synthase expression with p53 - regulated signaling pathways in tumor cells . P04818 ( TS ) is a chemotherapeutic target for the fluoropyrimidine 5 - fluorouracil ( ___MASK75___ ) and antifolate tomudex ( TDX ) . Using the MCF - 7 breast cancer line , we have developed a cell line with inducible TS expression termed M7TS90 . Inducible TS expression in this line resulted in a moderate ( approximately 3 - fold ) increase in ___MASK75___ 50 % inhibitory concentration at 72 hours ( IC - 50 ( 72 h ) ) dose and a dramatic ( approximately 24 - fold ) increase in the IC - 50 ( 72 h ) dose of TDX , but did not affect chemosensitivity to cisplatin , oxaliplatin , irinotecan , and paclitaxel . In the absence of drug treatment , inducible TS expression had no effect on expression of the p53 tumor suppressor gene . However , TS induction abrogated p53 , P38936 , Fas , and Bak induction in response to TDX , but not ___MASK75___ . Similarly , downregulation of Bcl - 2 was reversed by inducible TS expression in TDX , but not ___MASK75___ - treated cells . Our results indicate that inducible TS expression in M7TS90 cells modulates p53 and p53 target gene expression in response to TDX , but not ___MASK75___ .",
"' Neuron - specific ' protein gene product 9 . 5 ( P09936 ) is also expressed in glioma cell lines and its expression depends on cellular growth state . Protein gene product 9 . 5 ( P09936 ) , which in the normal nervous system is restricted to certain neurons , has been detected in two glioma cell lines , rat P13671 and human GL15 , by immunoblotting and immunocytochemistry . Its expression in these cells depends on the cellular growth state , being maximal between the first and second post - plating day . Only a faint P09936 immunoreactivity can be observed in glioma cells after the eleventh post - plating day , i . e . about one week after confluency has been reached . The present results suggest that P09936 in cultured glial cells is maximally expressed during the growth phase and that the protein could play a role during brain development in glial cells , in reactive gliosis , or in tumorigenesis of the glial lineage .",
"P10275 antagonism and an insulin sensitizer block the advancement of vaginal opening by high - fat diet in mice . Reduced hypothalamic sensitivity to steroid negative feedback may contribute to the onset of puberty . In high fat - fed rodents , the timing of vaginal opening ( VO ) is advanced , suggesting that puberty begins earlier . Because obesity can increase androgens , which interfere with normal steroid feedback in adult females , we hypothesized that androgens reduce hypothalamic sensitivity to negative feedback during puberty and that blocking androgen action would prevent advanced VO in high fat - fed mice . Age at VO was examined in mice fed high - fat or low - fat diets from weaning and treated with the androgen receptor antagonist flutamide or vehicle ( controls ) . VO was advanced in high - fat vs . low - fat controls , and flutamide blocked this advancement . VO was also delayed in low fat - fed flutamide - treated females , suggesting involvement of androgens in the timing of normal puberty . We next investigated if high - fat diet - induced insulin resistance contributes to early VO , as elevated insulin can stimulate androgen production . VO was examined in mice on either diet treated with the insulin sensitizer metformin . Metformin blocked high - fat advancement of VO but did not alter the timing of VO in low fat - fed mice . P01308 was elevated in high fat - fed females that had undergone VO compared with age - matched low fat - fed or metformin - treated animals on either diet that had not undergone VO . Together , these data suggest a model in which metabolic changes induced by high - fat diet , including transient increased circulating insulin , act in part by increasing androgen action to influence the timing of puberty in females .",
"Ontogeny of expression of P09936 antigen on TcR - 1 + ( P01730 / 8 ) and TcR delta + T cells . The frequency of blood mononuclear cells expressing the 180 - kDa splice variant of the common leukocyte antigen identified by the P09936 monoclonal antibody ( a characteristic of post - thymic cells which have been through a cycle of stimulation ) rose in a logarithmic relationship to age between birth and 16 years . At birth only a low frequency of P01730 + ( negative for CD 25 ) and no CD8 + T cells expressed P09936 . The subsequent increase in P09936 expression occurred in parallel on T cells expressing alpha / beta receptors and gamma / delta receptors , suggesting that these subsets participated in post - thymic proliferation in proportion to their numbers in blood . The frequency of P09936 expression on CD8 cells was 5 - 15 % less than on P01730 cells .",
"P10275 is expressed in murine choroid plexus and downregulated by 5alpha - dihydrotestosterone in male and female mice . The choroid plexuses ( CPs ) of the brain form a unique interface between the peripheral blood and the cerebrospinal fluid ( P04141 ) . CPs produce several neuroprotective peptides , which are secreted into the P04141 . Despite their importance in neuroprotection , the mechanisms underlying the regulation of most of these peptides in CPs remain unknown . Androgens regulate the expression of neuroprotective peptides in several tissues where the androgen receptor ( AR ) is coexpressed , including the brain . The presence of AR in CPs has never been investigated , but recent studies in our laboratory show that the CP is an androgen - responsive tissue . In order to fulfill this gap , we investigated and characterized AR distribution and expression in male and female rat CPs and in primary cultures from rat CP epithelial cells . In addition , the response of AR to 5alpha - dihydrotestosterone ( ___MASK67___ ) in castrated male and female mice subjected to ___MASK67___ replacement was analyzed . We show that rat CP epithelial cells contain AR mRNA and protein . Moreover , we demonstrate that AR is downregulated by ___MASK67___ in mice CPs .",
"Novel P0C6A0 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain . One of the symptoms of diabetes is the progressive development of neuropathies . One mechanism to replace neurons in the CNS is through the activation of stem cells and neuronal progenitor cells . We have tested the effects of the novel P0C6A0 mimetics exenatide ( exendin - 4 ; DB01276 ) and liraglutide ( DB06655 ; DB06655 ) , which are already on the market as treatments for type 2 diabetes , on the proliferation rate of progenitor cells and differentiation into neurons in the dentate gyrus of brains of mouse models of diabetes . P0C6A0 analogues were injected subcutaneously for 4 , 6 , or 10 weeks once daily in three mouse models of diabetes : ob / ob mice , db / db mice , or high - fat - diet - fed mice . Twenty - four hours before perfusion , animals were injected with 5 '- bromo - 2 '- deoxyuridine ( BrdU ) to mark dividing progenitor cells . By using immunohistochemistry and stereological methods , the number of progenitor cells or doublecortin - positive young neurons in the dentate gyrus was estimated . We found that , in all three mouse models , progenitor cell division was enhanced compared with nondiabetic controls after chronic i . p . injection of either liraglutide or exendin - 4 by 100 - 150 % ( P < 0 . 001 ) . We also found an increase in young neurons in the DG of high - fat - diet - fed mice after drug treatment ( P < 0 . 001 ) . The P43220 antagonist exendin ( 9 - 36 ) reduced progenitor cell proliferation in these mice . The results demonstrate that P0C6A0 mimetics show promise as a treatment for neurodegenerative diseases such as Alzheimer ' s disease , because these novel drugs cross the blood - brain barrier and increase neuroneogenesis .",
"Effects of systemic injections of vilazodone , a selective serotonin reuptake inhibitor and serotonin 1A receptor agonist , on anxiety induced by predator stress in rats . We examined the effect of ___MASK49___ , a selective serotonin reuptake inhibitor ( SSRI ) and serotonin 1A ( 5 - HT ( 1A ) ) receptor agonist [ Bartoszyk , G . D . , Hegenbart , R . , Ziegler , H . , 1997 . P50402 68843 , a serotonin reuptake inhibitor with selective presynaptic P08908 receptor agonistic properties . Eur . J . Pharmacol . 322 , 147 - 153 . ] , on change in affect following predator stress . ___MASK49___ and vehicle injection ( intraperitoneal ) occurred either 10 min after predator stress ( prophylactic testing ) , or 90 min prior to behavioral testing for the effects of predator stress ( therapeutic testing ) . Predator stress involved unprotected exposure of rats to a domestic cat . Behavioral effects of stress were evaluated with hole board , plus - maze , and acoustic startle tests 1 week after stress . Predator stress increased anxiety - like behavior in the plus - maze and elevated response to acoustic startle . In prophylactic testing , ___MASK49___ affected stress potentiation of startle at doses above 5 mg / kg . ___MASK49___ increased stress elevation of startle at 10 mg / kg . Higher doses of ___MASK49___ ( 20 and 40 mg / kg ) blocked stress potentiation of startle . In contrast , ___MASK49___ had no effect on stress potentiation of anxiety in the plus - maze . In therapeutic testing , ___MASK49___ increased stress elevation of startle at all doses . In contrast , therapeutic ___MASK49___ had no effect on stress potentiation of anxiety in the plus - maze . Taken together , the data suggest a prophylactic potential for ___MASK49___ in the treatment of changes in hypervigilance following severe stress .",
"___MASK1___ induces insulin sensitization in Zucker lean and fatty rats . BACKGROUND : The 3 - hydroxy - 3 - methyl glutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors ( ' statins ' ) have been implicated in preventing new onset type 2 diabetes , whereas the mechanism of this effect is not known . We investigated the effects of an P04035 inhibitor , atorvastatin , on insulin sensitization in Zucker lean and fatty rats . METHODS AND RESULTS : In vivo studies of insulin sensitization were performed in chow fed Zucker lean and fatty rats treated with atorvastatin 50mg / kg / day ( ATORVA_50 ) and results were compared to Zucker lean and fatty rats treated with drug vehicle only ( CONT ) . Additional Zucker lean rats were treated with an intermediate dose of atorvastatin 25mg / kg / day ( ATORVA_25 ) . Treatment with atorvastatin resulted in a dose - dependent improvement in whole body insulin sensitivity in both lean and fatty rats , with an approximately two - fold increase in glucose infusion rate and glucose disposal ( Rd ) in ATORVA_50 versus CONT ( p < 0 . 01 ) . ___MASK1___ 50mg / kg / day resulted in an increase in DB08831 ( 2 - DOG ) uptake by skeletal muscles ( approximately two - fold increase in 2 - DOG uptake in quadriceps ( p = 0 . 06 ) and gastrocnemius ( p < 0 . 01 ) ) in lean Zucker rats . P01308 - stimulated phosphorylation of Akt / P31749 was significantly increased in skeletal muscle of ATORVA_50 versus CONT in both lean and fatty rats . CONCLUSION : ___MASK1___ induces insulin sensitization in Zucker lean and fatty rats . This may be a clinically important pleiotropic effect if confirmed in insulin resistant humans .",
"P16109 - and heparanase - dependent antimetastatic activity of non - anticoagulant heparins . Vascular cell adhesion molecules , P - and L - selectins , facilitate metastasis of cancer cells in mice by mediating interactions with platelets , endothelium , and leukocytes . Q9Y251 is an endoglycosidase that degrades heparan sulfate of extracellular matrix , thereby promoting tumor invasion and metastasis . ___MASK66___ is known to efficiently attenuate metastasis in different tumor models . Here we identified modified , nonanticoagulant species of heparin that specifically inhibit selectin - mediated cell - cell interactions , heparanase enzymatic activity , or both . We show that selective inhibition of selectin interactions or heparanase with specific heparin derivatives in mouse models of MC - 38 colon carcinoma and B16 - BL6 melanoma attenuates metastasis . Selectin - specific heparin derivatives attenuated metastasis of MC - 38 carcinoma , but heparanase - specific derivatives had no effect , in accordance with the virtual absence of heparanase activity in these cells . ___MASK66___ derivatives had no further effect on metastasis in mice deficient in P - and P14151 , indicating that selectins are the primary targets of heparin antimetastatic activity . Selectin - specific and heparanase - specific derivatives attenuated metastasis of B16 - BL6 melanomas to a similar extent . When mice were injected with a derivative containing both heparanase and selectin inhibitory activity , no additional attenuation of metastasis could be observed . Thus , selectin - specific heparin derivatives efficiently attenuated metastasis of both tumor cell types whereas inhibition of heparanase led to reduction of metastasis only in tumor cells producing heparanase .",
"Nonlinkage of bipolar illness to tyrosine hydroxylase , tyrosinase , and D2 and D4 dopamine receptor genes on chromosome 11 . OBJECTIVE : Previous linkage and allelic association studies using DNA polymorphisms , cosegregation of cytogenetic abnormalities with psychiatric illness , and assignment of genes involved in neutotransmitter metabolism suggested that chromosome 11 may harbor a gene predisposing to bipolar illness . The authors examined linkage in the families of 14 probands with bipolar illness , with the candidate genes tyrosine hydroxylase ( TH ) , D4 dopamine receptor ( P21917 ) at 11p15 , tyrosinase ( P14679 ) at 11q14 - q21 , and D2 dopamine receptor ( P14416 ) at 11q22 - q23 , as well as with the c - Harvey - ras oncogene ( P01112 ) and insulin gene ( P01308 ) , both located at 11p15 , a region that previously showed linkage to bipolar illness . METHOD : The genetic data were analyzed with both lod score analysis ( parametric ) and affected - sib - pair analysis ( nonparametric ) ; both narrow and broad definitions of the clinical phenotype were used . Further influences of diagnostic uncertainties were accounted for by using diagnostic probability classes weighing the stability of each phenotype . RESULTS : Two - point linkage results excluded close linkage of bipolar illness to each candidate gene ; negative results were also obtained when the narrow definition of the clinical phenotype was used . Moreover , multipoint linkage analysis of P01112 and P01308 excluded the 11p15 region encompassing both P21917 and TH . In agreement with the negative linkage results , affected - sib - pair analysis did not show preferential sharing of marker alleles at any of the candidate genes . CONCLUSIONS : The negative results obtained under different genetic models exclude a frequent role for P21917 , TH , P14679 , and P14416 in the pathogenesis of bipolar illness .",
"P0C6A0 treatment reduces endogenous insulin resistance via activation of central P0C6A0 receptors in mice fed a high - fat diet . Glucagon - like peptide - 1 ( P0C6A0 ) improves insulin sensitivity in humans and rodents . It is currently unknown to what extent the ( metabolic ) effects of P0C6A0 treatment are mediated by central P0C6A0 receptors . We studied the impact of central P43220 ( P43220 ) antagonism on the metabolic effects of peripheral P0C6A0 administration in mice . High - fat - fed insulin - resistant C57Bl / 6 mice were treated with continuous subcutaneous infusion of P0C6A0 or saline ( PBS ) for 2 wk , whereas the P43220 antagonist exendin - 9 ( EX - 9 ) and cerebrospinal fluid ( P04141 ) were simultaneously infused in the left lateral cerebral ventricle ( icv ) . DB09341 and glycerol turnover were determined during a hyperinsulinemic euglycemic clamp . VLDL - triglyceride ( VLDL - TG ) production was determined in hyperinsulinemic conditions . Our data show that the rate of glucose infusion necessary to maintain euglycemia was significantly increased by P0C6A0 . Simultaneous icv infusion of EX - 9 diminished this effect by 62 % . The capacities of insulin to stimulate glucose disposal and inhibit glucose production were reinforced by P0C6A0 . Simultaneous icv infusion of EX - 9 significantly diminished the latter effect . Central P43220 antagonism alone did not affect glucose metabolism . Also , P0C6A0 treatment reinforced the inhibitory action of insulin on VLDL - TG production . In conclusion , peripheral administration of P0C6A0 reinforces the ability of insulin to suppress endogenous glucose and VLDL - TG production ( but not lipolysis ) and boosts its capacity to stimulate glucose disposal in high - fat - fed C57Bl / 6 mice . Activation of central GLP - 1Rs contributes substantially to the inhibition of endogenous glucose production by P0C6A0 treatment in this animal model .",
"[ Activation of coagulation cascade in children during an idiopathic nephrotic syndrome relapse ] . The objective of this study was to assess concentrations of selected markers of coagulation in children with relapse of idiopathic nephrotic syndrome during a 6 - week therapy . Study groups : 22 subjects ( 32 relapses ) -- 14 males , 8 females ( mean age 7 . 15 +/- 1 . 5 y . ) with no thrombotic complications were included into the study . All children were clinically steroid - sensitive . METHODS : Coagulation markers ( platelet count , thrombin time , APTT , INR , fibrinogen 1 + 2 fragments ( F1 + 2 ) , thrombin - antithrombin complexes ( TAT ) , serum levels of D - dimer ( DD ) , fibrin monomers ( FM ) and antithrombin activity ( P01008 ) ) were measured three times : on admission , after 2 and 6 weeks . The control group consisted of 13 healthy children . RESULTS : Serum concentration of TAT or F1 + 2 did not differ between 3 stages ( p > 0 . 05 ) . However , values at 0 and 2 weeks were significantly higher than in control group ( p < 0 . 05 ) . We found no correlation between TAT or F1 + 2 and FBG , ALB , TCH , TG levels . [ table : see text ] CONCLUSIONS : The coagulation cascade in relapse of NS was activated during first 6 weeks of therapy whereas metabolic disturbances ( low ALB , high P02675 , TCH , TG , high platelets ) normalized . It is speculative whether it was caused by active immunological process but definitely it resulted in \" prothrombotic state \" in P01308 patients .",
"Neuroprotective effect of the glucagon - like peptide - 1 receptor agonist , synthetic exendin - 4 , in streptozotocin - induced diabetic rats . BACKGROUND AND PURPOSE : Glucagon - like peptide - 1 ( P0C6A0 ) receptors are widely expressed in neural tissues and diminish neuronal degeneration or induce neuronal differentiation . The aim of this study was to investigate the effect of the P0C6A0 pathway on peripheral nerves in streptozotocin - induced diabetic rats . EXPERIMENTAL APPROACH : Diabetic and nondiabetic rats were treated with the P43220 agonist , synthetic exendin - 4 ( i . p . , 1 nmol · kg (- 1 )· day (- 1 ) ) or placebo for 24 weeks , and current perception threshold values , DB02527 levels and nerve fibre size in the sciatic nerve were measured . We also investigated P43220 expression , quantitative changes in P09936 - positive intraepidermal nerve fibres and cleaved caspase 3 - stained Schwann cells by immunohistochemistry . KEY RESULTS : P43220 expression was detected in the sciatic nerve and skin . After exendin - 4 treatment , the increase seen in current perception threshold values at 2000 and 250 Hz in diabetic rats was reduced . Also , the decrease in myelinated fibre size or axon / fibre area ratio in the sciatic nerve and the loss of intraepidermal nerve fibre in the skin of diabetic rats were ameliorated . These responses were closely associated with the attenuation of Schwann cell apoptosis and improvement in the DB02527 level in exendin - 4 - treated diabetic rats , compared with placebo - treated animals . CONCLUSION AND IMPLICATIONS : DB01276 may prevent peripheral nerve degeneration induced by diabetes in an animal model , supporting the hypothesis that P0C6A0 may be useful in peripheral neuropathy . The neuroprotection is probably attributable to P43220 activation , antiapoptotic effects and restoration of DB02527 content .",
"Statin Modulation of Human T - Cell Proliferation , IL - 1β and Q16552 Production , and IFN - γ T Cell Expression : Synergy with Conventional Immunosuppressive Agents . P04035 inhibitors ( statins ) have been demonstrated to be immunomodulatory for human immune - mediated disease and in experimental models . The aim of this study was to compare statin - mediated immunosuppressive effects on human T - cell responses in vitro with those of conventional immunosuppressives ( dexamethasone , cyclosporin A ( DB00091 ) , mycophenolate , and rapamycin ) . Statins ( atorvastatin , lovastatin , and simvastatin ) were investigated for their modulatory effects on human PBMC viability , cytokine profiles , and T - cell proliferation . At concentrations that inhibited anti - CD3 / 28 - stimulated T - cell proliferation ( P < 0 . 01 ) , simvastatin significantly decreased intracellular P01730 (+) T - cell expression of IFN - γ ( P < 0 . 01 ) to levels similar to those induced by conventional immunosuppressives . ___MASK1___ and lovastatin also decreased IFN - γ expression , although to a lesser degree ( P < 0 . 05 ) . All three statins reduced levels of Q16552 production ( P < 0 . 01 ) . However , in response to anti - CD3 / 28 stimulation , simvastatin significantly upregulated IL - 1β production ( P < 0 . 05 ) . The profile of cytokines produced in response to anti - CD3 / 28 stimulation was similar when both atorvastatin and dexamethasone were added as compared with dexamethasone alone , suggesting that atorvastatin can synergise with dexamethasone with respect to immunomodulation of cytokines . This data supports the hypothesis of selective statin - mediated immunomodulatory effects on human immune cells .",
"P01308 - induced NADPH oxidase activation promotes proliferation and matrix metalloproteinase activation in monocytes / macrophages . P01308 stimulates superoxide ( O ( 2 )(-) ) production in monocytes and macrophages . However , the mechanisms through which insulin induces O ( 2 )(-) production are not completely understood . In this study , we ( a ) characterized the enzyme and the pathways involved in insulin - stimulated O ( 2 )(-) production in human monocytes and murine macrophages , and ( b ) analyzed the consequences of insulin - stimulated O ( 2 )(-) production on the cellular phenotype in these cells . We showed that insulin stimulated O ( 2 )(-) production , and promoted p47 ( phox ) translocation to the plasma membrane . P01308 - induced O ( 2 )(-) production and p47 ( phox ) translocation were prevented in the presence of specific inhibitors of PI3K and PKC . P01308 - mediated NADPH oxidase activation stimulated P14780 activation in monocytes and cell proliferation in macrophages . The effect of insulin on these phenotypic responses was mediated through NFkappaB , p38MAPK , and P29323 1 / 2 activation . Small - interfering RNA - specific gene silencing targeted specifically against Nox2 reduced the cognate protein expression , decreased insulin - induced O ( 2 )(-) production , inhibited the turn on of NFkappaB , p38MAPK , and P29323 1 / 2 , and reduced cell proliferation in macrophages . These findings suggest a pivotal role for NADPH oxidase in insulin - induced proliferation and proteolytic activation in monocytes and macrophages , respectively , and identify a pathway that may play a pathological role in hyperinsulinemic states .",
"Prolonged treatment with bicalutamide induces androgen receptor overexpression and androgen hypersensitivity . BACKGROUND : Various hormone refractory prostate cancer cell models have been established with androgen depletion and have helped to clarify the mechanism for the transition into androgen - depletion independent status . However , the mechanism of bicalutamide resistance remains unclear because few cell models have been generated . METHODS : We generated a bicalutamide - resistant subline , LNCaP - O43633 , from LNCaP after prolonged treatment with bicalutamide . Androgen and / or bicalutamide responsiveness for proliferation and prostate - specific antigen ( PSA ) secretion were examined in vitro and in vivo . DB00624 and dihydrotestosterone ( ___MASK67___ ) levels in xenografted tumors were analyzed by liquid chromatography - tandem mass spectrometry . P10275 ( AR ) gene mutation and amplification and AR and pAR ( 210 ) expression were determined . RESULTS : LNCaP - O43633 did not grow in an androgen - depleted medium and proliferation was stimulated in a tenfold lower concentration of androgen than that of LNCaP . LNCaP - O43633 grew in castrated male mice , and the ___MASK67___ level in grafted LNCaP - O43633 tumors was 7 . 7 - fold lower than in LNCaP tumors . DB01128 stimulated LNCaP - O43633 proliferation and PSA secretion in vitro and the antitumor activity of bicalutamide against LNCaP - O43633 was weaker than that of LNCaP in vivo . Additional AR mutation and AR gene amplification were not detected in LNCaP - O43633 , but AR and pAR ( 210 ) expression and PSA secretion in LNCaP - O43633 were higher than in LNCaP . CONCLUSIONS : DB01128 - resistant LNCaP - O43633 exhibited AR overexpression and hypersensitivity to low levels of androgen . Our data suggests that AR overexpression is a significant mechanism of bicalutamide resistance similar to resistance from chronic androgen depletion . In addition , pAR ( 210 ) overexpression could be a potential mechanism for hypersensitivity to low androgen in LNCaP - O43633 .",
"Absence of genetic variation in some obesity candidate genes ( P43220 , ASIP , P32245 , P33032 ) among Pima indians . OBJECTIVE : To examine the obesity candidate genes glucagon - like - peptide receptor ( P43220 ) , agouti signaling protein ( ASIP ) and the melanocortin receptors 4 and 5 ( P32245 and P33032 ) for DNA polymorphisms in their coding regions . SUBJECTS : Unrelated , non - diabetic Pima Indians ( 8 to 12 from each extreme of body fat ) . MEASUREMENTS : DNA sequencing within the coding regions of each gene . RESULT : Only one variant was detected , a silent substitution in exon 6 of P43220 . CONCLUSION : The exclusion of any common amino - acid polymorphisms ( allele frequency > or = 0 . 20 ) . implies that structural variants of these genes do not contribute to variation in the high level of obesity observed among the Pima Indians .",
"Exendin - 4 alleviates angiotensin II - induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . Vascular aging has been implicated in the progression of diabetes and age - related cardiovascular disorders . Glucagon - like peptide - 1 ( P0C6A0 ) is an incretin hormone capable of cytoprotective actions in addition to its glucose - lowering effect . The present study was undertaken to examine whether Exendin - 4 , a specific ligand for the P43220 , could prevent angiotensin ( P03950 ) II - induced premature senescence in vascular smooth muscle cells ( VSMCs ) and to determine the underlying mechanism involved . Senescence - associated β - galactosidase ( SA β - gal ) assay showed that P03950 II induced premature senescence of VSMCs . Pretreatment with Exendin - 4 significantly attenuated P03950 II - induced generation of H2O2 and the subsequent VSMC senescence . These effects were , however , reversed in the presence of exendin fragment 9 - 39 , a P43220 antagonist , or PKI14 - 22 . Moreover , a marked increase in the levels of p53 and P38936 induced by P03950 II was blunted by the treatment with Exendin - 4 . Nevertheless , Exendin - 4 failed to decrease P03950 II - induced expression of NAD ( P ) H oxidase 1 ( Nox1 ) , NAD ( P ) H oxidase 4 ( Nox4 ) , O75935 ( phox ) , or p47 ( phox ) in VSMCs . Mechanistically , Exendin - 4 blocked P03950 II - induced Rac1 activation through the DB02527 / PKA signaling cascade . Specifically , NSC23766 , a Rac1 inhibitor , abrogated the suppressive effects of Exendin - 4 on P03950 II - induced premature senescence and H2O2 generation , respectively . Thus Exendin - 4 confers resistance to P03950 II - induced superoxide anion generation from NAD ( P ) H oxidase and the resultant VSMC senescence by inhibiting Rac1 activation via a DB02527 / PKA - dependent pathway . These findings demonstrate that P0C6A0 as well as its analogs ( P0C6A0 - related reagents ) may hold therapeutic potential in the treatment of diabetes with cardiovascular disease .",
"Role of central glucagon - like peptide - 1 in hypothalamo - pituitary - adrenocortical facilitation following chronic stress . Central glucagon - like peptide - 1 ( P0C6A0 ) regulates food intake , glucose homeostasis , and behavioral and neuroendocrine responses to acute stress . Given its pronounced role in acute stress regulation , the P0C6A0 system is a prime candidate for mediating the prolonged drive of the hypothalamo - pituitary - adrenocortical axis by chronic stress . To test this hypothesis , we evaluated the necessity and sufficiency of P0C6A0 for production of chronic stress - induced changes in Q9Y251 axis function . Exogenous P0C6A0 or the P43220 antagonist , dHG - exendin , were delivered into the 3rd ventricle of control animals or animals exposed to chronic variable stress ( CVS ) for 7 days . Animals in the CVS groups received P0C6A0 or dHG - exendin immediately prior to each stress exposure . Prior to and at the end of the 7 - day trial , chronically - stressed animals were subjected to a novel stressor to test for Q9Y251 axis facilitation . Neither P0C6A0 nor dHG - exendin affected CVS - associated increases in adrenal weight or decreases in basal plasma glucose levels . In addition , neither exogenous P0C6A0 nor dHG - exendin altered any index of Q9Y251 axis activity in unstressed rats . However , P0C6A0 enhanced CVS - induced facilitation of corticosterone ( but not DB01285 ) response to an acute stress , whereas dHG - exendin inhibited facilitation . In addition , P0C6A0 decreased body weight in chronically - stressed animals . dHG - exendin increased food intake and body weight in unstressed animals , consistent with a tonic role for P0C6A0 in body weight regulation . Overall , our data suggest that brain P0C6A0 modulates Q9Y251 axis activity within the context of chronic stress , perhaps at the level of the adrenal gland .",
"New insights into the role of DB02527 in the production and function of the incretin hormone glucagon - like peptide - 1 ( P0C6A0 ) . The proglucagon gene ( gcg ) encodes both glucagon and glucagon - like peptide - 1 ( P0C6A0 ) , produced in pancreatic alpha cells and intestinal endocrine L cells , respectively . The incretin hormone P0C6A0 stimulates insulin secretion and pro - insulin gene transcription . P0C6A0 also enhances pancreatic beta - cell proliferation , inhibits cell apoptosis , and has been utilized in the trans - differentiation of insulin producing cells . A long - term effective P43220 agonist , DB01276 , has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders . The expression of gcg and the production of P0C6A0 can be activated by the elevation of the second messenger cyclic AMP ( DB02527 ) . Recent studies suggest that in addition to protein kinase A ( PKA ) , exchange protein activated by DB02527 ( Epac ) , another effector of DB02527 , and the crosstalk between PKA and the Wnt signaling pathway , are involved in DB02527 - stimulated gcg transcription and P0C6A0 production as well . Finally , functions of P0C6A0 in pancreatic beta cells are also mediated by PKA , Epac , as well as the effector of the Wnt signaling pathway . Together , these novel findings bring us a new insight into the role of DB02527 in the production and function of the incretin hormone P0C6A0 .",
"Concurrent pharmacological modification of cannabinoid - 1 and glucagon - like peptide - 1 receptor activity affects feeding behavior and body weight in rats fed a free - choice , high - carbohydrate diet . To extend preliminary studies on the effects on food intake of the combined use of cannabinoid ( CB ) 1 and glucagon - like peptide - 1 ( P0C6A0 ) receptor agonists and antagonists , the effect of these drugs on the feeding behavior in rats maintained on a free - choice , high - carbohydrate diet was investigated over a longer period of time . Rats were fed a standard diet for 3 days and then fed with both the standard and the high - sucrose chow . After 4 days of the high - calorie diet , the following combination treatments were administered daily by an intraperitoneal injection for the next 3 days : 1 mg / kg AM 251 ( a P21554 receptor antagonist ) or 1 mg / kg Q08050 55 , 212 - 2 ( a P21554 receptor agonist ) together with 3 µg / kg exendin - 4 ( Ex - 4 , a P43220 agonist ) or 160 µg / kg exendin ( 9 - 39 ) [ Ex ( 9 - 39 ) , a P43220 antagonist ] . The total daily caloric intake and body weight were significantly reduced in rats treated with Ex - 4 and AM 251 or Q08050 55 , 212 - 2 compared with either of the drugs injected alone and the saline - injected controls . Both drug combinations selectively inhibited ingestion of the high - sucrose chow . Although Ex ( 9 - 39 ) administration did not significantly affect food consumption , it resulted in a marked body weight gain , indicating that the P43220 antagonist caused a positive energy balance . It is concluded that AM 251 or Q08050 55 , 212 - 2 and Ex - 4 , injected together , exert additive , inhibitory effects on the consumption of high - sugar food .",
"Molecular physiology of glucagon - like peptide - 1 insulin secretagogue action in pancreatic β cells . P01308 secretion from pancreatic β cells is stimulated by glucagon - like peptide - 1 ( P0C6A0 ) , a blood glucose - lowering hormone that is released from enteroendocrine L cells of the distal intestine after the ingestion of a meal . P0C6A0 mimetics ( e . g . , DB01276 ) and P0C6A0 analogs ( e . g . , DB06655 ) activate the β cell P43220 ( P43220 ) , and these compounds stimulate insulin secretion while also lowering levels of blood glucose in patients diagnosed with type 2 diabetes mellitus ( T2DM ) . An additional option for the treatment of T2DM involves the administration of dipeptidyl peptidase - IV ( DPP - IV ) inhibitors ( e . g . , Januvia , DB04876 ) . These compounds slow metabolic degradation of intestinally released P0C6A0 , thereby raising post - prandial levels of circulating P0C6A0 substantially . Investigational compounds that stimulate P0C6A0 secretion also exist , and in this regard a noteworthy advance is the demonstration that small molecule Q8TDV5 agonists ( e . g . , AR231453 ) stimulate L cell P0C6A0 secretion while also directly stimulating β cell insulin release . In this review , we summarize what is currently known concerning the signal transduction properties of the β cell P43220 as they relate to insulin secretion . Emphasized are the cyclic AMP , protein kinase A , and Epac2 - mediated actions of P0C6A0 to regulate DB00171 - sensitive K ⁺ channels , voltage - dependent K ⁺ channels , O94759 cation channels , intracellular Ca ⁺ release channels , and Ca ⁺- dependent exocytosis . We also discuss new evidence that provides a conceptual framework with which to understand why P43220 agonists are less likely to induce hypoglycemia when they are administered for the treatment of T2DM .",
"Improvement of psoriasis during exenatide treatment in a patient with diabetes . CONTEXT AND AIM : Psoriasis is an immune - mediated skin disorder frequently associated with obesity and type 2 diabetes ( T2D ) . This report is of a clinically significant improvement in psoriasis lesions in a patient with T2D during treatment with a P43220 agonist ( exenatide ) . OBSERVATION : A 61 - year - old male patient ( BMI : 25 . 5 kg / m ( 2 ) ) with T2D treated with metformin and sulphonylureas had also complained , since 1980 , of extensive psoriasis that required multiple steroid - based treatments [ Psoriasis Area and Sensitivity Index ( PASI ) score : 11 ] . In September 2008 , his diabetes treatment was intensified with exenatide ( DB01276 (®) ) to improve poor glycaemic control . The patient , as expected , lost weight and reduced HbA ( 1c ) levels from 65 mmol / mol to 56 mmol / mol . However , after just 1 month of treatment with exenatide , the patient also reported a dramatic improvement in psoriatic plaques that was confirmed at the 1 - year follow - up ( PASI : estimated at 3 - 4 ) . Withdrawal of exenatide was associated with weight gain , deterioration of glycaemic control and deterioration of psoriasis ( PASI : > 10 ) . After reinstating exenatide treatment , the patient again reported a prompt improvement in psoriasis ( PASI : 3 . 1 ) . CONCLUSION : There was a major and rapid improvement in psoriasis in our patient with T2D following treatment with exenatide . A possible mechanism might be through direct modulation of the immune system by P43220 agonists .",
"Exploring schizophrenia drug - gene interactions through molecular network and pathway modeling . In this study , we retrieved 39 schizophrenia - related antipsychotic drugs from the DrugBank database . These drugs had interactions with 142 targets , whose corresponding genes were defined as drug targeted genes . To explore the complexity between these drugs and their related genes in schizophrenia , we constructed a drug - target gene network . These genes were overrepresented in several pathways including : neuroactive ligand - receptor pathways , glutamate metabolism , and glycine metabolism . Through integrating the pathway information into a drug - gene network , we revealed a few bridge genes connected the sub - networks of the drug - gene network : Q12879 , O60391 , Q14957 , Q13224 , P21728 , and P14416 . These genes encode ionotropic glutamate receptors belonging to the DB01221 receptor family and dopamine receptors . DB00502 was the only drug to directly interact with these pathways and receptors and consequently may have a unique action at the drug - gene interaction level during the treatment of schizophrenia . This study represents the first systematic investigation of drug - gene interactions in psychosis .",
"P04150 antagonism disrupts the reconsolidation of social reward - related memories in rats . Reconsolidation is the process whereby consolidated memories are destabilized upon retrieval and restabilized to persist for later use . Although the neurobiology of the reconsolidation of both appetitive and aversive memories has been intensively investigated , reconsolidation of memories of physiologically relevant social rewards has received little attention . Social play , the most characteristic social behaviour displayed by young mammals , is highly rewarding , illustrated by the fact that it can induce conditioned place preference ( CPP ) . Here , we investigated the role of signalling mechanisms implicated in memory processes , including reconsolidation , namely glucocorticoid , mineralocorticoid , DB01221 glutamatergic and P21554 cannabinoid receptors , in the reconsolidation of social play - induced CPP in rats . Systemic treatment with the glucocorticoid receptor antagonist mifepristone before , but not immediately after , retrieval disrupted the reconsolidation of social play - induced CPP . ___MASK56___ did not affect social play - induced CPP in the absence of memory retrieval . Treatment with the DB01221 receptor antagonist MK - 801 modestly affected the reconsolidation of social play - induced CPP . However , the reconsolidation of social play - induced CPP was not affected by treatment with the mineralocorticoid and P21554 cannabinoid receptor antagonists spironolactone and rimonabant , respectively . We conclude that glucocorticoid neurotransmission mediates the reconsolidation of social reward - related memories in rats . These data indicate that the neural mechanisms of the reconsolidation of social reward - related memories only partially overlap with those underlying the reconsolidation of other reward - related memories .",
"[ ___MASK22___ in the management of functional dyspepsia and delayed gastric emptying ] . ___MASK22___ is a sulpiride isomer that exerts its prokinetic action through a dual mechanism : 1 ) as a P14416 antagonist and 2 ) as a serotonin 5HT ( 4 ) receptor agonist , conferring this drug with a cholinergic effect . At a dosage of 25mg three times daily , levosulpiride accelerates gastric and gallbladder emptying . Clinical trials have shown that this agent is more effective than placebo in reducing the symptoms of dyspepsia , while comparative studies have demonstrated that its effect is similar or superior to that of other dopamine antagonists . The safety profile of levosulpiride is good and the frequency of adverse events is similar to that of other D ( 2 ) dopamine antagonists . Therefore , this drug is a useful therapeutic option in the management of patients with functional dyspepsia , as well as in those with delayed gastric emptying .",
"Different expression of ubiquitin C - terminal hydrolase - Q9NUQ9 and αII - spectrin in ischemic and hemorrhagic stroke : Potential biomarkers in diagnosis . The two primary categories of stroke , ischemic and hemorrhagic , both have fundamentally different mechanisms and thus different treatment options . These two stroke categories were applied to rat models to identify potential biomarkers that can distinguish between them . Ischemic stroke was induced by middle cerebral artery occlusion ( MCAO ) without reperfusion while hemorrhagic stroke was induced by injecting collagenase IV into the striatum . Brain hemispheres and biofluids were collected at two time points : 3 and 6h after stroke . Known molecules were tested on the rat samples via quantitative immunoblotting ( injured brain , P04141 ) and Banyan ' s proprietary ELISA assays ( P04141 , serum ) . The injured brain quantitative analyses revealed that αII - spectrin breakdown products ( SBDP150 , SBDP145 ) were strongly increased after 6h ischemia . In P04141 , SBDP145 and ubiquitin C - terminal hydrolase - Q9NUQ9 ( P09936 ) levels were elevated after 6h ischemic stroke detected by Western blot and ELISA . In serum P09936 levels were increased after 3 and 6h of ischemia detected by ELISA . However , levels of those proteins in hemorrhagic stroke remain normal . In summary , in both the brain and the biofluids , SBDPs and P09936 were elevated after ischemic but not hemorrhagic stroke . These molecules behaved differently in the two stroke models and thus may be capable of being differentiated .",
"___MASK25___ inhibits tumor cell invasiveness and P14780 expression by suppressing IKK / NF - κB activation . The β2 adrenergic receptor ( P07550 ) is a G protein - coupled transmembrane receptor expressed in the human respiratory tract and widely recognized as a pharmacological target for treatments of asthma and chronic obstructive pulmonary disorder ( P48444 ) . Although a number of P07550 agonists have been developed for use in asthma therapy , indacaterol is the only ultra - long - acting inhaled β2 - agonist ( LABA ) approved by the FDA for relieving the symptoms in P48444 patients . The precise molecular mechanism underlying the pharmacological effect of indacaterol , however , remains unclear . Here , we show that β - arrestin - 2 mediates the internalization of P07550 following indacaterol treatment . Moreover , we demonstrate that indacaterol significantly inhibits tumor necrosis factor - α ( P01375 - α ) - induced NF - κB activity by reducing levels of both phosphorylated - IKK and - IκBα , thereby decreasing NF - κB nuclear translocation and the expression of P14780 , an NF - κB target gene . Subsequently , we show that indacaterol significantly inhibits P01375 - α / NF - κB - induced cell invasiveness and migration in a human cancer cell line . In conclusion , we propose that indacaterol may inhibit NF - κB activity in a β - arrestin2 - dependent manner , preventing further lung damage and improving lung function in P48444 patients ."
] |
[
"___MASK13___",
"___MASK1___",
"___MASK22___",
"___MASK25___",
"___MASK49___",
"___MASK56___",
"___MASK66___",
"___MASK67___",
"___MASK75___"
] |
___MASK67___
|
MH_train_493
|
interacts_with DB00921?
|
[
"[ Cell cycle analysis of endometrial cancer cells in vitro treated with growth factor and steroid hormone ] . The aim of this study was to overtake the mechanism of the control system in endometrial cancer cell line in vitro . Ishikawa cell ( IK cell ) and O14777 - 1 cell ( O14777 cell ) derived from endometrial cancers were cultured with serum free medium ( SFM - 101 ) . IK cell possessed P03372 ( ER ) , P06401 ( PR ) , Epidermal growth factor ( P01133 ) and its receptor ( P00533 ) . O14777 cell had PR , P01133 , and P00533 , however O14777 cell did not keep ER . P01133 stimulated the growth of IK cell , but the growth of O14777 cell was not stimulated by P01133 . S phase cells were increased by P01133 in IK cell , but were not increased by P01133 in O14777 cell . The growth of IK cell was stimulated significantly by P01133 and Estradiol - 17 beta ( E2 ) + P01133 than control . However , E2 + P01133 did not stimulate the growth of IK cell than P01133 significantly . ___MASK22___ ( D ) and D + P01133 inhibited the growth of IK cell significantly than control . S phase cells were decreased by the treatment of D and D + P01133 . From our results , P01133 stimulated the growth of ER positive endometrial cancer cell , but P01133 did not stimulate ER negative endometrial cancer cell . E2 + P01133 and P01133 stimulated the growth of IK cell as a same . However , D inhibited the growth of IK cell that was stimulated by P01133 .",
"Preparation of phosphorylated starch by dry - heating in the presence of pyrophosphate and its calcium - phosphate solubilizing ability . Starch was phosphorylated through dry - heating in the presence of pyrophosphate at various conditions , and the characteristics of phosphorylated starch ( PS ) were examined . Starch phosphorylation increases as the pH increases from 3 to 6 , but diminishes at pH 7 . Increased temperatures enhance phosphorylation . Data from ( 31 ) P NMR suggests that starch phosphorylation occurs mainly at the P01024 - OH and P13671 - OH of the glucose residue . The phosphate linkage is mainly due to monostarch monophosphate . Although starch had almost no calcium phosphate - solubilising capacity , this capacity was markedly enhanced by phosphorylation . X - ray diffraction analysis indicates that the crystal structure of hydroxyapatite was not present in the calcium phosphate - PS complex .",
"Role of the androgen receptor axis in prostate cancer . P10275 ( AR ) is expressed in nearly all prostate cancers , including treatment - refractory disease . The role of this receptor in the molecular endocrinology of prostate cancer has become increasingly clear in recent years . The AR is now known to participate in tumor progression through 3 mechanisms : expression ( activation and upregulation of receptor activity ) , point mutations , and ligand - independent activation . With regard to the latter mechanism , interleukin - 6 ( P05231 ) is among the most important nonsteroidal regulators of AR activity . In the absence of androgen , P05231 causes activation of AR that is approximately 50 % of the maximal activity induced by androgen . At low concentrations of androgen , P05231 and androgen synergistically activate AR . Nonsteroidal antiandrogens usually antagonize this activation , but they switch to an agonist effect in the presence of oncostatin M , an P05231 - related cytokine . The growth of parental LNCaP cells is initially inhibited by exposure to P05231 , but long - term treatment renders the cells resistant to such inhibition and confers a growth advantage . Both P05231 and oncostatin M stimulate AR activity , but only oncostatin M is associated with strong acquisition of the agonist properties of nonsteroidal antiandrogens . It is hoped that continuing research on AR expression and function in prostate cancer will pave the way for new therapeutic strategies .",
"Lack of evidence for the mu - opioid receptor splice variant MOR1C in rats . We previously reported the existence of P35372 ( C ) mRNA and P35372 ( C )- immunoreactivity ( - ir ) in rats . However , the sequence that we reported for rat P35372 ( C ) appears not to be present in the rat genome . We have therefore reexamined whether P35372 ( C ) mRNA or P35372 ( C )- ir exist in rats . We used reverse - transcription polymerase chain reaction ( RT - PCR ) to attempt to amplify P35372 , P35372 ( A ) , P35372 ( B ) , the rat P35372 ( C ) sequence we previously reported , and P35372 ( C1 ) and P35372 ( P06681 ) ( which have recently been reported to exist in rats ) . In RNA extracted from rats , we were able to demonstrate PCR products representing P35372 , P35372 ( A ) , and P35372 ( B ) splice variants . All three products were confirmed as related to P35372 by Southern blot . However , we were unable to detect either the P35372 ( C ) product reported previously by us or the P35372 ( C )- like products reported to exist in rats by others . In RNA extracted from mice we were able to detect P35372 , P35372 ( A ) , P35372 ( B ) , and P35372 ( D )- like products . To test the specificity of our P35372 ( C ) antiserum , we examined P35372 ( C )- ir in control and knockout mice . P35372 ( C )- ir had a distribution in control mice similar to that previously reported in rats , including coexisting with vGLUT2 . However , although P35372 - ir was absent in P35372 knockout mice , the density and distribution of P35372 ( C )- ir were unchanged , suggesting that the antiserum crossreacts with another molecule in tissue . We find no evidence for P35372 ( C ) mRNA in rats . Furthermore , we conclude that P35372 ( C )- ir represents crossreactivity .",
"Neurogenetics of aggressive behavior : studies in primates . Aggressive behavior can have adaptive value in certain environmental contexts , but when extreme or executed inappropriately , can also lead to maladaptive outcomes . Neurogenetic studies performed in nonhuman primates have shown that genetic variation that impacts reward sensitivity , impulsivity , and anxiety can contribute to individual differences in aggressive behavior . Genetic polymorphisms in the coding or promoter regions of the Mu - Opioid Receptor ( P35372 ) , DB01285 Releasing Hormone ( P06850 ) , Monoamine Oxidase A ( P21397 ) , Dopamine D4 Receptor ( P21917 ) , and Serotonin Transporter ( P31645 ) genes have been shown to be functionally similar in humans and rhesus macaques and have been demonstrated to contribute to individual differences in aggression . This body of literature suggests mechanisms by which genetic variation that promotes aggressivity could simultaneously increase evolutionary success while making modern humans more vulnerable to psychopathology .",
"OSU - 03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood - Brain Barrier : Implications for Anti - Cancer Therapies . We examined the interaction between OSU - 03012 ( also called AR - 12 ) with phosphodiesterase 5 ( O76074 ) inhibitors to determine the role of the chaperone glucose - regulated protein ( P11021 ) / P11021 / P11021 in the cellular response . ___MASK2___ ( Viagra ) interacted in a greater than additive fashion with OSU - 03012 to kill stem - like GBM cells . Treatment of cells with OSU - 03012 / sildenafil : abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of P11021 and other HSP70 and HSP90 family chaperone proteins . Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced Q9NZJ5 - eIF2α - P18848 - P35638 signaling and was blocked by P11021 over - expression . In vivo OSU - 03012 / sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of P08183 and Q9UNQ0 in the normal brain . The combination of OSU - 03012 / sildenafil synergized with low concentrations of sorafenib to kill tumor cells , and with lapatinib to kill P00533 over - expressing tumor cells . In multiplex assays on plasma and human tumor tissue from an OSU - 03012 / sildenafil treated mouse , we noted a profound reduction in uPA signaling and identified FGF and P23458 / 2 as response biomarkers for potentially suppressing the killing response . Inhibition of FGFR signaling and to a lesser extent P23458 / 2 signaling profoundly enhanced OSU - 03012 / sildenafil lethality .",
"Targeting eIF4GI translation initiation factor affords an attractive therapeutic strategy in multiple myeloma . BACKGROUND : Deregulation of protein synthesis is integral to the malignant phenotype and translation initiation is the rate limiting stage . Therefore , eIF4F translation initiation complex components are attractive therapeutic targets . METHODS : Protein lysates of myeloma cells ( cell lines / patients ' bone marrow samples ) untreated / treated with bevacizumab were assayed for eIF4GI expression , regulation ( P15559 / proteosome dependent fragmentation ) ( WB , ___MASK80___ , qPCR ) and targets ( WB ). eIF4GI was inhibited by knockdown and 4EGI - 1 . Cells were tested for viability ( ELISA ) , death ( FACS ) and eIF4GI targets ( WB ) . RESULTS : Previously , we have shown that manipulation of P15692 in myeloma cells attenuated P06730 dependent translation initiation . Here we assessed the significance of eIF4GI to MM cells . We demonstrated increased expression of eIF4GI in myeloma cells and its attenuation upon P15692 inhibition attributed to elevated P15559 / proteasome dependent fragmentation and diminished mRNA levels . Knockdown of eIF4GI was deleterious to myeloma cells phenotype and expression of specific molecular targets ( Q99717 / ERα / HIF1α / c - Myc ) . Finally , we showed that the small molecule 4EGI - 1 inhibits eIF4GI and causes a reduction in expression of its molecular targets in myeloma . CONCLUSION : Our findings substantiate that translation initiation of particular targets in MM is contingent on the function of eIF4GI , critical to cell phenotype , and mark it as a viable target for pharmacological intervention .",
"Palmitoylation and membrane cholesterol stabilize μ - opioid receptor homodimerization and G protein coupling . BACKGROUND : A cholesterol - palmitoyl interaction has been reported to occur in the dimeric interface of the β₂ - adrenergic receptor crystal structure . We sought to investigate whether a similar phenomenon could be observed with μ - opioid receptor ( P35372 ) , and if so , to assess the role of cholesterol in this class of G protein - coupled receptor ( GPCR ) signaling . RESULTS : P01024 . 55 ( 170 ) was determined to be the palmitoylation site of P35372 . Mutation of this DB00151 to Ala did not affect the binding of agonists , but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex . In addition , both attenuation of receptor palmitoylation ( by mutation of P01024 . 55 [ 170 ] to Ala ) and inhibition of cholesterol synthesis ( by treating the cells with simvastatin , a P04035 inhibitor ) impaired receptor signaling , possibly by decreasing receptor homodimerization and Gαi2 coupling ; this was demonstrated by co - immunoprecipitation , immunofluorescence colocalization and fluorescence resonance energy transfer ( FRET ) analyses . A computational model of the P35372 homodimer structure indicated that a specific cholesterol - palmitoyl interaction can facilitate P35372 homodimerization at the TMH4 - TMH4 interface . CONCLUSIONS : We demonstrate that P01024 . 55 ( 170 ) is the palmitoylation site of P35372 and identify a cholesterol - palmitoyl interaction in the P35372 complex . Our findings suggest that this interaction contributes to P35372 signaling by facilitating receptor homodimerization and G protein coupling . This conclusion is supported by computational modeling of the P35372 homodimer .",
"Determination of fenofibric acid concentrations by HPLC after anion exchange solid - phase extraction from human serum . Triglycerides are increasingly being recognized as a risk factor for cardiovascular disease . Research efforts to identify sources of variability in triglyceride - lowering response to the lipid - lowering drug fenofibrate require quantification of the active acidic form of this Q07869 agonist . Anion - exchange solid - phase extraction , in combination with reverse - phase high - performance liquid chromatography ( HPLC ) , rapidly and accurately determines steady - state fenofibric acid serum concentrations . Chromatographic separation under isocratic conditions , with use of ultraviolet detection at 285 nm , provides clean baseline and sharp peaks for clofibric acid , 1 - napthyl acetic acid ( internal standards ) , and fenofibric acid . Commonly prescribed and over - the - counter nonsteroidal anti - inflammatory drugs ( NSAIDs ) were screened for assay interference , and the assay was employed to quantify fenofibric acid in more than 800 human subject specimens . ___MASK68___ analysis was found to be linear over the range of 0 . 5 to 40 mg / L and was validated with either internal standard . Accuracies ranged from 98 . 65 % to 102 . 4 % , whereas the within - and between - day precisions ranged from 1 . 0 % to 2 . 2 % and 2 . 0 % to 6 . 2 % , respectively . NSAIDs had minimal interference with the assay , which succeeded in quantifying fenofibric acid in more than 843 of 846 serum samples from human subjects , many taking a variety of coadministered medications . Anion - exchange solid - phase extraction in combination with reverse - phase HPLC accurately determines steady - state fenofibric acid serum concentrations in humans without interference from NSAIDs or commonly administered medications . This method is suitable for quantification of fenofibric acid for clinical pharmacokinetic studies in patients with dyslipidemia .",
"P10275 rediscovered : the new biology and targeting the androgen receptor therapeutically . Discoveries over the past decade suggest that castration - resistant prostate cancer ( CRPC ) is sensitive , but not resistant to , further manipulation of the androgen - androgen receptor ( AR ) axis . Several new therapies that target this axis have demonstrated clinical activity . In this article , preclinical and clinical findings occurring in the field of AR - targeted therapies are reviewed . Reviews of scientific and clinical development are divided into those occurring prereceptor ( androgen production and conversion ) and at the level of the receptor ( AR aberrations and therapies targeting AR directly ) . Intracrine androgen production and AR amplification , among others , are among the principal aberrancies driving CRPC growth . Phase III data with abiraterone acetate and phase II data with ___MASK10___ , along with other similar therapies , confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease . Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way . The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling , even in the castrate state .",
"Synthesis , biological activity and HPLC validation of 1 , 2 , 3 , 4 - tetrahydroacridine derivatives as acetylcholinesterase inhibitors . The synthesis and biochemical evaluation of new hybrids of tacrine ( ___MASK75___ ) and 4 - fluorobenzoic acid ( 4 - FBA ) possessing activity towards acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) inhibition are presented . The compounds of interest were obtained from the reaction of activated 4 - FBA and diamino derivatives of 1 , 2 , 3 , 4 - tetrahydroacridine . The compounds P13671 - 2KW / HCl , P13671 - 4KW / HCl and P13671 - 3KW / HCl have four - fold higher antiacetylcholinesterase activity than ___MASK75___ . All of the acquired compounds present higher selectivity towards P22303 than ___MASK75___ and lower selectivity towards BuChE . In addition , a rapid , selective and stability - indicating HPLC method was developed and validated for the determination of P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl . ___MASK75___ and 4 - FBA were found to be the main impurities . Chromatographic separation was achieved isocratically on a Waters Symmetry C18 150 × 3 . 9 mm , 4 μm column with a mobile phase of acetonitrile / buffer ( 17 mM sodium dodecyl sulphate and 8 . 3 mM sodium dihydrogen phosphate , 50 : 50 v / v ) ( overall pH 4 ) . A 1 . 5 ml / min flow rate and a 247 nm wavelength were chosen for this method . P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl were subjected to acidic and basic hydrolysis , chemical oxidation , thermal exposition at 60 ° C and intense UV light . The limits of detection ( LOD ) and quantification ( LOQ ) were less than 2 μg / ml and 6 μg / ml for P13671 - 2KW / HCl , P13671 - 3KW / HCl and P13671 - 4KW / HCl , 0 . 04 μg / ml and 0 . 12 μg / ml for ___MASK75___ , 0 . 42 μg / ml and 1 . 41 μg / ml for 4 - FBA , respectively .",
"Rosiglitazone regulates P05231 - stimulated lipolysis in porcine adipocytes . Interleukin ( IL ) - 6 , a proinflammatory cytokine , stimulates adipocyte lipolysis and induces insulin resistance in obese and diabetic subjects . However , the effects of the anti - diabetic drug rosiglitazone on P05231 - stimulated lipolysis and the underlying molecular mechanism are largely unknown . In this study , we demonstrated that rosiglitazone suppressed P05231 - stimulated lipolysis in differentiated porcine adipocytes by inactivation of extracellular signal - related kinase ( P29323 ) . Meanwhile , rosiglitazone enhanced the lipolysis response of adipocytes to isoprenaline . In addition , rosiglitazone significantly reversed P05231 - induced down - regulation of several genes such as perilipin A , peroxisome proliferators activated receptor gamma ( Q07869 & gamma ; ) , and fatty acid synthetase , as well as the up - regulation of P05231 mRNA . However , mRNA expression of Q07869 & gamma ; coactivator - 1 alpha ( DB01053 - 1 & alpha ; ) was enhanced by rosiglitazone in P05231 - stimulated adipocytes . These results indicate that rosiglitazone suppresses P05231 - stimulated lipolysis in porcine adipocytes through multiple molecular mechanisms .",
"Predictive model for risk of severe gastrointestinal toxicity following chemotherapy using patient immune genetics and type of cancer : a pilot study . PURPOSE : Severe chemotherapy - induced gastrointestinal toxicity ( CIGT ) is common and results in treatment delays , dose reductions , and potential premature treatment discontinuation . Currently , there is no diagnostic marker to predict CIGT . Proinflammatory cytokines , produced via toll - like receptor signaling , are key mediators of this toxicity . Hence , this pilot study investigated the association between immune genetic variability and severe CIGT risk . METHODS : Genomic DNA from 34 patients ( 10 with severe CIGT ) who had received 5 - fluoruracil - based chemotherapy regimens was analyzed for variants of IL - 1B , P60568 , P05231 , IL - 6R , P22301 , P01375 , TGF - b , O60603 , O00206 , Q9Y6Y9 , Q99836 , P23560 , CRP , ICE , and P35372 . Multivariate logistic regression created a prediction model of severe CIGT risk . RESULTS : There were no significant differences between patients with and without severe CIGT with regards to age , sex , type of cancer , or chemotherapy treatment regimens . The prediction model of severe CIGT risk included O60603 and P01375 genetic variability and cancer type ( colorectal and gastric ) . This prediction model was both specific and sensitive , with a receiver operator characteristic area under the curve of 87 . 3 % . CONCLUSIONS : This is the first report of immune genetic variability , together with cancer type , being predictive of severe CIGT risk . These outcomes are being validated in a larger patient population .",
"mu - Opioid receptor agonists differentially regulate the expression of miR - 190 and Q13562 . The agonists of mu - opioid receptor ( P35372 ) induce extracellular signal - regulated kinase ( P29323 ) phosphorylation through different pathways : morphine uses the protein kinase C ( PKC ) - pathway , whereas fentanyl functions in a beta - arrestin2 - dependent manner . In addition , the two pathways result in the different cellular location of phosphorylated P29323 and the activation of different sets of transcriptional factors . In the current study , the influence of the two pathways on the expression of microRNAs ( miRNAs ) was investigated . After treating the primary culture of rat hippocampal neurons and the mouse hippocampi with morphine or fentanyl for 3 days , seven miRNAs regulated by one or two of the agonists were identified . One of the identified miRNAs , miR - 190 , was down - regulated by fentanyl but not by morphine . This down - regulation was attenuated by 1 , 4 - diamino - 2 , 3 - dicyano - 1 , 4 - bis ( methylthio ) butadiene ( U0126 ) , which blocks the phosphorylation of P29323 . When fentanyl - induced but not morphine - induced P29323 phosphorylation was blocked in the primary cultures from beta - arrestin2 (-/-) mouse , fentanyl did not decrease the expression of miR - 190 . However , a PKC inhibitor that blocked morphine - induced P29323 phosphorylation specifically had no effect on the miR - 190 down - regulation . Therefore the decrease in miR - 190 expression resulted from the agonist - selective P29323 phosphorylation . In addition , the expressional changes in one of the miR - 190 targets , neurogenic differentiation 1 ( Q13562 ) , correlated with those in miR - 190 expression , suggesting the P35372 could regulate the Q13562 pathways via the control of miR - 190 expression .",
"Shared and unique genetic contributions to attention deficit / hyperactivity disorder and substance use disorders : a pilot study of six candidate genes . The shared genetic basis of attention deficit / hyperactivity disorder ( ADHD ) and substance use disorders ( SUDs ) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders . One hundred seven methadone maintenance treatment patients , 36 having an ADHD diagnosis , 176 adult patients with ADHD without SUDs , and 500 healthy controls were genotyped for variants in the P21917 ( exon 3 VNTR ) , P21918 ( upstream VNTR ) , P28222 ( rs6296 ) , P09172 ( rs2519152 ) , P21964 ( rs4680 ; Val158Met ) , and P35372 ( rs1799971 ; 118A > G ) genes . Association with disease was tested using logistic regression models . This pilot study was adequately powered to detect larger genetic effects ( OR ≥ 2 ) of risk alleles with a low frequency . Compared to controls , ADHD patients ( with and without SUDs ) showed significantly increased frequency of the P09172 ( rs2519152 : OR 1 . 73 ; CI 1 . 15 - 2 . 59 ; P = 0 . 008 ) and the P35372 risk genotypes ( rs1799971 : OR 1 . 71 ; CI 1 . 17 - 2 . 50 ; P = 0 . 006 ) . The P09172 risk genotype was associated with ADHD diagnosis , with the association strongest in the pure ADHD group . The P35372 risk genotype increased the risk for the combined ADHD and SUD phenotype . The present study strengthens the evidence for a shared genetic basis for ADHD and addiction . The association of P35372 with the ADHD and SUD combination could help to explain the contradictory results of previous studies . The power limitations of the study restrict the significance of these findings : replication in larger samples is warranted .",
"P35372 phosphorylation , desensitization , and ligand efficacy . Mu opioid receptors are subject to phosphorylation and desensitization through actions of at least two distinct biochemical pathways : agonist - dependent mu receptor phosphorylation and desensitization induced by a biochemically distinct second pathway dependent on protein kinase C activation ( 1 ) . To better understand the nature of the agonist - induced mu receptor phosphorylation events , we have investigated the effects of a variety of opiate ligands of varying potencies and intrinsic activities on mu receptor phosphorylation and desensitization . Exposure to the potent full agonists sufentanil , dihydroetorphine , etorphine , etonitazine , and [ D - Ala2 , MePhe4 , Glyol5 ] enkephalin ( DAMGO ) led to strong receptor phosphorylation , while methadone , l - alpha - acetylmethadone ( DB01227 ) , morphine , meperidine , DADL , beta - endorphin ( 1 - 31 ) , enkephalins , and dynorphin A ( 1 - 17 ) produced intermediate effects . The partial agonist buprenorphine minimally enhanced receptor phosphorylation while antagonists failed to alter phosphorylation . DB00921 and full antagonists each antagonized the enhanced mu receptor phosphorylation induced by morphine or DAMGO . The rank order of opiate ligand efficacies in producing mu receptor - mediated functional desensitization generally paralleled their rank order of efficacies in producing receptor phosphorylation . Interestingly , the desensitization and phosphorylation mediated by methadone and DB01227 were disproportionate to their efficacies in two distinct test systems . This generally good fit between the efficacies of opiates in mu receptor activation , phosphorylation , and desensitization supports the idea that activated receptor / agonist / G - protein complexes and / or receptor conformational changes induced by agonists are required for agonist - induced mu receptor phosphorylation . Data for methadone and DB01227 suggest possible contribution from their enhanced desensitizing abilities to their therapeutic efficacies .",
"P35372 and P00533 contribute to skin pigmentation differences between Indigenous Americans and Europeans . Contemporary variation in skin pigmentation is the result of hundreds of thousands years of human evolution in new and changing environments . Previous studies have identified several genes involved in skin pigmentation differences among African , Asian , and European populations . However , none have examined skin pigmentation variation among Indigenous American populations , creating a critical gap in our understanding of skin pigmentation variation . This study investigates signatures of selection at 76 pigmentation candidate genes that may contribute to skin pigmentation differences between Indigenous Americans and Europeans . Analysis was performed on two samples of Indigenous Americans genotyped on genome - wide SNP arrays . Using four tests for natural selection -- locus - specific branch length ( LSBL ) , ratio of heterozygosities ( lnRH ) , Tajima ' s D difference , and extended haplotype homozygosity ( EHH ) -- we identified 14 selection - nominated candidate genes ( SNCGs ) . SNPs in each of the SNCGs were tested for association with skin pigmentation in 515 admixed Indigenous American and European individuals from regions of the Americas with high ground - level ultraviolet radiation . In addition to Q71RS6 and Q9UMX9 , genes previously associated with European / non - European differences in skin pigmentation , P35372 and P00533 were associated with variation in skin pigmentation in New World populations for the first time .",
"Pivotal role of the P06681 domain of the Smurf1 ubiquitin ligase in substrate selection . The P06681 - WW - HECT - type ubiquitin ligases Smurf1 and Smurf2 play a critical role in embryogenesis and adult bone homeostasis via regulation of bone morphogenetic protein , Wnt , and RhoA signaling pathways . The intramolecular interaction between P06681 and HECT domains autoinhibits the ligase activity of Smurf2 . However , the role of the Smurf1 P06681 domain remains elusive . Here , we show that the P06681 - HECT autoinhibition mechanism is not observed in Smurf1 , and instead its P06681 domain functions in substrate selection . The Smurf1 P06681 domain exerts a key role in localization to the plasma membrane and endows Smurf1 with differential activity toward RhoA versus Q99717 and Runx2 . Crystal structure analysis reveals that the Smurf1 P06681 domain possesses a typical anti - parallel β - sandwich fold . Examination of the sulfate - binding site analysis reveals two key lysine residues , Lys - 28 and Lys - 85 , within the P06681 domain that are important for Smurf1 localization at the plasma membrane , regulation on cell migration , and robust ligase activity toward RhoA , which further supports a Ca ( 2 +)- independent localization mechanism for Smurf1 . These findings demonstrate a previously unidentified role of the Smurf1 P06681 domain in substrate selection and cellular localization .",
"[ Moclobemide ( ___MASK25___ ) , the first P21397 - inhibitor : really something new ? ] .",
"A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men . ___MASK39___ is the major addictive substance in cigarettes , and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction . We studied six single - nucleotide polymorphisms ( SNPs ) in the P43681 gene and four SNPs in the P17787 gene with respect to nicotine dependence in a collection of 901 subjects ( 815 siblings and 86 parents ) from 222 nuclear families with multiple nicotine - addicted siblings . The subjects were assessed for addiction by both the Fagerstrom Test for ___MASK39___ Dependence ( FTND ) and the Revised Tolerance Questionnaire ( RTQ ) . Because only 5 . 8 % of female offspring were smokers , only male subjects were included in the final analyses ( 621 men from 206 families ) . Univariate ( single - marker ) family - based association tests ( FBATs ) demonstrated that variant alleles at two SNPs , rs1044396 and rs1044397 , in exon 5 of the P43681 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype ( i . e . , age - adjusted FTND and RTQ scores ) , which was consistent with the results of the global haplotype FBAT . Furthermore , the haplotype - specific FBAT showed a common ( 22 . 5 % ) P43681 haplotype , GCTATA , which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait ( Z =- 3 . 04 , P < . 005 ) and significant decreases of age - adjusted FTND ( Z =- 3 . 31 , P < . 005 ) or RTQ scores ( Z =- 2 . 73 , P =. 006 ) . Our findings provide strong evidence suggesting a common P43681 haplotype might be protective against vulnerability to nicotine addiction in men .",
"No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD . Results from pharmacogenetic investigations of methylphenidate ( ___MASK30___ ) response in patients with ADHD are still inconsistent , especially among adults . This study investigates the role of genetic variants ( P31645 , P28222 , Q8IWU9 , P09172 , P21917 , P21964 , and P60880 ) in the response to ___MASK30___ in a sample of 164 adults . Genes were chosen owing to previous evidence for an influence in ADHD susceptibility . No significant differences in allele or genotype frequencies between ___MASK30___ responders and nonresponders were detected . In conclusion , our findings do not support an effect of these genes in the pharmacogenetics of ___MASK30___ among adults with ADHD .",
"Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene ( P43681 ) , mu - opioid receptor gene ( P35372 ) , and ethanol - metabolizing enzyme genes with alcoholism in Korean patients . Findings obtained from several studies indicate that ethanol enhances the activity of alpha4beta2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor alpha4 subunit gene ( P43681 ) modulates enhancement of nicotinic receptor function by ethanol . To identify the association between the CfoI polymorphism of the P43681 and alcoholism , we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism ( n = 127 ) and Korean control subjects without alcoholism ( n = 185 ) with polymerase chain reaction - restriction fragment length polymorphism methods . We were able to detect the association between the CfoI polymorphism of the P43681 and alcoholism in Korean patients ( genotype P = . 023 ; allele frequency P = . 047 ) . The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes , such as alcohol metabolism - related genes [ alcohol dehydrogenase 2 ( P00325 ) , aldehyde dehydrogenase 2 ( P05091 ) , alcohol dehydrogenase 3 ( P00326 ) , and cytochrome P450 2E1 ( P05181 ) ] and mu - opioid receptor gene ( P35372 ) , were studied . The polymorphisms of P00325 , P05091 , and P05181 were significantly different in Korean patients with alcoholism and Korean control subjects without alcoholism , but P00326 and P35372 did not differ between the two groups ."
] |
[
"___MASK10___",
"___MASK22___",
"___MASK25___",
"___MASK2___",
"___MASK30___",
"___MASK39___",
"___MASK68___",
"___MASK75___",
"___MASK80___"
] |
___MASK25___
|
MH_train_494
|
interacts_with DB01277?
|
[
"How DB01277 activates its receptor . This study presents a new model for P08069 activation in which the transmembrane domains are held apart until ligand binding brings them together in an activated state .",
"P08069 mRNA expression and autophosphorylation in human myometrium and leiomyoma . Uterine leiomyomas are the most common tumors of the genital tract . Growth factors seem to be implicated in the development of leiomyoma . The aim of this study was to determine insulin - like growth factor 1 receptor ( DB01277 - R ) mRNA levels and DB01277 - R tyrosine kinase activity in normal myometrium and leiomyoma . Plasma membranes of myometrium and leiomyoma of 14 women subjected to hysterectomy were prepared , and samples were incubated in the absence or presence of recombinant human DB01277 to assess the tyrosine kinase activity ( Western blot ) . Reverse - transcriptase polymerase chain reaction with specific primers for DB01277 - R was used to determine DB01277 - R mRNA levels . DB01277 - R mRNA levels in myometrium ( 0 . 8216 +/- 0 . 096 ) and in leiomyoma ( 0 . 7905 +/- 0 . 136 ) were not statistically significantly different ( p = 0 . 648 ) . The degree of DB01277 - R autophosphorylation stimulated by recombinant DB01277 was not different in myometrium ( 1 . 020 +/- 0 . 120 ) and leiomyoma ( 1 . 620 +/- 0 . 656 ) either ( p = 0 . 075 ) . There was no difference in DB01277 - R expression and DB01277 - R autophosphorylation between normal myometrium and leiomyoma .",
"P01308 - like growth factors and their binding proteins in the venous effluents of ovary and adrenal gland in severely hyperandrogenic women . P01308 and insulin - like growth factors ( IGF ) are thought to play an important role in the pathogenesis of excessive androgen production . To explore this question further we measured the concentrations of P05019 and - II and their binding proteins ( P08833 and - 3 ) in adrenal and ovarian vein samples of severely hyperandrogenic women ( serum testosterone > 5 nmol / l ) collected as part of their diagnostic work - up . The concentration of P01344 was slightly but not significantly higher in the ovarian vein than in the adrenal and peripheral veins . The concentrations of P05019 and IGFBP were identical in both the adrenal and ovarian veins and did not differ from those in the peripheral circulation . The concentration of P08833 was negatively correlated ( r = - 0 . 60 , P > 0 . 05 ) with insulin and P17936 showed a strong positive correlation with DB01277 ( r = 0 . 90 , P > 0 . 01 ) . These results indicate that neither the ovary nor the adrenal gland contributes significantly to the circulating pool of IGF or their binding proteins in severely hyperandrogenic subjects . Hyperinsulinaemia is associated with low circulating P08833 concentrations and P17936 seems to be an excellent indicator of the peripheral P05019 concentration . The concentrations of P05019 suggested decreased somatotrophic activity in these obese , hyperinsulinaemic subjects .",
"Milk consumption and the prepubertal somatotropic axis . BACKGROUND : Nutrients , hormones and growth factors in dairy foods may stimulate growth hormone ( GH ) , insulin - like growth factor I ( P05019 ) , and raise the ratio of P05019 to its binding protein , P17936 . We conducted pilot studies in Mongolia and Massachusetts to test the extent to which milk intake raised somatotropic hormone concentrations in prepubertal children . METHODS : In Ulaanbaatar , we compared plasma levels before and after introducing 710 ml daily whole milk for a month among 46 10 - 11 year old schoolchildren . In a randomized cross - over study in Boston , we compared plasma hormone levels of 28 6 - 8 year old girls after one week of drinking 710 ml low fat ( 2 % ) milk with their hormone levels after one week of consuming a macronutrient substitute for milk . RESULTS : After a month of drinking whole milk , Mongolian children had higher mean plasma levels of P05019 ( p < 0 . 0001 ) , P05019 / P17936 ( p < 0 . 0001 ) , and 75th percentile of GH levels ( p = 0 . 005 ) . After a week of drinking low fat milk , Boston girls had small and non - significant increases in DB01277 , DB01277 / P17936 and GH . CONCLUSION : Milk drinking may cause increases in somatotropic hormone levels of prepubertal girls and boys . The finding that milk intake may raise GH levels is novel , and suggests that nutrients or bioactive factors in milk may stimulate endogenous GH production .",
"Evaluation of the antitumor effects and mechanisms of PF00299804 , a pan - HER inhibitor , alone or in combination with chemotherapy or targeted agents in gastric cancer . Recently , P04626 - directed treatment , such as trastuzumab , has shown clinical benefit in P04626 - amplified gastric cancer . On the basis of recent studies about epidermal growth factor receptor ( P00533 ) or P04626 - targeting agents ( including gefitinib , lapatinib , and trastuzumab ) in gastric cancer , the potent effects of pan - HER inhibitors targeting the HER family are anticipated . In this study , we evaluated the activity and mechanisms of PF00299804 , an irreversible pan - HER inhibitor , in gastric cancer in vitro and in vivo models . PF00299804 showed significant growth - inhibitory effects in P04626 - amplified gastric cancer cells ( SNU216 , N87 ) , and it had lower 50 % inhibitory concentration values compared with other P00533 tyrosine kinase inhibitors , including gefitinib , lapatinib , BIBW - 2992 , and DB05424 . PF00299804 induced apoptosis and G ( 1 ) arrest and inhibited phosphorylation of receptors in the HER family and downstream signaling pathways including P40763 , AKT , and extracellular signal - regulated kinases ( P29323 ) in P04626 - amplified gastric cancer cells . PF00299804 also blocked P00533 / P04626 , P04626 / P21860 , and P21860 / Q15303 heterodimer formation as well as the association of P21860 with p85α in SNU216 cells . The combination of PF00299804 with clinically relevant chemotherapeutic agents or molecular - targeted agents including trastuzumab ( an anti - P04626 monoclonal antibody ) , CP751871 ( an P08069 inhibitor ) , PD0325901 ( an P27361 / 2 inhibitor ) , and PF04691502 ( a PI3K / P42345 inhibitor ) produced synergistic effects . These findings indicate that PF00299804 can be used as a targeted therapy for the treatment of P04626 - amplified gastric cancer through inhibition of HER family heterodimer formation and may augment antitumor efficacy of chemotherapeutic and / or molecular - targeted agents .",
"Growth factors expression in patients with erosive esophagitis . Although the pathogenesis and treatment of erosive esophagitis ( EE ) is well recognized , little is known about the cellular and molecular mechanisms of mucosal healing in EE patients . In this pilot study , we enrolled typical EE patients to evaluate what kinds of growth factors and their receptors were activated in their injured esophageal mucosa . Forty endoscopically proved EE patients were consecutively enrolled . Messenger RNA expressions , which includes keratinocyte growth factor ( KGF ) and its receptor ( P21802 ) , epidermal growth factor ( P01133 ) and its receptor ( P00533 ) , hepatocyte growth factor ( P14210 ) and its receptor ( HGFR ) , basic fibroblast growth factor ( P09038 ) , vascular endothelial growth factor ( P15692 ) , and cyclooxygenase ( P36551 ) - 1 and P35354 , were measured using real - time polymerase chain reaction ( PCR ) . Data were compared between the injured EE mucosa and their normal esophageal mucosa above EE . The mRNA expressions of P14210 , HGFR , P01133 , P15692 , and P35354 , but not P00533 , KGF , P21802 , P09038 , and P23219 , were significantly increased in the injured mucosa of EE patients compared with those of normal mucosa ( P < 0 . 05 ) . The study found that P14210 , HGFR , P01133 , P15692 , and , P35354 are activated in the injured mucosa of EE patients ; their activation might be involved in mucosal repair and ulcer healing of EE .",
"P08069 - mediated endocytosis in Xenopus laevis oocytes . A role for receptor tyrosine kinase activity . Equilibrium analysis of [ 125I ] DB01277 binding to Xenopus oocytes yielded curvilinear Scatchards supporting the presence of multiple binding sites . High - affinity binding displayed an apparent KD of 9 . 0 +/- 3 . 0 nM DB01277 with maximum total binding of 1 . 6 +/- 0 . 3 fmole / oocyte after 90 min at 22 degrees C . Binding of 1 nM [ 125I ] DB01277 to oocytes was competitively displaced by unlabeled DB01277 or insulin with IC50 values of 6 and 560 nM , respectively . Chemical cross - linking of [ 125I ] - DB01277 to oocyte membranes specifically labeled a single 138 - kDa protein . Using the technique of acid stripping to analyze whole - cell binding , both total and surface binding of [ 125I ] DB01277 reached a plateau after 90 min , and internalized counts surpassed surface - associated counts 20 min after hormone addition . At the 90 - min plateau , 70 - 75 % of cell - associated counts were internalized . The tyrosine kinase inhibitor , tyrphostin 47 , prevented DB01277 - stimulated oocyte maturation with an apparent IC50 of 10 . 5 +/- 2 . 5 microM and also inhibited DB01277 receptor - mediated endocytosis in micromolar concentrations . Treatment of oocyte membrane samples with 10 nM DB01277 stimulated alkali - stable phosphorylation of a protein doublet ( M ( r ) 89 and 104 kDa ) . Tyrphostin 47 also inhibited DB01277 - stimulated phosphorylation of these putative receptor beta - subunits more effectively than tyrphostin 23 or genistein . These results suggest a necessary role for receptor - mediated endocytosis in DB01277 - induced oocyte maturation and a requirement for receptor kinase activity in oocyte receptor internalization .",
"P17936 , hypoxia and P01375 inhibit adiponectin transcription . The thiazolidinedione rosiglitazone , an agonist ligand for the nuclear receptor P37231 , improves insulin sensitivity in part by stimulating transcription of the insulin - sensitizing adipokine adiponectin . It activates P37231 - RXR - alpha heterodimers bound to P37231 response elements in the adiponectin promoter . Rosiglitazone - stimulated adiponectin protein synthesis in 3T3 - Q9NUQ9 mouse adipocytes has been shown to be inhibited by P17936 , which can be induced by hypoxia and the proinflammatory cytokine , P01375 , two inhibitors of adiponectin transcription . The present study demonstrates that P17936 , the hypoxia - mimetic agent cobalt chloride , and P01375 inhibit rosiglitazone - induced adiponectin transcription in mouse embryo fibroblasts that stably express Q07869 - gamma2 . Native P17936 can bind RXR - alpha and inhibited rosiglitazone stimulated promoter activity , whereas an P17936 mutant that does not bind RXR - alpha did not . These results suggest that P17936 may mediate the inhibition of adiponectin transcription by hypoxia and P01375 , and that P17936 binding to RXR - alpha may be required for the observed inhibition .",
"___MASK72___ : kinetic and dynamic profile in the treatment of pain . ___MASK72___ ( 4 , 5 - diphenyl - 2 - oxazolepropionic acid ) is a non - steroidal anti - inflammatory drug ( NSAID ) which is effective in models of inflammation , pain and pyrexia . It is effective and well tolerated in the clinical management of adult rheumatoid arthritis ( RA ) , osteoarthritis ( OA ) , ankylosing spondylitis , soft tissue disorders and post operative dental pain . ___MASK72___ has a high oral bioavailability ( 95 % ) , with peak plasma concentrations at 3 to 5 hours after dosing . It is metabolised in the liver by oxidative and conjugative pathways and readily eliminated by the renal and faecal routes . ___MASK72___ ' s strong analgesic qualities are particularly useful in painful musculoskeletal conditions such as periarthritis of the shoulder , since it exhibits actions such as inhibition of P23219 and P35354 isoenzymes , inhibition of nuclear translocation of NF - kappaB and of metalloproteases , and modulates the endogenous cannabinoid system . This editorial addresses the accompanying paper by Barbara Heller and Rosanna Tarricone on the management of shoulder periarthritis pain , in which they studied the efficacy and safety of oxaprozin compared to the comparator drug diclofenac over a 15 day period . Both oxaprozin and diclofenac compared well in the primary study endpoint of reduction in shoulder pain . ___MASK72___ and diclofenac were well tolerated and oxaprozin showed better improvement in shoulder function and in the mental health item of the SF - 36 quality of life component . The study by Heller and Tarricone is an addition to the large number of clinical trials which demonstrate that oxaprozin has equal efficacy in comparison with standard doses of commonly used anti - rheumatic agents such as aspirin , diclofenac , ibuprofen , indomethacin etc . in several different painful musculoskeletal conditions .",
"[ Analysis of clinical manifestations and genetic mutations in a child with Laron syndrome ] . OBJECTIVE : To analyze clinical manifestations and gene mutations in a child with severe short stature , explore its molecular mechanism and further clarify the diagnostic procedure for short stature . METHOD : We observed clinical characteristics of a patient with short stature and did diagnostic examinations , assessed the function of GH - DB01277 axis , and surveyed its family members . Genomic DNA was extracted from peripheral blood , P10912 , P35858 , STAT5b and P01241 gene were amplified by PCR for sequencing , including exons and splicing areas . RESULT : The patient presented symmetrical short stature ( height - 8 . 2 SDS ) and facial features , and other congenital abnormalities . It displayed non - growth hormone deficiency . The baseline value of GH was 21 µg / L , and the peak was 57 . 9 µg / L . The value of DB01277 was less than 25 µg / L , and the P17936 less than 50 µg / L . And DB01277 generation test showed no response . There was no similar patients in the family members . Sequencing of P10912 in the patient revealed a homozygous point mutation ( c . Ivs6 + 1G > A ) , and her father and mother had the same heterozygous mutation . The same mutation was not identified for her sister . No other candidate gene was found . CONCLUSION : As the result of combined clinical characteristics and lab examinations , as well as gene detection , the case was diagnosed with Laron syndrome and P10912 gene mutation is the molecular mechanism . We should explicit the etiological diagnosis for short stature , and avoid missed diagnosis and misdiagnosis .",
"Spectrum of insulin - like growth factor deficiency . There are eight known genetic causes of short stature characterized by low serum DB01277 ( DB01277 deficiency , IGFD ) and normal GH secretion . One of these ( Q92847 defect ) is a form of secondary IGFD , although the GH peak in provocation tests can be normal . Bioinactive GH ( P01241 mutations ) can disturb GH secretion , but also GH binding and signaling . The remaining conditions are classified as primary IGFD ( GH insensitivity ) . The clinical phenotype of P10912 ( P10912 ) defects is variable . Of the three GH signal transduction defects , a P51692 defect is well established , but abnormalities in the MAPK pathway ( such as Q06124 mutations in Noonan syndrome ) and NF - ĸB pathway ( IĸBα mutation ) may also cause IGFD . Homozygous P35858 defects are relatively common , and lead to moderate growth failure , very low serum DB01277 and even lower P17936 , while a heterozygous P35858 mutation decreases height by 1 SD . Most cases with a homozygous IGF1 defect are very short , microcephalic , and deaf , but heterozygous mutations may also lead to short stature . IGFD can also have a digenic or oligogenic origin . The diagnostic yield of genetic testing in children with a height < - 2 . 5 SDS and a serum DB01277 < - 2 appears sufficient to perform genetic tests for known candidate genes .",
"A Single 60 mg Dose of ___MASK45___ Might Improve Hepatic P01308 Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women . Background . The O14788 / Q9Y6Q6 / O00300 signaling pathway is crucial for the regulation of osteoclast activity and bone resorption being activated in osteoporosis . The pathway has been also suggested to influence glucose metabolism as observed in chronic low inflammation . Aim . To test whether systemic blockage of O14788 by the monoclonal antibody denosumab influences glucose metabolism in osteoporotic women . Study Design . This is a prospective study on the effect of a subcutaneously injected single 60 mg dose of denosumab in 14 postmenopausal severe osteoporotic nondiabetic women evaluated at baseline and 4 and 12 weeks after their first injection by an oral glucose tolerance test . Results . A single 60 mg dose of denosumab efficiently inhibited serum alkaline phosphatase while it did not exert any significant variation in fasting glucose , insulin , or HOMA - IR at both 4 and 12 weeks . No changes could be detected in glucose response to the glucose load , Matsuda Index , or insulinogenic index . Nonetheless , 60 mg denosumab induced a significant reduction in the hepatic insulin resistance index at 4 weeks and in HbA1c levels at 12 weeks . Conclusions . A single 60 mg dose of denosumab might positively affect hepatic insulin sensitivity though it does not induce clinical evident glucose metabolic disruption in nondiabetic patients .",
"Global transcriptome analysis of formalin - fixed prostate cancer specimens identifies biomarkers of disease recurrence . Prostate cancer remains the second leading cause of cancer death in American men and there is an unmet need for biomarkers to identify patients with aggressive disease . In an effort to identify biomarkers of recurrence , we performed global RNA sequencing on 106 formalin - fixed , paraffin - embedded prostatectomy samples from 100 patients at three independent sites , defining a 24 - gene signature panel . The 24 genes in this panel function in cell - cycle progression , angiogenesis , hypoxia , apoptosis , PI3K signaling , steroid metabolism , translation , chromatin modification , and transcription . Sixteen genes have been associated with cancer , with five specifically associated with prostate cancer ( P78543 , P17936 , Q96EB6 , P50539 , and P14324 ) . Validation was performed on an independent publicly available dataset of 140 patients , where the new signature panel outperformed markers published previously in terms of predicting biochemical recurrence . Our work also identified differences in gene expression between Gleason pattern 4 + 3 and 3 + 4 tumors , including several genes involved in the epithelial - to - mesenchymal transition and developmental pathways . Overall , this study defines a novel biomarker panel that has the potential to improve the clinical management of prostate cancer .",
"A new role for the P40763 inhibitor , Q9Y6X2 : a repressor of microphthalmia transcription factor . In vitro and in vivo evidence suggest that microphthalmia transcription factor ( O75030 ) plays a key regulatory role in tissue - specific gene regulation in several cell types , including melanocytes , osteoclasts , and mast cells . A yeast two - hybrid search , using a portion of a nonmutated O75030 gene as the bait in the screening of a mast cell library , resulted in the isolation of the P40763 inhibitor , Q9Y6X2 . Q9Y6X2 is a transcriptional inhibitor that acts by specifically inhibiting P40763 ' s DNA binding activity . We found that it can directly associate with O75030 using an in vitro pull - down assay . Immunoprecipitation of O75030 from rat basophilic leukemic cells or mouse melanocytes resulted in the specific co - immunoprecipitation of Q9Y6X2 . Co - transfection of O75030 with Q9Y6X2 in NIH 3T3 fibroblasts containing an mMCP - 6 promoter - luciferase reporter demonstrated up to 94 % inhibition of O75030 - mediated transcriptional activation . Using a gel - shift assay , it was shown that Q9Y6X2 can block DNA binding activity . It was also found that P40763 does not interfere , either in vitro or in vivo , with the interaction between Q9Y6X2 and O75030 . These data suggest that Q9Y6X2 functions in vivo as a key molecule in supressing the transcriptional activity of O75030 , a role of considerable importance in mast cell and melanocyte development .",
"Humanins , the neuroprotective and cytoprotective peptides with antiapoptotic and anti - inflammatory properties . Q8IVG9 ( HN ) is a newly discovered 24 - amino acid peptide , which may suppress neuronal cell death . HN cDNA includes an open reading frame ( HN - ORF ) of 75 bases located 950 bases downstream of the 5 ' end of the HN cDNA . It has been demonstrated that HN cDNA is 99 % identical to the mitochondrial DNA ( mtDNA ) sequence . HN homologs have been identified as expressed sequence tags ( ESTs ) in both rats and nematodes . Certain regions that are homologous to the HN cDNA exist on human chromosomes . HN forms homodimers and multimers and this action seems to be essential for peptide function . HN acts as a ligand for formyl peptide receptor - like 1 ( P25090 ) and 2 ( P25089 ) . It has been demonstrated that HN plays a protective role through its antiapoptotic activity that interferes with Bax activation , which suppresses Bax - dependent apoptosis . HN has also been shown to suppress the c - Jun N - terminal kinase ( JNK ) and ASK / JNK - mediated neuronal cell death . Several studies have also confirmed that HN could be important in the prevention of angiopathy - associated Alzheimer ' s disease dementia , diseases related to mitochondrial dysfunction ( MELAS ) , and other types of β - amyloid accumulation - associated neurodegeneration . Avery recent study demonstrated a pluripotent cytoprotective effect and mechanisms of HNs in cells not from the CNS , such as germ cells or pancreatic β - cells , and the potent physiological consequences that result from HN interaction with P17936 and P40763 . In vivo studies suggest that HN may also protect against cognitive impairment due to ischemia / reperfusion injury .",
"DB01277 pathway mutations and protein expression in resected non - small cell lung cancer . The purpose of this study was to characterize the prevalence of insulin - like growth factor 1 receptor ( P08069 ) mutations , single nucleotide polymorphisms ( SNP ) , and protein overexpression in surgically resected non - small cell lung cancers in relation to patient characteristics and prognosis . This retrospective study was conducted on 304 patients with non - small cell lung cancers who underwent curative pulmonary resection ( median follow - up for surviving patients , 3 . 6 years ) . P08069 gene alterations ( n = 304 ) and protein expression ( n = 181 ) were evaluated by polymerase chain reaction - based assays and immunohistochemistry , respectively . Membranous and cytoplasmic staining were analyzed separately . In an exploratory analysis , 1 silent mutation in exon 16 and 3 mutations in introns of the P08069 gene comprising the tyrosine kinase domain were detected . Moreover , evaluating selected P08069 SNPs , patients with adenocarcinomas and homozygous for the rs8038415 T - allele had a significantly better survival ( P = . 025 ) but no different disease - free survival . Regarding expression , membranous but not cytoplasmic P08069 staining was higher in squamous cell carcinomas versus other histologies ( P < . 0001 ) and showed a trend to longer survival ( P = . 08 ) . No association between SNP variations and protein expression was found . Membranous P08069 protein expression is higher in squamous cell versus other histologies but does not correlate with prognosis . SNPs and mutations can be detected and may harbor prognostic value . These alterations may be of interest when evaluating the P08069 as potential therapeutic target and should receive further research .",
"Specific Biomarkers Are Associated with Docetaxeland Gemcitabine - Resistant NSCLC Cell Lines . Five - year survival rate for lung cancer is limited to 10 % to 15 % . Therefore , the identification of novel therapeutic prognostic factors is an urgent requirement . The aim of this study is thus to highlight specific biomarkers in chemoresistant non - small cell lung cancer cell lines . Therefore , we checked - in the control condition as well as after short - term pharmacological treatment with either docetaxel or gemcitabine - the expression of genes such as tumor suppressor genes ( CDKN2A , P53355 , P49789 , P09211 , P16455 , RARβ2 , RASSF1A , and P35625 ) , genes associated with drug resistance ( P38398 , P35354 , P07992 , P17936 , P23921 , and Q13509 ) , and stemness - related genes ( CD133 , Q01860 , and O43623 ) in two cellular models of squamous carcinoma ( CAEP ) and adenocarcinoma ( RAL ) of the lung originally established . Their promoter methylation profile was also evaluated . Drug - related genes were upregulated . DB00515 resistance matched with high levels of P38398 and P07992 in both cell lines ; docetaxel sensitivity of CAEP cells was associated to levels of Q13509 lower than RAL cells . Although CAEP cells were more sensitive to gemcitabine , both cell lines showed high levels of P23921 . Stemness - related genes were downregulated in the control condition but became upregulated in docetaxel - resistant cells , indicating the selection of a population with stemness features . We did not find an unequivocal correspondence between gene expression and respective DNA promoter methylation status , suggesting the involvement of additional mechanisms of gene expression regulation . These results highlight specific biomarkers consistent with the different responses of the two cell lines to standard pharmacological treatments and indicate specific molecular traits for their chemoresistance .",
"Pathways targeted by antidiabetes drugs are enriched for multiple genes associated with type 2 diabetes risk . Genome - wide association studies ( GWAS ) have uncovered > 65 common variants associated with type 2 diabetes ( T2D ) ; however , their relevance for drug development is not yet clear . Of note , the first two T2D - associated loci ( P37231 and Q14654 / Q09428 ) encode known targets of antidiabetes medications . We therefore tested whether other genes / pathways targeted by antidiabetes drugs are associated with T2D . We compiled a list of 102 genes in pathways targeted by marketed antidiabetic medications and applied Gene Set Enrichment Analysis ( MAGENTA [ Meta - Analysis Gene - set Enrichment of variaNT Associations ] ) to this gene set , using available GWAS meta - analyses for T2D and seven quantitative glycemic traits . We detected a strong enrichment of drug target genes associated with T2D ( P = 2 × 10 (- 5 ) ; 14 potential new associations ) , primarily driven by insulin and thiazolidinedione ( TZD ) targets , which was replicated in an independent meta - analysis ( Metabochip ) . The glycemic traits yielded no enrichment . The T2D enrichment signal was largely due to multiple genes of modest effects ( P = 4 × 10 (- 4 ) , after removing known loci ) , highlighting new associations for follow - up ( P33121 , P19838 , P11168 , incretin targets ) . Furthermore , we found that TZD targets were enriched for LDL cholesterol associations , illustrating the utility of this approach in identifying potential side effects . These results highlight the potential biomedical relevance of genes revealed by GWAS and may provide new avenues for tailored therapy and T2D treatment design .",
"Growth response of Egyptian children with idiopathic short stature during four years of growth hormone therapy . BACKGROUND : Multiple factors affect the growth response to recombinant human growth hormone ( rhGH ) in children with idiopathic short stature ( ISS ) . AIM : To evaluate the growth responses of children with ISS treated with rhGH , aiming to identify the predictors of growth response . MATERIALS AND METHODS : We studied 120 cases , 90 males ( 75 % ) , with a mean age of 13 . 8 ± 2 . 7 years and 30 females ( 25 % ) , with a mean age of 12 . 3 ± 2 . 5 years . All patients received rhGH with a standard dose of 20 IU / m ( 2 )/ week . The calculated dose per week was divided into six days and given subcutaneous at night . RESULTS : A significant positive trend was detected in the delta changes of all anthropometric data . For the first year , the growth response was positively correlated to CA and BA delay and negatively correlated to height , weight and DB01277 SDSs . For the second year , the growth response was correlated positively to first year growth velocity , BA , triceps skin fold thickness SDS and deviation from target height , and negatively correlated to weight , P17936 SDS and target height SDS . For the third year , the growth response was positively correlated to five variables namely target height , 2 ( nd ) year growth velocity , DB01277 SDS , weight SDS and triceps skin fold thickness SDS . For the fourth year , growth response was positively correlated to 2 ( nd ) and 3 ( rd ) year growth velocity , BA , deviation from target height and weight / height SDS . CONCLUSION : Our study showed multiplicity of predictors that is responsible for response in ISS children treated with rhGH , and BA was an important predictor .",
"Disturbances in growth hormone secretion and action in adolescents with anorexia nervosa . Women in whom anorexia nervosa develops during adolescence have failure of linear growth associated with low levels of insulin - like growth factor I ( DB01277 ) . To investigate the pathophysiology of growth retardation in adolescents with anorexia nervosa , we measured basal growth hormone ( GH ) , growth hormone - binding protein ( P30043 ) , DB01277 , and insulin - like growth factor binding protein - 3 ( P17936 ) in three groups of patients : ( 1 ) 28 recently hospitalized female adolescents with anorexia nervosa , ( 2 ) 23 of the same patients after partial weight restoration , and ( 3 ) 28 healthy control subjects matched for age , sex , and pubertal stage . Fasting GH levels in group 1 did not differ significantly from those in group 3 . In contrast , serum P30043 ( p < 0 . 001 ) , DB01277 ( p < 0 . 001 ) , and P17936 ( p < 0 . 01 ) were significantly lower in group 1 than in group 3 . Serum P30043 and P17936 levels were positively correlated with body mass index . Serum P30043 levels were low in patients in all five pubertal stages and even in those shown to have adequate GH secretion . In group 2 ( after refeeding ) the serum DB01277 concentration increased significantly and P30043 and P17936 returned to normal . We conclude that patients with anorexia nervosa have diminished GH action resulting in decreased secretion of DB01277 . The positive correlation with body mass index and the reversibility with refeeding suggest that these changes are secondary to malnutrition . Altered GH function that occurs during the years of active growth can explain the growth retardation seen in anorexia nervosa .",
"___MASK45___ for joints and bones . ___MASK45___ is an investigational , fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor kappaB ligand ( O14788 ) , a cytokine member of the tumor necrosis factor family . O14788 , an essential mediator of osteoclast formation , function , and survival , plays a major role in the pathogenesis of postmenopausal osteoporosis , structural damage in rheumatoid arthritis , and bone loss associated with other skeletal disorders . ___MASK45___ suppresses bone turnover by inhibiting the action of O14788 on osteoclasts . ___MASK45___ reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density , reduces fracture risk in women with postmenopausal osteoporosis , and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment . It is generally well tolerated , with a good safety profile . Adverse and serious adverse events , including infections and malignancy , are similar in patients treated with denosumab or placebo .",
"Myocardial insulin - like growth factor - 1 and insulin - like growth factor binding protein - 3 gene expression in failing hearts harvested from patients undergoing cardiac transplantation . P01308 - like growth factor - 1 ( DB01277 ) and insulin - like growth factor binding proteins ( IGFBPs ) might play a pathogenic role in heart failure . We showed significantly increased myocardial P17936 expression ( investigated by real - time polymerase chain reaction ) and apoptosis ( detected by flow cytometry ) in 23 failing hearts from patients undergoing cardiac transplantation for end - stage dilated or ischemic cardiomyopathy , when compared with 10 controls . Higher DB01277 mRNA levels were shown only in end - stage dilated cardiomyopathy .",
"DB01277 and DB01686 levels are inversely correlated in nondiabetic ankylosing spondylitis patients undergoing anti - P01375 therapy . Like rheumatoid arthritis , ankylosing spondylitis ( AS ) is also an inflammatory disease associated with accelerated atherosclerosis and the presence of metabolic syndrome ( MeS ) features . AS patients often display osteoporosis as well as new bone formation . DB01277 ( DB01277 ) is a protein involved in both inflammation and bone metabolism . In the present study we assessed whether disease activity , systemic inflammation , MeS features , adipokines , and biomarkers of endothelial activation were associated with DB01277 and insulin - like growth factor binding protein - 3 ( P17936 ) levels in a series of 30 nondiabetic AS patients without CV disease undergoing P01375 - α antagonist - infliximab therapy . All determinations were made in the fasting state , immediately before an infliximab infusion . Although no association of DB01277 and P17936 levels with angiopoietin - 2 or osteopontin was found , an inverse correlation between DB01277 levels and asymmetric dimethylarginine ( DB01686 ) , an endogenous endothelial nitric oxide synthase inhibitor that impairs nitric oxide production and secretion promoting endothelial dysfunction , was found ( r =- 0 . 397 ; P = 0 . 04 ) . However , no significant association was found between DB01277 and P17936 levels and disease activity , systemic inflammation , metabolic syndrome features , or adipokines . In conclusion , in nondiabetic patients with AS undergoing periodic anti - P01375 - α therapy , DB01277 and DB01686 are inversely correlated .",
"Increased low density lipoprotein receptor expression mediated through the insulin - like growth factor - I receptor in cultured fibroblasts . Plasma insulin - like growth factor - I ( P05019 ) levels are inversely correlated with apolipoprotein B and low density lipoprotein ( LDL ) cholesterol in humans . To identify a molecular basis for this observation , the effects of P05019 on P01130 expression in fibroblasts were studied . P05019 increased LDL receptors in cultured human skin fibroblasts at concentrations greater than 25 ng / ml . However , P05019 effects were not easily quantitated due to secretion of inhibitory IGF - binding proteins by the cells . To circumvent this difficulty , QAYL , an P05019 analog that binds to the P08069 but not to IGF - binding proteins , was used . QAYL increased P01130 number 56 - 72 % with half - maximum effect at 0 . 6 ng / ml . alpha - IR3 , a monoclonal antibody directed toward the P08069 , blocked this effect . QAYL treatment increased synthesis of P01130 protein without increasing P01130 mRNA levels or altering protein stability . Both QAYL and P05019 increased LDL receptors prominently in cells that had been treated with physiological amounts of LDL cholesterol . P05019 , acting through the P08069 and modulated by IGF - binding proteins , may contribute to the regulation of LDL metabolism by increasing translation of P01130 message .",
"Prostate carcinoma cells that have resided in bone have an upregulated P05019 axis . BACKGROUND : Prostate cancer ( PC ) has a propensity to metastasize to the skeleton , inducing an osteoblastic response in the host . Recent epidemiological studies have suggested that circulating P05019 may be important for both the pathogenesis and dissemination of PC . We have postulated that tumor secreted P05019 in conjunction with endogenous P05019 contributes to the osteoblastic phenotype characteristic of metastatic PC . METHODS : To test this thesis we studied the established LNCaP PC progression model consisting of three genetically related human PC cell lines . RESULTS : Using RIA , we found serum - free conditioned media ( CM ) of LNCaP and C4 - 2 had no measurable P05019 , whereas P05019 was easily detected in CM from C4 - 2B cells at 24 hr ( i . e . , 1 . 8 +/- 0 . 53 ng / mg cell protein ) . Real - time PCR of P05019 mRNA showed that C4 - 2B expressed 100 - fold more P05019 mRNA than LNCaP cells . In addition , C4 - 2B expression of P05019 mRNA was substantially increased in the presence of exogenous P05019 to nearly twofold . While P17936 and P08833 were not detectable in the CM of any PC line , all cells secreted P18065 . C4 - 2B cells produced 40 % more P18065 than LNCaP or C4 - 2 cells ( C4 - 2B at 167 +/- 43 ng / mg cell protein ) . O14788 , a product of bone stromal cells , was also differentially expressed : LNCaP had threefold higher O14788 mRNA compared to C4 - 2 and C4 - 2B and at least equivalent protein expression . CONCLUSIONS : Our results suggest that PC cells that have metastasized to bone have an upregulated P05019 regulatory system . This suggests an activated P05019 axis contributes to the host - PC interaction in promoting osteoblastic metastases .",
"Bayesian analysis and the GUSTO trial . Global Utilization of ___MASK65___ and Tissue P00747 Activator in Occluded Arteries .",
"Ca2 +- calmodulin and janus kinase 2 are required for activation of sodium - proton exchange by the Gi - coupled 5 - hydroxytryptamine 1a receptor . The type 1 sodium - proton exchanger ( P19634 ) is expressed ubiquitously and regulates key cellular functions , including mitogenesis , cell volume , and intracellular pH . Despite its importance , the signaling pathways that regulate P19634 remain incompletely defined . In this work , we present evidence that stimulation of the 5 - hydroxytryptamine 1A ( P08908 ) receptor results in the formation of a signaling complex that includes activated O60674 ( Jak2 ) , Ca2 +/ calmodulin ( P62158 ) , and P19634 , and which involves tyrosine phosphorylation of P62158 . The signaling pathway also involves rapid agonist - induced association of P62158 and P19634 as assessed by coimmunoprecipitation studies and by bioluminescence resonance energy transfer studies in living cells . We propose that P19634 is activated through this pathway : P08908 receptor --> G ( i2 ) alpha and / or G ( i3 ) alpha --> Jak2 activation --> tyrosine phosphorylation of P62158 --> increased binding of P62158 to P19634 --> induction of a conformational change in P19634 that unmasks an obscured proton - sensing and / or proton - transporting region of P19634 --> activation of P19634 . The G ( i / o )- coupled P08908 receptor now joins a handful of Gq - coupled receptors and hypertonic shock as upstream activators of this emerging pathway . In the course of this work , we have presented clear evidence that P62158 can be activated through tyrosine phosphorylation in the absence of a significant role for elevated intracellular Ca2 + . We have also shown for the first time that the association of P62158 with P19634 in living cells is a dynamic process .",
"Differential expression of IGF components and insulin receptor isoforms in human seminoma versus normal testicular tissue . P01308 - like growth factors ( IGF ) have mitogenic and antiapoptotic functions , and may be involved in tumor growth . The purpose of the study was to investigate the role of IGF components in seminoma compared to normal testis . Normal testicular tissues from autopsy cases and seminoma from surgery cases were obtained for microarray and real - time reverse transcription polymerase chain reaction ( RT - PCR ) analysis of DB01277 , IGF - 2 , IGF receptor type 1 ( IGF - Q96GN5 ) , IGF - R2 , insulin receptor isoforms A ( IR - A ) and B ( IR - B ) , and IGF - binding proteins ( IGFBP ) 1 - 6 . IGF - 2 was localized by immunohistochemistry . P24593 protein expression was evaluated by Western blot analysis . mRNA expression in microarray and real - time RT - PCR showed similar tendencies : DB01277 , IGF - Q96GN5 , IGF - R2 , IR - A , and P18065 were not different in both groups . IGF - 2 , IR - B , P08833 , P22692 , and P24592 mRNA were downregulated in seminoma . P17936 tended to be upregulated in pT1 seminoma , but downregulated in pT2 stages . P24593 and IGF - 2 protein expression correlated with mRNA expression . In conclusion , downregulation of mainly inhibiting IGFBPs may allow a stimulated tumor growth . The downregulated IGF - 2 does not seem to be involved in the growth regulation of seminoma . Constantly expressed genes ( e . g . , DB01277 , IGF - Q96GN5 , IR - A , and P18065 ) may reflect an involvement in spermatogenesis , but may also play a major role in tumor growth as their expression is not downregulated despite the lack of spermatogenesis in tumor tissue .",
"Metabolic effect and receptor signalling profile of a non - metabolisable insulin glargine analogue . CONTEXT : P01308 glargine ( GLA ) is rapidly metabolized in vivo to metabolite M1 , which has in vitro metabolic and mitogenic profiles comparable with human insulin ( HI ) . OBJECTIVE : To investigate the pharmacologic and signalling profiles of a non - metabolizable analogue ( A21Gly , DiD - DB00125 ) insulin ( D - GLA ) . METHODS : Rats were injected s . c . with 1 , 12 . 5 or 200 U / kg of GLA or D - GLA ; blood glucose and phosphorylation status of the insulin receptor ( IR ) , Akt and DB01277 receptor ( P08069 ) in tissue samples were investigated after 1 h . Plasma samples were analysed for insulin by LC - MS / MS . RESULTS : Blood glucose lowering was prolonged with D - GLA . D - GLA comprised ≥ 98 % of insulin after D - GLA injection ; M1 comprised 76 - 92 % after GLA injection . IR and Akt phosphorylation were comparable with GLA and D - GLA . Neither analogue stimulated P08069 phosphorylation . CONCLUSIONS : Suprapharmacological doses of D - GLA did not activate P08069 in vivo . Mitogenic effects of insulin and insulin analogues might be solely based on IR growth - promoting activity .",
"Growth hormone , insulin - like growth factor - 1 , and the insulin - like growth factor binding proteins in rats maintaining reduced body protein following lesions of the lateral hypothalamus . Rats with lesions of the lateral hypothalamus ( LH ) maintain a reduced body protein mass that they effectively defend when challenged by under - or over - nutrition . The two studies reported here evaluate the potential contributions of growth hormone ( GH ) , insulin - like growth factor - 1 ( DB01277 ) , and the insulin - like growth factor - binding ( IGFBP ) to this persistent maintenance of a reduced body protein mass by LH rats . At 18 weeks postlesion , it was found that the serum levels of GH , DB01277 , total IGFBP , and P17936 of LH rats maintaining reduced body protein were not different from those of age - matched controls . However , closer to the time of surgery , at which time the lesion - induced body protein adjustments are known to occur , altered hormone and binding protein levels were observed . Specifically , at 3 weeks after lesioning , the IGF - binding proteins of LH rats were significantly elevated , whereas their GH levels were lower than those of controls . Because the GH , DB01277 , and IGF - binding proteins of LH rats were comparable to those of controls at 18 weeks after lesioning , none apparently underlie the chronically reduced body protein mass that LH rats display . Closer to the time of lesioning , however , altered GH and IGF binding protein levels may contribute to the postlesion adjustments by which the body protein mass of LH rats is lowered to its reduced level .",
"Hepatic osteodystrophy : does the osteoprotegerin / receptor activator of nuclear factor - kB ligand system play a role ? Multiple factors can contribute to the development of osteodystrophy in patients with chronic liver disease ( CLD ) . Recently , two new cytokines , osteoprotegerin ( O00300 ) and the receptor activator of nuclear factor - kB ligand ( O14788 ) , have been implicated in the pathogenesis of postmenopausal osteoporosis and other metabolic bone diseases . Therefore , the aim of our study was to evaluate bone metabolism , bone mineral density ( BMD ) and O00300 / O14788 system in 65 male patients with CLD and in 65 healthy controls . Our patients showed lower BMD values than controls both at lumbar and femoral levels . Moreover , they had an unbalanced bone turnover with an increased resorption phase , as shown by high levels of urinary deoxypyridinoline and a decreased formation phase , as shown by the slightly , but significant , low levels of bone - alkaline phosphatase . Patients showed lower plasma levels of free - testosterone than controls and higher - although not significantly so - plasma levels of 17 beta - estradiol . Furthermore , patients with CLD had higher levels of sex hormone - binding globulin and O00300 , and lower levels of 25 - hydroxyvitamin D ( 25 - Q9BPY8 ) and P05019 than the control group , while O14788 levels were similar in the two groups . In conclusion , our data do not confirm the hypothesis that the O00300 / O14788 system could exert a key role in the pathogenesis of hepatic osteodystrophy , but rather that the observed increase in O00300 levels may represent either the result of the inflammatory process per se or a compensation for the observed enhanced bone resorption .",
"___MASK100___ , a gastric proton pump inhibitor , inhibits melanogenesis by blocking Q04656 trafficking . ___MASK100___ is a proton pump inhibitor used in the treatment of peptic ulcer disease and gastrosophageal reflux disease and acts by irreversibly blocking P20648 , a P - type H +/ K + ATPase in gastric parietal cells . We found that omeprazole and its closely related congeners inhibited melanogenesis at micromolar concentrations in B16 mouse melanoma cells , normal human epidermal melanocytes , and in a reconstructed human skin model . ___MASK100___ topically applied to the skin of UV - irradiated human subjects significantly reduced pigment levels after 3 weeks compared with untreated controls . ___MASK100___ had no significant inhibitory effect on the activities of purified human tyrosinase or on the mRNA levels of tyrosinase , dopachrome tautomerase , Pmel17 , or O75030 mRNA levels . Although melanocytes do not express P20648 , they do express Q04656 , a copper transporting P - type ATPase in the trans - Golgi network that is required for copper acquisition by tyrosinase . Q04656 relocalization from the trans - Golgi network to the plasma membrane in response to elevated copper concentrations in melanocytes was inhibited by omeprazole . ___MASK100___ treatment increased the proportion of EndoH sensitive tyrosinase , indicating that tyrosinase maturation was impaired . In addition , omeprazole reduced tyrosinase protein abundance in the presence of cycloheximide , suggestive of increased degradation . Our findings are consistent with the hypothesis that omeprazole reduces melanogenesis by inhibiting Q04656 and by enhancing degradation of tyrosinase .",
"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation . Matrix metalloproteinases ( MMPs ) are essential for proper extracellular matrix remodeling , a process that takes place during obesity - mediated adipose tissue formation . Here , we examine expression profiles and the potential role of MMPs and their tissue inhibitors ( TIMPs ) in adipose tissue remodeling during obesity . Expression patterns are studied by Northern blot and real - time PCR in two genetic models of obesity ( ob / ob and db / db mice ) and in a diet - induced model of obesity ( AKR mice ) . Of the MMPs and TIMPs studied , mRNA levels for P08253 , P08254 , P39900 , P50281 , Q99542 , and P01033 are strongly induced in obese adipose tissues compared with lean tissues . In contrast , P09237 and P35625 mRNAs are markedly decreased in obesity . Interestingly , enzymatic activities of P39900 and of a new identified adipocyte - derived 30 - kDa metalloproteinase are enhanced in obese adipose tissue fractions , demonstrating that MMP / P01033 balance is shifted toward increased matrix degradation in obesity . Finally , we analyze the modulation of P08253 , Q99542 , and P01033 during 3T3 - Q9NUQ9 preadipocyte differentiation , and we explore the effect of inhibition of MMP activity on in vitro adipogenesis . We find that the synthetic MMP inhibitor BB - 94 ( ___MASK79___ ) decreases adipose conversion of 3T3 - Q9NUQ9 and primary rat preadipocytes . BB - 94 represses differentiation without affecting mitotic clonal expansion but prevents the early expression of P17676 , a transcription factor that is thought to play a major role in the adipogenic program . Such findings support a role for the MMP / P01033 system in the control of proteolytic events and adipogenesis during obesity - mediated fat mass development .",
"Apparent growth hormone deficiency in children with cerebral palsy . Ten children with cerebral palsy ( CP ) and growth failure underwent assessment of the growth hormone ( GH ) axis , including spontaneous GH secretion , GH secretion in response to pharmacological stimulation , and circulating levels of insulin - like growth factor - 1 ( DB01277 ) and IGF binding protein - 3 ( P17936 ) . Six of the children had subnormal GH secretion consistent with GH deficiency . Subnormal growth velocity was the best clinical predictor of GH deficiency . The large percentage of these children with apparent GH deficiency is surprising . Possible mechanisms include anatomic abnormalities of the hypothalamic - pituitary axis , psychosocial deprivation , and an interaction between suboptimal nutritional status and an abnormal central nervous system .",
"Influence of genetic polymorphisms on the pharmacokinetics and pharmaco - dynamics of sulfonylurea drugs . Sulfonylurea drugs including chlorpropamide , gliclazide , tolbutamide , glipizide , glibenclamide ( glyburide ) and glimepiride are the most widely used oral hypoglycaemic agents in people with type 2 diabetes . This review investigates the impact of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of sulfonylurea drugs . P11712 is the major enzyme involved in sulfonylurea drug metabolism . P11712 variant allele carriers have significant lower apparent clearance of these medicines . P33261 genotype is more influential for gliclazide pharmacokinetics when compared to P11712 . Sulfonylurea pharmacodynamics is affected by several genes . Q09428 ( Q09428 , Q09428 gene ) and K + inward rectifier Kir6 . 2 ( Q14654 ) have been correlated to significant variation in sulfonylurea response . Diabetics with the Q09428 exon 33 G allele are more sensitive to gliclazide and the rs5210 variant of the Q14654 gene was associated with improved clinical efficacy of gliclazide . Carriers of Q9NQB0 ( Q9NQB0 ) variants are more likely to fail sulfonylurea therapy . On the other hand , patients with HNF - 1alpha mutations had a significant greater response to gliclazide when compared to those with type 2 diabetes . The Arg972 polymorphism of insulin receptor substrate 1 ( P35568 ) may lead to secondary failure of sulfonylurea therapy . Calpain 10 gene ( Q9HC96 ) polymorphism has also been linked to sulfonylurea drug response . Despite the available evidence , larger population studies that investigate the pharmacokinetics and pharmacodynamics of sulfonylurea drugs are needed to investigate the influence of key SNPs amidst all potential contributing factors to variability in response to these which inturn will provide information to optimise sulfonylurea use in people with diabetes .",
"[ Effects of plasminogen and streptokinase on the vital functions of nervous tissue cells in culture ] . In the protein - deficient media plasminogen stimulated the vital functions of cells and in concentrations 10 (- 7 )- 10 (- 10 ) M it protected cells of sympathetic ganglia , neocortex and continues cell lines under damaging actions of H2O2 ( 0 . 0001 M ) , NH4CI ( 0 . 01 M ) and cooling . ___MASK65___ essentially influenced the mode of damaging effect of DB00171 ( 0 . 001 M ) . Even a short - term exposition ( 20 min ) of PC12 cells with both proteins ( each in the concentration 10 (- 9 ) M ) led to sharp alterations in intracellular DB00171 - or Ca ( 2 +)- activated proteolysis . In some cases plasminogen and streptokinase provided acceleration of cultured tissue maturation , improvement of cell adhesion , high survival rate , the increase in quantity and length of processes and their arborisation . Electronic microscopy established the character of structural rearrangements of nervous tissue cells ( neurons , astrocytes , oligodendrocytes ) , reflecting the protective action of plasminogen and streptokinase . In the presence of plasminogen and especially streptokinase , the total number of cultured glioma P13671 and neuroblastoma IMR - 32 cells , the intracellular contents of protein , RNA and DNA increased several - fold . Addition of plasminogen promoted formation of processes by neuroblastoma cells , this suggests initiation of differentiation of cellular elements . In cultures of sensitive and sympathetic ganglia streptokinase increased proliferation of Schwann cells . These proteins did not cause transformation of PC12 enterochromaffine cells to neurons , though plasminogen facilitated it . P00747 addition to cell cultures did not increase fibrinolytic activity of the culture medium in the culture medium , and streptokinase did not lose its plasminogen - activating capacity .",
"Associations of proinflammatory cytokine levels with lipid profiles , growth , and body composition in HIV - infected children initiating or changing antiretroviral therapy . OBJECTIVES : To measure proinflammatory cytokines ( PIC ) in HIV - infected children beginning or changing antiretroviral therapy ( O00253 ) , evaluating associations with virologic , immunologic , serum lipid , growth , and body composition measures , markers of growth hormone action and glucose metabolism . METHODS : Forty - nine prepubertal HIV - infected children had measurements of viral load ( VL ) , P01730 lymphocyte count and percentage , serum lipids , apolipoprotein AI / B , DB01277 , P08833 , and P17936 , anthropometry , bioelectrical impedance analysis , P01375 - α , IL - 1 β , and P05231 at baseline and 48 weeks of O00253 . RESULTS : Baseline levels were detectable ( > 0 . 1 pg / mL ) for IL - 1 β in 28 of 48 , and for P01375 - α and Il - 6 in all 49 children . P01375 - α decreased with O00253 ( P < 0 . 001 ) and P05231 demonstrated a similar trend ( P = 0 . 065 ) . Children with 48 - week VL < 400 copies / mL had greater declines in P01375 - α ( mean 45 % ) than subjects with higher VL ( 5 % ; P = 0 . 009 ) . Each 10 % improvement in P01730 % was associated with 26 % lower P01375 - α ( P = 0 . 002 ) and 31 % lower P05231 ( P = 0 . 016 ) . Greater reductions in P01375 - α were associated with lower total / HDL cholesterol ratio ( P = 0 . 003 ) at week 48 . CONCLUSIONS : In HIV - infected children initiating or changing O00253 , PIC were detectable at baseline and decreased over 48 weeks . Better immunologic responses were associated with greater reductions in P01375 - α and P05231 . Reductions in P01375 - α were associated with improved total / HDL cholesterol ratio .",
"Phenotypic characterization of human chondrocyte cell line C - 20 / A4 : a comparison between monolayer and alginate suspension culture . DNA microarray analysis was used to investigate the molecular phenotype of one of the first human chondrocyte cell lines , C - 20 / A4 , derived from juvenile costal chondrocytes by immortalization with origin - defective simian virus 40 large T antigen . Clontech Human Cancer Arrays 1 . 2 and quantitative PCR were used to examine gene expression profiles of C - 20 / A4 cells cultured in the presence of serum in monolayer and alginate beads . In monolayer cultures , genes involved in cell proliferation were strongly upregulated compared to those expressed by human adult articular chondrocytes in primary culture . Of the cell cycle - regulated genes , only two , the CDK regulatory subunit and histone H4 , were downregulated after culture in alginate beads , consistent with the ability of these cells to proliferate in suspension culture . In contrast , the expression of several genes that are involved in pericellular matrix formation , including P50281 , P12109 , fibronectin , biglycan and decorin , was upregulated when the C - 20 / A4 cells were transferred to suspension culture in alginate . Also , nexin - 1 , vimentin , and P17936 , which are known to be expressed by primary chondrocytes , were differentially expressed in our study . Consistent with the proliferative phenotype of this cell line , few genes involved in matrix synthesis and turnover were highly expressed in the presence of serum . These results indicate that immortalized chondrocyte cell lines , rather than substituting for primary chondrocytes , may serve as models for extending findings on chondrocyte function not achievable by the use of primary chondrocytes .",
"P01308 - like growth factors ( IGFs ) and IGF - binding proteins in nephrotic syndrome children on glucocorticoid . Growth failure is often seen in nephrotic children who fail to respond to glucocorticoid therapy or are glucocorticoid dependent . The underlying mechanism responsible for such growth defect remains poorly understood although long - term glucocorticoid use or nephrotic syndrome ( NS ) has been indicated to independently affect growth . Recent clinical evidence has suggested that changes in the serum levels of insulin - like growth factors ( IGFs ) and IGF - binding proteins ( IGFBPs ) among these children . The loss of insulin - like growth factor - I ( DB01277 ) and P17936 found in nephrotic children may directly prompt growth defect and retardation . In addition , glucocorticoid is believed to be associated with overt elevation of serum P05019 levels suggesting potential development of IGF resistance , one of the main factors responsible for persistent growth retardation . Growth hormone therapy has been shown to effectively reconcile this IGF resistance . The present review will discuss the complex relationship among IGF , IGFBPs , and glucocorticoid in children with NS .",
"Drug - induced activation of SREBP - controlled lipogenic gene expression in CNS - related cell lines : marked differences between various antipsychotic drugs . BACKGROUND : The etiology of schizophrenia is unknown , but neurodevelopmental disturbances , myelin - and oligodendrocyte abnormalities and synaptic dysfunction have been suggested as pathophysiological factors in this severe psychiatric disorder . DB04540 is an essential component of myelin and has proved important for synapse formation . Recently , we demonstrated that the antipsychotic drugs clozapine and haloperidol stimulate lipogenic gene expression in cultured glioma cells through activation of the sterol regulatory element - binding protein ( SREBP ) transcription factors . We here compare the action of chlorpromazine , haloperidol , clozapine , olanzapine , risperidone and ziprasidone on SREBP activation and SREBP - controlled gene expression ( ACAT2 , P04035 , Q01581 , P14324 , O75845 , Q9UBM7 , P01130 , P49327 and SCD1 ) in four CNS - relevant human cell lines . RESULTS : There were marked differences in the ability of the antipsychotic drugs to activate the expression of SREBP target genes , with clozapine and chlorpromazine as the most potent stimulators in a context of therapeutically relevant concentrations . Glial - like cells ( GaMg glioma and CCF - STTG1 astrocytoma cell lines ) displayed more pronounced drug - induced SREBP activation compared to the response in Q9UL51 human cortical neurons and SH - SY5Y neuroblastoma cells , indicating that antipsychotic - induced activation of lipogenesis is most prominent in glial cells . CONCLUSION : Our present data show a marked variation in the ability of different antipsychotics to induce SREBP - controlled transcriptional activation of lipogenesis in cultured human CNS - relevant cells . We propose that this effect could be relevant for the therapeutic efficacy of some antipsychotic drugs .",
"Expression of a protease - resistant insulin - like growth factor - binding protein - 4 inhibits tumour growth in a murine model of breast cancer . BACKGROUND : DB01277 ( IGF1 ) promotes breast cancer and disease progression . Bioavailability of IGF1 is modulated by IGF - binding proteins ( IGFBPs ) . P22692 inhibits IGF1 activity but cleavage by pregnancy - associated plasma protein - A ( Q13219 ) protease releases active IGF1 . METHODS : Expression of IGF pathway components and Q13219 was assessed by western blot or RT - PCR . P22692 ( dBP4 ) resistant to Q13219 cleavage , but retaining IGF - binding capacity , was used to block IGF activity in vivo . 4T1 . 2 mouse mammary adenocarcinoma cells transfected with empty vector , vector expressing wild - type P22692 or vector expressing dBP4 were implanted in the mammary fat pad of BALB / c mice and tumour growth was assessed . Tumour angiogenesis and endothelial cell apoptosis were assessed by immunohistochemistry . RESULTS : 4T1 . 2 cells expressed the P08069 receptor and P22692 . Q13219 was expressed within mammary tumours but not by 4T1 . 2 cells . Proliferation and vascular endothelial growth factor ( P15692 ) production by 4T1 . 2 cells was increased by IGF1 ( E3R ) ( recombinant IGF1 resistant to binding by IGFBPs ) but not by wild - type IGF1 . IGF1 - stimulated microvascular endothelial cell proliferation was blocked by recombinant P22692 . 4T1 . 2 tumours expressing dBP4 grew significantly more slowly than controls or tumours expressing wild - type P22692 . Inhibition of tumour growth by dBP4 was accompanied by the increased endothelial cell apoptosis . CONCLUSION : Protease - resistant P22692 blocks IGF activity , tumour growth and angiogenesis .",
"Permanent neonatal diabetes mellitus in China . BACKGROUND : Permanent neonatal diabetes mellitus ( PNDM ) is a rare disease , which is defined as the onset of diabetes before the age of 6 months with persistence through life . Infants with Q14654 or Q09428 genetic mutations may respond to oral sulfonylurea therapy . Currently , there are limited studies about the genetic analysis and long - term follow - up of PNDM . CASE PRESENTATION : We report four cases of PNDM . None of the infants or their parents had P01308 , Q14654 , or Q09428 genetic mutations . One infant underwent continuous subcutaneous insulin infusion ( CSII ) and the other infants underwent multiple injections of insulin ( MII ) . In these infants , PNDM persisted from 35 months to 60 months of follow - up . Three infants maintained fairly stable blood sugar levels , and one infant had poor sugar control . CONCLUSIONS : We suggest that all of the infants with PNDM should undergo genetic evaluation . For infants without Q14654 and Q09428 genetic mutations , oral sulfonylurea should not be considered as treatment . CSII is a useful method for overcoming the difficulties of diabetes , and it may also improve the quality of life of both infants and their parents .",
"Gene expression of malignant rhabdoid tumor cell lines by reverse transcriptase - polymerase chain reaction . Malignant rhabdoid tumors ( MRT ) are characterized by unique neoplastic cells demonstrating phenotypic diversity . By using the reverse transcriptase - polymerase chain reaction , we have detected expression of various genes before and after differentiation induction with four different agents in four established MRT cell lines ( TM87 - 16 , STM91 - 01 , TTC642 , and TTC549 ) . The agents used in this study were all - trans retinoic acid ( RA ) , 12 - O - tetradecanoylphorbol - 13 - acetate ( TPA ) , interleukin - 3 , or interferon - gamma . Before and after induction , c - myc , P01344 , P08069 , and P11717 were constitutively expressed by all four cell lines . The neurofilament medium - size ( P07197 ) was constitutively expressed by the TM87 - 16 and TTC642 , and the S100 protein alpha subunit was expressed by TM87 - 16 , TTC642 , and TTC549 . Chromogranin A was expressed by TM87 - 16 only after treatment with either TPA or RA . MyoD , N - myc , tyrosine hydroxylase , N - P62158 , trkA , and the S100 protein beta subunit were not expressed by any cell line before or after induction with these agents . All the MRT cell lines in this study except TM87 - 16 were highly resistant to differentiation induction . The proliferating cells in TM87 - 16 and TTC642 expressed mRNA profiles characteristic of neuroectoderm .",
"Synthesis and evaluation of ( S ) - 2 -( 2 -[ 18F ] fluoroethoxy )- 4 - ( [ 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butyl - carbamoyl ] - methyl ) - benzoic acid ( [ 18F ] repaglinide ) : a promising radioligand for quantification of pancreatic beta - cell mass with positron emission tomography ( PET ) . 18F - labeled non - sulfonylurea hypoglycemic agent ( S ) - 2 -( 2 -[( 18 ) F ] fluoroethoxy )- 4 - ( ( 3 - methyl - 1 -( 2 - piperidin - 1 - yl - phenyl )- butylcarbamoyl ) - methyl ) - benzoic acid ( [( 18 ) F ] repaglinide ) , a derivative of the sulfonylurea - receptor ( Q09428 ) ligand repaglinide , was synthesized as a potential tracer for the non - invasive investigation of the sulfonylurea 1 receptor status of pancreatic beta - cells by positron emission tomography ( PET ) in the context of type 1 and type 2 diabetes . [( 18 ) F ] ___MASK63___ could be obtained in an overall radiochemical yield ( RCY ) of 20 % after 135 min with a radiochemical purity higher than 98 % applying the secondary labeling precursor 2 -[( 18 ) F ] fluoroethyltosylate . Specific activity was in the range of 50 - 60 GBq / micromol . Labeling was conducted by exchanging the ethoxy - moiety into a 2 -[( 18 ) F ] fluoroethoxy group . To characterize the properties of fluorinated repaglinide , the affinity of the analogous non - radioactive ( 19 ) F - compound for binding to the human Q09428 isoform was assessed . [( 19 ) F ] ___MASK63___ induced a complete monophasic inhibition curve with a Hill coefficient close to 1 ( 1 . 03 ) yielding a dissociation constant ( K ( D ) ) of 134 nM . Biological activity was proven via insulin secretion experiments on isolated rat islets and was comparable to that of repaglinide . Finally , biodistribution of [( 18 ) F ] repaglinide was investigated in rats by measuring the concentration of the compound in different organs after i . v . injection . Pancreatic tissue displayed a stable accumulation of approximately 0 . 12 % of the injected dose from 10 min to 30 min p . i . 50 % of the radioactive tracer could be displaced by additional injection of unlabeled repaglinide , indicating that [( 18 ) F ] repaglinide might be suitable for in vivo investigation with PET .",
"Two new substrates in insulin signaling , Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 . We have identified two new human genes that encode proteins with tandem pleckstrin homology - phosphotyrosine binding ( PH - PTB ) domains at their amino termini . Because the other known PH - PTB proteins ( insulin receptor substrates : P35568 , Q9Y4H2 , P41252 - 3 , and O14654 , and the downstream of kinases : DOK - 1 , DOK - 2 , and DOK - 3 ) are substrates of insulin and insulin - like growth factor ( IGF ) - 1 receptors , we asked whether these new proteins , termed Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 , might also have roles in insulin and DB01277 signaling . Northern analyses indicate that Q8TEW6 / Q8TEW6 is ubiquitously expressed but most abundant in kidney and liver . Q9P104 / Q9P104 expression is highest in skeletal muscle . Both proteins are tyrosine - phosphorylated in response to insulin and DB01277 in transfected cells , although the kinetics differ . P06213 - phosphorylated Q8TEW6 / Q8TEW6 associates with P20936 , Crk , Src , and Fyn , but not phosphatidylinositol 3 - kinase p85 , Grb2 , Q06124 , Nck , or phospholipase Cgamma Src homology 2 domains , and activates MAPK in cells . Q9P104 / Q9P104 neither associates with these Src homology 2 domains nor activates MAPK . Q8TEW6 / Q8TEW6 and Q9P104 / Q9P104 represent two new signaling proteins with potential roles in insulin and DB01277 action .",
"Hormone stability in human whole blood . OBJECTIVE : To determine whether significant changes in the plasma concentrations of 17 hormones occur when human whole blood is held at 4 or 24 degrees C for up to 24 h before separation of the plasma fraction . DESIGN AND METHODS : Blood samples ( DB00974 ) from healthy human volunteers were held at 4 degrees C or 24 degrees C for 0 . 5 , 6 or 24 h before separation . Plasma concentrations of DB01285 , aldosterone , gonadotrophin alpha - subunits , AVP , C - peptide , estradiol , DB00094 , GH , glucagon , DB01277 , P17936 , insulin , leptin , LH , prolactin , PTH and P01282 were measured and the results compared to baseline values . Nonlinear regression was used to test for a significant mean rate of change . The time interval for median concentrations to change by 10 % was determined . RESULTS : Significant changes were observed for DB01285 ( decrease at 18 . 6 hr , 4 degrees C ; 17 . 5 hr , 24 degrees C ) ; AVP ( increase at 2 . 6 h , 24 degrees C ) ; insulin ( decrease at 16 . 8 hr , 4 degrees C ; 16 . 9 hr , 24 degrees C ) and P01282 ( increase at 18 . 6 h , 24 degrees C ) . No changes were detected for the remaining analytes . B CONCLUSIONS : The measurement of some hormones is compromised by a delay in plasma separation from normal human blood . While many hormones appear stable in normal whole blood , we recommend that processing occurs without delay .",
"Small interfering RNA knocks down the molecular target of alendronate , farnesyl pyrophosphate synthase , in osteoclast and osteoblast cultures . P14324 ( FPPS ) , an enzyme in the mevalonate pathway , is the inhibition target of alendronate , a potent FDA - approved nitrogen - containing bisphosphonate ( N - BP ) drug , at the molecular level . ___MASK58___ not only inhibits osteoclasts but also has been reported to positively affect osteoblasts . This study assesses the knockdown effects of siRNA targeting FPPS compared with alendronate in both osteoclast and osteoblast cultures . Primary murine bone marrow cell - induced osteoclasts and the preosteoblast MC3T3 - E1 cell line were used to assess effects of anti - FPPS siRNA compared with alendronate . Results show that both FPPS mRNA message and protein knockdown in serum - based culture is correlated with reduced osteoclast viability . FPPS siRNA is more potent than 10 μM alendronate , but less potent than 50 μM alendronate on reducing osteoclast viability . Despite FPPS knockdown , no significant changes were observed in osteoblast proliferation . FPPS knockdown promotes osteoblast differentiation significantly but not cell mineral deposition . However , compared with 50 μM alendronate dosing , FPPS siRNA does not exhibit cytotoxic effects on osteoblasts while producing significant effects on ostoblast differentiation . Both siRNA and alendronate at tested concentrations do not have significant effects on cultured osteoblast mineralization . Overall , results indicate that siRNA against FPPS could be useful for selectively inhibiting osteoclast - mediated bone resorption and improving bone mass maintenance by influencing both osteoclasts and osteoblasts in distinct ways .",
"Treatment of growth hormone - deficient adults with recombinant human growth hormone increases the concentration of growth hormone in the cerebrospinal fluid and affects neurotransmitters . In a double - blind , placebo - controlled trial , the effects of recombinant human growth hormone were studied on cerebrospinal fluid concentrations of growth hormone , insulin - like growth factor 1 ( DB01277 ) , insulin - like growth factor binding protein - 3 ( P17936 ) , monoamine metabolites , neuropeptides and endogenous opioid peptides . Twenty patients , 10 patients in each of 2 groups , with adult - onset , growth hormone deficiency were treated for 1 month with recombinant human growth hormone ( 0 . 25 U / kg / week ) or placebo . All the patients received the appropriate thyroid , adrenal and gonadal hormone replacement . In cerebrospinal fluid , the mean concentration of growth hormone increased from 13 . 3 +/- 4 . 4 to 149 . 3 +/- 22 . 2 muU / l ( p = 0 . 002 ) , during recombinant human growth hormone treatment . The cerebrospinal fluid P05019 concentration increased from 0 . 67 +/- 0 . 04 to 0 . 99 +/- 0 . 10 micrograms / l ( p = 0 . 005 ) and the P17936 concentration rose from 13 . 4 +/- 1 . 25 to 17 . 5 +/- 1 . 83 micrograms / l ( p = 0 . 002 ) . The dopamine metabolite homovanillic acid decreased from 282 . 1 +/- 36 . 0 to 234 . 3 +/- 26 . 5 nmol / l ( p = 0 . 02 ) and the vasoactive intestinal peptide decreased from 4 . 1 +/- 0 . 6 to 3 . 7 +/- 0 . 4 pmol / l ( p = 0 . 03 ) . Cerebrospinal fluid immunoreactive beta - endorphin increased from 24 . 4 +/- 1 . 8 to 29 . 9 +/- 2 . 1 pmol / l ( p = 0 . 002 ) . There were no significant changes compared to baseline in the cerebrospinal fluid concentrations of enkephalins , dynorphin A , the norepinephrine metabolite 3 - methoxy - 4 - hydroxyphenyl - ethyleneglycol , the serotonin metabolite 5 - hydroxyindoleacetic acid , gamma - aminobutyric acid , somatostatin or DB05394 . ( ABSTRACT TRUNCATED AT 250 WORDS )",
"___MASK26___ , a 3 - hydroxy - 3 - methylglutaryl coenzyme A reductase inhibitor , induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells . Although only 1 % of differentiated thyroid cancers transform into anaplastic thyroid cancer , this disease is always fatal . Differentiation therapy may provide a new therapeutic approach to increasing the survival rate in such patients . 3 - Hydroxy - 3 - methylglutaryl coenzyme A ( HMG - DB01992 ) reductase inhibitors are reported to promote cellular apoptosis and differentiation in many cancer cells ; these effects are unrelated to lipid reduction . Recently , we found that TNFalpha induces cytomorphological differentiation in anaplastic thyroid cancer cells and increases thyroglobulin expression ; however , P01375 is cytotoxic for normal human tissue . The aim of this study was to determine whether lovastatin , an P04035 inhibitor , could induce apoptosis and differentiation in anaplastic thyroid cancer cells . Anaplastic thyroid cancer cells were treated with lovastatin , then examined for cellular apoptosis and cytomorphological differentiation by DNA fragmentation , phosphatidylserine externalization / flow cytometry , and electron microscopy . Thyroglobulin levels in the culture medium were also measured . Our results showed that at a higher dose ( 50 micro M ) , lovastatin induced apoptosis of anaplastic thyroid cancer cells , whereas at a lower dose ( 25 micro M ) , it promoted 3 - dimensional cytomorphological differentiation . It also induced increased secretion of thyroglobulin by anaplastic cancer cells . Our results show that lovastatin not only induces apoptosis , but also promotes redifferentiation in anaplastic thyroid cancer cells , and suggest that it and other P04035 inhibitors merit further investigation as differentiation therapy for the treatment of anaplastic thyroid cancer .",
"Short stature caused by a natural growth hormone antagonist . Severe short stature in a male child due to a single mutation in the GH - 1 gene was first reported in 1996 by Takahashi et al . [ N Engl J Med 1996 ; 334 : 432 - 436 ] . This missense mutation was predicted to convert codon 77 from arginine ( R ) to cysteine ( C ) . The child ' s chronological age was 4 years and 11 months , and his bone age 2 years and 6 months , i . e . , equal to only 51 % of his chronological age . Body proportions were normal except for the prominent forehead and saddle nose . Pituitary size was normal on magnetic resonance imaging examinations . Serum DB01277 , P17936 and P30043 were all decreased or at the lower limit of the normal range . Nocturnal urinary growth hormone ( GH ) excretion was high . Isoelectric focusing analysis revealed the presence of an abnormal GH peak in addition to the normal one . The R77C mutant GH possessed a 6 times greater affinity to P30043 than the wild - type GH , and inhibited tyrosine phosphorylation in IM - 9 cells 10 times more potently than the wild - type GH , showing an antagonistic or a dominant negative action . In agreement with the antagonistic property of the mutant GH exhibited , the child did not show any increase in serum DB01277 levels after exogenous hGH administration . It should be noted that the child in this study is not a typical case of Kowarski syndrome in which endogenous GH is found to be simply bioinactive , as in the patient we recently described elsewhere . Therefore , this patient ' s condition should be categorized as a new syndrome of short stature caused by a natural GH antagonist .",
"Interleukin 10 blocks matrix metalloproteinase - 2 and membrane type 1 - matrix metalloproteinase synthesis in primary human prostate tumor lines . P01308 - like growth factor ( IGF ) I has been shown previously to up - regulate matrix metalloproteinase - 2 ( P08253 ) production , whereas the interleukin ( IL ) 10 / P22301 receptor axis has been found to down - regulate P08253 synthesis in tumor cells . In this paper , we showed that P22301 activation of the P22301 receptor blocked P08253 and membrane type 1 ( MT1 ) - MMP transcription and protein synthesis in nonimmortalized primary human prostate cell strains ( i . e . , P84074 - 10a and P84074 - 10c ) derived from high - grade cancer . Northern blots , Western blots , and ELISAs showed that P22301 suppressed P05019 induction of P08253 and P50281 mRNA synthesis in these cell strains ( P < 0 . 001 ) . Inhibition studies with P22301 and P08069 antibodies plus transfections experiments with P22301 sense , and P08069 antisense constructs confirmed these results . Finally , transient transfection experiments and chloramphenicol acetyltransferase assays with different regions of the 5 ' promoter region of the P08253 gene ( - 1659 to - 555 bp ) additionally showed that P05019 stimulated p53 - dependent plasmid catecholamine acetyltransferase activity and that P22301 blocked P05019 - induced plasmid catecholamine acetyltransferase activity . Electrophoretic mobility shift assays revealed that P22301 induced protein ( s ) binding to a putative \" silencer element \" ( - 1309 to - 555 fragment ) downstream of the p53 binding site ( - 1649 to - 1640 ) . The data show that P22301 blocks P05019 activation of P08253 and P50281 mRNA expression and protein synthesis in primary prostate cell strains .",
"8 - OH - DPAT ( P08908 agonist ) Attenuates 6 - Hydroxy - dopamine - induced catalepsy and Modulates Inflammatory Cytokines in Rats . OBJECTIVE ( S ) : Neuroinflammation in Parkinson disease ( PD ) is associated with glial cells activation and production of different inflammatory cytokines . In this study , we investigated the effect of chronic administration of 8 - OH - DPAT on 6 - OHDA - induced catalepsy and levels of inflammatory cytokines in cerebrospinal fluid ( P04141 ) . MATERIALS AND METHODS : Catalepsy was induced by unilateral infusion of 6 - OHDA ( 8 μg / 2 μl / rat ) into the central region of the sabstantia nigra pars compacta ( SNc ) being assessed by the bar - test , 5 , 60 , 120 and 180 min after intraperitoneal ( IP ) administration of 8 - OH - DPAT ( P08908 receptor agonist ; 0 . 25 , 0 . 5 and 1mg / kg , IP for 10 days ) . P04141 samples were collected on the tenth day of 8 - OH - DPAT administration and analyzed by ELISA method to measure levels of P01375 - α , IL - 1β and P05231 . RESULTS : Chronic injection of 8 - OH - DPAT decreased catalepsy in a dose dependent manner when compared with the control group . The most anti - cataleptic effect was observed at the dose of 1 mg / kg of 8 - OH - DPAT . Levels of P01375 - α in P04141 increased three weeks after 6 - OHDA injection while there was a significant decrease in P01375 - α level of parkinsonian animals treated with 8 - OH - DPAT ( 1 mg / kg , IP for 10 days ) . IL - 1β and P05231 decreased and increased in parkinsonian rats and in 8 - OH - DPAT - treated parkinsonian rats , respectively . CONCLUSION : Our study indicated that chronic administration of 8 - OH - DPAT improves catalepsy in 6 - OHDA - induced animal model of PD and restores central concentration of inflammatory cytokines to the basal levels . P08908 receptor agonists can be suggested as potential adjuvant therapy in PD by modulation of cerebral inflammatory cytokines .",
"Development of an absolute quantification method targeting growth hormone biomarkers using liquid chromatography coupled to isotope dilution mass spectrometry . A method to perform absolute quantification of two biomarkers ( DB01277 and P17936 ) of growth hormone abuse has been developed . Isotope dilution is used with synthetically labelled peptides as internal standards . Peptide selection and multiple reaction monitoring design are discussed . A simple sample preparation based on the reduction and alkylation of cysteine residues followed by tryptic digestion provides a sufficient digestion of proteins . Serum samples fortified with increasing amounts of target proteins are analysed by liquid chromatography - tandem mass spectrometry ( LC - MS / MS ) on a triple quadrupole mass spectrometer . Specificity is ensured by the selection of sequences with no homology in BLAST , as well as retention time deviation check , and ion ratio monitoring . Linearity is studied in terms of calibration curves . These curves for P17936 and DB01277 are generated with mean slopes of 0 . 055 and 0 . 065 , intercepts of 0 . 107 and - 0 . 011 , and with coefficients of correlation of 0 . 95 and 0 . 98 , respectively . These curves result from the addition of proteins to the serum . Risks of variations related to potential matrix effects are therefore reduced , as well as probable variations related to the digestion steps . The working concentration ranges are 4 - 10 ng / microl for P17936 and 2 - 8 ng / microl for DB01277 . Preliminary data regarding repeatability show that relative standard deviations ( RSDs ) range between 13 and 32 % for P17936 and between 7 and 29 % for DB01277 .",
"DB00133 phosphorylation of the insulin - like growth factor I ( DB01277 ) receptor C - terminal tail restrains kinase activity and cell growth . P08069 ( IGF - 1R ) signaling is essential for cell , organ , and animal growth . The C - terminal tail of the IGF - 1R exhibits regulatory function , but the mechanism is unknown . Here , we show that mutation of DB00133 - 1248 ( S1248A ) enhances IGF - 1R in vitro kinase activity , autophosphorylation , Akt / mammalian target of rapamycin activity , and cell growth . DB00133 - 1248 phosphorylation is mediated by GSK - 3β in a mechanism that involves a priming phosphorylation on DB00133 - 1252 . GSK - 3β knock - out cells exhibit reduced IGF - 1R cell surface expression , enhanced IGF - 1R kinase activity , and signaling . Examination of crystallographic structures of the IGF - 1R kinase domain revealed that the ( 1248 ) SFYYS ( 1252 ) motif adopts a conformation tightly packed against the kinase C - lobe when DB00133 - 1248 is in the unphosphorylated state that favors kinase activity . S1248A mutation is predicted to lock the motif in this position . In contrast , phosphorylation of DB00133 - 1248 will drive profound structural transition of the sequence , critically affecting connection of the C terminus as well as exposing potential protein docking sites . Decreased kinase activity of a phosphomimetic S1248E mutant and enhanced kinase activity in mutants of its predicted target residue Lys - 1081 support this auto - inhibitory model . Thus , the SFYYS motif controls the organization of the IGF - 1R C terminus relative to the kinase domain . Its phosphorylation by GSK - 3β restrains kinase activity and regulates receptor trafficking and signaling .",
"Nonalcoholic fatty liver disease is associated with increased P30043 and reduced GH / P05019 levels . INTRODUCTION : Nonalcoholic fatty liver disease ( NAFLD ) has been described in adult GH deficiency syndrome . Furthermore , chronic liver disease can be associated with significant changes in levels of P05019 , GH - binding protein ( P30043 ) , IGF - binding proteins ( IGFBPs ) and acid - labile subunit ( P35858 ) . However , the effect of liver steatosis on the P30043 production has not been investigated yet . AIM OF THE STUDY : To explore whether GH secretion and / or levels of P05019 , P17936 , P35858 and P30043 could be altered in obese patients in relation to the presence of liver steatosis . MATERIALS AND METHODS : A total of 115 obese patients ( BMI > 30 ) were enrolled in the protocol ( 65 patients with liver steatosis and 50 age - and BMI - matched controls ) . In all patients , the following parameters were studied : serum levels of glucose , insulin , the HOMA index , P05019 , P30043 , P17936 , P35858 and GH after P01286 and arginine stimulation test . RESULTS : As expected , patients with NAFLD had blood glucose , insulin , HOMA - R significantly higher than controls , indicating a more severe insulin - resistance state in NAFLD . Furthermore , patients with NAFLD had higher levels of P30043 and P17936 and lower GH peak and P05019 levels as compared to controls . No difference was found in P35858 levels between the groups . In a multivariate analysis , P30043 was positively associated with hepatic steatosis while DB01277 was negatively associated with hepatic steatosis . CONCLUSIONS : This study demonstrates that in patients with NAFLD , the P30043 levels are increased , and that the GH / P05019 axis is significantly altered probably leading to reduced P05019 bioavailability at tissue level .",
"Duodenal mucosal protection by bicarbonate secretion and its mechanisms . Proximal portion of duodenum is exposed to intermittent pulses of gastric H (+) discharged by the stomach . This review summarizes the mechanisms of duodenal mucosal integrity , mainly the role of mucus - alkaline secretion and the mucous barrier protecting surface epithelium against gastric H (+) . The mucous barrier protects the leaky duodenal epithelium against each pulse of gastric H (+) , which penetrates this barrier and diffuses into duodenocytes , but fails to damage them due to ; a ) an enhanced expression of cyclooxygenase - 1 ( P23219 ) , with release of protective prostaglandins ( PG ) and of nitric oxide ( NO ) synthase ( NOS ) with , however , production of NO , stimulating duodenal HCO ( 3 )(-) secretion and b ) the release of several neurotransmitters also stimulating HCO ( 3 )(-) secretion such as vasoactive intestinal peptide ( P01282 ) , pituitary adenylate - cyclase activating polypeptide ( PACAP ) , acetylcholine , melatonin , leptin and ghrelin released by enteric nerves and mucosal cells . At the apical duodenocyte membrane at least two HCO ( 3 )(-)/ Cl (-) anion exchangers operate in response to luminal H (+) to provide adequate extrusion of HCO ( 3 )(-) into duodenal lumen . In the basolateral portion of duodenocyte membrane , both non - electrogenic ( NBC ) and electrogenic ( NBC ( n ) ) Na (+) HCO ( 3 )(-) cotransporters are activated by the exposure to duodenal acidification , causing inward movement of HCO ( 3 )(-) from extracellular fluid to duodenocytes . There are also at least three Na (+)/ H (+) ( P19634 - 3 ) amiloride - sensitive exchangers , eliminating H (+) which diffused into these cells . The Helicobacter pylori ( Hp ) infection and gastric metaplasia in the duodenum with bacterium inoculating metaplastic mucosa and inhibiting HCO ( 3 )(-) secretion by its endogenous inhibitor , asymmetric dimethyl arginine ( DB01686 ) , may result in duodenal ulcerogenesis .",
"Serum insulin - like growth factor - 1 ( DB01277 ) and insulin - like growth factor binding protein - 3 ( P17936 ) in healthy Thai children and adolescents : relation to age , sex , and stage of puberty . The authors studied the serum concentrations of insulin - like growth factor - 1 ( DB01277 ) and IGF - binding protein - 3 ( P17936 ) in 260 healthy children and adolescents ( 115 males , 145 females ) aged 5 - 20 years . The subjects were divided into 12 groups according to age and sex . The serum DB01277 and P17936 concentrations increased with age and peaked at age 13 - 15 years in males , and 11 - 13 years in females . After the peak concentration , DB01277 and P17936 levels declined significantly in males , but were still high in females . Comparing between sexes , the concentrations of DB01277 and P17936 were greater in females than males in all age groups . However , when subjects were divided according to the stage of puberty , the different concentrations between sexes were not significant , except for children within Tanner stage V where concentrations of DB01277 and P17936 were significantly greater in females than males . Multiple regression analysis demonstrated the age , sex , and stage of puberty - dependent of DB01277 concentration , and only the age and sex - dependent of P17936 concentration .",
"P00747 activator system : implications for mammary cell growth and involution . Several tissue remodeling events that require extracellular proteolysis are thought to be mediated by plasminogen activators that convert the inactive proenzyme plasminogen to active plasmin . The involvement of plasminogen activator in many biological phenomena reflects the ubiquitous presence of plasminogen and the ability of numerous cell types to synthesize plasminogen activator in a highly regulated manner . Increased plasmin and plasminogen activator in bovine milk are correlated with gradual involution ( the declining phase of lactation ) . Treatment with bST prevented the increase in plasmin during gradual involution , indicating that bST interferes with conversion of plasminogen to plasmin . Concentrations of plasminogen activator in mammary tissue are high after cessation of milking . These results reinforce the association of the plasmin - plasminogen system with gradual involution postlactation . Recently , a role has been proposed for plasminogen activator in cell proliferation in several cellular systems . P01308 and P05019 increased synthesis of urokinase plasminogen activator and enhanced proliferation of cultured bovine mammary epithelial cells . In contrast , phorbol myristate acetate , which increased expression of urokinase plasminogen activator mRNA by mammary epithelial and myoepithelial cells , stimulated proliferation of myoepithelial cells , but not epithelial cells . Thus , expression of plasminogen activator is not simply related to mitogenesis but is likely to serve multiple functions in bovine mammary epithelial cells .",
"Q9H244 receptor signalling towards P31749 proceeds through P08069 cross - talk and requires activation of Src , Pyk2 and Rap1 . Previously it was shown that stimulation of the Q9H244 receptor activates P31749 signalling in P13671 glioma cells [ K . Van Kolen and H . Slegers , J . Neurochem . 89 , 442 . ] . In the present study , the mechanisms involved in this response were further elucidated . In cells transfected with the Gbetagamma - scavenger beta - O14965 / P25098 or Rap1GAPII , stimulation with 2MeSADP failed to enhance P31749 phosphorylation demonstrating that the signalling proceeds through Gbetagamma - subunits and Rap1 . Moreover , Rap1 - GTP pull - down assays revealed that Q9H244 receptor stimulation induced a rapid activation of Rap1 . Treatment of cells with the Ca2 + chelator BAPTA - AM and inhibition of Src and O14939 with Q99463 or 1 - butanol , respectively , abrogated Q9H244 receptor - mediated activation of Rap1 and P31749 . In addition inhibition of PKCzeta decreased basal and 2MeSADP - stimulated phosphorylation of P31749 indicating a role for this PKC isoform in P31749 signalling . Although the increased P31749 phosphorylation was abolished in the presence of the P08069 tyrosine kinase inhibitor AG 1024 , 2MeSADP did not significantly increase receptor phosphorylation . Nevertheless , phosphorylation of a 120 kDa P08069 - associated protein was observed . The latter protein was identified by MALDI - TOF / TOF - MS as the proline - rich tyrosine kinase 2 ( Pyk2 ) that co - operates with Src in a O14939 - dependent manner . Consistent with the signalling towards Rap1 and P31749 , activation of Pyk2 was abrogated by Ca2 + chelation , inhibition of O14939 and P08069 tyrosine kinase activity . In conclusion , the data reveal a novel type of cross - talk between Q9H244 and P05019 receptors that proceeds through Gbetagamma - , Ca2 +- and O14939 - dependent activation of the Pyk2 / Src pathway resulting in GTP - loading of Rap1 required for an increased P31749 phosphorylation .",
"Ex vivo binding of flibanserin to serotonin P08908 and 5 - Q13049 receptors . ___MASK94___ has been reported to be an agonist at P08908 - receptors and an antagonist at 5 - Q13049 receptors , with higher affinity for P08908 receptors . Despite the fact that less receptor occupation is required by full agonists than by antagonists to exert their effects , flibanserin was shown to exert 5 - Q13049 antagonism at doses ( 4 - 5 mg kg - 1 ) that are lower or equal to those required to stimulate P08908 receptors . In order to understand this phenomenon , the interaction of flibanserin with P08908 and 5 - Q13049 receptors was evaluated in ex vivo binding studies . This interaction was evaluated in the prefrontal cortex , hippocampus and midbrain by using [ 3H ] 8 - OH - DPAT and [ 3H ] ketanserin to label P08908 and 5 - Q13049 receptors , respectively . ___MASK94___ was given at 1 , 10 and 30 mg kg - 1 intraperitoneally . The dose of 1 mg kg - 1 displaced both radioligands preferentially in the frontal cortex . The doses of 10 and 30 mg kg - 1 reduced the binding of both radioligands in all the three brain regions non - selectively by about 50 % and 70 % , respectively . The displacement was maximal after 0 . 5 h and was reduced or not evident after 3 h . We conclude that 5 - HT2 antagonism brought about by low doses of flibanserin may reflect functional mechanisms more than receptor - mediated effects .",
"Neuronal ablation of p - Akt at Ser473 leads to altered P08908 / 2A receptor function . The serotonergic system regulates a wide range of behavior , including mood and impulsivity , and its dysregulation has been associated with mood disorders , autism spectrum disorder , and addiction . Diabetes is a risk factor for these conditions . P01308 resistance in the brain is specifically associated with susceptibility to psychostimulant abuse . Here , we examined whether phosphorylation of Akt , a key regulator of the insulin signaling pathway , controls serotonin ( 5 - HT ) signaling . To explore how impairment in Akt function regulates 5 - HT homeostasis , we used a brain - specific rictor knockout ( KO ) mouse model of impaired neuronal phosphorylation of Akt at Ser473 . Cortical P08908 and 5 - Q13049 receptor binding was significantly elevated in rictor KO mice . Concomitant with this elevated receptor expression , the P08908 receptor agonist 8 - Hydroxy - 2 -( di - n - propylamino ) tetralin ( 8 - OH - DPAT ) led to an increased hypothermic response in rictor KO mice . The increased cortical P08908 receptor density was associated with higher P08908 receptor levels on the cortical cell surface . In contrast , rictor KO mice displayed significantly reduced head - twitch response ( HTR ) to the 5 - Q13049 / C agonist 2 , 5 - dimethoxy - 4 - iodoamphetamine ( DOI ) , with evidence of impaired 5 - Q13049 / C receptor signaling . In vitro , pharmacological inhibition of Akt significantly increased P08908 receptor expression and attenuated DOI - induced 5 - Q13049 receptor signaling , thereby lending credence to the observed in vivo cross - talk between neuronal Akt signaling and 5 - HT receptor regulation . These data reveal that defective central Akt function alters 5 - HT signaling as well as 5 - HT - associated behaviors , demonstrating a novel role for Akt in maintaining neuronal 5 - HT receptor function .",
"P00749 and insulin - like growth factor - binding protein 3 mRNA expression in endometriotic lesions and eutopic endometrium : implications for the pathophysiology of endometriosis . The peritoneal fluid of women with endometriosis contains an increased insulin - like growth factor 1 ( DB01277 ) bioavailability , which is produced by limited hydrolysis of urokinase - type plasminogen activator ( uPA ) on P17936 ( P17936 ) . Recently , DB01277 was shown to inhibit apoptosis of endometrial - like cells in vitro , suggesting that a microenvironment of increased DB01277 bioavailability can optimize the survival of endometrial cells grown ectopically . Here the expression of mRNA of P17936 and uPA in tissue biopsies from eutopic endometrium and endometriotic lesions obtained at laparoscopy from women with endometriosis have been analyzed , and it is documented that both P17936 and uPA mRNA expression are increased from 3 - to 10 - fold in endometriotic lesions versus eutopic endometrium . Consequently , the necessary components ( uPA and P17936 expression ) of endocrine / autocrine / paracrine enhancement of local IGF bioavailability mediated by uPA hydrolysis of the P17936 were present in endometriotic lesions . These data possibly explain the origin of the increased content of uPA activity , DB01277 bioavailability , and NH ( 2 )- truncated forms of P17936 in the peritoneal fluid of women with endometriosis ."
] |
[
"___MASK100___",
"___MASK26___",
"___MASK45___",
"___MASK58___",
"___MASK63___",
"___MASK65___",
"___MASK72___",
"___MASK79___",
"___MASK94___"
] |
___MASK63___
|
MH_train_495
|
interacts_with DB01229?
|
[
"A phase I - II study of the histone deacetylase inhibitor vorinostat plus sequential weekly paclitaxel and doxorubicin - cyclophosphamide in locally advanced breast cancer . Histone deacetylases ( HDACs ) are a family of enzymes that regulate chromatin remodeling and gene transcription . ___MASK36___ is a panHDAC inhibitor that sensitizes breast cancer cells to taxanes and trastuzumab by suppressing Q9UBN7 and Hsp90 client proteins . Fifty - five patients with clinical stage IIA - IIIC breast cancer received 12 weekly doses of paclitaxel ( 80 mg / m ( 2 ) ) plus vorinostat ( 200 - 300 mg PO P55957 ) on days 1 - 3 of each paclitaxel dose plus trastuzumab ( for Her2 / neu positive disease only ) , followed by doxorubicin / cyclophosphamide ( 60 / 600 mg / m ( 2 ) every 2 weeks plus pegfilgrastim ) . The primary study endpoint was pathologic complete response ( pCR ). pCR occurred in 13 of 24 evaluable patients with Her2 - positive disease ( 54 , 95 % confidence intervals [ CI ] 35 - 72 % ) , which met the prespecified study endpoint . pCR occurred in 4 of 15 patients with triple negative disease ( 27 , 95 % CI 11 - 52 % ) and none of 12 patients with ER - positive , Her2 / neu negative disease ( 0 , 95 % CI 0 - 24 % ) , which did not meet the prespecified endpoint . ER - positive tumors exhibited lower Ki67 and higher Hsp70 expression , and Q9UBN7 , Hsp70 , P38936 , and p27 expression were not predictive of response . ___MASK36___ increased acetylation of Hsp90 and alpha tubulin , and reduced expression of Hsp90 client proteins and Q9UBN7 in the primary tumor . Combination of vorinostat with weekly paclitaxel plus trastuzumab followed by doxorubicin - cyclophosphamide is associated with a high pCR rate in locally advanced Her2 / neu positive breast cancer . Consistent with cell line and xenograft data , vorinostat increased acetylation of Hsp90 and alpha tubulin , and decreased Hsp90 client protein and Q9UBN7 expression in human breast cancers in vivo .",
"Recombinant human prothrombin kringle - 2 induces bovine capillary endothelial cell cycle arrest at G0 - P55008 phase through inhibition of cyclin D1 / P11802 complex : modulation of reactive oxygen species generation and up - regulation of cyclin - dependent kinase inhibitors . P00734 is a plasma glycoprotein involved in blood coagulation and , as we have previously reported , prothrombin kringles inhibit BCE ( bovine capillary endothelial ) cell proliferation . To reveal the mechanism , we investigated the influence of rk - 2 ( recombinant human prothrombin kringle - 2 ) on the BCE cell cycle progression and ROS ( reactive oxygen species ) generation using FACS ( fluorescence - activated cell sorter ) analysis . Cell cycle analysis showed a decrease of G ( 1 ) phase cells in cells treated with P09038 ( basic fibroblast growth factor ) and an increase in cells treated with rk - 2 , as compared with the control cells . But , the portion of the S phase was reversed . In Western blot analysis , P09038 induced cytoplasmic translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) and phosphorylation of p27 ( Kip1 ) but rk - 2 treatment inhibited translocation of P38936 ( Waf1 / Cip1 ) and p27 ( Kip1 ) from nucleus to cytoplasm and phosphorylation of p27 ( Kip1 ) . Also , rk - 2 induced up - regulation of p53 and nuclear P38936 ( Waf1 / Cip1 ) and inhibited the cyclin D1 / P11802 ( cyclin - dependent kinase 4 ) complex . The ROS level of rk - 2 - treated BCE cells was increased 2 - fold when compared with the control , but treatment with Q9C000 ( N - Acetyl - L : - cysteine ) , an anti - oxidant , decreased ROS generation about 55 % as compared with the rk - 2 treatment . Q9C000 treatment also restored cell cycle progression inhibited by rk - 2 and down - regulated p53 and nuclear P38936 ( Waf1 / Cip1 ) expression induced by rk - 2 . These data suggest that rk - 2 induces the BCE cell cycle arrest at G ( 0 )- G ( 1 ) phase through inhibition of the cyclin D1 / P11802 complex caused by increase of ROS generation and nuclear cyclin - dependent kinase inhibitors .",
"Molecular response of HL - 60 cells to mitotic inhibitors vincristine and taxol visualized with apoptosis - related gene expressions , including the new member Q9HB09 . DB01229 and vincristine belong to a group of anticancer drugs that target microtubules , subsequently arresting cells at the mitotic phase of the cell cycle and inducing programmed cell death . The P10415 ( bcl - 2 ) family of genes is of known implication in apoptosis induced by various stimuli , among which Q9HB09 , a new member of the family , cloned by our group . For further insights into the mechanisms and molecular targets implicated and modified as a result of apoptosis induced by these two mitosis - arresting drugs , we studied the possible alterations , at the mRNA level , of various apoptosis - related genes ( P10415 , Q07812 , Q9HB09 , CASPASE - 3 , FAS ) after leukemia cell ( HL - 60 ) treatment with these drugs . The kinetics of cell toxicity were evaluated by the MTT [ 3 -( 4 , 5 - dimethylthiazol - 2 - yl )- 2 , 5 - diphenyltetrazolium bromide ] method , trypan blue staining , and cell proliferation efficiency ; apoptosis induction was assayed by endonucleosomal cleavage of DNA ( DNA laddering ) ; and the expression levels of the genes were analysed by RT - PCR , using gene - specific primers . The percentage of nonviable cells was upregulated with increasing cell exposure time and drug concentrations to both taxol and vincristine . Distinct modulations of apoptosis - related genes at the mRNA level were also observed , mainly concerning P10415 and Q9HB09 along apoptosis induction . Our results indicate and support the hypothesis that the apoptosis - related genes P10415 and Q9HB09 respond similarly to treatment of the human , acute , myelocytic leukemia HL60 cells with the anticancer drugs vincristine and taxol though in a drug - specific and time - dependent manner .",
"Production of paired helical filament , tau - like proteins by PC12 cells : a model of neurofibrillary degeneration . Neuron - like cells derived from a rat pheochromocytoma cell line ( PC12 ) and differentiated with nerve growth factor produce a paired helical filament ( PHF ) - like antigen when they are subjected to heat shock ( Wallace et al . : Mol Brain Res 19 : 149 - 155 , 1993 ) . It accumulates in a localized region of the perinuclear cytoplasm and reacts with monoclonal antitau antibodies , which identify epitopes in the N - and C - terminal halves and the microtubule - binding domain of tau protein . The observed profile of immunoreactivity suggests the presence of full - length and C - terminally truncated tau in a region of perinuclear cytoplasm in which no structurally intact PHFs could be demonstrated by conventional transmission electron microscopy . The accumulated tau protein colocalized with antibodies raised against mitochondrial outer membrane proteins and was associated with the presence of numerous mitochondrial profiles that were demonstrated with electron microscopy . Because differentiated PC12 cells pretreated with colcemid or DB01229 prior to heat shock fail to exhibit perinuclear PHF - like immunoreactivity , the reported response to heat shock appears to require an intact system of intracellular microtubules . This PC12 system provides a model in which the metabolic and molecular biological underpinnings of neuronal degeneration in Alzheimer ' s disease can be manipulated . The system may eventually be applicable to the development of pharmaceutical agents that interfere with formation and / or degeneration of P10636 in Alzheimer ' s disease .",
"Generation of Epstein - Barr virus - specific cytotoxic T lymphocytes resistant to the immunosuppressive drug tacrolimus ( FK506 ) . Adoptive transfer of autologous Epstein - Barr virus - specific cytotoxic T lymphocytes ( EBV - CTLs ) to solid organ transplant ( SOT ) recipients has been shown safe and effective for the treatment of EBV - associated posttransplantation lymphoproliferative disorders ( PTLDs ) . SOT recipients , however , require the continuous administration of immunosuppressive drugs to prevent graft rejection , and these agents may significantly limit the long - term persistence of transferred EBV - CTLs , precluding their use as prophylaxis . ___MASK97___ ( FK506 ) is one of the most widely used immunosuppressive agents in SOT recipients , and its immunosuppressive effects are largely dependent on its interaction with the 12 - kDa FK506 - binding protein ( P62942 ) . We have knocked down the expression of P62942 in EBV - CTLs using a specific small interfering RNA ( siRNA ) stably expressed from a retroviral vector and found that P62942 - silenced EBV - CTLs are FK506 resistant . These cells continue to expand in the presence of the drug without measurable impairment of their antigen specificity or cytotoxic activity . We confirmed their FK506 resistance and anti - PTLD activity in vivo using a xenogenic mouse model , suggesting that the proposed strategy may be of value to enhance EBV - specific immune surveillance in patients at high risk of PTLD after transplantation .",
"Tyrosine kinase inhibition facilitates autophagic P37840 / α - synuclein clearance . The effects of P00519 / P00519 inhibition on clearance of P37840 / α - synuclein were evaluated in animal models of α - synucleinopathies . Parkinson disease ( PD ) is a movement disorder characterized by death of dopaminergic substantia nigra ( SN ) neurons and brain accumulation of P37840 . The tyrosine kinase P00519 is activated in several neurodegenerative diseases . An increase in P00519 activity is detected in human postmortem PD brains . Lentiviral expression of P37840 in the mouse SN activates P00519 via phosphorylation , while lentiviral Abl expression increases P37840 levels . Administration of the brain - penetrant tyrosine kinase inhibitor DB04868 decreases Abl activity and facilitates autophagic clearance of P37840 in transgenic and lentiviral gene transfer models . Subcellular fractionation demonstrates accumulation of P37840 and hyperphosphorylated P10636 / Tau ( p - P10636 ) in autophagic vacuoles in P37840 - expressing brains , while DB04868 treatment leads to protein deposition into the lysosomes , suggesting enhanced autophagic clearance . These data suggest that DB04868 may be a therapeutic strategy to degrade P37840 in PD and other α - synucleinopathies .",
"Induction of G2 / M arrest and inhibition of cyclooxygenase - 2 activity by curcumin in human bladder cancer T24 cells . Curcumin , a polyphenol compound derived from Curcuma longa Linn , has been recognized as a promising anti - cancer drug due to its multiple properties including anti - inflammatory , anti - oxidant and anti - carcinogenic activities . To elucidate the mechanisms by which curcumin inhibits human bladder carcinoma T24 cell proliferation , we tested the effects of curcumin on specific cell cycle pathways and on the expression of cyclooxygenases ( COXs ) . Curcumin inhibited the growth of T24 cells and induced G2 / M arrest in a concentration - dependent manner , effects associated with the down - regulation of cyclin A and up - regulation of cyclin - dependent kinase ( Cdk ) inhibitor P38936 ( P38936 / CIP1 ) . However , other G2 / M regulatory molecules , such as cyclin A , Cdc2 , Cdk2 , Wee1 and Cdc25C , were not modulated by curcumin treatment . Furthermore , curcumin decreased the levels of P35354 mRNA and protein expression without significant changes in the levels of P23219 , which correlated with a decrease in prostaglandin E2 ( DB00917 ) synthesis . These observations suggest that curcumin may have therapeutic potential for bladder cancer patients .",
"___MASK53___ - coupled Affi - Gel matrix for the purification of thrombin from plasma . Sometimes it is necessary to obtain thrombin from limited amounts of human plasma for laboratory assay . None of the available purification methods easily deals with this subject . The procedure described in the present paper uses a readily available pharmaceutical agent , argatroban , to construct an affinity matrix . ___MASK53___ has a high affinity for thrombin and its thrombin binding is reversible . P00734 derived from a Ba ( 2 +) precipitate of human plasma is used as the starting material . The crude prothrombin can be bulk activated to thrombin using taipan - snake ( Oxyuranus scutellatus ) venom and bound to the argatroban - coupled matrix without further processing steps . The thrombin product eluted from the argatroban matrix is very pure as judged by high specific activity and by electrophoresis . This purification scheme is rapid , yielding purified thrombin within 2 days .",
"Q03135 tyrosine phosphorylation enhances paclitaxel - mediated cytotoxicity . Q03135 ( Q03135 ) , a highly conserved membrane - associated protein , is a putative regulator of cellular transformation . Q03135 is localized in the plasmalemma , secretory vesicles , Golgi , mitochondria , and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton . Taxanes such as paclitaxel ( DB01229 ) are potent anti - tumor agents that repress the dynamic instability of microtubules and arrest cells in the G ( 2 )/ M phase . Src phosphorylation of DB00135 - 14 on Q03135 regulates its cellular localization and function . We report that phosphorylation of Q03135 on DB00135 - 14 regulates paclitaxel - mediated apoptosis in MCF - 7 breast cancer cells . Befitting its role as a multitasking molecule , we show that Q03135 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules P10415 , p53 , and P38936 . We demonstrate that phosphorylated Q03135 triggers apoptosis by inactivating P10415 and increasing mitochondrial permeability more efficiently than non - phosphorylated Q03135 . Furthermore , expression of P38936 , which correlates with taxane sensitivity , is regulated by Q03135 phosphorylation in a p53 - dependent manner . Collectively , our findings underscore the importance of Q03135 phosphorylation in apoptosis and suggest that events that negate Q03135 tyrosine phosphorylation may contribute to anti - microtubule drug resistance .",
"P35367 occupancy in human brains after single oral doses of histamine H1 antagonists measured by positron emission tomography . 1 . P35367 occupancy in the human brain was measured in 20 healthy young men by positron emission tomography ( PET ) using [ 11C ] - doxepin . 2 . (+)- ___MASK25___ , a selective and classical antihistamine , occupied 76 . 8 +/- 4 . 2 % of the averaged values of available histamine H1 receptors in the frontal cortex after its administration in a single oral dose of 2 mg . Intravenous administration of 5 mg (+)- chlorpheniramine almost completely abolished the binding of [ 11C ] - doxepin to H1 receptors ( H1 receptor occupancy : 98 . 2 +/- 1 . 2 % ) . 3 . Terfenadine , a nonsedative antihistamine , occupied 17 . 2 +/- 14 . 2 % of the available H1 receptors in the human frontal cortex after its administration in a single oral dose of 60 mg . 4 . There was no correlation between H1 receptor occupancy by terfenadine and the plasma concentration of the active acid metabolite of terfenadine in each subject . 5 . PET data on human brain were essentially compatible with those on H1 receptor occupancy in guinea - pig brain determined by in vivo binding techniques , although for the same H1 receptor occupancy the dose was less in human subjects than in guinea - pigs . 6 . The PET studies demonstrated the usefulness of measuring H1 receptor occupancy with classical and second - generation antihistamines in human brain to estimate their unwanted side effects such as sedation and drowsiness quantitatively .",
"Neuroprotective gene expression profiles in ischemic cortical cultures preconditioned with DB01277 or P09038 . The mechanisms underlying growth factor preconditioning of neurons are only partially elucidated , and no studies have been conducted in this area using a gene profiling approach . We used cDNA microarrays to compare the transcriptional profiles of cells preconditioned either with insulin - like growth factor I ( DB01277 ) or basic fibroblast growth factor ( P09038 ) , to identify differentially regulated genes that may function in growth factor signaling , response to oxygen - glucose deprivation ( OGD ) , and most importantly , cell survival . Primary rat cortical cultures were treated with P09038 or DB01277 for 2 , 24 , or 24 h followed by OGD for 90 min , and compared with cells that were subject to OGD without growth factor pretreatment . Although the majority of surveyed genes were unchanged in all experimental treatments , 175 genes ( 10 % of the cDNAs on the chip ) were found to be differentially regulated in at least one of the treatment conditions . Hierarchical clustering of these 175 genes was used to identify four expression clusters : DB01277 regulated , P09038 regulated , OGD regulated , and putative neuroprotective genes . Further analysis using realtime RT - PCR confirmed that we had identified genes that are regulated by single growth factors , as well as several more that are co - regulated by both DB01277 and P09038 . These genes can influence neuronal survival by affecting diverse pathways such as growth factor signal transduction ( P16070 , Q99075 , Q16828 , Q12929 , P17936 ) , DNA repair and transcription ( Q92949 ) , metabolic homeostasis ( P20936 , P34897 ) , cytoskeletal stability ( P26038 , P10636 ) and cholesterol biosynthesis ( P37268 , P14324 ) .",
"[ P35354 inhibitor non - steroidal anti - inflammatory drugs , myth or reality ? ] . The discovery of two isoforms of cyclooxygenase , Cox - 1 constitutive and Cox - 2 inducible , has prompted the development of new molecules with high Cox - 2 selectivity . These new NSAIDs belong to the coxib class and have theoretically a better digestive tolerability than classical NSAID have . In Belgium , rofecoxib ( ( Vioxx ) and celecoxib ( DB00482 ) are commercialized . DB00533 is indicated in the symptomatic treatment of osteoarthritis ( 12 . 5 to 25 mg / d ) and celecoxib is indicated in osteoarthritis ( 200 mg / d ) and in rheumatoid arthritis ( 200 to 400 mg / d ) . Several studies have demonstrated their efficacy , similarly to classical NSAID as diclofenac ( Voltaren ) , naproxen ( Naprosyne ) , ibuprofen ( ___MASK49___ ) and their superiority compared to placebo . Their safety profile for gastrointestinal events is proven in patients without ulcer history compared to classical NSAID . However , the concomitant use of aspirin decreases the benefit as demonstrated for celecoxib at 400 mg / d but not investigated for rofecoxib . The selective inhibition of Cox - 2 with no effect on Cox - 1 favors cardiovascular events in patients at risk . Other side effects are similar to classical NSAID . Thus Cox - 2 inhibitors NSAID are interesting molecules for their sparing gastrointestinal activity . They must be used with caution in patients with ulcer history , in the elderly and in patients requiring aspirin for cardiovascular prophylaxis .",
"Histone carbonylation occurs in proliferating cells . Chromatin is a dynamic structure formed mainly by DNA and histones , and chemical modifications on these elements regulate its compaction . Histone posttranslational modifications ( PTMs ) have a direct impact on chromatin conformation , controlling important cellular events such as cell proliferation and differentiation . Redox - related posttranslational modifications may have important effects on chromatin structure and function , offering a new intriguing area of research termed \" redox epigenetics . \" Little is known about histone carbonylation , a PTM that may be related to modifications in the cellular redox environment . The aim of our study was to determine the carbonylation of the various histones during cell proliferation , a moment in cell life during which important redox changes take place . Here , we describe changes in histone carbonylation during cell proliferation in NIH3T3 fibroblasts . In addition , we have studied the variations of poly ( ADP - ribosyl ) ation and phospho - P16104 at the same time , because both modifications are related to DNA damage responses . High levels of carbonylation on specific histones ( H1 , H1 ( 0 ) , and H3 . 1 dimers ) were found when cells were in an active phase of DNA synthesis . The modification decreased when nuclear proteasome activity was activated . However , these results did not correlate completely with poly ( ADP - ribosyl ) ation and phospho - P16104 levels . Therefore , histone carbonylation may represent a specific event during cell proliferation . We describe a new methodology named oxy - 2D - P10636 Western blot that allowed us to separate and analyze the carbonylation patterns of the histone variants . In addition we offer a new role for histone carbonylation and its implication in redox epigenetics . Our results suggest that histone carbonylation is involved in histone detoxification during DNA synthesis .",
"P23219 and - 2 expressions in sex - related organs of neonatally estrogen - treated rats and in activated and nonactivated macrophage RAW264 . 7 cells with phytoestrogen . Cyclooxygenase ( P36551 ) - 2 is an inducible isoform , expressed in inflamed leukocytes and cancer cells . It is known that estrogen causes prostate dysplasia , but little is known about P35354 expression and its influence on male reproductivity . In this study , we show that P35354 was abolished in the distal end of the vas deferens in neonatally estrogenized ( diethylstilbestrol , NeoDES ) Sprague - Dawley ( SD ) rats at age of 15 mo , but the control normal rats were found to remain constitutive expression at the same age , while the levels of P23219 in these rats remained intact . Furthermore , Q07812 , an indicator of sperm quality , was observed in the endothelium of vas deferens and sperm of the aged rats . However , P35354 was not detected in the inflamed lesions of NeoDES rat ' s prostate by immunohistochemistry . In addition to estrogen , hydroxymatairesinol ( P22736 ) , a phytoestrogen , was analyzed in vitro for possible regulation on P35354 . Through Western blot analysis , P22736 was shown to have no inhibitory affect on P35354 expression . These results indicated that estrogen treatment strongly influences the expression of P35354 that is associated with fertility , but no induction of P35354 by estrogen may not exclude P35354 ' s role in prostatitis , and the anti - tumor mechanism of P22736 largely remains elusive .",
"Prevention and treatment of pancreatic cancer by curcumin in combination with omega - 3 fatty acids . Pancreatic cancer BxPC - 3 cells were exposed to curcumin , docosahexaenoic acid ( DB01708 ) , or combinations of both and analyzed for proliferation and apoptosis . Pancreatic tumor xenografts were established by injecting BxPC - 3 cells into each flank of nude mice . After the tumors reached a size of approximately 190 - 200 mm ( 3 ) , animals were fed diets with or without 2 , 000 ppm curcumin in 18 % corn oil or 15 % fish oil + 3 % corn oil for 6 more wk before assessing the tumor volume and expression of inducible nitric oxide synthase ( P35228 ) , cyclooxygeanse - 2 ( P35354 ) , 5 - lipoxinase ( 5 - P28300 ) , and P38936 . A synergistic effect was observed on induction of apoptosis ( approximately sixfold ) and inhibition of cell proliferation ( approximately 70 % ) when cells were treated with curcumin ( 5 microM ) together with the DB01708 ( 25 microM ) . Mice fed fish oil and curcumin showed a significantly reduced tumor volume , 25 % ( P < 0 . 04 ) and 43 % ( P < 0 . 005 ) , respectively , and importantly , a combination of curcumin and fish oil diet showed > 72 % ( P < 0 . 0001 ) tumor volume reduction . Expression and activity of P35228 , P35354 , and 5 - P28300 are downregulated , and P38936 is upregulated in tumor xenograft fed curcumin combined with fish oil diet when compared to individual diets . The preceding results evidence for the first time that curcumin combined with omega - 3 fatty acids provide synergistic pancreatic tumor inhibitory properties .",
"Acute renal failure from hemoglobinuric and interstitial nephritis secondary to iodine and mefenamic acid . ___MASK65___ ingestion , usually in excess and over prolonged period is known to produce interstitial nephritis , or less commonly papillary necrosis , with acute renal failure . However , it is not dose - dependent for the induction of tubulointerstitial damage . Excess iodine ingestion is known to produce toxicity and possible death , but acute renal failure is rare . There is evidence from clinical and experimental data that iodine has toxic effect on tubular epithelial cells . Iodine has not been documented to produce red cell hemolysis and hemoglobinuria . We present a unique case of acute renal failure from hemoglobinuric and acute interstitial nephritis secondary to suicidal ingestion of potassium iodide solution and also ingestion of a few mefenamic acid tablets . These agents led to potentiation of the renal injury from hemoglobinuric tubulopathy , probably from the iodine , and renal dysfunction from alteration of renal perfusion by selective P23219 inhibition of prostaglandin production , and induction of acute interstitial nephritis from mefenamic acid , leading to acute renal failure which was reversible by hemodialysis and supportive therapy .",
"Metabolism of risperidone to 9 - hydroxyrisperidone by human cytochromes P450 2D6 and 3A4 . DB00734 is a relatively new antipsychotic drug that has been reported to improve both the positive and the negative symptoms of schizophrenia and produces relatively few extrapyramidal side effects at low doses . Formation of 9 - hydroxyrisperidone , an active metabolite , is the most important metabolic pathway of risperidone in human . In the present study , in vitro metabolism of risperidone ( 100 microM ) was investigated using the recombinant human cytochrome P450 ( CYP ) enzymes P04798 , P05177 , P10632 , P11712 - arg144 , P11712 - cys144 , P33261 , P10635 , P08684 and P20815 supplemented with an NADPH - generating system . ___MASK1___ was determined by a new HPLC method with an Hypersil CN column and a UV detector . Of these enzymes , CYPs 2D6 , 3A4 and 3A5 were found to be the ones capable of metabolising risperidone to 9 - hydroxyrisperidone , with activities of 7 . 5 , 0 . 4 and 0 . 2 pmol pmol (- 1 ) CYP min (- 1 ) , respectively . A correlation study using a panel of human liver microsomes showed that the formation of 9 - hydroxyrisperidone is highly correlated with P10635 and 3A activities . Thus , both P10635 and 3A4 are involved in the 9 - hydroxylation of risperidone at the concentration of risperidone used in this study . This observation is confirmed by the findings that both quinidine ( inhibitor of P10635 ) and ketoconazole ( inhibitor of P08684 ) can inhibit the formation of 9 - hydroxyrisperidone . Furthermore , inducers of CYP can significantly increase the formation of 9 - hydroxyrisperidone in rat . The formation of 9 - hydroxyrisperidone is highly correlated with testosterone 6beta - hydroxylase activities , suggesting that inducible CYP3A contributes significantly to the metabolism of risperidone in rat .",
"P62942 , the 12 - kDa FK506 - binding protein , is a physiologic regulator of the cell cycle . P62942 , the 12 - kDa FK506 - binding protein , is a ubiquitous abundant protein that acts as a receptor for the immunosuppressant drug FK506 , binds tightly to intracellular calcium release channels and to the transforming growth factor beta ( TGF - beta ) type I receptor . We now demonstrate that cells from P62942 - deficient ( P62942 (-/-) ) mice manifest cell cycle arrest in G ( 1 ) phase and that these cells can be rescued by P62942 transfection . This arrest is mediated by marked augmentation of P38936 ( P38936 / CIP1 ) levels , which can not be further augmented by TGF - beta1 . The P38936 up - regulation and cell cycle arrest derive from the overactivity of TGF - beta receptor signaling , which is normally inhibited by P62942 . Cell cycle arrest is prevented by transfection with a dominant - negative TGF - beta receptor construct . TGF - beta receptor signaling to gene expression can be mediated by SMAD , p38 , and P29323 / Q96HU1 kinase ( extracellular signal - regulated kinase / mitogen - activated protein kinase ) pathways . SMAD signaling is down - regulated in P62942 (-/-) cells . Inhibition of P29323 / Q96HU1 kinase fails to affect P38936 up - regulation . By contrast , activated phosphorylated p38 is markedly augmented in P62942 (-/-) cells and the P38936 up - regulation is prevented by an inhibitor of p38 . Thus , P62942 is a physiologic regulator of cell cycle acting by normally down - regulating TGF - beta receptor signaling .",
"Nodes and biological processes identified on the basis of network analysis in the brain of the senescence accelerated mice as an Alzheimer ' s disease animal model . Harboring the behavioral and histopathological signatures of Alzheimer ' s disease ( AD ) , senescence accelerated mouse - prone 8 ( SAMP8 ) mice are currently considered a robust model for studying AD . However , the underlying mechanisms , prioritized pathways and genes in SAMP8 mice linked to AD remain unclear . In this study , we provide a biological interpretation of the molecular underpinnings of SAMP8 mice . Our results were derived from differentially expressed genes in the hippocampus and cerebral cortex of SAMP8 mice compared to age - matched SAMR1 mice at 2 , 6 , and 12 months of age using cDNA microarray analysis . On the basis of PPI , MetaCore and the co - expression network , we constructed a distinct genetic sub - network in the brains of SAMP8 mice . Next , we determined that the regulation of synaptic transmission and apoptosis were disrupted in the brains of SAMP8 mice . We found abnormal gene expression of P04049 , P10636 , P35354 , CDKN2A , Q9UQM7 , Q16620 , Q15109 , P25098 , O60318 , and Q9UNE7 , which may have initiated the dysfunction of biological processes in the brains of SAMP8 mice . Specifically , we found microRNAs , including miR - 20a , miR - 17 , miR - 34a , miR - 155 , miR - 18a , miR - 22 , miR - 26a , miR - 101 , miR - 106b , and miR - 125b , that might regulate the expression of nodes in the sub - network . Taken together , these results provide new insights into the biological and genetic mechanisms of SAMP8 mice and add an important dimension to our understanding of the neuro - pathogenesis in SAMP8 mice from a systems perspective .",
"___MASK40___ : A novel agent for the treatment of homozygous familial hypercholesterolemia . PURPOSE : The pharmacology , pharmacokinetics , and clinical efficacy and safety of lomitapide in the management of homozygous familial hypercholesterolemia ( HoFH ) are reviewed . SUMMARY : ___MASK40___ ( Juxtapid , Aegerion Pharmaceuticals ) is an oral microsomal triglyceride transfer protein ( P55157 ) inhibitor indicated for the treatment of patients with HoFH , a rare form of hypercholesterolemia that can lead to premature atherosclerotic disease . In clinical trials , the use of lomitapide alone or in combination with other lipid - lowering modalities reduced plasma concentrations of low - density lipoprotein cholesterol ( LDL - C ) by a mean of more than 50 % . ___MASK40___ is associated with significant gastrointestinal adverse effects and increases in hepatic fat levels . ___MASK40___ undergoes hepatic metabolism via cytochrome P - 450 ( CYP ) isoenzyme 3A4 and interacts with P08684 substrates including atorvastatin and simvastatin ; dose adjustment is recommended when lomitapide is used concurrently with these agents . In patients receiving concomitant warfarin , the International Normalized Ratio ( INR ) should be closely monitored , as lomitapide use may increase INR values . The recommended initial dosage of lomitapide is 5 mg once daily , with subsequent upward dose adjustment at specified intervals according to tolerability . ___MASK40___ is contraindicated in patients with moderate - to - severe liver disease , patients with sustained abnormal liver function tests , patients taking strong or moderate P08684 inhibitors , and pregnant patients . CONCLUSION : ___MASK40___ is an oral P55157 inhibitor approved for the treatment of HoFH . This agent appears to be a realistic option for patients with HoFH who are unable to attain their LDL - C goal or can not tolerate statin therapy .",
"Allele frequencies of single nucleotide polymorphisms ( SNPs ) in 40 candidate genes for gene - environment studies on cancer : data from population - based Japanese random samples . Knowledge of genetic polymorphisms in gene - environment studies may contribute to more accurate identification of avoidable risks and to developing tailor - made preventative measures . The aim of this study was to describe the allele frequencies of single nucleotide polymorphisms ( SNPs ) of select genes , which may be included in future gene - environment studies on cancer in Japan . SNP typing was performed on middle - aged Japanese men randomly selected from the general population in five areas of Japan . We genotyped and calculated allele frequencies of 153 SNPs located on 40 genes : P04798 , Q16678 , P11712 , P33261 , P05181 , P05093 , P11511 , P35869 , P03372 , Q92731 , ERRRG , P06401 , P07099 , P34913 , P37059 , P37058 , P28161 , P21266 , GSTT2 , P09211 , NAT1 , NAT2 , P21964 , P07327 , P00325 , P00326 , P05091 , P35228 , NOS3 , P01583 , P01584 , O15527 , P36639 [ P36639 ] , P14416 , P35462 , P21917 , P31645 , P04150 [ GCCR ] , P42898 , and P15559 . In the present study , the Japanese allele frequencies were verified by using nationwide population samples .",
"___MASK97___ ( FK506 ) increases neuronal expression of P20936 - 43 and improves functional recovery after spinal cord injury in rats . ___MASK97___ ( FK506 ) , a widely used immunosuppressant drug , has neurite - promoting activity in cultured PC12 cells and peripheral neurons . The present study investigated whether tacrolimus affects the expression of the neuronal growth - associated protein , P20936 - 43 , as well as functional recovery after photothrombotic spinal cord injury in the rat . In injured animals receiving tacrolimus , the number of neurons expressing P20936 - 43 mRNA and protein approximately doubled compared to that in injured animals receiving vehicle alone . This increase in P20936 - 43 - positive cells was paralleled by a significant improvement in neurological function evaluated by open - field and inclined plane tests . Another P62942 ligand ( V - 10 , 367 ) had similar effects on P20936 - 43 expression and functional outcome , indicating that the observed effects of tacrolimus do not involve inhibition of the phosphatase calcineurin . Thus , tacrolimus , a drug which is already approved for use in humans , as well as other P62942 ligands which do not inhibit calcineurin , could potentially enhance functional outcome after CNS injury in humans .",
"Genotoxicity and induction of DNA damage responsive genes by food - borne heterocyclic aromatic amines in human hepatoma HepG2 cells . Heterocyclic aromatic amines ( HAAs ) are potential human carcinogens formed in well - done meats and fish . The most abundant are 2 - Amino - 1 - methyl - 6 - phenylimidazo [ 4 , 5 - b ] pyridine ( PhIP ) , 2 - Amino - 3 , 8 - dimethylimidazo [ 4 , 5 - f ] quinoxaline ( MeIQx ) , 2 - Amino - 3 , 4 , 8 - trimethyl - 3H - imidazo [ 4 , 5 - f ] quinoxaline ( 4 , 8 - DiMeIQx ) and 2 - Amino - 3 - methyl - 3H - imidazo [ 4 , 5 - f ] quinoline ( IQ ) . HAAs exert genotoxic activity after metabolic transformation by CYP1A enzymes , that is well characterized , however the genomic and intervening responses are not well explored . We have examined cellular and genomic responses of human hepatoma HepG2 cells after 24h exposure to HAAs . Comet assay revealed increase in formation of DNA strand breaks by PhIP , MeIQx and IQ but not 4 , 8 - DiMeIQx , whereas increased formation of micronuclei was not observed . The four HAAs up - regulated expression of genes encoding metabolic enzymes P04798 , P05177 and P22309 and expression of P04637 and its downstream regulated genes P38936 , GADD45α and Q07812 . Consistent with the up - regulation of P38936 and GADD45α the cell - cycle analysis showed arrest in S - phase by PhIP and IQ , and in P55008 - phase by 4 , 8 - DiMeIQx and MeIQx . The results indicate that upon exposure to HAAs the cells respond with the cell - cycle arrest , which enables cells to repair the damage or eliminate them by apoptosis . However , elevated expression of P10415 and down - regulation of Q07812 may indicate that HAAs could suppress apoptosis meaning higher probability of damaged cells to survive and mutate .",
"Selective inhibition of histone deacetylase 6 ( Q9UBN7 ) induces DNA damage and sensitizes transformed cells to anticancer agents . Q9UBN7 ( Q9UBN7 ) is structurally and functionally unique among the 11 human zinc - dependent histone deacetylases . Here we show that chemical inhibition with the Q9UBN7 - selective inhibitor tubacin significantly enhances cell death induced by the topoisomerase II inhibitors etoposide and doxorubicin and the pan - HDAC inhibitor ___MASK36___ ( vorinostat ) in transformed cells ( LNCaP , MCF - 7 ) , an effect not observed in normal cells ( human foreskin fibroblast cells ) . The inactive analogue of tubacin , nil - tubacin , does not sensitize transformed cells to these anticancer agents . Further , we show that down - regulation of Q9UBN7 expression by shRNA in LNCaP cells enhances cell death induced by etoposide , doxorubicin , and ___MASK36___ . Tubacin in combination with ___MASK36___ or etoposide is more potent than either drug alone in activating the intrinsic apoptotic pathway in transformed cells , as evidenced by an increase in PARP cleavage and partial inhibition of this effect by the pan - caspase inhibitor Z - VAD - fmk . Q9UBN7 inhibition with tubacin induces the accumulation of γ P16104 , an early marker of DNA double - strand breaks . Tubacin enhances DNA damage induced by etoposide or ___MASK36___ as indicated by increased accumulation of γ P16104 and activation of the checkpoint kinase Chk2 . Tubacin induces the expression of P35638 ( P35638 / P35638 ) , a transcription factor up - regulated in response to cellular stress . P35638 induction is further increased when tubacin is combined with ___MASK36___ . These findings point to mechanisms by which Q9UBN7 - selective inhibition can enhance the efficacy of certain anti - cancer agents in transformed cells .",
"Stress response genes are suppressed in mouse preimplantation embryos by granulocyte - macrophage colony - stimulating factor ( GM - P04141 ) . BACKGROUND : P04141 ( GM - P04141 ) is known to promote the development and survival of human and mouse preimplantation embryos ; however , the mechanism of action of GM - P04141 in embryos is not defined . METHODS : Mouse blastocysts were cultured from zygote stage in vitro with and without recombinant mouse GM - P04141 ( rmGM - P04141 ) , and in vivo developed blastocysts were flushed from Csf2 null mutant and wild - type mice . The effect of GM - P04141 on blastocyst expression of stress response and apoptosis genes was evaluated by microarray , qPCR and immunochemistry . RESULTS : Microarray analysis of the gene transcription profile showed suppression of stress response and apoptosis gene pathways in blastocysts exposed to rmGM - P04141 in vitro . qPCR analysis confirmed that rmGM - P04141 inhibited expression of heat shock protein ( HSP ) and apoptosis pathway genes Cbl , Hspa5 , Hsp90aa1 , Hsp90ab1 and Gas5 in in vitro blastocysts . Immunocytochemical analysis of HSP 1 ( P0DMV8 / 1B ; HSP70 ) , Q07812 , P10415 and TRP53 ( p53 ) in in vitro blastocysts showed that P0DMV8 / 1B and P10415 proteins were less abundant when embryos were cultured with rmGM - P04141 . Q07812 and TRP53 were unchanged at the protein level , but Bax mRNA expression was reduced after GM - P04141 treatment . In in vivo developed blastocysts , Csf2 null mutation caused elevated expression of Hsph1 but not other stress response genes . CONCLUSIONS : We conclude that GM - P04141 inhibits the cellular stress response and apoptosis pathways to facilitate embryo growth and survival , and the protective effects of GM - P04141 are particularly evident in in vitro culture media , whereas in vivo other cytokines can partly compensate for absence of GM - P04141 .",
"Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia . Mutations in microsomal triglyceride transfer protein ( P55157 ) cause abetalipoproteinemia ( P00519 ) , characterized by the absence of plasma apoB - containing lipoproteins . In this study , we characterized the effects of various P55157 missense mutations found in P00519 patients with respect to their expression , subcellular location , and interaction with protein disulfide isomerase ( P07237 ) . In addition , we characterized functional properties by analyzing phospholipid and triglyceride transfer activities and studied their ability to support apoB secretion . All the mutants colocalized with calnexin and interacted with P07237 . We found that R540H and N780Y , known to be deficient in triglyceride transfer activity , also lacked phospholipid transfer activity . Novel mutants S590I and G746E did not transfer triglycerides and phospholipids and did not assist in apoB secretion . In contrast , D384A displayed both triglyceride and phospholipid transfer activities and supported apoB secretion . These studies point out that P00519 is associated with the absence of both triglyceride and phospholipid transfer activities in P55157 .",
"Identification of an acetylation - dependant P12956 / FLIP complex that regulates FLIP expression and HDAC inhibitor - induced apoptosis . FLIP is a potential anti - cancer therapeutic target that inhibits apoptosis by blocking caspase 8 activation by death receptors . We report a novel interaction between FLIP and the DNA repair protein P12956 that regulates FLIP protein stability by inhibiting its polyubiquitination . Furthermore , we found that the histone deacetylase ( HDAC ) inhibitor ___MASK36___ ( ___MASK36___ ) enhances the acetylation of P12956 , thereby disrupting the FLIP / P12956 complex and triggering FLIP polyubiquitination and degradation by the proteasome . Using in vitro and in vivo colorectal cancer models , we further demonstrated that ___MASK36___ - induced apoptosis is dependant on FLIP downregulation and caspase 8 activation . In addition , an Q9UBN7 - specific inhibitor Tubacin recapitulated the effects of ___MASK36___ , suggesting that Q9UBN7 is a key regulator of P12956 acetylation and FLIP protein stability . Thus , HDAC inhibitors with anti - Q9UBN7 activity act as efficient post - transcriptional suppressors of FLIP expression and may , therefore , effectively act as ' FLIP inhibitors ' .",
"Biological differences between in vitro produced bovine embryos and parthenotes . Parthenotes may represent an alternate ethical source of stem cells , once biological differences between parthenotes and embryos can be understood . In this study , we analyzed development , trophectoderm ( TE ) differentiation , apoptosis / necrosis , and ploidy in parthenotes and in vitro produced bovine embryos . Subsequently , using real - time PCR , we analyzed the expression of genes expected to underlie the observed differences at the blastocyst stage . In vitro matured oocytes were either fertilized or activated with ionomycin + 6 - DMAP and cultured in simple medium . Parthenotes showed enhanced blastocyst development and diploidy and reduced TE cell counts . Apoptotic and necrotic indexes did not vary , but parthenotes evidenced a higher relative proportion of apoptotic cells between inner cell mass and TE . The pluripotence - related Q01860 and the methylation Q9Y6K1 genes were downregulated in parthenotes . Among pregnancy recognition genes , TP - 1 was upregulated in parthenotes , while O00264 and PLAC8 did not change . Expression of p66 ( shc ) and Q07812 / P10415 ratio were higher , and p53 lower , in parthenotes . Among metabolism genes , P11166 was downregulated , while P15121 , P35354 , O95479 , and P10599 were upregulated in parthenotes , and P22732 did not differ . Among genes involved in compaction / blastulation , P17302 was downregulated in parthenotes , but no differences were detected within P05023 and CDH1 . Within parthenotes , the expression levels of P11166 , TP - 1 , and O95479 , and possibly P15121 , resemble patterns described in female embryos . The pro - apoptotic profile is more pronounced in parthenotes than in embryos , which may differ in their way to channel apoptotic stimuli , through p66 ( shc ) and p53 respectively , and in their mechanisms to control pluripotency and de novo methylation .",
"Tau hyperphosphorylation and increased P56817 and RAGE levels in the cortex of PPARβ / δ - null mice . The role of peroxisome proliferator activator receptor ( Q07869 ) β / δ in the pathogenesis of Alzheimer ' s disease has only recently been explored through the use of PPARβ / δ agonists . Here we evaluated the effects of PPARβ / δ deficiency on the amyloidogenic pathway and tau hyperphosphorylation . PPARβ / δ - null mice showed cognitive impairment in the object recognition task , accompanied by enhanced DNA - binding activity of NF - κB in the cortex and increased expression of P05231 . In addition , two NF - κB - target genes involved in β - amyloid ( Aβ ) synthesis and deposition , the β site P05067 cleaving enzyme 1 ( Bace1 ) and the receptor for advanced glycation endproducts ( Rage ) , respectively , increased in PPARβ / δ - null mice compared to wild type animals . The protein levels of glial fibrillary acidic protein ( P14136 ) increased in the cortex of PPARβ / δ - null mice , which would suggest the presence of astrogliosis . Finally , tau hyperphosphorylation at Ser199 and enhanced levels of P10636 were associated with increased levels of the tau kinases Q00535 and phospho - P27361 / 2 in the cortex of PPARβ / δ (-/-) mice . Collectively , our findings indicate that PPARβ / δ deficiency results in cognitive impairment associated with enhanced inflammation , astrogliosis and tau hyperphosphorylation in the cortex .",
"Inhibition of histamine H1 receptor activity modulates proinflammatory cytokine production of dendritic cells through c - Rel activity . BACKGROUND : DB11320 exerts diverse effects on immune regulation through four types of histamine receptors ( HRs ) . Among them , type 1 receptor ( P35367 ) plays an important role in allergic inflammation . Dendritic cells ( DCs ) , which express at least three types of HRs , are professional antigen - presenting cells controlling the development of allergic inflammation . However , the molecular mechanisms involved in P35367 - mediated NF - ĸB signaling of DCs remain poorly defined . METHODS : Bone - marrow ( BM ) - derived DCs ( BM - DCs ) were treated with P35367 inverse agonists to interrupt basal P35367 - mediated signaling . The crosstalk of P35367 - mediated signaling and the NF - ĸB pathway was examined by NF - ĸB cellular activity using a luciferase reporter assay , NF - ĸB subunit analysis using Western blotting and P01375 - α promoter activity using chromatin immunoprecipitation . RESULTS : Blockage of P35367 signaling by inverse agonists significantly inhibited P01375 - α and P05231 production of BM - DCs . P35367 - specific agonists were able to enhance P01375 - α production , but this overexpression was significantly inhibited by NF - ĸB inhibitor . The P35367 inverse agonist ketotifen also suppressed cellular NF - ĸB activity , suggesting crosstalk between P35367 and NF - ĸB signaling in DCs . After comprehensive analysis of NF - ĸB subunits , c - Rel protein expression was significantly down - regulated in ketotifen - treated BM - DCs , which led to inhibition of the promoter activity of P01375 - α . Finally , adoptive transfer of the ketotifen - treated BM - DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo . CONCLUSIONS : Our results suggest that c - Rel controls P35367 - mediated proinflammatory cytokine production in DCs . This study provides a potential mechanism of P35367 - mediated signaling and NF - ĸB pathway crosstalk in allergic inflammation .",
"Linkage of cytokine genes to rheumatoid arthritis . Evidence of genetic heterogeneity . OBJECTIVE : To investigate linkage of candidate disease susceptibility genes to rheumatoid arthritis ( RA ) in affected sibling pair families stratified for specific clinical features . METHOD : Two hundred RA affected sibling pair families were genotyped for informative microsatellite markers mapping within or less than 3cM from : P27352 alpha , P27352 gamma , P27352 beta , IL1 alpha , IL1 beta , P14778 , P60568 , P05231 , Q01344 , IL8R , P10415 , P29965 , NOS3 , P49279 , alpha 1 anti - trypsin , and alpha 1 anti - chymotrypsin , using fluorescence based automated technology . Linkage was examined by defining allele sharing sibling pairs . This was assessed by maximum likelihood - inheritance by descent methods . RESULTS : An increase in allele sharing was seen for Q01344 in female sibling pairs ( LOD 0 . 91 , p = 0 . 03 ) , for P27352 gamma in sibling pairs with an affected male ( LOD 0 . 96 , p = 0 . 03 ) and most significantly for P60568 in sibling pairs where one or both were persistently seronegative ( LOD 1 . 05 , p = 0 . 02 ) . CONCLUSION : Weak evidence of linkage of RA to Q01344 , IFN gamma , and P60568 has been detected in clinical subsets of sibling pairs suggesting that RA is a genetically heterogeneous disease .",
"P00734 in normal human cerebrospinal fluid originates from the blood . In spite of the fact that prothrombin is produced by cells within the central nervous system , its presence in the cerebrospinal fluid ( P04141 ) has not been investigated . We determined the concentration of prothrombin in P04141 with reference to the concentration in plasma in paired samples from 18 \" normal \" control patients and 4 patients with relapsing - remitting type of multiple sclerosis ( MS ) . The newly developed ELISA was very specific ( no cross - reactivity with thrombin ) and sensitive ( detection limit -- 0 . 7 ng / ml ) with an imprecision of CV = 8 . 3 % ( intraseries ) and 7 . 0 % ( interassay ) . The mean prothrombin concentration in normal P04141 was 0 . 55 mg / l ( CV +/- 33 % , range : 0 . 28 - 0 . 93 mg / l ) , in normal plasma 121 . 8 mg / l +/- 21 % , resulting in a mean P04141 / plasma concentration quotient ( Q ( Proth ) -- 4 . 5 x 10 (- 3 ) ( CV +/- 35 % , range : 2 . 1 - 8 . 3 x 10 (- 3 ) ) corresponding to a mean albumin quotient in this group of subjects of Q ( Alb ) = 5 . 8 x 10 (- 3 ) . Due to the Q ( Proth ) and the molecular weight of prothrombin ( 72 kDa ) -- similar to that of albumin -- we conclude that prothrombin in normal human P04141 originates predominantly ( > 95 % ) from blood . The enzymatic activity in P04141 is conserved . Comparable results obtained in MS patients with only few small Q9BWK5 lesions suggest that local chronic inflammatory disease of the central nervous system does not influence prothrombin concentration in the P04141 if the blood - P04141 barrier function is normal .",
"c - P05412 promotes P11274 - P00519 - induced lymphoid leukemia by inhibiting methylation of the 5 ' region of Cdk6 . The transcription factor c - P05412 and its upstream kinase P45983 have been implicated in P11274 - P00519 - induced leukemogenesis . P45983 has been shown to regulate P10415 expression , thereby altering leukemogenesis , but the impact of c - P05412 remained unclear . In this study , we show that P45983 and c - P05412 promote leukemogenesis via separate pathways , because lack of c - P05412 impairs proliferation of p185 ( P11274 - P00519 )- transformed cells without affecting their viability . The decreased proliferation of c - Jun ( Δ / Δ ) cells is associated with the loss of cyclin - dependent kinase 6 ( Q00534 ) expression . In c - Jun ( Δ / Δ ) cells , Q00534 expression becomes down - regulated upon P11274 - P00519 - induced transformation , which correlates with CpG island methylation within the 5 ' region of Cdk6 . We verified the impact of Cdk6 deficiency using Cdk6 (-/-) mice that developed P11274 - P00519 - induced B - lymphoid leukemia with significantly increased latency and an attenuated disease phenotype . In addition , we show that reexpression of Q00534 in P11274 - P00519 - transformed c - Jun ( Δ / Δ ) cells reconstitutes proliferation and tumor formation in Nu / Nu mice . In summary , our study reveals a novel function for the activating protein 1 ( AP - 1 ) transcription factor c - P05412 in leukemogenesis by antagonizing promoter methylation . Moreover , we identify Q00534 as relevant and critical target of AP - 1 - regulated DNA methylation on P11274 - P00519 - induced transformation , thereby accelerating leukemogenesis .",
"Beyond statins : new lipid lowering strategies to reduce cardiovascular risk . Statins are the first - line therapy in LDL - DB04540 ( LDL - C ) reduction and its clinical use has contributed to significant prevention and treatment of atherosclerotic vascular disease . Yet , a significant proportion of patients remain at high risk . Recently , a number of new therapies have been developed to further lower LDL - C . These agents may provide clinical benefit on top of statin therapy in patients with high residual risk , severe hypercholesterolemia or as an alternative for patients who are intolerant to statins . We review four novel approaches based on the inhibition of proprotein convertase subtilisin / kexin type 9 ( Q8NBP7 ) , apolipoprotein - B100 ( apoB ) , Cholesteryl ester transport protein ( P11597 ) and microsomal triglyceride transfer protein ( P55157 ) . ApoB and P55157 inhibitors ( DB05528 and ___MASK40___ ) are indicated only for homozygous familial hypercholesterolemia patients . The results of ongoing trials with P11597 and Q8NBP7 inhibitors may warrant a wider employment in different categories of patients at high risk for cardiovascular disease .",
"An acidic pH environment increases cell death and pro - inflammatory cytokine release in osteoblasts : the involvement of Q07812 inhibitor - 1 . Q07812 Inhibitor - 1 ( P55061 ) , a transmembrane protein on the endoplasmic reticulum , has been studied previously in various physio / pathological conditions , but not in bone cells . In this study , using the MG63 osteoblast cell line and osteoblasts differentiated from stem cells , the role of P55061 was studied . First , expression of P55061 was confirmed in osteoblasts , as well as osteoclasts , in mouse tibiae bone immunohistochemistry . For evaluation of a recently published property of P55061 , an acidic pH - dependent Ca² ⁺ channel - like effect in osteoblasts , acidic pH - associated cell death , and pro - inflammatory cytokine release were examined . In MG63 osteoblasts , acidic pH induced a pH - dependent increase in cell death and ER stress , as determined by elevated expression of P11021 , P35638 , phospho - eIF2α , IRE - 1α , spliced P17861 , and phospho - JNK . In osteoblasts , mitochondrial Ca² ⁺ also showed a strong pH - dependent increase . P55061 knock - down using siRNA protected cells against acidic pH , regulating mitochondrial Ca² ⁺ accumulation , possibly via the acidic pH - dependent Ca² ⁺ channel - like effect of P55061 . P55061 knock - down also resulted in inhibition of acidic pH - induced release of pro - inflammatory cytokines , including IL - 1β , P05231 , and P01375 - α . In addition , bone marrow stem cells were differentiated into human osteoblasts , which showed increased expression of P55061 mRNA and protein . In differentiated primary human osteoblasts , acidic pH - associated cell death , mitochondrial Ca² ⁺ accumulation , and pro - inflammatory cytokine release were more significant than in non - differentiated stem cells . In summary , endogenous expression of P55061 is associated with acidic pH - induced Ca² ⁺ release , cell death , and pro - inflammatory cytokine release in human osteoblasts .",
"Investigation of the binding of isoform - selective inhibitors to prostaglandin endoperoxide synthases using fluorescence spectroscopy . Prostaglandin endoperoxide synthase ( PGHS ) is a heme protein that catalyzes the committed step in prostaglandin and thromboxane biosynthesis . Two isoforms of PGHS exist , a constitutive form termed P23219 and an inducible form termed P35354 . We report here fluorescence resonance energy transfer analysis of isoform - selective inhibitors interacting with P23219 and P35354 . By measuring fluorescence quenching due to the energy transfer of the inhibitor fluorescence to the heme prosthetic group of PGHS , we determined these inhibitors bind in the arachidonic acid substrate access channel with an R0 of 35 A for P23219 with the P23219 inhibitor and an R0 of 21 A for P35354 with the P35354 inhibitor . The observed fluorescence quenching is completely dynamic and dominated by quenching by the heme . Time - resolved results combined with molecular modeling determine the distance from the inhibitor to the heme moiety to be 20 A in P23219 and 18 A in P35354 . Preliminary stopped - flow kinetic studies reveal that the rate of quenching is limited by a first - order protein transition , which is slow , and that bound inhibitor undergoes rapid exchange .",
"JTT - 705 blocks cell proliferation and angiogenesis through p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways . The excessive proliferation and migration of vascular smooth muscle cells ( SMCs ) participate in the growth and instability of atherosclerotic plaque . We examined the direct role of a newly developed chemical inhibitor of cholesteryl ester transfer protein , JTT - 705 , on SMC proliferation and angiogenesis in endothelial cells ( ECs ) . JTT - 705 inhibited human coronary artery SMC proliferation . JTT - 705 induced the phosphorylation of p38 mitogen - activated protein kinase ( MAPK ) and extracellular - signal - regulated kinases ( P29323 ) in SMCs . In addition , the anti - proliferative effects of JTT - 705 in SMCs were blocked by p38 MAPK inhibitor . JTT - 705 induced the upregulation of p - P38936 ( waf1 ) , and this effect was blocked by dominant - negative Ras ( N17 ) , but not by inhibitors of p38 MAPK or P29323 . In addition , JTT - 705 also induced the upregulation of p27 ( kip1 ) , and this effect was blocked by p38 MAPK inhibitor . Interestingly , culture medium from JTT - 705 - treated SMCs blocked human coronary artery EC tube formation in an in vitro model of angiogenesis indirectly via a decrease in vascular endothelial growth factor ( P15692 ) from SMCs and directly via an anti - proliferative effect in ECs . JTT - 705 blocked the proliferation of SMCs through the activation of p38 kinase / p27 ( kip1 ) and Ras / P38936 ( waf1 ) pathways , and simultaneously blocked EC tube formation associated with a decrease in P15692 production from SMCs and an anti - proliferative effect in ECs . Our results indicate that JTT - 705 may induce a direct anti - atherogenic effect in addition to its inhibitory effect of P11597 activity .",
"Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration . BACKGROUND : Mutations in the progranulin gene ( PGRN ) were identified as the causal mechanism underlying frontotemporal lobar degeneration ( FTLD ) . Most of these mutations are predicted to create null alleles leading to a 50 % loss of progranulin transcript . METHODS : Patients underwent clinical and neurologic examination at the Memory Clinic of the IRCCS S . Giovanni di Dio - Fatebenefratelli , Brescia , Italy . We enrolled affected ( n = 6 ) and unaffected at risk members ( n = 73 ) of families carrying the FTLD associated progranulin Leu271LeufsX10 mutation ; additionally , we included subjects affected by sporadic / familial FTLD ( n = 65 ) , controls ( n = 75 ) , and a family carrying the tau P301L mutation . The presence of mutations in PGRN and P10636 genes was investigated by direct sequencing of exonic and flanking intronic regions . Progranulin plasma and P04141 levels were measured using ELISA . RESULTS : We demonstrated that progranulin protein is strongly reduced ( up to 3 . 93 - fold ) both in plasma and P04141 of affected and unaffected subjects carrying mutations in progranulin gene ( PGRN Leu271LeufsX10 and Q341X ) . We established a plasma progranulin protein cutoff level of 74 . 4 ng / mL that identifies , with specificity and sensitivity of 100 % , mutation carriers among unaffected subjects . In FTLD , values < or = 110 . 9 ng / mL give a specificity of 92 . 8 % and a sensitivity of 100 % for PGRN mutations . CONCLUSIONS : We propose the dosage of plasma progranulin as a useful tool for a quick and inexpensive large - scale screening of carriers of progranulin mutations and for monitoring future treatments that might boost the level of this protein .",
"Modification of alternative messenger RNA splicing of fibroblast growth factor receptors in human cardiac allografts during rejection . Accelerated coronary atherosclerosis in cardiac transplants ( cardiac allograft vasculopathy , Q03135 ) is characterized by coronary intimal hyperplasia . P05230 ( P05230 ) is a potent mitogen for vascular smooth muscle cells and endothelial cells , and its expression is increased in cardiac allografts , suggesting it may play a role in the pathogenesis of Q03135 . The activity of P05230 is dependent on binding to transmembrane receptors . To investigate whether receptors for P05230 are also induced after transplantation , polymerase chain reaction , in situ hybridization , and immunohistochemistry were used to analyze expression of four receptors for P05230 ( P11362 - P22455 ) . Expression of mRNA encoding extracellular immunoglobulin - like domains of P11362 was increased 35 - fold in cardiac allografts compared with normal hearts and was predominantly present in cardiac myocytes and vascular structures . Alternatively spliced mRNA that encodes transmembrane forms of P11362 , which contain the signal - transducing tyrosine kinase domains , was induced in allografts during rejection , in infiltrating cells , vascular structures , and myocytes . In vitro experiments showed that differential expression of FGF receptor isoforms was induced by P05230 , and also by P05231 and TGF - beta , which are expressed in cardiac allografts during rejection . The results show that expression of both P05230 and its receptors is altered in cardiac allografts and suggest that these events are important in the pathogenesis of Q03135 .",
"[ Signal transduction inhibitor -- STI571 -- a new treatment for chronic myeloid leukemia ( CML ) , which opens a new targeted approach to cancer therapy ] . Chronic myeloid leukemia ( CML ) , in most of the cases , is the molecular consequence of the t ( 9 , 22 ) translocation , resulting in the Philadelphia ( Ph ) chromosome and the creation of the fusion gene P11274 - P00519 . The fusion gene is translated to the protooncogen P11274 - P00519 , a constitutively activated tyrosine kinase that is linked to the malignant transformation . Thus , this tyrosine kinase became an attractive target for drug design . The development of the novel investigational drug ___MASK38___ is based on its potent and selective ability to inhibit this fusion tyrosine kinase . In preclinical studies , ___MASK38___ selectively inhibited the growth of CML cells that carry the Ph chromosome . In this review we discuss the drug development and design , its mechanism of action , the preclinical studies and the results of phase I and II clinical trials .",
"Assessment of Alzheimer ' s disease case - control associations using family - based methods . The genetics of Alzheimer ' s disease ( AD ) is heterogeneous and remains only ill - defined . We have recently created a freely available and continuously updated online database ( AlzGene ; http :// www . alzgene . org ) for which we collect all published genetic association studies in AD and perform systematic meta - analyses on all polymorphisms with sufficient genotype data . In this study , we tested 27 genes ( P12821 , P23560 , O95992 , P17787 , P01034 , P07339 , P53355 , Q9UBC7 , hCG2039140 , P01584 , P02545 , LOC439999 , LOC651924 , P10636 , P42898 , Q9UKX3 , P35558 , Q96JS3 , PRNP , P49768 , Q8WY21 , Q92673 , TF , Q00059 , Q13470 , GWA_14q32 . 13 , and GWA_7p15 . 2 ) , all showing significant association with AD risk in the AlzGene meta - analyses , in a large collection of family - based samples comprised of 4 , 180 subjects from over 1 , 300 pedigrees . Overall , we observe significant association with risk for AD and polymorphisms in P12821 , P17787 , TF , and an as yet uncharacterized locus on chromosome 7p15 . 2 [ rs1859849 ] . For all four loci , the association was observed with the same alleles as in the AlzGene meta - analyses . The convergence of case - control and family - based findings suggests that these loci currently represent the most promising AD gene candidates . Further fine - mapping and functional analyses are warranted to elucidate the potential biochemical mechanisms and epidemiological relevance of these genes .",
"Methylation of the nonhomologous end joining repair pathway genes does not explain the increase of translocations with aging . Chromosome translocations are especially frequent in human lymphomas and leukemias but are insufficient to drive carcinogenesis . Indeed , several of the so - called tumor specific translocations have been detected in peripheral blood of healthy individuals , finding a higher frequency of some of them with aging . The inappropriate repair of DNA double strand breaks by the nonhomologous end joining ( NHEJ ) pathway is one of the reasons for a translocation to occur . Moreover , fidelity of this pathway has been shown to decline with age . Although the mechanism underlying this inefficacy is unknown , other repair pathways are inactivated by methylation with aging . In this study , we analyzed the implication of NHEJ genes methylation in the increase of translocations with the age . To this aim , we determined the relationship between translocations and aging in 565 Spanish healthy individuals and correlated these data with the methylation status of 11 NHEJ genes . We found higher frequency of P10415 - JH and P11274 - P00519 ( major ) translocations with aging . In addition , we detected that two NHEJ genes ( P49917 and P12956 ) presented age - dependent promoter methylation changes . However , we did not observe a correlation between the increase of translocations and methylation , indicating that other molecular mechanisms are involved in the loss of NHEJ fidelity with aging .",
"Interaction of tacrolimus ( FK506 ) and its metabolites with FKBP and calcineurin . ___MASK97___ ( FK506 ) is a strong immuno - suppressant and shows its activity through inhibiting P60568 mRNA transcription by forming pentameric complex with intracellular receptor ( FK506 binding protein 12 kDa or P62942 ) , Ca2 + , calmodulin , and calcineurin . Here , we report the binding activity to P62942 , the pentameric complex formation and Con - A response inhibiting activities of 7 metabolites . C15 - demethylated metabolite ( M - 3 ) needed higher quantity to compete in Con - A assay and in pentamer formation assay , although it binds more strongly to P62942 . The result suggests that the ability to form a pentameric complex is not a two step reaction with the first binding to P62942 , but a single step reaction by components for the pentamer formation ."
] |
[
"___MASK1___",
"___MASK25___",
"___MASK36___",
"___MASK38___",
"___MASK40___",
"___MASK49___",
"___MASK53___",
"___MASK65___",
"___MASK97___"
] |
___MASK97___
|
MH_train_496
|
interacts_with DB01022?
|
[
"Comparison of the novel antipsychotic ziprasidone with clozapine and olanzapine : inhibition of dorsal raphe cell firing and the role of P08908 receptor activation . Ziprasidone is a novel antipsychotic agent which binds with high affinity to P08908 receptors ( Ki = 3 . 4 nM ) , in addition to P28221 , 5 - HT2 , and D2 sites . While it is an antagonist at these latter receptors , ziprasidone behaves as a P08908 agonist in vitro in adenylate cyclase measurements . The goal of the present study was to examine the P08908 properties of ziprasidone in vivo using as a marker of central P08908 activity the inhibition of firing of serotonin - containing neurons in the dorsal raphe nucleus . In anesthetized rats , ziprasidone dose - dependently slowed raphe unit activity ( ED50 = 300 micrograms / kg i . v . ) as did the atypical antipsychotics clozapine ( ED50 = 250 micrograms / kg i . v . ) and olanzapine ( ED50 = 1000 micrograms / kg i . v . ) . Pretreatment with the P08908 antagonist WAY - 100 , 635 ( 10 micrograms / kg i . v . ) prevented the ziprasidone - induced inhibition ; the same dose of WAY - 100 , 635 had little effect on the inhibition produced by clozapine and olanzapine . Because all three agents also bind to alpha 1 receptors , antagonists of which inhibit serotonin neuronal firing , this aspect of their pharmacology was assessed with desipramine ( ___MASK78___ ) , a NE re - uptake blocker previously shown to reverse the effects of alpha 1 antagonists on raphe unit activity . ___MASK78___ ( 5 mg / kg i . v . ) failed to reverse the inhibitory effect of ziprasidone but produced nearly complete reversal of that of clozapine and olanzapine . These profiles suggest a mechanism of action for each agent , P08908 agonism for ziprasidone and alpha 1 antagonism for clozapine and olanzapine . The P08908 agonist activity reported here clearly distinguishes ziprasidone from currently available antipsychotic agents and suggests that this property may play a significant role in its pharmacologic actions .",
"___MASK50___ for the treatment of primary myelofibrosis . PURPOSE : The pharmacology , pharmacokinetics , pharmacogenomics , clinical efficacy , and safety profile of ruxolitinib for the treatment of primary myelofibrosis are reviewed . SUMMARY : ___MASK50___ , an oral tyrosine kinase inhibitor that targets the Janus - associated kinases ( JAKs ) 1 and 2 , has been recently approved for the treatment of patients with intermediate - or high - risk myelofibrosis . Unlike previous treatment options for patients with myelofibrosis , ruxolitinib offers a targeted therapy option for these patients who often suffer with severe and debilitating symptoms associated with the disease process . After oral administration , ruxolitinib is rapidly absorbed and can be given without regard to meals . ___MASK50___ is primarily metabolized by the cytochrome P - 450 ( CYP ) 3A4 isoenzyme system ; therefore , if concomitant use with a strong P08684 inhibitor is unavoidable , an initial dosage reduction is warranted . Two Phase III randomized trials comparing ruxolitinib to either placebo or best available therapy found a rapid and sustained response in the reduction of spleen size and improvements in constitutional symptoms and quality of life , with one study demonstrating an improvement in overall survival . The most commonly reported serious adverse effects of ruxolitinib are anemia and thrombocytopenia . ___MASK50___ is administered as an oral tablet given twice daily , with the initial starting dosage based on the baseline platelet count . Dosage reductions are based on the development of thrombocytopenia . CONCLUSION : By directly targeting both P23458 and O60674 through small - molecule inhibition , ruxolitinib elicits a reduction in splenomegaly and disease - related symptoms in patients with intermediate - or high - risk myelofibrosis while maintaining an acceptable toxicity profile and a low treatment - discontinuation rate .",
"[ Construction of mammalian cell expression vector for pAcGFP - bFADD fusion protein and its expression in CHO - P04264 cell ] . Fas - associated death domain ( Q13158 ) is a signal connection protein in Fas / P48023 apoptotic path which might play a key role on apoptosis by transferring apoptotic signal . To reveal the intracellular signal transduction molecules involved in the procedure of follicular development in bovine ovary , we cloned Q13158 gene in bovine ovary tissue with RT - PCR , deleted the termination codon in its cDNA and directionally cloned the amplified Q13158 gene into eukaryotic expression vector pAcGFP - N1 including AcGFP , successfully constructed the fusion protein recombinant plasmid . After identifying by restrictive enzyme Bgl II / EcoR I and sequencing , transfected pAcGFP - bFADD into CHO - P04264 cell mediated by Lipofectamine 2000 , observed the expression of AcGFP and detected the transcription and expression of Q13158 by RT - PCR and Western blotting . The results showed that the cattle Q13158 was successfully cloned , the pAcGFP - bFADD fusion protein recombinant plasmid was successfully constructed by introducing Bgl II , EcoR I cloning site at two ends of Q13158 open reading frame and inserting a Kozak sequence before start codon . AcGFP expression was detected as early as 24 h after transfection . The percentage of AcGFP positive cells reached about 65 % after 24 h . A 654 bp transcription was amplified by RT - PCR , and 51 . 4 kD target protein was detected by Western blotting . Construction of pAcGFP - bFADD recombinant plasmid should be helpful for further understanding the mechanism of regulation of Q13158 on bovine oocytes formation and development .",
"Agonist - promoted down - regulation and functional desensitization in two naturally occurring variants of the human serotonin1A receptor . We recently reported two naturally occurring polymorphisms of the human serotonin1A ( P08908 ) receptor : glycine22 --> serine ( Ser22 ) and isoleucine28 --> valine ( Val28 ) in the putative aminoterminal domain of the receptor . To investigate the regulatory properties of these variants , the wild type ( WT ) and variant P08908 receptors were stably expressed in CHO - P04264 cells . WT , Ser22 , and Val28 displayed similar high - affinity binding to [ 3H ] - 8 - OH - DPAT . Competition experiments with P08908 agonists and antagonists demonstrated similar pharmacological profiles . Receptor agonist - promoted down - regulation was tested by exposure to 100 mumol / L 8 - OH - DPAT . After 24 - h exposure , WT and Val28 underwent 59 . 3 +/- 3 . 9 % and 59 . 5 +/- 1 . 4 % reduction in receptor density respectively , whereas the degree of down - regulation was significantly lower for Ser22 ( 21 . 4 +/- 4 . 2 % ) . Cell treatment for 24 h with 100 mumol / L 8 - OH - DPAT reduced the 5 - HT - induced inhibition of DB02527 accumulation by 24 . 9 +/- 5 . 1 % for WT and 16 . 4 +/- 0 . 8 % for Val28 , but only by 4 . 8 +/- 3 % for Ser22 . We conclude that the Ser22 variant is capable of attenuating agonist - mediated receptor down - regulation and desensitization .",
"The revised human liver cytochrome P450 \" Pie \" : absolute protein quantification of CYP4F and CYP3A enzymes using targeted quantitative proteomics . The CYP4F subfamily of enzymes has been identified recently to be involved in the metabolism of endogenous compounds ( arachidonic acid and leukotriene B4 ) , nutrients ( vitamins P04264 and E ) , and xenobiotics ( pafuramidine and fingolimod ) . P78329 and CYP4F3B are reported to be expressed in the human liver . However , absolute concentrations of these enzymes in human liver microsomes ( HLMs ) and their interindividual variability have yet to be determined because of the lack of specific antibodies . Here , an liquid chromatography with tandem mass spectrometry ( LC - MS / MS ) - based targeted quantitative proteomic approach was employed to determine the absolute protein concentrations of P78329 and CYP4F3B compared with CYP3A in two panels of HLMs ( n = 31 ) . As a result , the human hepatic cytochrome P450 ( P450 ) \" pie \" has been revised to include the contribution of CYP4F enzymes , which amounts to 15 % of the total hepatic cytochrome P450 enzymes . CYP4F3B displayed low interindividual variability ( 3 . 3 - fold ) in the HLM panels whereas P78329 displayed large variability ( 21 - fold ) . However , P78329 variability decreased to 3 . 4 - fold if the two donors with the lowest expression were excluded . In contrast , CYP3A exhibited 29 - fold interindividual variability in the same HLM panels . The proposed marker reaction for CYP4F enzymes pafuramidine / DB289 M1 formation did not correlate with CYP4F protein content , suggesting alternate metabolic pathways for DB289 M1 formation in HLMs . In conclusion , CYP4F enzymes are highly expressed in the human liver and their physiologic and pharmacologic roles warrant further investigation .",
"Developmental expression of CLC - P04264 in the postnatal rat kidney . CLC - P04264 , a kidney - specific chloride channel , has been demonstrated to be involved in the urine concentration mechanism . Here , we investigated the developmental expression of CLC - P04264 in the rat kidney . Using immunohistochemistry , we showed that CLC - P04264 was not present in the thin ascending limb of Henle ' s loop during the early prenatal stages but was significantly expressed during the adult stage . CLC - P04264 started to appear at day 5 and its expression increased during further development . In developing rats this increase coincided with the increase in the urine - concentrating capacity as the animals matured . We also investigated the expressions of other channels and transporters , including Q13621 , P29972 , and P41181 . Q13621 was strongly expressed throughout the inner medulla in neonatal rat kidneys but was entirely undetectable at the adult stage . The decline in its expression took the form of a gradual recession from the inner medulla together with reciprocal increases in the expression of CLC - P04264 . P29972 was weakly expressed in the inner medulla during early development and showed a rapid increase in expression at a later stage . The collecting duct cells significantly expressed P41181 even at birth and maintained its expression throughout the development . These results suggest that CLC - P04264 expression is one of the major determinants of the urine - concentrating capacity of the developing rat kidney .",
"Genome - wide association study identifies genetic determinants of warfarin responsiveness for Japanese . ___MASK97___ is a commonly used anticoagulant , whose dose needs to be determined for each individual patient owing to large inter - individual variability in its therapeutic dose . Although several clinical and genetic variables influencing warfarin dose have been identified , uncovering additional factors are critically important for safer use of warfarin . Through a genome - wide association study , we identified single - nucleotide polymorphism ( SNP ) rs2108622 [ cytochrome P450 , family 4 , subfamily F , polypeptide 2 ( P78329 ) ] as a genetic determinant of warfarin responsiveness for Japanese . Stratifying subjects who have been pre - classified according to the genotypes of SNP rs10509680 [ cytochrome P450 , family 2 , subfamily C , polypeptide 9 ( P11712 ) ] and SNP rs9923231 [ vitamin K epoxide reductase complex subunit 1 ( Q9BQB6 ) ] , based on their genotypes of rs2108622 allowed identification of subjects who require higher dose of warfarin . Incorporating genotypes of rs2108622 into a warfarin dosing algorithm that considers age , body surface area , status of amiodarone co - administration and genotypes of SNPs in the P11712 and Q9BQB6 genes improved the model ' s predictability to 43 . 4 % . In this study , the association of P78329 with warfarin dose of the Japanese has been established for the first time . Besides , a warfarin dosing algorithm that incorporates genotypes of rs2108622 and amiodarone co - administration status was suggested for the Japanese . Our study also implied that common SNPs other than those in the P11712 , Q9BQB6 and P78329 genes that show strong effect on the therapeutic warfarin dose might not exist .",
"[ Measurement of rifampicin and clarithromycin in serum by high - performance liquid chromatography with electrochemical detection ] . DB01045 ( RFP ) induces hepatic drug - metabolizing enzymes , making drug interactions a very important clinical problem . ___MASK91___ ( P62158 ) metabolism is reportedly enhanced by induction of hepatic drug - metabolizing enzymes ( P08684 ) by RFP , so that the blood lend of P62158 decreases when RFP is administered concurrently . We connected an electrochemical detector to a high - performance liquid chromatograph ( HPLC ) for simple , rapid , easy measurement of blood concentrations of RFP and P62158 . Using samples of patient serum , normal serum , and reference standards , we compared HPLC by an external laboratory and the results of LC / MS / MS analysis with those of this new assay . A strong correlation was seen between our HPLC results and those of the external laboratory in RFP levels ( r = 0 . 975 , p < 0 . 01 ) . A strong correlation was also seen between results we obtained for P62158 with the electrochemical detector in this assay and values measured by LC / MS / MS analysis ( r = 0 . 995 , p < 0 . 01 ) . Our method enabled simple , rapid measurement of RFP and P62158 by connecting the HPLC and electrochemical detector in tandem . This system was used to modulate dosage during combined therapy with RFP and P62158 . The therapeutic effect for nontuberculous mycobacteriosis is expected to improve , and our HPLC is expected to be useful for simple , rapid , easy measurement of blood concentrations .",
"5 - Azacitidine restores and amplifies the bicalutamide response on preclinical models of androgen receptor expressing or deficient prostate tumors . BACKGROUND : Epigenetic modifications play a key role in the in prostate cancer ( Pca ) progression to a hormone refractory state ( HRPC ) and the current use of agents targeting epigenetic changes has become a topic of intense interest in cancer research . In this regard , 5 - Azacitine ( 5 - Aza ) represents a promising epigenetic modulator . This study tested the hypothesis that 5 - Aza may restore and enhance the responsiveness of HRPC cells to anti - hormonal therapy on P10275 ( AR ) expressing ( 22rv1 ) and AR - deficient ( PC3 ) cells . METHODS : The effects were studied in vitro and in vivo models . This sequential treatment induced in vitro cell cycle arrest and apoptosis both in 22rv1 and PC3 tumor cell lines . RESULTS : This combined treatment up - regulated the expression of P48023 , phospho - Q13158 , p16 ( INKA ) , Bax , Bak , and P38936 ( P38936 ) , and inhibited FLIP , Bcl - 2 , and Bcl - XL expression . The re - activation of hormonal response of AR - negative PC3 cell line was partially due to the AR re - expression mediated by 5 - Aza treatment . In contrast , the increase in the response to anti - androgenic therapy in 22rv1 did not correlate with AR expression levels . Furthermore , xenograft studies revealed that the combined treatment of 5 - Aza with AR - antagonist ___MASK4___ had additive / synergistic effects in repressing tumor growth in vivo and the underlying mechanisms responsible for these effects seem to be in part mediated by induction of apoptosis . CONCLUSIONS : So , this study strongly suggests a therapeutic potential of 5 - Aza in combination with anti - androgen therapy in patients with in AR expressing and AR - deficient HRPC .",
"Direct binding of recombinant plasminogen kringle 1 - 3 to angiogenin inhibits angiogenin - induced angiogenesis in the chick embryo P62158 . P03950 is one of the most potent angiogenesis - inducing proteins . Angiostatin is one of the most potent angiogenesis inhibitors , and it contains the first four kringle domains of plasminogen ( P04264 - 4 ) . Recombinant human plasminogen kringle 1 - 3 ( rK1 - 3 ) was expressed in Escherichia coli and purified to homogeneity . The binding of t - 4 - aminomethylcyclohexanecarboxylic acid with the purified kringle 1 - 3 was determined by changes in intrinsic fluorescence . rK1 - 3 exhibits comparable ligand - binding properties as native human plasminogen kringle 1 - 3 . The purified rK1 - 3 inhibits neovascularization in the chick embryo chorioallantoic membrane ( P62158 ) assay . Interaction of angiogenin with rK1 - 3 was examined by immunological binding assay and surface plasmon resonance kinetic analysis , and the equilibrium dissociation constants for the complex , Kd , are 0 . 89 and 0 . 18 microM , respectively . rK1 - 3 inhibits angiogenin - induced angiogenesis in the chick embryo P62158 in a concentration - dependent manner . These results indicate that rK1 - 3 directly binds to angiogenin and thus rK1 - 3 inhibits the angiogenic activity of angiogenin .",
"___MASK19___ inhibits osmotic water permeability by interaction with aquaporin - 1 . DB09145 channel proteins , known as aquaporins , are transmembrane proteins that mediate osmotic water permeability . In a previous study , we found that acetazolamide could inhibit osmotic water transportation across Xenopus oocytes by blocking the function of aquaporin - 1 ( P29972 ) . The purpose of the current study was to confirm the effect of acetazolamide on water osmotic permeability using the human embryonic kidney 293 ( HEK293 ) cells transfected with pEGFP / P29972 and to investigate the interaction between acetazolamide and P29972 . The fluorescence intensity of HEK293 cells transfected with pEGFP / P29972 , which corresponds to the cell volume when the cells swell in a hyposmotic solution , was recorded under confocal laser fluorescence microscopy . The osmotic water permeability was assessed by the change in the ratio of cell fluorescence to certain cell area . ___MASK19___ , at concentrations of 1 and 10muM , inhibited the osmotic water permeability in HEK293 cells transfected with pEGFP / P29972 . The direct binding between acetazolamide and P29972 was detected by surface plasmon resonance . P29972 was prepared from rat red blood cells and immobilized on a CM5 chip . The binding assay showed that acetazolamide could directly interact with P29972 . This study demonstrated that acetazolamide inhibited osmotic water permeability through interaction with P29972 .",
"Alcohols inhibit N - methyl - D - aspartate receptors via a site exposed to the extracellular environment . N - Methyl - D - aspartate ( DB01221 ) receptors are important CNS target sites of alcohols , but the site and mechanism of action of alcohols on DB01221 receptors remains unclear . In CHO - P04264 cells transfected with Q9UHB4 / Q13224 DB01221 receptor subunits , ethanol inhibited DB01221 - activated current with an IC ( 50 ) of 138 mM . Truncation of the intracellular C - terminal domain of the Q9UHB4 subunit ( NR1T ) did not alter ethanol sensitivity when combined with the Q13224 subunit , but a similar truncation of the Q13224 subunit ( NR2BT ) slightly enhanced ethanol sensitivity of receptors formed from coexpression with either Q9UHB4 or NR1T subunits . 1 - Pentanol applied externally inhibited DB01221 receptors with an IC ( 50 ) of 9 . 9 mM , but intracellular application of 1 - pentanol ( 25 mM ) did not alter DB01221 receptor inhibition by externally applied ethanol or 1 - pentanol . In addition , the amplitude of DB01221 - activated current did not decrease during the time required for 1 - pentanol ( 25 mM ) to diffuse throughout the cytoplasm . DB00898 did not inhibit DB01221 receptors when bath - applied in cell - attached patches or when applied to the cytoplasmic face of inside - out membrane patches . These results appear to be best explained by an action of alcohols on the DB01221 receptor - channel protein , at a site located in a domain exposed to , or only accessible from , the extracellular environment .",
"Characterization of a thyroiditis - inducing thyroglobulin - specific T - cell clone restricted by the H - 2 molecule of a low responder mouse strain . We established a thyroglobulin ( Tg ) - specific , thyroiditis - inducing T - cell clone , B12G , from B6C3F1 mice by the immunization of mouse Tg with lipopolysaccharide ( LPS ) from Klebsiella strain LEN ( O3 : P04264 ) . B12G was Thy - 1 . 2 + , CD3 + , P01730 + , P05107 + , and CD8 - , and could transfer thyroiditis to recipient mice after in vitro stimulation with mouse or bovine Tg . Histological examination showed severe thyroiditis with predominant infiltrations of polymorphonuclear cells ; few mononuclear cells were observed . B12G proliferated in response to bovine , mouse , porcine , and rat Tg in the presence of irradiated spleen cells , but did not respond to chicken or human Tg . H - 2b , a low - responder haplotype of experimental autoimmune thyroiditis , governed the response of the clone to Tg . B12G produced interleukin - 4 ( P05112 ) and P05231 , but not P60568 or interferon - gamma ( P01579 ) , on stimulation with mouse Tg . These findings were different from characteristics of previously reported Tg - specific T - cell clones from high - responder mice in terms of epitope specificity and cytokine production pattern , raising the possibility that the specificities and functions of T cells involved in the development of autoimmune thyroiditis in low - responder mice differ from those in high responders .",
"Release of cytokines by blood monocytes during strenuous exercise . During strenuous exercise in endurance athletes , monocytes are activated and there is an acute inflammation and hypoxemia possibly due to lesional pulmonary edema . P05231 and P01375 released by monocytes may be implicated in the acute phase of lesional pulmonary edema . A study was carried out to determine whether P01375 and P05231 are released during strenuous exercise , and , if adrenalin released during exercise alters their generation . Ten young and six master athletes underwent an incremental exercise test . Arterial blood was drawn at rest , at the end of the exercise , and 20 minutes afterwards . Monocytes were isolated and incubated for 18 hours in the presence or absence of adrenalin . Il - 6 and P01375 were measured in monocyte supernatants . The spontaneous release of P05231 or P01375 was increased in young athletes when compared to older subjects . The spontaneous release of P01375 was increased , but not significantly , by exercise and there was no correlation between the release of P05231 and P01375 and lung function measured during hypoxemia . ___MASK8___ inhibited the release of P05231 or P01375 . Correlations were observed between the in vitro release of P05231 or P01375 and age , VO2max , maximal ventilation and maximal power output of the subjects .",
"Serial changes in serum vitamin P04264 , triglyceride , cholesterol , osteocalcin and 25 - hydroxyvitamin D3 in patients after hip replacement for fractured neck of femur or osteoarthritis . Serum vitamin P04264 concentrations were measured at presentation ( just before surgery ) and then at weekly intervals for 3 weeks in two groups of elderly patients requiring either hemiarthroplasty for fractured neck of femur ( FON , n = 13 ) or total hip replacement for osteoarthritis of the hip ( OA , n = 16 ) . In comparison with healthy elderly volunteers ( n = 25 ) , serum vitamin P04264 concentrations were significantly lower in both groups at presentation , and fell significantly within 24 h after surgery to concentrations approaching non - detectable , subsequently returning to pre - operative values within 3 weeks . Serum vitamin P04264 tended to be lower in the fracture group both before and after operation , although calculation of a vitamin P04264 - triglyceride ratio reduced the apparent difference as triglyceride concentrations were lower in the fracture group . P02818 concentrations were similar and fell significantly after operation in both groups , returning to pre - operative levels within 7 days . No differences in the two forms of osteocalcin ( carboxylated and undercarboxylated ) were observed either before or after operation in either group . DB00146 concentrations were not significantly different between the two groups at any time . DB01022 status may be lower than desirable in certain groups of the elderly population , and supplementation should be considered as prophylactic therapy .",
"___MASK58___ induces neurotoxicity by the DB01221 receptor downstream signaling pathway , alternative from glutamate excitotoxicity . The DB01221 receptor is believed to be important in a wide range of nervous system functions including neuronal migration , synapse formation , learning and memory . In addition , it is involved in excitotoxic neuronal cell death that occurs in a variety of acute and chronic neurological disorders . Besides of agonist / coagonist sites , other modulator sites , including butyrophenone site may regulate the N - methyl - D - aspartate receptor . It has been shown that haloperidol , an antipsychotic neuroleptic drug , interacts with the Q13224 subunit of DB01221 receptor and inhibits DB01221 response in neuronal cells . We found that DB01221 receptor was co - immunoprecipitated by anti - Ras antibody and this complex , beside NR2 subunit of DB01221 receptor contained haloperidol - binding proteins , P29475 and Ras - P01286 . Furthermore , we have shown that haloperidol induces neurotoxicity of neuronal cells via DB01221 receptor complex , accompanied by dissociation of Ras - P01286 from membranes and activation of c - Jun - kinase . Inclusion of insulin prevented relocalization of Ras - P01286 and subsequent neuronal death . ___MASK58___ - induced dissociation of Ras - P01286 leads to inhibition of membrane - bound form of Ras protein and changes downstream regulators activity that results in the initiation of the apoptotic processes via the mitochondrial way . Our results suggest that haloperidol induces neuronal cell death by the interaction with DB01221 receptor , but through the alternative from glutamate excitotoxicity signaling pathway .",
"Q01094 - mediated transactivation is inhibited by complex formation with the retinoblastoma susceptibility gene product . Previous studies have shown that the carboxyl - terminal region of Q01094 ( residues 368 - 437 ) can support transcriptional activation when linked to the DNA - binding domain of the yeast transcription factor GAL4 . This region also contains an 18 - residue retinoblastoma ( RB ) - binding sequence , raising the possibility that RB binding might inhibit the ability of Q01094 to form protein - protein contacts required for activation . Here we report a further analysis of the Q01094 activation domain . In addition , we show that overexpression of RB , but not the RB mutant , RBd22 , can inhibit GAL4 / Q01094 activity in vivo . Moreover , expression of the simian virus 40 large tumor antigen ( T antigen ) , but not the RB - binding defective T antigen point mutant , P04264 , can overcome this repression . Three different GAL4 / Q01094 mutants that activate transcription , but fail to bind to RB , are not significantly affected by overexpression of RB . These findings support a model wherein RB suppresses Q01094 - mediated transcriptional activation through direct physical association .",
"P29323 , Akt , and P42229 are Differentially Activated by the Two Growth Hormone Receptor Subtypes of a Teleost Fish ( Oncorhynchus Mykiss ) . Previously , we found that the teleost fish , rainbow trout , possesses two growth hormone receptor ( P10912 ) subtypes that display distinct ligand - binding and agonist - induced regulation features . In this study , we used Chinese hamster ovary - P04264 cells stably transfected individually with the two trout P10912 subtypes , GHR1 and GHR2 , to elucidate receptor - effector pathway linkages . Growth hormone ( GH ) stimulated rapid ( 5 - 10 min ) phosphorylation of P29323 , Akt , JAk2 , and P42229 in both GHR1 - and GHR2 - expressing cells ; however ; P42229 was activated to a greater extent through GHR1 than through GHR2 , whereas P29323 and Akt were activated to a greater through GHR2 than through GHR1 . Although blockade of the P29323 pathway had no effect on the activation of Akt , inhibition of PI3K - Akt partially prevented activation of P29323 , suggesting cross - talk between the P29323 and PI3K - Akt pathways . O60674 inhibition completely blocked activation of P29323 , Akt , and P42229 , suggesting that all of these pathways link to GHR1 and GHR2 via O60674 . These findings establish important receptor - effector pathway linkages and suggest that the P10912 subtypes of teleost fish may be functionally distinct .",
"17 ___MASK73___ - mediated growth inhibition of MDA - MB - 468 cells stably transfected with the estrogen receptor : cell cycle effects . P03372 ( ER ) - negative MDA - MB - 468 human breast cancer cells were stably transfected with wild - type human ER and utilized as a model for investigating estrogen - and aryl hydrocarbon ( Ah ) - responsiveness . Treatment of the stably transfected cells with 10 nM 17 beta - estradiol ( E2 ) resulted in a significant inhibition ( > 60 % ) of cell proliferation and DNA synthesis , which was blocked by 10 (- 7 ) M ICI 182 780 . Analysis by flow cytometry indicated that treatment with E2 increased the percentage of cells in G0 / P55008 ( from 68 . 8 to 89 . 4 ) and decreased cells in S ( from 18 . 4 to 3 . 4 ) and G2 / M ( from 12 . 8 to 7 . 2 ) phases of the cell cycle . The effects of E2 on the major cyclins , cyclin - dependent kinases and cyclin - dependent kinase inhibitors , retinoblastoma protein ( RB ) , Q01094 , and cyclin - dependent kinase activities were also investigated in the stably transfected MDA - MB - 468 cells . The results demonstrated that the growth inhibitory effects of 10 (- 8 ) M E2 in ER stably transfected MDA - MB - 468 cells were associated with modulation of several factors required for cell cycle progression and DNA synthesis , including significant induction of the cyclin - dependent kinase inhibitor p21cip - 1 ( > 4 - fold increase after 12 h ) and decreased Q01094 and P12004 protein levels . These results show that the growth - inhibitory effects of E2 in the stably transfected cells were due to multiple factors which result in growth arrest in G0 / P55008 and inhibition of DNA synthesis ."
] |
[
"___MASK19___",
"___MASK4___",
"___MASK50___",
"___MASK58___",
"___MASK73___",
"___MASK78___",
"___MASK8___",
"___MASK91___",
"___MASK97___"
] |
___MASK97___
|
MH_train_497
|
interacts_with DB01235?
|
[
"Role of phospholipase D2 in the agonist - induced and constitutive endocytosis of G - protein coupled receptors . We have recently shown that the mu - opioid receptor [ P35372 , also termed mu - opioid peptide ( MOP ) receptor ] is associated with the phospholipase D2 ( O14939 ) , a phospholipid - specific phosphodiesterase located in the plasma membrane . We further demonstrated that , in human embryonic kidney ( P29320 ) 293 cells co - expressing P35372 and O14939 , treatment with ( D - Ala2 , Me Phe4 , Glyol5 ) enkephalin ( DAMGO ) led to an increase in O14939 activity and an induction of receptor endocytosis , whereas morphine , which does not induce opioid receptor endocytosis , failed to activate O14939 . In contrast , a C - terminal splice variant of the mu - opioid receptor ( MOR1D , also termed MOP ( 1D ) ) exhibited robust endocytosis in response to both DAMGO and morphine treatment . We report here that MOR1D also mediates an agonist - independent ( constitutive ) O14939 - activation facilitating agonist - induced and constitutive receptor endocytosis . Inhibition of O14939 activity by over - expression of a dominant negative O14939 ( nPLD2 ) blocked the constitutive O14939 activation and impaired the endocytosis of MOR1D receptors . Moreover , we provide evidence that the endocytotic trafficking of the delta - opioid receptor [ Q8IXH6 , also termed delta - opioid peptide ( DOP ) receptor ] and cannabinoid receptor isoform 1 ( P21554 ) is also mediated by a O14939 - dependent pathway . These data indicate the generally important role for O14939 in the regulation of agonist - dependent and agonist - independent G protein - coupled receptor ( GPCR ) endocytosis .",
"CXC chemokine receptor 4 expression and function in human astroglioma cells . Chemokines constitute a superfamily of proteins that function as chemoattractants and activators of leukocytes . Astrocytes , the major glial cell type in the CNS , are a source of chemokines within the diseased brain . Specifically , we have shown that primary human astrocytes and human astroglioma cell lines produce the CXC chemokines P01579 - inducible protein - 10 and P10145 and the CC chemokines monocyte chemoattractant protein - 1 and RANTES in response to stimuli such as P01375 , IL - 1beta , and P01579 . In this study , we investigated chemokine receptor expression and function on human astroglioma cells . Enhancement of CXC chemokine receptor 4 ( P61073 ) mRNA expression was observed upon treatment with the cytokines P01375 and IL - 1beta . The peak of P61073 expression in response to P01375 and IL - 1beta was 8 and 4 h , respectively . P61073 protein expression was also enhanced upon treatment with P01375 and IL - 1beta ( 2 - to 3 - fold ) . To study the functional relevance of P61073 expression , stable astroglioma transfectants expressing high levels of P61073 were generated . Stimulation of cells with the ligand for P61073 , stromal cell - derived factor - 1alpha ( SDF - 1alpha ) , resulted in an elevation in intracellular Ca ( 2 +) concentration and activation of the mitogen - activated protein kinase cascade , specifically , extracellular signal - regulated kinase 2 ( P28482 ) mitogen - activated protein kinase . Of most interest , SDF - 1alpha treatment induced expression of the chemokines monocyte chemoattractant protein - 1 , P10145 , and P01579 - inducible protein - 10 . SDF - 1alpha - induced chemokine expression was abrogated upon inclusion of U0126 , a pharmacological inhibitor of P27361 / 2 , indicating that the P29323 signaling cascade is involved in this response . Collectively , these data suggest that P61073 - mediated signaling pathways in astroglioma cells may be another mechanism for these cells to express chemokines involved in angiogenesis and inflammation .",
"Gating properties of Q14524 mutations and the response to mexiletine in long - QT syndrome type 3 patients . BACKGROUND : ___MASK87___ ( Mex ) has been proposed as a gene - specific therapy for patients with long - QT syndrome type 3 ( LQT3 ) caused by mutations in the cardiac sodium channel gene ( Q14524 ) . The degree of QT shortening and the protection from arrhythmias vary among patients harboring different mutations . We tested whether the clinical response to Mex in LQT3 could be predicted by the biophysical properties of the different mutations . METHODS AND RESULTS : We identified 4 Q14524 mutations in 5 symptomatic LQT3 patients with different responses to Mex ( 6 to 8 mg . kg (- 1 ) . d (- 1 ) ) . We classified the mutations as sensitive to Mex ( P1332L , R1626P ; >/= 10 % of QTc shortening and QTc < 500 ms or no arrhythmias ) or insensitive to Mex ( S941N , M1652R ; negligible or no QTc shortening and sudden death ) . We measured Na (+) current from P29320 293 cells transfected with wild - type ( WT ) or mutant Nav1 . 5 . All mutations showed impaired inactivation of Na (+) current , but the mutations identified in patient responders to Mex ( P1332L , R1626P ) showed a hyperpolarizing shift of V ( 1 / 2 ) of steady - state inactivation . Furthermore , Mex produced use - dependent block with the order R1626P = P1332L > S941N = WT > M1652R , suggesting that Mex - sensitive mutants present prolonged recovery from Mex block . CONCLUSIONS : We propose that voltage dependence of channel availability and shifts of V ( 1 / 2 ) of steady - state inactivation correlate with the clinical response observed in LQT3 patients . This supports the view that the response to Mex is mutation specific and that in vitro testing may help to predict the response to therapy in LQT3 .",
"[ ___MASK39___ - beta - hydroxylaseaktivität im Plasma von Dialysepatienten ( author ' s transl ) ] . Plasma dopamin - b - hydroxylase ( P09172 ) was studied in 70 healthy control persons and in 37 hemodialysed patients . Basal P09172 in controls corresponded to 50 . 0 +/- 29 . 3 IU . There was was no significant difference between males ( 53 . 9 +/ 1 33 . 8 IU ) and females ( 47 . 4 +/- 25 IU ) ; no correlation could be found between age and plasma P09172 . In hemodialysed patients basal P09172 levels were significantly ( p less than 0 . 01 ) decreased ( 32 . 5 % /- 17 . 6 IU ) , suggesting lowered sympathetic activity and / or abnormalities in release , distribution space , or metabolism of P09172 . During hemodialysis plasma P09172 activity rose during ultrafiltration . This finding indicates a directionally appropriate sympathetic reflex response to volume depletion in dialysed patients .",
"Role of everolimus in pancreatic neuroendocrine tumors . Survival from pancreatic neuroendocrine tumors has not improved over the past two decades and , until recently , streptozocin was the last therapeutic agent approved for this malignancy . ___MASK9___ blocks P42345 , which plays an integral role in cell growth , mitosis and angiogenesis . Abnormal PI3K - Akt / P31749 - P42345 pathway signaling has been implicated in the pathogenesis of pancreatic neuroendocrine tumors . In a Phase III study , patients with low - and intermediate - grade advanced pancreatic neuroendocrine tumors were randomized to receive everolimus 10 mg / day or placebo . Median progression - free survival was significantly greater in patients treated with everolimus than placebo - 11 versus 4 . 6 months - and drug - related adverse events were consistent with the known side - effect profile of everolimus . ___MASK9___ represents a significant treatment development for pancreatic neuroendocrine tumors .",
"P21728 , but not dopamine D2 receptor , is a critical regulator for acute cocaine - enhanced gene expression . OBJECTIVE : The aim of present study is to investigate the roles of dopamine receptor subfamilies and their subsequent molecular events in cocaine - enhanced gene expression in striatum . METHODS : Acute cocaine - treated mice models were build to address this issue . Specific antagonists for dopamine D1 and D2 receptors ( P35240 23390 and raclopride , respectively ) and specific inhibitor for extracellular signal - regulated protein kinase 1 / 2 ( P27361 / 2 ) kinase were pretreated . Immunofluorescence was used to detect the expressions of c - Fos , phosphorylated DB02527 response element binding ( p - CREB ) and phosphorylated Elk - 1 ( p - Elk - 1 ) in striatum . RESULTS : Acute cocaine injection significantly enhanced expressions of c - Fos , p - CREB and p - Elk - 1 in the striatum . Notably , these enhancements were totally blocked to normal level by P35240 23390 pre - treatment , while no changes occurred in the presence of raclopride . Moreover , we found that dopamine D1 receptor was involved in acute cocaine - induced activation of P27361 / 2 in the striatum . Blockade of this dopamine D1 receptor - dependent P27361 / 2 activation by SL 327 could reduce cocaine - enhanced expressions of c - Fos , p - CREB and p - Elk - 1 in the striatum . DISCUSSION : These results suggest that dopamine D1 receptor , but not dopamine D2 receptor , plays a critical role in regulating acute cocaine - enhanced gene expression in the striatum , and P27361 / 2 pathway may contribute to this regulation .",
"Transcriptional modulation of monoaminergic neurotransmission genes by the histone deacetylase inhibitor trichostatin A in neuroblastoma cells . Histone deacetylase inhibitors are promising anti - tumor agents partly due to their ability to disrupt the hypoxic signaling pathway in human malignancies . However , little is known about any effects of these drugs on the central nervous system . The aim of the present study was to analyze the effects of trichostatin A ( P32119 ) -- a broad - spectrum histone deacetylase inhibitor -- on the transcriptional regulation of several genes involved in dopamine - and serotonergic neurotransmission . To this end , short - term parallel cultures of SK - NF - I neuroblastoma cells were treated with P32119 either alone or in combination with hypoxia , and mRNA levels of dopamine receptor D3 ( P35462 ) and D4 ( P21917 ) , dopamine transporter ( Q01959 ) , dopamine hydroxylase ( P09172 ) , dopamine receptor regulating factor ( DRRF ) , catechol - O - methyltransferase ( P21964 ) , serotonin receptor 1A ( P08908 ) , monoamino oxidase A ( P21397 ) , serotonin transporter ( P31645 ) and tryptophan hydroxylase 2 ( Q8IWU9 ) were determined by quantitative PCR . We found that P32119 did not antagonize the hypoxia - induced activation of D3 and D4 dopamine receptor genes , implying that induction of these genes is not mediated directly by hypoxia inducible factor - 1alpha . On the other hand , P32119 dramatically upregulated the expression of Q01959 and P31645 ( 45 - fold and 15 - fold , respectively ) , while transcript levels of P21397 and P21964 were significantly reduced ( by 70 % and by more than 90 % , respectively ) . Induction of Q01959 protein expression was detected by western blotting . These results suggest that inhibition of histone deacetylases might help restore presynaptic monoamine pools via suppression of catecholamine breakdown and facilitation of monoamine reuptake in neurons .",
"Bacterial superantigens bypass Lck - dependent T cell receptor signaling by activating a Galpha11 - dependent , P98160 - beta - mediated pathway . The paradigm to explain antigen - dependent T cell receptor ( TCR ) signaling is based on the activation of the P01730 or CD8 coreceptor - associated kinase Lck . It is widely assumed that this paradigm is also applicable to signaling by bacterial superantigens . However , these bacterial toxins can activate human T cells lacking Lck , suggesting the existence of an additional pathway of TCR signaling . Here we showed that this alternative pathway operates in the absence of Lck - dependent tyrosine - phosphorylation events and was initiated by the TCR - dependent activation of raft - enriched heterotrimeric Galpha11 proteins . This event , in turn , activated a phospholipase C - beta and protein kinase C - mediated cascade that turned on the mitogen - activated protein kinases P27361 and P28482 , triggered Ca ( 2 +) influx , and translocated the transcription factors NF - AT and NF - kappaB to the nucleus , ultimately inducing the production of interleukin - 2 in Lck - deficient T cells . The triggering of this alternative pathway by superantigens suggests that these toxins use a G protein - coupled receptor as a coreceptor on T cells .",
"Dopamine receptor D4 polymorphism predicts the effect of DB01235 on gambling behavior . BACKGROUND : There is ample evidence that a subgroup of Parkinson ' s disease patients who are treated with dopaminergic drugs develop certain behavioral addictions such as pathological gambling . The fact that only a subgroup of these patients develops pathological gambling suggests an interaction between dopaminergic drug treatment and individual susceptibility factors . These are potentially of genetic origin , since research in healthy subjects suggests that vulnerability for pathological gambling may be linked to variation in the dopamine receptor D4 ( P21917 ) gene . Using a pharmacogenetic approach , we investigated how variation in this gene modulates the impact of dopaminergic stimulation on gambling behavior in healthy subjects . METHODS : We administered 300 mg of L - dihydroxyphenylalanine ( DB01235 ) or placebo to 200 healthy male subjects who were all genotyped for their P21917 polymorphism . Subjects played a gambling task 60 minutes after DB01235 administration . RESULTS : Without considering genetic information , DB01235 administration did not lead to an increase in gambling propensity compared with placebo . As expected , however , an individual ' s P21917 polymorphism accounted for variation in gambling behavior after the administration of DB01235 . Subjects who carry at least one copy of the 7 - repeat allele showed an increased gambling propensity after dopaminergic stimulation . CONCLUSIONS : These findings demonstrate that genetic variation in the P21917 gene determines an individual ' s gambling behavior in response to a dopaminergic drug challenge . They may have implications for the treatment of Parkinson ' s disease patients by offering a genotype approach for determining individual susceptibilities for pathological gambling and may also afford insights into the vulnerability mechanisms underlying addictive behavior .",
"___MASK9___ ( RAD001 ) : an P42345 inhibitor for the treatment of metastatic renal cell carcinoma . The recent introduction of drugs that inhibit angiogenesis or the P42345 has provided new options for the treatment of metastatic renal cell carcinoma , a disease which often has a poor prognosis . Chemotherapy and cytokine therapy are largely ineffective . The 5 - year survival rate is under 10 % . ___MASK9___ , an immunosuppressive drug widely used for the prevention of allograft rejection and an P42345 inhibitor , is one of the latest drugs undergoing clinical trials in metastatic renal cell carcinoma . It has been tested in patients with progressive disease after therapy with tyrosine kinase receptor inhibitors ( sunitinib , sorafenib or both ) , which interfere with signaling pathways , such as the P15692 pathway . Clinical efficacy results ( progression - free survival ) for everolimus are promising and the safety profile is good .",
"Q9UD71 as a marker for D - 1 dopaminoceptive cells in the rat brain : prenatal development and presence in glial elements ( tanycytes ) in the basal hypothalamus . The present article reviews some aspects of the localization of a dopamine - and cyclic AMP - regulated phosphoprotein , Q9UD71 , which is assumed to be present in D - 1 dopaminoceptive neurons . Its prenatal development starts at day 14 of gestation , is to a large extent complete at birth and seems to be independent of ingrowing dopamine - containing afferents . Rearrangements occur in certain areas , and in some systems Q9UD71 appears to be only transiently expressed . The presence of Q9UD71 in glial structures , the tanycytes , in the arcuate nucleus - median eminence complex in the mediobasal hypothalamus , has given further support to the hypothesis that dopamine , by controlling the shape of the tanycytes and the extension of their processes , can regulate P01148 release by a ' mechanical mechanism ' . This hypothesis is now being examined in some experimental paradigms .",
"Shared and unique genetic contributions to attention deficit / hyperactivity disorder and substance use disorders : a pilot study of six candidate genes . The shared genetic basis of attention deficit / hyperactivity disorder ( ADHD ) and substance use disorders ( SUDs ) was explored by investigating the association of candidate risk factors in neurotransmitter genes with both disorders . One hundred seven methadone maintenance treatment patients , 36 having an ADHD diagnosis , 176 adult patients with ADHD without SUDs , and 500 healthy controls were genotyped for variants in the P21917 ( exon 3 VNTR ) , P21918 ( upstream VNTR ) , P28222 ( rs6296 ) , P09172 ( rs2519152 ) , P21964 ( rs4680 ; Val158Met ) , and P35372 ( rs1799971 ; 118A > G ) genes . Association with disease was tested using logistic regression models . This pilot study was adequately powered to detect larger genetic effects ( OR ≥ 2 ) of risk alleles with a low frequency . Compared to controls , ADHD patients ( with and without SUDs ) showed significantly increased frequency of the P09172 ( rs2519152 : OR 1 . 73 ; CI 1 . 15 - 2 . 59 ; P = 0 . 008 ) and the P35372 risk genotypes ( rs1799971 : OR 1 . 71 ; CI 1 . 17 - 2 . 50 ; P = 0 . 006 ) . The P09172 risk genotype was associated with ADHD diagnosis , with the association strongest in the pure ADHD group . The P35372 risk genotype increased the risk for the combined ADHD and SUD phenotype . The present study strengthens the evidence for a shared genetic basis for ADHD and addiction . The association of P35372 with the ADHD and SUD combination could help to explain the contradictory results of previous studies . The power limitations of the study restrict the significance of these findings : replication in larger samples is warranted .",
"P48061 and [ N33A ] P48061 in 5637 and HeLa cells : regulating P00533 phosphorylation via calmodulin / calcineurin . In the human neoplastic cell lines 5637 and HeLa , recombinant P48061 elicited , as expected , downstream signals via both G - protein - dependent and β - arrestin - dependent pathways responsible for inducing a rapid and a late wave , respectively , of P27361 / 2 phosphorylation . In contrast , the structural variant [ N33A ] P48061 triggered no β - arrestin - dependent phosphorylation of P27361 / 2 , and signaled via G protein - dependent pathways alone . Both P48061 and [ N33A ] P48061 , however , generated signals that transinhibited P00533 phosphorylation via intracellular pathways . 1 ) Prestimulation of P61073 / P00533 - positive 5637 or HeLa cells with P48061 modified the HB - P01133 - dependent activation of P00533 by delaying the peak phosphorylation of tyrosine 1068 or 1173 . 2 ) Prestimulation with the synthetic variant [ N33A ] P48061 , while preserving P61073 - related chemotaxis and P61073 internalization , abolished P00533 phosphorylation . 3 ) In cells knockdown of β - arrestin 2 , P48061 induced a full inhibition of P00533 like [ N33A ] P48061 in non - silenced cells . 4 ) P00533 phosphorylation was restored as usual by inhibiting PCK , calmodulin or calcineurin , whereas the inhibition of CaMKII had no discernable effect . We conclude that both recombinant P48061 and its structural variant [ N33A ] P48061 may transinhibit P00533 via G - proteins / calmodulin / calcineurin , but [ N33A ] P48061 does not activate β - arrestin - dependent P27361 / 2 phosphorylation and retains a stronger inhibitory effect . Therefore , we demonstrated that P48061 may influence the magnitude and the persistence of signaling downstream of P00533 in turn involved in the proliferative potential of numerous epithelial cancer . In addition , we recognized that [ N33A ] P48061 activates preferentially G - protein - dependent pathways and is an inhibitor of P00533 .",
"DB01235 - treatment in primates disrupts the expression of A ( 2A ) adenosine - CB ( 1 ) cannabinoid - P14416 heteromers in the caudate nucleus . The molecular basis of priming for DB01235 - induced dyskinesias in Parkinson ' s disease ( PD ) , which depends on the indirect pathway of motor control , is not known . In rodents , the indirect pathway contains striatopallidal GABAergic neurons that express heterotrimers composed of A ( 2A ) adenosine , CB ( 1 ) cannabinoid and D ( 2 ) dopamine receptors that regulate dopaminergic neurotransmission . The present study was designed to investigate the expression of these heteromers in the striatum of a primate model of Parkinson ' s disease and to determine whether their expression and pharmacological properties are altered upon DB01235 treatment . By using the recently developed in situ proximity ligation assay and by identification of a biochemical fingerprint , we discovered a regional distribution of A ( 2A )/ CB ( 1 ) / D ( 2 ) receptor heteromers that predicts differential D ( 2 )- mediated neurotransmission in the caudate - putamen of Macaca fascicularis . Whereas heteromers were abundant in the caudate nucleus of both naïve and MPTP - treated monkeys , DB01235 treatment blunted the biochemical fingerprint and led to weak heteromer expression . These findings constitute the first evidence of altered receptor heteromer expression in pathological conditions and suggest that drugs targeting A ( 2A )- CB ( 1 ) - D ( 2 ) receptor heteromers may be successful to either normalize basal ganglia output or prevent DB01235 - induced side effects .",
"P00797 inhibition with aliskiren . 1 . Initial attempts to inhibit renin in humans have faced numerous difficulties . Molecular modelling and X - ray crystallography of the active site of renin have led to the development of new orally active renin inhibitors , such as aliskiren . 2 . ___MASK77___ has a low bioavailability ( between 2 . 6 and 5 . 0 % ) compensated by its high potency to inhibit renin ( IC50 : 0 . 6 nmol / L ) and a long plasma half - life ( 23 - 36 h ) , which makes it suitable for once - daily dosing . 3 . The once - daily administration of aliskiren to hypertensive patients lowers BP as strongly as standard doses of established angiotensin II type 1 ( AT1 ) receptor blockers ( losartan , valsartan , irbesartan ) , hydrochlorothiazide , angiotensin converting enzyme inhibitors ( ramipril and lisinopril ) or long acting calcium channel blockers ( amlodipine ) . In combination therapy , aliskiren further decreases blood pressure when combined with either hydrochlorothiazide , amlodipine , irbesartan or ramipril . 4 . The biochemical consequences of renin inhibition differ from those of angiotensin I - converting enzyme ( P12821 ) inhibition and Ang II antagonism , particularly in terms of angiotensin profiles and interactions with the bradykinin - nitric oxide - cyclic guanosine monophosphate pathway and possibly the ( pro ) renin receptor . 5 . Blockade of the renin angiotensin system ( DB01367 ) with P12821 inhibitors , AT1 receptor blockers or a combination of these drugs has become one of the most successful therapeutic approaches in medicine . However , it remains unclear how to optimize DB01367 blockade to maximize cardiovascular and renal benefits . In this context , renin inhibition to render the DB01367 fully quiescent is a new possibility requiring further study .",
"Interaction between serotonin transporter gene , catechol - O - methyltransferase gene and stressful life events in mood disorders . It is well established that stress is a risk factor for onset of mood disorders . Emerging evidence suggests that genetic vulnerability may also moderate individual responsiveness to stress . The most compelling evidence regards the polymorphism within the promoter region of the serotonin transporter gene ( SERTPR ) , which has been reported to moderate the risk for depression , in conjunction with life stressors . In the present paper we analysed SERTPR in the onset of mood disorders , along with adverse life events , and other candidate genes : the serotonin receptor 1A ( P08908 ) , the dopamine receptor D4 ( P21917 ) and the catechol - O - methyltransferase ( P21964 ) . The sample was composed of 686 Italian subjects , affected by major depression and bipolar disorder . Patients were asked to report about life stressors within the year preceding onset of their first mood - disorder episode and genotyped . A ' case - only ' design was employed to investigate the interaction between genes and stressors . P21964 was associated with depression following exposure to stressors ( chi2 = 13 . 05 , d . f .= 2 , p = 0 . 0015 ) and SERTPR also showed a positive association ( chi2 = 6 . 70 , d . f .= 2 , p = 0 . 035 ) , mainly among women and among major depressives . The interaction between P21964 and SERTPR was also significant ( p = 0 . 0005 ) . In our retrospective study SERTPR is hypothesized to lead to the onset of major depression via its influence on reaction to adversities , particularly in females . Moreover , P21964 was risk factor for onset of both major depression and bipolar disorder , in conjunction with adversities .",
"Activation of gonadotropin - releasing hormone receptors induces a long - term enhancement of excitatory postsynaptic currents mediated by ionotropic glutamate receptors in the rat hippocampus . Whole - cell patch - clamp recordings were made from P00915 pyramidal neurons of the rat hippocampus to study the modulation of gonadotropin - releasing hormone ( DB00644 ) on synaptic transmission mediated by ionotropic glutamate receptors . ___MASK42___ ( 10 (- 9 )- 10 (- 7 ) M ) , a specific DB00644 analog , concentration - dependently elicited a long - lasting potentiation of excitatory postsynaptic currents ( EPSCs ) mediated by ionotropic glutamate receptors . P30968 - induced synaptic potentiation was blocked by 1 microM [ Acetyl - 3 , 4 - dehydro - Pro1 , D - p - F - Phe2 , D - Trp3 , 6 ] - P01148 , a specific P30968 antagonist . Furthermore , P30968 - induced synaptic potentiation was associated with the stimulation of protein kinase C ( PKC ) , being considerably attenuated by a potent PKC inhibitor ( 30 microM H - 7 ) . The results suggest a long - term enhanced modulation of DB00644 on synaptic transmission mediated by ionotropic glutamate receptors , possibly via the actions of PKC in the hippocampus that is an important integrative system in the regulation of reproductive processes .",
"Radiation hybrid map of 13 loci on the long arm of chromosome 5 . Radiation hybrid mapping was used in conjunction with a natural deletion mapping panel to predict the order of and distance between 13 loci in the distal portion of the long arm of human chromosome 5 . A panel of irradiation hybrids containing fragments of 5q was generated from an P00492 + Chinese hamster - human cell hybrid containing a derivative chromosome 5 [ der ( 5 ) t ( 4 ; 5 ) ( 5qter ---- 5p15 . 1 :: 4p15 . 1 ---- 4pter ) ] as its only human DNA . One hundred nine radiation hybrids containing human DNA were screened with polymerase chain reaction primer sets representing nine genes encoding growth factors , growth factor receptors , or hormone receptors ( P08700 , P05112 , P05113 , P07333 , P05230 , P07550 , GRL , P14867 , and P21728 ) as well as four other loci ( P16591 , P09486 , P62263 , and P08571 ) to generate a radiation hybrid map of the area 5q21 - q35 . A physical map predicting the order of and distance between the 13 loci was constructed based on segregation of the 13 loci in hybrid clones . The radiation hybrid panel will be useful as a mapping tool for determining the location and order of other genes and polymorphic loci in this region as well as for generating new DNA probes from specific regions .",
"P00797 - angiotensin system revisited . New components and functions of the renin - angiotensin system ( DB01367 ) are still being unravelled . The classical DB01367 as it looked in the middle 1970s consisted of circulating renin , acting on angiotensinogen to produce angiotensin I , which in turn was converted into angiotensin II ( Ang II ) by angiotensin - converting enzyme ( P12821 ) . Ang II , still considered the main effector of DB01367 was believed to act only as a circulating hormone via angiotensin receptors , AT1 and P50052 . Since then , an expanded view of DB01367 has gradually emerged . Local tissue DB01367 systems have been identified in most organs . Recently , evidence for an intracellular DB01367 has been reported . The new expanded view of DB01367 therefore covers both endocrine , paracrine and intracrine functions . Other peptides of DB01367 have been shown to have biological actions ; angiotensin 2 - 8 heptapeptide ( Ang III ) has actions similar to those of Ang II . Further , the angiotensin 3 - 8 hexapeptide ( Ang IV ) exerts its actions via insulin - regulated amino peptidase receptors . Finally , angiotensin 1 - 7 ( Ang 1 - 7 ) acts via mas receptors . The discovery of another Q9BYF1 was an important complement to this picture . The recent discovery of renin receptors has made our view of DB01367 unexpectedly complex and multilayered . The importance of DB01367 in cardiovascular disease has been demonstrated by the clinical benefits of P12821 inhibitors and AT1 receptor blockers . Great expectations are now generated by the introduction of renin inhibitors . Indeed , DB01367 regulates much more and diverse physiological functions than previously believed .",
"Sustained increase of PKA activity in the postcommissural putamen of dyskinetic monkeys . Levodopa - induced dyskinesias ( LID ) are a frequent complication of Parkinson ' s disease pharmacotherapy that causes significant disability and narrows the therapeutic window . Pharmacological management of LID is challenging partly because the precise molecular mechanisms are not completely understood . Here , our aim was to determine molecular changes that could unveil targetable mechanisms underlying this drug complication . We examined the expression and downstream activity of dopamine receptors ( DR ) in the striatum of 1 - methyl - 4 - phenyl - 1 , 2 , 3 , 6 tetrahydropiridine ( MPTP ) - lesioned monkeys with and without DB01235 treatment . Four monkeys were made dyskinetic and other four received a shorter course of DB01235 and did not develop LID . Our results show that DB01235 treatment induces an increase in P14416 and P35462 expression in the postcommissural putamen , but only P35462 is correlated with the severity of LID . Dyskinetic monkeys show a hyperactivation of the canonical P21728 - signaling pathway , measured by an increased phosphorylation of protein kinase A ( PKA ) and its substrates , particularly Q9UD71 . In contrast , activation of the P14416 - signaling pathway , visible in the levels of Akt phosphorylated on Thr308 and GSK3β on Ser9 , is associated with DB01235 treatment , independently of the presence of dyskinesias . Our data clearly demonstrate that dyskinetic monkeys present a dysregulation of the P35462 receptor and the P21728 pathway with a sustained increase of PKA activity in the postcommissural putamen . Importantly , we found that all signaling changes related to long - term DB01235 administration are exquisitely restricted to the postcommissural putamen , which may be related to the recurrent failure of pharmacological approaches .",
"The interleukin 10 promoter haplotype ACA and the long - form variant of the P21917 uVNTR polymorphism are associated with vulnerability to schizophrenia . A total of 934 patients with schizophrenia and 433 controls were genotyped for the interleukin - 10 ( P22301 ) promoter and P21917 uVNTR polymorphisms . P21917 long - form variants ( namely , those with ≥ 5 repeats ) , homozygosity for the 4 - repeat allele , and the P22301 haplotype ACA were associated with schizophrenia , respectively . No obvious interactions among the potential polymorphisms were found , which suggests that P22301 and P21917 confer vulnerability to schizophrenia independently .",
"A genomic insight into diversity among tribal and nontribal population groups of Manipur , India . Twenty autosomal markers , including linked markers at two gene markers , are used to understand the genomic similarity and diversity among three tribal ( Paite , Thadou , and Kom ) and one nontribal communities of Manipur ( Northeast India ) . Two of the markers ( P01730 and HB9 ) are monomorphic in Paite and one ( the P01730 marker ) in Kom . Data suggest the Meitei ( nontribal groups ) stand apart from the three tribal groups with respect to higher heterozygosity ( 0 . 366 ) and presence of the highest ancestor haplotypes of P14416 markers ( 0 . 228 ) ; this is also supported by principal co - ordinate analysis . These populations are found to be genomically closer to the Chinese population than to other Indian populations .",
"Q9UD71 increases interactions between epidermal growth factor receptor and P21860 to promote tumor resistance to gefitinib . BACKGROUND & AIMS : Dopamine and adenosine 3 ', 5 '- cyclic monophosphate - regulated phosphoprotein , Mr 32000 ( Q9UD71 ) , is overexpressed during gastric carcinogenesis . Gastric tumors can become resistant to gefitinib , an inhibitor of the epidermal growth factor receptor ( P00533 ) . We investigated the role of Q9UD71 in gastric tumor resistance to gefitinib . METHODS : Cell survival was determined by clonogenic survival and DB00171 - Glo Viability Assays . Apoptosis was assessed by Annexin - V and immunoblot analyses . The association between Q9UD71 and P00533 was evaluated by immunofluorescence and co - immunoprecipitation assays . Findings were validated in mice with gastric xenograft tumors . Q9UD71 expression was reduced using small hairpin RNAs in the human gastric cancer cell lines SNU - 16 and MKN - 45 cells . RESULTS : Overexpression of Q9UD71 in MKN - 28 cells , which do not normally express Q9UD71 , blocked gefitinib - induced apoptosis and increased the drug ' s IC ( 50 ) 10 - fold , compared to that of control cells ( P < . 01 ) . Reduced expression of Q9UD71 in SNU - 16 cells increased the sensitivity to gefitinib ( P < . 01 ) . Q9UD71 activated phosphatidylinositol - 3 - kinase - AKT signaling , increased stability of the P00533 , and suppressed P01133 - or gefitinib - induced degradation of the P00533 . Q9UD71 colocalized with P00533 on the cell membrane in a complex with P00533 and the P01133 receptor P21860 . Q9UD71 - mediated resistance to gefitinib resulted from increased phosphorylation of and interaction between P00533 and P21860 , which led to phosphorylation of AKT ( at serine 473 ) . Knockdown of Q9UD71 in gastric cancer cells reduced the mean size of tumors in mice and increased their response to gefitinib . CONCLUSIONS : Q9UD71 promotes resistance of gastric cancer cells to gefitinib by promoting interaction between P00533 and P21860 and activating phosphatidylinositol - 3 - kinase - AKT signaling .",
"Expression profile of genes associated with the dopamine pathway in vitiligo skin biopsies and blood sera . BACKGROUND : Dopamine has been proven to be toxic for melanocytes . In vitiligo patients the level of dopamine is increased and the functioning of several enzymes participating in the dopamine pathway is changed . METHODS : With the use of quantitative real - time polymerase chain reaction and ELISA the expression of genes connected to the dopamine pathway ( PAH , P61457 , TH , DDC , P09172 , PNMT , P07203 , P21397 , P27338 , P21964 , P21728 - P21918 , P54219 and Q05940 ) was observed in vitiligo patients ' and control subjects ' skin and blood . RESULTS : The mRNA expression of P07203 , DDC , P21397 , P21728 and P21918 differs in vitiligo skin and the protein level of DDC , P21397 , P27338 , P21728 and P21918 is changed in vitiligo patients ' skin and / or blood sera . CONCLUSIONS : The dopamine pathway probably influences melanogenesis directly or through the melanocortin pathway . We provide new data about changes of expression profile of the dopamine - synthesizing enzyme DDC , the dopamine - degrading enzymes P21397 and P27338 and the D1 - like family dopamine receptors in vitiligo skin and blood sera .",
"Dopamine receptor agonists reverse behavioral abnormalities of alpha - synuclein transgenic mouse , a new model of Parkinson ' s disease . Parkinson ' s disease ( PD ) is characterized by loss of nigral dopaminergic ( DAergic ) neurons and presence of Lewy bodies , whose major component is alpha - synuclein . We had previously generated transgenic mice termed Syn130m that express truncated human alpha - synuclein ( amino acid residues 1 - 130 ) in DAergic neurons . Syn130m mice showed significant loss of DAergic neurons in the substantia nigra pars compacta . Subsequently , the striatal DA level and spontaneous locomotor activity of the mice were decreased significantly . In the present study , we investigated behavioral responses of Syn130m mice to DB01235 and DA receptor agonists . Administration of DB01235 dose dependently ameliorated the reduction of spontaneous locomotor activity of Syn130m mice . Similarly , D ( 2 ) agonists , quinpirole and talipexole , and a D1 / D2 agonist , pergolide , were effective against the reduction . Syn130m mice also showed significant reduction in exploratory behavior compared with non - Tg littermates when they were placed in a novel environment , but this abnormality was ameliorated by treatment with pergolide . These results strongly suggest that the behavioral abnormalities of Syn130m mice were caused by low striatal DA content . On the other hand , the expression of postsynaptic D ( 2 )- like receptors ( P14416 ) in the striatum was not increased in Syn130m mice , although the low striatal DA level is known to induce compensatory expression of P14416 . Because the abnormalities could be rectified by treatment with DA receptor agonists , it is likely that Syn130m mice provide a useful tool to explore therapeutic possibilities for PD as a new animal model of the disease .",
"___MASK53___ inhibits effector T cells through regulatory T cells and TGF - β . The P10747 costimulatory receptor is a critical regulator of T cell function , making it an attractive therapeutic target for the treatment of immune - mediated diseases . ___MASK53___ , now approved for use in humans , prevents naive T cell activation by binding to P33681 proteins and blocking engagement of P10747 . However , ___MASK53___ suppresses inflammation even if administered when disease is established , suggesting alternative mechanisms . We identified a novel , P10747 - independent mechanism by which ___MASK53___ inhibits activated T cells . We show that in vitro , ___MASK53___ synergizes with NO from bone marrow - derived macrophages to inhibit T cell proliferation . Depletion of regulatory T cells ( Tregs ) or interference with TGF - β signaling abrogated the inhibitory effect of ___MASK53___ . Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells . Furthermore , ___MASK53___ was ineffective in P84022 - deficient mice , supporting a requirement for TGF - β signaling . Thus , in addition to preventing naive T cells from being fully activated , ___MASK53___ can turn off already activated effector T cells by an NO / regulatory T cell / TGF - β - dependent pathway . This mechanism is similar to cell - extrinsic effects of endogenous P16410 and may be particularly important in the ability of ___MASK53___ to treat chronic inflammatory disease .",
"P22301 - inducing adjuvants enhance sublingual immunotherapy efficacy in a murine asthma model . BACKGROUND : P22301 - inducing adjuvants could enhance the efficacy of allergy vaccines in establishing allergen - specific tolerance . The aim of this study was to identify such adjuvants using in vitro cultures of human and murine cells and to evaluate them in a therapeutic murine model of sublingual immunotherapy ( SLIT ) . METHODS : Adjuvants stimulating P22301 gene expression by human or murine immune cells were tested sublingually in BALB / c mice sensitized to ovalbumin ( OVA ) , assessing the reduction in airway hyperresponsiveness ( P35869 ) by whole - body plethysmography . The induction of regulatory T cells ( T ( reg ) ) was evaluated using phenotypic and functional assays . T - cell proliferation in cervical lymph nodes ( LNs ) was assessed following intravenous transfer of CFSE - labelled OVA - specific T cells and FACS analysis . RESULTS : A combination of 1 , 25 - dihydroxyvitamin D3 plus dexamethasone ( VitD3 / DB00514 ) as well as Lactobacillus plantarum were found to induce P22301 production by human and murine dendritic cells ( DCs ) . The former inhibits LPS - induced DC maturation , whereas L . plantarum induces DC maturation . Following stimulation with VitD3 / DB00514 - pretreated DCs , P01730 + naïve T cells exhibit a T ( reg ) profile . In contrast , a Th1 / T ( reg ) pattern of differentiation is observed in the presence of DCs treated with L . plantarum . Both adjuvants significantly enhance SLIT efficacy in mice , in association with either induction of Foxp3 + T ( reg ) cells ( for VitD3 / DB00514 ) or proliferation of OVA - specific T cells in cervical LNs ( for L . plantarum ) . CONCLUSIONS : Both VitD3 / DB00514 and L . plantarum polarize naïve T cells towards P22301 - expressing T cells , through distinct mechanisms . As adjuvants , they both enhance SLIT efficacy in a murine asthma model .",
"Adrenal and gonadal function in hypothyroid adult male rats . The functional relationship between thyroid , adrenal and gonadal hormones was investigated using adult male rats . Hypothyroidism was produced by the administration of 4 - methyl - 2 - thiouracil ( thiouracil ) in the drinking water for 2 weeks . Plasma concentrations of DB00024 dramatically increased , whereas plasma concentrations of tri - iodothyronine and thyroxine decreased in thiouraciltreated rats as compared with euthyroid rats . Hypothyroidism increased basal levels of plasma DB01285 and pituitary content of DB01285 . The pituitary responsiveness to P06850 for DB01285 release markedly increased , whereas the adrenal responsiveness to DB01285 for corticosterone release decreased . These results indicated that hypothyroidism causes adrenal dysfunction in adult male rats . Pituitary contents of LH and prolactin decreased in hypothyroid rats as compared with euthyroid rats . In addition , hypothyroidism lowered pituitary LH responsiveness to P01148 . Testicular responsiveness to human chorionic gonadotrophin for testosterone release , however , was not different between euthyroid and hypothyroid animals . These results indicated that hypothyroidism causes adrenal dysfunction and results in hypersecretion of DB01285 from the pituitary gland . Adrenal dysfunction may contribute to the inhibition of P01148 secretion from the hypothalamus , possibly mediated by excess P06850 .",
"P14416 - induced heterologous sensitization of adenylyl cyclase requires Galphas : characterization of Galphas - insensitive mutants of adenylyl cyclase V . Whereas acute stimulation of Galphai / o - coupled receptors inhibits the activity of adenylyl cyclase , a delayed consequence of persistent activation of the receptors is heterologous sensitization , an enhanced responsiveness of adenylyl cyclase to activators such as forskolin or agonists of Galphas - coupled receptors . Galphas - insensitive mutants of adenylyl cyclase type V were used to test the hypothesis that heterologous sensitization requires Galphas - dependent activation of adenylyl cyclase . When adenylyl cyclase was stably expressed in human embryonic kidney ( P29320 ) 293 cells with the D2L dopamine receptor , basal , forskolin - stimulated , and isoproterenol - stimulated cyclic AMP accumulation were all enhanced by 2 - h pretreatment with the D2 receptor agonist quinpirole . Transient expression of wild - type adenylyl cyclase and three Galphas - insensitive mutants ( F379L , R1021Q , and F1093S ) in HEK293 cells stably expressing the D2L receptor demonstrated that all three mutants had little or no responsiveness to beta - adrenergic receptor - mediated activation of Galphas but that the mutants retained sensitivity to forskolin and to D2L receptor - mediated inhibition . Transiently expressed adenylyl cyclase V was robustly sensitized by 2 - h pretreatment with quinpirole . In contrast , the Galphas - insensitive mutants displayed no sensitization of forskolin - stimulated cyclic AMP accumulation , indicating that responsiveness to Galphas is required for the expression of heterologous sensitization .",
"Prolonged effects of tumor necrosis factor - alpha on anterior pituitary hormone release . We examined the chronic ( 72 h ) effects of 30 ng / ml recombinant murine tumor necrosis factor ( P01375 ) - alpha on release of immunoreactive growth hormone ( GH ) , prolactin ( PRL ) , thyrotropin ( DB00024 ) , and DB00024 glycosylation , as assessed by lectin binding , in cultured rat anterior pituitary cells . In cultured cells from adult female rats , P01375 significantly suppressed basal and GH - releasing hormone ( P01148 ) - stimulated GH release . P01375 also suppressed basal PRL release and completely abolished the PRL response to TRH ( 0 . 1 - 10 nM ) . Whereas P01375 reduced basal DB00024 release , it significantly enhanced the maximal DB00024 response to TRH . P01375 did not affect the concanavalin A and lentil lectin binding of DB00024 accumulated in the medium during the 4 - day culture , but significantly decreased the lentil lectin binding of DB00024 released in response to acute TRH stimulation . P01375 significantly enhanced the inhibitory effect of somatostatin on stimulated PRL release , but not on GH or DB00024 release . Compared to cell cultures from adult female rats , in anterior pituitary cell cultures from 12 - day - old rats the effects of prolonged exposure to P01375 on hormone release were diminished or absent . Pituitary hormone release was unaffected by acute ( 3 h ) exposure to P01375 . These results demonstrate a direct effect of P01375 on anterior pituitary hormone release , which is cell - type specific and age dependent .",
"P12821 inhibitors could be therapeutic for antisocial personality disorder . Antisocial personality traits are an important topic for research . The societal cost of these behaviors encourages efforts at a better understanding of central nervous system causes . Catecholamine genes are being studied to facilitate this understanding , and some tentative findings are being reached about several of these genes . It seems that many genes play a role to produce antisocial behaviors so complexity of elucidating each gene is obvious . One conclusion that could be drawn from the current research findings is that DA2 like receptors ( P14416 , P35462 , P21917 ) with alleles that decrease neurotransmission are facilitatory of antisocial behaviors . DA2 like receptors cause neuronal firing to inhibit many peripheral functions through adenylyl cyclase inhibition . When these receptors are less active by genetically decreased density , lower affinity , or by low dopamine levels as final common pathways then inhibition is released and a state of disinhibition can be said to describe this state . Peripheral metabolism is increased and behavioral activation is noted . P00797 is disinhibited in this setting thus allowing sympathetic nervous system activation . The fight or flight behaviors thus produced , in the extreme , would be the setting of antisocial behavior . Research validates this hypothesis . Understanding this final common pathway toward antisocial behavior should lead to better treatment for individuals with this pattern of behavior before they have caused harm to themselves and others . P12821 inhibitors are well tolerated drugs used in the treatment of hypertension and heart failure and would also treat antisocial behavior disorders .",
"P21728 behavioral responsitivity following selective lesions of the striatal patch compartment during development . The behavioral effects of selective destruction of the dopamine ( DA ) input to the patch compartment of rat striatum early in development was investigated . Rat pups were given bilateral intrastriatal ( i . s . ) injections of the neurotoxin 6 - hydroxydopamine ( 6 - OHDA ) on day of birth ( P0 ) or postnatal day 1 ( P1 ) , which resulted in selective behavioral alterations following DA agonist treatment in adulthood . Neonatally - lesioned rats exhibited self - biting behavior following treatment with the DA precursor L - dihydroxyphenylalanine ( DB01235 ) . In response to treatment with the selective D1 agonist SKF38393 , there was an increased incidence of abnormal perioral movements . The cataleptogenic effects of the D1 antagonist SCH23390 and the D2 antagonist haloperidol were also studied . Neonatally - lesioned rats were significantly less cataleptic compared to control rats following D1 antagonist treatment , but not following D2 antagonist treatment . Autoradiographs of [ 3H ] mazindol binding to DA uptake sites ( a measure of DA terminal density ) showed a ' patchy ' loss of approx . 40 - 50 % in striatal tissue sections derived from the i . s . lesioned rats . These data suggest that injections of 6 - OHDA into the striatum during this early postnatal period cause a DA lesion that results in long - term effects on a D1 receptor system .",
"___MASK30___ - arginine conjugate , a novel HIV - 1 Tat antagonist : synthesis and anti - HIV activities . HIV - 1 transactivating protein Tat is essential for virus replication and progression of HIV disease . HIV - 1 Tat stimulates transactivation by binding to HIV - 1 transactivator responsive element ( TAR ) RNA , and while secreted extracellularly , it acts as an immunosuppressor , an activator of quiescent T - cells for productive HIV - 1 infection , and by binding to CXC chemokine receptor type 4 ( P61073 ) as a chemokine analogue . Here we present a novel HIV - 1 Tat antagonist , a neomycin B - hexaarginine conjugate ( NeoR ) , which inhibits Tat transactivation and antagonizes Tat extracellular activities , such as increased viral production , induction of P61073 expression , suppression of CD3 - activated proliferation of lymphocytes , and upregulation of the CD8 receptor . Moreover , Tat inhibits binding of fluoresceine isothiocyanate ( FITC ) - labeled NeoR to human peripheral blood mononuclear cells ( PBMC ) , indicating that Tat and NeoR bind to the same cellular target . This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to P61073 . Furthermore , NeoR suppresses HIV - 1 binding to cells . Importantly , NeoR accumulates in the cell nuclei and inhibits the replication of M - and T - tropic HIV - 1 laboratory isolates ( EC ( 50 ) = 0 . 8 - 5 . 3 microM ) . A putative model structure for the TAR - NeoR complex , which complies with available experimental data , is presented . We conclude that NeoR is a multitarget HIV - 1 inhibitor ; the structure , and molecular modeling and dynamics , suggest its binding to TAR RNA . NeoR inhibits HIV - 1 binding to cells , partially by blocking the P61073 HIV - 1 coreceptor , and it antagonizes Tat functions . NeoR is therefore an attractive lead compound , capable of interfering with different stages of HIV infection and AIDS pathogenesis .",
"Blockade of globus pallidus adenosine A ( 2A ) receptors displays antiparkinsonian activity in 6 - hydroxydopamine - lesioned rats treated with D ( 1 ) or P14416 agonists . We have recently demonstrated how antagonism of adenosine A ( 2A ) receptors within the globus pallidus ( GP ) ipsilateral to dopaminergic denervation potentiates contralateral rotational behavior induced by the dopamine precursor DB01235 in 6 - hydroxydopamine - lesioned hemiparkinsonian rats . To further characterize the influence of pallidal A ( 2A ) receptor blockade on the motor stimulant effects elicited by dopamine receptor activation , hemiparkinsonian rats were infused with the water - soluble A ( 2A ) antagonist P35240 BT2 in the GP , alone or in combination with systemic administration of either SKF 38393 or quinpirole , to stimulate dopamine D ( 1 ) or D ( 2 ) receptors , respectively . P35240 BT2 alone ( 5 mug / 1 mul ) neither altered motor behavior nor produced postural asymmetry . In contrast , the contralateral rotations elicited by SKF 38393 ( 1 . 5 mg / kg ) as well as quinpirole ( 0 . 05 mg / kg ) were potentiated by the concomitant intrapallidal infusion of P35240 BT2 . The results of this study demonstrate that blockade of pallidal A ( 2A ) receptors exerts a facilitatory influence on the motor effects produced by the selective stimulation of either D ( 1 ) or D ( 2 ) dopamine receptors in hemiparkinsonian rats and suggest an involvement of GP in the antiparkinsonian activity of A ( 2A ) receptor antagonists .",
"Identification and quantification of dopamine receptor 2 in human eutopic and ectopic endometrium : a novel molecular target for endometriosis therapy . Previous studies in an experimental mouse model of endometriosis have shown that the dopamine agonist ( DA ) cabergoline ( Cb2 ) reduces angiogenesis and endometriotic lesions , hypothetically binding to the dopamine receptor type - 2 ( P14416 ) . To date , this has not been described in human endometrium and / or endometriotic lesions . Thus , we aimed to investigate the presence of P14416 in said tissues . Endometrium fragments were implanted in nude mice treated with different doses of Cb2 . Polymerase chain reaction assays and immunohistochemistry were performed to analyze the gene and protein expressions ( respectively ) of P14416 , P15692 , and P15692 receptor - 2 ( P35968 ) . In addition , lesions and endometrium from women with mild and severe endometriosis and endometrium from healthy women were collected to analyze their gene expression profile . In experimental endometriosis , P14416 was expressed at gene and protein levels in all three groups . P15692 gene and protein expressions were significantly lower in lesions treated with Cb2 than in controls . P35968 protein expression was significantly lower in experimental lesions treated with Cb2 than in controls . In eutopic endometria , there was a significant decrease in P14416 expression and an increase in P15692 in women with mild and severe endometriosis with respect to healthy patients . In endometriosis , P35968 expression was significantly higher in red than in white and black lesions . P15692 expression was significantly lower in black than in red lesions . P14416 is present in the human eutopic and ectopic endometrium and is regulated by DA , which provides the rationale for pilot studies to explore its use in the treatment of endometriosis .",
"Genetics of Alzheimer ' s disease . A rapidly evolving field . Genetic factors have a variable impact on Alzheimer ' s Disease ( AD ) , ranging from familial forms that are transmitted in an autosomal dominant fashion to sporadic AD , where a polygenic component is present . Most genes conferring susceptibility to AD are related to amyloid - beta deposition ( P05067 ; P49768 ; PS2 ; P02649 ; P01034 ; ubiquilin - 1 ) , oxidative stress ( NOS2 ; NOS3 ) and inflammatory response ( P01583 ; P01584 ; P05231 ; P01375 ) . Genome - wide analyses , transcriptomics and proteomics approaches have pointed also to proapoptotic genes as increasing AD liability . Depression and psychotic symptoms that occur in a large proportion of AD patients have been associated with monoamine genes coding for metabolic enzymes ( P21964 ) , transporters ( 5 - HTTLPR ) and receptors ( P21728 ; P35462 ) . Genetic testing may be useful to confirm the diagnosis of AD in individuals with clinical signs of dementia , while it is generally not recommended as a predictive testing for AD in asymptomatic individuals . Drugs currently in use to treat AD are effective in only 20 % of patients ; their therapeutic effect is predominantly under genetic control ( O43174 gene ; P02649 ) . Environmental factors have been shown to moderate the effects of genes on psychiatric disorders such as depression , schizophrenia and ADHD . The study of gene - environment interactions in AD , that are still poorly understood , is essential to predict disease - risk in asymptomatic individuals . Genomics will provide a dynamic picture of biological processes in AD and new targets for the forthcoming anti - AD drugs .",
"Genetic basis of delay discounting in frequent gamblers : examination of a priori candidates and exploration of a panel of dopamine - related loci . INTRODUCTION : Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards . It has been consistently linked to pathological gambling and other forms of addictive behavior , and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders ( i . e . , an endophenotype ) . Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission . The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine - related variants in a sample of frequent gamblers . METHODS : Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva . RESULTS : In a priori tests , two loci previously associated with delayed reward discounting ( rs1800497 and rs4680 ) were not replicated , however , the long form of P21917 VNTR was significantly associated with lower discounting of delayed rewards . Exploratory analysis of the dopamine - related panel revealed 11 additional significant associations in genes associated with dopamine synthesis , breakdown , reuptake , and receptor function ( P35462 , Q01959 , DDC , P09172 , and Q05940 ) . An aggregate genetic risk score from the nominally significant loci accounted for 17 % of the variance in discounting . Mediational analyses largely supported the presence of indirect effects between the associated loci , delay discounting , and pathological gambling severity . CONCLUSIONS : These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting .",
"Single - nucleotide polymorphisms of the dopamine D2 receptor increase inflammation and fibrosis in human renal proximal tubule cells . The dopamine D2 receptor ( D2R ) negatively regulates inflammation in mouse renal proximal tubule cells ( RPTCs ) , and lack or downregulation of the receptor in mice increases the vulnerability to renal inflammation independent of blood pressure . Some common single - nucleotide polymorphisms ( SNPs ; rs6276 , rs6277 , and rs1800497 ) in the human P14416 gene are associated with decreased D2R expression and function , as well as high blood pressure . We tested the hypothesis that human RPTCs ( hRPTCs ) expressing these SNPs have increased expression of inflammatory and injury markers . We studied immortalized hRPTCs carrying D2R SNPs and compared them with cells carrying no D2R SNPs . RPTCs with D2R SNPs had decreased D2R expression and function . The expressions of the proinflammatory tumor necrosis factor - α and the profibrotic transforming growth factor - β1 and its signaling targets P84022 and Snail1 were increased in hRPTC with D2R SNPs . These cells also showed induction of epithelial mesenchymal transition and production of extracellular matrix proteins , assessed by increased vimentin , fibronectin 1 , and collagen I a1 . To test the specificity of these D2R SNP effects , hRPTC with D2R SNPs were transfected with a plasmid encoding wild - type P14416 . The expression of D2R was increased and that of transforming growth factor - β1 , P84022 , Snail1 , vimentin , fibronectin 1 , and collagen I a1 was decreased in hRPTC with D2R SNPs transfected with wild - type P14416 compared with hRPTC - D2R SNP transfected with empty vector . These data support the hypothesis that D2R function has protective effects in hRPTCs and suggest that carriers of these SNPs may be prone to chronic renal disease and high blood pressure .",
"Expression of P20839 and P12268 after transplantation and initiation of immunosuppression . BACKGROUND : ___MASK21___ ( DB00603 ) mediates immunosuppressive effects by inhibiting inosine monophosphate dehydrogenase ( IMPDH ) . Induction of IMPDH activity has been observed in whole blood and erythrocyte samples during immunosuppressive therapy . Information concerning the mechanisms for increased IMPDH activity is limited and the potential implications of induction have been debated . METHODS : Whole blood , P01730 + cell , and reticulocyte samples were collected from 30 renal transplant patients pre - and posttransplantation . The expressions of two IMPDH isoforms , type 1 and 2 , were analyzed by real - time reverse - transcription polymerase chain reaction and quantified using a housekeeping gene index . The IMPDH activity was determined by ultraviolet high - performance liquid chromatography . RESULTS : Transplantation and the initiation of immunosuppressive therapy was associated with increased P20839 ( 50 - 88 % , P < 0 . 0005 ) and decreased P12268 ( 42 - 56 % , P < 0 . 0005 ) expression . In P01730 + cells , however , P12268 increased ( 15 % , P = 0 . 009 ) . These changes are probably related to glucocorticoid effects . Two weeks posttransplant , DB00603 - treated patients displayed elevated P20839 and 2 in reticulocytes , suggesting enzyme induction in these cells during prolonged DB00603 therapy . Patients with acute rejection during follow - up demonstrated higher P12268 expression in P01730 + cells pretransplant than nonrejecting patients ( median expression 1 . 26 vs . 0 . 87 respectively , P = 0 . 017 ) . CONCLUSIONS : Knowledge of changes in P20839 and 2 expression after transplantation and initiation of immunosuppression is important considering the action of DB00603 on IMPDH and the potential for pharmacodynamic monitoring of DB00603 by measuring IMPDH activity . The expression of P12268 in P01730 + cells pretransplant may be an indicator of immune activation .",
"Neurogenetics of aggressive behavior : studies in primates . Aggressive behavior can have adaptive value in certain environmental contexts , but when extreme or executed inappropriately , can also lead to maladaptive outcomes . Neurogenetic studies performed in nonhuman primates have shown that genetic variation that impacts reward sensitivity , impulsivity , and anxiety can contribute to individual differences in aggressive behavior . Genetic polymorphisms in the coding or promoter regions of the Mu - Opioid Receptor ( P35372 ) , DB01285 Releasing Hormone ( P06850 ) , Monoamine Oxidase A ( P21397 ) , Dopamine D4 Receptor ( P21917 ) , and Serotonin Transporter ( P31645 ) genes have been shown to be functionally similar in humans and rhesus macaques and have been demonstrated to contribute to individual differences in aggression . This body of literature suggests mechanisms by which genetic variation that promotes aggressivity could simultaneously increase evolutionary success while making modern humans more vulnerable to psychopathology .",
"Variants of dopamine and serotonin candidate genes as predictors of response to risperidone treatment in first - episode schizophrenia . AIMS : Abnormalities in dopaminergic and serotonergic transmission systems are thought to be involved in the pathophysiology of schizophrenia and the mechanisms underlying the therapeutic effects of antipsychotics . We conducted a pharmacogenetic study to evaluate whether variants in dopamine - related genes ( P21728 - P21918 , P31749 and GSK3beta ) and serotonin receptor genes ( P08908 , P28222 , P28221 , P28223 , P28335 , P50406 and P34969 ) can be used to predict the efficacy of risperidone treatment for schizophrenia . MATERIALS & METHODS : A total of 120 first - episode neuroleptic - naive schizophrenia patients were treated with risperidone monotherapy for 8 weeks and clinical symptoms were evaluated by the Positive and Negative Syndrome Scale . RESULTS : Among the 30 variants that we examined , two SNPs in P14416 ( - 241A > G [ rs1799978 ] and TaqIA [ rs1800497 ] ) and two SNPs in P31749 ( P31749 - SNP1 [ rs3803300 ] and P31749 - SNP5 [ rs2494732 ] ) were significant predictors of treatment response to risperidone . CONCLUSION : These data suggest that the SNPs in P14416 and P31749 may influence the treatment response to risperidone in schizophrenia patients .",
"P35462 stimulation underlies the development of DB01235 - induced dyskinesia in animal models of Parkinson ' s disease . Development of DB01235 - induced dyskinesia ( LID ) remains a major problem in the long - term treatment of Parkinson ' s disease ( PD ) . Sensitization to DB01235 correlates with ectopic expression of D3 dopamine receptors in the striatum , implicating D3 receptors in development of LID . We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP - lesioned marmosets without effecting the anti - parkinsonian actions of DB01235 . Furthermore , following a 14 day washout , when challenged with DB01235 in the absence of S33084 , these animals continued to exhibit reduced LID . In the 6 - OHDA - lesioned rat , S33084 similarly attenuated development of behavioural sensitization to DB01235 . Additionally , DB01235 - induced elevations in striatal pre - proenkephalin - A ( PPE - A ) ( but not PPE - B , phospho [ DB00156 ( 34 )] Q9UD71 , D1 , and D2 receptor mRNA or D3 receptor levels ) were reduced in S33084 treated animals . Our data suggest a role for D3 receptors in the development of LID and suggest that initiating DB01235 treatment with a D3 antagonist may reduce the development of LID in PD .",
"D3 dopamine receptor activates phospholipase D through a pertussis toxin - insensitive pathway . Within the dopamine receptor family , the P35462 ' s function remains inadequately described . The D ( 3 ) receptor has been shown to couple to inhibition of adenylyl cyclase , stimulation of mitogenesis , and regulation of K (+) and Ca ( 2 +) currents , all in a pertussis toxin ( PTX ) - sensitive manner . Here we report D ( 3 ) receptor activation of the phospholipase D ( PLD ) enzyme in P29320 293 cells heterologously expressing the human D ( 3 ) receptor . Activation by agonist is dose dependent and displays the pharmacology expected of the D ( 3 ) receptor . The D ( 3 ) receptor specific antagonists AJ - 76 and U99194A ablated the increase in activity by the preferring D ( 3 ) agonist ( + ) 7 - OH DPAT . In addition , the D ( 3 ) receptor - mediated activation of PLD is not mediated by G - proteins of the G ( i )/ G ( o ) family , as pretreatment with PTX had no effect . PLD activation is a novel finding for the D ( 3 ) receptor , and is the first example of an effector system where D ( 3 ) signals without G ( i )/ G ( o ) protein intermediates .",
"The Akt / mTor signaling cascade is modified during placentation in the porcine uterine tissue . Recently we showed that essential components for the initiation of protein synthesis , namely the eukaryotic initiation factor 4E ( P06730 , mRNA - cap - binding protein ) and its repressors Q13541 as well as Q13542 , are proteolytically processed in the porcine endometrium during implantation . Here , the situation during placentation was compared with ovariectomized ( OVX ) animals and animals on pregnancy day 1 ( PD1 ) . Furthermore , the research was extended to factors which phosphorylate P06730 and 4E - BPs and regulate their activities . These are the protein kinase B / mammalian target of rapamycin kinase ( Akt / mTor ) with the regulators Q8N122 and Rictor as well as the mitogen activated protein kinases ( MAPKs ) : extra cellular - signal regulated kinase 1 and 2 ( P27361 and P28482 ) . Striking differences in the placentation site ( PS ) and the areas aside from PS ( peri - PS ) were observed . P06730 and Q13542 truncation as well as Q13541 degradation took place in the endometrium of the peri - PS on PD24 . Accompanied by a fragmentation of Akt / mTor , no expression of Rictor was observed , whereas the abundance of Q8N122 was not altered . On the contrary , MAPKs expression and phosphorylation remained almost stable in the peri - PS . In conclusion , the results indicated that on PD24 the translational regulation was shifted to Q13542 control . Furthermore , the Akt / mTor signaling cascade seemed to be down regulated which suggest reduced phosphorylation of Q13542 . Whereas Akt was proteolyzed , the observed mTor fragments represented most likely splicing variants . The results indicate that translational control of gene expression is an important feature in the porcine endometrium during early pregnancy .",
"The role of the subthalamic nucleus in DB01235 induced dyskinesia in 6 - hydroxydopamine lesioned rats . DB01235 is the most effective treatment for Parkinson ' s disease ( PD ) , but prolonged use leads to disabling motor complications including dyskinesia . Strong evidence supports a role of the subthalamic nucleus ( Q05639 ) in the pathophysiology of PD whereas its role in dyskinesia is a matter of controversy . Here , we investigated the involvement of Q05639 in dyskinesia , using single - unit extracellular recording , behavioural and molecular approaches in hemi - parkinsonian rats rendered dyskinetic by chronic DB01235 administration . Our results show that chronic DB01235 treatment does not modify the abnormal Q05639 activity induced by the 6 - hydroxydopamine lesion of the nigrostriatal pathway in this model . Likewise , we observed a loss of Q05639 responsiveness to a single DB01235 dose both in lesioned and sham animals that received daily DB01235 treatment . We did not find any correlation between the abnormal involuntary movement ( AIM ) scores and the electrophysiological parameters of Q05639 neurons recorded 24 h or 20 - 120 min after the last DB01235 injection , except for the axial subscores . Nonetheless , unilateral chemical ablation of the Q05639 with ibotenic acid resulted in a reduction in global AIM scores and peak - severity of dyskinesia . In addition , Q05639 lesion decreased the anti - dyskinetogenic effect of buspirone in a reciprocal manner . Striatal protein expression was altered in dyskinetic animals with increases in ΔFosB , phosphoDARPP - 32 , dopamine receptor ( DR ) D3 and P14416 / P21728 ratio . The Q05639 lesion attenuated the striatal molecular changes and normalized the P14416 / P21728 ratio . Taken together , our results show that the Q05639 plays a role , if modest , in the physiopathology of dyskinesias .",
"Synergistic activity of activin A and basic fibroblast growth factor on tyrosine hydroxylase expression through P84022 and P27361 / P28482 MAPK signaling pathways . Activin has previously been shown to act as a nerve cell survival factor and to have neurotrophic effects on neurons . However , the role of activin in regulating neurotransmitter expression in the central nervous system and the exact mechanisms involved in this process are poorly understood . In the present study , we report that activin A and basic fibroblast growth factor ( P09038 ) synergistically increased the protein level of tyrosine hydroxylase ( TH ) , and also greatly increased the TH mRNA level , in both mouse Q14207 striatal primary cell cultures and the hippocampal neuronal cell line HT22 . Activin A and P09038 cooperatively stimulated nuclear translocation of P84022 and specifically activated P27361 / 2 , but not p38 or JNK . Interestingly , a specific inhibitor for MEK , U0126 , efficiently blocked the induction of TH promoter activity by activin A and P09038 , indicating that activin A collaborated with P09038 signaling to induce the TH gene through selective activation of P29323 - type Q96HU1 kinase in mouse striatal and HT22 cells . These data suggest that activin A may act in concert with P09038 for the development of TH - positive neurons .",
"Polymorphisms associated with egg number at 300 days of age in chickens . We looked for variations that could be associated with chicken egg number at 300 days of age ( EN300 ) in seven genes of the hypothalamic - pituitary - gonadal axis , including gonadotrophin - releasing hormone - I ( DB00644 ) , P30968 ( GnRHR ) , neuropeptide Y ( P01303 ) , dopamine D2 receptor ( P14416 ) , vasoactive intestinal polypeptide ( P01282 ) , P01282 receptor - 1 ( VIPR - 1 ) , prolactin ( PRL ) , and the QTL region between 87 and 105 cM of the Z chromosome . Ten mutations in the seven genes were chosen to do marker - trait association analyses in a population comprising 1310 chickens , which were obtained from a company located in Guangdong Province of China . The C1704887T of VIPR - 1 was found to have a highly significant association with EN300 . The T5841629C of P14416 and the C1715301T of VIPR - 1 were significantly associated with EN300 . A highly significant association was also found between the C1704887T - C1715301T haplotypes of VIPR - 1 and EN300 . H1H3 had the highest EN300 . Four PCR - RFLP variations in the candidate QTL region were selected to investigate their genetic effects on EN300 . The haplotypes of T32742468C - G32742603A in this region showed a highly significant association with EN300 . Bioinformatics analyses showed that both T32742468C and G32742603A were located in intron 1 of the SH3 - domain P62993 - like 2 ( Q99962 ) gene . We conclude that five SNPs , including C1704887T and C1715301T of VIPR - 1 , T5841629C of P14416 , and T32742468C and G32742603A of Q99962 , would be useful as markers for breeding to increase chicken EN300 .",
"P05231 , P01579 and P01375 production by liver - associated T cells and acute liver injury in rats administered concanavalin A . The relationship between the development of acute hepatitis and the production of P01375 P01579 and P05231 by liver - associated T lymphocytes following intravenous injection of concanavalin A ( Con A ) was studied in rats . Following a single injection of Con A , there was a dose and time - dependent correlation in the serum levels of serum alanine aminotransferase ( ALT ) , P05231 , P01579 and P01375 . These increases correlated with an increase in the numbers of P01730 + , CD8 + and CD25 + T cells in blood and P01730 + and CD25 + T cells in the liver perfusate , but not with CD8 + T cells in liver perfusate . Increased levels of P05231 , P01579 and P01375 were constitutively produced by liver - associated P01730 + T cells when cultured . In Con A - stimulated cultures , liver - associated P01730 + T cells secreted increasing levels of P01375 in a time - dependent manner following Con A injection , but P01375 production by peripheral blood lymphocytes was transient with peak levels detected at 1 h which then declined over 24 h . Histological examination of the liver revealed fatty change , hepatocyte degeneration and necrosis , with an associated cell infiltrate of neutrophils and P01730 + T cells both in the portal areas and around the central veins . These results support the hypothesis that Con A - induced liver damage is mediated by P01730 + T cells acting within the liver , at least in part through the secretion of P01375 , P01579 and P05231 .",
"Task - dependent interactions between dopamine D2 receptor polymorphisms and DB01235 in patients with Parkinson ' s disease . Variants in genes regulating dopamine transmission affect performance on tasks including working memory and executive function as well as temporal processing and sequence learning . In the current study , we determined whether a dopamine D2 receptor DNA sequence polymorphism interacts with DB01235 during motor tasks in patients with Parkinson ' s disease ( PD ) . Forty - five PD patients were genotyped for the P14416 polymorphism ( rs 1076560 , G > T ) . Patients performed an explicit motor sequence learning task and the grooved pegboard test in both ON and OFF DB01235 states . For motor sequence learning , P14416 genotype mediated DB01235 effects such that DB01235 associated improvements were only observed in the minor T allele carriers ( associated with lower D2 receptor availability , t10 =- 2 . 71 , p = 0 . 022 ) , whereas G homozygotes showed no performance change with DB01235 . For the grooved pegboard test , performance improved with DB01235 independent of patients ' P14416 genotype . Collectively these results demonstrate that common P14416 allelic differences found in the human population may explain how dopamine differentially contributes to performance across tasks and individuals .",
"Aripiprazole : pharmacodynamics of a dopamine partial agonist for the treatment of schizophrenia . Aripiprazole is the first approved atypical antipsychotic with a mechanism of action that exerts a partial agonism with high affinity at ___MASK39___ D2 - and Serotonin - P08908 - receptors as well as an antagonism at Serotonin - 5 - Q13049 - receptors . Aripiprazole provides good clinical effectiveness and a favorable profile of safety and tolerability . The special pharmacodynamics of aripiprazole are described herein .",
"Buspirone anti - dyskinetic effect is correlated with temporal normalization of dysregulated striatal P21728 signalling in DB01235 - treated rats . Dopamine replacement with l - DOPA is the most effective therapy in Parkinson ' s disease . However , with chronic treatment , half of the patients develop an abnormal motor response including dyskinesias . The specific molecular mechanisms underlying dyskinesias are not fully understood . In this study , we used a well - characterized animal model to first establish the molecular differences between rats that did and did not develop dyskinesias . We then investigated the molecular substrates implicated in the anti - dyskinetic effect of buspirone , a 5HT1A partial agonist . Striatal protein expression profile of dyskinetic animals revealed increased levels of the dopamine receptor ( DR ) D3 , ΔFosB and phospho ( p ) CREB , as well as an over - activation of the P21728 signalling pathway , reflected by elevated ratios of phosphorylated Q9UD71 and P28482 . Buspirone reduced the abnormal involuntary motor response in dyskinetic rats in a dose - dependent fashion . Buspirone ( 4 mg / kg ) dramatically reduced the presence and severity of dyskinesias ( by 83 % ) and normalized Q9UD71 and P28482 phosphorylation ratios , while the increases in P35462 , ΔFosB and pCREB observed in dyskinetic rats were not modified . Pharmacological experiments combining buspirone with 5HT1A and P35462 antagonists confirmed that normalization of both pDARPP32 and pERK2 is required , but not sufficient , for blocking dyskinesias . The correlation between pDARPP32 ratio and dyskinesias was significant but not strong , pointing to the involvement of convergent factors and signalling pathways . Our results suggest that in dyskinetic rats P35462 striatal over - expression could be instrumental in the activation of P21728 - downstream signalling and demonstrate that the anti - dyskinetic effect of buspirone in this model is correlated with P21728 pathway normalization .",
"The leukocytes expressing Q9UD71 are reduced in patients with schizophrenia and bipolar disorder . Bipolar disorder ( BPD ) and schizophrenia ( SCZ ) are severe disorders representing an enormous social , familiar and individual burden , being SCZ the most disabling psychiatric disorder characterized by psychosis and cognitive impairment . It is well known that SCZ and BPD are associated with abnormalities in dopamine signaling pathway . Recent data in the literature have demonstrated altered expression levels of some proteins involved in the modulation of this pathway in both brain and peripheral tissues . It was shown that protein and mRNA levels of dopamine and DB02527 regulated phosphoprotein ( Q9UD71 ) were downregulated in dorsolateral prefrontal cortex ( DLPFC ) of patients with SCZ or BPD when compared to controls . Due to the difficulty to access brain tissue and the absence of objective laboratory tests for bio - markers , we measured Q9UD71 expression in blood cell sub - populations ( P01730 + T lymphocytes , CD56 + NK cells , P15391 + B lymphocytes and P08571 + monocytes ) taking advantage of the close relation of nervous and immune systems . Using flow cytometry as the analytical method , our results have shown that the Q9UD71 expression was diminished in P01730 + T lymphocytes , P15391 + B lymphocytes and P08571 + monocytes of BPD patients and was also decreased in P01730 + T lymphocytes and CD56 + NK cells of SCZ patients . These results showed that Q9UD71 expression in immune cells agrees with reports of reduced Q9UD71 protein in the DLPFC of BPD or SCZ patients . Our data suggest that Q9UD71 expression in PBMC could be used as a source of bio - markers to help in the treatment response of neuropsychiatry disorders as a window to the changes in the brain of those patients .",
"Dependence on phosphoinositide 3 - kinase and DB01367 - RAF pathways drive the activity of RAF265 , a novel RAF / P35968 inhibitor , and RAD001 ( ___MASK9___ ) in combination . Activation of phosphatidylinositol - 3 - kinase ( PI3K ) - AKT and Kirsten rat sarcoma viral oncogene homologue ( P01116 ) can induce cellular immortalization , proliferation , and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy . This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of P01116 , PI3K - AKT , or both . We investigated whether the combination of a novel RAF / vascular endothelial growth factor receptor inhibitor , RAF265 , with a mammalian target of rapamycin ( P42345 ) inhibitor , RAD001 ( everolimus ) , could lead to enhanced antitumoral effects in vitro and in vivo . To address this question , we used cell lines with different status regarding P01116 , P42336 , and P15056 mutations , using immunoblotting to evaluate the inhibitors , and MTT and clonogenic assays for effects on cell viability and proliferation . Subcutaneous xenografts were used to assess the activity of the combination in vivo . RAD001 inhibited P42345 downstream signaling in all cell lines , whereas RAF265 inhibited RAF downstream signaling only in P15056 mutant cells . In vitro , addition of RAF265 to RAD001 led to decreased AKT , S6 , and P06730 binding protein 1 phosphorylation in HCT116 cells . In vitro and in vivo , RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells ( both P01116 mut , P42336 mut ) ; in contrast , the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells . The combination of RAF and P42345 inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both DB01367 - RAF and PI3K , possibly through the cross - inhibition of 4E binding protein 1 and S6 protein .",
"The influence of costimulation and regulatory P01730 + T cells on intestinal IgA immune responses . It is thought that IgA B - cell differentiation is highly dependent on activated P01730 + T cells . In particular , cell - cell interactions in the Peyer ' s patches involving P25942 and / or P33681 / P42081 have been implicated in germinal - center formation and IgA B - cell development . Also soluble factors , such as P05112 , P05113 , P05231 , and TGF beta may be critical for IgA B - cell differentiation in vivo . Here we report on some paradoxical findings with regard to IgA B - cell differentiation and specific mucosal immune responses that we have recently made using gene knockout mice . More specifically , we have investigated to what extent absence of P01730 + T cells , relevant cytokines , or T - cell - B - cell interactions would influence IgA B - cell differentiation in vivo . Using P01730 - or P05112 - gene knockout mice or mice made transgenic for ___MASK53___ , we found that , although specific responses were impaired , total IgA production and IgA B - cell differentiation appeared to proceed normally . However , a poor correlation was found between , on the one hand , GC formation and IgA differentiation and , on the other hand , the ability to respond to T - cell - dependent soluble protein antigens in these mice . Thus , despite the various deficiencies in P01730 + T - cell functions seemingly intact IgA B - cell development was observed .",
"___MASK77___ : An orally active renin inhibitor . P00797 inhibitors are antihypertensive drugs that block the first step in the renin - angiotensin system . Their mechanism of action differs from that of the angiotensin - converting enzyme inhibitors and angiotensin - receptor antagonists , but like these drugs , renin inhibitors interrupt the negative feedback effects of angiotensin II on renin secretion . The renin - angiotensin - aldosterone system ( RAAS ) has long been recognized to play a significant role in hypertension pathophysiology . Certain agents that modify the RAAS can control blood pressure and improve cardiovascular outcomes . Optimization of this compound by Novartis led to the development of aliskiren - the only direct renin inhibitor which is clinically used as an antihypertensive drug . ___MASK77___ is the first of a new class of antihypertensive agents . ___MASK77___ is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once - daily oral dosing . In short - term studies , it was effective in lowering blood pressure either alone or in combination with valsartan and hydrochlorothiazide , and had a low incidence of serious adverse effects . It was approved by the Food and Drug Administration in 2007 for the use as a monotherapy or in combination with other antihypertensives . Greater reductions in blood pressure have been achieved when aliskiren was used in combination with hydrochlorothiazide or an angiotensin - receptor blocker . The most common adverse effects reported in clinical trials were headache , fatigue , dizziness , diarrhea , and nasopharyngitis . ___MASK77___ has not been studied in patients with moderate renal dysfunction ; as an RAAS - acting drug , it should be prescribed for such patients only with caution .",
"Comparison of rating scales used to evaluate DB01235 - induced dyskinesia in the 6 - OHDA lesioned rat . Abnormal involuntary movement ( AIM ) rating scales are frequently used to study the mechanisms underlying DB01235 - induced dyskinesia ( LID ) in 6 - OHDA lesioned rodents and the propensity of novel treatments for Parkinson ' s disease to induce or alleviate similar abnormal behaviours . Despite the existence of at least one well validated method , other AIM scales are also in use . Moreover , there have been developments and variations in the original scales and their methods of use , without re - validation . In this study , 6 - OHDA medial forebrain bundle lesioned Sprague - Dawley rats were treated with chronic DB01235 6 mg / kg / day for 5 weeks followed by 12 mg / kg / day for another 5 weeks . Rats were assessed weekly by simultaneous ratings on four published AIM and stereotypy scales with concurrent recording of rotation , over 3 hours following DB01235 injection . Three contemporary AIM scales have then been validated pharmacologically using agents that are known to reduce LID clinically and in primates ( amantadine ) or to interfere with the activity of DB01235 ( the D ( 1 ) and P14416 antagonists , P35240 - 23390 and raclopride ) respectively . We also demonstrate that AIM , stereotypic and rotational behaviour are distinct motor dysfunctions induced by chronic and acute treatment of DB01235 , and should be assessed separately . The undertaking of assessments at multiple time points is essential especially when testing the efficacy of new potential anti - dyskinetic treatments . Importantly critical to all AIM and rotation testing is the internal validation of both the scale being used and the environment being used .",
"P21728 - mediated inhibition of NADPH oxidase activity in human kidney cells occurs via protein kinase A - protein kinase C cross talk . Dopamine cellular signaling via the D ( 1 ) receptor ( D ( 1 ) R ) involves both protein kinase A ( PKA ) and protein kinase C ( PKC ) , but the PKC isoform involved has not been determined . Therefore , we tested the hypothesis that the D ( 1 ) R - mediated inhibition of NADPH oxidase activity involves cross talk between PKA and a specific PKC isoform ( s ) . In P29320 - 293 cells heterologously expressing human D ( 1 ) R ( P29320 - hD ( 1 ) ) , fenoldopam , a D ( 1 ) R agonist , and phorbol 12 - myristate 13 - acetate ( PMA ) , a PKC activator , inhibited oxidase activity in a time - and concentration - dependent manner . The D ( 1 ) R - mediated inhibition of oxidase activity ( 68 . 1 ± 3 . 6 % ) was attenuated by two PKA inhibitors , H89 ( 10μmol / L ; 88 ± 8 . 1 % ) and Rp - DB02527 ( 10μmol / L ; 97 . 7 ± 6 . 7 % ) , and two PKC inhibitors , bisindolylmaleimide I ( 1μmol / L ; 94 ± 6 % ) and staurosporine ( 10nmol / L ; 93 ± 8 % ) , which by themselves had no effect ( n = 4 - 8 / group ) . The inhibitory effect of PMA ( 1μmol / L ) on oxidase activity ( 73 ± 3 . 2 % ) was blocked by H89 ( 100 ± 7 . 8 % ; n = 5 or 6 / group ) . The PMA - mediated inhibition of NADPH oxidase activity was accompanied by an increase in PKCθ ( S676 ) , an effect that was also blocked by H89 . Fenoldopam ( 1μmol / L ) also increased PKCθ ( S676 ) in P29320 - hD ( 1 ) and human renal proximal tubule ( RPT ) cells . Knockdown of PKCθ with siRNA in RPT cells prevented the inhibitory effect of fenoldopam on NADPH oxidase activity . Our studies demonstrate for the first time that cross talk between PKA and PKCθ plays an important role in the D ( 1 ) R - mediated negative regulation of NADPH oxidase activity in human kidney cells .",
"Signatures of positive selection in genes associated with human skin pigmentation as revealed from analyses of single nucleotide polymorphisms . Phenotypic variation between human populations in skin pigmentation correlates with latitude at the continental level . A large number of hypotheses involving genetic adaptation have been proposed to explain human variation in skin colour , but only limited genetic evidence for positive selection has been presented . To shed light on the evolutionary genetic history of human variation in skin colour we inspected 118 genes associated with skin pigmentation in the Perlegen dataset , studying single nucleotide polymorphisms ( SNPs ) , and analyzed 55 genes in detail . We identified eight genes that are associated with the melanin pathway ( Q9UMX9 , Q04671 , P17643 , P40126 , P21583 , P00533 , P14416 and Q03181 ) and presented significant differences in genetic variation between Europeans , Africans and Asians . In six of these genes we detected , by means of the EHH test , variability patterns that are compatible with the hypothesis of local positive selection in Europeans ( Q04671 , P17643 and P21583 ) and in Asians ( Q04671 , P40126 , P21583 , P00533 and P14416 ) , whereas signals were scarce in Africans ( P40126 , P00533 and P14416 ) . Furthermore , a statistically significant correlation between genotypic variation in four pigmentation candidate genes and phenotypic variation of skin colour in 51 worldwide human populations was revealed . Overall , our data also suggest that light skin colour is the derived state and is of independent origin in Europeans and Asians , whereas dark skin color seems of unique origin , reflecting the ancestral state in humans .",
"Dopamine selectively reduces GABA ( B ) transmission onto dopaminergic neurones by an unconventional presynaptic action . The functioning of midbrain dopaminergic neurones is closely involved in mental processes and movement . In particular the modulation of the inhibitory inputs on these cells might be crucial in controlling firing activity and dopamine ( DA ) release in the brain . Here , we report a concentration - dependent depressant action of dopamine on the GABA ( B ) IPSPs intracellularly recorded from dopaminergic neurones . Such effect was observed in spite of the presence of D ( 1 )/ P14416 antagonists . A reduction of the GABA ( B ) IPSPs was also caused by noradrenaline ( norepinephrine ) and by L - beta - 3 , 4 - dihydroxyphenylalanine ( DB01235 ) , which is metabolically transformed into DA . The DA - induced depression of the IPSPs was partially antagonised by the alpha2 antagonists yohimbine and phentolamine . DA did not change the postsynaptic effects of the GABA ( B ) agonist baclofen , suggesting a presynaptic site of action . Furthermore , DA did not modulate the GABA ( A )- mediated IPSP . The DA - induced depression of the GABA ( B ) IPSP occluded the depression produced by serotonin and was not antagonized by serotonin antagonists . The DA - and 5 - HT - induced depression of the GABA ( B ) IPSP persisted when calcium and potassium currents were reduced in to the presynaptic terminals . These results describe an unconventional presynaptic , D ( 1 ) and D ( 2 ) independent action of DA on the GABA ( B ) IPSP . This might have a principal role in determining therapeutic / side effects of DB01235 and antipsychotics and could be also involved in drug abuse .",
"The A1 allele of the human D2 dopamine receptor gene is associated with increased activity of striatal L - amino acid decarboxylase in healthy subjects . The A1 allele of the TaqI restriction fragment length polymorphism ( RFLP ) of the human dopamine D2 receptor gene ( P14416 ) is associated with a low density of D2 dopamine receptors in the striatum . Because of the important role of D2 autoreceptors in regulating dopamine synthesis , we aimed to examine whether subjects with the A1 allele have altered presynaptic dopamine function in the brain . We also studied the effects of two other P14416 polymorphisms , C957 T and -- 141C Ins / Del , which have been suggested to affect D2 receptor levels in brain . The relationships between the TaqIA RFLP , C957 T and -- 141C Ins / Del polymorphisms and striatal dopamine synthesis in 33 healthy Finnish volunteers were studied using positron emission tomography and [ 18F ] fluorodopa ( [ 18F ] FDOPA ) , a radiolabelled analog of the dopamine precursor DB01235 . Heterozygous carriers of the A1 allele ( A1 / A2 ; 10 subjects ) had significantly higher ( 18 % ) [ 18F ] FDOPA uptake in the putamen than subjects without the A1 allele ( A2 / A2 ; 23 subjects ) . C957 T and -- 141C Ins / Del polymorphisms did not significantly affect [ 18F ] FDOPA Ki values . These results demonstrate that the A1 allele of P14416 gene is associated with increased striatal activity of aromatic L - amino acid decarboxylase , the final enzyme in the biosynthesis of dopamine and the rate - limiting enzyme for trace amine ( e . g . beta - phenylethylamine ) synthesis . The finding can be explained by lower D2 receptor expression leading to decreased autoreceptor function , and suggests that dopamine and / or trace amine synthesis rate is increased in the brains of A1 allele carriers .",
"Involvement of 5 - HT₇ receptors in vortioxetine ' s modulation of circadian rhythms and episodic memory in rodents . Since poor circadian synchrony and cognitive dysfunction have been linked to affective disorders , antidepressants that target key 5 - HT ( serotonin ) receptor subtypes involved in circadian rhythm and cognitive regulation may have therapeutic utility . ___MASK38___ is a multimodal antidepressant that inhibits P28221 , 5 - Q9H205 , P34969 receptor activity , 5 - HT reuptake , and enhances the activity of P08908 and P28222 receptors . In this study , we investigated the effects of vortioxetine on the period length of O15055 :: LUC expression , circadian behavior , and episodic memory , using tissue explants from genetically modified O15055 :: LUC mice , locomotor activity rhythm monitoring , and the object recognition test , respectively . Incubation of tissue explants from the suprachiasmatic nucleus of O15055 :: LUC mice with 0 . 1 μM vortioxetine increased the period length of O15055 bioluminescence . Monitoring of daily wheel - running activity of Sprague - Dawley rats treated with vortioxetine ( 10 mg / kg , s . c . ) , alone or in combination with the P08908 receptor agonist flesinoxan ( 2 . 5 mg / kg , s . c . ) or the P34969 receptor antagonist SB269970 ( 30 mg / kg , s . c . ) , just prior to activity onset revealed significant delays in wheel - running behavior . The increase in circadian period length and the phase delay produced by vortioxetine were abolished in the presence of the P34969 receptor partial agonist AS19 . Finally , in the object recognition test , vortioxetine ( 10 mg / kg , i . p . ) increased the time spent exploring the novel object during the retention test and this effect was prevented by AS19 ( 5 mg / kg , i . p . ) . In conclusion , the present study shows that vortioxetine , partly via its P34969 receptor antagonism , induced a significant effect on circadian rhythm and presented promnesic properties in rodents .",
"Polymorphisms of dopamine receptor / transporter genes and risk of non - small cell lung cancer . BACKGROUND : The dopaminergic pathway may be of interest in assessing risk of non - small cell lung cancer ( NSCLC ) . Dopamine receptors are expressed in alveolar epithelial cells and human lung tumours , and dopamine inhibits both cell proliferation in vitro and growth of lung tumour xenografts in nude mice . Moreover , dopamine selectively inhibits the vascular permeability and angiogenic activity of vascular endothelial growth factor ( P15692 / P15692 ) . The bioavailability of dopamine is regulated by dopamine receptors D2 ( P14416 ) , D4 ( P21917 ) and dopamine transporter 1 ( Q01959 / Q01959 ) genes . METHODS : We have analysed 10 single nucleotide polymorphisms in P14416 , P21917 and Q01959 / Q01959 genes in relation to lung cancer risk in a case - control study of smoking subjects . The study subjects were 413 healthy individuals from general population and 335 NSCLC cases . Both cases and controls were Caucasians of Norwegian origin . RESULTS : We demonstrate that P14416 polymorphisms - 141Cdel , 3208G > T , TaqIB ; P21917 - 521C > T and Q01959 / Q01959 - 1476T > G are associated with a two - to five - fold increased NSCLC risk . The variant alleles of P14416 1412A > G and 960C > G had protective effects . CONCLUSION : The dopamine receptor / transport gene polymorphisms are associated with the risk of NSCLC among smokers . The data show that the polymorphisms resulting in lower dopamine bioavailability were associated with increased risk of NSCLC .",
"Catalog of 178 variations in the Japanese population among eight human genes encoding G protein - coupled receptors ( GPCRs ) . We screened DNAs from 48 Japanese individuals for single - nucleotide polymorphisms ( SNPs ) in eight genes encoding G protein - coupled receptors ( GPCRs ) by directly sequencing the entire relevant genomic regions except for repetitive - sequence elements . This approach identified 147 SNPs and 31 insertion / deletion polymorphisms among the eight GPCR genes . On average , we identified one SNP in every 584 nucleotides . Of the 147 SNPs , 69 were identified in P30556 , 12 in P50052 , nine in P35414 , 20 in P37288 , nine in P30518 , 16 in P21728 , six in P08514 , and six in P43119 . Twenty - one SNPs were located in 5 ' flanking regions , 76 in introns , 32 in exons , and 18 in 3 ' flanking regions . These variants should contribute to investigations of possible correlations between genotypes and phenotypes as regards susceptibility to disease or responsiveness to drug therapy ."
] |
[
"___MASK21___",
"___MASK30___",
"___MASK38___",
"___MASK39___",
"___MASK42___",
"___MASK53___",
"___MASK77___",
"___MASK87___",
"___MASK9___"
] |
___MASK77___
|
MH_train_498
|
interacts_with DB00674?
|
[
"P01308 suppresses IKs ( P51787 / P15382 ) currents , which require β - subunit P15382 . Abnormal QT prolongation in diabetic patients has become a clinical problem because it increases the risk of lethal ventricular arrhythmia . In an animal model of type 1 diabetes mellitus , several ion currents , including the slowly activating delayed rectifier potassium current ( IKs ) , are altered . The IKs channel is composed of P51787 and P15382 subunits , whose genetic mutations are well known to cause long QT syndrome . Although insulin is known to affect many physiological and pathophysiological events in the heart , acute effects of insulin on cardiac ion channels are poorly understood at present . This study was designed to investigate direct electrophysiological effects of insulin on IKs ( P51787 / P15382 ) currents . P51787 and P15382 were co - expressed in Xenopus oocytes , and whole cell currents were measured by a two - microelectrode voltage - clamp method . Acute application of insulin suppressed the P51787 / P15382 currents and phosphorylated Akt and extracellular signal - regulated kinase ( P29323 ) , the two major downstream effectors , in a concentration - dependent manner . Wortmannin ( 10 (- 6 ) M ) , a phosphoinositide 3 - kinase ( PI3K ) inhibitor , attenuated the suppression of the currents and phosphorylation of Akt by insulin , whereas U0126 ( 10 (- 5 ) M ) , a mitogen - activated protein kinase kinase ( MEK ) inhibitor , had no effect on insulin - induced suppression of the currents . In addition , insulin had little effect on P51787 currents without P15382 , which indicated an essential role of P15382 in the acute suppressive effects of insulin . Mutagenesis studies revealed amino acid residues 111 - 118 within the distal third C - terminus of P15382 as an important region . P01308 has direct electrophysiological effects on IKs currents , which may affect cardiac excitability .",
"DB00674 ameliorates the impairment of recognition memory in mice repeatedly treated with methamphetamine : involvement of allosteric potentiation of nicotinic acetylcholine receptors and dopaminergic - P27361 / 2 systems . DB00674 , a drug used to treat Alzheimer ' s disease , inhibits acetylcholinesterase ( P22303 ) and allosterically modulates nicotinic acetylcholine receptors ( nAChRs ) resulting in stimulation of catecholamine neurotransmission . In this study , we investigated whether galantamine exerts cognitive - improving effects through the allosteric modulation of nAChRs in an animal model of methamphetamine ( Meth ) psychosis . The mice treated with Meth ( 1 mg / kg . d ) for 7 d showed memory impairment in a novel object recognition test . DB00674 ( 3 mg / kg ) ameliorated the memory impairment , and it increased the extracellular dopamine release in the prefrontal cortex ( P27918 ) of Meth - treated mice . Donepezil , an P22303 inhibitor ( 1 mg / kg ) increased the extracellular ACh release in the P27918 , whereas it had no effect on the memory impairment in Meth - treated mice . The nAChR antagonist , mecamylamine , and dopamine D1 receptor antagonist , P35240 23390 , blocked the ameliorating effect of galantamine on Meth - induced memory impairment , whereas the muscarinic AChR antagonist , scopolamine , had no effect . The effects of galantamine on extracellular dopamine release were also antagonized by mecamylamine . DB00674 attenuated the defect of the novelty - induced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) . The ameliorating effect of galantamine on recognition memory in Meth - treated mice was negated by microinjection of an P29323 inhibitor , PD98059 , into the P27918 . These results suggest that the ameliorating effect of galantamine on Meth - induced memory impairment is associated with indirect activation of dopamine D1 receptor - P27361 / 2 following augmentation with dopaminergic neurotransmission in the P27918 through the allosteric activation of nAChRs . DB00674 could be a useful therapeutic agent for treating cognitive deficits in schizophrenia / Meth psychosis , as well as Alzheimer ' s disease .",
"Very early - onset lone atrial fibrillation patients have a high prevalence of rare variants in genes previously associated with atrial fibrillation . BACKGROUND : Atrial fibrillation ( AF ) is the most common cardiac arrhythmia . Currently , 14 genes important for ion channel function , intercellular signaling , and homeostatic control have been associated with AF . OBJECTIVE : We hypothesized that rare genetic variants in genes previously associated with AF had a higher prevalence in early - onset lone AF patients than in the background population . METHODS : Sequencing results of P51787 , Q12809 , Q14524 , P22460 , Q9UK17 , P15382 , 2 , 5 , P63252 , P35498 - 3B , P01160 , and P36382 from 192 early - onset lone AF patients were compared with data from the National Heart , Lung , and Blood Institute Exome Variant Server consisting of 6503 persons from 18 different cohort studies . RESULTS : Among the lone AF patients , 29 ( 7 . 6 % ) alleles harbored a novel or very rare variant ( minor allele frequency < 0 . 1 in the Exome Variant Server ) , a frequency that was significantly higher than what was found in the reference database ( 4 . 1 % ; with minor allele frequency < 0 . 1 ; P = . 0012 ) . Previously published electrophysiological data showed that 96 % ( n = 23 ) of the rare variants that has been functionally investigated ( n = 24 ) displayed significant functional changes . CONCLUSIONS : We report a much higher prevalence of rare variants in genes associated with AF in early - onset lone AF patients than in the background population . By presenting these data , we believe that we are the first to provide quantitative evidence for the role of rare variants across AF susceptibility genes as a possible pathophysiological substrate for AF .",
"Successful thrombolysis of a stroke with a pulmonary embolism in a young woman . BACKGROUND : Paradoxical embolism is a rare event , accounting for < 2 % of all arterial emboli . The diagnosis is often difficult , and consequences for the patient can be severe . CASE REPORT : We describe the case of a 35 - year - old female physician who presented to our Emergency Department ( ED ) in severe hemodynamic compromise , with an altered level of consciousness and major expressive aphasia 1 day after undergoing a leg varicosal stripping procedure under regional anesthesia . She was successfully thrombolyzed with 0 . 9 mg / kg of Recombinant Tissue P00747 Activator ( rtPA , ___MASK65___ ) and had a full recovery . CONCLUSION : To our knowledge , this is the first description of a case of massive pulmonary embolism associated with a paradoxical stroke related to patent foramen ovale that was thrombolyzed for both conditions with a \" neurological dose \" of rtPA . Although thrombolysis was completely successful in this case , indications and contraindications should be thoroughly respected . A more conservative approach with anticoagulation , or a more aggressive approach with surgical thrombectomy , can each potentially have a place in particular cases . Intra - arterial catheter - directed thrombolysis and percutaneous embolectomy are additional options to be considered when available , especially if there are contraindications for systemic thrombolysis .",
"___MASK100___ improves hippocampal neurogenesis and depression - like behaviors via P08908 receptor stimulation in olfactory bulbectomized mice . ___MASK100___ is a non - competitive inhibitor of both acetylcholinesterase ( P22303 ) and butylcholinesterase ( BuChE ) used to treat mild to moderate dementia in Alzheimer ' s disease ( AD ) patients . Although rivastigmine reportedly ameliorates cognitive dysfunction in these patients , its ability to improve Behavioral and Psychological Symptoms of Dementia ( BPSD ) remains unclear . To determine whether rivastigmine treatment antagonizes depression - like behaviors , we chronically administered rivastigmine ( 0 . 1 - 1 . 0mg / kg ) to olfactory bulbectomized ( OBX ) mice once a day for 2weeks , starting 2weeks after bulbectomy . Chronic treatment at 0 . 3 or 1 . 0mg / kg dose dependently and significantly improved depression - like behaviors , as assessed by tail suspension ( Q16762 ) , forced swim ( P19883 ) , locomotion and novelty - suppressed feeding ( NSFT ) tests . Importantly , co - administration with WAY - 100635 ( 1 . 0mg / kg ) , a P08908 receptor antagonist , but not ketanserin ( 1 . 0mg / kg , ) , a 5 - Q13049 receptor antagonist , completely blocked rivastigmine - induced anti - depressive effects , suggesting that P08908 receptor stimulation mediates this activity . Consistent with this observation , rivastigmine treatment significantly rescued impaired neurogenesis observed in OBX mice in a P08908 receptor - dependent manner . Furthermore , enhanced protein kinase B ( Akt ) and extracellular signal - regulated kinase ( P29323 ) phosphorylation seen following rivastigmine treatment was closely associated with improved neurogenesis . These effects were blocked by WAY - 100635 but not ketanserin treatment . Finally , we confirmed that P08908 but not 5 - Q13049 receptor stimulation by specific agonists mimicked rivastigmine - induced anti - depression activity and promoted hippocampal neurogenesis . We conclude that , in addition to enhancing the cholinergic system , rivastigmine treatment restores normal function of the hippocampal serotonergic system , an activity that likely ameliorates depressive behaviors in AD patients .",
"Atrial natriuretic peptide : a possible mediator involved in dexamethasone ' s inhibition of cell proliferation in multiple myeloma . Atrial natriuretic peptide ( P01160 ) has been recognized for several decades for its role of regulating blood pressure . Recently , cumulating evidences show that P01160 plays an anticancer role in various solid tumors via blocking the kinase cascade of Ras - Q02750 / 2 - P27361 / 2 with the result of inhibition of DNA synthesis . P01160 , as well as its receptors ( P16066 and P17342 ) has been identified present in the embryonic stem cell and a wide range of cancer cells . Various lymphoid organs , such as lymph nodes , have been detected the presence of P01160 . Multiple myeloma ( MM ) , though the therapies have evolved significantly , is still an incurable disease as B lymphocyte cell neoplasm . Dexamethasone is the cornerstone in treatment of MM via inactivation of Ras - Q02750 / 2 - P27361 / 2 cascade reaction . Coincidently , dexamethasone can increase the expression of P01160 markedly . Nevertheless , the role of P01160 in MM is unclear . Based on these results above , we raise the hypothesis that P01160 is involved in mediating dexamethasone ' s inhibition of proliferation in MM cells , which suggests that P01160 may be a potential agent to treat MM .",
"The low - potency , voltage - dependent Q12809 blocker propafenone -- molecular determinants and drug trapping . The molecular determinants of high - affinity human ether - a - go - go - related gene ( Q12809 ) potassium channel blockade by methanesulfonanilides include two aromatic residues ( Phe656 and Tyr652 ) on the inner helices ( S6 ) and residues on the pore helices that face into the inner cavity , but determinants for lower - affinity Q12809 blockers may be different . In this study , alanine - substituted Q12809 channel mutants of inner cavity residues were expressed in Xenopus laevis oocytes and were used to characterize the Q12809 channel binding site of the antiarrhythmic propafenone . ___MASK26___ ' s blockade of Q12809 was strongly dependent on residue Phe656 but was insensitive or weakly sensitive to mutation of Tyr652 , Thr623 , Ser624 , Val625 , Gly648 , or Val659 and did not require functional inactivation . Homology models of Q12809 based on KcsA and MthK crystal structures , representing the closed and open forms of the channel , respectively , suggest propafenone is trapped in the inner cavity and is unable to interact exclusively with Phe656 in the closed state ( whereas exclusive interactions between propafenone and Phe656 are found in the open - channel model ) . These findings are supported by very slow recovery of wild - type Q12809 channels from block at - 120 mV , but extremely rapid recovery of D540K channels that reopen at this potential . The experiments and modeling suggest that the open - state propafenone binding - site may be formed by the Phe656 residues alone . The binding site for propafenone ( which may involve pi - stacking interactions with two or more Phe656 side - chains ) is either perturbed or becomes less accessible because of closed - channel gating . This provides further evidence for the existence of gating - induced changes in the spatial location of Phe656 side chains .",
"Augmentation of methamphetamine - induced behaviors in transgenic mice lacking the trace amine - associated receptor 1 . The trace amine - associated receptor 1 ( Q96RJ0 ) is a G protein - coupled receptor that is functionally activated by amphetamine - based psychostimulants , including amphetamine , methamphetamine and DB01454 . Previous studies have shown that in transgenic mice lacking the Q96RJ0 gene ( Q96RJ0 knockout ; KO ) a single injection of amphetamine can produce enhanced behavioral responses compared to responses evoked in wild - type ( WT ) mice . Further , the psychostimulant effects of cocaine can be diminished by selective activation of Q96RJ0 . These findings suggest that Q96RJ0 might be implicated in the rewarding properties of psychostimulants . To investigate the role of Q96RJ0 in the rewarding effects of drugs of abuse , the psychomotor stimulating effects of amphetamine and methamphetamine and the conditioned rewarding effects of methamphetamine and morphine were compared between WT and Q96RJ0 KO mice . In locomotor activity studies , both single and repeated exposure to ___MASK43___ or methamphetamine generated significantly higher levels of total distance traveled in Q96RJ0 KO mice compared to WT mice . In conditioned place preference ( CPP ) studies , Q96RJ0 KO mice acquired methamphetamine - induced CPP earlier than WT mice and retained CPP longer during extinction training . In morphine - induced CPP , both WT and KO genotypes displayed similar levels of CPP . Results from locomotor activity studies suggest that Q96RJ0 may have a modulatory role in the behavioral sensitization to amphetamine - based psychostimulants . That methamphetamine - but not morphine - induced CPP was augmented in Q96RJ0 KO mice suggests a selective role of Q96RJ0 in the conditioned reinforcing effects of methamphetamine . Collectively , these findings provide support for a regulatory role of Q96RJ0 in methamphetamine signaling .",
"Genetic markers in the EET metabolic pathway are associated with outcomes in patients with aneurysmal subarachnoid hemorrhage . Preclinical studies show that epoxyeicosatrienoic acids ( EETs ) regulate cerebrovascular tone and protect against cerebral ischemia . We investigated the relationship between polymorphic genes involved in EET biosynthesis / metabolism , cytochrome P450 ( CYP ) eicosanoid levels , and outcomes in 363 patients with aneurysmal subarachnoid hemorrhage ( aSAH ) . Epoxyeicosatrienoic acids and dihydroxyeicosatetraenoic acid ( DHET ) cerebrospinal fluid ( P04141 ) levels , as well as acute outcomes defined by delayed cerebral ischemia ( P42126 ) or clinical neurologic deterioration ( CND ) , were assessed over 14 days . Long - term outcomes were defined by Modified Rankin Scale ( P59665 ) at 3 and 12 months . P10632 * 4 allele carriers had 44 % and 36 % lower mean EET and DHET P04141 levels ( P = 0 . 003 and P = 0 . 007 ) and were 2 . 2 - and 2 . 5 - fold more likely to develop P42126 and CND ( P = 0 . 039 and P = 0 . 041 ) , respectively . P34913 55Arg , P51589 * 7 , P10632 * 1B , and P10632 g . 36785A allele carriers had lower EET and DHET P04141 levels . P10632 g . 25369T and P10632 g . 36755A allele carriers had higher EET levels . Patients with P10632 * 2C and P34913 404del variants had worse long - term outcomes while those with P34913 287Gln , P51589 * 7 , and P11712 g . 816G variants had favorable outcomes . Epoxyeicosatrienoic acid levels were associated with Fisher grade and unfavorable 3 - month outcomes . Dihydroxyeicosatetraenoic acids were not associated with outcomes . No associations passed Bonferroni multiple testing correction . These are the first clinical data demonstrating the association between the EET biosynthesis / metabolic pathway and the pathophysiology of aSAH .",
"Somatostatin preserved blood brain barrier against cytokine induced alterations : possible role in multiple sclerosis . Multiple sclerosis ( MS ) is an inflammatory neurological disorder associated with demyelination , impaired blood brain barrier ( BBB ) , axonal damage and neuronal loss . In the present study , we measured somatostatin ( P61278 ) and tumor necrosis factor - α ( P01375 - α ) like immunoreactivity in P04141 samples from MS and non - MS patients . We also examined the role of P61278 in cytokines and lipopolysaccharide ( LPS ) - induced damage to the BBB using human brain endothelial cells in culture . Most of the cerebrospinal fluid ( P04141 ) samples studied from definite MS patients exhibited lower somatostatin ( P61278 ) - like immunoreactivity and higher expression of P01375 - α in comparison to non - MS patients . Treatment of cells with cytokines and LPS blocked P61278 secretion and decreased P61278 expression . Human brain endothelial cells expressed all five somatostatin receptors ( SSTRs ) with increased expression of P30874 and 4 upon treatment with cytokines and LPS . Cytokines and LPS - induced disruption of the tight junction proteins Zonula occludens ( ZO - 1 ) organization was restored in presence of P61278 , P30874 or P31391 selective agonists . Furthermore , inflammation induced changes in extracellular signal - regulated kinases ( P27361 / 2 and Q13164 ) signaling and altered expression of endothelial and inducible nitric oxide synthase are modulated in presence of P61278 . These data indicate that decreased levels of P61278 contribute to failure of the BBB in MS .",
"Gambogic acid inhibits angiogenesis through suppressing vascular endothelial growth factor - induced tyrosine phosphorylation of P35968 / Flk - 1 . Previous studies revealed that gambogic acid ( GA ) , the major active ingredient of gamboge , a brownish to orange resin exuded from Garcinia hanburryi tree in Southeast Asia , possessed significant anticancer activity both in vitro and in vivo . In this study , we explored the high antiangiogenic activities of GA for the first time . GA inhibits the P15692 - stimulated proliferation , migration and tube formation of human umbilical vein endothelial cells ( HUVECs ) as well as microvessel sprouting from rat aortic rings in vitro . Moreover , GA inhibits vessel growth in matrigel plugs and P62158 in vivo and transplanted tumor in mice . The results also indicated that GA decreases P15692 production of cultured tumor cells and inhibits P15692 - induced tyrosine phosphorylation of P35968 / Flk - 1 . This inhibition of receptor phosphorylation is correlated with a significant decrease in P15692 - triggered phosphorylated forms of P29323 , AKT and p38 . Taken together , these findings strongly suggest that GA might be a structurally novel angiogenesis inhibitor .",
"Different cholinesterase inhibitor effects on P04141 cholinesterases in Alzheimer patients . BACKGROUND : The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase ( P22303 ) and butyrylcholinesterase ( BuChE ) activities and protein levels , in the cerebrospinal fluid ( P04141 ) of Alzheimer disease ( AD ) patients . METHODS AND FINDINGS : AD patients aged 50 - 85 years were randomized to open - label treatment with oral rivastigmine , donepezil or galantamine for 13 weeks . P22303 and BuChE activities were assayed by Ellman ' s colorimetric method . Protein levels were assessed by enzyme - linked immunosorbent assay ( ELISA ) . Primary analyses were based on the Completer population ( randomized patients who completed Week 13 assessments ) . 63 patients were randomized to treatment . ___MASK100___ was associated with decreased P22303 activity by 42 . 6 % and decreased P22303 protein levels by 9 . 3 % , and decreased BuChE activity by 45 . 6 % and decreased BuChE protein levels by 21 . 8 % . DB00674 decreased P22303 activity by 2 . 1 % and BuChE activity by 0 . 5 % , but increased P22303 protein levels by 51 . 2 % and BuChE protein levels by 10 . 5 % . Donepezil increased P22303 and BuChE activities by 11 . 8 % and 2 . 8 % , respectively . Donepezil caused a 215 . 2 % increase in P22303 and 0 . 4 % increase in BuChE protein levels . Changes in mean P22303 - Readthrough / Synaptic ratios , which might reflect underlying neurodegenerative processes , were 1 . 4 , 0 . 6 , and 0 . 4 for rivastigmine , donepezil and galantamine , respectively . CONCLUSION : The findings suggest pharmacologically - induced differences between rivastigmine , donepezil and galantamine . ___MASK100___ provides sustained inhibition of P22303 and BuChE , while donepezil and galantamine do not inhibit BuChE and are associated with increases in P04141 P22303 protein levels . The clinical implications require evaluation .",
"___MASK7___ and MEK inhibitors induce synthetic lethality through paradoxical activation of RAF in drug - resistant chronic myeloid leukemia . We show that imatinib , nilotinib , and dasatinib possess weak off - target activity against RAF and , therefore , drive paradoxical activation of P15056 and CRAF in a DB01367 - dependent manner . Critically , because DB01367 is activated by P11274 - P00519 , in drug - resistant chronic myeloid leukemia ( CML ) cells , DB01367 activity persists in the presence of these drugs , driving paradoxical activation of P15056 , CRAF , MEK , and P29323 , and leading to an unexpected dependency on the pathway . Consequently , nilotinib synergizes with MEK inhibitors to kill drug - resistant CML cells and block tumor growth in mice . Thus , we show that imatinib , nilotinib , and dasatinib drive paradoxical RAF / MEK / P29323 pathway activation and have uncovered a synthetic lethal interaction that can be used to kill drug - resistant CML cells in vitro and in vivo .",
"The dopamine metabolite 3 - methoxytyramine is a neuromodulator . Dopamine ( 3 - hydroxytyramine ) is a well - known catecholamine neurotransmitter involved in multiple physiological functions including movement control . Here we report that the major extracellular metabolite of dopamine , 3 - methoxytyramine ( 3 - MT ) , can induce behavioral effects in a dopamine - independent manner and these effects are partially mediated by the trace amine associated receptor 1 ( Q96RJ0 ) . Unbiased in vivo screening of putative trace amine receptor ligands for potential effects on the movement control revealed that 3 - MT infused in the brain is able to induce a complex set of abnormal involuntary movements in mice acutely depleted of dopamine . In normal mice , the central administration of 3 - MT caused a temporary mild hyperactivity with a concomitant set of abnormal movements . Furthermore , 3 - MT induced significant P29323 and CREB phosphorylation in the mouse striatum , signaling events generally related to PKA - mediated DB02527 accumulation . In mice lacking Q96RJ0 , both behavioral and signaling effects of 3 - MT were partially attenuated , consistent with the ability of 3 - MT to activate Q96RJ0 receptors and cause DB02527 accumulation as well as P29323 and CREB phosphorylation in cellular assays . Thus , 3 - MT is not just an inactive metabolite of DA , but a novel neuromodulator that in certain situations may be involved in movement control . Further characterization of the physiological functions mediated by 3 - MT may advance understanding of the pathophysiology and pharmacology of brain disorders involving abnormal dopaminergic transmission , such as Parkinson ' s disease , dyskinesia and schizophrenia .",
"A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population : role for P11712 , P08684 / 5 and Q9BQB6 genes polymorphisms . ___MASK95___ is widely used in prophylaxis and treatment of thromboembolic disorders . However , its pharmacokinetics and pharmacodynamics vary according to several genetic and non - genetic factors . ___MASK95___ metabolism is mediated by P11712 and CYP3A enzymes . Moreover , Q9BQB6 is phenprocoumon target of action . Therefore , the aim of this study was to evaluate the association of single nucleotide polymorphisms ( SNPs ) in Q9BQB6 , P11712 , P08684 and P20815 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors . A total of 198 patients with stable phenprocoumon dose , 81 % of European ancestry , were investigated . Genotypes were determined by allelic discrimination with TaqMan assays . Polymorphisms - 1639G > A and 1173C > T in Q9BQB6 and the presence of P11712 * 2 and / or P11712 * 3 are associated with lower doses . On the other hand , 3730G > A in Q9BQB6 gene is associated with higher doses . No association was found between P08684 * 1B , P20815 * 3 and P20815 * 6 polymorphisms . Among non - genetic factors , gender , height , age and use of captopril , omeprazole , simvastatin and β - blockers are associated with dose . Two algorithms were derived : one for the whole sample explained 42 % of dose variation and one for patients of European ancestry only which explained 46 % of phenprocoumon dose . The mean absolute difference between observed and predicted dose was low in both models ( 3 . 92 mg / week and 3 . 54 mg / week , for models 1 and 2 , respectively ) . However , more studies with other genes and environmental factors are needed to test and to improve the algorithm .",
"P50406 mediates defective brain development in monoamine oxidase A - deficient mouse embryos . Monoamine oxidases A and B ( P21397 and P27338 ) are enzymes of the outer mitochondrial membrane that metabolize biogenic amines . In the adult central nervous system , MAOs have important functions for neurotransmitter homeostasis . Expression of MAO isoforms has been detected in the developing embryo . However , suppression of P27338 does not induce developmental alterations . In contrast , targeted inhibition and knockdown of P21397 expression ( E7 . 5 - E10 . 5 ) caused structural abnormalities in the brain . Here we explored the molecular mechanisms underlying defective brain development induced by P21397 knockdown during in vitro embryogenesis . The developmental alterations were paralleled by diminished apoptotic activity in the affected neuronal structures . Moreover , dysfunctional P21397 expression led to elevated levels of embryonic serotonin ( 5 - hydroxytryptamine ( 5 - HT ) ) , and we found that knockdown of serotonin receptor - 6 ( 5 - Htr6 ) expression or pharmacologic inhibition of 5 - Htr6 activity rescued the P21397 knockdown phenotype and restored apoptotic activity in the developing brain . Our data suggest that excessive 5 - Htr6 activation reduces activation of caspase - 3 and - 9 of the intrinsic apoptotic pathway and enhances expression of antiapoptotic proteins Bcl - 2 and Bcl - XL . Moreover , we found that elevated 5 - HT levels in P21397 knockdown embryos coincided with an enhanced activation of extracellular signal - regulated kinase 1 / 2 ( P27361 / 2 ) and a reduction of proliferating cell numbers . In summary , our findings suggest that excessive 5 - HT in P21397 - deficient mouse embryos triggers cellular signaling cascades via 5 - Htr6 , which suppresses developmental apoptosis in the brain and thus induces developmental retardations .",
"Estrogenic chemicals at puberty change ERalpha in the hypothalamus of male and female rats . The effects of two environmental endocrine disruptors , the synthetic pharmaceutical estrogen ___MASK1___ ( EE ) and bisphenol - A ( Q03001 ) , were analysed in male and female rats in a very sensitive developmental period , puberty . Immunohistochemistry was used to evaluate changes in the number of cells expressing estrogen receptors ( P03372 ) in the arcuate nucleus ( ARC ) , ventromedial nucleus ( VMH ) and medial preoptic area ( DB00603 ) of the hypothalamus . Animals were treated during early puberty , from P01160 23 to P01160 30 , with EE and Q03001 given orally every day . They were then sacrificed and perfused on P01160 37 or P01160 90 , and blood and brains were collected for hormonal determination ( testosterone and estradiol ) and immunohistochemistry ( estrogen receptors , ER ) . At P01160 37 , ER - labelled neurons were higher in males than in females in the ARC and DB00603 . EE and Q03001 increased ER - labelled neurons in the ARC and DB00603 . At P01160 90 , females showed higher ER - labelled neurons in the VMH . EE and Q03001 increased ER - labelled neurons in the DB00603 in females . EE increased testosterone in males at P01160 37 and estradiol in females at P01160 90 . These results indicate the ability of estrogenic chemicals to change the reproductive neural circuits during puberty in male and female rats .",
"___MASK20___ binding to human and rat dopamine and 5 - HT receptors . ___MASK20___ ( ___MASK20___ ; 1 - [ 4 -[ 3 -[ 4 -( 6 - fluoro - 1 , 2 - benzisoxazol - 3 - yl )- 1 - piperidinyl ] propoxy ] - 3 - methoxyphenyl ] ethanone ) is a compound currently in clinical trials for the treatment of schizophrenia . ___MASK20___ displays affinity for dopamine D2 receptors and for 5 - Q13049 receptors and has a variety of in vivo activities suggestive of an atypical antipsychotic . Here we present an examination of the affinity of iloperidone to a variety of human and rat homologs of dopamine and 5 - HT receptor subtypes . We employed receptor binding assays using membranes from cells stably expressing human dopamine D1 , D2S , D2L , D3 , D4 and D5 and 5 - Q13049 and P28335 receptors and rat P50406 and P34969 receptors . ___MASK20___ displayed higher affinity for the dopamine D3 receptor ( Ki = 7 . 1 nM ) than for the dopamine D4 receptor ( Ki = 25 nM ) . ___MASK20___ displayed high affinity for the P50406 and P34969 receptors ( Ki = 42 . 7 and 21 . 6 nM , respectively ) , and was found to have higher affinity for the 5 - Q13049 ( Ki = 5 . 6 nM ) than for the P28335 receptor ( Ki = 42 . 8 nM ) . The potential implications of this receptor binding profile are discussed in comparison with data for other antipsychotic compounds .",
"Fibrinolytic activity in the inner ear of human beings and guinea pigs . Fibrinolytic activity in the inner ear of human beings and guinea pigs was assayed qualitatively and quantitatively . It was found that fibrinolytic activity of the stria vascularis was caused by a conversion of plasminogen to plasmin by tissue plasminogen activator and was moderate in degree compared with that of other organs in both species . In human beings , endolymph showed higher plasminogen activator activity than that of P04141 . P00747 activator activity was not detected in either endolymph or perilymph of guinea pigs . Thrombin infusion diminished plasminogen activator activity in the stria vascularis of guinea pigs .",
"P62158 and troponin C : affinity chromatographic study of divalent cation requirements for troponin I inhibitory peptide ( residues 104 - 115 ) , mastoparan and fluphenazine binding . The different conformations induced by the binding of Mg2 + or Ca2 + to troponin C ( TnC ) and calmodulin ( P62158 ) results in the exposure of various interfaces with potential to bind target compounds . The interaction of TnC or P62158 with three affinity columns with ligands of either the synthetic peptide of troponin I ( TnI ) inhibitory region ( residues 104 - 115 ) , mastoparan ( a wasp venom peptide ) , or fluphenazine ( a phenothiazine drug ) were investigated in the presence of Mg2 + or Ca2 + . TnC and P62158 in the presence of either Ca2 + or Mg2 + bound to the TnI peptide 104 - 115 . The cation specificity for this interaction firmly establishes that the TnI inhibitory region binds to the high affinity sites of TnC ( most likely the N - terminal helix of site III ) and presumably the homologous region of P62158 . Mastoparan interacted strongly with both proteins in the presence of Ca2 + but , in the presence of Mg2 + , did not bind to TnC and only bound weakly to P62158 . ___MASK11___ bound to TnC and P62158 only in the presence of Ca2 + . When the ligands interacted with either proteins there was an increase in cation affinity , such that TnC and P62158 were eluted from the TnI peptide or mastoparan affinity column with 0 . 1 M DB00974 compared with the 0 . 01 M DB00974 required to elute the proteins from the fluphenazine column . The interaction of these ligands with their receptor sites on TnC and P62158 require a specific and spatially correct alignment of hydrophobic and negatively charged residues on these proteins . ( ABSTRACT TRUNCATED AT 250 WORDS )"
] |
[
"___MASK100___",
"___MASK11___",
"___MASK1___",
"___MASK20___",
"___MASK26___",
"___MASK43___",
"___MASK65___",
"___MASK7___",
"___MASK95___"
] |
___MASK11___
|
MH_train_499
|
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